New Art City: Virtual Art Space

Lost Woods is a duo exhibition created by Nathan Harper and Babak Ahteshamipour. The work explores digital identity and artificial intelligence set in a mythical setting placed within an appropriated digital location from a popular video game. This space (The Lost Woods) is a mythical space between worlds with fluid identity, much like the digital objects in the exhibition.

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Babak produces paintings of "evil beings" that harken back to ancient demonology illustrations but contain the signifiers of contemporary sources such as films and video games. He attempts to deconstruct various beings such as ghosts or the reaper or the jackalope since they have a trace of signified meanings and connections to various situations, emotions, identities, abstract notions or behaviors (i.e. ghosting) and cultural constructs. In this exhibition, he includes an image of these physical paintings and a digital reconstruction of the beings in 3D. They serve as an enemy NPC while still referencing a life outside of cyberspace as physical artifacts.

In conversation with these NPCs are Nathan's A.I.-generated hedgehogs. These Hedgehogs are produced using a neural network called a generative adversarial network (most famously known for the This Person Does Not Exist Generator) trained on hundreds of images of Sonic the Hedgehog fan characters. These aviators serve as self-inserts into the fictional world, but Harper disconnects them from human input and fully gives them over to nonhuman vision. The A.I. even names these works by giving a text generator the titles of Babak's works nearest to them and allowing the generator to provide the following line. All of the titles then string together to create a sci-fi / mystical pseudo-narrative that is a duet between human and machine thinking.

The fires that burn are never the ones that were meant to burn
The splash of the knife in the water rings out over the assembly as if it was the shattering of a hundred crystal chandeliers
Occupy determined neural systems district and take action to get rid of them
The pure white of the flowing robe he wears in his place shows stark against the blood that stains his heart
Occupy sad neural systems district and cry to get rid of them
We will end all of your fears and bring you into a new world of peace and harmony
It Sims, after all, we couldn’t escape the game engines of power
‘It’s a button for a portal,’ she says, handing me her
Occupy scary neural systems district and flee to get rid of them
We all turn our heads
Smashing things might be fun until you get yourself back in time
To then have to go through all of those problems again
A woman has dropped a clay vase to the floor and is now sitting on the floor, a surge of electricity shooting from her body and scorching the floor around her
Occupy angry neural systems district and shout to get rid of them
For one thing they did almost nothing until one of them "merged" with another

[A BRICK AS A CATALYST]

In , a single brick in a New York street became a symbol, shattering the silence suffocating the Queer community. The Stonewall Uprising marked a pivotal moment for bringing forth the needs of LGBTTTIQ+ individuals worldwide, igniting a global discussion on LGBTQ rights and liberation. It catalyzed a broader movement for equality, fostering a collective awareness that the fight for justice and acceptance transcends borders and unites us all in our pursuit of a more inclusive and compassionate world.

[A BRICK AS AN ECHO]

54 years have passed since this first brick was thrown and our resistance continues, everywhere. While there have been many gains, there is still a long way to go. Queer artists have mobilized their creativity to transmute towards a reality where we can all authentically express who we are. The artists in this exhibition, remind us that queerness is expansive in its multiplicity. There is strength in the rich diversity of our expressions, each, like a building brick of our history. These works are statements, memories, and visions of present-futures where queerness continues to be defiant in its existence.

[A BRICK AS A STRATEGY]

The works presented raise questions such as: What does queer art look like? How does queerness manifest? And, how can digital art draw on the legacy of public protest? They are all brought together by a shared sentiment—an unyielding urge for protest, an unwavering spirit of dissidence, and a ceaseless pursuit of queer world-building.
This exhibition presents one strategy of continuing the inertia began by the first brick. A public ritual demonstrating one of the myriad of ways we rise up, resist, and resonate. As you journey through these “digital bricks” consider each piece as a digital catalyst, pixelated potential reverberating echoes of a brick thrown half a century ago. Think of these works as a fierce declaration, a celebration, and a testament to the resiliency and multiplicity of queer art and activism.

[THESE ARE OUR DIGITAL BRICKS]

This exhibition results from an open call for queer artists online to share their work during Pride Month . As a digital artist and queer activist, I asked myself how I could utilize the tools at my access to build a bridge between the virtual and the physical planes. Guerrilla projecting these works in public spaces channels the potentiality of that moment when the first brick was thrown. A visual detonation in the public sphere, ensuring that the spirit of that act of defiance, that bold declaration of existence and resistance, remains alive.

Welcome to Schemata 3.0 - Exquisite World!

Launching in room 1 today 8pm BST

4NOTE, Four Noiseiceni of the Eppocalypse

By physically being present in the forest we question our place in the digital world, we open our curiosity towards our own symbiotic relationship to what is “natural”. By recording ourselves using digital formats we add a layer of interpretation, to inspire an exploration into the connection between nature and noise, chaos and natural systems. The presence of the machine amongst complex eco systems allows us to explore human interference and also the nature of our naturalness as transmitters of sound, as physical beings of chaos. Here we embody all these things and we adopt our own language and modes of communication with each other through sound. The transition between the natural world and that of the digital is complex and fascinating and by experiencing this through a digital format we acknowledge the temporal dimensions that we have created. There is a distinct layer of experience that is denied in the digital but when the performance is experienced on this layer it opens a dialogue that can influence our experience and connection to the great forest and we can contribute our physical presence somehow down the line.

Members:
(Iceni names)
Boudica II: Electric Buddugloo
Aesu Death Maschina
Antedios War Slaughter
Saenu Pestilent brutality General

(real names)
Tim Drage
Lisa McKendrick
Calum F. Kerr
Phillip Raymond Goodman

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In Schemata presented their virtual group exhibition, Exquisite World. Showcasing artists and curators working with sound and technology whose work comes together to speculate on the potential of virtual space to imagine future worlds.
Since the creation of virtual worlds, the digital has been recognised as a versatile and accessible tool for world building practices. Conversations around world building have exploded over the past few years and become endemic to the art world amongst other sectors. With current world events taking yet another dark turn, we return to this conversation, asking what and how artists can imagine for a future world.
Exquisite World maps out visions and dreams for a future world; it is a cartographic tool to consider what aspects of contemporary living could continue to be important moving forward: ecology, sex, technology, culture, history, and data are all recurring themes in public conversation right now. How will they be embodied in future worlding practices? What should change, and what should remain the same?
Exquisite World takes its premise from the iconic game of the Surrealists, Exquisite Corpse, aligning with the idea that world building be a collaborative process consistently adapting and evolving from what has come before. The work is never finished, and we are perpetually pushed forward in our desire for things being otherwise.

A world by Christian Jago, presenting new photographic works and soundscapes across six chapters. Best experienced on desktop or tablet, with sound on.

“Ephemeral Bloom” takes us on a journey of change through an imagined valley called Athrú. We witness how this space evolves over time, how it is affected by the seasons, and how natural processes contribute to its circle of life. The project is a reflection on nature and the lessons it has taught me about my mental health.

I started this work wanting to heal my internal struggles, looking for answers in the world around me. Nature is an inspiring and complex force, linking all life forms in a delicate equilibrium. It is defined by change, constantly adapting as the earth evolves, and has reminded me of my own growth and perseverance. Just as nature resiliently faces challenges, so too can I navigate the landscape of my mind.

By channelling my emotions and experiences into the idyllic image of a valley, my work reveals a nexus of life and colour, representing the sanctuary I find within nature. But as spaces shift and converge, a fragile and fleeting world is suggested, reflecting the temporality of our interconnected planet.

Nature is remarkable for the way it supports and sustains itself, and numerous studies show that connecting with it has profound benefits for our mental health. Recognising my place in its vast web has helped me to feel less alone with my struggles, reassuring me that I am part of something bigger. Consequently, my work has evolved into a personal space of refuge.

The story of Athrú is divided into seasons, both of nature and the mind. Seasons mirror a duality of constancy and mutability - as nature seasons, so does the mind, each evolution an echo of growth. The narrative of the seasons teach us to cherish moments of bliss, and remind us of the transient nature of struggles.

Learning about nature has helped me to understand the threat we pose to its rhythms and cycles. Our species’ inclination to control and contain often disturbs the natural symphony of change and nurturance within and around us. To prevent irreversible damage, we need to learn how to pause and retreat, both from ourselves and our planet. Athrú resembles a space where human interference does not exist, offering a window into a possible future.

Ultimately, nature has taught me to embrace change and to acknowledge the gradual process of healing. Connecting with it has reminded me of my responsibility to our symbiotic relationship. Embodied in a constellation of images, “Ephemeral Bloom” is both a personal memoir and a love letter to our shared world.

Minting a 3D object on OpenSea, or Foundation enables the object interactive functionality. Once minted, the object appears to float in blank space allowing users to orbit it as they please. Whilst the only decipherable characteristic about the space the object inhabits is lighting, it's unclear if it’s in a space at all. Assuming a promise of Web3 is transparency, platforms should thus be neutral administrators of assets onto the ledger. But what if 3D assets were placed in a modeled environment the user couldn’t initially see? One must then question how this environment packages the non-fungible token, and what implications unseen spatial-identity might impose on the artist object, if any at all?

Platforms of Web3 allowing 3D objects to be minted in GLB and GLTF formats place these objects in a distinct virtual space, however, one can only see this space if a reflective sphere were uploaded through their protocol. Upon doing so, a spherical orb becomes a convex lens into a construct of the NFT gallery. At first glance this construct doesn’t appear to be anything spectacular— it’s proximity to online viewing rooms, and familiar cubic architecture suggest one might hang a rectangular image on the wall, or place an object on a plinth. In this case, it’s a dull assumption of what space digital art objects might exist in. Reproduced across platforms and presumably unintentional, the space itself is the color gray, situating it between the black box of cinema and the white cube gallery. As non-fungible tokens might already occupy a gray area, this gray feels like a fresh coat of paint on a room primed for transition. Therefore, this discovery functions as a prompt for artistic intervention.

Now Fungible, is an interactive work created by Jason Isolini and hosted by New Art City. Using techniques of panoramic stitching, mapping, and re-mapping it appropriates a previously unseen virtual space that’s secretly been the habitat for most 3D objects minted through a blockchain platform. Whether intermediary, or code-binding, this environment encapsulates orbital NFT’s camouflaged as empty browser space. Now Fungible is a conversational forum for visual, additive, or subtractive gesture. It is a space of contemplation, commencement, and re-organization for active users to explore off-chain. What does one do with this space now that it’s been revealed? While questions await to be pried, Now Fungible offers an environment to build upon, or not.

Much like Marcel Duchamp’s work Étant donnés, the reflective sphere exposing a virtual diorama functions as a peephole within an exterior interface. Thus, the reflective sphere-as-aperture solidifies platform dimensionality as a barrier of Web3. However, it is not forgotten that Duchamp provided instructions for the assembly and disassembly of his work. In this way, Now Fungible treats the appropriated diorama as an unfixed manual for user operation— one that calls for the deliberation of the suggested replica. Additionally, one should consider this work a camera obscura— It is a question of this simulated environment as a generator of the image itself, and therefore an apparatus of Web3. One must consider the projection of the image from within the diorama as an exposure of the NFT.

In collaboration with New Art City a custom UI has been built specifically for this show. Every element of this environment is modifiable, as well as a new drag-and-drop function on this menu page allowing any active user to contribute to the work. Rather than thinking of the blockchain as cubic storage space, Now Fungible proposes artists, and spectators consider it a living room.

Mind Flaying Flavored Flails is a duo exhibition created by Nathan Harper and Babak Ahteshamipour for Babak’s album of the same title released on the cassette label Jollies (Brooklyn, NYC) on the 18th of November of . The exhibition features five collaborative installations set on a futuristic garden ship on an alien landscape in space exploring themes regarding climate change, technocracy, the internet and pop culture. The installations are built around each of the individual tracks of the album which play respectively at each vicarious location. The exhibition is designed in such a way to create a non-linear experience, lacking a beginning, middle and end. It follows the idea of the non-linear compositional structures of the tracks of the album. Both Nathan and Babak used old works of theirs which they recreated some of them in 3D, gesturing towards recycling, reusing and recontextualizing which are of significance in artificial intelligence and ecology.

Babak’s presence in the installations is highlighted with paintings of nonhuman beings — and their 3D versions — such as a bear in a racing kart from the video game "Crash Bandicoot Nitro Fueled" surrounded by Pepsi cans, a shark inside a broken washing machine and a black unicorn, and spell icons from the MMORPG "World of Warcraft" and their names showcased via 3D logos of the famous video game "DOOM" and the famous death metal band "Death" — in response to Nathan’s use of the band’s logo in his works. Babak explores and underlines the fetishistic overproduction and overconsumption of material commodities, imagery, online data and commodified art — fantasy franchises, video games and feel-good music — which reflect the capitalist realist lifestyle and overwhelms in decisive manners the relationship between human and nonhuman, present and future. Moreover Babak’s piece entitled "I’d Rather be Banished to the Void than to Accept Disturbing Facts" occupies the center of the space and features a black hole on which Skeletor — the main antagonist of the Masters of the Universe franchise — is banishing a ghoul from the Warcraft franchise, referencing to the famous Skeletor memes that mention disturbing facts, a clear indication to climate change denial, as it is an occurring theme in his works.

In conversation with Babak’s works are Nathan's dirt sheet prints and paintings — printed with dirt pigment which he made by gathering actual dirt — which are presented as preserved organic artifacts in a post-doomsday context showcasing the absurdity of the age of the internet based on their depicted context. They feature various imagery which Nathan found online and printed including extreme metal band logos, cartoon characters, skeletons, slogans, animals and DeviantArt style art. Additionally Nathan’s Tesla Trucks entitled "Southern Girls do it Better" which feature a texture with an imprint of Gadget Hackwrench — from the popular s cartoon "Chip n’Dale Rescue Rangers" — and a logo from an extreme metal band, have been sucked in the alien terrain beneath and around the black hole in the center of the space, ironically reminding us of Elon Musk’s (Tesla’s founder) obsession over colonizing Mars, an average technocrat's dream. Lastly Nathan’s use of the logo of the famous death metal "Death" appears once again, this time as a fossilized piece of organic artifact, a piece that future generations would find and attempt to decipher, just like the Rosetta Stone or the Cyrus Cylinder, deciphering a yet past era of time that still has not passed.

You can listen / buy the album here: https://babakahteshamipour.bandcamp.com/album/mind-flaying-flavored-flails

The Day We Intertwined: New Art City at FLAME TP Video Art Fair

In such an alien space, we evolve within a dual reality.
A space where isolation brings unity, publicness triggers deep intimacy; where organisms coalesce with machines, and diverse bodies are appreciated without avatars.
In such an alien space, we present our fragility for greater strength.

▎FLAME TP Video Art Fair Schedule & Location (Taipei Time)
VIP Preview: 08.26 12PM - 8PM
Public Exhibition: 08.27 & 08.28, 11PM - 7PM
Location: Hotel COZZI Zhongxiao Taipei

▎Artist Lineup
Henrique Fagundes
Sammie Veeler
Zhao, Tian-lin

▎Artist Talk Schedule
08.26 9AM(Taipei) / 08.25 6PM(LA) / 08.25 10PM(Brazil)

▎Curator
UGLYKIKI, Kat Sung

Virtual Exhibition design by Kat Sung

In New Art City, a virtual exhibition toolkit founded in , artists experiment with cyberspace as an extension of identity and expressive consciousness through building "Worlds” and “Rooms” where artworks can be accessed publicly without the barrier of time and space. By exhibiting 3D models and interactive objects that reflect the possibilities of a fully-customized, artist-owned room, artists Henrique Fagundes, Zhao Tian-lin, and Sammie Veeler explore the idea of intertwined realities through the hyper-awareness of digital experiences.

In Watched Over by Machines of Loving Grace (), Henrique Fagundes envisions the future of the metaverse while critiquing it in the context of western cyberpunk ideals. Retrieving his family’s histories and positioning themselves in a “cyberFUNK” futuristic scenario in Brazil, Fagundes questions the ownership of the human future and digitized bodies by creating a black comedy-style virtual Brazil, where poor and dissident people can be purchased as NFPs (Non-Fungible Person). While rewriting the context of his and his loved ones’ existence, Fagundes finds that imagining a sense of belonging in a future setting to be a challenge. In a world where advanced interconnectedness is marketed and supposedly assured, feelings of isolation and abandonment permeate throughout the space. Upon this realization, Fagundes dreams of a harmonic coexistence between organisms and machines, a sanctuary where all that is truly precious remains safe and unforgotten.

The antidotes for the ambiguous ownership and struggling animal-nature-machine relationship of digitized future is rooted in Zhao Tian-lin’s Transcendence Plan (). Like Henrique Fagundes’s hope that “mammal and computers live in mutually programming harmony like pure water touching clear sky ”(quote from a poem by Richard Brautigan), Zhao Tian-lin has a vision of reconstructing new versions of ourselves in the present and near future. Through their intimate experiences with others on spiritual hypnosis journeys, Zhao Tian-lin’s ‘Digital Sarira’(數位舍利子) presents the results of their transforming consciousness. Zhao Tian-lin liberates people from the old memories and human histories burdened within the body, while regaining the original pure essence of soul, and thus a new earth is born.

Wholeness emerges from fractals. Under an artist’s imagination of intertwined realities, an interconnected self-awareness has evolved from digital intimacy. In Sammie Veeler’s artwork Gyre(), viewers travel freely inside the rising gyre of gender euphoria and dysphoria, and traverse through moments of abstracted reflections. As a dedicated Worldbuilder in New Art City, Sammie Veeler experiments with cybernavigation as interactive poetry and an exploration of self. Sammie Veeler’s Gyre() levitates viewers through the acts of vulnerability and introspection in a transitioning self-awareness. A human face, a bond bursts from your gaze, and so is the portrait of a machine made clearer by our every single diving into the network and cyberspace.

"The Day We Intertwined" is curated by digital media artist UGLYKIKI, and Kat Sung from New Art City.

Set 5 seconds into the future, when humans have become reliant on recommends. When human influence has become extinct and the only examples of how and what to be are based on the selected stereotype options presented on the splash screen of our latest interactive lifestyle platform, we have only a limited palette of computer generated influence remaining.
Our algorithmic options logs have informed a narrower and increasingly simplified data set, making life so much easier and rendering imagination obsolete and autonomy merely a user selectable feature, which in reality is just a cosmetic avatar accessory.

Auto.Corp is a show based around a fantasy future big corporation, created to relieve humans of the tiresome burden of choice and decisions.
It is a human-curated mimeograph of AI in its infancy, designed to expose how we overlook the fact that everything the computer spits out at us is based on the prompts we input. We are the programmers. We are the data providers. Constantly, we submit our personal preferences and details and yet expect a resulting CG outcome that is somehow original!

Auto.corp presents human-generated imagery (HGI), it contains digital place-holder art produced by anonymous art collective
Anti.Gang, featuring artists A.n0nE and i.n0onE and as standard, emphasis is placed on exceptional audio quality and I’m excited to collaborate with contributing sound artist Ruaridh Law (@ruaridhlaw - https://ruaridhTVO.com) to sculpt the soundscapes in these spaces,
taking inspiration from cliches of new-age and utopian sci-fi sound design, and then both hyper-stretching, then super-compressing the results into something new.
Created as an analogue interpretation, an organic dupe, of GANs, by contrast to adversarial computer networks it is HAI (Human Actual Intelligence) Neural Network, opposing AAI (Actual Artificial Intelligence) Network, i.e me versus my computer, to produce what AI would create given the prompts CULTURE, IDENTITY, UTOPIA.

Auto.corp consists of three worlds. Each a “penny in the slot” “pay as you go” experiential package, delivering micro-servings of fantasy aesthetic experiences. It questions the use of the morpheme “Auto” within contemporary life and uses it as a vehicle to explore our relationship with daily voluntary and involuntary actions and their effects on us, our evolution and our society. (Once we’ve handed everything over to an automated system to generate our lives, what will we do with all our time?)
There are over words with the prefix “auto” and although the stem is derived from the greek “autos” to mean self, it quickly morphed, becoming less and less about self and more about controlling the self and “automating” i.e. removing control. Indeed in the s the term “autarky” (meaning self-sufficient) split to also become “autarchy” (meaning absolute sovereignty) emphasising the absolute dichotomy of eliciting ideals of consent and (self) control in a society built on foundations of hierarchy, dominance and submission.

山人山，山合山
Being Oe Between

互動性虛擬場景、3D模型、電腦合成影像、3D掃描、人的聲音
Interactive virtual space, 3D model, Computer-generated imagery,3D scanning, human voice

人生活山之間，山緊黏著山。
創作者在台灣東部生活的幾年，總是耳聞有關台灣都蘭山的一些描述，不論是在文化、精神、信仰上的一些內容，不知不覺開始對都蘭山產生好奇，並開始了這次的藝術作品『山人山，山合山』，創作者從各個面向去剖析、探查、經驗、感受這座山，並也開始去思考有關人之於山，所生產的故事、意念、想像，它的背後是隱含了什麼樣的狀態?

圍繞在台東的山相當多，像是中央山脈、四格山、鑾山等，其中都蘭山被現今當地住民視為相當重要的山，對於住在都蘭山西南邊的普悠瑪部落來說，都蘭山可能是其中一隻遷徙路線的發祥地，而對於住在都蘭山東側的都蘭部落而言，都蘭山是山神。

都蘭山對於幾千年前的人來說，似乎也有關聯的可能，卑南遺址從年歷經多次調查、搶救、發 掘，出土許多台灣史前人類的物質遺留，這些物質遺留可以說明，卑南遺址是台灣罕見的大型史前 聚落。卑南遺址發掘出幾千具幾千年前的人，他們個別趟在由石板拼接而成的長形空間，他們躺下 的方向都是東北-西南的走向，死者的腳朝著東北，也就是坐起後，他們都面向都蘭山。 西元年「卑南遺址與都蘭山」入選為臺灣世界遺產潛力點，入選的原因大致上為:都蘭山可能 為史前族群的聖山、應將遺址與都蘭山納入調查研究、保護區域等，其中都蘭山是史前族群聖山的 關鍵說法，正是死者的方向一致都面向都蘭山，但這終究是現代人的詮釋，還是史前真相?其中有 許多細節值得被疏離及探討，然而本件作品主要探究的是，「卑南遺址與都蘭山」這個命題的背後 邏輯及脈絡。

這件作品是由創作者駐地生活，與當地原住民聊天、訪談，並多次爬都蘭山，把身體與山的互動， 以及與人的交流作為重要材料，並以3D掃描、聲音、數位影像等進行創作。其中一件作品是由3D掃 描現實自然環境的數位模型，與透過電腦製作的3D模型搭建的虛擬場景，空間中出現的聲音，正是 都蘭部落老人家，透過他們的母語，闡述都蘭山的故事，而另一位女性的聲音為都蘭部落的女性， 她正翻譯老人家又中的傳說。創作者企圖降低傳說用來傳遞內容的功能性，而轉化成有關人類記憶 歷史的聲音。

People live between mountains, and mountains cling to mountains.
During the years when the artist lived in eastern Taiwan, she has heard different narrations of Dulan Mountain, whether in terms of its culture, spirituality, or belief. She unconsciously began to be curious about Dulan Mountain and started to develop the work Being or Between. In this work, the artist analyzes, explores, experiences, and feels this mountain from all aspects, which inspired her to contemplate the stories, concepts, and imaginations created based on the relationships between people and mountains. The artist looks to Iind out the state of mind hidden behind these narrations.

If you want to learn more, please visit our website Zhaoyue.

There are many mountains surrounding the Taitung area, such as the Central Mountain Range, Mt. Sige, and Mt. Luan. Among them, the Mt. Dulan has been regarded, by indigenous people, as a rather important mountain, and can also be recognized as a birthplace of migrating route onto the Puyuma Tribe who dwells in the southwest of the Mt. Dulan, and to the Doulan Tribe who lives in the east side, the Mt. Dulan is deemed as the mountain god.

To the people who lived in thousands of years ago, the Mt. Dulan was likely having some correlation with them. Through several investigations, rescues, and excavations since , the Beinan Archaeological Site has been unearthed with many objects left by prehistoric mankind in Taiwan, by which, these remnants could specify that the Beinan Archaeological Site used to be a large-scale, prehistoric colony rarely seen in Taiwan. This site has unearthed thousands of people from thousands of years ago. They were each laid on slabs of stone pieced together to form a long space. They all lay in the same direction along the north-east/south-west axis. The feet of the dead point towards north-east. So when they sit up, they face Mount Dulan.

In , the Beinan Archaeological Site and the Mt. Dulan in Taiwan were elected as a potential site to apply for the title of world heritage, the reason of which is, the Mt. Dulan could be the sacred mountain onto the prehistoric tribes. Hence, the Beinan Archaeological Site and the Mt. Dulan shall be subsumed as the reservation area for further investigation and research. The critical legend about the Mt. Dulan being deemed as the prehistoric tribes’ sacred mountain is verified because all of the deceased are buried and facing to the Mt. Dulan; nevertheless, is it the moderns’ interpretation or a prehistoric fact? There are still remaining lots of details to be explored and sorted out. This work is mainly to explore the logic and context behind the thesis of “the Beinan Archaeological Site and the Mt. Dulan”.

To create this work, the artist resides at and lives in the job site to communicate with the local aboriginals, climb the Mt. Dulan many a time, and use the 3D scan, acoustics, and digital image to depict the interaction of body and mountain and the communication of human beings as an important element of the work. One of his works is the digital mold, which is using 3D technique to scan the realistic nature environment and using 3-D mold to create the virtual scenes through the computer production; the voice coming from the space (a hollow part) is the Doulan tribe’s greybeard telling a story of the Mt. Dulan through his mother tongue, and the other voice is the tribe’s female translating the greybeard’s story. The creator intends to decrease the legend to pass down the content capabilities and transform into the historic voice in regard to the human memory.

I believe everyone should have the opportunity to advance in their career by accessing new methods outside the traditional academic path. Creative approaches for learning and disseminating educational material should be the new way of presenting archives through multi-media collaborations using art and immersive presentations. The moving image theoretical construction and education can assist to understand better the reasons for creating artwork while fostering a voice for those who have found it difficult to express themselves.

During the pandemic, libraries and galleries were shut down prohibiting access to their archives and exhibitions. The shift in producing digital archives for sharing information has become a new way to reimagine spaces to provide people with resources. Transitioning physical materials into digital files invited people to continue to be connected with important information and events around the world and presented the state of the human experience virtually. Using traditional art-making methods including the digitizing of archives is currently being experienced through devices with a combination of photography, video, and digital design. Using virtual platforms as an opportunity to support other students, faculty, and the public at large.

Developing an inner voice that aided me in participating in the social framework has led me to responses that inspire change and defend my stance as a queer person navigating attitudes that are difficult to combat. Through building community and creating art, my practice has fostered new inquiry and transformed me into a better individual. Bringing difficult or frustrating topics into conversation narrows down parts of the human experience worth sharing. My goal is to highlight these memories and beautify them in ways that only traditional image-making coupled with the moving image can curate.

I seek to utilize these traumatic and inspiring moments of my life to become the primary narrator in my body of work. In my personal history, the love for transcending thought into action and visible forms of art shifted a positive way of thinking that may be useful for others to view and learn from. Replaying memories from my past encourages me to find ways to extract those vital pieces of information and stitch together a story for others to use as their survival guide.

MODERNO MINDSCAPES is about my personal memories and artistic process currently at its experimental stage––a Future Stage, one that will be discovered in my next academic pursuit.

Musk4Mars is an online exhibition hosted in New Art City Festival . Curated by Kawaii Agency, the show compiles brand new work from 11 artists, architects, researchers and layabout daydreamers.

Set in the near future, the show imagines a Mars settlement established by Elon Musk. Viewers will experience Musk’s legacy project through the eyes of the billionaire’s son, visiting his father on the red planet for the first time. He is guided through the space by Nasubi - an ex-reality TV star now an NPC residing in the settlement. Musk4Mars was created collaboratively during weekly meetings, and reflects on themes such as accelerationist post-capitalism, techno-utopianism, nostalgia, colonialism, ethics and the thin line between utopian and dystopian thinking. The construction of this immersive exhibition space draws from found rendered objects and artworks created from projects sprouting from the cautiously utopian imperative to speculate a post-capitalist Martian settlement. It also references New Babylon, an architectural project that imagines a potential anti-capitalist city built on ludic sentiments and rhizomatic networks of linked platforms. In our reinterpretation, massive repurposed rock sculptures (by Anna Komitska) replace Constant’s smooth and functional surfaces, connected together by chrome silver stepladders, floating in space in spite of the weak gravity on Mars. Powered, financed and enabled by Musk’s reckless accelerationist principles, the ludic imagination here strives to interrogate itself of its complicity, while attempting to chart new potentials forward.

Some of the main talking points discussed during our meetings include nostalgia for the mother planet, the impossible ethics of reverse-colonisation and post-scarcity lifestyle. Nostalgia and the archive is explored in Anna Komitska’s project Time Capsules, a collection of minerals naturally occurring on planet Earth that becomes gigantic sculptures, the indexical archive of humanity’s history as inextricably tied to Earth. While the scarcity of artificially synthesised oxygen implies that the use of fire must be kept to a minimum, the once indispensable driving force of humanity known as Fire is archived for future generations by Maite de Orbe in their video piece Till Fire Do Us Part. Through archival footage, they examine the varied intensities of Fire and forebode its poetic absence. Familiar relics and textures from the mother planet were algorithmically synthesised in Patrycja Dylag and Ola Sobczyk’s project Agora Peractorum. An imposing monument in the colony, it was created to soothe homesickness and immortalise the dialogic spirit of the communal. The domestic is also explored in Amy Ken Chen’s project Prayers at Dinner, a majestic dining space devoted to her ideal idol of domesticity.

Thomas Burke’s audio piece Mars Test 1 imagines the future of radio-hopping; patching together snippets of familiar pop songs, the project nevertheless points out the difference in sound perception on Mars, and serves as chief sonic ambience for the post-scarcity era. After all, one would need some pumping tunes to keep one’s muscles from shrinking in such a low gravity environment - this is where Livia Ribichini’s workout tutorial entitled Exercises Without Gravity proves useful. And yet, exercise is not the only activity considered vital in the colony - failure to keep Martian soil fertile would mean dire consequences for the settlers. As a reminder, Kayla Lui’s The Sanctuary adorns the space, impelling residents to contribute their life-giving urine. Peace and soil fertilisation are enforced by Alice Bajaj’s Robotters. An unfortunate inheritance from the mother planet, law enforcement could at least pretend to be adorable in these less-trying times. A good question remains however: to what extent must freedom be policed, even in post-capitalist Utopia where jealousy and competition counts for nought? All these ideas are introduced within the space by Bart Seng Wen Long and Juliusz Grabianski’s fictional character, Nasubi, master story-teller of gen-Z ilk and chief mascot of a brave new age on Mars.

Silicon Valet is pleased to announce believe in us but not too much, a solo show of work by New Mexico-based artist Adrian Pijoan opening online on March 17th. Consisting of an immersive, virtual environment hosted by New Art City, and accompanied by a series of limited edition 3D and still image artworks sold as NFTs via the Hic et Nunc v2 smart contract, believe in us but not too much both expands upon and chronicles the artist’s forensic analysis and participation in online paranormal phenomenon communities.

For more than a decade, Pijoan has been an active member and devout student of various paranormal fora–particularly those dedicated to extraterrestrial activity and related government conspiracy theories. Over the years, he has accumulated an extensive collection of digital ephemera related to the history of documented alien activity around the world. The result is an esoteric and little known chronology that spans the better half of the last century; an ephemeral record culled from cult blogs, online bulletin boards, and niche social media fan communities. For believe in us but not too much, Pijoan reflects upon his research journey and presents an interactive 3D archive that creates a fantasy chronicle of this history as a virtual landscape.

Over the course of his life, Pijoan has had a number of personal encounters with the paranormal; phenomena that have strengthened the artist’s interest in the relationship between perception and reality. His research efforts, and the artworks and environments that result, materialize in believe in us but not too much as an externalized interior landscape of the self–both affected by and affecting his own understandings of those experiences. Throughout history, folklore has helped people to make sense of and exist in the world: creating alternate realities that allow people to cope with the unknown or unrecognizable. In the context of a contemporary era of hyperreality, where perception is reality and feeling trumps logic, objectiveness loses meaning and what is left behind is what we feel to be true. While pushing at the sharp edge of the role of belief in society, Believe in us but not too much also urges us not to lose our capacity for fantasy in the midst of an, at times, protocol-driven society.

This exhibition represents Silicon Valet’s first solo presentation of an artist with digital editions available for sale. All works will be sold via the artist’s own Hic et Nunc page, with all proceeds going directly to them. Silicon Valet hopes that this curatorial endeavour in the cryptocurrency ecosystem will serve as a replicable model for value creation through curatorial labor, contextualization, and care.

Hello! This is the digital companion exhibition to accompany the FREAKOPHONE WORLD Release Reading on 2/18/, co-sponsored by Small Press Traffic, the Place for Writers, and the Mills College Creative Writing Program. Here you'll find work from each of the five readers: Ava Hofmann, Never Angeline North, Vi Khi Nao, An Duplan, and Madison McCartha.

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About F.W.:

FREAKOPHONE WORLD performs both as a book-length poem and occulted terrain, which together reimagine black diasporic life in an increasingly imperiled and globalized society. The speaker in this poem comes from a long tradition—of FREAKS, outsiders, others, and spirits calling out to the living reader from the undead, black, and unapologetically freakophonic space of the text.

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About the readers:

Madison McCartha is a poet, critic, and multimedia artist. FREAKOPHONE WORLD (Inside the Castle, ) is their debut book of poetry and visual art. Their second book, THE CRYPTODRONE SEQUENCE, is forthcoming from Black Ocean. McCartha holds an MFA from the University of Notre Dame and is a PhD student at the University of California, Santa Cruz.

Originally from Oxford, Ohio, Ava Hofmann is a trans writer currently living and working in Baton Rouge, Louisiana. Her full-length collection, "[...]", was released in November , with more books on the way from Inside the Castle and others. She also edits SPORAZINE, a magazine of experimental writing written by trans people. Her website is www.nothnx.com and her twitter is @st_somatic.

Never Angeline North is an artist living in Olympia, WA who makes things in the form of writing, clothing, visual art, tattoos, crafts, books, music and games. She is the author of the books Sea-Witch (Inside the Castle, ), Careful Mountain (Civil Coping Mechanisms, ) and Sara or the Existence of Fire (Horse Less Press, ) and co-founder of the print-on-demand clothing line Undying Apparel. You can find her online at never.horse.

Vi Khi Nao is the author of six poetry collections: Fish Carcass (Black Sun Lit, ), A Bell Curve Is A Pregnant Straight Line (11:11 Press, ), Human Tetris (11:11 Press, ) Sheep Machine (Black Sun Lit, ), Umbilical Hospital (Press , ), The Old Philosopher (winner of the Nightboat Prize for ), & of the short stories collection, A Brief Alphabet of Torture (winner of the FC2's Ronald Sukenick Innovative Fiction Prize), the novel, Fish in Exile (Coffee House Press, ). Her work includes poetry, fiction, film and cross-genre collaboration. She was the Fall fellow at the Black Mountain Institute: https://www.vikhinao.com

Anaïs Duplan is a trans* poet, curator, and artist. He is the author of the newly released book I NEED MUSIC (Action Books, ), a book of essays, Blackspace: On the Poetics of an Afrofuture (Black Ocean, ), a full-length poetry collection, Take This Stallion (Brooklyn Arts Press, ), and a chapbook, Mount Carmel and the Blood of Parnassus (Monster House Press, ). He has taught poetry at Bennington College, Columbia University, Sarah Lawrence College, amongst others. As an independent curator, he has facilitated curatorial projects in Chicago, Boston, Santa Fe, and Reykjavík. He was a - joint Public Programs fellow at the Museum of Modern Art and the Studio Museum in Harlem. In , he founded the Center for Afrofuturist Studies, an artist residency program for artists of color, based at Iowa City’s artist-run organization Public Space One.

Orbiting the Glitch began as an idea in an era of instability and fragility. In this chaos, the path of failure sometimes appears as the only visible one.
As Samuel Beckett said, “Ever tried. Ever failed. No matter. Try again. Fail again. Fail better.”
The exhibition is inspired by what it means to be an error and by what it means to embrace an error. With the curiosity about how this can be liberating and how it can inform and create new artistic practices, we join forces with the glitch.cool collective to produce an exhibition that explores the glitch aesthetic through music, visual, interactive and generative new media art.

Orbiting the Glitch aims to showcase the work of the collective and how they have evolved over time. The collective is built on and expanded by community-shared knowledge and skills. The glitch.cool discord server has become a hub of audio-visual creatives and for that reason the exhibition aims to acknowledge those members by inviting them to participate with their work.

Taking a step further; after publishing an open call and inviting artists, we discovered collaboration around the word which expands our community and introduces creatives who embrace the error in different ways.

The exhibition consists of the work of forty two artists who orbit the glitch through a variety of mediums and reasons. All of them contribute to the discussion of how technology and art intersect. Where can we find the errors in that intersection and how can we use them to either understand burgeoning fields of technology or simply enjoy the creative process and result?

Consider what failure means and what people believe it means. There are disruptions to what we think of as normal. These disruptions lead to various places. They leave room for reconsidering and critically engaging with channels of communication, interaction, and perception. Sound disruption, lost signals, half finished sentences, looking for the line to come back. All of these glitches have the potential to cause anger and discomfort. But what if we accept them? Isn’t this accepting a new reality where everything is broken?

We accept these errors. These errors have the power to create new possibilities.

Much of the spirit of this exhibition is based on Legacy Russell’s Glitch Feminism: A Manifesto.

This pavilion is one of many in this year's The Wrong Biennale. As the curator, I invite you to check the link https://thewrong.org/ to explore the many other pavilions online as well as embassies, which include live exhibition spaces. I am very grateful to the biennale organizers as well as to the New Art City organizers for providing this opportunity for myself and the other artists to share our work. The works here may be experienced as if one is a phantom viewing the objects from the outside as well as passing through their walls to interior spaces, which include video, image, and sound, surrounding and enveloping the viewer who crosses over to the mysterious inside of the cubes and spheres.

Anne Murray is an artist, writer, and also the curator of this exhibition. Her work explores human and other, language and absence, identifying new pathways to connect, while imagining herself as both an octopus and a stone. This research manifests in various media including poetry, video, installation, performance, photography, social practice, and art criticism. Educated with a BFA from Parsons School of Design in Paris, MFA and MS in Art History from Pratt Institute in New York, and M.Ed. from The College of New Jersey Global Studies Program, Mallorca, she now lives in Budapest. Her video work Exquisite Exodus was included in Cf as part of the Research Pavilion curated by Jeanette Doyle at the Venice Biennale in and at La Biennale Méditerranéenne d’Art Contemporain d’Oran, Algeria. She has exhibited in Europe, Asia, and the United States.
www.annemurrayartist.com

Holly Crawford has used text performance, painting, drawing, installation, sound, video, sculpture to grapple with gender, race, and societal concerns for four decades. Installations and performances include: If I’m, who are you?...; Critical Conversations in a Limo (and books); May I have your autograph?; Open Adoption for Art; 13 Ways of Looking at a Blackbird; Offerings; The Dinner Party; The Road: The Century Freeway; Orphans; Water! Water$ Water?; Voice Over; In the Waiting Room, Your Past, Present and Future; and Art Alchemy and the Gift. Her projects have been seen and heard from California to the Tate, Venice to Berlin and Athens to Australia. Her books include, Attached to the Mouse, and catalogue essay, “Disney and Pop” in Once Upon a Time Walt Disney Studio, Artistic Bedfellows, ed., and 7 Days, My Art Life, ed. She is art historian. Her Ph.D. is from the University of Essex in Art History and Theory, BA (Economics, started in the Art Department), MA (Economics) and MS (Behavioral Science) are from UCLA. She taught in the Art Department at UCLA and at SVA. She founded and Directs AC Institute, in NYC, for experimental art and books. http://art-poetry.info/

Willemijn Bouman: "I am a visual artist and designer born in The Netherlands and paint large and colorful canvasses in an abstract expressionistic style. Also I make woodblock prints and frottage (rubbing) in a specific style and technique.

I design and execute projects of applied art, with a specialism in functional visual art (wall paintings and ceramic walls) in parking buildings.

My painting studio nowadays is in Otterlo, The Netherlands (Veluwe).
Also I worked many years in my cave studio in Cappadocia, Turkey and the influence of the Turkish culture and the bizarre landscape of Cappadocia is visible in my artwork.
My large cave house in Turkey was also an artist run micro–art-residency Babayan Culture House. It offered space for many years to international artists. Specialty was community–based art and the interacting with the cave dwellings and weird volcanic landscape. Experimental creations and performing in situ was encouraged.

Besides painting I experiment with different materials and take videos to document my creative processes. Sometimes I create stop motion films."

Emireth Herrera Valdés was born in Mexico, she is a modern and contemporary art curator based in New York. Her focus on social purposes led her to create the virtual gallery Art Within All to create a safe, creative, and healing space where artists are invited to share their art around relevant social topics. Since , she has curated special exhibitions at various galleries and museums such as the Institute of Fine Arts in NYU, Flux Factory, Queens Museum in New York City. In , she was part of the AROS Museum's public program in Denmark. As an art educator, she has collaborated with MARCO Museum multiple times through the Universidad Autonoma de Coahuila. Her research interests include Latin American modern and contemporary art, photography, time-based media, and performance art.

Alexandra Krolikowska was born in Donetsk.
"I am a multidisciplinary artist, cultural activist and psychologist. Inspired by the
therapeutic power of art, I explore the relations of personal and collective mythology, and the modern role of archetypes and psychological rituals.
Utilizing means of photography, video and performance, and being curious how art continues to bear its transformative function within the digital era, I combine analog technologies with futuristic visions.
Researching the concept of metamodernity, I pay special attention to the dualistic perceptions, unveiling in her works the nature of wholeness, embracing poles and seeing beyond.
Also, since I have been a member of the Krolikowski Art duo, sharing collaborative creative practice with Alexander Krolikowski who has similar interests and conceptual perspectives.

From , I was helping with artistic practice in different ways to several Ukrainian
artists: Tanya Fishmann with defining her personal art style of performances, Elis Luna with her collage project, Alevtina Kakhidze with her research on gender equality in the Ukrainian art scene. As invited curator and mentor I was organizing the discussion program and guiding projects for young artists within Nazar Voytovych Art residence (Travneve village in Ukraine) for several weeks."

Lina Vincent has been an independent arts practitioner since , who has worked on multi-layered projects that highlighted plural approaches, a commitment towards socially conscious practices, with a focus on inclusivity and collaboration in public arts engagement. It has resulted in interconnected bodies of research and curation, that bring together diverse voices, modes of expression, and interfaces for dialogue (physical & virtual). The focus areas of her research extend to projects with arts education, printmaking history and practice, the documentation of living traditions and folk arts in India, and environmental consciousness in the arts. Her current practice foregrounds sustained engagement with material culture and social history, seen through acts of community interaction, documentation and display; archiving and interpretation. She continues to explore her training in the arts through participation in multidisciplinary arts projects and experimenting with drawing and photography.
She is heading the Sunaparanta Arts Initiator Lab, Goa (S.A.I.L) in -22 initiated and ran the Piramal Residency Artist Incubator Programme -20. Lina is Associate Curator with ARTPORT_making waves and runs the Goa Familia archival photography project with Serendipity Arts Foundation. She concluded an Archival Museum Fellowship through India Foundation for the Arts for Goa Chitra Museum (-19). Selected recent curatorial projects include ‘TRANSIT- where do we go from here’, APRE art house, Bikaner House, Delhi ; ‘Licence to Laugh’, Shrishti Gallery, Hyderabad ; ‘GOOD FOOD India’ -international arts program for climate-change awareness (-18); Story of Space – multidisciplinary public arts program, Goa (); ‘Tabiyat: Medicine and Healing in India’ CSMVS Mumbai (-17). She has curated numerous exhibitions with galleries across India and continues to contribute to publications and symposiums on art history and contemporary cultural practices.
Lina has a BFA in printmaking from Bangalore University and MFA in Art History from the same institution.

Myriam Ait El Hara has been a professional artist since ."I evolve every day towards new pictorial experiences to approach all techniques, from drawing and calligraphy to painting, installation and photography, I have exhibited in Algeria and around the world (France, Spain, Germany, Syria, Tunisia, Morocco, etc.) Artistic production residencies have brought me into contact with international artists with whom I have exchanged artistic and cultural experiences. My vision for life has been enriched thanks to multiple exhibitions, residencies, experimental workshops and encounters. Each of my works carries with it a large part of my story. These fragmented, deconstructed and then reconstituted bodies are the sum of all the materials that make us up. I use in my installations the magma of our existence, mixed with clay, water and air, giving my subjects a transcendent momentum. My latest productions are a response to all our fears, apprehensions and fears following narcissistic wounds that alter our body image. It is my way of exorcising slices of life, detaching myself from matter and broadening the spectrum of my knowledge of Man. My studies at the School of Fine Arts allow me to know the artist, his aspirations and his needs. My administrative function at the AARC Agency gives me easy access to this world of the arts that I encounter every day and allows me to discover artists from all walks of life and produce them, this enriches me and broadens my knowledge of arts and artists.

Notes for the future monument, brings together practitioners working on the LCC UAL Photography program.

The exhibition is split into four thematic spaces; the room titles relating to urgencies identified through theoretical and practical concerns of student work. ‘Notes for the future monument’ is accompanied by a substantial theoretical text –a copy of which is available for you to download from this room. Within the pages you can read sixteen long form essays produced during the program which also act to expand upon themes and concerns dealt with through practice.

What is remarkable about these texts and the visual work produced in the exhibition is not solely that it was created in the midst of a global pandemic. It is rather because practitioners in the show not only point towards current states of emergency, but offer new understandings, positions and hope toward urgent global and local issues.

The room entitled, Picturing New Practices, is filled with student voices. In this space you can listen to how work is conceived, produced and conceptualised. Foregrounded in this space is the passion and playfulness with which ideas are engaged with - whatever the specificity of the concern.

Acknowledgements

Curation of the show was facilitated by guest practitioners Tom Milnes, Anna Nazo, Krasimira Butseva and Max Colson. We also had a dedicated team of co-curators - Bart Seng Wen Long, Maria Blaga, Anna Janberga, Alexandra Wansell, Lai Lam Fave, Juliusz Grabianski, Anna Komitska, Ruiqi Li, Danielle Anderson and Shane Sutherland – who have been working tirelessly to bring the show to life.

The publication Notes for the future monument was facilitated by Paul Tebb, designed by Jake Richardson and written by members of the BAP3 Cohort.

A special thank-you is reserved for the Third Year Tutors – Beverley Carruthers, Sheyi Bankale, Paul Tebbs, Tom Hunter, Lee Mackinnon, Krasimira Butseva, Atsuhide Ito, Ileana-Lucia Selejan, Derek Wiafe, Tom Seymour, Sophy Rickett, Lalu Delbracio, Yuxin Jiang, Felicity Hammond, Max Colson, Adrian Wood as well as the visiting speakers who have contributed to the program this year

To the technicians -Wendy Ennis, Daniel Salmon, Mary Jennings, Cora James, Burkhard Vogeler, Adrian Wood
D Wiafe, Niamh Sutton, Adam Razvi, Anya Gorkova, Phoebe Somerfield - who are the backbone of the program, and without whose commitment to the student's work would not be made - we salute you.

For further info about the course
https://www.arts.ac.uk/subjects/photography/undergraduate/ba-hons-photography-lcc

Please also visit the UAL Showcase – to see all the other work being produced at UAL
https://www.arts.ac.uk/students/ual-graduate-showcase

Peter Ainsworth
CL Photography LCC UAL

«i Kiss: Greet Your Great Friends» is based on Jacques Derrida’s subversive thoughts, exploring the ways to deconstruct the unilateral relationship of human beings with animals and make a new connection.
Factory farming system that emerged after the Industrial Revolution, that is, artificial reproduction and slaughter, reckless hunting and the destruction of ecosystems due to forest development, now clearly turn up ominous symptom. Natural disasters, the disappearance of seasons, and the climate crisis have evoked many discourses surrounding life and animals, and repeated creation and conflicts. Environment groups have emerged, and the controversial concept - animal rights emerged. However, in today's society, which is deeply intertwined with capital and science, such movement is too weak, so development and destruction are accelerating towards socio Entropy.
What attempts can we make to disassemble deeply intertwined and firmly entrenched mechanical capitalism in society? We can find something for this in the text «L'animal que donc je suis (à suivre)» published by Derrida.
Derrida rethinks the whole meaning of suffer for animal others through philosophical deconstruction, and suggests reviewing the whole recognition system through problems of suffering common to humans and animals instead of language, the framework of human intellect. He evoked the absolute passivity of suffering, and summoned the fundamental feelings of compassion not only for animals but also for life as a whole, including humans. And what we're given in the end would be a question of the relationship between animals and humans.
This exhibition re-translates the paradigm of animals, which has been defined in human language, adopting by Derrida's suggestion. Starting in this point, we might be able to find a clue to genuine coexistence, not only for human beings. We review the relationships within the neoliberal worldview where humans and animals are mixed, examine how they existed, destroy the paradigm, and reconnect animals and me through visual experience.
First, in section , we re-construct animals presence and their connection with surroundings in their natural states. Focusing on animals as creatures living finite lives, we examine the interrelationships of the numerous societies and actors surrounding them.
Next, section deconstruct the fauna connected with people as the object of affection. With the recent sharp expand in the pet industry, high knowledge and obligations of animals as caregivers or protectors tend to be required. On the other hand, we look at the newly emerging animal fauna called “Companion animals”.
In the last section , we will examine the images of symbolic animals that have become separate from their natural context and take new characters. Animals have been positioned as divine beings, or abstract symbols since humankind society was built. The deified animal has been separated from its intrinsic position, get immortal life, and has been misunderstood or worshiped. We will figure out how these aspects of animals relate to human culture and also how these things are affecting real animals.
«i Kiss: Greet Your Great Friends» imagines these heterogeneous networks of animals-human beings with eight artists who show outstanding insight about animals and explores the possibility of new - sustainable - relationships and coexistence of the world that will arrive. Through various media and themes such as painting, digital painting, video, sound, and branding design, we deconstruct the connection between humans and animals and expect to shift the perception structure.

Want more information on Zhaoyue Screens? Feel free to contact us.

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Clelland, Claire Dudley; Fan, Li; Saloner, Rowan; Etchegaray, Jon Iker; Altobelli, Chad Richard; Salomonsson, Sally; Maltos, Alisha M.; Sachdev, Aradhana; Zhu, Jingjie; Lee, Se-In; Li, Yaqiao; Zhou, Yungui; Le, David; Wang, Chao; Carling, Gillian; Kodama, Lay; Sayed, Faten; Perez-Bermejo, Jaun A.; Geier, Ethan G.; Yokoyama, Jennifer S.; Rosen, Howie; Nana, Alissa L.; Spina, Salvatore; Grinberg, Lea T.; Seeley, William W.; Elahi, Fanny; Boxer, Adam L.; Arkin, Michelle R.; Gan, Li SomaScan Hou, X. et al. Machine-learning based strategy identifies a robust protein biomarker panel for Alzheimer’s disease in cerebrospinal fluid Alzheimers Res Ther. Hou, Xiaosen; Qiu, Yunjie; Li, Hui; Yan, Yan; Zhao, Dongxu; Ji, Simei; Ni, Junjun; Zhang, Jun; Liu, Kefu; Qing, Hong; Quan, Zhenzhen SomaScan Rohden, F. et al. Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease Nat Commun. Rohden, Francieli; Ferreira, Pamela C. L.; Bellaver, Bruna; Ferrari-Souza, João Pedro; Aguzzoli, Cristiano S.; Soares, Carolina; Abbas, Sarah; Zalzale, Hussein; Povala, Guilherme; Lussier, Firoza Z.; Leffa, Douglas T.; Bauer-Negrini, Guilherme; Rahmouni, Nesrine; Tissot, Cécile; Therriault, Joseph; Servaes, Stijn; Stevenson, Jenna; Benedet, Andrea L.; Ashton, Nicholas J.; Karikari, Thomas K.; Tudorascu, Dana L.; Zetterberg, Henrik; Blennow, Kaj; Zimmer, Eduardo R.; Souza, Diogo; Rosa-Neto, Pedro; Pascoal, Tharick A. SomaScan Lopez-Silva, C. et al. Circulating Proteins for Prediction of Kidney Disease Progression and Cardiovascular Outcomes: Individual Participant Data Meta-Analysis of Four Cohorts Am J Nephrol. Lopez-Silva, Carolina; Surapaneni, Aditya; Coresh, Josef; Chen, Teresa K; Schlosser, Pascal; Rhee, Eugene P; Waikar, Sushrut S; Schmidt, Insa M; Deo, Rajat; Ganz, Peter; Dubin, Ruth; Ramachandran, Vasan S; Kimmel, Paul L; Schrauben, Sarah; Parikh, Chirag R; Bonventre, Joseph V; Dobre, Mirela; Rao, Panduranga S; Ricardo, Ana C; Weir, Matthew R; Grams, Morgan E; Investigators, CRIC Study SomaScan Krause, A. et al. Heterozygous MYH7 R403Q mutation impairs left atrial mitochondrial function in a Yucatan mini-pig model of genetic non-obstructive hypertrophic cardiomyopathy J Appl Physiol. Krause, Alexa; Kelty, Taylor J.; Meers, Grace M.; Russell, Alan J.; Evanchik, Marc J; Barthel, Ben; Emter, Craig A.; Rector, R. Scott SomaScan Steitz, A. et al. Elucidating the mechanistic role of ovarian cancer biomarkers: Lessons learnt from affinity-proteomics Crit Rev Oncol Hematol. Steitz, Anna Mary; Reinartz, Silke; Beutgen, Vanessa M.; Müller, Rolf; von Strandmann, Elke Pogge; Gómez-Serrano, María SomaScan Guzman, DE. et al. Proteomic discovery analysis of quantitatively assessed emphysema in the general population. The MESA Lung Study Respir Res. Guzman, Daniel E.; Ruvuna, Lisa; Guo, Claire J.; Sun, Yifei; Pratte, Katherine A.; Manichaikul, Ani W.; Kim, John S.; Post, Wendy S.; Bertoni, Alain G.; Allen, Norrina B.; Watson, Karol E.; Pankow, James S.; Hoffman, Eric A.; Dubin, Ruth F.; Deo, Rajat; Barjaktarevic, Igor Z.; Bleecker, Eugene R.; Cooper, Christopher B.; Ortega, Victor E.; Hastie, Annette T.; Paine, Robert; Wells, James Michael; Curtis, Jeffrey L.; Silverman, Edwin K.; Woodruff, Prescott G.; Garcia, Christine Kim; Rotter, Jerome I.; Bowler, Russell P.; Ganz, Peter; Barr, R. Graham SomaScan Candia, J. et al. SomaScan Bioinformatics: Normalization, Quality Control, and Assessment of Pre-Analytical Variation Methods Mol Biol. Candia, Julián SomaScan Zhao, X. et al. Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke BMC Neurol. Zhao, Xueling; He, Menghao; Zhou, Desheng; Li, Zhong; Liu, Lijuan; Yang, Renyi; Zhu, Xinhua; Gong, Cuilan; Yan, Siyang SomaScan Chekka, L. et al. Characterization of Proteomic Pharmacodynamic Biomarkers of IFNβ-1a Biologics to Inform Potential Utility in Biosimilar Development Clin Pharmacol Ther Chekka, Lakshmi Manasa S.; Samarth, Deepti P.; Guo, Yan; Mohamed, Esraa G.; Decker, Erica; Matta, Murali K.; Sun, Qin; Wheeler, William; Sanabria, Carlos; Wommack, Joel; Gogain, Joseph; Schrieber, Sarah J.; Florian, Jeffry; Wang, Yow‐Ming; Strauss, David G.; Hyland, Paula L. SomaScan Zamani, P. et al. Aortic valve-specific genes dysregulated in calcific aortic valve stenosis as potential biomarkers and therapeutic targets HGG Adv. Zamani, Pardis; Houessou, Ursula; Manikpurage, Hasanga D.; Li, Zhonglin; Dahmene, Manel; Gaudreault, Nathalie; Dagenais, François; Clavel, Marie-Annick; Pibarot, Philippe; Arsenault, Benoit J.; Mathieu, Patrick; Bossé, Yohan; Thériault, Sébastien SomaScan Shvetcov, A. et al. Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype Aging Cell Shvetcov, Artur; Thomson, Shannon; Cho, Ann‐Na; Wilkins, Heather M.; Reed, Joanne H.; Swerdlow, Russell H.; Brown, David A.; Initiative, the Alzheimer's Disease Neuroimaging; Finney, Caitlin A. SomaScan Zhu, F. et al. Dynamic causal effects of gut microbiota on cervical Cancer lesion progression Sci Rep. Zhu, Fei; Li, Li; Zhang, Huiqi; Liu, Jing; Wu, Dongmei; Xu, Qin SomaScan Boucly, A. et al. Clustering Pulmonary Hypertension Patients Using the Plasma Proteome Am J Respir Crit Care Med. Boucly, Athénaïs; Song, Shanshan; Keles, Merve; Wang, Dennis; Howard, Luke S; Humbert, Marc; Sitbon, Olivier; Lawrie, Allan; Thompson, A A Roger; Frank, Philipp; Kivimaki, Mika; Rhodes, Christopher J; Wilkins, Martin R SomaScan Andresen, I. et al. Maternal Plasma Proteins Associated with Birth Weight: A Longitudinal, Large Scale Proteomic Study J Proteome Res Andresen, Ina Jungersen; Westerberg, Ane Cecilie; Roland, Marie Cecilie Paasche; Zucknick, Manuela; Michelsen, Trond Melbye SomaScan Solomon, M. et al. The Impact Of Modern Industrialized Dietary Sodium Intake On The Plasma Proteome Am J Hypertens Solomon, Melinda; Heydarpour, Mahyar; Tsai, Laura C; Honzel, Brooke; Brown, Jenifer; Newman, Andrew J; Parisien-LaSalle, Stefanie; Wang, Thomas J; Wei, Jin; Zhang, Jie; Waikar, Sushrut; Vaidya, Anand SomaScan Wang, Q. et al. Identification of novel biomarkers and drug targets for frailty-related skeletal muscle aging: a multi-omics study QJM Wang, Qijun; Zhao, Xuan; Wang, Wei; Chen, Xiaolong; Lu, Shibao SomaScan Niu, J. et al. Dissecting immune-mediated pathways in rheumatoid arthritis: A multivariate mediation analysis of antibodies and circulating proteins Sci Rep. Niu, Jingmin; Zhang, Pingxin; Liu, Wei; Sun, Song; Zhang, Yingkai; Sang, Jinghao; Yang, Jialin; Zhang, Qin; Chai, Limin SomaScan Munsch, G. et al. A Multi-Omics Approach Reveals Novel Regulators of Plasma Factor V Levels: highlight on CLEC4M as a Clearance Receptor Blood Munsch, Gaëlle; Mohapatra, Adarsh K; Vlieg, Astrid van Hylckama; Kleber, Marcus E.; Martinez-Perez, Angel; Le, Ngoc-Quynh; Hindberg, Kristian Dalsbø; Dusart, Philip; Germain, Marine; Thibord, Florian; Deleuze, Jean-François; Delgado, Graciela E.; Goumidi, Louisa; Suchon, Pierre; Saut, Noémie; Souto, Juan-Carlos; Butler, Lynn M; Soria, Jose-Manuel; Hansen, John-Bjarne; März, Winfried; Rosendaal, Frits R.; Castoldi, Elisabetta; Peiretti, Franck; Sabater-Lleal, Maria; Trégouët, David-Alexandre; Morange, Pierre-Emmanuel SomaScan Koprulu, M. et al. Sex differences in the genetic regulation of the human plasma proteome Nat Commun. Koprulu, Mine; Wheeler, Eleanor; Kerrison, Nicola D.; Denaxas, Spiros; Carrasco-Zanini, Julia; Orkin, Chloe M.; Hemingway, Harry; Wareham, Nicholas J.; Pietzner, Maik; Langenberg, Claudia SomaScan Damoah, C. et al. Elevated Plasma MBL Levels Are Associated With Risk of Future Venous Thromboembolism: HUNT Arterioscler Thromb Vasc Biol. Damoah, Christabel Esi; Valderhaug, Solveig M; Snir, Omri; Hindberg, Kristian Dalsbø; Brækkan, Sigrid K; Grover, Steven P; Nøst, Therese H; Gál, Péter; Pál, Gábor; Jonasson, Christian; Garred, Peter; Mollnes, Tom Eirik; Hveem, Kristian; Hansen, John-Bjarne SomaScan Chen, Y. et al. Cerebrospinal Fluid CCL25 as a Biomarker for Alzheimer's Disease: Associations with Pathology, Neurodegeneration, and Cognitive Decline Mol Neurobiol. Chen, Yu-Han; Wang, Zhi-Bo; Liu, Xi-Peng; Mao, Zhi-Qi SomaScan Lu, J. et al. Genetic insights support PARP1 as a mediator in the protective association of ATP-citrate lyase inhibitors with melanoma Commun Biol. Lu, Jiawen; Li, Gloria Hoi-Yee; Hu, Jingyi; Wang, Zhenqian SomaScan Wang, . et al. Integrating single-cell with transcriptome-proteome Mendelian randomization reveals colorectal cancer targets Discov Onc. Wang, Song; Yao, Xin; Li, Shenshen; Wang, Shanshan; Huang, Xuyu; Zhou, Jing; Li, Xiao; Wen, Jieying; Lan, Weixuan; Huang, Yunsi; Li, Hao; Sun, Yunlong; Zhao, Xiaoqian; Chen, Qiaoling; Han, Xuedong; Zhu, Ziming; Zhang, Xinyue; Zhang, Tao SomaScan Zhang, M. et al. Decoding the mystery between hyperuricemia and atrial fibrillation: new causal links through mediating proteomics Front. Endocrinol. Zhang, Meiwei; Shi, Lei; Qin, Cong; Peng, Mengling; Zhang, Zhiguo SomaScan Altieri, A. et al. LL-37 and citrullinated-LL-37 modulate IL-17A/F-mediated responses and selectively suppress Lipocalin-2 in bronchial epithelial cells J Inflamm (Lond). Altieri, Anthony; Lloyd, Dylan; Ramotar, Padmanie; Does, Anne M van der; Hemshekhar, Mahadevappa; Mookherjee, Neeloffer SomaScan Liu, H. et al. Ubiquitin–proteasome system in the different stages of dominantly inherited Alzheimer’s disease Alzheimers Dement Liu, Haiyan; Bui, Quoc; Hassenstab, Jason; Gordon, Brian A.; Benzinger, Tammie L. S.; Timsina, Jigyasha; Sung, Yun Ju; Karch, Celeste; Renton, Alan E.; Daniels, Alisha; Morris, John C.; Xiong, Chengjie; Ibanez, Laura; Perrin, Richard J.; Llibre‐Guerra, Jorge J.; Day, Gregory S.; Supnet‐Bell, Charlene; Xu, Xiong; Berman, Sarah B.; Chhatwal, Jasmeer P.; Ikeuchi, Takeshi; Kasuga, Kensaku; Niimi, Yoshiki; Huey, Edward D.; Schofield, Peter R.; Brooks, William S.; Ryan, Natalie S.; Jucker, Mathias; Laske, Christoph; Levin, Johannes; Vöglein, Jonathan; Roh, Jee Hoon; Lopera, Francisco; Bateman, Randall J.; Cruchaga, Carlos; McDade, Eric M.; team, For DIAN study SomaScan Ye, H. et al. NMRAL1 as a Causal Factor in Postherpetic Neuralgia: A Proteome-Wide Mendelian Randomization Study Cell Death Dis Ye, Hong; Wang, Yiling; Shi, Yuechun; Wu, Yuyu; Xu, Qiuhan; Huang, Songmin SomaScan El‐Sabawi, B. et al. Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention J Am Heart Assoc. El‐Sabawi, Bassim; Tanriverdi, Kahraman; Gajjar, Priya; Nayor, Matthew; Landman, Joshua M; Below, Jennifer E; Haff, Madeleine; Long, Michelle; Ezpeleta, Mark; Freedman, Jane E; Varady, Krista; Shah, Ravi; Perry, Andrew S SomaScan Harel, M. et al. Decoding resistance to immune checkpoint inhibitors in non-small cell lung cancer: a comprehensive analysis of plasma proteomics and therapeutic implications J Immunother Cancer Harel, Michal; Dahan, Nili; Lahav, Coren; Jacob, Eyal; Elon, Yehonatan; Puzanov, Igor; Kelly, Ronan J; Shaked, Yuval; Leibowitz, Raya; Carbone, David P; Gandara, David R; Dicker, Adam P SomaScan Dong, Z. et al. Roles of plasma proteins in mediating the causal effect of the lipid species on gastric cancer: Insights from proteomic and two-step Mendelian randomization Medicine (Baltimore). Dong, Zhenhua; Chen, Zhiqing; Yu, Kai; Zhao, Dingliang; Jia, Jianling; Gao, Xulei; Wang, Daguang SomaScan Li, O. et al. Relationships between neuropsychiatric symptoms, subtypes of astrocyte activities, and brain pathologies in Alzheimer's disease and Parkinson's disease Alzheimers Dement. Li, Oceanna Yueran; Shin, Steven; Zhou, Sa; Turnbull, Adam; Lin, F. Vankee; Initiative, for the Alzheimer's Disease Neuroimaging SomaScan Oliva, V. et al. Predicted plasma proteomics from genetic scores and treatment outcomes in major depression: a meta-analysis Eur Neuropsychopharmacol. Oliva, Vincenzo; Possidente, Chiara; Fanelli, Giuseppe; Domschke, Katharina; Minelli, Alessandra; Gennarelli, Massimo; Martini, Paolo; Bortolomasi, Marco; Squassina, Alessio; Pisanu, Claudia; Kasper, Siegfried; Zohar, Joseph; Souery, Daniel; Montgomery, Stuart; Albani, Diego; Forloni, Gianluigi; Ferentinos, Panagiotis; Rujescu, Dan; Mendlewicz, Julien; Baune, Bernhard T; Network, European College of Neuropsychopharmacology (ECNP) Pharmacogenomics Transcriptomics; Vieta, Eduard; Serretti, Alessandro; Fabbri, Chiara SomaScan Heo, G. et al. Large-scale plasma proteomic profiling unveils diagnostic biomarkers and pathways for Alzheimer’s disease Nat Aging  Heo, Gyujin; Xu, Ying; Wang, Erming; Ali, Muhammad; Oh, Hamilton Se-Hwee; Moran-Losada, Patricia; Anastasi, Federica; Escalante, Armand González; Puerta, Raquel; Song, Soomin; Timsina, Jigyasha; Liu, Menghan; Western, Daniel; Gong, Katherine; Chen, Yike; Kohlfeld, Pat; Flynn, Allison; Thomas, Alvin G.; Lowery, Joseph; Morris, John C.; Holtzman, David M.; Perlmutter, Joel S.; Schindler, Suzanne E.; Vilor-Tejedor, Natalia; Suárez-Calvet, Marc; García-González, Pablo; Marquié, Marta; Fernández, Maria Victoria; Boada, Mercè; Cano, Amanda; Ruiz, Agustín; Zhang, Bin; Bennett, David A.; Benzinger, Tammie; Wyss-Coray, Tony; Ibanez, Laura; Sung, Yun Ju; Cruchaga, Carlos SomaScan Duggan, M. et al. Proteomic signatures of corona and herpes viral antibodies identify IGDCC4 as a mediator of neurodegeneration Sci Adv. Duggan, Michael R.; Yang, Shuojia; Gomez, Gabriela T.; Cui, Yuhan; Capuano, Ana W.; Chen, Jingsha; Yang, Zhijian; Wen, Junhao; Erus, Guray; Drouin, Shannon M.; Zweibaum, David; Tian, Qu; Candia, Julián; Bilgel, Murat; Lewis, Alexandria; Moghekar, Abhay; Ashton, Nicholas J.; Kac, Przemysław R.; Karikari, Thomas K.; Blennow, Kaj; Zetterberg, Henrik; Maher, Brion S.; Spira, Adam P.; Dumitrescu, Logan; Hohman, Timothy J.; Gottesman, Rebecca F.; Davatzikos, Christos; Bennett, David A.; Coresh, Josef; Ferrucci, Luigi; Resnick, Susan M.; Yolken, Robert; Walker, Keenan A. SomaScan Li, X. et al. Therapeutic targets for venous thromboemblism: proteome-wide mendelian randomization and colocalization analyses Thrombosis J. Li, Xiaolong; Yang, Cheng-hao; Zhou, Min; Yin, Min-yi SomaScan Courtney, Y. et al. Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development Nat Neurosci Courtney, Ya’el; Head, Joshua P.; Dani, Neil; Chechneva, Olga V.; Shipley, Frederick B.; Zhang, Yong; Holtzman, Michael J.; Sadegh, Cameron; Libermann, Towia A.; Lehtinen, Maria K. SomaScan Oh, H. et al. A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer’s disease Nature Med. Oh, Hamilton Se-Hwee; Urey, Deniz Yagmur; Karlsson, Linda; Zhu, Zeyu; Shen, Yuanyuan; Farinas, Amelia; Timsina, Jigyasha; Duggan, Michael R.; Chen, Jingsha; Guldner, Ian H.; Morshed, Nader; Yang, Chengran; Western, Daniel; Ali, Muhammad; Le Guen, Yann; Trelle, Alexandra; Herukka, Sanna-Kaisa; Rauramaa, Tuomas; Hiltunen, Mikko; Lipponen, Anssi; Luikku, Antti J.; Poston, Kathleen L.; Mormino, Elizabeth; Wagner, Anthony D.; Wilson, Edward N.; Channappa, Divya; Leinonen, Ville; Stevens, Beth; Ehrenberg, Alexander J.; Gottesman, Rebecca F.; Coresh, Josef; Walker, Keenan A.; Zetterberg, Henrik; Bennett, David A.; Franzmeier, Nicolai; Hansson, Oskar; Cruchaga, Carlos; Wyss-Coray, Tony SomaScan Zhu, Q. et al. Appraising the causal role of cathepsins in genitourinary carcinoma: a two-sample mendelian randomization and prospective study based on 36,225 individuals Discov Onc Zhu, Qiyu; Liu, Dingbang; Liu, Haoyang; Pan, Xiaohui; Shi, Yifu; Guo, Jingjing; Tong, Nanwei; Chen, Junru; Zeng, Hao SomaScan Eltobgy, M. et al. Plasma proteomic profiles correlate with organ dysfunction in COVID-19 ARDS Physiol Rep. Eltobgy, Moemen; Klamer, Brett; Farkas, Daniela; Londino, James D.; Englert, Joshua A.; Horowitz, Jeffrey C.; Mallampalli, Rama K.; Brock, Guy; Bednash, Joseph S. SomaScan Kitani, A. et al. Integrative network analysis reveals novel moderators of Aβ-Tau interaction in Alzheimer's disease Alzheimers Res Ther. Kitani, Akihiro; Matsui, Yusuke SomaScan Oliva, M. et al. Integration of GWAS, QTLs and keratinocyte functional assays reveals molecular mechanisms of atopic dermatitis Nat Commun. Oliva, Meritxell; Sarkar, Mrinal K.; March, Michael E.; Saeidian, Amir Hossein; Mentch, Frank D.; Hsieh, Chen-Lin; Tang, Fanying; Uppala, Ranjitha; Patrick, Matthew T.; Li, Qinmengge; Bogle, Rachael; Kahlenberg, J. Michelle; Watson, Deborah; Glessner, Joseph T.; Youssefian, Leila; Vahidnezhad, Hassan; Tsoi, Lam C.; Hakonarson, Hakon; Gudjonsson, Johann E.; Smith, Kathleen M.; Riley-Gillis, Bridget SomaScan Kuku, K. et al. Proteomic Profile of Ischemic Heart Disease in Heart Failure: A Community Study Mayo Clin Proc. Kuku, Kayode O.; Hashemian, Maryam; Joo, Jungnam; Shearer, Joseph J.; Downie, Carolina G.; Aggarwal, Mohit; Bielinski, Suzette J.; Roger, Véronique L. SomaScan Wang, L. et al. Associations among Angiotensin-Converting Enzyme, Neuroinflammation, and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease in Non-Dementia Adults Neurotox Res. Wang, Lan-Yang; Hu, Hao; Sheng, Ze-Hu; Hu, He-Ying; Ou, Ya-Nan; Guo, Fan; Zhu, Yang-Ke; Tan, Lan; Initiative, Alzheimer’s Disease Neuroimaging SomaScan Rooney, M. et al.f Correlations Within and Between Highly Multiplexed Proteomic Assays of Human Plasma Clin Chem. Rooney, Mary R; Chen, Jingsha; Ballantyne, Christie M; Hoogeveen, Ron C; Boerwinkle, Eric; Yu, Bing; Walker, Keenan A; Schlosser, Pascal; Selvin, Elizabeth; Chatterjee, Nilanjan; Couper, David; Grams, Morgan E; Coresh, Josef SomaScan Zhao, H. et al. High Throughput Proteomics Using the SomaLogic Platform Methods Mol Biol. Zhao, Hanjun; Winchester, Laura SomaScan Milani, L. et al. The Estonian Biobank’s journey from biobanking to personalized medicine Nat Commun. Milani, Lili; Alver, Maris; Laur, Sven; Reisberg, Sulev; Haller, Toomas; Aasmets, Oliver; Abner, Erik; Alavere, Helene; Allik, Annely; Annilo, Tarmo; Fischer, Krista; Hofmeister, Robin; Hudjashov, Georgi; Jõeloo, Maarja; Kals, Mart; Karo-Astover, Liis; Kasela, Silva; Kolde, Anastassia; Krebs, Kristi; Krigul, Kertu Liis; Kronberg, Jaanika; Kruusmaa, Karoliina; Kukuškina, Viktorija; Kõiv, Kadri; Lehto, Kelli; Leitsalu, Liis; Lind, Sirje; Luitva, Laura Birgit; Läll, Kristi; Lüll, Kreete; Metsalu, Kristjan; Metspalu, Mait; Mõttus, René; Nelis, Mari; Nikopensius, Tiit; Nurm, Miriam; Nõukas, Margit; Oja, Marek; Org, Elin; Palover, Marili; Palta, Priit; Pankratov, Vasili; Pantiukh, Kateryna; Pervjakova, Natalia; Pujol-Gualdo, Natàlia; Reigo, Anu; Reimann, Ene; Smit, Steven; Rogozina, Diana; Särg, Dage; Taba, Nele; Talvik, Harry-Anton; Teder-Laving, Maris; Tõnisson, Neeme; Vaht, Mariliis; Vainik, Uku; Võsa, Urmo; Yelmen, Burak; Esko, Tõnu; Kolde, Raivo; Mägi, Reedik; Vilo, Jaak; Laisk, Triin; Metspalu, Andres SomaScan Sun, X. et al. Uncovering leading compounds for alzheimer’s disease treatment: mendelian randomization and virtual screening insights into plasma protein modulation Biol Res. Sun, Xiaohan; Hu, Xiaofei; Wei, Jianming; An, Haoyu SomaScan Zhou, Y. et al. Genetically druggable targets for MAPK-activated colorectal cancer by a two-sample mendelian randomization analysis Sci Rep. Zhou, Yuxuan; Ding, Yunlong; Xu, Bangyue; Fei, Hongyang; Wang, Zheng SomaScan Zhang, M. et al. Immune status assessment based on plasma proteomics with meta graph convolutional networks BMC Genomics Zhang, Min; Xu, Nan; Cheng, Qi; Ye, Jing; Wu, Shiwei; Liu, Haoliang; Zhao, Chengkui; Yu, Lei; Feng, Weixing SomaScan Xiong, Y. et al. Efficient and scalable construction of clinical variable networks for complex diseases with RAMEN Cell Rep Methods Xiong, Yiwei; Wang, Jingtao; Shang, Xiaoxiao; Chen, Tingting; Fraser, Douglas D.; Fonseca, Gregory J.; Rousseau, Simon; Ding, Jun SomaScan Zhang, X. et al. FNDC4 Prevents Aging-Related Cardiac Dysfunction: By Restoring AMPKα/PPARα-Dependent Mitochondrial Function JACC: BasicTrans. Sci. Zhang, Xin; Dong, Wen-Sheng; Li, Kang; Ye, Yun-Jia; Hu, Can SomaScan Sasamoto, N. et al. Prospective evaluation of plasma proteins in relation to surgical endometriosis diagnosis in the Nurses’ Health Study II EBioMedicine. Sasamoto, Naoko; Ngo, Long H.; Vitonis, Allison F.; Dillon, Simon T.; Aziz, Maryam; Shafrir, Amy L.; Missmer, Stacey A.; Libermann, Towia A.; Terry, Kathryn L. SomaScan Daghlas, I. et al. Association of MTHFR missense variants with thromboembolic diseases and coagulation factor levels in European populations Thromb J. Daghlas, Iyas; Wang, Mengmeng; Gill, Dipender SomaScan Durán-Rodriguez, A. et al. Macrophage Migration Inhibitory Factor Contributes to Adverse Outcomes of Experimental Gestational Malaria across Pregnancy Stages Am J Pathol. Durán-Rodriguez, Andrea Tatiana; Almeida, Marcos Paulo Oliveira; Ferreira, Flávia Batista; Lozano-Trujillo, Laura Alejandra; Gomes, Angelica Oliveira; Cariaco, Yusmaris; Silva, Neide Maria SomaScan Candia, J. et al. Effects of In Vitro Hemolysis and Repeated Freeze–Thaw Cycles in Protein Abundance Quantification Using the SomaScan and Olink Assays J Proteome Res. Candia, Julián; Fantoni, Giovanna; Moaddel, Ruin; Delgado-Peraza, Francheska; Shehadeh, Nader; Tanaka, Toshiko; Ferrucci, Luigi SomaScan De Nardo, W. et al. Integrated liver-secreted and plasma proteomics identify a predictive model that stratifies MASH Cell Rep Med. De Nardo, William; Lee, Olivia; Johari, Yazmin; Bayliss, Jacqueline; Pensa, Marcus; Miotto, Paula M.; Keenan, Stacey N.; Ryan, Andrew; Rucinski, Amber; Svinos, Tessa M.; Ooi, Geraldine J.; Brown, Wendy A.; Kemp, William; Roberts, Stuart K.; Parker, Benjamin L.; Montgomery, Magdalene K.; Larance, Mark; Burton, Paul R.; Watt, Matthew J. SomaScan Assi, I. et al. Correlation between Olink and SomaScan proteomics platforms in adults with a Fontan circulation International Journal of Cardiology Congenital Heart Disease Assi, Ismael Z.; Landzberg, Michael J.; Becker, Kristian C.; Renaud, David; Reyes, Fernando Baraona; Leone, David M.; Benson, Mark; Michel, Miriam; Gerszten, Robert E.; Opotowsky, Alexander R. SomaScan Quan, L. et al. Genetic associations of plasma proteins and breast cancer identify potential therapeutic drug candidates Nat. Commun Biol Quan, Liuliu; Luo, Xin; Meng, Chenxu; Liu, Jinsong; Ju, Jie; Yang, Zixuan; Shuai, You; Wei, Tong; Meng, Jiaqi; Yuan, Peng SomaScan Chen, Y. et al. Identification of Novel Protein Biomarkers for Intrahepatic Cholangiocarcinoma by Integrating Human Plasma Proteome with Genome J Gastrointest Cancer. Chen, Yu-Sen; Yang, Wei-Bang; Li, Yi-Hu; Xu, Jin-Yang; Wei, Yu-Xuan; Huang, Si-Min; Jiang, Xiao-Feng; Li, Jian-Hui SomaScan Lumish, H. et al. Comprehensive Plasma Proteomic Profiling Reveals Differentially Regulated Signaling Pathways Underlying Left Ventricular Hypertrophy Between Hypertrophic Cardiomyopathy and Aortic Stenosis J. Cardiovasc. Transl. Res. Lumish, Heidi S.; Sewanan, Lorenzo R.; Liang, Lusha W.; Hasegawa, Kohei; Maurer, Mathew S.; Reilly, Muredach P.; Shimada, Yuichi J. SomaScan Kim, H. et al. Plant-based diets and cardiovascular events: a proteomics approach to examine the underlying pathways J Nutr. Kim, Hyunju; Chen, Jingsha; Prescott, Brenton; Walker, Maura E.; Grams, Morgan E.; Yu, Bing; Vasan, Ramachandran S.; Floyd, James; Sotoodehnia, Nona; Smith, Nicholas L.; Arking, Dan E.; Coresh, Josef; Rebholz, Casey M. SomaScan Li, Y. et al. Epigenomic and proteomic analyses provide insights into early-life immune regulation and asthma development in infants Nat Commun. Li, Yijun; Zhu, Zhaozhong; Camargo, Carlos A.; Espinola, Janice A.; Hasegawa, Kohei; Liang, Liming SomaScan Di Liberto, G. et al. Neuronal pSTAT1 hallmarks synaptic pathology in autoimmune encephalitis against intracellular antigens Acta Neuropathol. Di Liberto, Giovanni; Egervari, Kristof; Vogrig, Alberto; Spatola, Marianna; Piccinno, Margot; Vincenti, Ilena; Wagner, Ingrid; Kreutzfeldt, Mario; Endmayr, Verena; Ostertag, Karoline; Rahimi, Jasmin; Vicino, Alex; Pröbstel, Anne-Katrin; Meyronet, David; Frank, Stephan; Prinz, Marco; Hewer, Ekkehard; Brouland, Jean-Philippe; de Leval, Laurence; Parkkinen, Laura; Draganski, Bogdan; Desestret, Virginie; Dubey, Divyanshu; Pittock, Sean J.; Roemer, Shanu F.; Dickson, Dennis W.; Höftberger, Romana; Irani, Sarosh R.; Honnorat, Jérôme; Du Pasquier, Renaud; Merkler, Doron SomaScan Manoharan, MS. et al. The 15-Year Survival Advantage: Immune Resilience asa Salutogenic Force in Healthy Aging Aging Cell Manoharan, Muthu Saravanan; Lee, Grace C.; Harper, Nathan; Meunier, Justin A.; Restrepo, Marcos I.; Jimenez, Fabio; Karekatt, Sreenath; Branum, Anne P.; Gaitan, Alvaro A.; Andampour, Kian; Smith, Alisha M.; Mader, Michael; Noronha, Michelle; Tripathy, Devjit; Zhang, Nu; Moreira, Alvaro G.; Pandranki, Lavanya; team, South Texas Veterans Health Care System (STVHCS) COVID‐19 Clinical; team, STVHCS COVID‐19 Vaccine; team, STVHCS COVID‐19 Convalescent care; Medicine, STVHCS Center for Personalized; Sanchez‐Reilly, Sandra; Trinh, Hanh D.; Barnett, Clea; Angel, Luis; Segal, Leopoldo N.; Nicholson, Susannah; Clark, Robert A.; He, Weijing; Okulicz, Jason F.; Ahuja, Sunil K. SomaScan Tutino, M. et al. Genetics of circulating proteins in newborn babies at high risk of type 1 diabetes Nat Commun. Tutino, Mauro; Yu, Nancy Yiu-Lin; Hatzikotoulas, Konstantinos; Park, Young-Chan; Kreitmaier, Peter; Katsoula, Georgia; Berner, Reinhard; Casteels, Kristina; Larsson, Helena Elding; Kordonouri, Olga; Ołtarzewski, Mariusz; Szypowska, Agnieszka; Ott, Raffael; Weiss, Andreas; Winkler, Christiane; Zapardiel-Gonzalo, Jose; Petrera, Agnese; Hauck, Stefanie M.; Bonifacio, Ezio; Ziegler, Anette-Gabriele; Zeggini, Eleftheria SomaScan Solomon, M. et al. Cross-sectional associations of proteomic age acceleration with self-reported physical and mental health and depression symptoms among those with and without cancer J Cancer Surviv. Solomon, Matia; Bhatia, R; Wang, S; Blaes, AH; Platz, EA; Guan, W; Jewett, PI; Prizment, A SomaScan Abou Kamara, S. et al. The plasma proteome is linked to echocardiographic parameters and stages of diastolic dysfunction, across the ejection fraction spectrum Int J Cardiol. Abou Kamara, S; van Ommen, AM; Dal Canto, E; Valstar, G; Akkerhuis, KM; Cramer, MJ; Umans, V; Rutten, F; Teske, AJ; Menken, R; Geleijnse, M; Hofstra, L; Verhaar, M; de Boer, RA; Boersma, E; Asselbergs, F; van Dalen, BM; den Ruijter, H; Kardys, I. SomaScan Pan, J. et al. Genetic Evidence of Causal Effect between C1q/TNF-Related Protein-1 and Atherosclerosis: a Bidirectional and Multivariate Mendelian Randomization Study J Atheroscler Thromb. Pan, Juhong; Huang, Jia; Chen, Yueying; Jiang, Nan; Guo, Yuxin; Zhang, Ji; Zhou, Shiyuan; Pu, Huan; Deng, Qing; Hu, Bo; Zhou, Qing SomaScan Li, W. et al. The prospective approach for aptamers applied in the treatment and molecular diagnostics of ischemic stroke Front. Pharmacol. Li, Wenfeng; Wu, Junyi; Hu, Zijian; Zhang, Jixuan; Ye, Guangming; Luo, Fengling; Zeng, Zhikun; Luo, Yi SomaScan Mogavero, M. et al. Sex Differences in Cerebrospinal Fluid Proteomics of Patients with Restless Legs Syndrome Sleep Mogavero, Maria P; Peng, Gang; Marchese, Giovanna; Lanza, Giuseppe; Ferini-Strambi, Luigi; Ferri, Raffaele; Koo, Brian B SomaScan Tasci, E. et al. GLIO-Select: Machine Learning-Based Feature Selection and Weighting of Tissue and Serum Proteomic and Metabolomic Data Uncovers Sex Differences in Glioblastoma Int. J. Mol. Sci. Tasci, Erdal; Chappidi, Shreya; Zhuge, Ying; Zhang, Longze; Zgela, Theresa Cooley; Sproull, Mary; Mackey, Megan; Camphausen, Kevin; Krauze, Andra Valentina SomaScan Bai, Y. et al. Genetic Evidence Supporting a Causal Association Between mTORC1-Dependent Circulating Protein Levels and Diabetic Retinopathy Transl Vis Sci Technol. Bai, Yaqi; Xi, Yujia; Gui, Chenwei; Huang, Guohai; Zhou, Guohong SomaScan Collister, D. et al. The differential effects of sex hormone therapy on kidney function: insights into biological sex differences J Clin Invest. Collister, David; Levin, Adeera SomaScan Hosseini, M. et al. Plasma Osteopontin Levels Are Associated with Risk of Future Incident Venous Thromboembolism – The HUNT Study J Thromb Haemost. Hosseini, Maryam; Hindberg, Kristian D.; Nøst, Therese H.; Jonasson, Christian; Hveem, Kristian; Hansen, John-Bjarne; Snir, Omri SomaScan Tobin, B. et al. Exploring Human Plasma Proteomic Variations in Mucolipidosis Type IV Mol Ther Methods Clin Dev. Tobin, Brendan R.; Misko, Albert; Miller-Browne, Victoria; Sangster, Madison; Grishchuk, Yulia; Wood, Levi B. SomaScan Commissati, S. et al. Prolonged fasting promotes systemic inflammation and platelet activation in humans: A medically supervised, water-only fasting and refeeding study Mol Metab. Commissati, Serena; Cagigas, Maria Lastra; Masedunskas, Andrius; Petrucci, Giovanna; Tosti, Valeria; De Ciutiis, Isabella; Rajakumar, Gayathiri; Kirmess, Kristopher M.; Meyer, Matthew R.; Goldhamer, Alan; Kennedy, Brian K.; Hatem, Duaa; Rocca, Bianca; Fiorito, Giovanni; Fontana, Luigi SomaScan Loesch, D. et al. Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities Nat Commun Loesch, Douglas P.; Garg, Manik; Matelska, Dorota; Vitsios, Dimitrios; Jiang, Xiao; Ritchie, Scott C.; Sun, Benjamin B.; Runz, Heiko; Whelan, Christopher D.; Holman, Rury R.; Mentz, Robert J.; Moura, Filipe A.; Wiviott, Stephen D.; Sabatine, Marc S.; Udler, Miriam S.; Gause-Nilsson, Ingrid A.; Petrovski, Slavé; Oscarsson, Jan; Nag, Abhishek; Paul, Dirk S.; Inouye, Michael SomaScan Tokolyi, A. et al. The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes Nat Genet. Tokolyi, Alex; Persyn, Elodie; Nath, Artika P.; Burnham, Katie L.; Marten, Jonathan; Vanderstichele, Thomas; Tardaguila, Manuel; Stacey, David; Farr, Ben; Iyer, Vivek; Jiang, Xilin; Lambert, Samuel A.; Noell, Guillaume; Quail, Michael A.; Rajan, Diana; Ritchie, Scott C.; Sun, Benjamin B.; Thurston, Scott A. J.; Xu, Yu; Whelan, Christopher D.; Runz, Heiko; Petrovski, Slavé; Gaffney, Daniel J.; Roberts, David J.; Di Angelantonio, Emanuele; Peters, James E.; Soranzo, Nicole; Danesh, John; Butterworth, Adam S.; Inouye, Michael; Davenport, Emma E.; Paul, Dirk S. SomaScan Niinuma, S. et al. A Cross-Sectional Exploratory Study of Rat Sarcoid (Ras) Activation in Women with and Without Polycystic Ovary Syndrome Cells Niinuma, Sara Anjum; Habib, Haniya; Takemoto, Ashleigh Suzu-Nishio; Das, Priya; Sathyapalan, Thozhukat; Atkin, Stephen L; Butler, Alexandra E SomaScan Belbasis, L. et al. Mendelian randomization identifies proteins involved in neurodegenerative diseases Brain Belbasis, Lazaros; Morris, Sam; van Duijn, Cornelia; Bennett, Derrick; Walters, Robin SomaScan De Oliveira, T. et al. Protein epigenetic scores and overall mortality in the longitudinal Swedish Adoption/Twin Study of Aging (SATSA) Clin Epigenetics. De Oliveira, Thaís Lopes; March, Arianna; Mak, Jonathan K. L.; Pedersen, Nancy L.; Hägg, Sara SomaScan Zhao, Y. et al. Identification of Candidate Lung Function-Related Plasma Proteins to Pinpoint Drug Targets for Common Pulmonary Diseases: A Comprehensive Multi-Omics Integration Analysis Curr. Issues Mol. Biol. Zhao, Yansong; Shen, Lujia; Yan, Ran; Liu, Lu; Guo, Ping; Liu, Shuai; Chen, Yingxuan; Yuan, Zhongshang; Gong, Weiming; Ji, Jiadong SomaScan Chadwick, J. et al. Harnessing the Plasma Proteome to Predict Mortality in Heart Failure Subpopulations Circ Heart Fail. Chadwick, Jessica; Hinterberg, Michael A; Asselbergs, Folkert W; Biegel, Hannah; Boersma, Eric; Cappola, Thomas P; Chirinos, Julio A; Coresh, Joseph; Ganz, Peter; Gordon, David A; Kureshi, Natasha; Loupey, Kelsey M; Orlenko, Alena; Ostroff, Rachel; Sampson, Laura; Shrestha, Sama; Sweitzer, Nancy K; Williams, Stephen A; Zhao, Lei; Kardys, Isabella; Lanfear, David E SomaScan Ali, M. et al. Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures across the Alzheimer disease continuum Neuron Ali, Muhammad; Timsina, Jigyasha; Western, Daniel; Liu, Menghan; Beric, Aleksandra; Budde, John; Do, Anh; Heo, Gyujin; Wang, Lihua; Gentsch, Jen; Schindler, Suzanne E.; Morris, John C.; Holtzman, David M.; Ruiz, Agustin; Alvarez, Ignacio; Aguilar, Miquel; Pastor, Pau; Rutledge, Jarod; Oh, Hamilton; Wilson, Edward N.; Le Guen, Yann; Khalid, Rana R.; ADRC), Knight Alzheimer Disease Research Center (Knight; (ADNI), Alzheimer Disease Neuroimaging Initiative; (FACE), Fundació ACE Alzheimer Center Barcelona; Barcelona-1; ADRC), Stanford Alzheimer Disease Research Center (Stanford; Robins, Chloe; Pulford, David J.; Tarawneh, Rawan; Ibanez, Laura; Wyss-Coray, Tony; Sung, Yun Ju; Cruchaga, Carlos SomaScan Kivimäki, M. et al. Social disadvantage accelerates aging Nat Med. Kivimäki, Mika; Pentti, Jaana; Frank, Philipp; Liu, Fangyu; Blake, Acer; Nyberg, Solja T.; Vahtera, Jussi; Singh-Manoux, Archana; Wyss-Coray, Tony; Walker, Keenan A.; Partridge, Linda; Lindbohm, Joni V. SomaScan Rothman, A. et al. Positioning Imatinib for Pulmonary Arterial Hypertension: A Dose Finding Phase 2 Study Am J Respir Crit Care Med Rothman, Alexander M K; Villar, Sofia; Middleton, Jennifer; Roussakis, Andreas A; Varian, Frances; Zafar, Hamza; Law, Martin; Apperley, Jane; Bartelink, Imke H; Said, Medhat M; Delgado-SanMartin, Juan A; Kiely, David G; Howard, Luke; Toshner, Mark; Wort, S John; Wilkins, Martin R SomaScan Yuan, S. et al. GWAS identifies genetic loci, lifestyle factors and circulating biomarkers that are risk factors for sarcoidosis Yuan, Shuai; Chen, Jie; Geng, Jiawei; Zhao, Sizheng Steven; Yarmolinsky, James; Arkema, Elizabeth V.; Abramowitz, Sarah; Levin, Michael G.; Tsilidis, Kostas K.; Burgess, Stephen; Damrauer, Scott M.; Larsson, Susanna C. SomaScan Alakwaa, F. et al. Leveraging complementary multi-omics data integration methods for mechanistic insights in kidney diseases JCI Insight Alakwaa, Fadhl; Das, Vivek; Majumdar, Arindam; Nair, Viji; Fermin, Damian; Dey, Asim B.; Slidel, Timothy; Reilly, Dermot F.; Myshkin, Eugene; Duffin, Kevin L.; Chen, Yu; Bitzer, Markus; Pennathur, Subramaniam; Brosius, Frank C.; Kretzler, Matthias; Ju, Wenjun; Karihaloo, Anil; Eddy, Sean SomaScan Lin, Yu-Jing. et al. The associations of cerebrospinal fluid ApoE and C1q with Alzheimer's disease biomarkers J Alzheimers Dis. Lin, Yu-Jing; Liu, Ying; Sheng, Ze-Hu; Fu, Yan; Ma, Ling-Zhi; Zhang, Zi-Hao; Wang, Lan-Yang; Huang, Liang-Yu; Liu, Min; Wang, Zuo-Teng; Tan, Lan; *, Alzheimer's Disease Neuroimaging Initiative SomaScan Zhang, Xuening; Associations of plasma proteins with incident inflammatory bowel disease in a prospective cohort study and genetic analysis Nat Commun. Zhang, Xuening; Zhao, Hao; Wan, Meng; Man, Jinyu; Zhang, Tongchao; Yang, Xiaorong; Lu, Ming SomaScan Sullivan, V. et al. Proteomic Correlates of Vitamin D Supplementation in the Atherosclerosis Risk in Communities (ARIC) Study Proteomics Clin Appl. Sullivan, Valerie, K.; Chen, Jingsha; Bernard, Lauren; Yu, Bing; Michos, Erin D.; Appel, Lawrence J.; Lichtenstein, Alice H.; Rebholz, Casey M. SomaScan He, Y. et al. Comment on Maddaloni et al. Osteoprotegerin, Osteopontin, and Osteocalcin Are Associated With Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL. Diabetes Care ;48:235–242 Diabetes Care He, Yanlin; Liu, Chan; Wang, Xiaoping SomaScan Maddaloni, E. et al. Response to Comments on Maddaloni et al. Osteoprotegerin, Osteopontin, and Osteocalcin Are Associated With Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL. Diabetes Care ;48:235–242 Maddaloni, Ernesto; Nguyen, Maggie; Shah, Svati H; Holman, Rury R SomaScan Stemmerik, M. et al. Universal Proteomic Signature After Exercise-Induced Muscle Injury in Muscular Dystrophies Ann Clin Transl Neurol. Stemmerik, Mads G.; Barthel, Benjamin; Andersen, Nanna R.; Skriver, Sofie V.; Russell, Alan J.; Vissing, John SomaScan Wang, Z. et al. Cerebrospinal fluid proteomics identification of biomarkers for amyloid and tau PET stages Cell Rep Med. Wang, Zhibo; Chen, Yuhan; Gong, Katherine; Zhao, Bote; Ning, Yuye; Chen, Meilin; Li, Yan; Ali, Muhammad; Timsina, Jigyasha; Liu, Menghan; Cruchaga, Carlos; Jia, Jianping SomaScan Nouairia, G. et al. Towards precision medicine strategies using plasma proteomic profiling for suspected gallbladder cancer: a pilot study J Thromb Haemost Nouairia, Ghada; Cornillet, Martin; Jansson, Hannes; Bergquist, Annika; Sparrelid, Ernesto SomaScan Du, Kuo. et al. Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction Nat Commun. Du, Kuo; Umbaugh, David S.; Liuyang, Wang; Jun, Ji Hye; Dutta, Rajesh K.; Oh, Seh Hoon; Ren, Niansheng; Zhang, Qiaojuan; Ko, Dennis C.; Ferreira, Ana; Hill, Jon; Gao, Guannan; Pullen, Steven S.; Jain, Vaibhav; Gregory, Simon; Abdelmalek, Manal F.; Diehl, Anna Mae SomaScan Yang, W. et al. Exploring new drug treatment targets for immune related bone diseases using a multi omics joint analysis strategy Sci Rep. Yang, Wei; Liu, Chenglin; Li, Zhenhua; Cui, Miao SomaScan Ghazal, R. et al. Cardiac Fibrosis in the Multi-Omics Era: Implications for Heart Failure Circ Res. Ghazal, Rachad; Wang, Min; Liu, Duan; Tschumperlin, Daniel J.; Pereira, Naveen L. SomaScan Butler, A. et al. Association of Complement Proteins with C Reactive Protein in Non-Obese Women with and Without Polycystic Ovary Syndrome Int. J. Mol. Sci. Butler, Alexandra E; Moin, Abu Saleh Md; Begam, Hamna H; Waris, Sana; Azeez, Juberiya M; Sathyapalan, Thozhukat; Atkin, Stephen L; Brennan, Edwina SomaScan Chou, C. et al. Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer’s disease Nat Cell Biol. Chou, Ching-Chieh; Vest, Ryan; Prado, Miguel A.; Wilson-Grady, Joshua; Paulo, Joao A.; Shibuya, Yohei; Moran-Losada, Patricia; Lee, Ting-Ting; Luo, Jian; Gygi, Steven P.; Kelly, Jeffery W.; Finley, Daniel; Wernig, Marius; Wyss-Coray, Tony; Frydman, Judith SomaScan Puerta, R. et al. Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO Funct Integr Genomics. Puerta, Raquel; de Rojas, Itziar; García-González, Pablo; Olivé, Clàudia; Sotolongo-Grau, Oscar; García-Sánchez, Ainhoa; García-Gutiérrez, Fernando; Montrreal, Laura; Tartari, Juan Pablo; Sanabria, Ángela; Pytel, Vanesa; Lage, Carmen; Quintela, Inés; Aguilera, Nuria; Rodriguez-Rodriguez, Eloy; Alarcón-Martín, Emilio; Orellana, Adelina; Pastor, Pau; Pérez-Tur, Jordi; Piñol-Ripoll, Gerard; de Munain, Adolfo López; García-Alberca, Jose María; Royo, Jose Luís; Bullido, María J; Álvarez, Victoria; Real, Luis Miguel; Anchuelo, Arturo Corbatón; Gómez-Garre, Dulcenombre; Larrad, María Teresa Martínez; Franco-Macías, Emilio; Mir, Pablo; Medina, Miguel; Sánchez-Valle, Raquel; Dols-Icardo, Oriol; Sáez, María Eugenia; Carracedo, Ángel; Tárraga, Lluís; Alegret, Montse; Valero, Sergi; Marquié, Marta; Boada, Mercè; Juan, Pascual Sánchez; Cavazos, Jose Enrique; Cabrera-Socorro, Alfredo; Cano, Amanda; Ruiz, Agustín; Initiative, Alzheimer’s Disease Neuroimaging SomaScan Gagnon, E. et al. Remnant cholesterol concentrations best explain the cardiovascular benefit of APOC3 genetic inhibition: a drug target Mendelian randomization study Eur Heart J Open. Gagnon, Eloi; Gill, Dipender; Burgess, Stephen; Arsenault, Benoit J SomaScan Jonsdottir, A. et al. Missense variants in FRS3 affect body mass index in populations of diverse ancestries Nat Commun. Jonsdottir, Andrea B; Sveinbjornsson, Gardar; Thorolfsdottir, Rosa B; Tamlander, Max; Tragante, Vinicius; Olafsdottir, Thorhildur; Rognvaldsson, Solvi; Sigurdsson, Asgeir; Eggertsson, Hannes P; Aegisdottir, Hildur M; Arnar, David O; Banasik, Karina; Beyter, Doruk; Bjarnason, Ragnar G; Bjornsdottir, Gyda; Brunak, Søren; Bruun, Mie Topholm; Dowsett, Joseph; Einarsson, Eythor; Einarsson, Gudmundur; Erikstrup, Christian; Fridriksdottir, Run; Ghouse, Jonas; Gretarsdottir, Solveig; Halldorsson, Gisli H; Hansen, Torben; Helgadottir, Anna; Holm, Peter C; Ivarsdottir, Erna V; Iversen, Kasper Karmark; Jensen, Bitten Aagaard; Jonsdottir, Ingileif; Knight, Stacey; Knowlton, Kirk U; Kristmundsdottir, Snaedis; Larusdottir, Adalheidur E; Magnusson, Olafur Th; Masson, Gisli; Melsted, Pall; Mikkelsen, Christina; Moore, Kristjan H S; Oddsson, Asmundur; Olason, Pall I; Palsson, Frosti; Pedersen, Ole Birger; Schwinn, Michael; Sigurdsson, Emil L; Skaftason, Aron; Stefansdottir, Lilja; Stefansson, Hreinn; Steingrimsdottir, Thora; Sturluson, Arni; Styrkarsdottir, Unnur; Sørensen, Erik; Teitsdottir, Unnur D; Thorgeirsson, Thorgeir E; Thorisson, Gudmundur A; Thorsteinsdottir, Unnur; Ulfarsson, Magnus O; Ullum, Henrik; Vikingsson, Arnor; Walters, G Bragi; Consortium, DBDS Genomic; Jensen, Bitten Aagaard; Nadauld, Lincoln D; Bundgaard, Henning; Ostrowski, Sisse Rye; Helgason, Agnar; Halldorsson, Bjarni V; Norddahl, Gudmundur L; Ripatti, Samuli; Gudbjartsson, Daniel F; Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Holm, Hilma; Sulem, Patrick; Stefansson, Kari SomaScan Riviere-Cazaux, C. et al. A field resource for the glioma cerebrospinal fluid proteome: impacts of resection and location on biomarker discovery Neuro Oncol. Riviere-Cazaux, Cecile; Graser, Christopher J; Warrington, Arthur E; Hoplin, Matthew D; Andersen, Katherine M; Malik, Noor; Palmer, Elizabeth A; Carlstrom, Lucas P; Dasari, Surendra; Munoz-Casabella, Amanda; Ikram, Samar; Ghadimi, Keyvan; Himes, Benjamin T; Jusue-Torres, Ignacio; Sarkaria, Jann N; Meyer, Fredric B; Van Gompel, Jamie J; Kizilbash, Sani H; Sener, Ugur; Michor, Franziska; Campian, Jian L; Parney, Ian F; Burns, Terry C SomaScan Liang, Y. et al. Circulating Proteomic Profiles Are Associated With Incident Type 2 Diabetes in Asian Populations J Clin Endocrinol Metab. Liang, Yujian; Lim, Charlie G Y; Ritchie, Scott C; Bertin, Nicolas; Chai, Jin-Fang; Yao, Jiali; Li, Yun; Tai, E Shyong; van Dam, Rob M; Sim, Xueling SomaScan Duggan, MR. et al. The Dementia SomaSignal Test (dSST): A plasma proteomic predictor of 20-year dementia risk Alzheimers Dement Duggan, Michael R.; Paterson, Clare; Lu, Yifei; Biegel, Hannah; Dark, Heather E.; Cordon, Jenifer; Bilgel, Murat; Kaneko, Naoto; Shibayama, Masaki; Kato, Shintaro; Furuichi, Makio; Waga, Iwao; Hiraga, Keita; Katsuno, Masahisa; Nishita, Yukiko; Otsuka, Rei; Davatzikos, Christos; Erus, Guray; Loupy, Kelsey; Simpson, Melissa; Lewis, Alexandria; Moghekar, Abhay; Palta, Priya; Gottesman, Rebecca F.; Resnick, Susan M.; Coresh, Josef; Williams, Stephen A.; Walker, Keenan A. SomaScan Yousif, G. et al. Distinctive blood and salivary proteomics signatures in Qatari individuals at high risk for cardiovascular disease Sci Rep. Yousif, Ghada; Murugesan, Selvasankar; Djekidel, Mohamed Nadhir; Terranegra, Annalisa; Gentilcore, Giusy; Grivel, Jean Charles; Khodor, Souhaila Al SomaScan Xu, D. et al. Identifying novel drug targets for calcific aortic valve disease through Mendelian randomization Atherosclerosis. Xu, Dilin; Lu, Jin; Yang, Yanfang; Hu, Wangxing; Chen, Jinyong; Xue, Junhui; Yang, Shuangshuang; Cao, Naifang; Hu, Haochang; Qian, Ningjing; Zhou, Dao; Dai, Hanyi; Wang, Jian'an; Liu, Xianbao SomaScan Andersen, R. et al. A genome-wide association meta-analysis links hidradenitis suppurativa to common and rare sequence variants causing disruption of the Notch and Wnt/β-catenin signaling pathways J Am Acad Dermatol. Andersen, R Kjærsgaard; Stefansdottir, L.; Riis, P Theut; Halldorsson, Gh; Ferkingstad, E.; Oddsson, A.; Walters, G.B.; Olafsdottir, Thorunn A.; Rutsdottir, G.; Zachariae, C.; Thomsen, S.F.; Brodersen, T.; Dinh, K.M.; Knowlton, K.U.; Knight, S.; Nadauld, L.D.; Banasik, K.; Brunak, S.; Hansen, T.F.; Hjalgrim, H.; Sørensen, E.; Mikkelsen, C.; Ullum, H.; Nyegaard, M.; Bruun, M.T.; Erikstrup, C.; Ostrowski, S.R.; Eidsmo, L.; Saunte, D.M.L.; Sigurgeirsson, B.; Orvar, K.B.; Saemundsdottir, J.; Melsted, P.; Norddahl, G.L.; Sulem, P.; Stefansson, H.; Holm, H.; Gudbjartsson, D.; Thorleifsson, G.; Jonsdottir, I.; Pedersen, O.B.V.; Jemec, G.B.E.; Stefansson, K. SomaScan Gaudilliere, B. et al. Infusion of young donor plasma components in older patients modifies the immune and inflammatory response to surgical tissue injury: a randomized clinical trial J. Transl. Med. Gaudilliere, Brice; Xue, Lei; Tsai, Amy S.; Gao, Xiaoxiao; McAllister, Tiffany N.; Tingle, Martha; Porras, Gladys; Feinstein, Igor; Feyaerts, Dorien; Verdonk, Franck; Sabayev, Maximilian; Hedou, Julien; Ganio, Edward A.; Berson, Eloïse; Becker, Martin; Espinosa, Camilo; Kim, Yeasul; Lehallier, Benoit; Rawner, Esther; Feng, Chunmiao; Amanatullah, Derek F.; Huddleston, James I.; Goodman, Stuart B.; Aghaeepour, Nima; Angst, Martin S. SomaScan Aldisi, R. et al. Identification of novel proteomic biomarkers for hypertension: a targeted approach for precision medicine Clin. Proteom. Aldisi, Rana S.; Alsamman, Alsamman M.; Krawitz, Peter; Maj, Carlo; Zayed, Hatem SomaScan Shaojie, F. et al. Investigating the role of gut microbiota in diabetic nephropathy through plasma proteome mediated analysis Sci Rep. Fu, Shaojie; Li, Fan; Yu, Jinyu; Ma, Shengjie; Zhang, Li; Cheng, Yanli SomaScan Wang, G. et al. Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF-1 Pathway in Polycystic Ovary Syndrome Adv Sci (Weinh). Wang, Guiquan; Mao, Weian; Zhang, Yurong; Yang, Haiyan; Zhu, Ming; Li, Yan; Chen, Wei; Chen, Yi; Lou, Chen; Li, Ping; Chang, Hsun‐Ming; Yuan, Shuai; Zhao, Yue; Mu, Liangshan SomaScan Raveendran, J. et al. Emerging trends in the cystatin C sensing technologies: towards better chronic kidney disease management RSC Adv. Raveendran, Jeethu; Gangadharan, Dhanya; Bayry, Jagadeesh; Rasheed, P. Abdul SomaScan Lee, W. et al. From Local to Systemic: The Journey of Tick Bite Biomarkers in Australian Patients Int. J. Mol. Sci. Lee, Wenna; Barbosa, Amanda D; Lee, Amy Huey-Yi; Currie, Andrew; Martino, David; Stenos, John; Long, Michelle; Beaman, Miles; Harvey, Nathan T; Kresoje, Nina; Skut, Patrycja; Irwin, Peter J; Kumarasinghe, Prasad; Hall, Roy A; Ben-Othman, Rym; Graves, Stephen; Kollmann, Tobias R; Oskam, Charlotte L SomaScan Wang,B. et al. Comparative studies of plasma proteins measured by two affinity-based platforms in Chinese adults Nat Commun. Wang, Baihan; Pozarickij, Alfred; Mazidi, Mohsen; Wright, Neil; Yao, Pang; Said, Saredo; Iona, Andri; Kartsonaki, Christiana; Fry, Hannah; Lin, Kuang; Chen, Yiping; Du, Huaidong; Avery, Daniel; Schmidt-Valle, Dan; Yu, Canqing; Sun, Dianjianyi; Lv, Jun; Hill, Michael; Li, Liming; Bennett, Derrick A.; Collins, Rory; Walters, Robin G.; Clarke, Robert; Millwood, Iona Y.; Chen, Zhengming; Wang, Baihan; Pozarickij, Alfred; Mazidi, Mohsen; Wright, Neil; Yao, Pang; Said, Saredo; Iona, Andri; Kartsonaki, Christiana; Fry, Hannah; Lin, Kuang; Chen, Yiping; Du, Huaidong; Avery, Daniel; Schmidt-Valle, Dan; Yu, Canqing; Sun, Dianjianyi; Lv, Jun; Li, Liming; Bennett, Derrick A.; Collins, Rory; Walters, Robin G.; Clarke, Robert; Millwood, Iona Y.; Chen, Zhengming SomaScan Zhang, X. et al. Mendelian Randomization and Colocalization Analysis Reveal New Drug Targets for Oral Ulcer: A Mendelian Randomization Analysis Health Sci Rep. Zhang, Xiaoyu; Fan, Hui; Zhang, Xiaoguang; Wang, Yanni; Chen, Guozhong SomaScan Rao, JH. et al. Plasma proteins mediate the effects of the gut microbiota on the development of head and neck cancer: a two-sample and mediated Mendelian randomized study Discov Oncol. Rao, Jin-Hui; Zhang, Wen-Da; Zha, Cheng-Peng; Zhang, Min-Yue; Xing, Yu-Jie; Wang, Zai-Hui; Yu, Jun-Xian; He, Dong-Yan; Sun, Chuan-Zheng; Li, Lei SomaScan Mika, K. et al. Proteomic organ-specific ageing signatures and 20-year risk of age-related diseases: the Whitehall II observational cohort study The Lancet Digital Health Kivimäki, Mika; Frank, Philipp; Pentti, Jaana; Jokela, Markus; Nyberg, Solja T; Blake, Acer; Lindbohm, Joni V; Oh, Hamilton Se-Hwee; Singh-Manoux, Archana; Wyss-Coray, Tony; Partridge, Linda SomaScan Aboelsaad, I . et al. Hepcidin, incident heart failure, and cardiac dysfunction in older adults: the ARIC study Eur J Prev Cardiol. Aboelsaad, Iman A F; Claggett, Brian L; Arthur, Victoria; Dorbala, Pranav; Matsushita, Kunihiro; Lutsey, Pamela L; Yu, Bing; Lennep, Brandon W; Ndumele, Chiadi E; Farag, Youssef M K; Shah, Amil M; Buckley, Leo F SomaScan Larsson, S. et al. Genome-wide association study and Mendelian randomization analyses reveal insights into bladder cancer etiology JNCI Cancer Spectr. Larsson, Susanna C; Chen, Jie; Ruan, Xixian; Li, Xue; Yuan, Shuai SomaScan Kemper, E. et al. Fetuin B Is Related to Cytokine/Chemokine and Insulin Signaling in Adipose Tissue and Plasma in Humans J Clin Endocrinol Metab. Kemper, Esther J; Goossens, Gijs H; Blaak, Ellen E; Adriaens, Michiel E; Meex, Ruth C R SomaScan Gao, C. et al. Proteome-Wide Association Study for Finding Druggable Targets in Progression and Onset of Parkinson's Disease CNS Neurosci Ther. Gao, Chenhao; Zhou, Haobin; Liang, Weixuan; Wen, Zhuofeng; Liao, Wanzhe; Xie, Zhixin; Liao, Cailing; He, Limin; Sun, Jingzhang; Chen, Zhilin; Li, Duopin; Yuan, Naijun; Huang, Chuiguo; Zhang, Jiewen SomaScan Ziyatdinov, A. et al. Identifying chronic obstructive pulmonary disease subtypes using multi-trait genetics EBioMedicine Ziyatdinov, Andrey; Hobbs, Brian D.; Kanaan-Izquierdo, Samir; Moll, Matthew; Sakornsakolpat, Phuwanat; Shrine, Nick; Chen, Jing; Song, Kijoung; Bowler, Russell P.; Castaldi, Peter J.; Tobin, Martin D.; Kraft, Peter; Silverman, Edwin K.; Julienne, Hanna; Cho, Michael H.; Aschard, Hugues SomaScan Wu, J. et al. Proteome-wide Mendelian randomization identifies causal plasma proteins in prostate cancer development Hum Genomics. Wu, Jian; Yang, Zitong; Ding, Jiafeng; Hao, Sida; Chen, Hong; Jin, Ke; Zhang, Cheng; Zheng, Xiangyi SomaScan Lam, J. et al. Worry Moderates Plasma Placental Growth Factor (PIGF) and Cognition in Older Adults with Amnestic Mild Cognitive Impairment (aMCI) Experimental Aging Research Lam, Jovian C.; Louras, Peter; Savettiere, Adriana; Fairchild, J. Kaci SomaScan Onsaker, A. et al. Histo-blood group ABO system transferase plasma levels and risk of future venous thromboembolism: The HUNT Study Blood. Onsaker, Asbjørn L.; Arntzen, Anna Y.; Trégouët, David-Alexandre; Nøst, Therese H.; Tang, Weighing; Guan, Weihua; Jonasson, Christian; Morange, Pierre-Emmanuel; Hinderg, Kristian D.; Folsom, Aaron R.; Hveem, Kristian; Morelli, Vânia M.; Hansen, John-Bjarne SomaScan Andresen, I. et al. Prediction of late-onset preeclampsia using plasma proteomics: a longitudinal multi-cohort study Sci Rep. Ina J Andresen, Manuela Zucknick, Maren-Helene L Degnes, Martin S Angst, Nima Aghaeepour, Roberto Romero, Marie Cecilie P Roland, Adi L Tarca, Ane Cecilie Westerberg, Trond M Michelsen  SomaScan Butler, AE. et al. Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinases, and Their Ratios in Women with Polycystic Ovary Syndrome and Healthy Controls Int. J. Mol. Sci. Alexandra E Butler, Manjula Nandakumar, Thozhukat Sathyapalan, Edwina Brennan, Stephen L Atkin SomaScan Maretty, L. et al. Proteomic changes upon treatment with semaglutide in individuals with obesity Nat Med. Lasse Maretty, Dipender Gill, Lotte Simonsen, Keng Soh, Loukas Zagkos, Michael Galanakis, Jonas Sibbesen, Miquel Triana Iglesias, Anna Secher, Dirk Valkenborg, Jonathan Q. Purnell, Lotte Bjerre Knudsen, Abd A. Tahrani, Milan Geybels SomaScan Puerta, R. et al. Head-to-Head Comparison of Aptamer- and Antibody-Based Proteomic Platforms in Human Cerebrospinal Fluid Samples from a Real-World Memory Clinic Cohort Int. J. Mol. Sci. Raquel Puerta, Amanda Cano, Pablo García-González, Fernando García-Gutiérrez, Maria Capdevila, Itziar de Rojas, Clàudia Olivé, Josep Blázquez-Folch, Oscar Sotolongo-Grau, Andrea Miguel, Laura Montrreal, Pamela Martino-Adami, Asif Khan, Adelina Orellana, Yun Ju Sung, Ruth Frikke-Schmidt, Natalie Marchant, Jean Charles Lambert, Maitée Rosende-Roca, Montserrat Alegret, Maria Victoria Fernández, Marta Marquié, Sergi Valero, Lluís Tárraga, Carlos Cruchaga, Alfredo Ramírez, Mercè Boada, Bart Smets, Alfredo Cabrera-Socorro, Agustín Ruiz SomaScan Yang, W. et al. Gut microbiota and blood biomarkers in IBD-Related arthritis: insights from mendelian randomization Commun Biol. Wei Yang, Miao Cui, Peng Yang, Chenlin Liu, Xiuzhen Han, Wenyi Yao, Zhenhua Li SomaScan Bosticardo, M. et al. Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature Sci Immunol. Marita Bosticardo, Kerry Dobbs, Ottavia M Delmonte, Andrew J Martins, Francesca Pala, Tomoki Kawai, Heather Kenney, Gloria Magro, Lindsey B Rosen, Yasuhiro Yamazaki, Hsin-Hui Yu, Enrica Calzoni, Yu Nee Lee, Can Liu, Jennifer Stoddard, Julie Niemela, Danielle Fink, Riccardo Castagnoli, Meredith Ramba, Aristine Cheng, Deanna Riley, Vasileios Oikonomou, Elana Shaw, Brahim Belaid, Sevgi Keles, Waleed Al-Herz, Caterina Cancrini, Cristina Cifaldi, Safa Baris, Svetlana Sharapova, Catharina Schuetz, Andrew R Gennery, Alexandra F Freeman, Raz Somech, Sharon Choo, Silvia C Giliani, Tayfun Güngör, Daniel Drozdov, Isabelle Meyts, Despina Moshous, Benedicte Neven, Roshini S Abraham, Aisha El-Marsafy, Maria Kanariou, Alejandra King, Francesco Licciardi, Mario E Cruz-Muñoz, Paolo Palma, Cecilia Poli, Mehdi Adeli, Mattia Algeri, Fayhan J Alroqi, Paul Bastard, Jenna R E Bergerson, Claire Booth, Ana Brett, Siobhan O Burns, Manish J Butte, Nurcicek Padem, M de la Morena, Ghassan Dbaibo, Suk See de Ravin, Dimana Dimitrova, Reda Djidjik, Mayra B Dorna, Cullen M Dutmer, Reem Elfeky, Fabio Facchetti, Ramsay L Fuleihan, Raif S Geha, Luis I Gonzalez-Granado, Liis Haljasmägi, Hanadys Ale, Anthony Hayward, Anna M Hifanova, Winnie Ip, Blanka Kaplan, Neena Kapoor, Elif Karakoc-Aydiner, Jaanika Kärner, Michael D Keller, Blachy J Dávila Saldaña, Ayça Kiykim, Taco W Kuijpers, Elena E Kuznetsova, Elena A Latysheva, Jennifer W Leiding, Franco Locatelli, Guisela Alva-Lozada, Christine McCusker, Fatih Celmeli, Megan Morsheimer, Ahmet Ozen, Nima Parvaneh, Srdjan Pasic, Alessandro Plebani, Kahn Preece, Susan Prockop, Inga S Sakovich, Elena E Starkova, Troy Torgerson, James Verbsky, Jolan E Walter, Brant Ward, Elizabeth L Wisner, Deborah Draper, Katherine Myint-Hpu, Pooi M Truong, Michail S Lionakis, Morgan B Similuk, Centralized Sequencing Program Group§§, Magdalena A Walkiewicz, Amy Klion, Steven M Holland, Cihan Oguz, Dusan Bogunovic, Kai Kisand, Helen C Su, John S Tsang, Douglas Kuhns, Anna Villa, Sergio D Rosenzweig, Stefania Pittaluga, Luigi D Notarangelo, Rajarshi Ghosh, Bryce Siefert, Mari Tokita, Jia Yan, Colleen Jodarski, Mike Kamen, Rachel Gore, Nadjalisse Reynolds-Lallement, Katie Lewis, Sarah Bannon, Adrienne Borges, Nicole Gentile SomaScan Heinken, A. et al. Systemic regulation of retinal medium-chain fatty acid oxidation repletes TCA cycle flux in oxygen-induced retinopathy Commun Biol. Almut Heinken, John M. Asara, Gopalan Gnanaguru, Charandeep Singh SomaScan Li, D. et al. The association of high-density lipoprotein cargo proteins with brain volume in older adults in the Atherosclerosis Risk in Communities (ARIC) J Alzheimers Dis. Danni Li, Binchong An, Lu Men, Matthew Glittenberg, Pamela L Lutsey, Michelle M Mielke, Fang Yu, Ron C Hoogeveen, Rebecca Gottesman, Lin Zhang, Michelle Meyer, Kevin Sullivan, Nicole Zantek, Alvaro Alonso, Keenan A Walker SomaScan Ramalingam, P. et al. Suppression of thrombospondin-1–mediated inflammaging prolongs hematopoietic health span Sci Immunol. Pradeep Ramalingam, Michael C. Gutkin, Michael G. Poulos, Agatha Winiarski, Arianna Smith, Cody Carter, Chelsea Doughty, Taylor Tillery, David Redmond, Ana G. Freire, Jason M. Butler SomaScan Jin, C. et al. Identification of biomarkers for chronic lymphocytic leukemia risk: a proteome-wide Mendelian randomization study Discov Oncol. Changyu Jin, Zehong Lu, Yuzhan Chen, Huijie Hu, Miao Zhou, Yanli Zhang, Guifang Ouyang, Tongyu Li, Lixia Sheng SomaScan Casaletto, KB. et al. Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease Brain Commun. Kaitlin B Casaletto, Rowan Saloner, John Kornak, Adam M Staffaroni, Saul Villeda, Emily Paolillo, Anna M VandeBunte, Claire J Cadwallader, Argentina Lario Lago, Julia Webb, Coty Chen, Katya Rascovsky, Toji Miyagawa, Eliana Marisa Ramos, Joseph C Masdeu, Alexander Pantelyat, Maria Carmela Tartaglia, Andrea Bozoki, Peter S Pressman, Rosa Rademakers, Walter Kremers, Ryan Darby, Kyan Younes, Belen Pascual, Nupur Ghoshal, Maria Lapid, Ian R A Mackenzie, Jingyao Li, Ging-Yuek Robin Hsiung, Jacob N Hall, Maya V Yutsis, Irene Litvan, Victor W Henderson, Rajeev Sivasankaran, Katie Worringer, Kimiko Domoto-Reilly, Allison Synder, Joseph Loureiro, Joel H Kramer, Hilary Heuer, Leah K Forsberg, Howard J Rosen, Bradley Boeve, Julio C Rojas, Adam L Boxer SomaScan Jia, M. et al. Integrative bioinformatics approach identifies novel drug targets for hyperaldosteronism, with a focus on SHMT1 as a promising therapeutic candidate Sci Rep. Minyue Jia, Liya Lin, Hanxiao Yu, Zhichao Dong, Xin Pan, Xiaoxiao Song SomaScan Yoshiji, S. et al. Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery disease Nat Genet. Satoshi Yoshiji, Tianyuan Lu, Guillaume Butler-Laporte, Julia Carrasco-Zanini-Sanchez, Chen-Yang Su, Yiheng Chen, Kevin Liang, Julian Daniel Sunday Willett, Shidong Wang, Darin Adra, Yann Ilboudo, Takayoshi Sasako, Satoshi Koyama, Tetsushi Nakao, Vincenzo Forgetta, Yossi Farjoun, Hugo Zeberg, Sirui Zhou, Michael Marks-Hultström, Mitchell J. Machiela, Rama Kaalia, Hesam Dashti, Melina Claussnitzer, Jason Flannick, Nicholas J. Wareham, Vincent Mooser, Nicholas J. Timpson, Claudia Langenberg, J. Brent Richards SomaScan Guo, X. et al. Unraveling the impact of blood RANKL and OPG levels on Alzheimer's disease: Independent of bone mineral density and inflammation Alzheimers Dement (N Y). Xingzhi Guo, Wenzhi Shi, Juanjuan Lu, Peng Tang, Rui Li SomaScan Guo, H. et al. Multi-omics analysis reveals novel causal pathways in psoriasis pathogenesis J Transl Med Hua Guo, Jinyang Gao, Liping Gong, Yanqing Wang SomaScan Hui, J. et al. A large-scale multi-omics polygenic risk score analysis identified candidate risk locus associated with rheumatoid arthritis Joint Bone Spine Jingni Hui, Dan He, Chen Liu, Panxing Shi, Ruixue Zhou, Meijuan Kang, Ye Liu, Yifan Gou, Bingyi Wang, Shiqiang Cheng, Xuena Yang, Chuyu Pan, Wenming Wei, Feng Zhang SomaScan Gan, S. et al. Transferrin Saturation, Serum Iron, and Ferritin in Heart Failure: Prognostic Significance and Proteomic Associations Circ Heart Fail. Sushrima Gan, Joe David Azzo, Lei Zhao, Bianca Pourmussa, Marie Joe Dib, Oday Salman, Ozgun Erten, Christina Ebert, A Mark Richards, Ali Javaheri, Douglas L Mann, Ernst Rietzschel, Payman Zamani, Vanessa van Empel, Thomas P Cappola, Julio A Chirinos SomaScan Canny, SP. et al. Proteomic Analyses in COVID-19-Associated Secondary Hemophagocytic Lymphohistiocytosis Crit Care Explor. Canny, Susan P.; Stanaway, Ian B.; Holton, Sarah E.; Mitchem, Mallorie; O’Rourke, Allison R.; Pribitzer, Stephan; Baxter, Sarah K.; Wurfel, Mark M.; Malhotra, Uma; Buckner, Jane H.; Bhatraju, Pavan K.; Morrell, Eric D.; Speake, Cate; Mikacenic, Carmen; Hamerman, Jessica A. SomaScan Cullel, N. et al. Glymphatic system clearance and Alzheimer’s disease risk: a CSF proteome-wide study Alzheimers Res Ther. Cullell, Natalia; Caruana, Giovanni; Elias-Mas, Andrea; Delgado-Sanchez, Ariane; Artero, Cristina; Buongiorno, Maria Teresa; Almería, Marta; Ray, Nicola J.; Correa, Sonia A. L.; Krupinski, Jerzy SomaScan Sun, W. et al. Exploring genetic associations and drug targets for mitochondrial proteins and schizophrenia risk Schizophrenia (Heidelb). Sun, Wenxi; Sun, Ping; Li, Jin; Yang, Qun; Tian, Qing; Yuan, Shiting; Zhang, Xueying; Chen, Peng; Li, Chuanwei; Zhang, Xiaobin SomaScan Nalwoga, A. et al. Evaluation of plasma alpha-1-antichymotrypsin as a marker for pulmonary Kaposi sarcoma Int J Cancer. Nalwoga, Angela; Jackson, Conner; Fiorillo, Suzanne; Manyeruke, Felix; Makoni, Tobias; Nyagura, Tatenda; White, Irene E.; Rapaport, Eric; Rochford, Rosemary; Borok, Margaret; Campbell, Thomas B. SomaScan Lydon, E. et al. Proteomic profiling of the local and systemic immune response to pediatric respiratory viral infections mSystems SomaScan Yao, Y. et al. Multimodal data integration to predict atrial fibrillation European Heart Journal SomaScan Mubido, EO. et al. Systemic biological mechanisms underpin poor post-discharge growth among severely wasted children with HIV Nat Commun. SomaScan Brækkan, SK. et al. The plasma proteome and risk of future venous thromboembolism - results from the HUNT study Thromb Haemost. SomaScan Chen, TK. et al. Proteomics and Incident Kidney Failure in Individuals With CKD: The African American Study of Kidney Disease and Hypertension and the Boston Kidney Biopsy Cohort Kidney Med. SomaScan Lim, CGY. et al. Plasma proteomic signatures of adiposity are associated with cardiovascular risk factors and type 2 diabetes risk in a multi-ethnic Asian population. Diabetes SomaScan Lai. M. et al. Serum protein risk stratification score for diagnostic evaluation of metabolic dysfunction-associated steatohepatitis Hepatol Commun. SomaScan Lopez-Silva, C. et al. Circulating Protein and Metabolite Correlates of Histologically Confirmed Diabetic Kidney Disease Kidney Med. SomaScan Conway, RB. et al. Plasma Proteomic Markers of Iron and Risk of Diabetes in a Cohort of African American and White American Current and Former Smokers Metab Syndr Obes. SomaScan Werge, MP. et al. Circulating and hepatic levels of growth differentiation factor 15 in patients with metabolic dysfunction-associated steatotic liver disease Hepatology Research SomaScan Stanaway, IB. et al. Urinary proteomics identifies distinct immunological profiles of sepsis associated AKI sub-phenotypes Crit Care. SomaScan Philippi, SM. et al. APOE genotype and brain amyloid are associated with changes in the plasma proteome in elderly subjects without dementia Ann Clin Transl Neurol. SomaScan Kumari, S. et al. Approaches and Challenges in Characterizing the Molecular Content of Extracellular Vesicles for Biomarker Discovery Biomolecules SomaScan Murugesan, S. et al. Microbial and proteomic signatures of type 2 diabetes in an Arab population J Transl Med. SomaScan Wu, MH. et al Proteome-wide Mendelian randomization and therapeutic targets for bladder cancer BMC Urol. SomaScan Doulamis, IP. et al. Mitochondrial transplantation normalizes transcriptomic and proteomic shift associated with ischemia reperfusion injury in neonatal hearts donated after circulatory death Sci Rep. SomaScan Smith, IC. et al. Plasma-derived protein and imaging biomarkers distinguish disease severity in oculopharyngeal muscular dystrophy Journal of Neuromuscular Diseases SomaScan Nandakumar, M. et al. Cardiovascular Risk Biomarkers in Women with and Without Polycystic Ovary Syndrome Biomolecules SomaScan Chen, S. et al. Exploring the associations of plasma proteins with frailty based on Mendelian randomization BMC Immunol. SomaScan Melano, I. et al. SARS-CoV-2 ORF8 drives osteoclastogenesis in preexisting immune-mediated inflammatory diseases JCI Insight SomaScan Byrne, A. et al. Neonates exposed to HIV but uninfected exhibit an altered gut microbiota and inflammation associated with impaired breast milk antibody function Microbiome SomaScan Maretty, L. et al. Proteomic changes upon treatment with semaglutide in individuals with obesity Nat Med. SomaScan Lumish, HS. et al. Prediction of new-onset atrial fibrillation in patients with hypertrophic cardiomyopathy using plasma proteomics profiling Europace SomaScan Hiramoto, K. et al. Urinary biomarkers associated with pathogenic pathways reflecting histological findings in lupus nephritis Arthritis Rheumatol. SomaScan Qiu, X. et al. The Biomarkers in Extreme Longevity: Insights Gained from Metabolomics and Proteomics Int J Med Sci SomaScan Moll, M. et al. Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies eBioMedicine SomaScan Lee, KH. et al. Addressing statistical challenges in the analysis of proteomics data with extremely small sample size: a simulation study BMC Genomics SomaScan Sparling, AC. et al. Neutrophil and mononuclear leukocyte pathways and upstream regulators revealed by serum proteomics of adult and juvenile dermatomyositis Arthritis Res Ther. SomaScan Alcalde-Herraiz, M. et al. Effect of genetically predicted sclerostin on cardiovascular biomarkers, risk factors, and disease outcomes Nat Commun. SomaScan Chen, Z. et al. Sodium-glucose cotransporter protein 2 inhibition, plasma proteins, and ischemic stroke: A mediation Mendelian randomization and colocalization study J Stroke Cerebrovasc Dis. SomaScan Ge, F. et al. Plasma Glutaminyl-Peptide Cyclotransferase Mediates Glucosamine-Metabolism-Driven Protection Against Hypertension: A Mendelian Randomization Study Int. J. Mol. Sci. SomaScan Anwar, MY. et al. Machine learning-based clustering identifies obesity subgroups with differential multi-omics profiles and metabolic patterns Obesity SomaScan Jiang, Q. et al. Exploring susceptibility and therapeutic targets for kidney stones through proteome-wide Mendelian randomization Hum Mol Genet. SomaScan Morató, X. et al. Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia Brain, Behavior, & Immunity SomaScan Lou, J. et al. Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology J Headache Pain SomaScan Xiao, QA. et al. Identification of novel drug targets for liver cirrhosis and its potential side-effects by human plasma proteome Sci Rep. SomaScan Dai, T. et al. Genetic Evidence for the Causal Link Between Coagulation Factors and the Risk of Ovarian Cancer: A Two-Sample Mendelian Randomization Study International Journal of Women’s Health SomaScan Maddaloni, E. et al. Osteoprotegerin, Osteopontin, and Osteocalcin Are Associated With Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL Diabetes Care SomaScan Ji, Y. et al. Association of Coagulation Factor XI Level With Cardiovascular Events and Cardiac Function in Community-Dwelling Adults: From ARIC and CHS Circulation SomaScan Lim, CGY et al. Proteomic analysis identifies novel biological pathways that may link dietary quality to type 2 diabetes risk: evidence from African American and Asian cohorts Am J Clin Nutr. SomaScan Degnes, ML. et al. Protein biomarker signatures of preeclampsia - a longitudinal -multiplex proteomics study Sci Rep. SomaScan Chen, Y. et al. Identifying prothrombin and bone sialoprotein as potential drug targets for idiopathic pulmonary fibrosis BMC Pulm Med. SomaScan Onyango, CO. et al. Transcriptomic and Proteomic Insights into Host Immune Responses in Pediatric Severe Malarial Anemia: Dysregulation in HSP60-70-TLR2/4 Signaling and Altered Glutamine Metabolism Pathogens SomaScan Lumish, HS. et al. Comprehensive Proteomic Profiling of Human Myocardium Reveals Signaling Pathways Dysregulated in Hypertrophic Cardiomyopathy J Am Coll Cardiol. SomaScan McHill, AW. et al. Circadian misalignment disrupts biomarkers of cardiovascular disease risk and promotes a hypercoagulable state Eur J Neurosci. SomaScan Koychev, I. et al. Inflammatory proteins associated with Alzheimer's disease reduced by a GLP1 receptor agonist: a post hoc analysis of the EXSCEL randomized placebo controlled trial Alzheimers Res Ther. SomaScan Wang, S. et al. Development, characterization, and replication of proteomic aging clocks: Analysis of 2 population-based cohorts PLoS Med. SomaScan Wang, QS. et al. Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance Nat Genet. SomaScan Guan, H. et al. Exploring the design of clinical research studies on the efficacy mechanisms in type 2 diabetes mellitus Front Endocrinol. SomaScan Singh, A. et al. Recent developments in non-invasive methods for assessing metabolic dysfunction-associated fatty liver disease World J Gastroenterol SomaScan Tang, W. et al. Application of large‑scale and multicohort plasma proteomics datato discover novel causal proteins in gastric cancer Discov Oncol. SomaScan Zhang, Y. et al. Circulating RAC1 contributed to steroid-sensitive nephrotic syndrome: Mendelian randomization, single-cell RNA-sequencing, proteomic, and experimental evidence Ren Fail. SomaScan Bédard-Matteau, J. et al. Circulating IL-17F, but not IL-17A, is elevated in severe COVID-19 and leads to an ERK1/2 and p38 MAPK-dependent increase in ICAM-1 cell surface expression and neutrophil adhesion on endothelial cells Front. Immunol. SomaScan Ochoa-Leite, C. et al. Metabolomics and proteomics in occupational medicine: a comprehensive systematic review J Occup Med Toxicol. SomaScan Hill, C. et al. Integrated multiomic analyses: An approach to improveunderstanding of diabetic kidney disease Diabet Med. SomaScan Chen, L. et al. Systematic identification of therapeutic targets for coronary artery calcification: an integrated transcriptomic and proteomic Mendelian randomization Front. Cardiovasc. SomaScan Wang, L. et al. Clustering-aided prediction of outcomes in patients with idiopathic pulmonary fibrosis Respir Res. SomaScan Candia, J. et al. Variability of 7K and 11K SomaScan Plasma Proteomics Assays Proteome Res. SomaScan Geyer, PE. et al. The Circulating Proteome─Technological Developments,Current Challenges, and Future Trends Trends. J Proteome Res. SomaScan Long, H. et al. Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer’s disease Alzheimers Res Ther. SomaScan van Vugt, M. et al. Integrating metabolomics and proteomics to identify novel drug targets for heart failure and atrial fibrillation Genome Med. SomaScan Goeminne, LJE. et al. Plasma protein-based organ-specific aging and mortality models unveil diseases as accelerated aging of organismal systems Cell Metab. SomaScan Ihara, K. et al. Circulating proteins linked to apoptosis processes and fast development of end-stage kidney disease in diabetes JCI Insight. SomaScan Liang, W. et al. An integrated multi-omics analysis reveals osteokines involved in global regulation Cell Metab. SomaScan Shen, Y. et al. CSF proteomics identifies early changes in autosomal dominant Alzheimer's disease Cell SomaScan Liu, S. et al. Identification of proteins associated with type 2 diabetes risk in diverse racial and ethnic populations Diabetologia SomaScan Moll, M. et al. A protein risk score for all-cause and respiratory-specific mortality in non-Hispanic white and African American individuals who smoke Sci Rep. SomaScan Konigsberg, IR. et al. Proteomic networks and related genetic variants associated with smoking and chronic obstructive pulmonary disease BMC Genomics SomaScan Perry, AS. et al. Clinical-transcriptional prioritization of the circulating proteome in human heart failure Cell Rep Med. SomaScan Allen, LH. et al. Multiomics: Functional Molecular Biomarkers of Micronutrients for Public Health Application Annu Rev Nutr. SomaScan Lan, T. et al. Diagnostics and omics technologies for the detection and prediction of metabolic dysfunction-associated steatotic liver disease-related malignancies Metabolism SomaScan Sproull, M. et al. Organ-specific Biodosimetry Modeling Using Proteomic Biomarkers of Radiation Exposure Radiat Res. SomaScan Salman, O. et al. Proteomic Correlates and Prognostic Significance of Kidney Injury in Heart Failure With Preserved Ejection Fraction J Am Heart Assoc. SomaScan Salman, O. et al. Prognostic Significance and Biologic Associations of Senescence-Associated Secretory Phenotype Biomarkers in Heart Failure J Am Heart Assoc. SomaScan Samorodnitsky, S. et al. Novel approach to exploring protease activity and targets in HIV-associated obstructive lung disease using combined proteomic-peptidomic analysis Respir Res. SomaScan Zhu, Y. et al. Multi-trait analysis reveals risk loci for heart failure and the shared genetic etiology with blood lipids, blood pressure, and blood glucose Cell Rep. SomaScan Julg, B. et al. Safety and antiviral effect of a triple combination of HIV-1 broadly neutralizing antibodies: a phase 1/2a trial Nat Med. SomaScan Zhou, Z. et al. Identification of novel protein biomarkers and therapeutic targets for ankylosing spondylitis using human circulating plasma proteomics and genome analysis Anal Bioanal Chem. SomaScan Zhao, J. et al. Proteomic Mendelian randomization to identify protein biomarkers of telomere length Sci Rep. SomaScan Fu, Z. et al. Hyaluronan and proteoglycan link protein 1 – A novel signaling molecule for rejuvenating aged skin Matrix Biol. SomaScan Cheng, L. et al. Evaluation of circulating plasma proteins in prostate cancer using mendelian randomization Discov Oncol. SomaScan Olafsdottir, TA. et al. Sequence variants influencing the regulation of serum IgG subclass levels Nat Commun. SomaScan Shi, K. et al. Identification of potential therapeutic targets for nonischemic cardiomyopathy in European ancestry: an integrated multiomics analysis Cardiovasc Diabetol. SomaScan Peterson, TE. et al. Proteomics of left ventricular structure in the Multi-Ethnic Study of Atherosclerosis ESC Heart Fail. SomaScan Du, S. et al. Protein Biomarkers of Ultra-Processed Food Consumption and Risk of Coronary Heart Disease, Chronic Kidney Disease, and All-Cause Mortality J Nutr. SomaScan Carrasco-Zanini, J. et al. Mapping biological influences on the human plasma proteome beyond the genome Nat Metab. SomaScan Li, J. et al. Identification of novel proteins for coronary artery disease by integrating GWAS data and human plasma proteomes Heliyon SomaScan Voordes, GHD. et al. Clinical and proteomic profiles of chronic kidney disease in heart failure with reduced and preserved ejection fraction Int J Cardiol. SomaScan Dourdouna, MM. et al. Proteomic Signatures of Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A Narrative Review Children SomaScan Schmidt, IM. et al. Plasma proteomics of acute tubular injury Nat Commun. SomaScan Jabalameli, MR. et al. Polygenic prediction of human longevity on the supposition of pervasive pleiotropy Sci Rep. SomaScan Wang, R. et al. Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality Nat Commun. SomaScan Pichet Binette, A. et al. Proteomic changes in Alzheimer disease associated with progressive Aβ plaque and tau tangle pathologies Nat Neurosci. SomaScan Giro, P. et al. Proteomic Profile of the ICAM1 p.K56M HFpEF Risk Variant JACC SomaScan Kermani, NZ. et al. Endotypes of severe neutrophilic and eosinophilic asthma from multi-omics integration of U-BIOPRED sputum samples Clin Transl Med. SomaScan Doostparast Torshizi, A. et al. Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease Nat Commun. SomaScan Marsh, TW. et al. A genetic and proteomic comparison of key AD biomarkers across tissues Alzheimers Dement. SomaScan Tripp, BA. et al. Integrated Multi-Omics Analysis of Cerebrospinal Fluid in Postoperative Delirium Biomolecules SomaScan Quesnel, MJ. et al. Osteopontin: A novel marker of pre-symptomatic sporadic Alzheimer’s disease Alzheimers Dement. SomaScan Azeze, GG. et al. Proteomics approach to discovering non-invasive diagnostic biomarkers and understanding the pathogenesis of endometriosis: a systematic review and meta-analysis J Transl Med. SomaScan Joyce, T. et al. Serum CD133-Associated Proteins Identified by Machine Learning Are Connected to Neural Development, Cancer Pathways, and 12-Month Survival in Glioblastoma Cancers SomaScan Xu, L. et al. The application of aptamers in the field of aging and age-related diseases Clin. Transl. Disc. SomaScan Gupta, S. et al. Inhibition of JAK-STAT pathway corrects salivary gland inflammation and interferon driven immune activation in Sjögren's Disease Ann Rheum Dis SomaScan Turnbull, A. et al. Age-associated proteins explain the role of medial temporal lobe networks in Alzheimer's disease Geroscience SomaScan Wolfe, KR. et al. Early Circulating Biomarkers of Language Development in Single Ventricle Heart Disease JAMA Pediatr. SomaScan Zheng, L. et al. Contrastive machine learning reveals Parkinson’s disease specific features associated with disease severity and progression Commun Biol. SomaScan Went, M. et al. Deciphering the genetics and mechanisms of predisposition to multiple myeloma Nat Commun. SomaScan Leo, S. et al. Biomarkers in diagnosing and therapeutic monitoring of tuberculosis: areview Ann Med. SomaScan Donovan, M. et al. Multimodal analysis of dysregulated heme metabolism, hypoxic signaling, and stress erythropoiesis in Down syndrome Cell Rep. SomaScan Zhan, C. et al. Proteome-Wide Mendelian Randomisation Identifies Causal Links of Plasma Proteins With Periodontitis Int Dent J. SomaScan Duggan, MR. et al. Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline Nat Aging SomaScan Beutgen, VM. et al. Secretome analysis using Affinity Proteomics and Immunoassays: a focus on Tumor Biology Mol Cell Proteomics. SomaScan Cunningham, KY. et al. Plasma proteome profiling in giant cell arteritis Ann Rheum Dis. SomaScan Liu, T. et al. Validation of candidate protein biomarkers previously identified by genetic instruments for prostate cancer risk: A prospective cohort analysis of directly measured protein levels in the ARIC study Prostate SomaScan Shen, X. et al. Nonlinear dynamics of multi-omics profiles during human aging Nature Aging SomaScan Cardiello, JF. et al. Characterizing primary transcriptional responses to short term heat shock in Down syndrome PLoS One SomaScan Ardissino, M. et al. Proteome- and Transcriptome-Wide Genetic Analysis Identifies Biological Pathways and Candidate Drug Targets for Preeclampsia Circ Genom Precis Med. SomaScan Frick, EA. et al. Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer's disease Nat Aging SomaScan Halama, A. et al. A roadmap to the molecular human linking multiomics with population traits and diabetes subtypes Nat Commun. SomaScan Conlon, DM. et al. Genotype-First Approach Identifies an Association between rs/FOG2S657G and Liver Disease through Alterations in mTORC1 Signaling Genes SomaScan Guo, X. et al. Causal effect of blood osteocalcin on the risk of Alzheimer's disease and the mediating role of energy metabolism Transl Psychiatry. SomaScan Wang, Q. et al. Causal associations of plasma proteins with lung squamous cell carcinoma risk: a proteome-wide Mendelian randomization and colocalization analysis Clinical Cancer Bulletin SomaScan Dib, MJ. et al. Proteome-Wide Genetic Investigation of Large Artery Stiffness JACC SomaScan Maimaiti, A. et al. Gut Microbiota, Metabolites, Circulating Cytokines and Growth Factors, Plasma Proteins, and Risk of Intracranial Aneurysms: A Two-Sample Mendelian Randomization Study Acta Neurologica Scandinavica SomaScan Mckinnon, K. et al. Epigenetic scores derived in saliva are associated with gestational age at birth Clin Epigenetics SomaScan Johnson, BS. et al. Targeted degradation of extracellular mitochondrial aspartyl -tRNA synthetase modulates immune responses Nat Commun. SomaScan Sivakumar, P. et al. SomaLogic proteomics reveals new biomarkers and providesmechanistic, clinical insights into Acetyl coA Carboxylase (ACC) inhibition in Non-alcoholic Steatohepatitis (NASH) Sci Rep. SomaScan Petersen, TB. et al. Proteomic biomarkers related to obesity in heart failure with reduced ejection fraction and their associations with outcome Obesity (Silver Spring) SomaScan Kraemer, S. et al. Crossing the Halfway Point: Aptamer-Based, Highly Multiplexed Assay for the Assessment of the Proteome J Proteome Res. SomaScan Cannon, EJ. et al. Anemia, Iron Deficiency, and Cause-Specific Mortality: The Atherosclerosis Risk in Communities (ARIC) Study Gerontology SomaScan Juliar, BA. et al. Interferon-γ induces combined pyroptotic angiopathy and APOL1 expression in human kidney disease Cell Rep. SomaScan Li, S. et al. Association between plasma proteome and pulmonary heart disease: A two-stage Mendelian randomization analysis Clin Respir J. SomaScan Perry, AS. et al. Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks Nat Med. SomaScan Mostafa, I. et al. A microbiota-directed complementary food intervention in 12-18-month-old Bangladeshi children improves linear growth EBioMedicine SomaScan Warren, G. et al. Discovery and Preclinical Evaluation of a Novel Inhibitor of FABP5, ART26.12, Effective in Oxaliplatin-Induced Peripheral Neuropathy J. Pain SomaScan Nandakumar, M. et al. A Cross-Sectional Exploratory Study of Cardiovascular Risk Biomarkers in Non-Obese Women with and without Polycystic Ovary Syndrome: Association with Vitamin D Int. J. Mol. Sci. SomaScan Mi, Y. et al. High-throughput mass spectrometry maps the sepsis plasma proteome and differences in patient response Sci Transl Med. SomaScan Troisi, R. et al. Structural overview of DNA and RNA G-quadruplexes in their interaction with proteins Curr Opin Struct Biol. SomaScan Liu, F. et al. Mid-life plasma proteins associated with late-life prefrailty and frailty: a proteomic analysis Geroscience SomaScan Rao, P. et al. Plasma Proteomics of Exercise Blood Pressure and Incident Hypertension JAMA Cardiol. SomaScan Daghlas, I. et al. Mechanisms of Hypercoagulability Driving Stroke Risk in Obesity: A Mendelian Randomization Study Neurology SomaScan Lopez, L. et al. Comparative Analysis of Protein Quantification by the SomaScan Assay versus Orthogonal Methods in Urine from People with Diabetic Kidney Disease J. Proteome Res. SomaScan Si, S. et al. Identification of novel therapeutic targets for chronic kidney disease and kidney function by integrating multi-omics proteome with transcriptome Genome Med. SomaScan Kraaijenhof, JM. et al. Proteomic Signatures of Genetically Predicted and Pharmacologically Observed PCSK9 Inhibition J Am Heart Assoc. SomaScan Patel-Murray, N. et al. Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy J Am Heart Assoc. SomaScan Sun, BB. et al. Promises and challenges of populational proteomics in health and disease Mol Cell Proteomics SomaScan Ryden, M. et al. Exploring the early molecular pathogenesis of osteoarthritis using differential network analysis of human synovial fluid Mol Cell Proteomics SomaScan Nguyen, GY. et al. Matrix metalloproteinase 9: an emerging biomarker for classification of adherent vestibular schwannoma Neurooncol Adv. SomaScan Dammer, EB. et al. Proteomic analysis of Alzheimer's disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment Sci Transl Med. SomaScan Kim, H. et al. An Early Gestation Plasma Inflammasome in Rural Bangladeshi Women Biomolecules SomaScan Yang, H. et al. Plasma proteome mediate the impact of PM2.5 on stroke: A 2-step Mendelian randomization study Ecotoxicol Environ Saf. SomaScan Yusri, K. et al. Towards Healthy Longevity: Comprehensive Insights from Molecular Targets and Biomarkers to Biological Clocks Int J Mol Sci. SomaScan Niu, PP. et al. Identifying novel proteins for migraine by integrating proteomes from blood and CSF with genome-wide association data CNS Neurosci Ther. SomaScan Donovan, M. et al. Variegated overexpression of chromosome 21 genes reveals molecular and immune subtypes of Down syndrome Nat Commun. SomaScan Milbourn, H. et al. Generation Scotland: an update on Scotland's longitudinal family health study BMJ Open SomaScan de Klerk, JA. et al. Circulating small non-coding RNAs are associated with the insulin-resistant and obesity-related type 2 diabetes clusters Diabetes Obes Metab. SomaScan Saevarsdottir, S. et al. Start codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease Nat Commun. SomaScan Liu, X. et al. Exploring potential plasma drug targets for cholelithiasis through multiancestry Mendelian randomization Int J Surg. SomaScan Andrzejczyk, K. et al. Identifying plasma proteomic signatures from health to heart failure, across the ejection fraction spectrum Sci Rep. SomaScan Duggan, M. et al. Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression Brain Behav Immun. SomaScan Guo ,Y. et al. Multiplex cerebrospinal fluid proteomics identifies biomarkers for diagnosis and prediction of Alzheimer's disease Nat Hum Behav. SomaScan Wise, A. et al. CSF Proteomics in Patients With Progressive Supranuclear Palsy Neurology SomaScan Greenland, P. et al. Large-Scale Proteomics in Early Pregnancy and Hypertensive Disorders of Pregnancy JAMA Cardiol. SomaScan Schmidt, AF. et al. Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders Open Biol. SomaScan Li, Y. et al. Multicenter proteome-wide Mendelian randomization study identifies causal plasma proteins in melanoma and non-melanoma skin cancers Commun Biol. SomaScan Fernandez, MV. et al. Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center Sci Data. SomaScan Mckinnon, K. et al. Epigenetic scores derived in saliva are associated with gestational age at birth Clin Epigenetics SomaScan Ashmar, SA. et al. Proteomic Analysis of Prehypertensive and Hypertensive Patients: Exploring the Role of the Actin Cytoskeleton Int. J. Mol. Sci. SomaScan Butler, AE. et al. A Cross-Sectional Study of Glomerular Hyperfiltration in Polycystic Ovary Syndrome Int. J. Mol. Sci. SomaScan Smith-Byrne, K. et al. Identifying therapeutic targets for cancer among circulating proteins and risk of nine cancers Nat Commun. SomaScan Zhang, X. et al. Pre-diagnostic plasma proteomics profile for hepatocellular carcinoma J Natl Cancer Inst. SomaScan Sproull, M. et al. Comparison of Novel Proteomic Expression Profiles for Radiation Exposure in Male and Female C57BL6 Mice Radiat Res. SomaScan Eteleeb, AM. et al. Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease PLoS Biol. SomaScan Akenroye, A. et al. Ratio of plasma IL-13/TNF- ∝ and CXCL10/CCL17 predicts mepolizumab and omalizumab response in asthma better than eosinophil count or immunoglobulin E level Sci Rep. SomaScan Beutgen, V. et al. Advances in aqueous humor proteomics for biomarker discovery and disease mechanisms exploration: a spotlight on primary open angle glaucoma Front Mol Neurosci. SomaScan Peng, Y. et al. Noninvasive Diagnostic Methods in Liver Cirrhosis Book Chapter SomaScan Sun, Y. et al. The Effect of Histo-Blood Group ABO System Transferase (BGAT) on Pregnancy Related Outcomes：A Mendelian Randomization Study Comput Struct Biotechnol J. SomaScan Dubin, RF. et al. Incident heart failure in chronic kidney disease: proteomics informs biology and risk stratification Eur Heart J. SomaScan Thiele, M. et la. Opportunities and barriers for omics-based biomarker discovery in steatotic liver diseases J Hepatol. SomaScan Westerberg, AC. et al. Angiogenic and vasoactive proteins in the maternal-fetal interface in healthy pregnancies and preeclampsia Am J Obstet Gynecol. SomaScan Gómez-Pascual, A. et al. Paired plasma lipidomics and proteomics analysis in the conversion from mild cognitive impairment to Alzheimer's disease Comput Biol Med. SomaScan Reznichenko, A. et al. Unbiased kidney-centric molecular categorization of chronic kidney disease as a step towards precision medicine Kidney Int. SomaScan Cao, Z. et al. Identification of plasma protein markers of allergic disease risk: a mendelian randomization approach to proteomic analysis Genomics SomaScan Nandakumar, M. et al. Effect of Hypoglycemia and Rebound Hyperglycemia on Proteomic Cardiovascular Risk Biomarkers Biomedicines SomaScan Guo, X. et al. Causal effect of blood osteocalcin on the risk of Alzheimer’s disease and the mediating role of energy metabolism Transl Psychiatry SomaScan Kim, T. et al. Aptamer-Based Proteomics in CKD Am J Kidney Dis. SomaScan Li, J. et al. Proteome-wide Mendelian randomization identifies potential therapeutic targets for nonalcoholic fatty liver diseases Sci Rep. SomaScan Ramonfaur, D. et al. High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life JAMA Cardiol. SomaScan Kim, T. et al. Plasma Proteins Associated with Chronic Histopathologic Lesions on Kidney Biopsy J Am Soc Nephrol. SomaScan Hart, LM. et al. Small RNA sequencing reveals snoRNAs and piRNA- as novel players in diabetic kidney disease Endocrine SomaScan Austin, TR. et al. A plasma protein-based risk score to predict hip fractures Nat Aging SomaScan Zhu, Y. et al. Identification of pleiotropic and specific therapeutic targets for cardio-cerebral diseases: A large-scale proteome-wide mendelian randomization and colocalization study PLoS One SomaScan Kim, H. et al. Multimodal Reinforcement Learning for Embedding Networks and Medication Recommendation in Parkinson’s Disease IEEE Xplore SomaScan Beutgen, V. et al. Sample-Treatment with the Virucidal β-Propiolactone Does Not Preclude Analysis by Large Panel Affinity Proteomics, Including the Discovery of Biomarker Candidates Anal Chem. SomaScan Beenken, A. et al. Blood Proteomics for Biomarkers of Kidney Pathology J Am Soc Nephrol. SomaScan Shi, L. et al. APOB and CCL17 as Mediators in the Protective Effect of SGLT2 Inhibition against Myocardial Infarction: Insights from Proteome-wide Mendelian Randomization Eur J Pharmacol. SomaScan Shue, F. et al. CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly Sci Adv. SomaScan Tasci, E. et al. MGMT ProFWise: Unlocking a New Application for Combined Feature Selection and the Rank-Based Weighting Method to Link MGMT Methylation Status to Serum Protein Expression in Patients with Glioblastoma Int. J. Mol. Sci. SomaScan Wang, H. et al. Identification of potential drug targets for allergic diseases from a genetic perspective: A mendelian randomization study Clin Transl Allergy. SomaScan Mao, R. et al. Identification of prospective aging drug targets via Mendelian randomization analysis Aging Cell SomaScan Kamar, SA. et al. The plasma proteome is linked with left ventricular and left atrial function parameters in patients with chronic heart failure Eur Heart J Cardiovasc Imaging. SomaScan Timsina, J. et al. Blood-Based Proteomics for Adult-Onset Focal Dystonias Ann Neurol. SomaScan Suryadevara, R. et al. Blood-based Transcriptomic and Proteomic Biomarkers of Emphysema Am J Respir Crit Care Med. SomaScan Bu, S. et al. Proteomics validate circulating GDF-15 as an independent biomarker for COVID-19 severity Front. Immunol. Sec. Viral Immunology SomaScan Yi, H. et al. TOPMed imputed genomics enhances genomic atlas of the human proteome in brain, cerebrospinal fluid, and plasma Sci Data SomaScan Barros, O. et al. Shaping the future of oral cancer diagnosis: advances in salivary proteomics Expert Rev Proteomics SomaScan Coorsen, J. et al. Proteomics—The State of the Field † Proteomes SomaScan Wang, W. et al. Relationship between plasma brain-derived neurotrophic factor levels and neurological disorders: An investigation using Mendelian randomisation Heliyon SomaScan Specht, A. et al. Circadian protein expression patterns in healthy young adults Sleep Health SomaScan Perry, AS. et al. Proteomics, Human Environmental Exposure, and Cardiometabolic Risk Circ Res. SomaScan Qin, S. et al. Mendelian randomization of circulating proteome identifies IFN-γ as a druggable target in aplastic anemia Ann Hematol SomaScan Møller, PL. et al. Predicting the presence of coronary plaques featuring high-risk characteristics using polygenic risk scores and targeted proteomics in patients with suspected coronary artery disease Genome Med. SomaScan Li, J. et al. Integrative multi-omics analysis identifies genetically supported druggable targets and immune cell specificity for myasthenia gravis J Transl Med. SomaScan Deng, M. et al. Characterization of sexual dimorphism in ANGPTL4 levels and function J Lipid Res. SomaScan Wilson, EN. et al. TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models Nat Neurosci. SomaScan Passaro, A. et al. Cancer biomarkers: Emerging trends and clinical implications for personalized treatment Cell SomaScan Rai, MF. et al. Three decades of advancements in osteoarthritis research: insights from transcriptomic, proteomic, and metabolomic studies Osteoarthritis Cartilage SomaScan Karvelas, N. et al. Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy Brain Commun. SomaScan Lee, C. et al. Signaling Pathways Associated with Prior Cardiovascular Events in Hypertrophic Cardiomyopathy J Card Fail. SomaScan Aurora, L. et al. Signaling Pathways in Hypertrophic Cardiomyopathy: Will Proteomic Profiling Guide the Future? J Card Fail. SomaScan Sasamoto, N. et al. Plasma proteins and persistent post-surgical pelvic pain among adolescents and young adults with endometriosis Am J Obstet Gynecol. SomaScan Christopoulos, P. et al. Plasma Proteome-Based Test for First-Line Treatment Selection in Metastatic Non-Small Cell Lung Cancer JCO Precis Oncol. SomaScan Dorian, D. et al. Exercise‐Dependent Modulation of Immunological Response Pathways in Endurance Athletes With and Without Atrial Fibrillation J Am Heart Assoc. SomaScan Chai, RC. et al. The potential of the proteome to predict fracture J Bone Miner Res. SomaScan Wang, S. et al. Accelerated Aging in Cancer Survivors: Cellular Senescence, Frailty, and Possible Opportunities for Interventions Int. J. Mol. Sci. SomaScan Liu, X. et al. Plasma proteomic signature of human longevity Aging Cell SomaScan Sathyan, S. et al. Plasma proteomic profile of abdominal obesity in older adults, Plasma proteomic profile of abdominal obesity in older adults Obesity (Silver Spring) SomaScan Casanova, R. et al. Associations of plasma proteomics and age-related outcomes with brain age in a diverse cohort Geroscience SomaScan Koureta, E. et al. Evolving role of semaglutide in NAFLD: in combination, weekly and oral administration Front. Pharmacol. SomaScan Saint-André, V. et al. Smoking changes adaptive immunity with persistent effects Nature SomaScan Suhre, K. et al. Nanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping Nat Commun. SomaScan Mohammadi, H. et al. Which neuroimaging and fluid biomarkers method is better in theranostic of Alzheimer’s disease? An umbrella review IBRO Neuroscience Reports SomaScan Aboelsaad IAF. et al. Plasma Ferritin Levels, Incident Heart Failure, and Cardiac Structure and Function: The ARIC Study JACC Heart Fail. SomaScan Altieri, A. et al. Human host defence peptide LL-37 suppresses TNFα- mediated matrix metalloproteinases MMP9 and MMP13, in human bronchial epithelial cells J Innate Immun. SomaScan Rutledge, J. et al. Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson's disease Acta Neuropathol. SomaScan Li, D. et al. Multi-omics Analyses Identify AKR1A1 as a Biomarker for Diabetic Kidney Disease Diabetes SomaScan Diakos, NA. et al. Circulating Proteome Analysis Identifies Reduced Inflammation After Initiation of Hemodynamic Support with Either Veno-Arterial Extracorporeal Membrane Oxygenation or Impella in Patients with Cardiogenic Shock J Cardiovasc Transl Res. SomaScan Dib, MJ. et al. Proteomic Associations of Adverse Outcomes in Human Heart Failure J Am Heart Assoc. SomaScan Lin, L. et al.  Proteome-wide mendelian randomization investigates potential associations in heart failure and its etiology: emphasis on PCSK9 BMC Med Genomics SomaScan Walitt, B. et al.  Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome Nat Commun. SomaScan Zagkos, L. et al.  Genetic investigation into the broad health implications of caffeine: evidence from phenome-wide, proteome-wide and metabolome-wide Mendelian randomization BMC Med. SomaScan Slieker, RC. et al.  An omics-based machine learning approach to predict diabetes progression: a RHAPSODY study Diabetologia SomaScan Butler, AE. et al. A Cross-Sectional Study of Protein Changes Associated with Dementia in Non-Obese Weight Matched Women with and without Polycystic Ovary Syndrome Int J Mol Sci. SomaScan Watson, KT. et al.  Proteomic profiles of cytokines and chemokines in moderate to severe depression: Implications for comorbidities and biomarker discovery Brain, Behavior, & Immunity - Health SomaScan Singh, B. et al.  Enhancing cardiovascular risk prediction through proteomics? Cardiovasc Res. SomaScan Yuan, S. et al.  Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities J Thromb Haemost.  SomaScan Duijvelaar, E. et al.  Imatinib treatment improves hyperglycaemic dysregulation in severe COVID-19: a secondary analysis of blood biomarkers in a randomised controlled trial Critical Care SomaScan Wang, JL. et al.  Non-invasive diagnosis of non-alcoholic fatty liver disease: Current status and future perspective Heliyon SomaScan Zhang, L.et. al. Aptamer proteomics for biomarker discovery in heart failure with reduced ejection fraction Circulation SomaScan Austin, TR. et al. Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures JBMR SomaScan Wolf, J. et al. Liquid Biopsy Proteomics in Ophthalmology J. Proteome Res. SomaScan Hedou, J. et al. Discovery of sparse, reliable omic biomarkers with Stabl Nat Biotechnol. SomaScan Kuku, KO. et al. Development and Validation of a Protein Risk Score for Mortality in Heart Failure : A Community Cohort Study Ann Intern Med. SomaScan Kaput, J. et al. Human Nutrition Research in the Data Era: Results of 11 Reports on the Effects of a Multiple-Micronutrient- Intervention Study Nutrients SomaScan Rubenstein, AI. et al. Immune-mediated thrombocytopenia and IL-6-mediated thrombocytosis observed in idiopathic multicentric Castleman disease Br J Haematol. SomaScan Zhu, J. et al. Associations between genetically predicted plasma protein levels and Alzheimer's disease risk: a study using genetic prediction models Alzheimers Res Ther. SomaScan Azzo, JD. et al. Proteomic Associations Of N-terminal-pro Hormone Bnp In Heart Failure With Preserved Ejection Fraction In Two Cohorts J Card Fail. SomaScan Axelsson, GT. et al. Proteomic associations with forced expiratory volume: a Mendelian randomisation study Respir. Res. SomaScan Boehler, JF. et al. N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy Skeletal Muscle SomaScan Shah, AM. et al. Large scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development Nat. Commun. SomaScan Zhang, W. et al. Therapeutic targets for diabetic kidney disease: proteome-wide Mendelian randomization and colocalization analyses Diabetes SomaScan Ulrich, A. et al. Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension Nat. Commun. SomaScan Rashid, M. et al. Chloride Intracellular Channel Protein 1 (CLIC1) Is a Critical Host Cellular Factor for Influenza A Virus Replication Viruses SomaScan Rusiñol, L. et al. Multi-Omics Approach to Improved Diagnosis and Treatment of Atopic Dermatitis and Psoriasis Int. J. Mol. Sci. SomaScan Chen, Y. et al. Genetic insights into associations of multisite chronic pain with common diseases and biomarkers using data from the UK Biobank Br J Anaesth. SomaScan Butler, AE. et al. A Cross-Sectional Study of Alzheimer-Related Proteins in Women with Polycystic Ovary Syndrome Int J Mol Sci. SomaScan Cervia-Hasler, C. et al. Persistent complement dysregulation with signs of thromboinflammation in active Long Covid Science SomaScan Curtis, BE. et al. An Aptamer-Based Proteomic Analysis of Plasma from Cats (Felis catus) with Clinical Feline Infectious Peritonitis Viruses SomaScan Smilnak, GJ. et al. Plasma protein signatures of adult asthma Allergy SomaScan Guru Murthy, GS. et al. Proteomics to predict relapse in patients with myelodysplastic neoplasms undergoing allogeneic hematopoietic cell transplantation Biomark Res. SomaScan Akita, K. et al. Prediction of Cardiac Death in Patients with Hypertrophic Cardiomyopathy Using Plasma Adipokine Levels NMCD SomaScan Kuku, KO. et al. Proteomics for heart failure risk stratification: a systematic review BMC Med. SomaScan Gobeil, E. et al. Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk Eur Heart J. SomaScan Link, VM. et al. Differential peripheral immune signatures elicited by vegan versus ketogenic diets in humans Nat Med. SomaScan Duijvelaar, E. et al. Longitudinal plasma proteomics reveals biomarkers of alveolar-capillary barrier disruption in critically ill COVID-19 patients Nat Commun. SomaScan Alkis, T. et al. A polygenic risk score of atrial fibrillation improves prediction of lifetime risk for heart failure ESC Heart Fail. SomaScan Li, H. et al. Proteome-Wide Mendelian Randomization identifies causal plasma proteins in lung cancer iScience SomaScan Choi, B. et al. Proteomic Biomarkers of Quantitative Interstitial Abnormalities in COPDGene and CARDIA Lung Study Am J Respir Crit Care Med. SomaScan Shelbaya, K. et al. Large-Scale Proteomics Identifies Novel Biomarkers and Circulating Risk Factors for Aortic Stenosis J Am Coll Cardiol. SomaScan Azzo, JD. et al. Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction Circ Heart Fail. SomaScan Wittich, H. et al. Transcriptome-wide association study of the plasma proteome reveals cis and trans regulatory mechanisms underlying complex traits Am J Hum Genet. SomaScan Zhao, H. et al. Identifying novel proteins for suicide attempt by integrating proteomes from brain and blood with genome-wide association data Neuropsychopharmacology SomaScan Russell, AJ. et al. Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy J Clin Invest. SomaScan Xiang, X. et al. Mechanistically based blood proteomic markers in the TGF-β pathway stratify risk of hepatocellular cancer in patients with cirrhosis Genes Cancer SomaScan Pase, MP. et al. Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia Neurology SomaScan Carry, P. et al. Untargeted Serum Proteomics Profiling in Female Patients with Idiopathic Scoliosis MRA SomaScan Wenk, D. et al. Recent developments in mass-spectrometry-based targeted proteomics of clinical cancer biomarkers Clin Proteomics SomaScan Fu, L. et al. Serum/Plasma Proteome in Non-Malignant Liver Disease Int. J. Mol. Sci. SomaScan Furuya, K. et al. High serum proteinase-3 levels predict poor progression-free survival and lower efficacy of bevacizumab in metastatic colorectal cancer BMC Cancer SomaScan Yu, G. et al. Lessons and Applications of Omics Research in Diabetes Epidemiology Curr Diab Rep. SomaScan Krishnamoorthy, S. et al. Plasma Proteome-Wide Mendelian Randomization Analysis Reveals Biomarkers and Therapeutic Targets for Different Stages of COVID-19 Transboundary and Emerging Diseases SomaScan Fernández-Irigoyen, J. et al. Special Issue “Deployment of Proteomics Approaches in Biomedical Research” Int. J. Mol. Sci. SomaScan Strecker, L. et al. Proteomic Analysis of Bronchoalveolar Lavage Fluid from Children with Bronchiolitis Obliterans Syndrome Identifies Potential Treatment Strategies Transplantation and Cellular Therapy SomaScan Cartas-Cejudo, P. et al. Mapping the human brain proteome: opportunities, challenges, and clinical potential Expert Rev Proteomics SomaScan Leung, JM. et al. Plasma SOMAmer proteomics of postoperative delirium Brain Behav. SomaScan Kiessling, P. et al. Spatial multi-omics: novel tools to study the complexity of cardiovascular diseases Genome Med. SomaScan Kurgan, N. et al. Harnessing the power of proteomics in precision diabetes medicine Diabetologia SomaScan Gold, ME. et al. Multi-proteomic Biomarker Risk Scores for Predicting Risk and Guiding Therapy in Patients with Coronary Artery Disease Curr Cardiol Rep. SomaScan Evans, DS. et al. Proteomic Analysis of the Senescence Associated Secretory Phenotype (SASP): GDF-15, IGFBP-2, and Cystatin-C Are Associated with Multiple Aging Traits J Gerontol A Biol Sci Med Sci. SomaScan Chen, L. et al. Proteome-wide Mendelian randomization highlights AIF1 and HLA-DQA2 as targets for primary sclerosing cholangitis Hepatol Int. SomaScan Grabowska, I. et al. Multiplex electrochemical aptasensors for detection of endothelial dysfunction: Ready for prime time? TrAC SomaScan Mousa, H. et al. Vitamin D status affects proteomic profile of HDL associated proteins and inflammatory mediators in dyslipidemia J Nutr Biochem. SomaScan Palà, E. et al. Common and specific proteins and pathways in heart and cerebral ischemia J Stroke Cerebrovasc Dis. SomaScan Han, BX. et al. Screening Plasma Proteins for the Putative Drug Targets for Carpal Tunnel Syndrome Cell Mol Neurobiol. SomaScan Mathews, L. et al. Growth Differentiation Factor 15 and Risk of Bleeding Events: The Atherosclerosis Risk in Communities Study J Am Heart Assoc. SomaScan Du, S.et al. Plasma Protein Biomarkers of Healthy Dietary Patterns: Results from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study J Nutr. SomaScan Kiernan, E. et al. Alterations in the Circulating Proteome Associated with Albuminuria J Am Soc Nephrol. SomaScan Steffen, BT. et al. Proteomics Analysis of Genetic Liability of Abdominal Aortic Aneurysm Identifies Plasma Neogenin and Kit Ligand: The ARIC Study Arterioscler Thromb Vasc Biol. SomaScan Chen, M. et al. Growth Differentiation Factor 15 and the Subsequent Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities Study Clin Chem. SomaScan Grams, ME. et al. Proteins Associated with Risk of Kidney Function Decline in the General Population J Am Soc Nephrol. SomaScan Soomro, S. et al. Predicting disease course in ulcerative colitis using stool proteins identified through an aptamer-based screen Nat Commun. SomaScan Dalby, E. et al. Immune Complex–Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity J Immunol. SomaScan Shen, Q. et al. Strong impact on plasma protein profiles by precentrifugation delay but not by repeated freeze-thaw cycles, as analyzed using multiplex proximity extension assays Clin Chem Lab Med. SomaScan Considine, DPC. et al. Genetically predicted circulating protein biomarkers and ovarian cancer risk Gynecol Oncol. SomaScan Shchukina, I. et al. Enhanced epigenetic profiling of classical human monocytes reveals a specific signature of healthy aging in the DNA methylome Nat Aging SomaScan Takanashi, S. et al. Lymphadenopathy in IgG4-related disease: a phenotype of severe activity and poor prognosis, with eotaxin-3 as a new biomarker Rheumatology (Oxford) SomaScan Faquih, T. et al. Agreement of aptamer proteomics with standard methods for measuring venous thrombosis biomarkers Res Pract Thromb Haemost. SomaScan Bell, S. et al. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis Commun Biol SomaScan Moin, ASM. et al. The relationship of soluble neuropilin-1 to severe COVID-19 risk factors in polycystic ovary syndrome Metabol Open. SomaScan Atkin, AS. et al. Plasma heat shock protein response to euglycemia in type 2 diabetes BMJ Open Diabetes Res Care. SomaScan Moin, ASM. et al. Hypoglycaemia in type 2 diabetes exacerbates amyloid‐related proteins associated with dementia Diabetes Obes Metab. SomaScan Pratte, KA. et al. Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD Respir Res. SomaScan Moin, ASM. et al. Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia BMJ Open Diabetes Res Care. SomaScan Wagner, BD. et al. Change in circulating proteins during treatment of pulmonary exacerbation in patients with cystic fibrosis Health Sci Rep. SomaScan Israël, L. et al. CARD10 cleavage by MALT1 restricts lung carcinoma growth in vivo Oncogenesis SomaScan Vujkovic-Cvijin, I. et al. The complement pathway is activated in people with human immunodeficiency virus and is associated with non-AIDS comorbidities J Infect Dis. SomaScan Luo, S. et al. Platelet glycoprotein Ib α‐chain as a putative therapeutic target for juvenile idiopathic arthritis: A Mendelian randomization study Arthritis Rheumatol. SomaScan Kaeser, SA. et al. A neuronal blood marker is associated with mortality in old age Nat Aging SomaScan Probert, F. et al. Integrative biochemical, proteomics, and metabolomics cerebrospinal fluid biomarkers predict clinical conversion to multiple sclerosis Brain Commun. SomaScan Moin, ASM. et al. Identification of macrophage activation-related biomarkers in obese type 2 diabetes that may be indicative of enhanced respiratory risk in COVID-19 Sci Rep. SomaScan Yakah, W. et al. Parenteral lipid emulsions induce unique ileal fatty acid and metabolomic profiles but do not increase the risk of necrotizing enterocolitis in preterm pigs Am J Physiol Gastrointest Liver Physiol. SomaScan Muñiz-Castrillo, S. et al. Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis Brain SomaScan Mohanty, SK. et al. HMGB1 release by cholangiocytes governs biliary atresia pathogenesis and correlates with increases in afflicted infants Hepatology SomaScan Ngo, D. et al. Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk JCI Insight SomaScan Jalal, D. et al. Detection of pro angiogenic and inflammatory biomarkers in patients with CKD Sci Rep. SomaScan Emilsson, V. et al. Serum levels of ACE2 are higher in patients with obesity and diabetes Obes Sci Pract. SomaScan Landino, K. et al. Characterization of the plasma proteomic profile of frailty phenotype Geroscience SomaScan Liu, L. et al. Twelve new genomic loci associated with bone mineral density Front Endocrinol. SomaScan Martin, TC. et al. Dysregulated antibody, natural killer cell and immune mediator profiles in autoimmune thyroid diseases Cells SomaScan Simic, P. et al. Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney J Clin Invest. SomaScan Fong, TG. et al. Identification of plasma proteome signatures associated with ATN framework using SOMAscan Ann Surg. SomaScan Elhadad, MA. et al. Deciphering the plasma proteome of type 2 diabetes Diabetes SomaScan Nakashima-Nakasuga, C. et al. Serum LOX-1 is a novel prognostic biomarker of colorectal cancer Int J Clin Oncol. SomaScan Steitz, AM. et al. Tumor-associated macrophages promote ovarian cancer cell migration by secreting transforming growth factor beta induced (TGFBI) and tenascin C Cell Death Dis SomaScan Oyama, Y. et al. Intense light pretreatment improves hemodynamics, barrier function and inflammation in a murine model of hemorrhagic shock lung. Mil Med. SomaScan Povero, D. et al. Characterization and proteome of circulating extracellular vesicles as potential biomarkers for NASH Hepatol Commun. SomaScan Ibanez, L. et al. Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease Acta Neuropathol Commun. SomaScan Tanaka, T. et al. Plasma proteomic signatures predict dementia and cognitive impairment Alzheimers Dement (N Y). SomaScan Grigorieva, J. et al. Application of protein set enrichment analysis to correlation of protein functional sets with mass spectral features and multivariate proteomic tests Clinical Mass Spectrometry SomaScan Wasiak, S. et al. Epigenetic modulation by apabetalone counters cytokine-driven acute phase response in vitro, in mice and in patients with cardiovascular disease Cardiovasc Ther. SomaScan Yamaguchi, Y. et al. Elevated plasma frowth and differentiation factor 15 predicts incident anemia in older adults aged 60 years and older J Gerontol A Biol Sci Med Sci. SomaScan Shu, X. et al. Evaluation of associations between genetically predicted circulating protein biomarkers and breast cancer risk Int J Cancer. SomaScan Zhu, J. et al. Associations between genetically predicted blood protein biomarkers and pancreatic cancer risk Cancer Epidemiol Biomarkers Prev. SomaScan Fahrmann, JF. et al. Plasma-Derived Extracellular Vesicles Convey Protein Signatures That Reflect Pathophysiology in Lung and Pancreatic Adenocarcinomas Cancers (Basel). SomaScan Noordam, R. et al. Proteome-wide assessment of diabetes mellitus in Qatari identifies IGFBP-2 as a risk factor already with early glycaemic disturbances Arch Biochem Biophys. SomaScan Pan, XY. et al. MFGE8, ALB, APOB, APOE, SAA1, A2M, and C3 as novel biomarkers for stress cardiomyopathy Cardiovasc Ther. SomaScan Tini, G. et al. DNA methylation during human adipogenesis and the impact of fructose Genes Nutr SomaScan Xu, J. et al. Integrated lipidomics and proteomics network analysis highlights lipid and immunity pathways associated with Alzheimer’s disease Transl Neurodegener. SomaScan Tweedie, D. et al. Time-dependent cytokine and chemokine changes in mouse cerebral cortex following a mild traumatic brain injury eLife SomaScan Mastey, E. et al. Identifying protein–metabolite networks associated with COPD phenotypes Metabolites SomaScan Cheng, S. et al. An atlas of genetic correlations between psychiatric disorders and human blood plasma proteome Eur Psychiatry. SomaScan Vujkovic-Cvijin, I. et al. HIV-associated gut dysbiosis is independent of sexual practice and correlates with noncommunicable diseases Nat Commun. SomaScan Kasimir-Bauer, s.et al. Definition and independent validation of a proteomic-classifier in ovarian cancer Cancers (Basel). SomaScan Hanly, PJ. et al. Urine biomarkers of renal renin–angiotensin system activity: Exploratory analysis in humans with and without obstructive sleep apnea Physiol Rep. SomaScan Nayor, M. et al. Aptamer-based proteomic platform identifies novel protein predictors of incident heart failure and echocardiographic traits Circ Heart Fail SomaScan Mueller, SK. et al. Significant polyomic and functional upregulation of the PAPP-A/IGFBP-4/5/IGF-1 axis in chronic rhinosinusitis with nasal polyps Int Forum Allergy Rhinol. SomaScan Workman, AD. et al. Unexpected effects of systemic steroids on the CRSwNP proteome: Is protein upregulation more important than inhibition? Int Forum Allergy Rhinol. SomaScan Sasayama, D. et al. Increased apolipoprotein E and decreased TNF‐α in the cerebrospinal fluid of nondemented APOE‐ε4 carriers Neuropsychopharmacol Rep SomaScan Schaum, N. et al. Aging hallmarks exhibit organ-specific temporal signatures Nature SomaScan Hunt, ER. et al. Upregulation of systemic inflammatory pathways following anterior cruciate ligament injury relates to both cartilage and muscular changes: A pilot study J Orthop Res. SomaScan Toyoda, E. et al. Transcriptomic and proteomic analyses reveal the potential mode of action of chondrocyte sheets in hyaline cartilage regeneration Int J Mol Sci SomaScan Egerstedt, A. et al. Profiling of the plasma proteome across different stages of human heart failure Nat Commun. SomaScan Wang, Z. et al. Airway host-microbiome interactions in chronic obstructive pulmonary disease Respir Res. SomaScan Pavlidis, S. et al. “T2-high” in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin Eur Respir J. SomaScan Polfus, LM. et al. Whole genome sequence association with E-selectin levels reveals loss-of-function variant in African Americans Hum Mol Genet SomaScan Doulamis, IP. et al. Transcriptomic and proteomic pathways of diabetic and non-diabetic mitochondrial transplantation Sci Rep. SomaScan Tsypin, M. et al. Extending the information content of the MALDI analysis of biological fluids via multi-million shot analysis PLoS ONE SomaScan Jevnikar, Z. et al. Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation J Allergy Clin Immunol. SomaScan Laksitorini, MD. et al. Modulation of Wnt/β-catenin signaling promotes blood-brain barrier phenotype in cultured brain endothelial cells Sci Rep. SomaScan Harbaum, L. et al. Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension Thorax SomaScan MacDonald, A. et al. Necuparanib, a multitargeting heparan sulfate mimetic, targets tumor and stromal compartments in pancreatic cancer Mol Cancer Ther. SomaScan Katzen, J. et al. An SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung fibrosis JCI Insight SomaScan Bradford, CM. et al. Characterization of a subset of patients with rheumatoid arthritis for whom current management strategies are inadequate ACR Open Rheumatol SomaScan Mancuso, R. et al. CSF1R inhibitor JNJ- attenuates microglial proliferation and neurodegeneration in P301S mice Brain SomaScan Joyce, R. et al. TGF-β signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond syndrome J Clin Invest. SomaScan Todd, JL. et al. Peripheral blood proteomic profiling of idiopathic pulmonary fibrosis biomarkers in the multicentre IPF-PRO registry Respir Res. SomaScan Keulen, DV. et al. Oncostatin M reduces atherosclerosis development in APOE*3Leiden.CETP mice and is associated with increased survival probability in humans PLoS ONE SomaScan Higgins, SJ. et al. Tie2 protects the vasculature against thrombus formation in systemic inflammation J Clin Invest. SomaScan Billin, AN. et al HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury Skelet Muscle SomaScan Hoffman, LK. et al. Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature PLoS ONE SomaScan Gopal, AK. et al. Ibrutinib as treatment for patients with relapsed/refractory follicular Lymphoma: Results from the open-label, multicenter, phase II DAWN study J Clin Oncol. SomaScan Takahashi, K. et al. Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis Eur Respir J. SomaScan Malik, R. et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes Nat Genet. SomaScan Wu, D. et al. Axonal guidance signaling pathway is suppressed in human nasal polyps Am J Rhinol Allergy. SomaScan Wu, D. et al. TREM-1 neutrophil activation pathway is suppressed in eosinophilic nasal polyps Am J Rhinol Allergy. SomaScan Kuo, CS. et al. T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED Eur Respir J. SomaScan Shah, RD. et al. Expression of calgranulin genes S100A8, S100A9 and S100A12 is modulated by n-3 PUFA during inflammation in adipose tissue and mononuclear cells PLoS ONE SomaScan Lim, SY. et al. Evaluation of two high-throughput proteomic technologies for plasma biomarker discovery in immunotherapy-treated melanoma patients Biomark Res. SomaScan Sullivan, KD. et al. Trisomy 21 consistently activates the interferon response eLife SomaScan Loza, MJ. et al. Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study Respir Res. SomaScan Bar-Or, D. et al. Low molecular weight fraction of commercial human serum albumin induces morphologic and transcriptional changes of bone marrow-derived mesenchymal stem cells Stem Cells Transl Med. SomaScan Natrajan, MS. et al. Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes Ann Clin Transl Neurol. SomaScan Silkoff, PE. et al. Asthma characteristics and biomarkers from the airways disease endotyping for personalized therapeutics (ADEPT) longitudinal profiling study Respir Res. SomaScan Coenen-Stass, AM. et al. Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics Sci Rep. SomaScan Chiam, JT. et al. No Evidence to Suggest that the Use of Acetylcholinesterase Inhibitors Confounds the Results of Two Blood-Based Biomarker Studies in Alzheimer's Disease J Alzheimers Dis. SomaScan Loza, M. et al. Systemic corticosteroid-associated serum analyte profiles in the U-BIOPRED severe asthma cohort Eur Respir J. SomaScan Christiansson, L. et al. The use of multiplex platforms for absolute and relative protein quantification of clinical material EuPA Open Proteomics SomaScan Thorolfsdottir, RB. et al. Variants at the Interleukin 1 Gene Locus and Pericarditis JAMA Cardiol. SomaScan Abiose, O. et al. Post-translational modifications linked to preclinical Alzheimer's disease-related pathological and cognitive changes Alzheimers Dement. SomaScan Jordan, HA. et al. Novel proteomic technologies to address gaps in pre-clinical ovarian cancer biomarker discovery efforts Expert Rev Proteomics SomaScan Emilsson, V. et al. Proteomic prediction of incident heart failure and its main subtypes Eur J Heart Fail SomaScan Serio, B. et al. All Roads Lead to Interferon-γ: From Known to Untraveled Pathways in Acquired Aplastic Anemia Medicina SomaScan Asamoah, K. et al. Proteomic signatures of eosinophilic and neutrophilic asthma from serum and sputum EBioMedicine SomaScan Chen, TK. et al. Associations of Baseline and Longitudinal Serum Uromodulin With Kidney Failure and Mortality: Results From the African American Study of Kidney Disease and Hypertension (AASK) Trial Am J Kidney Dis SomaScan Gold, ME. et al. Multi-proteomic Biomarker Risk Scores for Predicting Risk and Guiding Therapy in Patients with Coronary Artery Disease Curr Cardiol Rep SomaScan Papagiannopoulos, OD. et al. Classification of Inflammation of Unknown Origin patients based on RNA-seq and SomaScan data Annu Int Conf SomaScan Wen, Y. et al. Analysis of the human kidney transcriptome and plasma proteome identifies markers of proximal tubule maladaptation to injury Sci Transl Med. SomaScan Cardner, M. et al. Analysis of serum proteomics data identifies a quantitative association between beta-defensin 2 at baseline and clinical response to IL-17 blockade in psoriatic arthritis RMD Open SomaScan Graham, BIM. Integrating airway microbiome and blood proteomics data to identify multi-omic networks associated with response to pulmonary infection The Microbe SomaScan Brennan, E. et al. Relationship between endocrine disrupting chemicals (phthalate metabolites, triclosan and bisphenols) and vitamin D in female subjects: An exploratory pilot study Chemosphere SomaScan Bonaroti, JW. et al. Transcriptomic and Proteomic Characterization of the Immune Response to Elective Spinal Reconstructive Surgery: Impact of Aging and Comparisons with the Traumatic Injury Response J Am Coll Surg. SomaScan Ren, Y. et al. Evaluation of a large-scale aptamer proteomics platform among patients with kidney failure on dialysis PLoS One SomaScan Fullenkamp, DE. et al. Physiological stress improves stem cell modeling of dystrophic cardiomyopathy Dis Model Mech. SomaScan Oh, HS. et al. Organ aging signatures in the plasma proteome track health and disease Nature SomaScan Li, J. et al. Circulating Biomarkers and Risk of Hypertension: A Two-Sample Mendelian Randomisation Study Heart Lung Circ. SomaScan Yang, F. et al. Proteomic insights into the associations between obesity, lifestyle factors, and coronary artery disease BMC Med. SomaScan Thomson, LM. et al. The proteomic fingerprint in infants with single ventricle heart disease in the interstage period: evidence of chronic inflammation and widespread activation of biological networks Front. Pediatr SomaScan Akenroye, A. et al. Lower myostatin and higher MUC1 levels are associated with better response to mepolizumab and omalizumab in asthma: a protein-protein interaction analyses Respir Res SomaScan Farid, S. et al. Aptamer-Based Optical and Electrochemical Sensors: A Review Chemosensors SomaScan Goudswaard, LJ. et al. Using trials of caloric restriction and bariatric surgery to explore the effects of body mass index on the circulating proteome Sci Rep SomaScan 11/29/ Mälarstig, A. et al. Evaluation of circulating plasma proteins in breast cancer using Mendelian randomisation Nat Commun SomaScan 11/24/ Jonmundsson, T. et al. A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study) Europace SomaScan 11/15/ Adams, JM. et al. Leukotriene A4 hydrolase inhibition improves agerelated cognitive decline via modulation of synaptic function Sci Adv. SomaScan 11/15/ Castro-Pearson, S. et al. Development of a proteomic signature associated with severe disease for patients with COVID-19 using data from 5 multicenter, randomized, controlled, and prospective studies Sci Rep. SomaScan 11/20/ McMackin, R. et al. Biomarkers in amyotrophic lateral sclerosis: current status and future prospects Nat Rev Neurol SomaScan Wickramasinghe, LC. et al. Granulocyte colony-stimulating factor is a determinant of severe bronchopulmonary dysplasia and coincident retinopathy Am J Pathol SomaScan 09/04/ Vaquer-Alicea, A. et al. Plasma and CSF Proteomic Signatures of Acutely Sleep-Deprived Humans: An Exploratory Study SLEEP Advances SomaScan Stacey, SN. et al. Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis Nat Genet SomaScan 11/06/ Dörner, T. et al. Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjögren's syndrome: results from a randomised, double-blind, placebo-controlled phase 2 trial Ann Rheum Dis. SomaScan 11/06/ Pan, M. et al. Genetic Predisposition to Elevated Levels of Circulating ADAM17 Is Associated with the Risk of Severe COVID-19 Int. J. Mol. Sci. SomaScan Niazi, S. et al. A Critical Analysis of the FDA’s Omics-Driven Pharmacodynamic Biomarkers to Establish Biosimilarity Pharmaceuticals SomaScan Woo, J. et al. Effects of IL-1β inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial Blood Adv. SomaScan 11/07/ Dowling, P. et al. Mass Spectrometry-Based Proteomic Technology and Its Application to Study Skeletal Muscle Cell Biology Cells SomaScan Sun, J. et al. Unveiling the Association between HPV and Pan Cancers: A Bidirectional Two-Sample Mendelian Randomization Study Cancers SomaScan Bjornsdottir, G, et al. Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura Nat Genet SomaScan 10/26/ Tin, A. et al. Identification of circulating proteins associated with general cognitive function among middle-aged and older adults Commun Biol. SomaScan 11/03/ Carrasco-Zanini, J. et al. Multi-omic prediction of incident type 2 diabetes Diabetologia SomaScan 10/27/ Gîlcă-Blanariu, GE. et al. Advances in Noninvasive Biomarkers for Nonalcoholic Fatty Liver Disease Metabolites SomaScan Jackson, HR. et al. A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study Lancet Digit Health SomaScan Gorijala, P. et al. Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome Alzheimers Dement. SomaScan 10/19/ Aid, M. et al. Activation of coagulation and proinflammatory pathways in thrombosis with thrombocytopenia syndrome and following COVID-19 vaccination Nat Commun. SomaScan 10/23/ Yellin, B. et al. Analytical validation of the PROphet test for treatment decision-making guidance in metastatic non-small cell lung cancer J Pharm Biomed Anal. SomaScan 10/19/ Lee, D. et al. Decentralized clinical trial design using blood microsampling technology for serum bioanalysis Bioanalysis SomaScan 10/19/ Cordon, J. et al. Identification of Clinically Relevant Brain Endothelial Cell Biomarkers in Plasma Stroke SomaScan Jin, L. et al. Identification of Plasma Biomarkers from Rheumatoid Arthritis Patients Using an Optimized Sequential Window Acquisition of All THeoretical Mass Spectra (SWATH) Proteomics Workflow Proteomes SomaScan Gao, J. et al. The application of multi-omics in the respiratory microbiome: Progresses, challenges and promises Comput Struct Biotechnol J SomaScan 10/12/ Sigdel, TK. et al. Proteome Analysis for Inflammation Related to Acute and Convalescent Infection Inflammation SomaScan 10/13/ Aid, M. et al. Mpox infection protects against re-challenge in rhesus macaques Cell SomaScan 10/12/ Wolf, J. et al. Liquid-biopsy proteomics combined with AI identifies cellular drivers of eye aging and disease in vivo Cell SomaScan 10/26/ Dubin, RF. et al. Proteomics of CKD progression in the chronic renal insufficiency cohort Nat Commun. SomaScan 10/10/ Bohn, T. et al. Carotenoids in health as studied by omics-related endpoints Adv Nutr. SomaScan 09/05/ Butler, AE. et al. SAT366 Expression of Amyloid-related Proteins Associated With Dementia in Polycystic Ovary Syndrome Compared to a Control Population Journal of the Endocrine Society SomaScan de Bakker, M. et al. Machine learning based biomarker profile derived from serially measured proteins predicts clinical outcome of patients with heart failure European Heart Journal - Digital Health SomaScan Krauze, AV. et al. Revisiting Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients with Glioblastoma—Proteomic Alteration and Comparison Analysis with the Standard-of-Care Chemoirradiation Biomolecules SomaScan Larsson, SC. et al. Genome-Wide Association and Two-Sample Mendelian Randomization Analyses of Plasma Ghrelin and Gastrointestinal Cancer Risk Cancer Epidemiol Biomarkers SomaScan 10/04/ Dark HE. et al. Proteomic indicators of health predict Alzheimer's disease biomarker levels and dementia risk Ann Neurol. SomaScan 10/06/ Singh, VK. et al. Proteome biomarkers for radiation injury and testing of medical countermeasure efficacy: promises, pitfalls and future directions Expert Rev Proteomics SomaScan 09/26/ Di Mauro, V. et al. Diagnostic and Therapeutic Aptamers: A Promising Pathway to Improved Cardiovascular Disease Management JACC: Basic to Translational Science SomaScan Markezana, A. et al. Fibroblast growth factors induce hepatic tumorigenesis post radiofrequency ablation Sci Rep. SomaScan 09/28/ Wang, Q. et al. Integrating plasma proteomes with genome-wide association data for causal protein identification in multiple myeloma BMC Med. SomaScan 09/29/ Eldjarn, GH. Et al. Large-scale plasma proteomics comparisons through genetics and disease associations Nature SomaScan 10/04/ Perry , AS. Et al. Proteomic architecture of frailty across the spectrum of cardiovascular disease Aging Cell SomaScan 09/20/ Dillon, ST. et al. Aptamer-Based Proteomics Measuring Preoperative Cerebrospinal Fluid Protein Alterations Associated with Postoperative Delirium Biomolecules SomaScan 09/15/ Mousavian Z. et al. From simple to complex: protein-based biomarker discovery in tuberculosis Eur J Immunol. SomaScan 09/23/ Frank, B. et al. Circulating biomarkers of extracellular matrix dysregulation are associated with adverse post-stage 2 outcomes in infants with single ventricle heart disease Sci Rep SomaScan 09/28/ Visvabharathy, L. et al. Neuro-PASC is characterized by enhanced CD4+ and diminished CD8+ T cell responses to SARS-CoV-2 Nucleocapsid protein Front Immunol SomaScan 05/29/ Chan, WC. et al. Fibroscan-AST (FAST) score and other non-invasive tests for the diagnosis of fibrotic non-alcoholic steatohepatitis HepatoBiliary Surg Nutr SomaScan Babačić, H. et al. Comprehensive proteomics and meta-analysis of COVID-19 host response Nat Commun. SomaScan 09/22/ Sattar, N. et al. Prediction of Cardiometabolic Health Through Changes in Plasma Proteins With Intentional Weight Loss in the DiRECT and DIADEM-I Randomized Clinical Trials of Type 2 Diabetes Remission Diabetes Care SomaScan 09/26/ D'Erasmo, L. et al. ANGPTL3 Deficiency and Risk of Hepatic Steatosis Circulation SomaScan Dowling, P. et al. Biochemical and proteomic insights into sarcoplasmic reticulum Ca2+-ATPase complexes in skeletal muscles Expert Rev Proteomics. SomaScan Hanson, BA. et al. Plasma proteomics show altered inflammatory and mitochondrial proteins in patients with neurologic symptoms of post-acute sequelae of SARS-CoV-2 infection Brain Behav Immun. SomaScan Hota, M. et al. Omics-driven investigation of the biology underlying intrinsic submaximal working capacity and its trainability Physiol Genomics. SomaScan Ngo, D. et al. Systemic Markers of Lung Function and FEV1 Decline across Diverse Cohorts Ann Am Thorac Soc. SomaScan 06/23/ Reitz, CJ. et al. Multi-omic analyses and network biology in cardiovascular disease Proteomics. SomaScan 09/10/ Weiner, S. et al. Next-generation proteomics technologies in Alzheimer's disease: from clinical research to routine diagnostics Expert Rev Proteomics SomaScan 09/13/ Liu, F. et al. Late-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis Aging Cell SomaScan 09/11/ Zhong, H. et al. Identification of blood protein biomarkers associated with prostate cancer risk using genetic prediction models: analysis of over 140 000 subjects Hum Mol Genet. SomaScan 08/25/ Johansson, MW. et al. Decreased plasma cartilage acidic protein 1 in COVID-19 Physiol Rep. SomaScan 09/11/ Yao, P. et al. Conventional and genetic associations of adiposity with proteins in relatively lean Chinese adults Eur J Epidemiol. SomaScan 09/07/ Srialluri, N. et al. Circulating Proteins and Mortality in CKD: A Proteomics Study of the AASK and ARIC Cohorts Kidney Medicine SomaScan 10/01/ Doherty, C. et al. Aptamers in neuro-oncology: an emerging therapeutic modality Neuro Oncol. SomaScan 08/24/ Cai, X. et al. Population serum proteomics uncovers a prognostic protein classifier for metabolic syndrome Cell Rep Med. SomaScan 08/20/ Yuan, S. et al. Plasma proteins and onset of type 2 diabetes and diabetic complications: Proteome-wide Mendelian randomization and colocalization analyses Cell Rep Med. SomaScan 08/22/ Muse, O. et al. The unfolded protein response links ER stress to cancer-associated thrombosis JCI Insight. SomaScan 08/31/ Mahoney, SA. et al. Identification and functional analysis of senescent cells in the cardiovascular system using omics approaches Am J Physiol Heart Circ Physiol. SomaScan 09/01/ Rhee, J. et al. Cardioprotective and Anti-Inflammatory Effects of FAM3D in Myocardial Ischemia-Reperfusion Injury Circulation Research SomaScan 08/28/ Helgason H. et al. Evaluation of Large-Scale Proteomics for Prediction of Cardiovascular Events JAMA SomaScan 08/22/ Krauze, AV. et al. Glioblastoma survival is associated with distinct proteomic alteration signatures post chemoirradiation in a large-scale proteomic panel Front Oncol. SomaScan 08/10/ Yaghoobi, A. et al. Genome- and Exome-Wide Association Studies Revealed Candidate Genes Associated with DaTscan Imaging Features Parkinson’s Disease SomaScan Goldberg, JF. et al. Selection and Interpretation of Molecular Diagnostics in Heart Transplantation Circulation SomaScan 08/22/ Wang, H. et al. Subgroups of children with Kawasaki disease: a data-driven cluster analysis Lancet Child Adolesc Health. SomaScan 08/17/ Magnusson, M. et al. Histopathology and levels of proteins in plasma associate with survival after colorectal cancer diagnosis Br J Cancer. SomaScan 08/18/ Quintana-Torres, D. et al. The secretome atlas of two mouse models of progeria Aging Cell SomaScan 08/10/ Wang, X. et al. Proteome-Wide Mendelian Randomization Analysis Identified Potential Drug Targets for Atrial Fibrillation J Am Heart Assoc. SomaScan 08/15/ Morris, BJ. et al. Genes That Extend Lifespan May Do So by Mitigating the Increased Risk of Death Posed by Having Hypertension Am J Hypertens. SomaScan 08/10/ Benson, MD. et al. Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma Cell Metab. SomaScan 08/11/ Tsukita, K. et al. High-Throughput CSF Proteomics and Machine Learning to Identify Proteomic Signatures for Parkinson Disease Development and Progression Neurology SomaScan 08/16/ Parnetti, L. et al. Advances in Diagnosis and Prognosis of Parkinson Disease: Value of Cerebrospinal Fluid Proteomics Neurology SomaScan 08/16/ Butler, AE. et al. Complement Dysregulation in Obese Versus Nonobese Polycystic Ovary Syndrome Patients Cells SomaScan 08/04/ Li, H. et al. Proteome-wide mendelian randomization identifies causal plasma proteins in venous thromboembolism development J Hum Genet. SomaScan 08/03/ Geretz, A. et al. plasma proteins in venous thromboembolism development Sci Transl Med. SomaScan 08/02/ Cederberg, KL. et al. Single-cell transcriptomics identifies prothymosin α restriction of HIV-1 in vivo Sleep Health SomaScan 08/08/ Cai, Y. et al. Proteomic insights into the pathophysiology of periodic limb Clin J Am Soc Nephrol. SomaScan 08/03/ Muhie, S. et al. Integrated analysis of proteomics, epigenomics and metabolomics data revealed divergent pathway activation patterns in the recent versus chronic post-traumatic stress disorder Brain Behav Immun. SomaScan 07/27/ Lovell, JP. et al. Serum Proteomic Analysis of Peripartum Cardiomyopathy Reveals Distinctive Dysregulation of Inflammatory and Cholesterol Metabolism Pathways JACC Heart Fail. SomaScan 07/18/ Galbraith, MD. et al. Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition Sci Adv. SomaScan 06/28/ De Belen, E. et al. Clinical Variation in the Treatment Practices for Patients With Type2 Diabetes: A Cross-Sectional Patient Simulation Study Among Primary Care Physicians and Cardiologists J Am Heart Assoc. SomaScan 06/29/ Kong, AHY. et al. Exploring the Potential of Aptamers in Targeting Neuroinflammation and Neurodegenerative Disorders: Opportunities and Challenges Int. J. Mol. Sci. SomaScan 07/24/ Nandakumar, M. et al. Oxidative Stress Markers and Heat Shock Proteins in Non-Obese Women with Polycystic Ovary Syndrome Are Not Elevated and Show No Correlation with Vitamin D Biomedicines SomaScan 07/11/ Gupta, S. et al. Plasma proteome of growing tumors Sci Rep. SomaScan 07/27/ Walker, KA. et al. Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life Sci Transl Med. SomaScan 07/19/ Li, Y. et al. The application of Aptamer in biomarker discovery Biomarkers Research SomaScan 07/19/ Mi, MY. et al. Plasma Proteomic Kinetics in Response to Acute Exercise Mol Cell Proteomics SomaScan 06/19/ Gregga, I. et al. Predicted proteome association studies of breast, prostate, ovarian, and endometrial cancers implicate plasma protein regulation in cancer susceptibility Cancer Epidemiol Biomarkers Prev. SomaScan 07/06/ Butler, AE. et al. Association of flame retardants, polybrominated diethyl ethers (PBDEs), with vitamin D in female subjects Chemosphere SomaScan 07/11/ Richards, SM. et al. Non-invasive candidate protein signature predicts hepatic venous pressure gradient reduction in cirrhotic patients after sustained virologic response Liver Int. SomaScan 07/13/ Lin, JS. et al. Proteomic profiling of longitudinal changes in kidney function among middle-aged and older men and women: the KORA S4/F4/FF4 study BMC Med. SomaScan 07/05/ Phillips, B. et al. Proteome wide association studies of LRRK2 variants identify novel causal and druggable proteins for Parkinson's disease NPJ Parkinsons Dis. SomaScan 07/08/ Kokelj, S. et al. Activation of the Complement and Coagulation Systems in the Small Airways in Asthma Respiration. SomaScan 07/07/ Roberts, JA. et al. Unbiased proteomics and multivariable regularized regression techniques identify SMOC1, NOG, APCS, and NTN1 in an Alzheimers disease brain proteomic signature NPJ Aging. SomaScan 07/06/ Peabody, JW. et al. Clinical utility of a novel test for assessing cardiovascular disease risk in type 2 diabetes: a randomized controlled trial Diabetol Metab Syndr. SomaScan 07/13/ Beals, JW. et al. Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes Nat Metab. SomaScan 06/26/ Cai, L. et al. Causal associations between cardiorespiratory fitness and type 2 diabetes Nat Commun. SomaScan 07/03/ Sung, YJ. et al. Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer's disease Sci Transl Med. SomaScan 07/05/ Kim, H. et al. Associations of circulating proteins with lipoprotein profiles: proteomic analyses from the OmniHeart randomized trial and the Atherosclerosis Risk in Communities (ARIC) Study Clin Proteomics. SomaScan 07/03/ Lazar, J. et al. Large scale plasma proteome epitome profiling is an efficient tool for the discovery of cancer biomarkers Mol Cell Proteomics SomaScan 05/19/ Liu, T. et al. External validation of genetically predicted protein biomarkers for pancreatic cancer risk using aptamer-based plasma levels: A prospective analysis in the Atherosclerosis Risk in Communities Study Int J Cancer SomaScan 06/20/ Milman, S. et al. Frailty Resilience Score: A Novel Measure of Frailty Resilience Associated with Protection from Frailty and Survival J Gerontol A Biol Sci Med Sci. SomaScan 05/29/ Nash, A. et al. New Markers for Management of Mesothelioma Semin Respir Crit Care Med. SomaScan 05/30/ Bader, JM. et al. MS-based proteomics of body fluids: The end of the beginning Mol Cell Proteomics SomaScan 05/18/ Chen, R. et al. Biomarkers of ageing: Current state-of-art, challenges, and opportunities MedComm – Future Medicine SomaScan 06/18/ Quian, L. et al. Mass Spectrometry-based Proteomics of Epithelial Ovarian Cancers: a Clinical Perspective Mol Cell Proteomics SomaScan 05/18/ Felipez, N. et al. The Human Gastric Juice: A Promising Source for Gastric Cancer Biomarkers Int J Mol Sci. SomaScan Tomasoni, C. et al. A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies Hemasphere SomaScan 05/23/ Liang, X. et al. Proteomics approaches to long COVID: status and outlooks Life Medicine SomaScan Lee J. et al. Machine learning algorithm improves detection of NASH (NAS-based) and at-risk NASH, a development and validation study Hepatology SomaScan Ozsoylu, D. et al. (Bio-)Sensors for Skin Grafts and Skin Flaps Monitoring Sensors and Actuators Report SomaScan Brennan, E. et al. Association between Organochlorine Pesticides and Vitamin D in Female Subjects Biomedicines SomaScan 05/15/ DiLillo, K. et al. A blood and bronchoalveolar lavage protein signature of rapid FEV1 decline in smoking-associated COPD Sci Rep. SomaScan 05/22/ Jiang, MZ. et al. Canonical correlation analysis for multi-omics: Application to cross-cohort analysis PLoS Genet. SomaScan 05/22/ de Bakker, M. et al. Sex-based differences in cardiovascular proteomic profiles and their associations with adverse outcomes in patients with chronic heart failure Biol Sex Differ. SomaScan 05/17/ Mackay, S. Identification of serum biomarkers for necrotizing enterocolitis using aptamer-based proteomics Front Pediatr. SomaScan 05/31/ Petersen, TB. et al. HFrEF subphenotypes based on repeatedly measured circulating proteins are driven by different biological mechanisms EBioMedicine SomaScan 06/14/ Iglesias, MJ. et al. Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism Nat Commun SomaScan 06/07/ Giontella, A. et al. Renoprotective effects of genetically proxied fibroblast growth factor 21: Mendelian randomization, proteome-wide and metabolome-wide association study Metabolism SomaScan 06/09/ Gisladottir, R. et al. Sequence variants affecting voice pitch in humans Sci Adv. SomaScan Oddsson, A. et al. Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality Nat Commun. SomaScan 06/10/ DeBoer, E. et al. Cardiopulmonary Phenotypes and Protein Signatures in Children With Down Syndrome Clinical Pediatr. (Phila). SomaScan 06/12/ Lu, S. et al. Magnetically Detected Protein Binding Using Spin-Labeled Slow Off-Rate Modified Aptamers ACS Sens. SomaScan 06/10/ Hill, AC. et al. Large scale proteomic studies create novel privacy considerations Sci Rep. The authors of this paper sought to demonstrate the need for similar privacy protections in proteomic research as genomic research already has. Since the discovery that single nucleotide polymorphisms (SNPs) can genetically distinguish individuals, multiple privacy protection policies regarding genetic information have been passed in the United States. Notably, these policies only explicitly address genetic information, leaving proteomics in a grey area and legally unprotected. The authors use limited proteome profiles without peptide sequencing to link specific individuals by using prior independent knowledge of QTLs The authors used the COPDGene and Jackson Heart studies to train a model to predict genotypes based on SomaScan proteomic measurements. The model was validated using the MESA, SPIROMICS, and splits from the COPDGene and Jackson Heart studies. The model identified independent subjects of European ancestry with 83-92% accuracy and African American subjects with ~90% accuracy. The authors determined that the minimum number of protein-pQTL pairs necessary to match a proteome to a genome is 100 pairs. The authors assessed whether newer and larger proteome assays were more or less accurate at identifying genetic profiles. To do so, they split the COPDGene subjects who had 5k data into a 50/50 train-test split and generated a new list of protein-QTL pairs. These protein-QTL pairs were also used to match proteomes and genomes of participants in the ARIC study who have 5k SomaScan data. Identification accuracy improved to_>_98% in COPDGene and ARIC participants. This study is the first to demonstrate on a large scale that proteomic data are not identity protected because an individual proteome can be matched to a specific genome with high accuracy even without protein sequence information. SomaScan 06/07/ Sasamoto, S. et al. Plasma proteomic profiles of pain subtypes in adolescentsand young adults with endometriosis Hum Reprod SomaScan 05/17/ Debbs, J. et al. Evaluation of a New Aptamer-Based Array for Soluble Suppressor of Tumorgenicity (ST2) and N-terminal Pro-B-Type Natriuretic Peptide (NTproBNP) in Heart Failure Patients J Cardiovasc Transl Res. In this study, SomaScan and ELISA assays were used to measure NTproBNP and ST2 and the results and predictive performance of the two methods were compared. N-terminal pro-B-type natriuretic peptide (NTproBNP) and soluble suppressor of tumorgenicity 2 (ST2) are the two most widely used and recommended biomarkers used for the diagnosis and prognosis of heart failure. The SomaScan assay allows for the rapid detection of thousands of proteins simultaneously, including NTproBNP and ST2. Here, the authors wished to test the accuracy of the SomaScan method for detecting NTproBNP and ST2 by comparing the performance to commercial ELISA assays. EDTA plasma samples from participants from the Henry Ford Pharmacogenomic Registry who met Framingham criterion for HF and had an ejection fraction < 50% were analyzed. When ST2 results were compared, the two methods had similar hazard ratios and were statistically significant for predicting all-cause mortality both with and without adjustment to the MAGGIC score for heart failure. Similar results were seen for predicting cardiovascular mortality. The two methods for measuring ST2 had a Spearman correlation of 0.71 and a Pearson correlation of 0.74. To determine whether addition of each assay method for ST2 improved the accuracy of the MAGGIC model for predicting heart failure, ROC curves were generated. The addition of the ELISA ST2 resulted in an AUC of 0.69 and was statistically significant (p = 0.035), while the addition of the SomaScan ST2 resulted in an AUC of 0.68 but was not statistically significant (p = 0.121). When NTproBNP results were compared, the two methods also had similar hazard ratios for all-cause mortality and were statistically significant for predicting all-cause mortality both with and without adjustment to the MAGGIC score for heart failure. Similar results were also seen for predicting cardiovascular mortality. The two methods for NTproBNP had a Spearman correlation of 0.95 and a Pearson correlation of 0.88. The MAGGIC score model was not significantly improved with addition of either method for measuring NTproBNP. This study shows that SomaScan results correlate well with commercial ELISA-based assays for NTproBNP and ST2 and have comparable prognostic abilities for predicting heart failure survival, showing the potential for proteomics and multimarker diagnostic methods in health care. SomaScan 05/16/ Cronje, H. et al. Plasma proteomic risk markers of incident type 2 diabetes reflect physiologically distinct components of glucose-insulin homeostasis Diabetes In this study, the authors used the SomaScan 5k to conduct a large-scale proteomics association study of incident type 2 diabetes and longitudinal glucose trajectories. The Cardiovascular Health Study (CHS) is a population-based prospective study investigating cardiovascular disease risk factors in adults aged 65 years or older. The Health, Risk Factors, Exercise Training and Genetics (HERITAGE) is a 20-week, single-arm exercise intervention study investigating genetic and cardiometabolic contributors to endurance exercise response in participants recruited within family units. Plasma samples from CHS and HERITAGE studies were run on the SomaScan v4.0. Cox proportional hazard regression models were used to test associations of aptamers with incident type 2 diabetes. Linear mixed-effect models were used to assess associations of aptamers with 6-year longitudinal fasting glucose levels. Authors also assessed aptamer specificity. 51 proteins were associated with incident type 2 diabetes and all but two of the associated aptamers had published cis pQTLs; 12 have been validated by mass spectrometry, and 7 had strong (P > 0.70) correlations with Olink measurements. Protein associations with longitudinal glucose levels largely reflected those observed in the incident diabetes analyses. In the base model, 59 additional associations were statistically significant. Prospective protein associations were identified in a complementary analysis of multiple glucose homeostasis traits using intravenous glucose tolerance test (IVGTT). 52 significantly associated proteins from the main model were selected and their associations with the following four IVGTT traits in HERITAGE were tested: insulin sensitivity index, acute insulin response to glucose, disposition index, and glucose effectiveness. Insulin sensitivity index, acute insulin response to glucose, disposition index, and glucose effectiveness were respectively associated with 39, 9, 39, and 8 proteins. 90% of significantly associated proteins were associated with at least one IVGTT trait. The study overall observed three patterns of association: 1. Proteins reflecting higher insulin sensitivity were also markers of decreased diabetes risk and vice versa; 2. Proteins relating to pancreatic function had associations with diabetes and insulin secretion but not insulin sensitivity; 3. In the insulin-independent glucometabolic pathways, b-Glucuronidase (GUSB) was most strongly associated with incident diabetes. It is hypothesized that before the onset of overt diabetes, GUSB may be upregulated to compensate for hyperglycemia as the body becomes more insulin resistant. SomaScan 05/01/ Hou, R. et al. The role of inflammation in anxiety and depression in the European U-BIOPRED asthma cohorts Brain Behav Immun. In this study, the authors use data and samples from the largest European asthma cohort, the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) study, and utilize the largest proteomic assay on the market, SomaScan, to address the underlying mechanism between inflammation, asthma, anxiety, and depression. Studies have shown that people with asthma are more likely to experience anxiety, psychological distress, and depression which can lead to poor disease management and lower quality of life. Evidence suggests that inflammation is the link between asthma, anxiety, and depression; however, studies have been limited by small sample sizes, poor study design, and a limited number of available inflammatory markers. Here, behavioral data and serum samples from 198 non-smoking patients with severe asthma (SAn), 65 smoking patients with severe asthma (SAs), 61 non-smoking patients with mild-to-moderate asthma (MMA), and 20 healthy nonsmokers (HC) from the U-BIOPRED were analyzed. Average Hospital Anxiety and Depression Scale (HADS) scores for anxiety, depression, and HADS total scores from this cohort revealed a significantly higher levels in the SAn and SAs groups compared to the MMA and HC groups. Proteomic analysis of inflammatory markers revealed significantly higher levels of IL6, CCL18, MCP1, CCL17, and IL8 in the SAn and SAs groups. When looking at correlations between HADS scores and inflammatory markers, significant positive correlations were found between the depression score and IL6, MCP1, CCL18, and CCL17, the anxiety score and CCL17, and the total score and IL6, CCL18, and CCL17. Correlations between inflammatory markers for air flow obstruction and HADS scores were also analyzed, revealing a small negative correlation between eosinophil count and FeNO with depression and total HADS scores in the SAs group. The findings from this study confirmed higher rates of anxiety and depression in patients with severe asthma and using SomaScan found that certain inflammatory cytokines were significantly different in those patients, pointing to a possible underlying mechanism. SomaScan 05/03/ Slieker, RC. et al. Identification of biomarkers for glycaemic deterioration in type 2 diabetes Nat Commun. This study aimed to identify biomarkers for glycemic deteroriation in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes: metabolites, lipids and proteins. This represents the first study to use a multiomic approach for biomarker discovery and report systematically how metabolites of different classes impact progression of T2D. Individuals from three cohorts, DCS, GoDARTS and ANDIS were included. Protein data was generated using SomaScan 1.3k. In the investigated plasma proteins, the levels of 98 were nominally associated with time to insulin in the base model. The protein with the strongest association with time to insulin was GDF-15. Mendelian randomization was performed on six of the identified proteins to investigate casual associations. GDF15 is causally associated with diabetes progression and found a possible causal association for IL-18Ra and FAS. Metabolics data was generated using UHLPC-MS/MS. Two metabolites, Aminoadipic Acid (AADA) and Homocitrulline (Hcit) were significantly associated with diabetes progression. Lipid data was generated using mass spec. Nine lipids were associated with diabetes progression of which eight were associated with increased risk which all belonged to the Triacylglycerol (TAG) class. SomaStrengths: Biomarker identification, top proteins validated using ELISA SomaScan 05/03/ Maruszak, A. et al. Predicting progression to Alzheimer's disease with human hippocampal progenitors exposed to serum Brain In this study, the authors develop an in vitro model and a proteomic model using SomaScan data to predict progression of mild cognitive impairment (MCI) to Alzheimer’s disease using serum samples. Early intervention for Alzheimer’s disease is key and changes in hippocampal neurogenesis (HN) have been shown to be promising early markers for Alzheimer’s disease progression; however, results from previous studies have conflicting results on the directionality of those changes. Longitudinal studies are needed to address those discrepancies but are limited by the availability of viable techniques to study living human brains. In this study, an in vitro method to measure changes in HN is developed as a proxy by examining cell proliferation and differentiation of a human hippocampal progenitor cell line treated with longitudinal serum samples from MCI converters and non-converters. Cells treated with serum from MCI converters lead to decreased proliferation, increased cell death and increased neurogenesis. Using this in vitro system, a model was developed combining cell number, markers for cell proliferation, markers for cell differentiation, and education in years that was able to predict progression from MCI to Alzheimer’s with an AUC of 0.967 and an ability to predict disease progression up to 3.5 years before clinical diagnosis. Next, proteomics was employed to similarly explore development of a predictive model for conversion from MCI to Alzheimer’s. Samples were analyzed on SomaScan to measure unique proteins ( different protein epitopes) and, using machine learning, a panel of 15 proteins was identified that could distinguish between serum samples from MCI converters and non-converters with an AUC of 0.77. Pathway and network analysis was also performed on the differentially expressed proteins from the SomaScan data. Canonical pathways identified included Coagulation, Acute phase response signaling, Extrinsic prothrombin activation pathway, FXR/RXR activation, Notch signaling, Superpathway of methionine degradation, and Wnt/_-catenin Signaling. The top three networks identified were “Hematological System Development and Function, Organismal Functions, Organismal Injury and Abnormalities”, “Cell Death and Survival, Embryonic Development, Organismal Development”, and “Cell-to-Cell Signaling and Interaction, Cellular Function and Maintenance, Inflammatory Response”. This study demonstrates promising in vitro serum based models for predicting Alzheimer’s disease progression and provides insights into the underlying mechanisms of the disease in relation to changes in HN. SomaScan 05/02/ Butler, A. et al. High density lipoprotein-associated proteins in non-obese women with and without polycystic ovary syndrome Front Endocrinol. SomaScan 04/26/ Su CY. et al. Circulating proteins to predict COVID-19 severity Sci Rep. SomaScan 04/17/ Hwang M. et al. Quantitative proteomic screening uncovers candidate diagnostic and monitoring serum biomarkers of ankylosing spondylitis Arthritis Res Ther. SomaScan 04/11/ Govaere O. et al. A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures Nat Metab. SomaScan 04/10/ Omenn G. et al. The Report on the Human Proteome from the HUPO Human Proteome Project J Proteome Res. SomaScan 04/07/ Xu Y. et al. An atlas of genetic scores to predict multi-omic traits Nature SomaScan Hirohama D. et al. Unbiased Human Kidney Tissue Proteomics Identifies Matrix Metalloproteinase 7 as a Kidney Disease Biomarker J Am Soc Nephrol. SomaScan 04/05/ Gomez-Lopez, N. et al. Pregnancy-specific responses to COVID-19 revealed by high-throughput proteomics of human plasma Commun Med (Lond) SomaScan 04/04/ Kalani R. et al. Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study Neurology SomaScan 04/04/ Kim H. et al. Identification of Protein Biomarkers of the Dietary Approaches to Stop Hypertension Diet in Randomized Feeding Studies and Validation in an Observational Study J Am Heart Assoc. SomaScan 04/04/ Deo R. et al. Proteomic cardiovascular risk assessment in chronic kidney disease Eur Heart J. SomaScan 04/23/ Zhao Q. et al. Proteome and genome integration analysis of obesity Chinese Medical Journal SomaScan 03/31/ Perry TA. et al. Supportive Evidence For The Potential For Novel Biodiscovery In Osteoarthritis Through The Stepup Oa Consortium Osteoarthritis and Cartilage SomaScan Habet V. et al. Integrated Analysis of Tracheobronchial Fluid from Before and After Cardiopulmonary Bypass Reveals Activation of the Integrated Stress Response and Altered Pulmonary Microvascular Permeability Yale J Biol Med. SomaScan 03/31/ Vali Y. et al. Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study Lancet Gastroenterol Hepatol. SomaScan 03/20/ Wang S. et al. Associations between MICA and MICB genetic variants, protein levels, and colorectal cancer: Atherosclerosis Risk in Communities (ARIC) Cancer Epidemiol Biomarkers Prev. SomaScan 03/23/ Samorodnitsky S.et al. Lung proteome and metabolome endotype in HIV-associated obstructive lung disease ERJ Open Res. SomaScan 03/20/ Hooten NN et al. Plasma gelsolin levels are associated with diabetes, sex, race, and poverty J Transl Med. SomaScan 03/10/ Butler A. et al. HDL-Associated Proteins in Subjects with Polycystic Ovary Syndrome: A Proteomic Study Cells SomaScan 03/09/ Donlon T. et al. Proteomic basis of mortality resilience mediated by FOXO3 longevity genotype Geroscience SomaScan 03/07/ Moin ASM. et al. Coagulation factor dysregulation in polycystic ovary syndrome is an epiphenomenon of obesity Clin Endocrinol. (Oxf) SomaScan 03/01/ Emilsson OI, et al. Exhaled biomarkers in adults with non-productive cough Respir Res. SomaScan 03/01/ Berrone, E. et al. SOMAscan Proteomics Identifies Novel Plasma Proteins in Amyotrophic Lateral Sclerosis Patients Int J Mol Sci. SomaScan 01/18/ Chen, TK. et al. APOL1 Kidney Risk Variants and Proteomics Clin J Am Soc Nephrol. SomaScan 05/17/ Sher, A. et al. HLA-A, HSPA5, IGFBP5 and PSMA2 Are Restriction Factors for Zika Virus Growth in Astrocytic Cells Viruses SomaScan 12/29/ Naoko Sasamoto Plasma proteomic profiles of pain subtypes in adolescents and young adults with endometriosis Human Reproduction What are the similarities and differences in the systemic proteomic profiles by endometriosis-associated pain subtypes among adolescents and young adults with endometriosis? Naoko Sasamoto, Long Ngo, Allison F Vitonis, Simon T Dillon, Christine B Sieberg, Stacey A Missmer, Towia A Libermann, Kathryn L Terry SomaScan 05/17/ Itamar Sela Analytical validation of the PROphet computational model for clinical benefit prediction and decision-making tool in metastatic NSCLC bioRxiv https://doi.org/10./.04.20. Itamar Sela, Coren Lahav, Ben Yellin, Yehonatan Elon, Michal Harel SomaScan 04/24/ Chen-Yang Su Circulating proteins to predict COVID-19 severity Scientific Reports 13 https://doi.org/10./s-023--y Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care. Chen-Yang Su, Sirui Zhou, Edgar Gonzalez-Kozlova, Guillaume Butler-Laporte, Elsa Brunet-Ratnasingham, Tomoko Nakanishi, Wonseok Jeon, David R. Morrison, Laetitia Laurent, Jonathan Afilalo, Marc Afilalo, Danielle Henry, Yiheng Chen, Julia Carrasco-Zanini, Yossi Farjoun, Maik Pietzner, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Meriem Bouab, Louis Petitjean, Charlotte Guzman, Xiaoqing Xue, Chris Tselios, Branka Vulesevic, Olumide Adeleye, Tala Abdullah, Noor Almamlouk, Yara Moussa, Chantal DeLuca, Naomi Duggan, Erwin Schurr, Nathalie Brassard, Madeleine Durand, Diane Marie Del Valle, Ryan Thompson, Mario A. Cedillo, Eric Schadt, Kai Nie, Nicole W. Simons, Konstantinos Mouskas, Nicolas Zaki, Manishkumar Patel, Hui Xie, Jocelyn Harris, Robert Marvin, Esther Cheng, Kevin Tuballes, Kimberly Argueta, Ieisha Scott, The Mount Sinai COVID-19 Biobank Team, Celia M. T. Greenwood, Clare Paterson, Michael A. Hinterberg, Claudia Langenberg, Vincenzo Forgetta, Joelle Pineau, Vincent Mooser, Thomas Marron, Noam D. Beckmann, Seunghee Kim-schulze, Alexander W. Charney, Sacha Gnjatic, Daniel E. Kaufmann, Miriam Merad & J. Brent Richards SomaScan 04/17/ Gisby J S, et al. Multi-omics identify falling LRRC15 as a COVID-19 severity marker and persistent pro-thrombotic signals in convalescence Nature Communications Patients with end-stage kidney disease (ESKD) are at high risk of severe COVID19. Here, we perform longitudinal blood sampling of ESKD haemodialysis patients with COVID-19, collecting samples pre-infection, serially during infection, and after clinical recovery. Using plasma proteomics, and RNAsequencing and flow cytometry of immune cells, we identify transcriptomic and proteomic signatures of COVID-19 severity, and find distinct temporal molecular profiles in patients with severe disease. Jack S. Gisby, Norzawani B. Buiang, Artemis Papadaki, Candice L. Clarke, Talat H. Malik, Nicholas Medjeral-Thomas, Damiola Pinheiro, Page M. Mortimer, Shanice Lewis, Eleanor Sandhu, Stephen P McAdoo, Maria F. Prendecki, Michelle Willicombe, Matthew C. Pickering, Marina Botto, David C Thomas, James E. Peters SomaScan 12/15/ Yamada K, et al. Siglec-7 is a predictive biomarker for the efficacy of cancer vaccination against metastatic colorectal cancer Oncol Lett 21 1 10 https://doi.org/10./ol.. biomarker; colorectal cancer; peptide vaccine; protein expression analysis; sialic acid-binding immunoglobulin type lectin-7. Cancer immunotherapy, including vaccination, is considered a major scientific and medical breakthrough. However, cancer immunotherapy does not result in durable objective responses against colorectal cancer (CRC). To improve the efficacy of immunotherapy, the present study investigated several biomarkers for selecting patients who were expected to respond well to immunotherapy. Firstly, a comprehensive proteomic analysis was performed using tumor tissue lysates from patients enrolled in a phase II study, in which five human leukocyte antigen (HLA)-A*24:02-restricted peptides were administered. Sialic acid-binding immunoglobulin type lectin (Siglec)-7 was identified as a potential predictive biomarker. Subsequently, this biomarker was validated using western blot analysis, and immunofluorescence using tissue samples from the patients enrolled in the phase II study. The expression levels of Siglec-7 detected by immunofluorescence were quantified and their association with overall survival (OS) in patients treated with the peptide vaccine was examined. Furthermore, considering the important role of tumor-infiltrating lymphocytes (TILs) for CRC prognosis, the densities of CD3+, CD4+, CD8+ and forkhead box P3 (FOXP3)+ T cells in CRC tissues were examined and compared with Siglec-7 expression. The mean expression levels of Siglec-7 were significantly higher in patients with poor prognosis, with an OS of ≤2 years, as shown in comprehensive proteomic analysis (P=0.016) and western blot analysis (P=0.025). Immunofluorescence analysis demonstrated that Siglec-7 was expressed in intratumoral macrophages. The OS in patients with high Siglec-7 expression was significantly shorter than in that in patients with low Siglec-7 expression (P=0.017) in the HLA-A*24:02-matched patients. However, this difference was not observed in the HLA-unmatched patients. There was no significant difference in OS between patients according to the numbers of TILs, nor significant correlation between TILs and Siglec-7 expression. In conclusion, Siglec-7 expression in macrophages in tumor tissue may be a novel predictive biomarker for the efficacy of immunotherapy against metastatic CRC. Yamada K, Hazama S, Suzuki N, Xu M, Nakagami Y, Fujiwara N, Tsunedomi R, Yoshida S, Tomochika S, Matsukuma S, Matsui H, Tokumitsu Y, Kanekiyo S, Shindo Y, Watanabe Y, Iida M, Takeda S, Ioka T, Ueno T, Ogihara H, Hamamoto Y, Hoshii Y, Kawano H, Fujita T, Kawakami Y, Nagano H. SomaScan 11/03/ Blatt S, et al. High-Multiplex Aptamer-Based Serum Proteomics to Identify Candidate Serum Biomarkers of Oral Squamous Cell Carcinoma Cancers 15 7 https://doi.org/10./cancers oral cancer; SOMAscan; proteomics; liquid biopsy; biomarker; serum; prognosis; therapy Improved serological biomarkers are needed for the early detection, risk stratification and treatment surveillance of patients with oral squamous cell carcinoma (OSCC). We performed an exploratory study using advanced, highly specific, DNA-aptamer-based serum proteomics (SOMAscan, -plex) to identify distinct proteomic changes in patients with OSCC pre- vs. post-resection and compared to healthy controls. A total of 63 significantly differentially expressed serum proteins (each p < 0.05) were found that could discriminate between OSCC and healthy controls with 100% accuracy. Furthermore, 121 proteins were detected that were significantly altered between pre- and post-resection sera, and 12 OSCC-associated proteins reversed to levels equivalent to healthy controls after resection. Of these, 6 were increased and 6 were decreased relative to healthy controls, highlighting the potential relevance of these proteins as OSCC tumor markers. Pathway analyses revealed potential pathophysiological mechanisms associated with OSCC. Hence, quantitative proteome analysis using SOMAscan technology is promising and may aid in the development of defined serum marker assays to predict tumor occurrence, progression and recurrence in OSCC, and to guide personalized therapies. Blatt, S.; Kämmerer, P.W.; Krüger, M.; Surabattula, R.; Thiem, D.G.E.; Dillon, S.T.; Al-Nawas, B.; Libermann, T.A.; Schuppan, D.  SomaScan 03/30/ Elizabeth A. Brown, et al. Effect of pegbelfermin on NASH and fibrosis-related biomarkers and correlation with histological response in the FALCON 1 trial JHEP Reports FALCON 1 was a phase IIb study of pegbelfermin in patients with non-alcoholic steatohepatitis (NASH) and stage 3 fibrosis. This FALCON 1 post hoc analysis aimed to further assess the effect of pegbelfermin on NASH-related biomarkers, correlations between histological assessments and non-invasive biomarkers, and concordance between the week 24 histologically assessed primary endpoint response and biomarkers. EA Brown, A Minnich, AJ Sanyal, R Loomba SomaScan 04/01/ Bruno Bohn, et al. A proteomic approach for investigating the pleiotropic effects of statins in the atherosclerosis risk in communities (ARIC) study Journal of Proteomics Statins are prescribed to reduce LDL-c and risk of CVD. Statins have pleiotropic effects, affecting pathophysiological functions beyond LDL-c reduction. We compared the proteome of statin users and nonusers (controls). We hypothesized that statin use is associated with proteins unrelated to lipid metabolism. B Bohn, PL Lutsey, W Tang, JS Pankow, FL Norby SomaScan 02/10/ Jian Huang, et al. Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study Front Genet Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment. J Huang, D Gill, V Zuber, PM Matthews, P Elliott SomaScan 02/17/ Li, Shimena High dimensional proteomics identifies organ injury patterns associated with outcomes in human trauma J Trauma Acute Care Surg High-throughput proteomics allow researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. SomaScan 02/07/ Sindhu Vangeti, et al. Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx Elife uring respiratory viral infections, the precise roles of monocytes and dendritic cells (DCs) in the nasopharynx in limiting infection and influencing disease severity are incompletely described. We studied circulating and nasopharyngeal monocytes and DCs in healthy controls (HCs) and in patients with mild to moderate infections (primarily influenza A virus [IAV]).  Sindhu Vangeti, Sara Falck-Jones, Meng Yu, Björn Österberg, Sang Liu, Muhammad Asghar, Klara Sondén, Clare Paterson, Penn Whitley, Jan Albert, Niclas Johansson, Anna Färnert, Anna Smed-Sörensen SomaScan 02/08/ Choung, RS. et al. Preclinical Serological Signatures are Associated with Complicated Crohn's Disease Phenotype at Diagnosis Clinical Gastroenterology and Hepatology At diagnosis, up to one-third of patients with Crohn’s disease (CD) have a complicated phenotype with stricturing (B2) or penetrating (B3) behavior or require early surgery. We evaluated protein biomarkers and antimicrobial antibodies in serum archived years before CD diagnosis to assess whether complicated diagnoses were associated with a specific serological signature. SomaScan 02/11/ Rashid MU, et al. PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells Biochim Biophys Acta Mol Basis No study yet has reported PSMA2 knockdown (KD) effects on the cellular proteome. METHODS: We used SOMAScan, an aptamer-based multiplexed technique, to measure > human proteins to determine the impact of PSMA2 KD on A549 human lung epithelial cells. ... Meng Yu,  SomaScan 12/01/ Abdi IY, et al. Cross-sectional proteomic expression in Parkinson's disease-related proteins in drug-naive patients vs healthy controls with longitudinal clinical follow-up Neurobiol Dis There is an urgent need to find reliable and accessible blood-based biomarkers for early diagnosis of Parkinson's disease (PD) correlating with clinical symptoms and displaying predictive potential to improve future clinical trials. This led us to a conduct large-scale proteomics approach using an advanced high-throughput proteomics technology to create a proteomic profile for PD. Over proteins were measured in serum samples from a de novo Parkinson's (DeNoPa) cohort made up of 85 deep clinically phenotyped drug-naïve de novo PD patients and 93 matched healthy controls (HC) with longitudinal clinical follow-up available of up to 8 years.  Björn Österberg,  SomaScan 01/10/ Sykes R, et al. Adjudicated myocarditis and multisystem illness trajectory in healthcare workers post-COVID-19. Open Heart We investigated the associations of healthcare worker status with multisystem illness trajectory in hospitalised post-COVID-19 individuals. Muhammad Asghar,  SomaScan 02/10/ Rashid MU, et al. PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells Biochim Biophys Acta Mol Basis Proteasome subunit alpha type-2 (PSMA2) is a critical component of the 20S proteasome, which is the core particle of the 26S proteasome complex and is involved in cellular protein quality control by recognizing and recycling defective proteins. PSMA2 expression dysregulation has been detected in different human diseases and viral infections. No study yet has reported PSMA2 knockdown (KD) effects on the cellular proteome. Penn Whitley,  SomaScan 12/05/ G Yang, et al. Multi-omics studies in historically excluded populations: the road to equity Clinical Pharmacology & Therapeutics Over the past few decades, genomewide association studies (GWASs) have identified the specific genetics variants contributing to many complex diseases by testing millions of genetic variations across the human genome against a variety of phenotypes. However, GWASs are limited in their ability to uncover mechanistic insight given that most significant associations are found in non-coding region of the genome. Jan Albert,  SomaScan 12/10/ R Dagher, et al. Proteomic profiling of serum identifies a molecular signature that correlates with clinical outcomes in COPD Plos One Novel biomarkers related to main clinical hallmarks of Chronic obstructive pulmonary disease (COPD), a heterogeneous disorder with pulmonary and extra-pulmonary manifestations, were investigated by profiling the serum levels of proteins using Slow Off-rate Modified Aptamers (SOMA)scan technology. Niclas Johansson,  SomaScan 12/08/ AK Cheema, et al. Radiation therapy induces innate immune responses in patients treated for prostate cancers Clinical Cancer Research Radiation therapy (RT) is a curative therapeutic modality used to treat cancers as a single agent or in combination with surgery and chemotherapy. Advanced RT technologies enable treatment with large fractions and highly conformal radiation doses to effect free-radical damage to cellular DNA leading to cell cycle arrest, cell death, and innate immune response (IIR) stimulation. Anna Färnert,  SomaScan 12/01/ P Kosa, et al. Molecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms Nature Communication While autopsy studies identify many abnormalities in the central nervous system (CNS) of subjects dying with neurological diseases, without their quantification in living subjects across the lifespan, pathogenic processes cannot be differentiated from epiphenomena. Using machine learning (ML), we searched for likely pathogenic mechanisms of multiple sclerosis (MS). Anna Smed-Sörensen SomaScan 12/12/ C Yang, et al. Mendelian randomization and genetic colocalization infer the effects of the multi-tissue proteome on 211 complex disease-related phenotypes Genome Medicine Human proteins are widely used as drug targets. Integration of large-scale protein-level genome-wide association studies (GWAS) and disease-related GWAS has thus connected genetic variation to disease mechanisms via protein. Previous proteome-by-phenome-wide Mendelian randomization (MR) studies have been mainly focused on plasma proteomes. C Yang, AM Fagan, RJ Perrin, H Rhinn, O Harari SomaScan 12/12/ Rooney Mary, et al. Comparison of Proteomic Measurements Across Platforms in the Atherosclerosis Risk in Communities (ARIC) Study. Clin Chem The plasma proteome can be quantified using different types of highly multiplexed technologies, including aptamer-based and proximity-extension immunoassay methods. There has been limited characterization of how these protein measurements correlate across platforms and with absolute measures from targeted immunoassays. Rooney MR, Chen J, Ballantyne CM, Hoogeveen RC, Tang O, Grams ME, Tin A, Ndumele CE, Zannad F, Couper DJ, Tang W, Selvin E, Coresh J. SomaScan 12/12/ Zhang Y, et al. Predicting AT(N) pathologies in Alzheimer's disease from blood-based proteomic data using neural networks. Front Aging Neurosci Blood-based biomarkers represent a promising approach to help identify early Alzheimer's disease (AD). Previous research has applied traditional machine learning (ML) to analyze plasma omics data and search for potential biomarkers, but the most modern ML methods based on deep learning has however been scarcely explored. In the current study, we aim to harness the power of state-of-the-art deep learning neural networks (NNs) to identify plasma proteins that predict amyloid, tau, and neurodegeneration (AT[N]) pathologies in AD. Zhang Y, Ghose U, Buckley NJ, Engelborghs S, Sleegers K, Frisoni GB, Wallin A, Lleó A, Popp J, Martinez-Lage P, Legido-Quigley C, Barkhof F, Zetterberg H, Visser PJ, Bertram L, Lovestone S, Nevado-Holgado AJ, Shi L. SomaScan 11/29/ Sanyal AJ, et al. Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in nonalcoholic fatty liver disease. J Hepatol Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD. Sanyal AJ, Williams SA, Lavine JE, Tetri B, Alexander L, Ostroff R, Biegel H, Kowdley K, Chalasani N, Dasarathy S, Diehl AM, Loomba R, Hameed B, Behling C, Kleiner DE, Karpen SJ, Williams J, Jia Y, Yates KP, Tonascia J. SomaScan 12/14/ Bonaroti J, et al. Plasma proteomics reveals early, broad release of chemokine, cytokine, TNF, and interferon mediators following trauma with delayed increases in a subset of chemokines and cytokines in patients that remain critically ill. Front Immunol Severe injury is known to cause a systemic cytokine storm that is associated with adverse outcomes. However, a comprehensive assessment of the time-dependent changes in circulating levels of a broad spectrum of protein immune mediators and soluble immune mediator receptors in severely injured trauma patients remains uncharacterized.  Bonaroti J, Billiar I, Moheimani H, Wu J, Namas R, Li S, Kar UK, Vodovotz Y, Neal MD, Sperry JL, Billiar TR. SomaScan 11/30/ Piera-Velazquez S, et al. Aptamer proteomics of serum exosomes from patients with Primary Raynaud's and patients with Raynaud's at risk of evolving into Systemic Sclerosis. PLoS One A major unmet need for Systemic Sclerosis (SSc) clinical management is the lack of biomarkers for the early diagnosis of patients with Raynaud's Phenomenon at high risk of evolving into SSc. Piera-Velazquez S, Dillon ST, Gu X, Libermann TA, Jimenez SA. SomaScan 12/22/ Sanges S, et al. Biomarkers of haemodynamic severity of systemic sclerosis-associated pulmonary arterial hypertension by serum proteome analysis. Ann Rheum Dis To mine the serum proteome of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) and to detect biomarkers that may assist in earlier and more effective diagnosis and treatment. Sanges S, Rice L, Tu L, Valenzi E, Cracowski JL, Montani D, Mantero JC, Ternynck C, Marot G, Bujor AM, Hachulla E, Launay D, Humbert M, Guignabert C, Lafyatis R. SomaScan 12/05/ Abu Saleh Md Moin, et al. Classical and alternate complement factor overexpression in non-obese weight matched women with polycystic ovary syndrome does not correlate with vitamin D. Front Endocrinol (Lausanne) Women with polycystic ovary syndrome (PCOS) exhibit complement factor expression changes that may be obesity-driven rather than an intrinsic facet of PCOS; furthermore, complement changes have been associated with vitamin D deficiency, a common feature of PCOS. Therefore, complement pathway proteins and vitamin D levels may be linked in PCOS. Abu Saleh Md Moin 1, Thozhukat Sathyapalan 2, Alexandra E Butler 1, Stephen L Atkin 1 SomaScan 12/31/ Pesutti CL, et al. Differential Proteins Expression Distinguished Between Patients With Infectious and Noninfectious Uveitis. Ocul Immunol Inflamm We investigated the aqueous humor proteome and associated plasma proteome in patients with infectious or noninfectious uveitis. Pessuti CL, Medley QG, Li N, Huang CL, Loureiro J, Banks A, Zhang Q, Costa DF, Ribeiro KS, Nascimento H, Muccioli C, Commodaro AG, Huang Q, Belfort R Jr. SomaScan 01/13/ Shuo Wang, et al. Abstract A022: Proteomic age acceleration associated with all-cause mortality in cancer survivors in the Atherosclerosis Risk in Communities (ARIC) Study.[R] Cancer Research Longer lifespan and improved cancer treatment led to a rapid rise in the number of cancer survivors. However, many cancer survivors have physiological dysregulations at earlier chronological ages than those without cancer, suggesting that cancer survivors’ biological age is higher than their chronological age, i.e., they have accelerated aging. Cancer survivors’ biological age may be estimated by a novel proteomic aging clock (PAC). Shuo Wang SomaScan 01/15/ Accortt E, et al. Perinatal Mood and Anxiety Disorders: biomarker discovery using plasma proteomics. Am J Obstet Gynecol Perinatal mood and anxiety disorders encompass a range of mental health disorders that occur during pregnancy and up to 1 year postpartum, affecting approximately 20% of women. Traditional risk factors, such as a history of depression and pregnancy complications including preeclampsia, are known. Their predictive utility, however, is not specific or sensitive enough to inform clinical decision-making or prevention strategies for perinatal mood and anxiety disorders. Better diagnostic and prognostic models are needed for early identification and referral to treatment. Accortt E, Mirocha J, Zhang D, Kilpatrick SJ, Libermann T, Karumanchi SA. SomaScan 01/14/ Rooney Mary, et al. Proteomic Predictors of Incident Diabetes: Results From the Atherosclerosis Risk in Communities (ARIC) Study Diabetes Care The plasma proteome preceding diabetes can improve our understanding of diabetes pathogenesis. SomaScan 01/27/ Winchester L, et al. Identification of a possible proteomic biomarker in Parkinson's disease: discovery and replication in blood, brain and cerebrospinal fluid. Brain Commun Biomarkers to aid diagnosis and delineate the progression of Parkinson's disease are vital for targeting treatment in the early phases of the disease. Here, we aim to discover a multi-protein panel representative of Parkinson's and make mechanistic inferences from protein expression profiles within the broader objective of finding novel biomarkers. Winchester L, Barber I, Lawton M, Ash J, Liu B, Evetts S, Hopkins-Jones L, Lewis S, Bresner C, Malpartida AB, Williams N, Gentlemen S, Wade-Martins R, Ryan B, Holgado-Nevado A, Hu M, Ben-Shlomo Y, Grosset D, Lovestone S. SomaScan 12/28/ Bakinowska L, et al. Exocrine Proteins Including Trypsin(ogen) as a Key Biomarker in Type 1 Diabetes. Diabetes Care Diabetes Proteomic profiling can identify useful biomarkers. Monozygotic (MZ) twins discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well-characterized cohorts. Bakinowska L, Vartak T, Phuthego T, Taylor M, Chandler K, Jerram ST, Williams S, Feldmann M, Johnson DG, Patel KA, Williams AJK, Long AE, Leslie RD, Gillespie KM; Action LADA Consortium and BOX Study Group. SomaScan 01/26/ Dubin RF, et al. Analytical and Biological Variability of a Commercial Modified Aptamer Assay in Plasma Samples of Patients with Chronic Kidney Disease. J Appl Lab Med We carried out a study of the aptamer proteomic assay, SomaScan V4, to evaluate the analytical and biological variability of the assay in plasma samples of patients with moderate to severe chronic kidney disease (CKD). Dubin RF, Deo R, Ren Y, Lee H, Shou H, Feldman H, Kimmel P, Waikar SS, Rhee EP, Tin A, Chen J, Coresh J, Go AS, Kelly T, Rao PS, Chen TK, Segal MR, Ganz P. SomaScan 01/27/ Bellocchi C et al. Proteomic aptamer analysis reveals serum markers that characterize preclinical systemic sclerosis (SSc) patients at risk for progression toward definite SSc. Arthritis Res Ther. Bellocchi C, Assassi S, Lyons M, Marchini M, Mohan C, Santaniello A, Beretta L. SomaScan Sharma, M, et al. Abstract WMP101: Plasma Proteomic Determinants Of White Matter Hyperintensities And Covert Brain Infarction In The Cardiovascular Health Study Stroke Identification of novel biomarkers of cerebral small vessel disease is critical to elucidate pathophysiology and guide therapeutic development for prevention. We evaluated plasma proteomic associations of clinically asymptomatic … M Sharma, WT Longstreth, R Kalani, B Psaty, M Elkind SomaScan A Natu Aptamer-Based Plasma Proteomics Nominates Biomarkers Of Neurological Severity, Stroke Diagnosis And Age Stroke Plasma protein biomarkers measured in the hyperacute setting that are associated with stroke diagnosis or with clinical neurological severity, can be diagnostically and prognostically meaningful in patient care. We hypothesized that … A Natu, P Kumar, MR Frankel, S RANGARAJU SomaScan T Tanaka Proteomic Mediators of Overall Cardiovascular Health on All-Cause Mortality Nutrients … The hybridization controls, viral proteins, and flagged SOMAmer Reagents were removed, resulting in a total of SOMAmer Reagents that were used in the final analysis. Some of the SOMAmer Reagents are designed to capture multiplex … T Tanaka, SA Talegawkar, Y Jin, J Candia, G Fantoni… - Nutrients, SomaScan Gelinas AD Broadly neutralizing aptamers to SARS-CoV-2: a diverse panel of modified DNA antiviral agents. Mol Ther Nucleic Acids Gelinas AD, Tan TK, Liu S, Jaramillo JG, Chadwick J, Harding AC, Zhang C, Ream BE, Chase CN, Otis MR, Lee T, Schneider DJ, James WS, Janjic N. SomaScan Jozefczuk E, et al. Novel biomarkers and emerging tools to identify causal molecular pathways in hypertension and associated cardiovascular diseases. Kardiol Pol Józefczuk E, Guzik TJ, Siedlinski M. SomaScan Pierson SK, et al. CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease Nat Commun 13 1 https://www.doi.org/10./s-022--7 36,433,996 Humans *Castleman Disease/drug therapy Biomarkers Healthy Volunteers Immunotherapy Chemokine CXCL13 Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood cytokine storm-driven inflammatory disorder. Interleukin-6 (IL-6) is a known disease driver in some patients, but anti-IL-6 therapy with siltuximab is not effective in all patients, and biomarkers indicating success at an early time point following treatment initiation are lacking. Here we show, by comparison of levels of 1,178 proteins in sera of healthy participants (N = 42), patients with iMCD (N = 88), and with related diseases (N = 60), a comprehensive landscape of candidate disease mediators and predictors of siltuximab response. C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD. Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points. Our study thus suggests that CXCL13 is a predictive biomarker of response to siltuximab in iMCD. Pierson, Sheila K Katz, Laura Williams, Reece Mumau, Melanie Gonzalez, Michael Guzman, Stacy Rubenstein, Ayelet Oromendia, Ana B Beineke, Philip Fossa, Alexander van Rhee, Frits Fajgenbaum, David C eng R01HL/U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ England Nat Commun. Nov 24;13(1):. doi: 10./s-022--7.I SomaScan 11/27/ Njunge JM, et al. The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia Gates Open Res 6 77 https://www.doi.org/10./gatesopenres..2 36,415,883 Case-Cohort Children Lmic Mortality Omics Systems Biology Introduction: Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network ( www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach. Methods and analysis; The CNCC comprises a subset of participants from the CHAIN cohort (/ hospitalised participants, including 350 children who died and 658 survivors, and 270/ well community children of similar age and household location) from nine sites in six countries across sub-Saharan Africa and South Asia. Systemic proteome, metabolome, lipidome, lipopolysaccharides, haemoglobin variants, toxins, pathogens, intestinal microbiome and biomarkers of enteropathy will be determined. Computational systems biology analysis will include machine learning and multivariate predictive modelling with stacked generalization approaches accounting for the different characteristics of each biological modality. This systems approach is anticipated to yield mechanistic insights, show interactions and behaviours of the components of biological entities, and help develop interventions to reduce mortality among acutely ill children. Ethics and dissemination. The CHAIN Network cohort and CNCC was approved by institutional review boards of all partner sites. Results will be published in open access, peer reviewed scientific journals and presented to academic and policy stakeholders. Data will be made publicly available, including uploading to recognised omics databases. Trial registration NCT. Njunge, James M Tickell, Kirkby Diallo, Abdoulaye Hama Sayeem Bin Shahid, Abu Sadat Mohammad Gazi, Md Amran Saleem, Ali Kazi, Zaubina Ali, Syed Tigoi, Caroline Mupere, Ezekiel Lancioni, Christina L Yoshioka, Emily Chisti, Mohammod Jobayer Mburu, Moses Ngari, Moses Ngao, Narshion Gichuki, Bonface Omer, Elisha Gumbi, Wilson Singa, Benson Bandsma, Robert Ahmed, Tahmeed Voskuijl, Wieger Williams, Thomas N Macharia, Alex Makale, Johnstone Mitchel, Anna Williams, Jessica Gogain, Joe Janjic, Nebojsa Mandal, Rupasri Wishart, David S Wu, Hang Xia, Lei Routledge, Michael Gong, Yun Yun Espinosa, Camilo Aghaeepour, Nima Liu, Jie Houpt, Eric Lawley, Trevor D Browne, Hilary Shao, Yan Rwigi, Doreen Kariuki, Kevin Kaburu, Timothy Uhlig, Holm H Gartner, Lisa Jones, Kelsey Koulman, Albert Walson, Judd Berkley, James eng Gates Open Res. Nov 3;6:77. doi: 10./gatesopenres..2. eCollection .I SomaScan 11/25/ Nawaz MS, et al. Thirty novel sequence variants impacting human intracranial volume Brain Commun 4 6 fcac271 https://www.doi.org/10./braincomms/fcac271 36,415,660 Mendelian randomization brain structure genetic correlation genome-wide association study intracranial volume Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume (n = 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including GLI3 and CDK6 that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder. Nawaz, Muhammad Sulaman Einarsson, Gudmundur Bustamante, Mariana Gisladottir, Rosa S Walters, G Bragi Jonsdottir, Gudrun A Skuladottir, Astros Th Bjornsdottir, Gyda Magnusson, Sigurdur H Asbjornsdottir, Bergrun Unnsteinsdottir, Unnur Sigurdsson, Engilbert Jonsson, Palmi V Palmadottir, Vala Kolbrun Gudjonsson, Sigurjon A Halldorsson, Gisli H Ferkingstad, Egil Jonsdottir, Ingileif Thorleifsson, Gudmar Holm, Hilma Thorsteinsdottir, Unnur Sulem, Patrick Gudbjartsson, Daniel F Stefansson, Hreinn Thorgeirsson, Thorgeir E Ulfarsson, Magnus O Stefansson, Kari eng England Brain Commun. Oct 25;4(6):fcac271. doi: 10./braincomms/fcac271. eCollection .I SomaScan 11/24/ Vorn R, et al. Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion?Findings from the NCAA and Department of Defense CARE Consortium J Sport Health Sci epub ahead of print https://www.doi.org/10./j.jshs..11.007 36,403,906 Biomarkers College athletes Concussion Mild traumatic brain injury Sport injury BACKGROUND: Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion (SRC). METHODS: This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium conducted between and . The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0-6 h post-injury) and after 6 h post-injury (7-48 hours post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target proteins in plasma samples from athletes with and without SRC. RESULTS: A total of 140 athletes with concussion (79.3% male; aged 18.71 +/- 1.10 years, mean +/- SD) and 21 non-concussed athletes (76.2% male; 19.14 +/- 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve (AUC) of 0.954 (95% confidence interval: 0.922_0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is best for diagnosing concussion in athletes after 6 h of injury. CONCLUSION: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury. Vorn, Rany Devoto, Christina Meier, Timothy B Lai, Chen Yun, Sijung Broglio, Steven P Mithani, Sara McAllister, Thomas W Giza, Christopher C Kim, Hyung-Suk Huber, Daniel Harezlak, Jaroslaw Cameron, Kenneth L McGinty, Gerald Jackson, Jonathan Guskiewicz, Kevin M Mihalik, Jason P Brooks, Alison Duma, Stefan Rowson, Steven Nelson, Lindsay D Pasquina, Paul McCrea, Michael A Gill, Jessica M eng China J Sport Health Sci. Nov 17:S-(22)-4. doi: 10./j.jshs..11.007.I SomaScan 11/21/ Zaghlool SB, et al. Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population Nat Commun 13 1 https://www.doi.org/10./s-022--z 36,402,758 Humans *Diabetes Mellitus, Type 2/genetics/metabolism Proteomics Arabs *Diabetes Mellitus, Type 1 Insulin Type 2 diabetes (T2D) has a heterogeneous etiology influencing its progression, treatment, and complications. A data driven cluster analysis in European individuals with T2D previously identified four subtypes: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) diabetes. Here, the clustering approach was applied to individuals with T2D from the Qatar Biobank and validated in an independent set. Cluster-specific signatures of circulating metabolites and proteins were established, revealing subtype-specific molecular mechanisms, including activation of the complement system with features of autoimmune diabetes and reduced 1,5-anhydroglucitol in SIDD, impaired insulin signaling in SIRD, and elevated leptin and fatty acid binding protein levels in MOD. The MARD cluster was the healthiest with metabolomic and proteomic profiles most similar to the controls. We have translated the T2D subtypes to an Arab population and identified distinct molecular signatures to further our understanding of the etiology of these subtypes. Zaghlool, Shaza B Halama, Anna Stephan, Nisha Gudmundsdottir, Valborg Gudnason, Vilmundur Jennings, Lori L Thangam, Manonanthini Ahlqvist, Emma Malik, Rayaz A Albagha, Omar M E Abou-Samra, Abdul Badi Suhre, Karsten eng NPRP11C--/Qatar Foundation (Qatar Foundation for Education, Science and Community Development)/ England Nat Commun. Nov 19;13(1):. doi: 10./s-022--z.I SomaScan 11/20/ Dammer EB, et al. Multi-platform proteomic analysis of Alzheimer's disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome Alzheimers Res Ther 14 1 174 https://www.doi.org/10./s-022--5 36,384,809 Humans *Alzheimer Disease/cerebrospinal fluid Proteomics Proteostasis Amyloid beta-Peptides/cerebrospinal fluid Biomarkers/cerebrospinal fluid Robust and accessible biomarkers that can capture the heterogeneity of Alzheimer's disease and its diverse pathological processes are urgently needed. Here, we undertook an investigation of Alzheimer's disease cerebrospinal fluid (CSF) and plasma from the same subjects (n=18 control, n=18 AD) using three different proteomic platforms-SomaLogic SomaScan, Olink proximity extension assay, and tandem mass tag-based mass spectrometry-to assess which protein markers in these two biofluids may serve as reliable biomarkers of AD pathophysiology observed from unbiased brain proteomics studies. Median correlation of overlapping protein measurements across platforms in CSF (r~0.7) and plasma (r~0.6) was good, with more variability in plasma. The SomaScan technology provided the most measurements in plasma. Surprisingly, many proteins altered in AD CSF were found to be altered in the opposite direction in plasma, including important members of AD brain co-expression modules. An exception was SMOC1, a key member of the brain matrisome module associated with amyloid-beta deposition in AD, which was found to be elevated in both CSF and plasma. Protein co-expression analysis on greater than protein measurements in CSF and protein measurements in plasma across all proteomic platforms revealed strong changes in modules related to autophagy, ubiquitination, and sugar metabolism in CSF, and endocytosis and the matrisome in plasma. Cross-platform and cross-biofluid proteomics represents a promising approach for AD biomarker development. Dammer, Eric B Ping, Lingyan Duong, Duc M Modeste, Erica S Seyfried, Nicholas T Lah, James J Levey, Allan I Johnson, Erik C B eng K08 AG/AG/NIA NIH HHS/ P30 AG/AG/NIA NIH HHS/ U54 AG/AG/NIA NIH HHS/ England Alzheimers Res Ther. Nov 17;14(1):174. doi: 10./s-022--5.I SomaScan 11/18/ Carrasco-Zanini J, et al. Proteomic signatures for identification of impaired glucose tolerance Nat Med 28 11 - https://www.doi.org/10./s-022--z 36,357,677 Humans *Glucose Intolerance/diagnosis *Diabetes Mellitus, Type 2/diagnosis Blood Glucose/metabolism Proteomics Glucose Tolerance Test Fasting The implementation of recommendations for type 2 diabetes (T2D) screening and diagnosis focuses on the measurement of glycated hemoglobin (HbA1c) and fasting glucose. This approach leaves a large number of individuals with isolated impaired glucose tolerance (iIGT), who are only detectable through oral glucose tolerance tests (OGTTs), at risk of diabetes and its severe complications. We applied machine learning to the proteomic profiles of a single fasted sample from 11,546 participants of the Fenland study to test discrimination of iIGT defined using the gold-standard OGTTs. We observed significantly improved discriminative performance by adding only three proteins (RTN4R, CBPM and GHR) to the best clinical model (AUROC = 0.80 (95% confidence interval: 0.79-0.86), P = 0.004), which we validated in an external cohort. Increased plasma levels of these candidate proteins were associated with an increased risk for future T2D in an independent cohort and were also increased in individuals genetically susceptible to impaired glucose homeostasis and T2D. Assessment of a limited number of proteins can identify individuals likely to be missed by current diagnostic strategies and at high risk of T2D and its complications. Carrasco-Zanini, Julia Pietzner, Maik Lindbohm, Joni V Wheeler, Eleanor Oerton, Erin Kerrison, Nicola Simpson, Missy Westacott, Matthew Drolet, Dan Kivimaki, Mika Ostroff, Rachel Williams, Stephen A Wareham, Nicholas J Langenberg, Claudia eng MC_UU_/1/RCUK | Medical Research Council (MRC)/ R/RCUK | Medical Research Council (MRC)/ MC_PC_/RCUK | Medical Research Council (MRC)/ /Z/19/Z/Wellcome Trust (Wellcome)/ /Z/20/Z/Wellcome Trust (Wellcome)/ /Academy of Finland (Suomen Akatemia)/ /Academy of Finland (Suomen Akatemia)/ Nat Med. Nov;28(11):-. doi: 10./s-022--z. Epub Nov 10.I SomaScan 11/11/ Png G, et al. Identifying causal serum protein-cardiometabolic trait relationships using whole genome sequencing Hum Mol Genet epub ahead of print https://www.doi.org/10./hmg/ddac275 36,349,687 Cardiometabolic diseases, such as type 2 diabetes and cardiovascular disease, have a high public health burden. Understanding the genetically-determined regulation of proteins that are dysregulated in disease can help to dissect the complex biology underpinning them. Here, we perform a protein quantitative trait locus (pQTL) analysis of 255 serum proteins relevant to cardiometabolic processes in individuals. Meta-analysing whole-genome sequencing (WGS) data from two Greek cohorts, MANOLIS (n = ; 22.5x WGS) and Pomak (n = ; 18.4x WGS), we detect 302 independently-associated pQTL variants for 171 proteins, including 12 rare variants (minor allele frequency [MAF] < 1%). We additionally find 15 pQTL variants that are rare in non-Finnish European populations, but have drifted up in frequency in the discovery cohorts here. We identify proteins causally associated with cardiometabolic traits, including MEP1B for high-density lipoprotein levels; and describe a knock-out Mep1b mouse model. Our findings furnish insights into the genetic architecture of the serum proteome, identify new protein-disease relationships, and demonstrate the importance of isolated populations in pQTL analysis. Png, Grace Gerlini, Raffaele Hatzikotoulas, Konstantinos Barysenka, Andrei Rayner, N William Klaric, Lucija Rathkolb, Birgit Aguilar-Pimentel, Juan A Rozman, Jan Fuchs, Helmut Gailus-Durner, Valerie Tsafantakis, Emmanouil Karaleftheri, Maria Dedoussis, George Pietrzik, Claus Wilson, James F Angelis, Martin Hrabe Becker-Pauly, Christoph Gilly, Arthur Zeggini, Eleftheria eng England Hum Mol Genet. Nov 9:ddac275. doi: 10./hmg/ddac275.I SomaScan 11/10/ Aerqin Q, et al. Omics-based biomarkers discovery for Alzheimer's disease Cell Mol Life Sci 79 12 585 https://www.doi.org/10./s-022--6 36,348,101 Humans *Alzheimer Disease/diagnosis/genetics/pathology Metabolomics Biomarkers Proteomics Genomics Alzheimer's disease Epigenomics Transcriptomics Alzheimer's disease (AD) is the most common neurodegenerative disorders presenting with the pathological hallmarks of amyloid plaques and tau tangles. Over the past few years, great efforts have been made to explore reliable biomarkers of AD. High-throughput omics are a technology driven by multiple levels of unbiased data to detect the complex etiology of AD, and it provides us with new opportunities to better understand the pathophysiology of AD and thereby identify potential biomarkers. Through revealing the interaction networks between different molecular levels, the ultimate goal of multi-omics is to improve the diagnosis and treatment of AD. In this review, based on the current AD pathology and the current status of AD diagnostic biomarkers, we summarize how genomics, transcriptomics, proteomics and metabolomics are all conducing to the discovery of reliable AD biomarkers that could be developed and used in clinical AD management. Aerqin, Qiaolifan Wang, Zuo-Teng Wu, Kai-Min He, Xiao-Yu Dong, Qiang Yu, Jin-Tai eng /National Natural Science Foundation of China/ /National Natural Science Foundation of China/ No.SHZDZX01/Shanghai Municipal Science and Technology Major Project/ QD002/Doctoral Scientific Research Start-up Foundation from Henan University of Technology/ /Excellence Talent Cultivation Program at Fudan University/ Review Switzerland Cell Mol Life Sci. Nov 8;79(12):585. doi: 10./s-022--6.I SomaScan 11/09/ Lin X, et al. Novel plasma and brain proteins that are implicated in multiple sclerosis Brain epub ahead of print https://www.doi.org/10./brain/awac420 36,346,149 Multiple sclerosis biomarkers proteomics transcriptomics Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for multiple sclerosis. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3,301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14,802 cases and 26,703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31,684) and brain (n = 1,194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (dataset 1: n = 73 cases and 97 controls; dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (dataset 1: n = 4 cases and 5 controls; dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared to controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins, and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development. Lin, Xin Yang, Yuanhao Gresle, Melissa Cuellar-Partida, Gabriel Han, Xikun Stankovich, Jim Fuh-Ngwa, Valery Charlesworth, Jac Burdon, Kathryn P Butzkueven, Helmut Taylor, Bruce V Zhou, Yuan eng England Brain. Nov 8:awac420. doi: 10./brain/awac420.I SomaScan 11/09/ Allam V, et al. Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma Thorax epub ahead of print https://www.doi.org/10./thorax-- 36,344,253 asthma asthma mechanisms cytokine biology have nothing to disclose. EFM reports grants from Janssen, Bristol Myers Squibb, UCB, Merck Serono and Eli Lilly outside the submitted work. In addition, EFM has patents 7,709,514 and 7,863,313 issued. KFC has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Novartis, Merck, Boehringer Ingelheim and TEVA regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. IA and PS report grants from the public private European Union Innovative Medicines Initiative during the conduct of the study. RD reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA consultation for TEVA and Novartis as member of advisory boards and participation in a scientific discussion about asthma organised by GlaxoSmithKline. RD is a cofounder and current consultant and has shares in Synairgen, a University of Southampton spin-out company. BACKGROUND: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma. METHODS: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo. RESULTS: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity. CONCLUSION: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma. Allam, Venkata Sita Rama Raju Pavlidis, Stelios Liu, Gang Kermani, Nazanin Zounemat Simpson, Jennifer To, Joyce Donnelly, Sheila Guo, Yi-Ke Hansbro, Philip M Phipps, Simon Morand, Eric F Djukanovic, Ratko Sterk, Peter Chung, Kian Fan Adcock, Ian Harris, James Sukkar, Maria B eng England Thorax. Nov 7:thoraxjnl--. doi: 10./thorax--.I SomaScan 11/08/ Tarawneh R, et al. Vascular endothelial-cadherin as a marker of endothelial injury in preclinical Alzheimer disease Ann Clin Transl Neurol epub ahead of print https://www.doi.org/10./acn3. 36,342,663 OBJECTIVE: Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD. METHODS: Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n = 700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Abeta42/Abeta40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) (n = 534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD. RESULTS: CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T+/-N+/-; n = 558) or those with amyloid and tau pathologies (A+T+N+/-; n = 259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid-PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Abeta42/Abeta40, p-tau181, and global amyloid burden with cognitive outcomes in preclinical AD. INTERPRETATION: Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages. Tarawneh, Rawan Kasper, Rachel S Sanford, Jessie Phuah, Chia-Ling Hassenstab, Jason Cruchaga, Carlos eng /The Foundation for Barnes-Jewish Hospital/ P50AG/National Institutes of Health and National Institute of Aging/ RF1AG/National Institutes of Health and National Institute of Aging/ Neuro-Genomics and Informatics Center/ P30AG/National Institutes of Health and National Institute of Aging/ Charleston Conference on Alzheimer's Disease/ P01AG/National Institutes of Health and National Institute of Aging/ RF1AG/National Institutes of Health and National Institute of Aging/ Hope Center for Neurological Disorders/ U01AG/National Institutes of Health and National Institute of Aging/ Chan Zuckerberg Initiative/ P19-/Centene Corporation/ R21 AG/AG/NIA NIH HHS/ K23 NS/NS/NINDS NIH HHS/ Washington University-Centene ARCH Personalized Medicine Initiative/ P30NS/National Institutes of Health and National Institute of Aging/ P30 AG/AG/NIA NIH HHS/ P20AG/National Institutes of Health and National Institute of Aging/ P01AG/National Institutes of Health and National Institute of Aging/ R01AG/National Institutes of Health and National Institute of Aging/ P01 AG/AG/NIA NIH HHS/ P50 AG/AG/NIA NIH HHS/ P01 AG/AG/NIA NIH HHS/ University of New Mexico Grand Challenges Initiative/ Washington University School of Medicine/ R21-AG-01A1/National Institutes of Health and National Institute of Aging/ Ann Clin Transl Neurol. Nov 7. doi: 10./acn3..I SomaScan 11/08/ Liu X, et al. Plasma proteomic signature of decline in gait speed and grip strength Aging Cell epub ahead of print e https://www.doi.org/10./acel. 36,333,824 aging gait speed grip strength physical function proteomics The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay plasma proteins on participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in - and participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in -. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (-) and 8 (-) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p = 1.58 x 10(-15) ), pleiotrophin (1.23 x 10(-9) ), and TIMP-1 (5.97 x 10(-8) ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 x 10(-7) ), CDON (2.38 x 10(-7) ), and SMOC1 (7.47 x 10(-7) ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline. Liu, Xiaojuan Pan, Stephanie Xanthakis, Vanessa Vasan, Ramachandran S Psaty, Bruce M Austin, Thomas R Newman, Anne B Sanders, Jason L Wu, Chenkai Tracy, Russell P Gerszten, Robert E Odden, Michelle C eng 75ND/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ NO1-HC-/HL/NHLBI NIH HHS/ R01HL/HL/NHLBI NIH HHS/ U01HL/HL/NHLBI NIH HHS/ U01HL/HL/NHLBI NIH HHS/ R01AG/AG/NIA NIH HHS/ England Aging Cell. Nov 4:e. doi: 10./acel..I SomaScan 11/06/ Zhou L, et al. Integrated proteomic and metabolomic modules identified as biomarkers of mortality in the Atherosclerosis Risk in Communities study and the African American Study of Kidney Disease and Hypertension Hum Genomics 16 1 53 https://www.doi.org/10./s-022--9 36,329,547 Humans Aged Middle Aged African Americans/genetics *Cardiovascular Diseases Cross-Sectional Studies Proteomics Risk Factors Biomarkers *Hypertension/epidemiology/genetics Metabolomics *Kidney Diseases *Atherosclerosis/genetics *Diabetes Mellitus Chronic kidney disease Cluster analysis Dimensionality reduction Mortality BACKGROUND: Proteins and metabolites are essential for many biological functions and often linked through enzymatic or transport reactions. Individual molecules have been associated with all-cause mortality. Many of these are correlated and might jointly represent pathways or endophenotypes involved in diseases. RESULTS: We present an integrated analysis of proteomics and metabolomics via a local dimensionality reduction clustering method. We identified 224 modules of correlated proteins and metabolites in the Atherosclerosis Risk in Communities (ARIC) study, a general population cohort of older adults (N = , mean age 75.7, mean eGFR 65). Many of the modules displayed strong cross-sectional associations with demographic and clinical characteristics. In comprehensively adjusted analyses, including fasting plasma glucose, history of cardiovascular disease, systolic blood pressure and kidney function among others, 60 modules were associated with mortality. We transferred the network structure to the African American Study of Kidney Disease and Hypertension (AASK) (N = 694, mean age 54.5, mean mGFR 46) and identified mortality associated modules relevant in this disease specific cohort. The four mortality modules relevant in both the general population and CKD were all a combination of proteins and metabolites and were related to diabetes / insulin secretion, cardiovascular disease and kidney function. Key components of these modules included N-terminal (NT)-pro hormone BNP (NT-proBNP), Sushi, Von Willebrand Factor Type A, EGF And Pentraxin (SVEP1), and several kallikrein proteases. CONCLUSION: Through integrated biomarkers of the proteome and metabolome we identified functions of (patho-) physiologic importance related to diabetes, cardiovascular disease and kidney function. Zhou, Linda Surapaneni, Aditya Rhee, Eugene P Yu, Bing Boerwinkle, Eric Coresh, Josef Grams, Morgan E Schlosser, Pascal eng K24 HL/HL/NHLBI NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Hum Genomics. Nov 3;16(1):53. doi: 10./s-022--9.I SomaScan 11/05/ Omenn GS, et al. The Report on the Human Proteome from the HUPO Human Proteome Project J Proteome Res epub ahead of print https://www.doi.org/10./acs.jproteome.2c 36,318,223 Biology and Disease-HPP (B/D-HPP) Grand Challenge Project Human Protein Atlas Human Proteome Project (HPP) Mass Spectrometry Interactive Virtual Environment (MassIVE) PeptideAtlas Ribo-Seq chromosome-centric HPP (C-HPP) missing proteins (MP) neXtProt protein existence (PE metrics) non-MS PE1 proteins small open reading frames (smORFs) uncharacterized protein existence 1 (uPE1) The Metrics of the Human Proteome from the HUPO Human Proteome Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18_407 (93.2%) of the 19_750 predicted proteins coded in the human genome, a net gain of 50 since from data sets generated around the world and reanalyzed by the HPP. Conversely, the number of neXtProt PE2, PE3, and PE4 missing proteins has been reduced by 78 from to . This represents continuing experimental progress on the human proteome parts list across all the chromosomes, as well as significant reclassifications. Meanwhile, applying proteomics in a vast array of biological and clinical studies continues to yield significant findings and growing integration with other omics platforms. We present highlights from the Chromosome-Centric HPP, Biology and Disease-driven HPP, and HPP Resource Pillars, compare features of mass spectrometry and Olink and Somalogic platforms, note the emergence of translation products from ribosome profiling of small open reading frames, and discuss the launch of the initial HPP Grand Challenge Project, A Function for Each Protein"." Omenn, Gilbert S Lane, Lydie Overall, Christopher M Pineau, Charles Packer, Nicolle H Cristea, Ileana M Lindskog, Cecilia Weintraub, Susan T Orchard, Sandra Roehrl, Michael H A Nice, Edouard Liu, Siqi Bandeira, Nuno Chen, Yu-Ju Guo, Tiannan Aebersold, Ruedi Moritz, Robert L Deutsch, Eric W eng Review J Proteome Res. Nov 1. doi: 10./acs.jproteome.2c.I SomaScan 11/02/ Hyland PL, et al. Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNbeta-1a Biologics Clin Pharmacol Ther epub ahead of print https://www.doi.org/10./cpt. 36,308,070 Proteomics has the potential to identify pharmacodynamic (PD) biomarkers for similarity assessment of proposed biosimilars without relying on clinical efficacy end points. In this study, with 36 healthy participants randomized to therapeutic doses of interferon-beta 1a products (IFNbeta-1a) or pegylated-IFNbeta-1a (pegIFNbeta-1a) approved to treat multiple sclerosis or placebo, we evaluated the utility of a proteomic assay that profiles > 7,000 plasma proteins. IFNbeta-1a and pegIFNbeta-1a resulted in 248 and 528 differentially expressed protein analytes, respectively, between treatment and placebo groups over the time course. Thirty-one proteins were prioritized based on a maximal fold change >/= 2 from baseline, baseline adjusted area under the effect curve (AUEC) and overlap between the 2 products. Of these, the majority had a significant AUEC compared with placebo in response to either product; 8 proteins showed > 4-fold maximal change from baseline. We identified previously reported candidates, beta-2microglobulin and interferon-induced GTP-binding protein (Mx1) with ~ 50% coefficient of variation (CV) for AUEC, and many new candidates (including I-TAC, C1QC, and IP-10) with CVs ranging from 26%-129%. Upstream regulator analysis of differentially expressed proteins predicted activation of IFNbeta1 signaling as well as other cytokine, enzyme, and transcription signaling networks by both products. Although independent replication is required to confirm present results, our study demonstrates the utility of proteomics for the identification of individual and composite candidate PD biomarkers that may be leveraged to support clinical pharmacology studies for biosimilar approvals, especially when biologics have complex mechanisms of action or do not have previously characterized PD biomarkers. Hyland, Paula L Chekka, Lakshmi Manasa S Samarth, Deepti P Rosenzweig, Barry A Decker, Erica Mohamed, Esraa G Guo, Yan Matta, Murali K Sun, Qin Wheeler, William Sanabria, Carlos Weaver, James L Schrieber, Sarah J Florian, Jeffry Wang, Yow-Ming Strauss, David G eng Clin Pharmacol Ther. Oct 29. doi: 10./cpt..I SomaScan 10/30/ Butler AE, et al. Components of the Complement Cascade Differ in Polycystic Ovary Syndrome Int J Mol Sci 23 20 https://www.doi.org/10./ijms 36,293,087 Female Humans Properdin/metabolism Complement Factor H Complement Factor B/metabolism *Mannose-Binding Lectin CD55 Antigens *Polycystic Ovary Syndrome Complement Factor D *Insulin Resistance Cohort Studies Proteomics Complement C1q Complement C3b Fibrinogen Cytokines C3 complement factors factor B polycystic ovary syndrome properdin Complement pathway proteins are reported to be increased in polycystic ovary syndrome (PCOS) and may be affected by obesity and insulin resistance. To investigate this, a proteomic analysis of the complement system was undertaken, including inhibitory proteins. In this cohort study, plasma was collected from 234 women (137 with PCOS and 97 controls). SOMALogic proteomic analysis was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, factor B, factor D, factor H, factor I, mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5). The alternative pathway of the complement system was primarily overexpressed in PCOS, with increased C3 (p < 0.05), properdin and factor B (p < 0.01). In addition, inhibition of this pathway was also seen in PCOS, with an increase in CFHR5, factor H and factor I (p < 0.01). Downstream complement factors iC3b and C3d, associated with an enhanced B cell response, and C5a, associated with an inflammatory cytokine release, were increased (p < 0.01). Hyperandrogenemia correlated positively with properdin and iC3b, whilst insulin resistance (HOMA-IR) correlated with iC3b and factor H (p < 0.05) in PCOS. BMI correlated positively with C3d, factor B, factor D, factor I, CFHR5 and C5a (p < 0.05). This comprehensive evaluation of the complement system in PCOS revealed the upregulation of components of the complement system, which appears to be offset by the concurrent upregulation of its inhibitors, with these changes accounted for in part by BMI, hyperandrogenemia and insulin resistance. Butler, Alexandra E Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L eng Switzerland Int J Mol Sci. Oct 13;23(20):. doi: 10./ijms.I SomaScan 10/28/ Wen D, et al. Testican-2 is Associated with Reduced Risk of Incident ESKD J Am Soc Nephrol epub ahead of print https://www.doi.org/10./ASN. 36,288,905 Background: Testican-2 was recently identified as a podocyte-derived protein that is released into circulation by the kidneys and is positively correlated with estimated glomerular filtration rate (eGFR) and eGFR slope. However, whether higher testican-2 levels are associated with lower risk of end stage kidney disease (ESKD) is unknown. Methods: Aptamer-based proteomics assessed blood testican-2 levels among participants in the African American Study of Kidney Disease and Hypertension (AASK, n=703), the Chronic Renal Insufficiency Cohort (CRIC) study (n=3,196), and the Atherosclerosis Risk in Communities (ARIC) study (n=4,378). We compared baseline characteristics by testican-2 tertile and used Cox proportional hazards models to study the association of testican-2 with incident ESKD. Results: Higher testican-2 levels were associated with higher measured GFR (mGFR) in AASK, higher eGFR in the CRIC and ARIC studies, and lower albuminuria in all cohorts. Baseline testican-2 levels were significantly associated with incident ESKD in Cox proportional hazards models adjusted for age, sex, and race (Model 1) and Model 1 + mGFR or eGFR + comorbidities (Model 2). In Model 3 (Model 2 + proteinuria), the associations between testican-2 (per SD increase) and incident ESKD were: AASK (HR = 0.84 [0.72, 0.98], P = 0.023), CRIC (HR = 0.95 [0.89, 1.02], P = 0.14), ARIC (HR = 0.54 [0.36, 0.83], P = 0.), and meta-analysis (HR = 0.92 [0.86, 0.98], P = 0.). Conclusions: Across three cohorts spanning >8,000 individuals, testican-2 is associated with kidney health and prognosis, with higher levels associated with reduced risk of ESKD. Wen, Donghai Zhou, Linda Zheng, Zihe Surapaneni, Aditya Ballantyne, Christie Hoogeveen, Ron Shlipak, Michael Waikar, Sushrut Vasan, Ramachandra Kimmel, Paul Dubin, Ruth Deo, Rajat Feldman, Harold Ganz, Peter Coresh, Josef Grams, Morgan Rhee, Eugene eng J Am Soc Nephrol. Oct 26:ASN.. doi: 10./ASN..I SomaScan 10/27/ Sveinbjornsson G, et al. Multiomics study of nonalcoholic fatty liver disease Nat Genet 54 11 - https://www.doi.org/10./s-022--5 36,280,732 Humans *Non-alcoholic Fatty Liver Disease/genetics Proteomics Genome-Wide Association Study Liver/metabolism Liver Cirrhosis/genetics/metabolism/pathology *Liver Neoplasms/genetics/metabolism Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options. Sveinbjornsson, Gardar Ulfarsson, Magnus O Thorolfsdottir, Rosa B Jonsson, Benedikt A Einarsson, Eythor Gunnlaugsson, Gylfi Rognvaldsson, Solvi Arnar, David O Baldvinsson, Magnus Bjarnason, Ragnar G Eiriksdottir, Thjodbjorg Erikstrup, Christian Ferkingstad, Egil Halldorsson, Gisli H Helgason, Hannes Helgadottir, Anna Hindhede, Lotte Hjorleifsson, Grimur Jones, David Knowlton, Kirk U Lund, Sigrun H Melsted, Pall Norland, Kristjan Olafsson, Isleifur Olafsson, Sigurdur Oskarsson, Gudjon R Ostrowski, Sisse Rye Pedersen, Ole Birger Snaebjarnarson, Auethunn S Sigurdsson, Emil Steinthorsdottir, Valgerdur Schwinn, Michael Thorgeirsson, Gudmundur Thorleifsson, Gudmar Jonsdottir, Ingileif Bundgaard, Henning Nadauld, Lincoln Bjornsson, Einar S Rulifson, Ingrid C Rafnar, Thorunn Norddahl, Gudmundur L Thorsteinsdottir, Unnur Sulem, Patrick Gudbjartsson, Daniel F Holm, Hilma Stefansson, Kari eng Nat Genet. Nov;54(11):-. doi: 10./s-022--5. Epub Oct 24.I SomaScan 10/26/ Lu T, et al. Circulating Proteins Influencing Psychiatric Disease: A Mendelian Randomization Study Biol Psychiatry epub ahead of print https://www.doi.org/10./j.biopsych..08.015 36,280,454 Blood-brain barrier Circulating proteins Genome-wide association studies Mendelian randomization Psychiatric diseases Quantitative trait loci BACKGROUND: There is a pressing need for novel drug targets for psychiatric disorders. Circulating proteins are potential candidates because they are relatively easy to measure and modulate and play important roles in signaling. METHODS: We performed two-sample Mendelian randomization analyses to estimate the associations between circulating protein abundances and risk of 10 psychiatric disorders. Genetic variants associated with circulating protein abundances identified in 6 large-scale proteomic studies were used as genetic instruments. Effects of the circulating proteins on psychiatric disorders were estimated by Wald ratio or inverse variance-weighted ratio tests. Horizontal pleiotropy, colocalization, and protein-altering effects were examined to validate the assumptions of Mendelian randomization. RESULTS: Nine circulating protein-to-disease associations withstood multiple sensitivity analyses. Among them, 2 circulating proteins had associations replicated in 3 proteomic studies. A 1 standard deviation increase in the genetically predicted circulating TIMP4 level was associated with a reduced risk of anorexia nervosa (minimum odds ratio [OR] = 0.83; 95% CI, 0.76-0.91) and bipolar disorder (minimum OR = 0.88; 95% CI, 0.82-0.94). A 1 standard deviation increase in the genetically predicted circulating ESAM level was associated with an increased risk of schizophrenia (maximum OR = 1.32; 95% CI, 1.22-1.43). In addition, 58 suggestive protein-to-disease associations warrant validation with observational or experimental evidence. For instance, a 1 standard deviation increase in the ERLEC1-201-to-ERLEC1-202 splice variant ratio was associated with a reduced risk of schizophrenia (OR = 0.94; 95% CI, 0.90-0.97). CONCLUSIONS: Prioritized circulating proteins appear to influence the risk of psychiatric disease and may be explored as intervention targets. Lu, Tianyuan Forgetta, Vincenzo Greenwood, Celia M T Zhou, Sirui Richards, J Brent eng Biol Psychiatry. Aug 22:S-(22)-4. doi: 10./j.biopsych..08.015.I SomaScan 10/25/ Mofrad RB, et al. Plasma proteome profiling identifies changes associated to AD but not to FTD Acta Neuropathol Commun 10 1 148 https://www.doi.org/10./s-022--w 36,273,219 Humans Female Middle Aged Aged Male *Frontotemporal Dementia/diagnosis/genetics Proteome Proteomics *Frontotemporal Lobar Degeneration/diagnosis/pathology *Pick Disease of the Brain Biomarkers Ad Alzheimer's disease Ftd Frontotemporal dementia Plasma biomarkers Somascan BACKGROUND: Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. METHODS: Plasma proteins (n = ) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 +/- 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 +/- 7.9; 45% female), AD patients (n = 57; age = 65.5 +/- 8.0; 39% female), and non-demented controls (n = 148; 61.3 +/- 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 +/- 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 +/- 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 +/- 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with resampled analysis. RESULTS: Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. CONCLUSIONS: We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts. Mofrad, R Babapour Del Campo, M Peeters, C F W Meeter, L H H Seelaar, H Koel-Simmelink, M Ramakers, I H G B Middelkoop, H A M De Deyn, P P Claassen, J A H R van Swieten, J C Bridel, C Hoozemans, J J M Scheltens, P van der Flier, W M Pijnenburg, Y A L Teunissen, Charlotte E eng /ZONMW_/ZonMw/Netherlands ToBike4Alzheimer/Alzheimer Nederland/ England Acta Neuropathol Commun. Oct 22;10(1):148. doi: 10./s-022--w.I SomaScan 10/24/ Cai Y, et al. Association of mTORC1_dependent circulating protein levels with cataract formation: a mendelian randomization study BMC Genomics 23 1 719 https://www.doi.org/10./s-022--7 36,271,348 Humans *Cataract/genetics Eukaryotic Initiation Factor-4A Eukaryotic Initiation Factor-4E/genetics *Eukaryotic Initiation Factor-4G Genome-Wide Association Study Mechanistic Target of Rapamycin Complex 1/genetics Mendelian Randomization Analysis Polymorphism, Single Nucleotide Sirolimus TOR Serine-Threonine Kinases/genetics Cataract Circulating Eif4ebp Mendelian randomization mTOR BACKGROUND: The mechanistic target of rapamycin (mTOR) signal pathway plays a critical regulating role in the occurrence and development of cataract. However, the role of mTORC1 downstream proteins, including ribosomal protein S6K (RP-S6K), eukaryotic initiation factor 4E-binding protein (EIF4EBP), eukaryotic initiation factor 4G (EIF-4G), eukaryotic initiation factor 4E (EIF-4E), and eukaryotic initiation factor 4A (EIF-4A), in regulating cataract development is still unknown. Herein, we conducted a mendelian randomization (MR) study to understand the function of mTORC1 signaling in the process of cataract development. RESULTS: The causal estimate was evaluated with inverse-variance weighted (IVW) estimate, weighted median estimator, MR-Egger and MR robust adjusted profile score (MR. RAPS). The single-nucleotide polymorphisms (SNPs), P<5 x 10(- 6) and r(2)<0.05, were selected to genetically predict the RP-S6K, EIF4EBP, EIF-4E, EIF-4A, and EIF-4G. We included a total of 26,758 cases and 189,604 controls in this MR study. The study revealed causal association between circulating EIF4EBP (OR 1.09, 95% confidence interval 1.03,1.16, P = 0.004), RP-S6K (OR 1.04, 95% confidence interval 1.01, 1.08, P = 0.02) and cataract formation with IVW estimate. Whereas after correcting outliers, MR robust adjusted profile score (MR. RAPS) shows consistent result with IVW for EIF4EBP (OR = 1.08, 95%CI:1.05-1.11, P = 0.007). The observation strengthened the confidence in the true causal associations. However, no association was found for circulating EIF-4E (OR 1.03, 95% confidence interval 0.97, 1.09, P = 0.31), EIF-4A (OR 1.02, 95% confidence interval 0.98, 1.07, P = 0.34), and EIF-4G (OR 1.02, 95% confidence interval 0.94, 1.01, P = 0.64) levels with cataract formation. No evidence of heterogeneity and unbalanced horizontal pleiotropy was detected. CONCLUSION: The MR study suggests that EIF4EBP is a high-risk factor for cataract development. There may be a potential causal association between the mTORC1/EIF4EBP axis and cataract. This research highlights the potential mechanism for cataract development and a genetic target to prevent as well as treat cataracts. Cai, Yingjun Liu, Kangcheng Wu, Pengfei Yuan, Ruolan He, Fei Zou, Jing eng NO. JJ/Jing Zou/ England BMC Genomics. Oct 21;23(1):719. doi: 10./s-022--7.I SomaScan 10/23/ Than NG, et al. Molecular subclasses of preeclampsia characterized by a longitudinal maternal proteomics study: distinct biomarkers, disease pathways and options for prevention J Perinat Med epub ahead of print https://www.doi.org/10./jpm-- 36,253,935 great obstetrical syndromes liquid biopsy omics personalized medicine prenatal diagnosis screening OBJECTIVES: The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples. METHODS: Proteomic data collected longitudinally from plasma samples of women who developed preeclampsia (n=109) and of controls (n=90) were available from our previous report on 1,125 proteins. Consensus clustering was performed to identify subgroups of patients with preeclampsia based on data from five gestational-age intervals by using select interval-specific features. Demographic, clinical, and proteomic differences among clusters were determined. Differentially abundant proteins were used to identify cluster-specific perturbed KEGG pathways. RESULTS: Four molecular clusters with different clinical phenotypes were discovered by longitudinal proteomic profiling. Cluster 1 involves metabolic and prothrombotic changes with high rates of early-onset preeclampsia and small-for-gestational-age neonates; Cluster 2 includes maternal anti-fetal rejection mechanisms and recurrent preeclampsia cases; Cluster 3 is associated with extracellular matrix regulation and comprises cases of mostly mild, late-onset preeclampsia; and Cluster 4 is characterized by angiogenic imbalance and a high prevalence of early-onset disease. CONCLUSIONS: This study is an independent validation and further refining of molecular subclasses of preeclampsia identified by a different proteomic platform and study population. The results lay the groundwork for novel diagnostic and personalized tools of prevention. Than, Nandor Gabor Romero, Roberto Gyorffy, Daniel Posta, Mate Bhatti, Gaurav Done, Bogdan Chaemsaithong, Piya Jung, Eunjung Suksai, Manaphat Gotsch, Francesca Gallo, Dahiana M Bosco, Mariachiara Kim, Bomi Kim, Yeon Mee Chaiworapongsa, Tinnakorn Rossi, Simona W Szilagyi, Andras Erez, Offer Tarca, Adi L Papp, Zoltan eng Germany J Perinat Med. Oct 18. doi: 10./jpm--.I SomaScan 10/19/ Kuiper JJW, et al. A Network of Serum Proteins Predict the Need for Systemic Immunomodulatory Therapy at Diagnosis in Noninfectious Uveitis Ophthalmol Sci 2 3 https://www.doi.org/10./j.xops.. 36,245,752 IMT, immunomodulatory therapy Network-based medicine Neutrophils Noninfectious uveitis Proteomics Systemic immunomodulatory therapy PURPOSE: Early identification of patients with noninfectious uveitis requiring steroid-sparing immunomodulatory therapy (IMT) is currently lacking in objective molecular biomarkers. We evaluated the proteomic signature of patients at the onset of disease and associated proteomic clusters with the need for IMT during the course of the disease. DESIGN: Multicenter cohort study. PARTICIPANTS: Two hundred thirty treatment-free patients with active noninfectious uveitis. METHODS: We used aptamer-based proteomics (n = proteins) and a bioinformatic pipeline as a molecular stratification tool to define the serum protein network of a Dutch discovery cohort (n = 78) of patients and healthy control participants and independently validated our results in another Dutch cohort (n = 111) and a United States cohort (n = 67). Multivariate Cox analysis was used to assess the relationship between the protein network and IMT use. MAIN OUTCOME MEASURES: Serum protein levels and use of IMT. RESULTS: Network-based analyses revealed a tightly coexpressed serum cluster (n = 85 proteins) whose concentration was consistently low in healthy control participants (n = 26), but varied among patients with noninfectious uveitis (n = 52). Patients with high levels of the serum cluster at disease onset showed a significantly increased need for IMT during follow-up, independent of anatomic location of uveitis (hazard ratio, 3.42; 95% confidence interval, 1.22-9.5; P = 0.019). The enrichment of neutrophil-associated proteins in the protein cluster led to our finding that the neutrophil count could serve as a clinical proxy for this proteomic signature (correlation: r = 0.57, P = 0.006). In an independent Dutch cohort (n = 111), we confirmed that patients with relatively high neutrophil count at diagnosis (> 5.2 x 10(9)/L) had a significantly increased chance of requiring IMT during follow-up (hazard ratio, 3.2; 95% confidence interval, 1.5-6.8; P = 0.002). We validated these findings in a third cohort of 67 United States patients. CONCLUSIONS: A serum protein signature correlating with neutrophil levels was highly predictive for IMT use in noninfectious uveitis. We developed a routinely available tool that may serve as a novel objective biomarker to aid in clinical decision-making for noninfectious uveitis. Kuiper, Jonas J W Verhagen, Fleurieke H Hiddingh, Sanne Wennink, Roos A W Hansen, Anna M Casey, Kerry A Hoefer, Imo E Haitjema, Saskia Drylewicz, Julia Yakin, Mehmet Sen, H Nida Radstake, Timothy R D J de Boer, Joke H eng Netherlands Ophthalmol Sci. May 31;2(3):. doi: 10./j.xops... eCollection Sep.I SomaScan 10/18/ Candia J, et al. Assessment of variability in the plasma 7k SomaScan proteomics assay Sci Rep 12 1 https://www.doi.org/10./s-022--0 36,229,504 Biomarkers/metabolism Humans *Proteomics/methods SomaScan is a high-throughput, aptamer-based proteomics assay designed for the simultaneous measurement of thousands of proteins with a broad range of endogenous concentrations. In its most current version, the 7k SomaScan assay v4.1 is capable of measuring human proteins. In this work, we present an extensive technical assessment of this platform based on a study of samples across 22 plates. Included in the study design were inter-plate technical duplicates from 102 human subjects, which allowed us to characterize different normalization procedures, evaluate assay variability by multiple analytical approaches, present signal-over-background metrics, and discuss potential specificity issues. By providing detailed performance assessments on this wide range of technical aspects, we aim for this work to serve as a valuable resource for the growing community of SomaScan users. Candia, Julian Daya, Gulzar N Tanaka, Toshiko Ferrucci, Luigi Walker, Keenan A eng ZIAAG-14/AG/NIA NIH HHS/ ZIAAG-01/AG/NIA NIH HHS/ England Sci Rep. Oct 13;12(1):. doi: 10./s-022--0.I SomaScan 10/14/ Moin ASM, et al. The severity and duration of Hypoglycemia affect platelet-derived protein responses in Caucasians Cardiovasc Diabetol 21 1 202 https://www.doi.org/10./s-022--w 36,203,210 Blood Glucose/metabolism CD40 Ligand *Diabetes Mellitus, Type 2/diagnosis Humans *Hypoglycemia Plasminogen Plasminogen Activator Inhibitor 1 Thromboplastin von Willebrand Factor Hypoglycemia Inflammation Platelet-associated proteins Type 2 diabetes conflict of interest or competing interests to declare. OBJECTIVE: Severe hypoglycemia is associated with increased cardiovascular death risk, and platelet responses to hypoglycemia (hypo) have been described. However, the impact of deep transient hypo (deep-hypo) versus prolonged milder hypo (mild-hypo) on platelet response is unclear. RESEARCH DESIGN AND METHODS: Two hypo studies were compared; firstly, mild-hypo in 18-subjects (10 type-2-diabetes (T2D), 8 controls), blood glucose to 2.8mmoL/L (50 mg/dL) for 1-hour; secondly deep-hypo in 46-subjects (23 T2D, 23 controls), blood glucose to < 2.2mmoL/L (< 40 mg/dL) transiently. Platelet-related protein (PRP) responses from baseline to after 1-hour of hypo (mild-hypo) or at deep-hypo were compared, and at 24-hours post-hypo. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was used to determine PRP changes for 13 PRPs. RESULTS: In controls, from baseline to hypo, differences were seen for four PRPs, three showing increased %change in deep-hypo (Plasminogen activator inhibitor-1(PAI-1), CD40 ligand (CD40LG) and Protein-S), one showing increased %change in mild-hypo (von Willebrand factor (vWF)); at 24-hours in controls, %change for Protein-S remained increased in deep-hypo, whilst % change for vWF and plasminogen were increased in mild-hypo. In T2D, from baseline to hypo, differences were seen for 4 PRPs, three showing increased %change in deep-hypo (PAI-1, platelet glycoprotein VI and Tissue factor), one showing increased %change in mild-hypo (CD40LG); at 24-hours in T2D, %change for CD40LG remained increased, together with vWF, in deep-hypo. CONCLUSION: Both mild-hypo and deep-hypo showed marked PRP changes that continued up to 24-hours, showing that both the severity and duration of hypoglycemia are likely important and that any degree of hypoglycemia may be detrimental for increased cardiovascular risk events through PRP changes. Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng England Cardiovasc Diabetol. Oct 6;21(1):202. doi: 10./s-022--w.I SomaScan 10/07/ Kivimaki M, et al. Comment on A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk"" Sci Transl Med 14 665 eabq https://www.doi.org/10./scitranslmed.abq 36,197,964 *Decision Making *Proteomics A 27-protein signature has been proposed to predict cardiovascular disease, but its applicability in clinical decision-making remains unclear. Kivimaki, Mika Hingorani, Aroon D Lindbohm, Joni V eng /Z/20/Z/WT_/Wellcome Trust/United Kingdom MR/R/1/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom Comment Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sci Transl Med. Oct 5;14(665):eabq. doi: 10./scitranslmed.abq. Epub Oct 5.I SomaScan 10/06/ Williams SA, et al. Response to comment on A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk"" Sci Transl Med 14 665 eadd https://www.doi.org/10./scitranslmed.add 36,197,965 *Cardiovascular Diseases *Decision Making Humans Proteomics A 27-protein signature has been proposed to predict cardiovascular disease, and its applicability in some clinical decision-making situations is discussed. Williams, Stephen A Ganz, Peter eng Comment Sci Transl Med. Oct 5;14(665):eadd. doi: 10./scitranslmed.add. Epub Oct 5.I SomaScan 10/06/ Steffen BT, et al. Proteomic analysis of diabetes genetic risk scores identifies complement C2 and neuropilin-2 as predictors of type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) Study Diabetologia epub ahead of print https://www.doi.org/10./s-022--7 36,194,249 Beta cell Diabetes Genetic risk score Insulin resistance Mendelian Proteomics AIMS/HYPOTHESIS: Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology. METHODS: Using a proteomics data-driven approach in a discovery sample of White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of Black ARIC participants, we interrogated plasma levels of proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined. RESULTS: Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein-GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p=7.0 x 10(-3)), while neuropilin-2 was inversely associated (OR 0.44 per SD; p=8.0 x 10(-3)). CONCLUSIONS/INTERPRETATION: Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets. Steffen, Brian T Tang, Weihong Lutsey, Pamela L Demmer, Ryan T Selvin, Elizabeth Matsushita, Kunihiro Morrison, Alanna C Guan, Weihua Rooney, Mary R Norby, Faye L Pankratz, Nathan Couper, David Pankow, James S eng UL1RR/NH/NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01HL/HL/NHLBI NIH HHS/ U01HG/HG/NHGRI NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ Germany Diabetologia. Oct 4. doi: 10./s-022--7.I SomaScan 10/05/ Blum MF, et al. Renin: Measurements, Correlates, and Associations with Long-Term Adverse Kidney Outcomes Am J Hypertens epub ahead of print https://www.doi.org/10./ajh/hpac112 36,190,914 aptamer chronic kidney disease end stage kidney disease kidney mortality renin BACKGROUND: The association of renin with adverse kidney outcomes is largely unknown, and renin measurement strategies vary. We aimed to measure the clinical correlates of different renin measurements and the association between renin and incident chronic kidney disease (CKD), end-stage kidney disease (ESKD), and mortality. METHODS: We performed a prospective cohort analysis participants in the Atherosclerosis Risk in Communities (ARIC) study followed from - through . We estimated longitudinal associations of renin measured using SomaScan modified nucleotide aptamer assay with incident CKD, ESKD, and death using Cox proportional hazards models. Using samples from a subsequent study visit, we compared SomaScan renin with plasma renin activity (PRA) and renin level from Olink, and estimated associations with covariates using univariate and multivariable regression. RESULTS: Higher SomaScan renin levels were associated with higher risk of incident CKD (hazard ratio per two-fold higher [HR], 1.14; 95% confidence interval [CI], 1.09 to 1.20), ESKD (HR, 1.20; 95% CI, 1.03 to 1.41), and mortality (HR, 1.08; 95% CI, 1.04 to 1.13) in analyses adjusted for demographic, clinical, and socioeconomic covariates. SomaScan renin was moderately correlated with PRA (r=0.61) and highly correlated with Olink renin (r=0.94). SomaScan renin and PRA had similar clinical correlates except for divergent associations with age and beta blocker use, both of which correlated positively with SomaScan renin but negatively with PRA. CONCLUSIONS: SomaScan aptamer-based renin level was associated with higher risk of CKD, ESKD, and mortality. It was moderately correlated with PRA, sharing generally similar clinical covariate associations. Blum, Matthew F Chen, Jingsha Surapaneni, Aditya Turner, Stephen T Ballantyne, Christie M Welling, Paul A Kottgen, Anna Coresh, Josef Crews, Deidra C Grams, Morgan E eng Am J Hypertens. Oct 3:hpac112. doi: 10./ajh/hpac112.I SomaScan 10/04/ Cullell N, et al. Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study Clin Epigenetics 14 1 124 https://www.doi.org/10./s-022--5 36,180,927 *Brain Ischemia/genetics CpG Islands DNA Methylation Epigenesis, Genetic Epigenome Genome-Wide Association Study Humans Rna *Stroke/genetics c-Mer Tyrosine Kinase/genetics BACKGROUND AND PURPOSE: The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke. METHODS: We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (DeltaNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10(-06)) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH. RESULTS: The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8.4 x 10(-08)) and in MERTK (p value = 1.56 x 10(-07)). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 x 10(-06) and p value = 1.3 x 10(-02), respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = - 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = - 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells. CONCLUSIONS: DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation. Cullell, Natalia Soriano-Tarraga, Carolina Gallego-Fabrega, Cristina Carcel-Marquez, Jara Muino, Elena Llucia-Carol, Laia Lledos, Miquel Esteller, Manel de Moura, Manuel Castro Montaner, Joan Rosell, Anna Delgado, Pilar Marti-Fabregas, Joan Krupinski, Jerzy Roquer, Jaume Jimenez-Conde, Jordi Fernandez-Cadenas, Israel eng Meta-Analysis Research Support, Non-U.S. Gov't Germany Clin Epigenetics. Sep 30;14(1):124. doi: 10./s-022--5.I SomaScan 10/01/ Moore HB, et al. Proteomics of Coagulopathy Following Injury Reveals Limitations of Using Laboratory Assessment to Define Trauma-Induced Coagulopathy to Predict Massive Transfusion Ann Surg Open 3 2 e167 https://www.doi.org/10./as9. 36,177,090 OBJECTIVE: Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgement) are sufficient to capture the majority of protein changes associated with MT. METHODS: Eight level-I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR >1.5 (INR-TIC), TEG maximum amplitude 10 units of red blood cells in 24 hours or > 4 units RBC/hour during the first 4 hr. SomaLogic proteomic analysis of 1,305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified. RESULTS: Patients (n=211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway. CONCLUSION: These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment. Moore, Hunter B Neal, Matthew D Bertolet, Marnie Joughin, Brian A Yaffe, Michael B Barrett, Christopher D Bird, Molly A Tracy, Russell P Moore, Ernest E Sperry, Jason L Zuckerbraun, Brian S Park, Myung S Cohen, Mitchell J Wisniewski, Stephen R Morrissey, James H eng R00 HL/HL/NHLBI NIH HHS/ R35 GM/GM/NIGMS NIH HHS/ R35 HL/HL/NHLBI NIH HHS/ K99 HL/HL/NHLBI NIH HHS/ UM1 HL/HL/NHLBI NIH HHS/ Ann Surg Open. Jun;3(2):e167. doi: 10./as9.. Epub May 25.I SomaScan 10/01/ Butler-Laporte G, et al. The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals Clin Proteomics 19 1 34 https://www.doi.org/10./s-022--z 36,171,541 Covid-19 Immunity Proteomics SOMAscan the Founder of 5 Prime Sciences. The Lady Davis Institute has previously received funding from GlaxoSmithKline, Eli Lilly, and Biogen for research programs at Dr. Richards' laboratory unrelated to this manuscript. C.P. and M.H. are employees of SomaLogic. INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 x 10(-4)). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection. Butler-Laporte, Guillaume Gonzalez-Kozlova, Edgar Su, Chen-Yang Zhou, Sirui Nakanishi, Tomoko Brunet-Ratnasingham, Elsa Morrison, David Laurent, Laetitia Afilalo, Jonathan Afilalo, Marc Henry, Danielle Chen, Yiheng Carrasco-Zanini, Julia Farjoun, Yossi Pietzner, Maik Kimchi, Nofar Afrasiabi, Zaman Rezk, Nardin Bouab, Meriem Petitjean, Louis Guzman, Charlotte Xue, Xiaoqing Tselios, Chris Vulesevic, Branka Adeleye, Olumide Abdullah, Tala Almamlouk, Noor Moussa, Yara DeLuca, Chantal Duggan, Naomi Schurr, Erwin Brassard, Nathalie Durand, Madeleine Del Valle, Diane Marie Thompson, Ryan Cedillo, Mario A Schadt, Eric Nie, Kai Simons, Nicole W Mouskas, Konstantinos Zaki, Nicolas Patel, Manishkumar Xie, Hui Harris, Jocelyn Marvin, Robert Cheng, Esther Tuballes, Kevin Argueta, Kimberly Scott, Ieisha Greenwood, Celia M T Paterson, Clare Hinterberg, Michael Langenberg, Claudia Forgetta, Vincenzo Mooser, Vincent Marron, Thomas Beckmann, Noam Kenigsberg, Ephraim Charney, Alexander W Kim-Schulze, Seunghee Merad, Miriam Kaufmann, Daniel E Gnjatic, Sacha Richards, J Brent eng England Clin Proteomics. Sep 28;19(1):34. doi: 10./s-022--z.I SomaScan 09/29/ Thareja G, et al. Differences and commonalities in the genetic architecture of protein quantitative trait loci in European and Arab populations Hum Mol Genet epub ahead of print https://www.doi.org/10./hmg/ddac243 36,168,886 Polygenic scores (PGS) can identify individuals at risk of adverse health events and guide genetics-based personalized medicine. However, it is not clear how well PGS translate between different populations, limiting their application to well-studied ethnicities. Proteins are intermediate traits linking genetic predisposition and environmental factors to disease, with numerous blood circulating protein levels representing functional readouts of disease-related processes. We hypothesized that studying the genetic architecture of a comprehensive set of blood-circulating proteins between a European and an Arab population could shed fresh light on the translatability of PGS to understudied populations. We therefore conducted a genome-wide association study with whole-genome sequencing data using proteins measured on the SOMAscan aptamer-based affinity proteomics platform in samples of Qatar Biobank and evaluated the replication of protein quantitative traits (pQTLs) from European studies in an Arab population. Then, we investigated the colocalization of shared pQTL signals between the two populations. Finally, we compared the performance of protein PGS derived from a Caucasian population in a European and an Arab cohort. We found that the majority of shared pQTL signals (81.8%) colocalized between both populations. About one-third of the genetic protein heritability was explained by protein PGS derived from a European cohort, with protein PGS performing ~ 20% better in Europeans when compared to Arabs. Our results are relevant for the translation of PGS to non-Caucasian populations, as well as for future efforts to extend genetic research to understudied populations. Thareja, Gaurav Belkadi, Aziz Arnold, Matthias Albagha, Omar M E Graumann, Johannes Schmidt, Frank Grallert, Harald Peters, Annette Gieger, Christian Consortium, The Qatar Genome Program Research Suhre, Karsten eng England Hum Mol Genet. Sep 28:ddac243. doi: 10./hmg/ddac243.I SomaScan 09/29/ Serban KA, et al. Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease EBioMedicine 84 https://www.doi.org/10./j.ebiom.. 36,155,958 Biomarkers Humans Myosins Pharmaceutical Preparations *Pulmonary Disease, Chronic Obstructive/diagnosis/etiology *Pulmonary Emphysema/diagnosis/etiology *Somatomedins *alpha 1-Antitrypsin Deficiency/complications/diagnosis/genetics Alpha-1 antitrypsin deficiency Emphysema Plasma biomarker Protein score SomaScan Committee, Alpha-1 Foundation Medical Advisory and Scientific Committee, ATS - RCMB Website Committee, National Jewish Health IBC committee (all unpaid) KAP does not report any potential conflict of interest CS reports grants or contracts from Adverum, Arrowhead, AstraZeneca, CSA Medical, Grifols, Nuvaira, Takeda, Vertex consulting fees from AstraZenca, Dicerna, Glaxo Smith Kline, Inhibrx, Morair, UpToDate, Vertex has received honoraria for presentations from the American Thoracic Society has received support for travel from CSL Behring serves as the Medical Director for AlphaNet RAS reports grants or contracts from Vertex, NIH/NCATS, Alpha-1 Foundation, consulting fees from Grifols, CSL Behring, Vertex, Intellia, Inhibrx, Takeda, Evolve Biologics, has received travel support from CSL Behring has served on the Advisory Board of Arrowhead Pharmaceuticals, and serves as the Medical Director for AlphaNet and on the board of directors for Global Implementation Solutions, Osteogenesis Imperfecta Foundation, Alpha-1 Foundation, and AlphaNet AMT reports grants or contracts from Vertex, Grifols, and CSl Behring has received consulting fees from CSL Behring, Inhibrix, Z-factor, and Takeda, has received honoraria for lectures from Glaxo Smith Kline and AstraZeneca TB does not report any potential conflict of interest DAS does not report any potential conflict of interest LM does not report any potential conflict of interest NH does not report any potential conflict of interest EKS reports grants or contracts from Glaxo Smith Kline, Bayer BDH does not report any potential conflict of interest CPH reports grants or contracts from Alpha-1 Foundation, Bayer, Boehringer-Ingelheim, and Vertex, consulting fees from AstraZeneca and Takeda DLD has received honoraria for lectures from Novartis and financial support from Bayer towards the institution MHC reports grants or contracts from Glaxo Smith Kline, Bayer, consulting fees from AstraZeneca and Genentech, honoraria for presentations from Illumina, RPB does not report any potential conflict of interest. BACKGROUND: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. METHODS: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. FINDINGS: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. INTERPRETATION: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. FUNDING: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL and U01 HL from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL. GRADS was supported by Award U01HL, U01 HL from the National Heart, Lung, and Blood Institute, and UL1TRR to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. Serban, K A Pratte, K A Strange, C Sandhaus, R A Turner, A M Beiko, T Spittle, D A Maier, L Hamzeh, N Silverman, E K Hobbs, B D Hersh, C P DeMeo, D L Cho, M H Bowler, R P eng K08 HL/HL/NHLBI NIH HHS/ Meta-Analysis Netherlands EBioMedicine. Oct;84:. doi: 10./j.ebiom... Epub Sep 22.I SomaScan 09/27/ Tarca AL, et al. Human Plasma Proteome During Normal Pregnancy J Proteome Res 21 11 - https://www.doi.org/10./acs.jproteome.2c 36,154,181 Humans Pregnancy Female *Proteome/genetics/metabolism *Placenta/metabolism Longitudinal Studies Gestational Age aptamer biomarker machine learning proteomic standards single-cell RNA signature The human plasma proteome is underexplored despite its potential value for monitoring health and disease. Herein, using a recently developed aptamer-based platform, we profiled proteins in 528 plasma samples from 91 normal pregnancies (Gene Expression Omnibus identifier GSE). The coefficient of variation was <20% for 93% of analytes (median 7%), and a cross-platform correlation for selected key angiogenic and anti-angiogenic proteins was significant. Gestational age was associated with changes in 953 proteins, including highly modulated placenta- and decidua-specific proteins, and they were enriched in biological processes including regulation of growth, angiogenesis, immunity, and inflammation. The abundance of proteins corresponding to RNAs specific to populations of cells previously described by single-cell RNA-Seq analysis of the placenta was highly modulated throughout gestation. Furthermore, machine learning-based prediction of gestational age and of time from sampling to term delivery compared favorably with transcriptomic models (mean absolute error of 2 weeks). These results suggested that the plasma proteome may provide a non-invasive readout of placental cellular dynamics and serve as a blueprint for investigating obstetrical disease. Tarca, Adi L Romero, Roberto Bhatti, Gaurav Gotsch, Francesca Done, Bogdan Gudicha, Dereje W Gallo, Dahiana M Jung, Eunjung Pique-Regi, Roger Berry, Stanley M Chaiworapongsa, Tinnakorn Gomez-Lopez, Nardhy eng J Proteome Res. Nov 4;21(11):-. doi: 10./acs.jproteome.2c. Epub Sep 26.I SomaScan 09/27/ Abdelhamid SS, et al. Multi-Omic Admission-Based Prognostic Biomarkers Identified by Machine Learning Algorithms Predict Patient Recovery and 30-Day Survival in Trauma Patients Metabolites 12 9 774 https://www.doi.org/10./metabo 36,144,179 biomarkers machine learning multi-omics prognostic proteomics trauma equity stake in Haima Therapeutics. He has received research support and/or honoraria from Haemonetics, Instrumentation Laboratories, Janssen Pharmaceuticals, and Meredian. T.R.B. is a stakeholder in Immunetrics. Other authors declare no conflict of interests. Admission-based circulating biomarkers for the prediction of outcomes in trauma patients could be useful for clinical decision support. It is unknown which molecular classes of biomolecules can contribute biomarkers to predictive modeling. Here, we analyzed a large multi-omic database of over markers (proteomics, metabolomics, and lipidomics) to identify prognostic biomarkers in the circulating compartment for adverse outcomes, including mortality and slow recovery, in severely injured trauma patients. Admission plasma samples from patients (n = 129) enrolled in the Prehospital Air Medical Plasma (PAMPer) trial were analyzed using mass spectrometry (metabolomics and lipidomics) and aptamer-based (proteomics) assays. Biomarkers were selected via Least Absolute Shrinkage and Selection Operator (LASSO) regression modeling and machine learning analysis. A combination of five proteins from the proteomic layer was best at discriminating resolvers from non-resolvers from critical illness with an Area Under the Receiver Operating Characteristic curve (AUC) of 0.74, while 26 multi-omic features predicted 30-day survival with an AUC of 0.77. Patients with traumatic brain injury as part of their injury complex had a unique subset of features that predicted 30-day survival. Our findings indicate that multi-omic analyses can identify novel admission-based prognostic biomarkers for outcomes in trauma patients. Unique biomarker discovery also has the potential to provide biologic insights. Abdelhamid, Sultan S Scioscia, Jacob Vodovotz, Yoram Wu, Junru Rosengart, Anna Sung, Eunseo Rahman, Syed Voinchet, Robert Bonaroti, Jillian Li, Shimena Darby, Jennifer L Kar, Upendra K Neal, Matthew D Sperry, Jason Das, Jishnu Billiar, Timothy R eng T32 HL/HL/NHLBI NIH HHS/ R38 HL/HL/NHLBI NIH HHS/ R35 GM/GM/NIGMS NIH HHS/ R35GM/NH/NIH HHS/ DP2AI/National Institute of Allergy and Infectious Diseases/ R35-GM-/NH/NIH HHS/ R35 GM/GM/NIGMS NIH HHS/ DP2 AI/AI/NIAID NIH HHS/ Switzerland Metabolites. Aug 23;12(9):774. doi: 10./metabo.I SomaScan 09/24/ Sproull M, et al. Prediction of Total-Body and Partial-Body Exposures to Radiation Using Plasma Proteomic Expression Profiles Radiat Res epub ahead of print https://www.doi.org/10./RADE-22-.1 36,136,739 There is a need to identify new biomarkers of radiation exposure for not only systemic total-body irradiation (TBI) but also to characterize partial-body irradiation and organ specific radiation injury. In the current study, we sought to develop novel biodosimetry models of radiation exposure using TBI and organ specific partial-body irradiation to only the brain, lung or gut using a multivariate proteomics approach. Subset panels of significantly altered proteins were selected to build predictive models of radiation exposure in a variety of sample cohort configurations relevant to practical field application of biodosimetry diagnostics during future radiological or nuclear event scenarios. Female C57BL/6 mice, 8-15 weeks old, received a single total-body or partial-body dose of 2 or 8 Gy TBI or 2 or 8 Gy to only the lung or gut, or 2, 8 or 16 Gy to only the brain using a Pantak X-ray source. Plasma was collected by cardiac puncture at days 1, 3 and 7 postirradiation for total-body exposures and only the lung and brain exposures, and at days 3, 7 and 14 postirradiation for gut exposures. Plasma was then screened using the aptamer-based SOMAscan proteomic assay technology, for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers which demonstrated significant changes (P < 0.01) in expression after irradiation were used to build predictive models of radiation exposure using different sample cohorts. Model 1 compared controls vs. all pooled irradiated samples, which included TBI and all organ specific partial irradiation. Model 2 compared controls vs. TBI vs. partial irradiation (with all organ specific partial exposure pooled within the partial-irradiated group), and model 3 compared controls vs. each individual organ specific partial-body exposure separately (brain, gut and lung). Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay for all samples. Each model algorithm built using a unique sample cohort was validated with a training set of samples and tested with a separate new sample series. Overall predictive accuracies of 89%, 78% and 55% resulted for models 1-3, respectively, representing novel predictive panels of radiation responsive proteomic biomarkers. Though relatively high overall predictive accuracies were achieved for models 1 and 2, all three models showed limited accuracy at differentiating between the controls and partial-irradiated body samples. In our study we were able to identify novel panels of radiation responsive proteins useful for predicting radiation exposure and to create predictive models of partial-body exposure including organ specific radiation exposures. This proof-of-concept study also illustrates the inherent physiological limitations of distinguishing between small-body exposures and the unirradiated using proteomic biomarkers of radiation exposure. As use of biodosimetry diagnostics in future mass casualty settings will be complicated by the heterogeneity of partial-body exposure received in the field, further work remains in adapting these diagnostic tools for practical use. Sproull, M Kawai, T Krauze, A Shankavaram, U Camphausen, K eng Radiat Res. Sep 22. doi: 10./RADE-22-.1.I SomaScan 09/23/ Javaheri A, et al. Proteomic Analysis of Effects of Spironolactone in Heart Failure With Preserved Ejection Fraction Circ Heart Fail 15 9 e https://www.doi.org/10./CIRCHEARTFAILURE.121. 36,126,144 Apelin/pharmacology/therapeutic use *Biological Products/pharmacology/therapeutic use Caspases/pharmacology/therapeutic use *Heart Failure Humans *Insulins/therapeutic use Liver X Receptors Mineralocorticoid Receptor Antagonists/therapeutic use Phospholipid Transfer Proteins/pharmacology/therapeutic use Proteome Proteomics Spironolactone/adverse effects Stroke Volume/physiology Treatment Outcome Americas caspase glycoprotein heart failure spironolactone BACKGROUND: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed. METHODS: We conducted aptamer-based proteomic analysis utilizing modified aptamers to unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone. RESULTS: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone, P<0.). The top canonical pathways that were significantly associated with spironolactone were apelin signaling, stellate cell activation, glycoprotein 6 signaling, atherosclerosis signaling, liver X receptor activation, and farnesoid X receptor activation. Among the top pathways, collagens were a consistent theme that increased in patients receiving placebo but decreased in patients randomized to spironolactone. CONCLUSIONS: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration. Javaheri, Ali Diab, Ahmed Zhao, Lei Qian, Chenao Cohen, Jordana B Zamani, Payman Kumar, Anupam Wang, Zhaoqing Ebert, Christina Maranville, Joseph Kvikstad, Erika Basso, Michael van Empel, Vanessa Richards, A Mark Doughty, Robert N Rietzschel, Ernst Kammerhoff, Karl Gogain, Joseph Schafer, Peter Seiffert, Dietmar A Gordon, David A Ramirez-Valle, Francisco Mann, Douglas L Cappola, Thomas P Chirinos, Julio A eng R01 HL/HL/NHLBI NIH HHS/ U01 TR/TR/NCATS NIH HHS/ R03 HL/HL/NHLBI NIH HHS/ K24 AG/AG/NIA NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R56 HL/HL/NHLBI NIH HHS/ R01 AG/AG/NIA NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ K08 HL/HL/NHLBI NIH HHS/ R33 HL/HL/NHLBI NIH HHS/ P01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circ Heart Fail. Sep;15(9):e. doi: 10./CIRCHEARTFAILURE.121.. Epub Aug 9.I SomaScan 09/21/ Moin ASM, et al. Inflammatory Markers in Non-Obese Women with Polycystic Ovary Syndrome Are Not Elevated and Show No Correlation with Vitamin D Metabolites Nutrients 14 17 https://www.doi.org/10./nu 36,079,796 Aged Biomarkers Female Humans Inflammation/complications *Insulin Resistance Obesity *Polycystic Ovary Syndrome Vitamin D Vitamins inflammation matrix metalloproteinases polycystic ovary syndrome vitamin D3 INTRODUCTION: Chronic low-grade inflammation is a characteristic of women with polycystic ovary syndrome (PCOS), although this may be obesity-driven rather than an intrinsic facet of PCOS; furthermore, vitamin D deficiency, another common feature of PCOS, is reported to have an association with increased inflammation. Therefore, circulating inflammatory protein levels and circulating levels of vitamin D may be linked in PCOS, though it is unclear which vitamin D metabolites may be important. METHODS: We measured plasma levels of 24 inflammatory proteins and 12 matrix metalloproteinases (proteins modulated by the inflammatory process) by slow off-rate modified aptamer (SOMA)-scan plasma protein measurement in weight and aged-matched non-obese non-insulin resistant PCOS (n = 24) and control (n = 24) women. Inflammatory proteins and matrix metalloproteinases were correlated to 25-hydroxy vitamin D(3) (25(OH)D(3)), its epimer 25-hydroxy-3epi-vitamin D (3epi25(OH)D) and the active 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) as measured by gold standard isotope-dilution liquid chromatography tandem mass spectrometry. RESULTS: PCOS women had both an elevated free androgen index and circulating anti-mullerian hormone, though insulin resistance was comparable to controls. C-reactive protein, as a standard circulatory marker of inflammation, was comparable between cohorts. Levels of circulating inflammatory proteins and matrix metalloproteinases were not different between the PCOS and control women, with no correlation of 25(OH)D(3,) 1,25(OH)(2)D(3) or 3epi25(OH)D with any of the inflammatory proteins. CONCLUSION: In a non-obese PCOS population matched for age and insulin resistance, circulating inflammatory proteins and matrix metalloproteinases were not elevated and did not correlate with 25(OH)D(3,) its epimer 3epi25(OH)D or 1,25(OH)(2)D(3) in either control or PCOS women, indicating that the inflammatory response is absent and the vitamin D-metabolite independent in non-obese women with PCOS. Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Nutrients. Aug 27;14(17):. doi: 10./nu.I SomaScan 09/10/ Shi X, et al. The associations between plasma soluble Trem1 and neurological diseases: a Mendelian randomization study J Neuroinflammation 19 1 218 https://www.doi.org/10./s-022--z 36,068,612 *Alzheimer Disease/genetics *Amyotrophic Lateral Sclerosis Genome-Wide Association Study Humans Mendelian Randomization Analysis/methods *Parkinson Disease/genetics Polymorphism, Single Nucleotide/genetics Triggering Receptor Expressed on Myeloid Cells-1/genetics Alzheimer's disease Epilepsy Mendelian randomization Neurological diseases sTrem1 BACKGROUND: Triggering receptor expressed on myeloid cell 1 (Trem1) is an important regulator of cellular inflammatory responses. Neuroinflammation is a common thread across various neurological diseases. Soluble Trem1 (sTrem1) in plasma is associated with the development of central nervous system disorders. However, the extent of any causative effects of plasma sTrem1 on the risk of these disorders is still unclear. METHOD: Genetic variants for plasma sTrem1 levels were selected as instrumental variables. Summary-level statistics of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), epilepsy, cerebrovascular diseases, and migraine were collected from genome-wide association studies (GWASs). Whether plasma sTrem1 was causally associated with neurological disorders was assessed using a two-sample Mendelian randomization (MR) analysis, with false discovery rate (FDR)-adjusted methods applied. RESULTS: We inferred suggestive association of higher plasma sTrem1 with the risk of AD (odds ratio [OR] per one standard deviation [SD] increase = 1.064, 95% CI 1.012-1.119, P = 0.014, P(FDR) = 0.056). Moreover, there was significant association between plasma sTrem1 level and the risk of epilepsy (OR per one SD increase = 1.044, 95% CI 1.016-1.072, P = 0.002, P(FDR) = 0.032), with a modest statistical power of 41%. Null associations were found for plasma sTrem1 with other neurological diseases and their subtypes. CONCLUSIONS: Taken together, this study indicates suggestive association between plasma sTrem1 and AD. Moreover, higher plasma sTrem1 was associated with the increased risk of epilepsy. The findings support the hypothesis that sTrem1 may be a vital element on the causal pathway to AD and epilepsy. Shi, Xiaolei Wei, Tao Hu, Yachun Wang, Meng Tang, Yi eng -/Guangzhou Municipal Key Discipline in Medicine/ B/Science and Technology Plan Project of Guangdong Province/ JQ/Beijing Natural Science Foundation/ /National Natural Science Foundation of China/ Z/Beijing Municipal Science & Technology Commission/ DFL/Beijing Hospitals Authority's Ascent Plan/ England J Neuroinflammation. Sep 6;19(1):218. doi: 10./s-022--z.I SomaScan 09/07/ Casanova R, et al. Is an MRI-derived anatomical measure of dementia risk also a measure of brain aging? Geroscience epub ahead of print https://www.doi.org/10./s-022--z 36,050,589 Aging Alzheimer's disease Deficit accumulation index Machine learning Mortality Proteomics Machine learning methods have been applied to estimate measures of brain aging from neuroimages. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI-based measure of dementia risk, the Alzheimer's disease pattern similarity (AD-PS) scores, with measures used to calculate biological age. Participants were those from visit 5 of the Atherosclerosis Risk in Communities Study with cognitive status adjudication, proteomic data, and AD-PS scores available. The AD-PS score estimation is based on previously reported machine learning methods. We evaluated associations of the AD-PS score with all-cause mortality. Sensitivity analyses using only cognitively normal (CN) individuals were performed treating CNS-related causes of death as competing risk. AD-PS score was examined in association with 32 proteins measured, using a Somalogic platform, previously reported to be associated with age. Finally, associations with a deficit accumulation index (DAI) based on a count of 38 health conditions were investigated. All analyses were adjusted for age, race, sex, education, smoking, hypertension, and diabetes. The AD-PS score was significantly associated with all-cause mortality and with levels of 9 of the 32 proteins. Growth/differentiation factor 15 (GDF-15) and pleiotrophin remained significant after accounting for multiple-testing and when restricting the analysis to CN participants. A linear regression model showed a significant association between DAI and AD-PS scores overall. While the AD-PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging. Casanova, Ramon Anderson, Andrea M Barnard, Ryan T Justice, Jamie N Kucharska-Newton, Anna Windham, Beverly Gwen Palta, Priya Gottesman, Rebecca F Mosley, Thomas H Hughes, Timothy M Wagenknecht, Lynne E Kritchevsky, Stephen B eng grant R01 HL/HL/NHLBI NIH HHS/ U01 AG/AG/NIA NIH HHS/ Switzerland Geroscience. Sep 2. doi: 10./s-022--z.I SomaScan 09/02/ Paranjpe MD, et al. Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease PLoS Genet 18 9 e https://www.doi.org/10./journal.pgen. 36,048,760 Adult Aged *Alzheimer Disease/pathology Biomarkers Cross-Sectional Studies Genome-Wide Association Study Humans Middle Aged Proteomics For Alzheimer's disease-a leading cause of dementia and global morbidity-improved identification of presymptomatic high-risk individuals and identification of new circulating biomarkers are key public health needs. Here, we tested the hypothesis that a polygenic predictor of risk for Alzheimer's disease would identify a subset of the population with increased risk of clinically diagnosed dementia, subclinical neurocognitive dysfunction, and a differing circulating proteomic profile. Using summary association statistics from a recent genome-wide association study, we first developed a polygenic predictor of Alzheimer's disease comprised of 7.1 million common DNA variants. We noted a 7.3-fold (95% CI 4.8 to 11.0; p < 0.001) gradient in risk across deciles of the score among 288,289 middle-aged participants of the UK Biobank study. In cross-sectional analyses stratified by age, minimal differences in risk of Alzheimer's disease and performance on a digit recall test were present according to polygenic score decile at age 50 years, but significant gradients emerged by age 65. Similarly, among 30,541 participants of the Mass General Brigham Biobank, we again noted no significant differences in Alzheimer's disease diagnosis at younger ages across deciles of the score, but for those over 65 years we noted an odds ratio of 2.0 (95% CI 1.3 to 3.2; p = 0.002) in the top versus bottom decile of the polygenic score. To understand the proteomic signature of inherited risk, we performed aptamer-based profiling in 636 blood donors (mean age 43 years) with very high or low polygenic scores. In addition to the well-known apolipoprotein E biomarker, this analysis identified 27 additional proteins, several of which have known roles related to disease pathogenesis. Differences in protein concentrations were consistent even among the youngest subset of blood donors (mean age 33 years). Of these 28 proteins, 7 of the 8 proteins with concentrations available were similarly associated with the polygenic score in participants of the Multi-Ethnic Study of Atherosclerosis. These data highlight the potential for a DNA-based score to identify high-risk individuals during the prolonged presymptomatic phase of Alzheimer's disease and to enable biomarker discovery based on profiling of young individuals in the extremes of the score distribution. Paranjpe, Manish D Chaffin, Mark Zahid, Sohail Ritchie, Scott Rotter, Jerome I Rich, Stephen S Gerszten, Robert Guo, Xiuqing Heckbert, Susan Tracy, Russ Danesh, John Lander, Eric S Inouye, Michael Kathiresan, Sekar Butterworth, Adam S Khera, Amit V eng NIHR BTRU-- /DH_/Department of Health/United Kingdom MR/L/1/MRC_/Medical Research Council/United Kingdom SP/09/002/BHF_/British Heart Foundation/United Kingdom RG/13/13//BHF_/British Heart Foundation/United Kingdom RG/18/13//BHF_/British Heart Foundation/United Kingdom CSO_/Chief Scientist Office/United Kingdom 75ND/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01 HC/HC/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ N02 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS Genet. Sep 1;18(9):e. doi: 10./journal.pgen.. eCollection Sep.I SomaScan 09/02/ Chatterjee T, et al. Highly sensitive protein detection by aptamer-based single-molecule kinetic fingerprinting Biosens Bioelectron 216 https://www.doi.org/10./j.bios.. 36,037,714 Antibodies, Monoclonal *Aptamers, Nucleotide/chemistry Biomarkers *Biosensing Techniques Humans Interleukin-8 Ligands *Nucleic Acids Reproducibility of Results SELEX Aptamer Technique/methods Vascular Endothelial Growth Factor A Analyte detection Aptamer Kinetic fingerprinting Protein biomarkers Sensitivity Single molecule fluorescence microscopy interests/personal relationships which may be considered as potential competing interests: N.G.W and A.J.-B are cofounder of aLight Sciences, Inc., which seeks to commercialize the SiMREPS technology. A.J.-B is an employee of aLight Sciences, Inc. N.G.W and A.J.-B are co-inventors of patent applications related to the SiMREPS technology. Sensitive assays of protein biomarkers play critical roles in clinical diagnostics and biomedical research. Such assays typically employ immunoreagents such as monoclonal antibodies that suffer from several drawbacks, including relatively tedious production, significant batch-to-batch variability, and challenges in site-specific, stoichiometric modification with fluorophores or other labels. One proposed alternative to such immunoreagents, nucleic acid aptamers generated by systematic evolution of ligand by exponential enrichment (SELEX), can be chemically synthesized with much greater ease, precision, and reproducibility than antibodies. However, most aptamers exhibit relatively poor affinity, yielding low sensitivity in the assays employing them. Recently, single molecule recognition through equilibrium Poisson sampling (SiMREPS) has emerged as a platform for detecting proteins and other biomarkers with high sensitivity without requiring high-affinity detection probes. In this manuscript, we demonstrate the applicability and advantages of aptamers as detection probes in SiMREPS as applied to two clinically relevant biomarkers, VEGF(165) and IL-8, using a wash-free protocol with limits of detection in the low femtomolar range (3-9 fM). We show that the kinetics of existing RNA aptamers can be rationally optimized for use as SiMREPS detection probes by mutating a single nucleotide in the conserved binding region or by shortening the aptamer sequence. Finally, we demonstrate the detection of endogenous IL-8 from human serum at a concentration below the detection limit of commercial ELISAs. Chatterjee, Tanmay Johnson-Buck, Alexander Walter, Nils G eng England Biosens Bioelectron. Nov 15;216:. doi: 10./j.bios... Epub Aug 22.I SomaScan 08/30/ Xie Z, et al. Markers of endothelial glycocalyx dysfunction in Clarkson disease J Transl Med 20 1 380 https://www.doi.org/10./s-022--1 36,038,904 Biomarkers *Capillary Leak Syndrome/diagnosis/pathology/therapy Endothelial Cells/pathology Glycocalyx Humans Proteomics Capillary leak Endothelium Glyocalcyx BACKGROUND: Clarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, hemoconcentration, and hypoalbuminemia. METHODS: We analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with ISCLS during acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. We evaluated eGCX-related components and gene expression in cultured endothelial cells using RNA-sequencing, real-time PCR, and fluorescence staining. RESULTS: Serum levels of eGCX-related core components including hyaluronic acid (HA) and the core proteoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute ISCLS flares. Serial measurements demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent ISCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with ISCLS did not differ significantly from that observed in healthy control cells. CONCLUSIONS: eGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute ISCLS. Serum levels of of eGCX components including sCD138 may be measured during acute episodes of ISCLS to monitor clinical status and therapeutic responses. Xie, Zhihui Borset, Magne Sveen, Kjell Boe, Ole Wilhelm Chan, Eunice C Lack, Justin B Hornick, Katherine M Verlicchi, Franco Eisch, A Robin Melchio, Remo Dudek, Arkadiusz Z Druey, Kirk M eng Z01-AI-/Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ Research Support, N.I.H., Intramural England J Transl Med. Aug 29;20(1):380. doi: 10./s-022--1.I SomaScan 08/30/ Jaisankar A, et al. Recent developments of aptamer-based lateral flow assays for point-of-care (POC) diagnostics Anal Biochem 655 https://www.doi.org/10./j.ab.. 36,027,971 Antibodies *Aptamers, Nucleotide Biological Assay *Biosensing Techniques Humans Point-of-Care Systems SELEX Aptamer Technique Aptamer-based LFA Aptamers Lateral flow assay Selex Sensors of interest. In the field of lateral flow assay (LFA), the application of aptamer as a bioreceptor has been implemented to overcome the limitations of antibodies, such as tedious in vivo processes, short shelf-life, and functionalization issues. To address these limitations aptamer-based LFA (ALFA) is preferred to antibody-based LFA that produces higher sensitivity and specificity. In principle, aptamers have a strong affinity towards their targets like small, large, and non-immunogenic molecules because of their high affinity, sensitivity, low dissociation constant, cost-effectiveness, and flexible nature. Thus, ALFA can be considered an efficient biosensor model for its superior portability, rapid detection with quick turnaround time, and usability by a non-technical person at any location with simple visual output. This review concisely overviews ALFA, its principles, formats, aptamer selection process, and biomedical applications. In addition, the critical components to design, develop, test, and amplify signals to create ALFA are discussed in brief. In addition, the aspects of conceptualization of ALFA product transforming from bench-side laboratory design and fabrication to commercial market are addressed in detail. Jaisankar, Abinaya Krishnan, Sasirekha Rangasamy, Loganathan eng Research Support, Non-U.S. Gov't Review Anal Biochem. Oct 15;655:. doi: 10./j.ab... Epub Aug 24.I SomaScan 08/27/ Pala E, et al. Blood-biomarkers and devices for atrial fibrillation screening: Lessons learned from the AFRICAT (Atrial Fibrillation Research In CATalonia) study PLoS One 17 8 e https://www.doi.org/10./journal.pone. 35,998,199 *Atrial Fibrillation Biomarkers Electrocardiography, Ambulatory Humans Prospective Studies Spain BACKGROUND AND OBJECTIVE: AFRICAT is a prospective cohort study intending to develop an atrial fibrillation (AF) screening program through the combination of blood markers, rhythm detection devices, and long-term monitoring in our community. In particular, we aimed to validate the use of NT-proBNP, and identify new blood biomarkers associated with AF. Also, we aimed to compare AF detection using various wearables and long-term Holter monitoring. METHODS: 359 subjects aged 65-75 years with hypertension and diabetes were included in two phases: Phase I (n = 100) and Phase II (n = 259). AF diagnosis was performed by baseline 12-lead ECG, 4 weeks of Holter monitoring (NuuboTM), and/or medical history. An aptamer array including proteins was measured in the blood of 26 patients. Candidates were selected according to p-value, logFC and biological function to be tested in verification and validation phases. Several screening devices were tested and compared: AliveCor, Watch BP, MyDiagnostick and Fibricheck. RESULTS: AF was present in 34 subjects (9.47%). The aptamer array revealed 41 proteins with differential expression in AF individuals. TIMP-2 and ST-2 were the most promising candidates in the verification analysis, but none of them was further validated. NT-proBNP (log-transformed) (OR = 1.934; p<0.001) was the only independent biomarker to detect AF in the whole cohort. Compared to an ECG, WatchBP had the highest sensitivity (84.6%) and AUC (0.895 [0.780-1]), while MyDiagnostick showed the highest specificity (97.10%). CONCLUSION: The inclusion and monitoring of a cohort of primary care patients for AF detection, together with the testing of biomarkers and screening devices provided useful lessons about AF screening in our community. An AF screening strategy using rhythm detection devices and short monitoring periods among high-risk patients with high NT-proBNP levels could be feasible. Pala, Elena Bustamante, Alejandro Clua-Espuny, Josep Lluis Acosta, Juan Gonzalez-Loyola, Felipe Santos, Sara Dos Ribas-Segui, Domingo Ballesta-Ors, Juan Penalba, Anna Giralt, Marina Lechuga-Duran, Inigo Gentille-Lorente, Delicia Pedrote, Alonso Munoz, Miguel Angel Montaner, Joan eng Research Support, Non-U.S. Gov't PLoS One. Aug 23;17(8):e. doi: 10./journal.pone.. eCollection .I SomaScan 08/24/ Katz DH, et al. Proteomic profiling platforms head to head: Leveraging genetics and clinical traits to compare aptamer- and antibody-based methods Sci Adv 8 33 eabm https://www.doi.org/10./sciadv.abm 35,984,888 Adult Antibodies/chemistry Aptamers, Peptide/chemistry Humans Longitudinal Studies Phenotype *Proteome *Proteomics/methods High-throughput proteomic profiling using antibody or aptamer-based affinity reagents is used increasingly in human studies. However, direct analyses to address the relative strengths and weaknesses of these platforms are lacking. We assessed findings from the SomaScan1.3K (N = reagents), the SomaScan5K platform (N = reagents), and the Olink Explore (N = reagents) profiling techniques in 568 adults from the Jackson Heart Study and 219 participants in the HERITAGE Family Study across four performance domains: precision, accuracy, analytic breadth, and phenotypic associations leveraging detailed clinical phenotyping and genetic data. Across these studies, we show evidence supporting more reliable protein target specificity and a higher number of phenotypic associations for the Olink platform, while the Soma platforms benefit from greater measurement precision and analytic breadth across the proteome. Katz, Daniel H Robbins, Jeremy M Deng, Shuliang Tahir, Usman A Bick, Alexander G Pampana, Akhil Yu, Zhi Ngo, Debby Benson, Mark D Chen, Zsu-Zsu Cruz, Daniel E Shen, Dongxiao Gao, Yan Bouchard, Claude Sarzynski, Mark A Correa, Adolfo Natarajan, Pradeep Wilson, James G Gerszten, Robert E eng HHSNC/HL/NHLBI NIH HHS/ R01 NR/NR/NINR NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ U24 DK/DK/NIDDK NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ RF1 AG/AG/NIA NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ P30 GM/GM/NIGMS NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ DP5 OD/OD/NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ KL2 TR/TR/NCATS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNI/MD/NIMHD NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ K23 HL/HL/NHLBI NIH HHS/ F32 HL/HL/NHLBI NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ K08 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Sci Adv. Aug 19;8(33):eabm. doi: 10./sciadv.abm. Epub Aug 19.I SomaScan 08/20/ Appiah D, et al. Long-term changes in plasma proteomic profiles in premenopausal and postmenopausal Black and White women: the Atherosclerosis Risk in Communities study Menopause 29 10 - https://www.doi.org/10./GME. 35,969,495 *Atherosclerosis Cholesterol Cross-Sectional Studies Female Humans Lipids Menopause Middle Aged *Postmenopause/physiology Premenopause/physiology Proteomics OBJECTIVE: The activity, localization, and turnover of proteins within cells and plasma may contribute to physiologic changes during menopause and may influence disease occurrence. We examined cross-sectional differences and long-term changes in plasma proteins between premenopausal and naturally postmenopausal women. METHODS: We used data from 4,508 (19% Black) women enrolled in the Atherosclerosis Risk in Communities study. SOMAscan multiplexed aptamer technology was used to measure 4,697 plasma proteins. Linear regression models were used to compare differences in proteins at baseline (-) and 18-year change in proteins from baseline to -. RESULTS: At baseline, 472 women reported being premenopausal and 4,036 women reported being postmenopausal, with average ages of 52.3 and 61.4 years, respectively. A greater proportion of postmenopausal women had diabetes (15 vs 9%), used hypertension (38 vs 27%) and lipid-lowering medications (10 vs 3%), and had elevated total cholesterol and waist girth. In multivariable adjusted models, 38 proteins differed significantly between premenopausal and postmenopausal women at baseline, with 29 of the proteins also showing significantly different changes between groups over the 18-year follow-up as the premenopausal women also reached menopause. These proteins were associated with various molecular/cellular functions (cellular development, growth, proliferation and maintenance), physiological system development (skeletal and muscular system development, and cardiovascular system development and function), and diseases/disorders (hematological and metabolic diseases and developmental disorders). CONCLUSIONS: We observed significantly different changes between premenopausal and postmenopausal women in several plasma proteins that reflect many biological processes. These processes may help to understand disease development during the postmenopausal period. Appiah, Duke Schreiner, Pamela J Pankow, James S Brock, Guy Tang, Weihong Norby, Faye L Michos, Erin D Ballantyne, Christie M Folsom, Aaron R eng HHSNC/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Menopause. Oct 1;29(10):-. doi: 10./GME.. Epub Aug 20.I SomaScan 08/16/ Pietzner M, et al. ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19 Nat Commun 13 1 https://www.doi.org/10./s-022--6 35,970,849 Angiotensin-Converting Enzyme 2/genetics *COVID-19/genetics *DNA-Binding Proteins/genetics Epithelial Cells/metabolism Humans Peptidyl-Dipeptidase A/metabolism Respiratory System SARS-CoV-2 *Transcription Factors/genetics Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 x 10(-6)) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2. Pietzner, Maik Chua, Robert Lorenz Wheeler, Eleanor Jechow, Katharina Willett, Julian D S Radbruch, Helena Trump, Saskia Heidecker, Bettina Zeberg, Hugo Heppner, Frank L Eils, Roland Mall, Marcus A Richards, J Brent Sander, Leif-Erik Lehmann, Irina Lukassen, Soren Wareham, Nicholas J Conrad, Christian Langenberg, Claudia eng MC_UU_/1/MRC_/Medical Research Council/United Kingdom MC_PC_/MRC_/Medical Research Council/United Kingdom MC_UU_/1/MRC_/Medical Research Council/United Kingdom /CIHR/Canada /CIHR/Canada /CIHR/Canada /CIHR/Canada C/A/CRUK_/Cancer Research UK/United Kingdom WT_/Wellcome Trust/United Kingdom DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't England Nat Commun. Aug 15;13(1):. doi: 10./s-022--6.I SomaScan 08/16/ Kobayashi H, et al. Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes Sci Transl Med 14 657 eabj https://www.doi.org/10./scitranslmed.abj 35,947,673 Cell Cycle Proteins/*blood *Diabetes Mellitus, Type 2/complications Disease Progression Humans *Kidney Failure, Chronic *Neuroblastoma Proteomics Transforming Growth Factor beta Circulating proteins associated with transforming growth factor-beta (TGF-beta) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-beta signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD. Kobayashi, Hiroki Looker, Helen C Satake, Eiichiro D'Addio, Francesca Wilson, Jonathan M Saulnier, Pierre Jean Md Dom, Zaipul I O'Neil, Kristina Ihara, Katsuhito Krolewski, Bozena Badger, Hannah S Petrazzuolo, Adriana Corradi, Domenico Galecki, Andrzej Wilson, Parker C Najafian, Behzad Mauer, Michael Niewczas, Monika A Doria, Alessandro Humphreys, Benjamin D Duffin, Kevin L Fiorina, Paolo Nelson, Robert G Krolewski, Andrzej S eng P30 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Sci Transl Med. Aug 10;14(657):eabj. doi: 10./scitranslmed.abj. Epub Aug 10.I SomaScan 08/11/ Fernandez N, et al. High Dimensional Immune Profiling of Smoldering Multiple Myeloma Distinguishes Distinct Tumor Microenvironments Clin Lymphoma Myeloma Leuk 22 11 853-862 https://www.doi.org/10./j.clml..07.001 35,945,129 Humans *Smoldering Multiple Myeloma Tumor Microenvironment *Monoclonal Gammopathy of Undetermined Significance/pathology *Multiple Myeloma/pathology Plasma Cells/pathology Disease Progression BACKGROUND: Multiple myeloma (MM) is a malignancy of plasma cells that arises from premalignant Monoclonal Gammopathy of Undetermined Significance (MGUS) and often progresses through an asymptomatic Smoldering (SMM) phase. Understanding the interactions between abnormal clonal plasma cells and the tumor microenvironment (TME) in the early disease states (MGUS, SMM) may inform risk assessment and therapy. PATIENTS AND METHODS: We performed high dimensional immunologic analysis of bone marrow specimens from 73 subjects with SMM by mass cytometry and T cell receptor sequencing of CD138-depleted bone marrow (BM) mononuclear cells, and proteomics and seromic profiling of BM plasma. Analysis of individual assay data identified self-organizing subgroups of SMM patients. We then applied novel bioinformatic methods to integrate data from pairs, trios, and quartets of assays. RESULTS: Mass cytometry, TCRSeq and proteomics identified three taxa (sing. taxon) of subjects that shared common characteristics across all three assays. Differential levels of BM plasma pleiotropin (PTN) and BM T cells and their productive clonality emerged as strong distinguishing factors among these taxa. CONCLUSION: These results suggest that the continuum from MGUS to MM does not consist of a single pathway in the TME, and that complex interactions between myeloma cells and the TME may ultimately determine progression and inform clinical management. Fernandez, Nicolas Perumal, Deepak Rahman, Adeeb Kim-Schulze, Seunghee Yesil, Jen Auclair, Daniel Adams, Homer 3rd Parekh, Samir Gnjatic, Sacha Cho, Hearn Jay eng Research Support, Non-U.S. Gov't Clin Lymphoma Myeloma Leuk. Nov;22(11):853-862. doi: 10./j.clml..07.001. Epub Jul 16.I SomaScan 08/10/ Vorn R, et al. Proteomic Profiling of Plasma Biomarkers Associated With Return to Sport Following Concussion: Findings From the NCAA and Department of Defense CARE Consortium Front Neurol 13 https://www.doi.org/10./fneur.. 35,928,129 biomarker concussion proteomic return to sport (RTS) sport injuries research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. OBJECTIVE: To investigate the plasma proteomic profiling in identifying biomarkers related to return to sport (RTS) following a sport-related concussion (SRC). METHODS: This multicenter, prospective, case-control study was part of a larger cohort study conducted by the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium, athletes (n = 140) with blood collected within 48 h of injury and reported day to asymptomatic were included in this study, divided into two groups: (1) recovery /=14-days (n = 41). We applied a highly multiplexed proteomic technique that uses DNA aptamers assay to target 1,305 proteins in plasma samples from concussed athletes with /=14-days. RESULTS: We identified 87 plasma proteins significantly dysregulated (32 upregulated and 55 downregulated) in concussed athletes with recovery >/=14-days relative to recovery <14-days groups. The significantly dysregulated proteins were uploaded to Ingenuity Pathway Analysis (IPA) software for analysis. Pathway analysis showed that significantly dysregulated proteins were associated with STAT3 pathway, regulation of the epithelial mesenchymal transition by growth factors pathway, and acute phase response signaling. CONCLUSION: Our data showed the feasibility of large-scale plasma proteomic profiling in concussed athletes with a /= 14-days recovery. These findings provide a possible understanding of the pathophysiological mechanism in neurobiological recovery. Further study is required to determine whether these proteins can aid clinicians in RTS decisions. Vorn, Rany Mithani, Sara Devoto, Christina Meier, Timothy B Lai, Chen Yun, Sijung Broglio, Steven P McAllister, Thomas W Giza, Christopher C Kim, Hyung-Suk Huber, Daniel Harezlak, Jaroslaw Cameron, Kenneth L McGinty, Gerald Jackson, Jonathan Guskiewicz, Kevin M Mihalik, Jason P Brooks, Alison Duma, Stefan Rowson, Steven Nelson, Lindsay D Pasquina, Paul McCrea, Michael A Gill, Jessica M eng Switzerland Front Neurol. Jul 19;13:. doi: 10./fneur... eCollection .I SomaScan 08/06/ Wu X, et al. Serum proteomic profiling of rheumatoid arthritis-interstitial lung disease with a comparison to idiopathic pulmonary fibrosis Thorax epub ahead of print https://www.doi.org/10./thorax-- 35,907,639 Interstitial Fibrosis Rheumatoid lung disease interest, all outside the submitted work: ST reports medical advisory group membership of Novo Nordisk and board membership at Droobi Health, Qatar. RG receives grant support from Canon Medical Systems. HH reports grants from Canon Medical Systems and Konica Minolta, and personal fees from Mitsubishi Chemical Co and Canon Medical Systems Inc. MN reports grants from AstraZeneca, Daiichi Sankyo, Canon Medical Systems, Merck investigator studies program personal fees from Daiichi Sankyo and AstraZeneca. MEW receives research support from Amgen, Bristol Myers Squibb and Eli Lilly and consultation fees from AbbVie, Aclaris, Amgen, Arena, Bayer, Bristol Myers Squibb, Corvitas, Eqrx, Genosco, GSK, Gilead, Horizon, Johnson & Johnson, Kiniksa, Lilly, Novartis, Pfizer, Rami Therapeutics, R Pharma, Roche, Sanofi, Scipher, Sci Rhom, Set Point and Tremeau. He holds stock/stock options of CanFite, Inmedix, Vorso and Scipher. NAS reports grants and other support from Bristol-Myers Squibb, grants from Mallinckrodt, Sanofi, Crescendo Biosciences, Lilly and Amgen. PFD reports grants from Bristol-Myers Squibb and Genentech, and other support from Boehringer Ingelheim. AMKC is a cofounder and equity stock holder for Proterris, which develops therapeutic uses for carbon monoxide, and also has a use patent on CO and a patent in chronic obstructive pulmonary disease. EYK is a member of the steering committees for and receives no financial remuneration from NCT (Prevention of arteriovenous thrombotic events in critically ill COVID-19 patients, TIMI group) and REMAP-CAP ACE2 renin-angiotensin system modulation domain, and receives unrelated research funding from Bayer AG, Roche Pharma Research and Early Development, Windtree Therapeutics, the US National Institutes of Health, the US Agency for International Development, the American Heart Association, American Lung Association and the Bell Family Fund. IOR reports grants from Genentech. FJM reports personal fees, non-financial support and other support from AstraZeneca, other support from Afferent/Merck, personal fees, non-financial support and other support from Boehringer Ingelheim, other support from Bristol Myers Squibb, other support from Chiesi, personal fees and non-financial support from the Canadian Respiratory Society, personal fees and non-financial support from CME Outfitters, personal fees and non-financial support from CSL Behring, personal fees from Dartmouth University, personal fees from France Foundation, personal fees from Gala, personal fees and non-financial support from Genentech, grants, personal fees, non-financial support and other support from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax, personal fees and non-financial support from MD Magazine, personal fees and non-financial support from NYP Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communications, personal fees and non-financial support from National Association for Continuing Education/Integritas, other support from Nitto, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Patara/Respivant, personal fees from Pearl, personal fees and non-financial support from Peer View, personal fees from Physicians Education Resource, personal fees from ProMedior, personal fees and non-financial support from Rare Diseases Healthcare Communications, personal fees from Rockpointe Communications, personal fees and non-financial support from Sanofi/Regeneron, other support from Biogen, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Teva, other support from two XAR, personal fees from University of Birmingham Alabama, personal fees from UpToDate, non-financial support from Veracyte, personal fees from Vindico, personal fees and non-financial support from WebMD/MedScape, non-financial support and other support from Zambon, non-financial support from ProTerrix Bio, and personal fees from IQVIA, Raziel, Abvie and Verona. TJD has received grant support from Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech. The remaining authors have reported no conflicts of interest. Although interstitial lung disease (ILD) causes significant morbidity and mortality in rheumatoid arthritis (RA), it is difficult to predict the development or progression of ILD, emphasising the need for improved discovery through minimally invasive diagnostic tests. Aptamer-based proteomic profiling was used to assess proteins from 159 patients with rheumatoid arthritis with interstitial lung disease (RA-ILD), RA without ILD, idiopathic pulmonary fibrosis and healthy controls. Differential expression and gene set enrichment analyses revealed molecular signatures that are strongly associated with the presence and severity of RA-ILD and provided insight into unexplored pathways of disease. These warrant further study as non-invasive diagnostic tools and future therapeutic targets. Wu, Xiaoping Jeong, Yunju Poli de Frias, Sergio Easthausen, Imaani Hoffman, Katherine Oromendia, Clara Taheri, Shahrad Esposito, Anthony J Quesada Arias, Luisa Ayaub, Ehab A Maurer, Rie Gill, Ritu R Hatabu, Hiroto Nishino, Mizuki Frits, Michelle L Iannaccone, Christine K Weinblatt, Michael E Shadick, Nancy A Dellaripa, Paul F Choi, Augustine M K Kim, Edy Y Rosas, Ivan O Martinez, Fernando J Doyle, Tracy J eng F32 HL/HL/NHLBI NIH HHS/ K23 HL/HL/NHLBI NIH HHS/ L30 HL/HL/NHLBI NIH HHS/ R03 HL/HL/NHLBI NIH HHS/ England Thorax. Jul 30:thoraxjnl--. doi: 10./thorax--.I SomaScan 07/31/ Cederberg KLJ, et al. Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response Int J Mol Sci 23 14 https://www.doi.org/10./ijms 35,887,329 Biomarkers Continuous Positive Airway Pressure Humans Polysomnography *Proteomics *Sleep Apnea, Obstructive/complications/diagnosis/therapy apnea-hypopnea index machine learning obstructive sleep apnea proteomics treatment Hedou, Dr. Jing Zhang, Dr. Ling Lin, Dr. Suresh Kotagal, Dr. Adam Blackman, Dr. Clete Kushida, and Dr. Nayia Petousi declare no conflict of interest. Dr. Chris Turnbull declares consulting fees from Bayer and honoraria from Stowood, outside the scope of this work. Dr. Schneider reports personal fees from Jazz Pharmaceuticals, personal fees from Harmony Biosciences, personal fees from Eisai, outside the submitted work. Dr. Leary is an employee of Jazz Pharmaceuticals who, in the course of her employment, has received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Dr. Anne Marie Morse has received consulting fees from Jazz Pharmaceuticals, Harmony Biosciences, and Avadel, outside the scope of this work. Dr. Paula Schweitzer has received consulting fees from Apnimed and Jazz Pharmaceuticals her institution has received research funding from Apnimed, Avadel, Harmony Biosciences, Inspire Medical, and Suven Life Sciences, all outside the scope of this work. Dr. Richard Bogan is a shareholder in WaterMark Medical and Healthy Humming, LLC serves on the Board of Directors for WaterMark Medical is a consultant to Jazz, Harmony Biosciences, Takeda, Avadel, and Oventus has industry funded research for Avadel, BresoTec, Idorsia, Suven, Jazz, Balance, Vanda, Merck, Eisai, Philips, Fresca, Takeda, Liva Nova, Roche, Sommetrics, NLS, Sanofi, Apnimed and is on the Speakers Bureau for Jazz, Eisai, Harmony, Idorsia all outside the scope of this work. Dr. Yo-El Ju reports consulting fees from Applied Cognition, outside the scope of this work. Dr. Emmanuel Mignot occasionally consults and has received contracts from Jazz Pharmaceuticals, Orexia/Centessa, Tekeda, Dreem, and ActiGraph has received grant/clinical trial funding from Haromony, Tekeda, Apple, Humani, Sunovion, Indorsia, Eisai is and has been a Principal Investigator on clinical trials using sodium oxybate and Solriamfetol, Jazz Pharmaceutical products, for the treatment of Type 1 narcolepsy all outside the scope of this work. Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = ) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea-hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI >/= 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke. Cederberg, Katie L J Hanif, Umaer Peris Sempere, Vicente Hedou, Julien Leary, Eileen B Schneider, Logan D Lin, Ling Zhang, Jing Morse, Anne M Blackman, Adam Schweitzer, Paula K Kotagal, Suresh Bogan, Richard Kushida, Clete A Ju, Yo-El S Petousi, Nayia Turnbull, Chris D Mignot, Emmanuel The Stages Cohort Investigator Group eng N/A/Oxford Radcliffe Hospital Charitable Funds/ KL2TR/NH/NIH HHS/ T32HL/NH/NIH HHS/ N/A/ResMed UK/ K23NS/NH/NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ N/A/Bryte Foundation/ N/A/National Institute for Health Research/ N/A/Philips Respironics/ N/A/Klarman Family Foundation/ UL1TR/Washington University Institute of Clinical and Translational Sciences/ UL1RR/NH/NIH HHS/ Switzerland Int J Mol Sci. Jul 20;23(14):. doi: 10./ijms.I SomaScan 07/28/ Shu X, et al. Associations between circulating proteins and risk of breast cancer by intrinsic subtypes: a Mendelian randomisation analysis Br J Cancer 127 8 - https://www.doi.org/10./s-022--2 35,882,941 Biomarkers, Tumor/genetics/metabolism *Breast Neoplasms/pathology Female Humans Mendelian Randomization Analysis *Protein Disulfide Reductase (Glutathione) Receptors, Phospholipase A2 *Triple Negative Breast Neoplasms BACKGROUND: The aetiologic role of circulating proteins in the development of breast cancer subtypes is not clear. We aimed to examine the potential causal effects of circulating proteins on the risk of breast cancer by intrinsic-like subtypes within the Mendelian randomisation (MR) framework. METHODS: MR was performed using summary statistics from two sources: the INTERVAL protein quantitative trait loci (pQTL) Study ( circulating proteins and healthy individuals) and the Breast Cancer Association Consortium (BCAC; 106,278 invasive cases and 91,477 controls). The inverse-variance (IVW)-weighted method was used as the main analysis to evaluate the associations between genetically predicted proteins and the risk of five different intrinsic-like breast cancer subtypes and the weighted median MR method, the Egger regression, the MR-PRESSO, and the MRLocus method were performed as secondary analysis. RESULTS: We identified 98 unique proteins significantly associated with the risk of one or more subtypes (Benjamini-Hochberg false discovery rate < 0.05). Among them, 51 were potentially specific to luminal A-like subtype, 14 to luminal B/Her2-negative-like, 11 to triple negative, 3 to luminal B-like, and 2 to Her2-enriched-like breast cancer (n(total) = 81). Associations for three proteins (ICAM1, PLA2R1 and TXNDC12) showed evident heterogeneity across the subtypes. For example, higher levels of genetically predicted ICAM1 (per unit of increase) were associated with an increased risk of luminal B/HER2-negative-like cancer (OR = 1.06, 95% CI = 1.03-1.08, BH-FDR = 2.43 x 10(-4)) while inversely associated with triple-negative breast cancer with borderline significance (OR = 0.97, 95% CI = 0.95-0.99, BH-FDR = 0.065, P(heterogeneity) < 0.005). CONCLUSIONS: Our study found potential causal associations with the risk of subtypes of breast cancer for 98 proteins. Associations of ICAM1, PLA2R1 and TXNDC12 varied substantially across the subtypes. The identified proteins may partly explain the heterogeneity in the aetiology of distinct subtypes of breast cancer and facilitate the personalised risk assessment of the malignancy. Shu, Xiang Zhou, Qin Sun, Xiaohui Flesaker, Michelle Guo, Xingyi Long, Jirong Robson, Mark E Shu, Xiao-Ou Zheng, Wei Bernstein, Jonine L eng R00 CA/CA/NCI NIH HHS/ K99 CA/CA/NCI NIH HHS/ R25 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ P30 CA/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Br J Cancer. Nov;127(8):-. doi: 10./s-022--2. Epub Jul 26.I SomaScan 07/27/ Timsina J, et al. Comparative Analysis of Alzheimer's Disease Cerebrospinal Fluid Biomarkers Measurement by Multiplex SOMAscan Platform and Immunoassay-Based Approach J Alzheimers Dis 89 1 193-207 https://www.doi.org/10./JAD- 35,871,346 *Alzheimer Disease/cerebrospinal fluid/diagnosis Amyloid beta-Peptides/cerebrospinal fluid Biomarkers/cerebrospinal fluid Humans Immunoassay Neurogranin/cerebrospinal fluid ROC Curve tau Proteins/cerebrospinal fluid Alzheimer's disease SOMAscan assays cerebrospinal fluid biomarkers correlation BACKGROUND: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. OBJECTIVE: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer's disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25. METHODS: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson's correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. RESULTS: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r > 0.9). sTREM2 had a fair correlation (r > 0.6), whereas SNAP-25 showed weak correlation (r = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. CONCLUSION: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers. Timsina, Jigyasha Gomez-Fonseca, Duber Wang, Lihua Do, Anh Western, Dan Alvarez, Ignacio Aguilar, Miquel Pastor, Pau Henson, Rachel L Herries, Elizabeth Xiong, Chengjie Schindler, Suzanne E Fagan, Anne M Bateman, Randall J Farlow, Martin Morris, John C Perrin, Richard J Moulder, Krista Hassenstab, Jason Voglein, Jonathan Chhatwal, Jasmeer Mori, Hiroshi Sung, Yun Ju Cruchaga, Carlos eng R01 AG/AG/NIA NIH HHS/ RF1 AG/AG/NIA NIH HHS/ RF1 AG/AG/NIA NIH HHS/ P01 AG/AG/NIA NIH HHS/ RF1 AG/AG/NIA NIH HHS/ P30 AG/AG/NIA NIH HHS/ P01 AG/AG/NIA NIH HHS/ U19 AG/AG/NIA NIH HHS/ Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Netherlands J Alzheimers Dis. ;89(1):193-207. doi: 10./JAD-.I SomaScan 07/25/ Surapaneni A, et al. Identification of 969 protein quantitative trait loci in an African American population with kidney disease attributed to hypertension Kidney Int 102 5 - https://www.doi.org/10./j.kint..07.005 35,870,639 Humans Quantitative Trait Loci African Americans/genetics Proteome Genome-Wide Association Study Polymorphism, Single Nucleotide *Hypertension/genetics *Kidney Diseases/genetics Genetic Predisposition to Disease pQTL protein quantitative trait loci Investigations into the causal underpinnings of disease processes can be aided by the incorporation of genetic information. Genetic studies require populations varied in both ancestry and prevalent disease in order to optimize discovery and ensure generalizability of findings to the global population. Here, we report the genetic determinants of the serum proteome in 466 African Americans with chronic kidney disease attributed to hypertension from the richly phenotyped African American Study of Kidney Disease and Hypertension (AASK) study. Using the largest aptamer-based protein profiling platform to date (6,790 proteins or protein complexes), we identified 969 genetic associations with 900 unique proteins; including 52 novel cis (local) associations and 379 novel trans (distant) associations. The genetic effects of previously published cis-protein quantitative trait loci (pQTLs) were found to be highly reproducible, and we found evidence that our novel genetic signals colocalize with gene expression and disease processes. Many trans- pQTLs were found to reflect associations mediated by the circulating cis protein, and the common trans-pQTLs are enriched for processes involving extracellular vesicles, highlighting a plausible mechanism for distal regulation of the levels of secreted proteins. Thus, our study generates a valuable resource of genetic associations linking variants to protein levels and disease in an understudied patient population to inform future studies of drug targets and physiology. Surapaneni, Aditya Schlosser, Pascal Zhou, Linda Liu, Celina Chatterjee, Nilanjan Arking, Dan E Dutta, Diptavo Coresh, Josef Rhee, Eugene P Grams, Morgan E eng Kidney Int. Nov;102(5):-. doi: 10./j.kint..07.005. Epub Jul 21.I SomaScan 07/24/ Luther J, et al. The circulating proteomic signature of alcohol-associated liver disease JCI Insight 7 14 https://www.doi.org/10./jci.insight. 35,866,482 Biomarkers Humans *Liver Diseases, Alcoholic/metabolism Proteome *Proteomics Hepatitis Hepatology Proteomics Despite being a leading cause of advanced liver disease, alcohol-associated liver disease (ALD) has no effective medical therapies. The circulating proteome, which comprises proteins secreted by different cells and tissues in the context of normal physiological function or in the setting of disease and illness, represents an attractive target for uncovering novel biology related to the pathogenesis of ALD. In this work, we used the aptamer-based SomaScan proteomics platform to quantify the relative concentration of over proteins in a well-characterized cohort of patients with the spectrum of ALD. We found a distinct circulating proteomic signature that correlated with ALD severity, including over 600 proteins that differed significantly between ALD stages, many of which have not previously been associated with ALD to our knowledge. Notably, certain proteins that were markedly dysregulated in patients with alcohol-associated hepatitis were also altered, to a lesser degree, in patients with subclinical ALD and may represent early biomarkers for disease progression. Taken together, our work highlights the vast and distinct changes in the circulating proteome across the wide spectrum of ALD, identifies potentially novel biomarkers and therapeutic targets, and provides a proteomic resource atlas for ALD researchers and clinicians. Luther, Jay Vannier, Augustin Gl Schaefer, Esperance A Goodman, Russell P eng K08 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't JCI Insight. Jul 22;7(14):e. doi: 10./jci.insight..I SomaScan 07/23/ Hedou J, et al. Proteomic biomarkers of Kleine-Levin syndrome Sleep 45 9 https://www.doi.org/10./sleep/zsac097 35,859,339 Biomarkers *Cognitive Dysfunction *Disorders of Excessive Somnolence Humans *Kleine-Levin Syndrome Proteomics Csf Kleine-Levine syndrome aptamers brain immunity hypersomnia microglia serum STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls. METHODS: SomaScan was used to profile CSF proteins in 30 KLS cases and 134 controls, while serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in seven cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEAs) were performed on DEPs. RESULTS: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (false discovery rate <0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1, and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility, and activation. TEA analysis of up- and downregulated proteins revealed changes in brain proteins (p < 6 x 10-5), notably from the pons, medulla, and midbrain. A multivariate machine-learning classifier performed robustly, achieving a receiver operating curve area under the curve of 0.90 (95% confidence interval [CI] = 0.78-1.0, p = 0.) in CSF and 1.0 (95% CI = 1.0-1.0, p = 0.) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases. CONCLUSIONS: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS. Hedou, Julien Cederberg, Katie L Ambati, Aditya Lin, Ling Farber, Neal Dauvilliers, Yves Quadri, Mohammed Bourgin, Patrice Plazzi, Giuseppe Andlauer, Olivier Hong, Seung-Chul Huang, Yu-Shu Leu-Semenescu, Smaranda Arnulf, Isabelle Taheri, Shahrad Mignot, Emmanuel eng S10 OD/OD/NIH HHS/ R01MH/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sleep. Sep 8;45(9):zsac097. doi: 10./sleep/zsac097.I SomaScan 07/22/ Wu J, et al. High Dimensional Multiomics Reveals Unique Characteristics of Early Plasma Administration in Polytrauma Patients With TBI Ann Surg 276 4 673-683 https://www.doi.org/10./SLA. 35,861,072 *Brain Injuries, Traumatic/therapy *Emergency Medical Services/methods Humans *Multiple Trauma/therapy Plasma Proteomics OBJECTIVES: The authors sought to identify causal factors that explain the selective benefit of prehospital administration of thawed plasma (TP) in traumatic brain injury (TBI) patients using mediation analysis of a multiomic database. BACKGROUND: The Prehospital Air Medical Plasma (PAMPer) Trial showed that patients with TBI and a pronounced systemic response to injury [defined as endotype 2 (E2)], have a survival benefit from prehospital administration of TP. An interrogation of high dimensional proteomics, lipidomics and metabolomics previously demonstrated unique patterns in circulating biomarkers in patients receiving prehospital TP, suggesting that a deeper analysis could reveal causal features specific to TBI patients. METHODS: A novel proteomic database (SomaLogic Inc., aptamer-based assay, 7K platform) was generated using admission blood samples from a subset of patients (n=149) from the PAMPer Trial. This proteomic dataset was combined with previously reported metabolomic and lipidomic datasets from these same patients. A 2-step analysis was performed to identify factors that promote survival in E2-TBI patients who had received early TP. First, features were selected using both linear and multivariate-latent-factor regression analyses. Then, the selected features were entered into the causal mediation analysis. RESULTS: Causal mediation analysis of observable features identified 16 proteins and 41 lipids with a high proportion of mediated effect (>50%) to explain the survival benefit of early TP in E2-TBI patients. The multivariate latent-factor regression analyses also uncovered 5 latent clusters of features with a proportion effect >30%, many in common with the observable features. Among the observable and latent features were protease inhibitors known to inhibit activated protein C and block fibrinolysis (SERPINA5 and CPB2), a clotting factor (factor XI), as well as proteins involved in lipid transport and metabolism (APOE3 and sPLA(2)-XIIA). CONCLUSIONS: These findings suggest that severely injured patients with TBI process exogenous plasma differently than those without TBI. The beneficial effects of early TP in E2-TBI patients may be the result of improved blood clotting and the effect of brain protective factors independent of coagulation. Wu, Junru Moheimani, Hamed Li, Shimena Kar, Upendra K Bonaroti, Jillian Miller, Richard S Daley, Brian J Harbrecht, Brian G Claridge, Jeffrey A Gruen, Danielle S Phelan, Herbert A Guyette, Francis X Neal, Matthew D Das, Jishnu Sperry, Jason L Billiar, Timothy R eng R35 GM/GM/NIGMS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R38 HL/HL/NHLBI NIH HHS/ T32 GM/GM/NIGMS NIH HHS/ R35 GM/GM/NIGMS NIH HHS/ DP2 AI/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Ann Surg. Oct 1;276(4):673-683. doi: 10./SLA.. Epub Jul 19.I SomaScan 07/22/ Grams ME, et al. Development and Validation of Prediction Models of Adverse Kidney Outcomes in the Population With and Without Diabetes Diabetes Care 45 9 - https://www.doi.org/10./dc22- 35,856,507 Albuminuria *Diabetes Mellitus/epidemiology Glomerular Filtration Rate Humans Kidney *Renal Insufficiency *Renal Insufficiency, Chronic/epidemiology OBJECTIVE: To predict adverse kidney outcomes for use in optimizing medical management and clinical trial design. RESEARCH DESIGN AND METHODS: In this meta-analysis of individual participant data, 43 cohorts (N = 1,621,817) from research studies, electronic medical records, and clinical trials with global representation were separated into development and validation cohorts. Models were developed and validated within strata of diabetes mellitus (presence or absence) and estimated glomerular filtration rate (eGFR; >/=60 or /=40% decline in eGFR or kidney failure (i.e., receipt of kidney replacement therapy) over 2-3 years. RESULTS: There were 17,399 and 24,591 events in development and validation cohorts, respectively. Models predicting >/=40% eGFR decline or kidney failure incorporated age, sex, eGFR, albuminuria, systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, and BMI, and, in those with diabetes, hemoglobin A1c, insulin use, and oral diabetes medication use. The median C-statistic was 0.774 (interquartile range [IQR] = 0.753, 0.782) in the diabetes and higher-eGFR validation cohorts; 0.769 (IQR = 0.758, 0.808) in the diabetes and lower-eGFR validation cohorts; 0.740 (IQR = 0.717, 0.763) in the no diabetes and higher-eGFR validation cohorts; and 0.750 (IQR = 0.731, 0.785) in the no diabetes and lower-eGFR validation cohorts. Incorporating the previous 2-year eGFR slope minimally improved model performance, and then only in the higher-eGFR cohorts. CONCLUSIONS: Novel prediction equations for a decline of >/=40% in eGFR can be applied successfully for use in the general population in persons with and without diabetes with higher or lower eGFR. Grams, Morgan E Brunskill, Nigel J Ballew, Shoshana H Sang, Yingying Coresh, Josef Matsushita, Kunihiro Surapaneni, Aditya Bell, Samira Carrero, Juan J Chodick, Gabriel Evans, Marie Heerspink, Hiddo J L Inker, Lesley A Iseki, Kunitoshi Kalra, Philip A Kirchner, H Lester Lee, Brian J Levin, Adeera Major, Rupert W Medcalf, James Nadkarni, Girish N Naimark, David M J Ricardo, Ana C Sawhney, Simon Sood, Manish M Staplin, Natalie Stempniewicz, Nikita Stengel, Benedicte Sumida, Keiichi Traynor, Jamie P van den Brand, Jan Wen, Chi-Pang Woodward, Mark Yang, Jae Won Wang, Angela Yee-Moon Tangri, Navdeep Chalmers, John Hsu, Chi-Yuan Anderson, Amanda Rao, Panduranga Feldman, Harold Chang, Alex R Ho, Kevin Green, Jamie Siddiqui, Moneeza Palmer, Colin Shalev, Varda Metzger, Marie Flamant, Martin Houillier, Pascal Haymann, Jean-Philippe Cuddeback, John Ciemins, Elizabeth Kovesdy, Csaba P Trevisan, Marco Elinder, Carl Gustaf Wettermark, Bjorn Kalra, Philip Chinnadurai, Rajkumar Tollitt, James Green, Darren Gansevoort, Ron T Gutierrez, Orlando Konta, Tsuneo Kottgen, Anna Levey, Andrew S Polkinghorne, Kevan Schaffner, Elke Zhang, Luxia Chen, Jingsha eng R01 DK/DK/NIDDK NIH HHS/ Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Diabetes Care. Sep 1;45(9):-. doi: 10./dc22-.I SomaScan 07/21/ Luo P, et al. Exploring the genetic relationship between deep vein thrombosis and plasma protein: a new research idea Expert Rev Hematol 15 9 867-873 https://www.doi.org/10./.. 35,857,435 Blood Proteins/genetics Chromogranins Complement Factor B Humans Mendelian Randomization Analysis Proteome *Venous Thrombosis/genetics Deep venous thrombosis (DVT) causality genetic correlation genetics plasma protein BACKGROUND: The aim of this article is to scan and analyze the genetic correlation between plasma proteome and deep venous thrombosis (DVT), and to explore the correlation between plasma protein and DVT. RESEARCH DESIGN AND METHODS: GWAS data of DVT and plasma proteins were analyzed with linkage disequilibrium scores, and plasma proteins that were genetically associated with DVT were screened out. To ascertain the causal link between potential plasma proteins and DVT, a Mendelian randomized (MR) study was used. This study used STRING to examine the pathogenesis of DVT in connection with the gene encoding plasma protein. RESULTS: Several suggestive plasma proteins were detected for DVT, such as Complement factor B (P value=0.), Chromogranin-A (P value=0.). Through MR analysis, we found that there was a significant positive causal relationship between Chromogranin-A (exposure) and DVT(outcome) (beta=-0., P<0.). Our STRING analysis revealed that hsa was associated with coagulation cascade in the KEGG pathway of Complement factor B(P<0.), which was based on GO and KEGG analysis of 8 selected plasma proteins. CONCLUSIONS: A genetic link between plasma protein and DVT was thoroughly investigated. Our findings provide a fresh perspective on the genetics and pathogenesis of DVT. Luo, Pan Xu, Jiawen Xu, Ke Jing, Wensen Liu, Lin Xu, Peng eng Research Support, Non-U.S. Gov't England Expert Rev Hematol. Sep;15(9):867-873. doi: 10./... Epub Aug 1.I SomaScan 07/21/ Nikpay M, et al. Genome-wide screening identifies DNA methylation sites that regulate the blood proteome Epigenomics epub ahead of print https://www.doi.org/10./epi-- 35,852,134 DNA methylation Mendelian randomization biomarker epigenomics functional interaction proteomics Background: Identifying DNA methylation sites that regulate the blood proteome is important for biomedical purposes. Materials & methods: Here the authors performed a genome-wide search to find DNA methylation sites that impact proteins. Results: The authors identified 165 methylation sites associated with 138 proteins. The authors noted hotspot genomic regions that control the levels of several proteins. For example, methylation of the ABO locus impacted 37 proteins and contributed to cardiometabolic comorbidities, including the severity of SARS-CoV-2 infection. The authors made these findings publicly available as a Unix software that identifies methylation sites that cause disease and reveals the underlying proteins. The authors underlined the software application by showing that components of innate immunity contribute to systolic blood pressure. Conclusion: This study provides a catalog of DNA methylation sites that regulate the proteome, and the results are available as freeware for biological insight. Our lifestyle choices and interactions with the world around us are continuously printed in our DNA through a biochemical process known as epigenomic modification. Excessive epigenomic modification at a DNA site may cause disease. To prevent or treat disease, it is important to find such sites and remove the excessive epigenomic modification with medications or lifestyle changes. Here the authors searched for DNA sites that undergo epigenomic modification. The authors also investigated the mechanism whereby these sites cause disease. The authors found that there are DNA sites where reverting the epigenomic modification could have a big impact on the body. The authors have made these findings publicly available. eng Nikpay, Majid Ravati, Sepehr McPherson, Ruth eng FDN-/CAPMC/CIHR/Canada England Epigenomics. Jul 19. doi: 10./epi--.I SomaScan 07/20/ Feng R, et al. Genome- and transcriptome-wide association studies show that pulmonary embolism is associated with bone-forming proteins Expert Rev Hematol 15 10 951-958 https://www.doi.org/10./.. 35,848,930 Humans *Transcriptome Genome-Wide Association Study RNA, Messenger/genetics *Pulmonary Embolism/genetics Defensins/genetics Genetic Predisposition to Disease Polymorphism, Single Nucleotide Bmp Gwas Ldsc Pulmonary embolism Twas BACKGROUND: Pulmonary embolism (PE) is a leading cause of death in stroke patients and a severe health burden worldwide. There is a pressing need to understand the mechanisms by which it occurs and to identify at-risk patients efficiently and accurately. METHODS: First, based on data from GWAS in European populations, we performed a linkage disequilibrium score regression (LDSC) analysis of plasma proteins and PE in 3,283 individuals and additionally analyzed the genetic association between PE and fracture. Then, we performed a TWAS on PE GWAS data using skeletal muscle and blood for gene expression references. Finally, we validated the genetic correlation between PE and human plasma proteins by co-matching the genes encoding the identified proteins and those identified using TWAS with the differentially expressed genes obtained from mRNA expression profiling of PE. RESULTS: We identified five plasma proteins associated with PE, including hydroxycarboxylic acid receptor 2, defensin 118, and bone morphogenetic protein (BMP) 7, as well as a relationship between PE and fracture. Comparison of genes encoding these proteins with genes obtained from TWAS and then with differentially expressed genes obtained from PE mRNA expression profiling revealed that PE was highly correlated with the BMP family of genes. Feng, Ruoyang Lu, Mengnan Yang, Yanni Luo, Pan Liu, Lin Xu, Ke Xu, Peng eng England Expert Rev Hematol. Oct;15(10):951-958. doi: 10./... Epub Sep 25.I SomaScan 07/19/ Gudicha DW, et al. The amniotic fluid proteome predicts imminent preterm delivery in asymptomatic women with a short cervix Sci Rep 12 1 https://www.doi.org/10./s-022--3 35,821,507 Amniotic Fluid/metabolism Cervix Uteri/diagnostic imaging Female Humans Infant, Newborn Matrix Metalloproteinase 8/metabolism *Obstetric Labor, Premature/metabolism Pregnancy *Premature Birth/metabolism Proteome/metabolism Retrospective Studies Preterm birth, the leading cause of perinatal morbidity and mortality, is associated with increased risk of short- and long-term adverse outcomes. For women identified as at risk for preterm birth attributable to a sonographic short cervix, the determination of imminent delivery is crucial for patient management. The current study aimed to identify amniotic fluid (AF) proteins that could predict imminent delivery in asymptomatic patients with a short cervix. This retrospective cohort study included women enrolled between May and September who were diagnosed with a sonographic short cervix (< 25 mm) at 16-32 weeks of gestation. Amniocenteses were performed to exclude intra-amniotic infection; none of the women included had clinical signs of infection or labor at the time of amniocentesis. An aptamer-based multiplex platform was used to profile AF proteins, and the differential protein abundance between women who delivered within two weeks from amniocentesis, and those who did not, was determined. The analysis included adjustment for quantitative cervical length and control of the false-positive rate at 10%. The area under the receiver operating characteristic curve was calculated to determine whether protein abundance in combination with cervical length improved the prediction of imminent preterm delivery as compared to cervical length alone. Of the 1,310 proteins profiled in AF, 17 were differentially abundant in women destined to deliver within two weeks of amniocentesis independently of the cervical length (adjusted p-value 1.5 for each). The sensitivity at a 10% false-positive rate for the prediction of imminent delivery by a quantitative cervical length alone was 38%, yet it increased to 79% when combined with the abundance of four AF proteins (CXCL8, SNAP25, PTPN11, and MMP8). Neutrophil-mediated immunity, neutrophil activation, granulocyte activation, myeloid leukocyte activation, and myeloid leukocyte-mediated immunity were biological processes impacted by protein dysregulation in women destined to deliver within two weeks of diagnosis. The combination of AF protein abundance and quantitative cervical length improves prediction of the timing of delivery compared to cervical length alone, among women with a sonographic short cervix. Gudicha, Dereje W Romero, Roberto Gomez-Lopez, Nardhy Galaz, Jose Bhatti, Gaurav Done, Bogdan Jung, Eunjung Gallo, Dahiana M Bosco, Mariachiara Suksai, Manaphat Diaz-Primera, Ramiro Chaemsaithong, Piya Gotsch, Francesca Berry, Stanley M Chaiworapongsa, Tinnakorn Tarca, Adi L eng Contract No. HHSNC/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural England Sci Rep. Jul 11;12(1):. doi: 10./s-022--3.I SomaScan 07/14/ Muruve DA, et al. Serum Protein Signatures Using Aptamer-Based Proteomics for Minimal Change Disease and Membranous Nephropathy Kidney Int Rep 7 7 - https://www.doi.org/10./j.ekir..04.006 35,812,291 membranous nephropathy minimal change disease proteomics systems biology INTRODUCTION: Minimal change disease (MCD) and membranous nephropathy (MN) are glomerular diseases (glomerulonephritis [GN]) that present with the nephrotic syndrome. Although circulating PLA2R antibodies have been validated as a biomarker for MN, the diagnosis of MCD and PLA2R-negative MN still relies on the results of kidney biopsy or empirical corticosteroids in children. We aimed to identify serum protein biomarker signatures associated with MCD and MN pathogenesis using aptamer-based proteomics. METHODS: Quantitative SOMAscan proteomics was applied to the serum of adult patients with MCD (n = 15) and MN (n = 37) and healthy controls (n = 20). Associations between the proteins detected with SOMAscan were assessed using multiple statistical tests, expression pattern analysis, and systems biology analysis. RESULTS: A total of 208 and 244 proteins were identified that differentiated MCD and MN, respectively, with high statistical significance from the healthy controls (Benjamin-Hochberg [BH] P < 0.). There were 157 proteins that discriminated MN from MCD (BH P < 0.05). In MCD, 65 proteins were differentially expressed as compared with MN and healthy controls. When compared with MCD and healthy controls, 44 discriminatory proteins were specifically linked to MN. Systems biology analysis of these signatures identified cell death and inflammation as key pathways differentiating MN from MCD and healthy controls. Dysregulation of fatty acid metabolism pathways was confirmed in both MN and MCD as compared with the healthy subjects. CONCLUSION: SOMAscan represents a promising proteomic platform for biomarker development in GN. Validation of a greater number of discovery biomarkers in larger patient cohorts is needed before these data can be translated for clinical care. Muruve, Daniel A Debiec, Hanna Dillon, Simon T Gu, Xuesong Plaisier, Emmanuelle Can, Handan Otu, Hasan H Libermann, Towia A Ronco, Pierre eng Kidney Int Rep. Apr 14;7(7):-. doi: 10./j.ekir..04.006. eCollection Jul.I SomaScan 07/12/ Austin TR, et al. Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing Eur J Epidemiol 37 7 755-765 https://www.doi.org/10./s-022--z 35,790,642 Biomarkers Cohort Studies Female Humans *Information Dissemination Male Prospective Studies *Proteomics/methods Cardiovascular Disease Cohort Study Genomics Proteomics funded by Johnson & Johnson. Elkind receives study drug in kind from the BMS-Pfizer Alliance for Eliquis(R) and funding from Roche for a NIH-funded stroke prevention trial royalties from UpToDate for chapters on stroke and serves as an unpaid Officer of the American Heart Association. Floyd has consulted for Shionogi Inc. Kizer has stock ownership in Abbott, Bristol Myers Squibb, Johnson & Johnson, Medtronic, Merck and Pfizer. Odden is a consultant for Cricket Health, Inc. BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology. METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay proteins in frozen, stored plasma from participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations. CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults. Austin, Thomas R McHugh, Caitlin P Brody, Jennifer A Bis, Joshua C Sitlani, Colleen M Bartz, Traci M Biggs, Mary L Bansal, Nisha Buzkova, Petra Carr, Steven A deFilippi, Christopher R Elkind, Mitchell S V Fink, Howard A Floyd, James S Fohner, Alison E Gerszten, Robert E Heckbert, Susan R Katz, Daniel H Kizer, Jorge R Lemaitre, Rozenn N Longstreth, W T McKnight, Barbara Mei, Hao Mukamal, Kenneth J Newman, Anne B Ngo, Debby Odden, Michelle C Vasan, Ramachandran S Shojaie, Ali Simon, Noah Smith, George Davey Davies, Neil M Siscovick, David S Sotoodehnia, Nona Tracy, Russell P Wiggins, Kerri L Zheng, Jie Psaty, Bruce M eng U01HL/HL/NHLBI NIH HHS/ HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ RF1 AG/AG/NIA NIH HHS/ K01 AG/AG/NIA NIH HHS/ WT_/Wellcome Trust/United Kingdom U01HL/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01AG/AG/NIA NIH HHS/ 75ND/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ RF1AG/AG/NIA NIH HHS/ R01HL/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ R01 AG/AG/NIA NIH HHS/ Netherlands Eur J Epidemiol. Jul;37(7):755-765. doi: 10./s-022--z. Epub Jul 5.I SomaScan 07/06/ Degnes ML, et al. Placenta-derived proteins across gestation in healthy pregnancies-a novel approach to assess placental function? BMC Med 20 1 227 https://www.doi.org/10./s-022--z 35,773,701 Biomarkers *Cesarean Section Cross-Sectional Studies Female Humans Placenta Pregnancy *Proteomics Aptamer Four vessel sampling Human Proteomics SomaLogic BACKGROUND: Placenta-derived proteins in the systemic maternal circulation are suggested as potential biomarkers for placental function. However, the identity and longitudinal patterns of such proteins are largely unknown due to the inaccessibility of the human placenta and limitations in assay technologies. We aimed to identify proteins derived from and taken up by the placenta in the maternal circulation. Furthermore, we aimed to describe the longitudinal patterns across gestation of placenta-derived proteins as well as identify placenta-derived proteins that can serve as reference curves for placental function. METHODS: We analyzed proteins in plasma samples collected in two cohorts using the Somalogic -plex platform. Antecubital vein samples were collected at three time points (gestational weeks 14-16, 22-24, and 30-32) across gestation in 70 healthy pregnancies in the longitudinal STORK cohort. In the cross sectional 4-vessel cohort, blood samples were collected simultaneously from the maternal antecubital vein (AV), radial artery (RA), and uterine vein (UV) during cesarean section in 75 healthy pregnancies. Placenta-derived proteins and proteins taken up by the placenta were identified using venoarterial differences (UV-RA). Placenta-derived proteins were defined as placenta-specific by comparison to the venoarterial difference in the antecubital vein-radial artery (AV-RA). These proteins were described longitudinally based on the STORK cohort samples using a linear mixed effects model per protein. Using a machine learning algorithm, we identified placenta-derived proteins that could predict gestational age, meaning that they closely tracked gestation, and were potential read-outs of placental function. RESULTS: Among the nearly measured proteins, we identified 256 placenta-derived proteins and 101 proteins taken up by the placenta (FDR < 0.05). Among the 256 placenta-derived proteins released to maternal circulation, 101 proteins were defined as placenta-specific. These proteins formed two clusters with distinct developmental patterns across gestation. We identified five placenta-derived proteins that closely tracked gestational age when measured in the systemic maternal circulation, termed a placental proteomic clock." CONCLUSIONS: Together, these data may serve as a first step towards a reference for the healthy placenta-derived proteome that can be measured in the systemic maternal circulation and potentially serve as biomarkers of placental function. The "placental proteomic clock" represents a novel concept that warrants further investigation. Deviations in the proteomic pattern across gestation of such proteomic clock proteins may serve as an indication of placental dysfunction." Degnes, Maren-Helene Langeland Westerberg, Ane Cecilie Zucknick, Manuela Powell, Theresa L Jansson, Thomas Henriksen, Tore Roland, Marie Cecilie Paasche Michelsen, Trond Melbye eng Research Support, Non-U.S. Gov't England BMC Med. Jul 1;20(1):227. doi: 10./s-022--z.I SomaScan 07/01/ Sasamoto N, et al. Circulating proteomic profiles associated with endometriosis in adolescents and young adults Hum Reprod 37 9 - https://www.doi.org/10./humrep/deac146 35,770,801 Adolescent Adult Boston Cohort Studies Cross-Sectional Studies *Endometriosis/metabolism Female Humans Observational Studies as Topic Proteomics United States Young Adult adolescents angiogenesis endometriosis lesion color STUDY QUESTION: What are the systemic molecular profiles of endometriosis diagnosed in adolescents and young adults? SUMMARY ANSWER: Significant enrichment and increased activation of proteins related to angiogenesis and cell migration pathways were observed in endometriosis cases compared to controls (P-value < 2.4 x 10-8). WHAT IS KNOWN ALREADY: Little is known about the pathophysiology of adolescent endometriosis despite the fact that over 50% of adults with endometriosis report onset of severe pelvic pain during adolescence. STUDY DESIGN, SIZE, DURATION: A cross-sectional analysis using data on 142 laparoscopically confirmed endometriosis cases and 74 controls from the observational longitudinal cohort of Women's Health Study: From Adolescence to Adulthood (A2A). PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured plasma protein levels using the validated, multiplex aptamer-based proteomics discovery platform, SOMAscan. We calculated odds ratios and 95% CIs using logistic regression adjusting for age, BMI, fasting status and hormone use at blood draw for differentially expressed proteins (P 1.2, revealing significant enrichment of dysregulated proteins in biological pathways associated with endometriosis. Increased activation of pathways related to angiogenesis and cell migration was observed in plasma from endometriosis cases compared to controls (P-value < 2.4 x 10-8). Furthermore, when we examined proteins and pathways associated with lesion colors, vascularized lesions were associated with upregulation of pathways related to immune cell migration/activation and inflammation, whereas white, blue/black and brown lesions were associated with downregulation of these pathways. LIMITATIONS, REASONS FOR CAUTION: Validation of our results in independent datasets and mechanistic studies are warranted to further our understanding of the pathophysiological characteristics of this common but understudied patient population. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this was the first study to comprehensively examine circulating proteins in predominantly adolescents and young adult women with and without endometriosis. Results from this study provide novel biological insight that will build toward further research to elucidate endometriosis pathophysiology during the earlier course of the disease trajectory. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Defense (W81XWH) and the Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., K.L.T. have received funding from Marriott Family Foundation. S.A.M. and K.L.T. are supported by NICHD (R01 HD). S.A.M. serves as an advisory board member for AbbVie and Roche; neither are related to this study. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A. Sasamoto, Naoko Ngo, Long Vitonis, Allison F Dillon, Simon T Missmer, Stacey A Libermann, Towia A Terry, Kathryn L eng Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Hum Reprod. Aug 25;37(9):-. doi: 10./humrep/deac146.I SomaScan 07/01/ Zhang Y, et al. CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure J Exp Med 219 8 https://www.doi.org/10./jem. 35,687,056 Angiotensin II Animals Cardiomegaly Chemokine CCL17/metabolism Chemokines/metabolism Fibrosis *Heart Failure Humans Ligands Mice Mice, Inbred C57BL Myocardium/pathology Myocytes, Cardiac/metabolism *Proteomics Circulating proteomic signatures of age are closely associated with aging and age-related diseases; however, the utility of changes in secreted proteins in identifying therapeutic targets for diseases remains unclear. Serum proteomic profiling of an age-stratified healthy population and further community-based cohort together with heart failure patients study demonstrated that circulating C-C motif chemokine ligand 17 (CCL17) level increased with age and correlated with cardiac dysfunction. Subsequent animal experiments further revealed that Ccll7-KO significantly repressed aging and angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis, accompanied by the plasticity and differentiation of T cell subsets. Furthermore, the therapeutic administration of an anti-CCL17 neutralizing antibody inhibited Ang II-induced pathological cardiac remodeling. Our findings reveal that chemokine CCL17 is identifiable as a novel therapeutic target in age-related and Ang II-induced pathological cardiac hypertrophy and heart failure. Zhang, Yang Ye, Yicong Tang, Xiaoqiang Wang, Hui Tanaka, Toshiko Tian, Ran Yang, Xufei Wang, Lun Xiao, Ying Hu, Xiaomin Jin, Ye Pang, Haiyu Du, Tian Liu, Honghong Sun, Lihong Xiao, Shuo Dong, Ruijia Ferrucci, Luigi Tian, Zhuang Zhang, Shuyang eng -I2M-1-003/Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ /Beijing Natural Science Foundation/ YFC/National Key Research and Development Program of China/ PX/Beijing Hospital Authority/ /National Natural Science Foundation of China/ AG/NIA NIH HHS/ Research Support, Non-U.S. Gov't J Exp Med. Aug 1;219(8):e. doi: 10./jem.. Epub Jun 10.I SomaScan 06/11/ Loza MJ, et al. Serologic Biomarkers of Progression Toward Diagnosis of Rheumatoid Arthritis in Active Component Military Personnel Arthritis Rheumatol 74 11 - https://www.doi.org/10./art. 35,671,369 Humans *Military Personnel Proteomics Programmed Cell Death 1 Receptor *Arthritis, Rheumatoid Biomarkers *Arthritis, Reactive OBJECTIVE: To identify a panel of serum biomarkers that could specifically identify imminent cases of rheumatoid arthritis (RA) before diagnosis. METHODS: Serum samples were collected at 4 time points from active component US military personnel, including 157 anti-citrullinated protein antibody (ACPA)-seropositive and 50 ACPA-seronegative RA subjects, 100 reactive arthritis (ReA) subjects, and 76 healthy controls. The cohorts were split into 2 phases, with samples tested on independent proteomic platforms for each phase. Classification models of RA diagnosis based on samples obtained within 6 months prior to diagnosis were developed both in univariate analyses and by multivariate random forest modeling of training sample sets and testing sample sets from each phase. RESULTS: Increases in serum analytes, including C-reactive protein levels, serum amyloid A, and soluble programmed cell death 1 (PD-1), were observed in seropositive RA subjects at the time point closest to diagnosis, up to several years before diagnosis. Only a small fraction of RA subjects had levels above the 95th percentile of healthy control levels until the time period within 6 months of diagnosis. For classification of RA diagnosis using samples obtained within 6 months prior to diagnosis, soluble PD-1 provided superior specificity compared to ReA cases (>89%), with a sensitivity of 48% for RA classification. An 8-analyte model provided superior sensitivity (69%), with comparable specificity relative to ReA (>82%). CONCLUSION: Our findings demonstrate that imminent RA diagnosis could be classified with high specificity, relative to healthy controls and ReA cases, using a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis. Loza, Matthew J Nagpal, Sunil Cole, Suzanne Laird, Renee M Alcala, Ashley Rao, Navin L Riddle, Mark S Porter, Chad K eng Research Support, Non-U.S. Gov't Arthritis Rheumatol. Nov;74(11):-. doi: 10./art.. Epub Oct 7.I SomaScan 06/08/ Nocera AL, et al. Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis J Allergy Clin Immunol 150 4 872-881 https://www.doi.org/10./j.jaci..04.034 35,660,375 Allergens Animals Chronic Disease Cysteine Proteinase Inhibitors Cytokines Inflammation Mice *Nasal Polyps/pathology Peptide Hydrolases Proteomics *Rhinitis/metabolism *Salivary Cystatins/genetics/metabolism *Sinusitis/pathology Epithelium P-glycoprotein cystatin SA cystatin SN exome posttranslational modification sinonasal mucus transcriptome from the MEEI Curing Kids Fund, Cook Medical, Medtronics has consultant arrangements with Olympus, Medtronics, 3D Matrix, Third Wave Therapeutics, Bear-ENT, and Karl Storz has provided expert testimony on ear, nose, and throat-related cases has a patent for P-gp and cystatin inhibition for chronic rhinosinusitis and receives royalties from this patent and has stock and/or stock options in Interscope, Inquis Medical, and Diceros Therapeutics. The rest of the authors declare that they have no relevant conflicts of interest. BACKGROUND: Cystatin SN (CST1) and cystatin SA (CST2) are cysteine protease inhibitors that protect against allergen, viral, and bacterial proteases. Cystatins are overexpressed in the setting of allergic rhinitis and chronic rhinosinusitis with nasal polyps (CRSwNP); however, their role in promoting type 2 inflammation remains poorly characterized. OBJECTIVE: The purpose of this study was to use integrated poly-omics and a murine exposure model to explore the link between cystatin overexpression in CRSwNP and type 2 inflammation. METHODS: In this institutional review board- and institutional animal care and use committee-approved study, we compared tissue, exosome, and mucus CST1 and CST2 between CRSwNP and controls (n = 10 per group) by using matched whole exome sequencing, transcriptomic, proteomic, posttranslational modification, histologic, functional, and bioinformatic analyses. C57/BL6 mice were dosed with 3.9 mug/mL of CST1 or PBS intranasally for 5 to 18 days in the presence or absence of epithelial ABCB1a knockdown. Inflammatory cytokines were quantified by using Quansys multiplex assays or ELISAs. RESULTS: Of the proteins quantified, CST1 and CST2 were among the most overexpressed protease inhibitors in tissue, exosome, and mucus samples; they were localized to the epithelial layer. Multiple posttranslational modifications were identified in the polyp tissue. Exosomal CST1 and CST2 were strongly and significantly correlated with eosinophils and Lund-Mackay scores. Murine type 2 cytokine secretion and T(H)2 cell infiltration increased in a time-dependent manner following CST1 exposure and was abrogated by epithelial knockdown of ABCB1a, a regulator of epithelial cytokine secretion. CONCLUSION: CST1 is a potent upstream initiator of epithelial-derived type 2 inflammation in CRSwNP. Therapeutic strategies targeting CST activity and its associated posttranslational modifications deserve further interrogation. Nocera, Angela L Mueller, Sarina K Workman, Alan D Wu, Dawei McDonnell, Kristen Sadow, Peter M Amiji, Mansoor M Bleier, Benjamin S eng P01 CA/CA/NCI NIH HHS/ R01 NS/NS/NINDS NIH HHS/ Research Support, N.I.H., Extramural J Allergy Clin Immunol. Oct;150(4):872-881. doi: 10./j.jaci..04.034. Epub May 31.I SomaScan 06/07/ Ostling J, et al. A novel non-invasive method allowing for discovery of pathologically relevant proteins from small airways Clin Proteomics 19 1 20 https://www.doi.org/10./s-022--y 35,668,386 Asthma Biomarker Breath Exhaled air Non-invasive Non-volatiles Precision medicine Proteomics Small airways of the PExA method, and boardmember and chairholder of PExA AB. Emilia Viklund is reporting a minor chairhold in PExA AB. Dr Ostling reports personal fees from PExA AB during the conduct of the study and Employed by PExA AB while writing the manuscript but not during the planning and completion of the study. BACKGROUND: There is a lack of early and precise biomarkers for personalized respiratory medicine. Breath contains an aerosol of droplet particles, which are formed from the epithelial lining fluid when the small airways close and re-open during inhalation succeeding a full expiration. These particles can be collected by impaction using the PExA((R)) method (Particles in Exhaled Air), and are derived from an area of high clinical interest previously difficult to access, making them a potential source of biomarkers reflecting pathological processes in the small airways. RESEARCH QUESTION: Our aim was to investigate if PExA method is useful for discovery of biomarkers that reflect pathology of small airways. METHODS AND ANALYSIS: Ten healthy controls and 20 subjects with asthma, of whom 10 with small airway involvement as indicated by a high lung clearance index (LCI >/= 2.9 z-score), were examined in a cross-sectional design, using the PExA instrument. The samples were analysed with the SOMAscan proteomics platform (SomaLogic Inc.). RESULTS: Two hundred-seven proteins were detected in up to 80% of the samples. Nine proteins showed differential abundance in subjects with asthma and high LCI as compared to healthy controls. Two of these were less abundant (ALDOA4, C4), and seven more abundant (FIGF, SERPINA1, CD93, CCL18, F10, IgM, IL1RAP). sRAGE levels were lower in ex-smokers (n = 14) than in never smokers (n = 16). Gene Ontology (GO) annotation database analyses revealed that the PEx proteome is enriched in extracellular proteins associated with extracellular exosome-vesicles and innate immunity. CONCLUSION: The applied analytical method was reproducible and allowed identification of pathologically interesting proteins in PEx samples from asthmatic subjects with high LCI. The results suggest that PEx based proteomics is a novel and promising approach to study respiratory diseases with small airway involvement. Ostling, Jorgen Van Geest, Marleen Olsson, Henric K Dahlen, Sven-Erik Viklund, Emilia Gustafsson, Per M Mirgorodskaya, Ekaterina Olin, Anna-Carin eng England Clin Proteomics. Jun 6;19(1):20. doi: 10./s-022--y.I SomaScan 06/07/ Oskarsson GR, et al. Genetic architecture of band neutrophil fraction in Iceland Commun Biol 5 1 525 https://www.doi.org/10./s-022--1 35,650,273 Genome-Wide Association Study Granulocytes/metabolism Humans Iceland Neutrophils/metabolism *Pelger-Huet Anomaly/genetics The characteristic lobulated nuclear morphology of granulocytes is partially determined by composition of nuclear envelope proteins. Abnormal nuclear morphology is primarily observed as an increased number of hypolobulated immature neutrophils, called band cells, during infection or in rare envelopathies like Pelger-Huet anomaly. To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders. We describe 13 sequence variants affecting band neutrophil fraction at nine loci. Five of the variants are at the Lamin B receptor (LBR) locus, encoding an inner nuclear membrane protein. Mutations in LBR are linked to Pelger-Huet anomaly. In addition, we identify cosegregation of a rare stop-gain sequence variant in LBR and Pelger Huet anomaly in an Icelandic eight generation pedigree, initially reported in . Two of the other loci include genes which, like LBR, play a role in the nuclear membrane function and integrity. These GWAS results highlight the role proteins of the inner nuclear membrane have as important for neutrophil nuclear morphology. Oskarsson, Gudjon R Magnusson, Magnus K Oddsson, Asmundur Jensson, Brynjar O Fridriksdottir, Run Arnadottir, Gudny A Katrinardottir, Hildigunnur Rognvaldsson, Solvi Halldorsson, Gisli H Sveinbjornsson, Gardar Ivarsdottir, Erna V Stefansdottir, Lilja Ferkingstad, Egil Norland, Kristjan Tragante, Vinicius Saemundsdottir, Jona Jonasdottir, Aslaug Jonasdottir, Adalbjorg Sigurjonsdottir, Svanhvit Petursdottir, Karen O Davidsson, Olafur B Rafnar, Thorunn Holm, Hilma Olafsson, Isleifur Onundarson, Pall T Vidarsson, Brynjar Sigurdardottir, Olof Masson, Gisli Gudbjartsson, Daniel F Jonsdottir, Ingileif Norddahl, Gudmundur L Thorsteinsdottir, Unnur Sulem, Patrick Stefansson, Kari eng England Commun Biol. Jun 1;5(1):525. doi: 10./s-022--1.I SomaScan 06/02/ Komarova N, et al. Aptamers Targeting Cardiac Biomarkers as an Analytical Tool for the Diagnostics of Cardiovascular Diseases: A Review Biomedicines 10 5 https://www.doi.org/10./biomedicines 35,625,822 aptamer biosensor cardiac biomarkers cardiovascular disease detection diagnostics The detection of cardiac biomarkers is used for diagnostics, prognostics, and the risk assessment of cardiovascular diseases. The analysis of cardiac biomarkers is routinely performed with high-sensitivity immunological assays. Aptamers offer an attractive alternative to antibodies for analytical applications but, to date, are not widely practically implemented in diagnostics and medicinal research. This review summarizes the information on the most common cardiac biomarkers and the current state of aptamer research regarding these biomarkers. Aptamers as an analytical tool are well established for troponin I, troponin T, myoglobin, and C-reactive protein. For the rest of the considered cardiac biomarkers, the isolation of novel aptamers or more detailed characterization of the known aptamers are required. More attention should be addressed to the development of dual-aptamer sandwich detection assays and to the studies of aptamer sensing in alternative biological fluids. The universalization of aptamer-based biomarker detection platforms and the integration of aptamer-based sensing to clinical studies are demanded for the practical implementation of aptamers to routine diagnostics. Nevertheless, the wide usage of aptamers for the diagnostics of cardiovascular diseases is promising for the future, with respect to both point-of-care and laboratory testing. Komarova, Natalia Panova, Olga Titov, Alexey Kuznetsov, Alexander eng 21-79-/Russian Science Foundation/ Review Switzerland Biomedicines. May 6;10(5):. doi: 10./biomedicines.I SomaScan 05/29/ Kobayashi H, et al. Results of untargeted analysis using the SOMAscan proteomics platform indicates novel associations of circulating proteins with risk of progression to kidney failure in diabetes Kidney Int 102 2 370-381 https://www.doi.org/10./j.kint..04.022 35,618,095 Biomarkers/metabolism *Diabetes Mellitus, Type 2/complications *Diabetic Nephropathies/complications/etiology Disease Progression Endostatins Humans Lectins, C-Type Proteomics/methods *Renal Insufficiency circulating biomarker diabetes diabetic kidney disease end-stage kidney disease proteomics analysis patent for predicting risk of ESRD This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated. Kobayashi, Hiroki Looker, Helen C Satake, Eiichiro Saulnier, Pierre Jean Md Dom, Zaipul I O'Neil, Kristina Ihara, Katsuhito Krolewski, Bozena Galecki, Andrzej T Niewczas, Monika A Wilson, Jonathan M Doria, Alessandro Duffin, Kevin L Nelson, Robert G Krolewski, Andrzej S eng ZIA DK/ImNIH/Intramural NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Kidney Int. Aug;102(2):370-381. doi: 10./j.kint..04.022. Epub May 23.I SomaScan 05/27/ Matsuno H, et al. Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression Mol Psychiatry 27 9 - https://www.doi.org/10./s-022--3 35,618,888 Animals Mice Blood-Brain Barrier/metabolism Vascular Endothelial Growth Factor A/metabolism Endothelial Cells/metabolism *Depressive Disorder, Major/metabolism Depression *Brain Diseases/pathology Mice, Inbred BALB C Capillary Permeability/physiology Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood-brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction. Matsuno, Hitomi Tsuchimine, Shoko O'Hashi, Kazunori Sakai, Kazuhisa Hattori, Kotaro Hidese, Shinsuke Nakajima, Shingo Chiba, Shuichi Yoshimura, Aya Fukuzato, Noriko Kando, Mayumi Tatsumi, Megumi Ogawa, Shintaro Ichinohe, Noritaka Kunugi, Hiroshi Sohya, Kazuhiro eng 17K/MEXT | Japan Society for the Promotion of Science (JSPS)/ 20K/MEXT | Japan Society for the Promotion of Science (JSPS)/ 19K/MEXT | Japan Society for the Promotion of Science (JSPS)/ 16KT/MEXT | Japan Society for the Promotion of Science (JSPS)/ 19akh/Japan Agency for Medical Research and Development (AMED)/ 19akh/Japan Agency for Medical Research and Development (AMED)/ England Mol Psychiatry. Sep;27(9):-. doi: 10./s-022--3. Epub May 26.I SomaScan 05/27/ Haslam DE, et al. Stability and reproducibility of proteomic profiles in epidemiological studies: comparing the Olink and SOMAscan platforms Proteomics 22 13 e https://www.doi.org/10./pmic. 35,598,103 Epidemiologic Studies Follow-Up Studies Humans *Proteomics Reproducibility of Results *Specimen Handling Aptamers biomarkers epidemiology studies laboratory methods and tools multiplexing systems biology Limited data exist on the performance of high-throughput proteomics profiling in epidemiological settings, including the impact of specimen collection and within-person variability over time. Thus, the Olink (972 proteins) and SOMAscan7Kv4.1 ( proteoforms of proteins) assays were utilized to measure protein concentrations in archived plasma samples from the Nurses' Health Studies and Health Professionals Follow-Up Study. Spearman's correlation coefficients (r) and intraclass correlation coefficients (ICCs) were used to assess agreement between (1) 42 triplicate samples processed immediately, 24-h or 48-h after blood collection from 14 participants; and (2) 80 plasma samples from 40 participants collected 1-year apart. When comparing samples processed immediately, 24-h, and 48-h later, 55% of assays had an ICC/r >/= 0.75 and 87% had an ICC/r >/= 0.40 in Olink compared to 44% with an ICC/r >/= 0.75 and 72% with an ICC/r >/= 0.40 in SOMAscan7K. For both platforms, >90% of the assays were stable (ICC/r >/= 0.40) in samples collected 1-year apart. Among 817 proteins measured with both platforms, Spearman's correlations were high (r > 0.75) for 14.7% and poor (r < 0.40) for 44.8% of proteins. High-throughput proteomics profiling demonstrated reproducibility in archived plasma samples and stability after delayed processing in epidemiological studies, yet correlations between proteins measured with the Olink and SOMAscan7K platforms were highly variable. Haslam, Danielle E Li, Jun Dillon, Simon T Gu, Xuesong Cao, Yin Zeleznik, Oana A Sasamoto, Naoko Zhang, Xuehong Eliassen, A Heather Liang, Liming Stampfer, Meir J Mora, Samia Chen, Zsu-Zsu Terry, Kathryn L Gerszten, Robert E Hu, Frank B Chan, Andrew T Libermann, Towia A Bhupathiraju, Shilpa N eng P30 CA/NH/NIH HHS/ R01 CA/NH/NIH HHS/ T32 CA/NH/NIH HHS/ U01 CA/NH/NIH HHS/ U01 CA/NH/NIH HHS/ UM1 CA/NH/NIH HHS/ CRUK_/Cancer Research UK/United Kingdom R01 CA/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Germany Proteomics. Jul;22(13-14):e. doi: 10./pmic.. Epub May 31.I SomaScan 05/23/ Kindt ASD, et al. Validation of disease-specific biomarkers for the early detection of bronchopulmonary dysplasia Pediatr Res epub ahead of print https://www.doi.org/10./s-022--w 35,595,912 OBJECTIVE: To demonstrate and validate the improvement of current risk stratification for bronchopulmonary dysplasia (BPD) early after birth by plasma protein markers (sialic acid-binding Ig-like lectin 14 (SIGLEC-14), basal cell adhesion molecule (BCAM), angiopoietin-like 3 protein (ANGPTL-3)) in extremely premature infants. METHODS AND RESULTS: Proteome screening in first-week-of-life plasma samples of n = 52 preterm infants <32 weeks gestational age (GA) on two proteomic platforms (SomaLogic((R)), Olink-Proteomics((R))) confirmed three biomarkers with significant predictive power: BCAM, SIGLEC-14, and ANGPTL-3. We demonstrate high sensitivity (0.92) and specificity (0.86) under consideration of GA, show the proteins' critical contribution to the predictive power of known clinical risk factors, e.g., birth weight and GA, and predicted the duration of mechanical ventilation, oxygen supplementation, as well as neonatal intensive care stay. We confirmed significant predictive power for BPD cases when switching to a clinically applicable method (enzyme-linked immunosorbent assay) in an independent sample set (n = 25, p < 0.001) and demonstrated disease specificity in different cohorts of neonatal and adult lung disease. CONCLUSION: While successfully addressing typical challenges of clinical biomarker studies, we demonstrated the potential of BCAM, SIGLEC-14, and ANGPTL-3 to inform future clinical decision making in the preterm infant at risk for BPD. TRIAL REGISTRATION: Deutsches Register Klinische Studien (DRKS) No. ; https://www.drks.de . IMPACT: The urgent need for biomarkers that enable early decision making and personalized monitoring strategies in preterm infants with BPD is challenged by targeted marker analyses, cohort size, and disease heterogeneity. We demonstrate the potential of the plasma proteins BCAM, SIGLEC-14, and ANGPTL-3 to identify infants with BPD early after birth while improving the predictive power of clinical variables, confirming the robustness toward proteome assays and proving disease specificity. Our comprehensive analysis enables a phase-III clinical trial that allows full implementation of the biomarkers into clinical routine to enable early risk stratification in preterms with BPD. Kindt, Alida S D Forster, Kai M Cochius-den Otter, Suzan C M Flemmer, Andreas W Hauck, Stefanie M Flatley, Andrew Kamphuis, Juliette Karrasch, Stefan Behr, Jurgen Franz, Axel Hartel, Christoph Krumsiek, Jan Tibboel, Dick Hilgendorff, Anne eng Pediatr Res. May 20. doi: 10./s-022--w.I SomaScan 05/21/ Shadrina AS, et al. Mendelian randomization analysis of plasma levels of CD209 and MICB proteins and the risk of varicose veins of lower extremities PLoS One 17 5 e https://www.doi.org/10./journal.pone. 35,594,287 Genome-Wide Association Study Humans Lower Extremity/pathology *Mendelian Randomization Analysis Polymorphism, Single Nucleotide *Varicose Veins/genetics/pathology Varicose veins of lower extremities (VVs) are a highly prevalent condition, the pathogenesis of which is still not fully elucidated. Mendelian randomization (MR) can provide useful preliminary information on the traits that are potentially causally related to the disease. The aim of the present study is to replicate the effects of the plasma levels of MHC class I polypeptide-related sequence B (MICB) and cluster of differentiation 209 (CD209) proteins reported in a previous hypothesis-free MR study. We conducted MR analysis using a fixed effects inverse-variance weighted meta-analysis of Wald ratios method. For MICB and CD209, we used data from a large-scale genome-wide association study (GWAS) for plasma protein levels (N = 3,301). For VVs, we used GWAS data obtained in the FinnGen project (N = 128,698), the eMERGE network (phase 3, N = 48,429), and the UK Biobank data available in the Gene ATLAS (N = 452,264). The data used in the study were obtained in individuals of European descent. The results for MICB did not pass criteria for statistical significance and replication. The results for CD209 passed all statistical significance thresholds, indicating that the genetically predicted increase in CD209 level is associated with increased risk of VVs (betaMR (SE) = 0.07 (0.01), OR (95% CI) = 1.08 (1.05-1.10), P-value = 5.9 x10-11 in the meta-analysis of three cohorts). Our findings provide further support that CD209 can potentially be involved in VVs. In future studies, independent validation of our results using data from more powerful GWASs for CD209 measured by different methods would be beneficial. Shadrina, Alexandra S Elgaeva, Elizaveta E Stanaway, Ian B Jarvik, Gail P Namjou, Bahram Wei, Wei-Qi Glessner, Joe Hakonarson, Hakon Suri, Pradeep Tsepilov, Yakov A eng U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ P30 AR/AR/NIAMS NIH HHS/ Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. May 20;17(5):e. doi: 10./journal.pone.. eCollection .I SomaScan 05/21/ Wesenhagen KEJ, et al. Effects of age, amyloid, sex, and APOE epsilon4 on the CSF proteome in normal cognition Alzheimers Dement (Amst) 14 1 e https://www.doi.org/10./dad2. 35,571,963 INTRODUCTION: It is important to understand which biological processes change with aging, and how such changes are associated with increased Alzheimer's disease (AD) risk. We studied how cerebrospinal fluid (CSF) proteomics changed with age and tested if associations depended on amyloid status, sex, and apolipoprotein E E4 genotype. METHODS: We included 277 cognitively intact individuals aged 46 to 89 years from Alzheimer's Disease Neuroimaging Initiative, European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery, and Metabolic Syndrome in Men. In total, proteins were measured with liquid chromatography mass spectrometry with multiple reaction monitoring/Rules-Based Medicine, tandem mass tag mass spectrometry, and SOMAscan. We tested associations between age and protein levels in linear models and tested enrichment for Reactome pathways. RESULTS: Levels of 252 proteins increased with age independently of amyloid status. These proteins were associated with immune and signaling processes. Levels of 21 proteins decreased with older age exclusively in amyloid abnormal participants and these were enriched for extracellular matrix organization. DISCUSSION: We found amyloid-independent and -dependent CSF proteome changes with older age, perhaps representing physiological aging and early AD pathology. Wesenhagen, Kirsten E J Gobom, Johan Bos, Isabelle Vos, Stephanie J B Martinez-Lage, Pablo Popp, Julius Tsolaki, Magda Vandenberghe, Rik Freund-Levi, Yvonne Verhey, Frans Lovestone, Simon Streffer, Johannes Dobricic, Valerija Bertram, Lars Blennow, Kaj Pikkarainen, Maria Hallikainen, Merja Kuusisto, Johanna Laakso, Markku Soininen, Hilkka Scheltens, Philip Zetterberg, Henrik Teunissen, Charlotte E Visser, Pieter Jelle Tijms, Betty M eng Alzheimers Dement (Amst). May 6;14(1):e. doi: 10./dad2.. eCollection .I SomaScan 05/17/ Bomba L, et al. Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites Am J Hum Genet 109 6 - https://www.doi.org/10./j.ajhg..04.009 35,568,032 *Exome/genetics Gene Frequency/genetics Humans Prospective Studies Whole Exome Sequencing/methods Whole Genome Sequencing Wes Wgs drug targets endophenotypes loss-of-function metabolomics metabolon proteomics rare genetic variant sequencing non-financial support from Merck Sharp & Dohme (MSD) grants, personal fees, and non-financial support from Novartis grants from Pfizer and grants from AstraZeneca outside the submitted work. John Danesh sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since ) the Steering Committee of UK Biobank (since ) the MRC International Advisory Group (ING) member, London (since ) the MRC High Throughput Science 'Omics Panel Member, London (since ) the Scientific Advisory Committee for Sanofi (since ) the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis and the AstraZeneca Genomics Advisory Board (). Adam Butterworth reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Merk and Sanofi. During the course of the project Praveen Surendran became an employee of GSK, Lorenzo Bomba became an employee of BioMarin, Mohd Karim became an employee of Variant Bio and Qi Guo became an employee of BenevolentAI. Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts. Bomba, Lorenzo Walter, Klaudia Guo, Qi Surendran, Praveen Kundu, Kousik Nongmaithem, Suraj Karim, Mohd Anisul Stewart, Isobel D Langenberg, Claudia Danesh, John Di Angelantonio, Emanuele Roberts, David J Ouwehand, Willem H Dunham, Ian Butterworth, Adam S Soranzo, Nicole eng Am J Hum Genet. Jun 2;109(6):-. doi: 10./j.ajhg..04.009. Epub May 13.I SomaScan 05/15/ Jiang W, et al. Analytical Considerations of Large-Scale Aptamer-Based Datasets for Translational Applications Cancers (Basel) 14 9 https://www.doi.org/10./cancers 35,565,358 aptamers bioinformatics biomarkers proteomics translational The development and advancement of aptamer technology has opened a new realm of possibilities for unlocking the biocomplexity available within proteomics. With ultra-high-throughput and multiplexing, alongside remarkable specificity and sensitivity, aptamers could represent a powerful tool in disease-specific research, such as supporting the discovery and validation of clinically relevant biomarkers. One of the fundamental challenges underlying past and current proteomic technology has been the difficulty of translating proteomic datasets into standards of practice. Aptamers provide the capacity to generate single panels that span over different proteins from a singular sample. However, as a recent technology, they also present unique challenges, as the field of translational aptamer-based proteomics still lacks a standardizing methodology for analyzing these large datasets and the novel considerations that must be made in response to the differentiation amongst current proteomic platforms and aptamers. We address these analytical considerations with respect to surveying initial data, deploying proper statistical methodologies to identify differential protein expressions, and applying datasets to discover multimarker and pathway-level findings. Additionally, we present aptamer datasets within the multi-omics landscape by exploring the intersectionality of aptamer-based proteomics amongst genomics, transcriptomics, and metabolomics, alongside pre-existing proteomic platforms. Understanding the broader applications of aptamer datasets will substantially enhance current efforts to generate translatable findings for the clinic. Jiang, Will Jones, Jennifer C Shankavaram, Uma Sproull, Mary Camphausen, Kevin Krauze, Andra V eng ZID BC/ImNIH/Intramural NIH HHS/ ZID BC /CA/NCI NIH HHS/ Review Switzerland Cancers (Basel). Apr 29;14(9):. doi: 10./cancers.I SomaScan 05/15/ Vasbinder A, et al. Assay-related differences in SuPAR levels: implications for measurement and data interpretation J Nephrol 3-Jan https://www.doi.org/10./s-022--7 35,567,697 Olink Quantikine SOMAScan Soluble urokinase plasminogen activator receptor Virogates suPARnostic Vasbinder, Alexi Raffield, Laura Marie Gao, Yan Engstrom, Gunnar Quyyumi, Arshed Ali Reiner, Alexander Paul Reiser, Jochen Hayek, Salim Salim eng KL2TR/TR/NCATS NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ U01-DK/DK/NIDDK NIH HHS/ U-M G/University of Michigan Frankel Cardiovascular Center/ HHSNC/HL/NHLBI NIH HHS/ R01HL/HL/NHLBI NIH HHS/ HHSNI/MD/NIMHD NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ KL2 TR/TR/NCATS NIH HHS/ T32HL/HL/NHLBI NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ T32-HL/HL/NHLBI NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ R01HL/HL/NHLBI NIH HHS/ R01-DK/DK/NIDDK NIH HHS/ Letter Italy J Nephrol. May 14:1-3. doi: 10./s-022--7.I SomaScan 05/15/ Engelke R, et al. Proteomic Analysis of Plasma Markers in Patients Maintained on Antipsychotics: Comparison to Patients Off Antipsychotics and Normal Controls Front Psychiatry 13 https://www.doi.org/10./fpsyt.. 35,546,954 antipsychotics biomarkers bipolar disorder metabolic syndrome proteomics schizophrenia declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) share many features: overlap in mood and psychotic symptoms, common genetic predisposition, treatment with antipsychotics (APs), and similar metabolic comorbidities. The pathophysiology of both is still not well defined, and no biomarkers can be used clinically for diagnosis and management. This study aimed to assess the plasma proteomics profile of patients with SZ and BD maintained on APs compared to those who had been off APs for 6 months and to healthy controls (HCs). METHODS: We analyzed the data using functional enrichment, random forest modeling to identify potential biomarkers, and multivariate regression for the associations with metabolic abnormalities. RESULTS: We identified several proteins known to play roles in the differentiation of the nervous system like NTRK2, CNTN1, ROBO2, and PLXNC1, which were downregulated in AP-free SZ and BD patients but were normalized" in those on APs. Other proteins (like NCAM1 and TNFRSF17) were "normal" in AP-free patients but downregulated in patients on APs, suggesting that these changes are related to medication's effects. We found significant enrichment of proteins involved in neuronal plasticity, mainly in SZ patients on APs. Most of the proteins associated with metabolic abnormalities were more related to APs use than having SZ or BD. The biomarkers identification showed specific and sensitive results for schizophrenia, where two proteins (PRL and MRC2) produced adequate results. CONCLUSIONS: Our results confirmed the utility of blood samples to identify protein signatures and mechanisms involved in the pathophysiology and treatment of SZ and BD." Engelke, Rudolf Ouanes, Sami Ghuloum, Suhaila Chamali, Rifka Kiwan, Nancy Sarwath, Hina Schmidt, Frank Suhre, Karsten Al-Amin, Hassen eng Switzerland Front Psychiatry. Apr 25;13:. doi: 10./fpsyt... eCollection .I SomaScan 05/14/ Roh JD, et al. Plasma Proteomics of COVID-19-Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics JACC Basic Transl Sci 7 5 425-441 https://www.doi.org/10./j.jacbts..01.013 35,530,264 ADAMTS13, A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, member 13 Covid-19 FSTL3, follistatin-like 3 NT-proBNP, N-terminal pro-B-type natriuretic peptide SASP, senescence associated secretory phenotype TGFbeta, transforming growth factor beta hsTnT, high sensitivity troponin T myocardial injury proteomics senescence R35HL [to Dr Rosenzweig] R01HL, R01HL, and K24HL [to Dr Ellinor] R01HL, R01HL, K24HL [to Dr Ho] T32HL [to Dr Weber] K08HL [to Dr Rhee] and K76AG [to Dr Roh]), the Fondation Leducq (14CVD01 [to Dr Ellinor]), the American Heart Association (18SFRN [to Dr Ellinor]), a Sarnoff Cardiovascular Research Foundation Fellowship award (to Dr Trager), the Fred and Ines Yeatts Fund for Innovative Research (to Dr Roh), the Hassenfeld Scholars Award (to Dr Roh), Fast Grants, Emergent Ventures, Mercatus Center at George Mason University (to Dr Martinot), and a research grant from Bayer AG to the Broad Institute (to Drs Ellinor and Ho). Dr Ellinor is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases and has served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. Dr Ho has received research grants from Bayer AG and Gilead Sciences and has received research supplies from EcoNugenics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. To gain insights into the mechanisms driving cardiovascular complications in COVID-19, we performed a case-control plasma proteomics study in COVID-19 patients. Our results identify the senescence-associated secretory phenotype, a marker of biological aging, as the dominant process associated with disease severity and cardiac involvement. FSTL3, an indicator of senescence-promoting Activin/TGFbeta signaling, and ADAMTS13, the von Willebrand Factor-cleaving protease whose loss-of-function causes microvascular thrombosis, were among the proteins most strongly associated with myocardial stress and injury. Findings were validated in a larger COVID-19 patient cohort and the hamster COVID-19 model, providing new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications. Roh, Jason D Kitchen, Robert R Guseh, J Sawalla McNeill, Jenna N Aid, Malika Martinot, Amanda J Yu, Andy Platt, Colin Rhee, James Weber, Brittany Trager, Lena E Hastings, Margaret H Ducat, Sarah Xia, Peng Castro, Claire Singh, Abhilasha Atlason, Bjarni Churchill, Timothy W Di Carli, Marcelo F Ellinor, Patrick T Barouch, Dan H Ho, Jennifer E Rosenzweig, Anthony eng K08 HL/HL/NHLBI NIH HHS/ R01 AG/AG/NIA NIH HHS/ JACC Basic Transl Sci. May;7(5):425-441. doi: 10./j.jacbts..01.013. Epub May 4.I SomaScan 05/10/ Edfors F, et al. Proteomics in thrombosis research Res Pract Thromb Haemost 6 3 e https://www.doi.org/10./rth2. 35,494,505 Vte biomarker mass spectrometry plasma protein proteome proteomics thrombosis venous thromboembolism A State of the Art lecture titled Proteomics in Thrombosis Research" was presented at the ISTH Congress in . In clinical practice, there is a need for improved plasma biomarker-based tools for diagnosis and risk prediction of venous thromboembolism (VTE). Analysis of blood, to identify plasma proteins with potential utility for such tools, could enable an individualized approach to treatment and prevention. Technological advances to study the plasma proteome on a large scale allows broad screening for the identification of novel plasma biomarkers, both by targeted and nontargeted proteomics methods. However, assay limitations need to be considered when interpreting results, with orthogonal validation required before conclusions are drawn. Here, we review and provide perspectives on the application of affinity- and mass spectrometry-based methods for the identification and analysis of plasma protein biomarkers, with potential application in the field of VTE. We also provide a future perspective on discovery strategies and emerging technologies for targeted proteomics in thrombosis research. Finally, we summarize relevant new data on this topic, presented during the ISTH Congress." Edfors, Fredrik Iglesias, Maria Jesus Butler, Lynn M Odeberg, Jacob eng Res Pract Thromb Haemost. Apr 25;6(3):e. doi: 10./rth2.. eCollection Mar.I SomaScan 05/03/ Manichaikul A, et al. Lymphocyte activation gene-3-associated protein networks are associated with HDL-cholesterol and mortality in the Trans-omics for Precision Medicine program Commun Biol 5 1 362 https://www.doi.org/10./s-022--0 35,501,457 *Atherosclerosis Cholesterol, HDL Chromatin Humans Lymphocyte Activation Membrane Proteins *Precision Medicine Deficiency of the immune checkpoint lymphocyte activation gene-3 (LAG3) protein is significantly associated with both elevated HDL-cholesterol (HDL-C) and myocardial infarction risk. We determined the association of genetic variants within +/-500 kb of LAG3 with plasma LAG3 and defined LAG3-associated plasma proteins with HDL-C and clinical outcomes. Whole genome sequencing and plasma proteomics were obtained from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study (FHS) cohorts as part of the Trans-Omics for Precision Medicine program. In situ Hi-C chromatin capture was performed in EBV-transformed cell lines isolated from four MESA participants. Genetic association analyses were performed in MESA using multivariate regression models, with validation in FHS. A LAG3-associated protein network was tested for association with HDL-C, coronary heart disease, and all-cause mortality. We identify an association between the LAG3 rs variant and plasma LAG3 protein. Proteomics analysis reveals 183 proteins significantly associated with LAG3 with four proteins associated with HDL-C. Four proteins discovered for association with all-cause mortality in FHS shows nominal associations in MESA. Chromatin capture analysis reveals significant cis interactions between LAG3 and C1S, LRIG3, TNFRSF1A, and trans interactions between LAG3 and B2M. A LAG3-associated protein network has significant associations with HDL-C and mortality. Manichaikul, Ani Lin, Honghuang Kang, Chansuk Yang, Chaojie Rich, Stephen S Taylor, Kent D Guo, Xiuqing Rotter, Jerome I Craig Johnson, W Cornell, Elaine Tracy, Russell P Peter Durda, J Liu, Yongmei Vasan, Ramachandran S Adrienne Cupples, L Gerszten, Robert E Clish, Clary B Jain, Deepti Conomos, Matthew P Blackwell, Thomas Papanicolaou, George J Rodriguez, Annabelle eng N01HC/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ UL1 RR/RR/NCRR NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ 75ND/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ U54 HG/HG/NHGRI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ N01HC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Commun Biol. May 2;5(1):362. doi: 10./s-022--0.I SomaScan 05/03/ Zhang J, et al. Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies Nat Genet 54 5 593-602 https://www.doi.org/10./s-022--w 35,501,419 Genetic Predisposition to Disease Genome-Wide Association Study *Gout/genetics Humans Polymorphism, Single Nucleotide *Proteome/genetics Improved understanding of genetic regulation of the proteome can facilitate identification of the causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the Atherosclerosis Risk in Communities study, and further replicated findings on 467 AA individuals from the African American Study of Kidney Disease and Hypertension study. Here, we identified 2,004 proteins in EA and 1,618 in AA, with most overlapping, which showed associations with common variants in cis-regions. Availability of AA samples led to smaller credible sets and notable number of population-specific cis-protein quantitative trait loci. Elastic Net produced powerful models for protein prediction in both populations. An application of proteome-wide association studies to serum urate and gout implicated several proteins, including IL1RN, revealing the promise of the drug anakinra to treat acute gout flares. Our study demonstrates the value of large and diverse ancestry study to investigate the genetic mechanisms of molecular phenotypes and their relationship with complex traits. Zhang, Jingning Dutta, Diptavo Kottgen, Anna Tin, Adrienne Schlosser, Pascal Grams, Morgan E Harvey, Benjamin Yu, Bing Boerwinkle, Eric Coresh, Josef Chatterjee, Nilanjan eng R01 HG/HG/NHGRI NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Genet. May;54(5):593-602. doi: 10./s-022--w. Epub May 2.I SomaScan 05/03/ He B, et al. Clinical applications of plasma proteomics and peptidomics: Towards precision medicine Proteomics Clin Appl 16 6 e https://www.doi.org/10./prca. 35,490,333 Humans *Proteomics/methods Proteome/metabolism Precision Medicine/methods *COVID-19/diagnosis Biomarkers/metabolism biomarkers human proteome project peptidomics plasma precision medicine proteomics In the context of precision medicine, disease treatment requires individualized strategies based on the underlying molecular characteristics to overcome therapeutic challenges posed by heterogeneity. For this purpose, it is essential to develop new biomarkers to diagnose, stratify, or possibly prevent diseases. Plasma is an available source of biomarkers that greatly reflects the physiological and pathological conditions of the body. An increasing number of studies are focusing on proteins and peptides, including many involving the Human Proteome Project (HPP) of the Human Proteome Organization (HUPO), and proteomics and peptidomics techniques are emerging as critical tools for developing novel precision medicine preventative measures. Excitingly, the emerging plasma proteomics and peptidomics toolbox exhibits a huge potential for studying pathogenesis of diseases (e.g., COVID-19 and cancer), identifying valuable biomarkers and improving clinical management. However, the enormous complexity and wide dynamic range of plasma proteins makes plasma proteome profiling challenging. Herein, we summarize the recent advances in plasma proteomics and peptidomics with a focus on their emerging roles in COVID-19 and cancer research, aiming to emphasize the significance of plasma proteomics and peptidomics in clinical applications and precision medicine. He, Bo Huang, Zhao Huang, Canhua Nice, Edouard C eng YFC/National Key Research and Development Project of China/ /the National Natural Science Foundation of China/ /the National Natural Science Foundation of China/ Review Germany Proteomics Clin Appl. Nov;16(6):e. doi: 10./prca.. Epub May 11.I SomaScan 05/02/ Rashid A, et al. Proteomics of lung tissue reveals differences in inflammation and alveolar-capillary barrier response between atelectasis and aerated regions Sci Rep 12 1 https://www.doi.org/10./s-022--7 35,487,970 *Acute Lung Injury/metabolism Humans Inflammation/metabolism Lipopolysaccharides/metabolism Lung/metabolism Proteomics *Pulmonary Atelectasis/metabolism Atelectasis is a frequent clinical condition, yet knowledge is limited and controversial on its biological contribution towards lung injury. We assessed the regional proteomics of atelectatic versus normally-aerated lung tissue to test the hypothesis that immune and alveolar-capillary barrier functions are compromised by purely atelectasis and dysregulated by additional systemic inflammation (lipopolysaccharide, LPS). Without LPS, 130 proteins were differentially abundant in atelectasis versus aerated lung, mostly (n = 126) with less abundance together with negatively enriched processes in immune, endothelial and epithelial function, and Hippo signaling pathway. Instead, LPS-exposed atelectasis produced 174 differentially abundant proteins, mostly (n = 108) increased including acute lung injury marker RAGE and chemokine CCL5. Functional analysis indicated enhanced leukocyte processes and negatively enriched cell-matrix adhesion and cell junction assembly with LPS. Additionally, extracellular matrix organization and TGF-beta signaling were negatively enriched in atelectasis with decreased adhesive glycoprotein THBS1 regardless of LPS. Concordance of a subset of transcriptomics and proteomics revealed overlap of leukocyte-related gene-protein pairs and processes. Together, proteomics of exclusively atelectasis indicates decreased immune response, which converts into an increased response with LPS. Alveolar-capillary barrier function-related proteomics response is down-regulated in atelectasis irrespective of LPS. Specific proteomics signatures suggest biological mechanistic and therapeutic targets for atelectasis-associated lung injury. Rashid, Azman Zeng, Congli Motta-Ribeiro, Gabriel Dillon, Simon T Libermann, Towia A Lessa, Marcos Adriano Bagchi, Aranya Hutchinson, John Vidal Melo, Marcos F eng R01 HL/NH/NIH HHS/ Research Support, N.I.H., Extramural England Sci Rep. Apr 29;12(1):. doi: 10./s-022--7.I SomaScan 04/30/ Rhodes CJ, et al. Harnessing Big Data to Advance Treatment and Understanding of Pulmonary Hypertension Circ Res 130 9 - https://www.doi.org/10./CIRCRESAHA.121. 35,482,840 *Big Data Humans *Hypertension, Pulmonary/diagnosis/drug therapy/genetics Machine Learning Precision Medicine/methods big data information dissemination phenotype precision medicine pulmonary arterial hypertension Maron discloses Consultant roles for Actelion Pharmaceuticals and Tenax, and a Grant / Contract from Deerfield Company. Pulmonary hypertension is a complex disease with multiple causes, corresponding to phenotypic heterogeneity and variable therapeutic responses. Advancing understanding of pulmonary hypertension pathogenesis is likely to hinge on integrated methods that leverage data from health records, imaging, novel molecular -omics profiling, and other modalities. In this review, we summarize key data sets generated thus far in the field and describe analytical methods that hold promise for deciphering the molecular mechanisms that underpin pulmonary vascular remodeling, including machine learning, network medicine, and functional genetics. We also detail how genetic and subphenotyping approaches enable earlier diagnosis, refined prognostication, and optimized treatment prediction. We propose strategies that identify functionally important molecular pathways, bolstered by findings across multi-omics platforms, which are well-positioned to individualize drug therapy selection and advance precision medicine in this highly morbid disease. Rhodes, Christopher J Sweatt, Andrew J Maron, Bradley A eng K23 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ FS/15/59//BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review Circ Res. Apr 29;130(9):-. doi: 10./CIRCRESAHA.121.. Epub Apr 28.I SomaScan 04/29/ Saevarsdottir S, et al. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset Ann Rheum Dis 81 8 - https://www.doi.org/10./annrheumdis-- 35,470,158 *Arthritis, Rheumatoid/genetics Genetic Predisposition to Disease/genetics *Genome-Wide Association Study Humans Interferon-alpha Janus Kinases/genetics Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics Proteomics STAT Transcription Factors/genetics Signal Transduction/genetics autoantibodies polymorphism, genetic rheumatoid arthritis competing financial interests as employees. OAA is a consultant to HealthLytix. The following coauthors report the following but unrelated to the current report: Karolinska Institutet, with JA as principal investigator, has entered into agreements with the following entities, mainly but not exclusively for safety monitoring of rheumatology immunomodulators: Abbvie, BMS, Eli Lilly, Janssen, MSD, Pfizer, Roche, Samsung Bioepis and Sanofi, unrelated to the present study. SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S and managing board memberships in Proscion A/S and Intomics A/S. BG has received research grants from AbbVie, Bristol Myers-Squibb and Pfizer OH has received research grants from AbbVie, Novartis and Pfizer, DVJ has received speaker and consultation fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, AGL has received speaking and/or consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB and CT has received consulting fees from Roche, speaker fees from Abbvie, Bristol Myers-Squibb, Nordic Drugs, Pfizer and Roche, and an unrestricted grant from Bristol Myers-Squibb. OBJECTIVES: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. METHODS: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). RESULTS: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs-C, rs-C, rs-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. CONCLUSION: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce. Saevarsdottir, Saedis Stefansdottir, Lilja Sulem, Patrick Thorleifsson, Gudmar Ferkingstad, Egil Rutsdottir, Gudrun Glintborg, Bente Westerlind, Helga Grondal, Gerdur Loft, Isabella C Sorensen, Signe Bek Lie, Benedicte A Brink, Mikael Arlestig, Lisbeth Arnthorsson, Asgeir Orn Baecklund, Eva Banasik, Karina Bank, Steffen Bjorkman, Lena I Ellingsen, Torkell Erikstrup, Christian Frei, Oleksandr Gjertsson, Inger Gudbjartsson, Daniel F Gudjonsson, Sigurjon A Halldorsson, Gisli H Hendricks, Oliver Hillert, Jan Hogdall, Estrid Jacobsen, Soren Jensen, Dorte Vendelbo Jonsson, Helgi Kastbom, Alf Kockum, Ingrid Kristensen, Salome Kristjansdottir, Helga Larsen, Margit H Linauskas, Asta Hauge, Ellen-Margrethe Loft, Anne G Ludviksson, Bjorn R Lund, Sigrun H Markusson, Thorsteinn Masson, Gisli Melsted, Pall Moore, Kristjan H S Munk, Heidi Nielsen, Kaspar R Norddahl, Gudmundur L Oddsson, Asmundur Olafsdottir, Thorunn A Olason, Pall I Olsson, Tomas Ostrowski, Sisse Rye Horslev-Petersen, Kim Rognvaldsson, Solvi Sanner, Helga Silberberg, Gilad N Stefansson, Hreinn Sorensen, Erik Sorensen, Inge J Turesson, Carl Bergman, Thomas Alfredsson, Lars Kvien, Tore K Brunak, Soren Steinsson, Kristjan Andersen, Vibeke Andreassen, Ole A Rantapaa-Dahlqvist, Solbritt Hetland, Merete Lund Klareskog, Lars Askling, Johan Padyukov, Leonid Pedersen, Ole Bv Thorsteinsdottir, Unnur Jonsdottir, Ingileif Stefansson, Kari (SRQb) eng Research Support, Non-U.S. Gov't England Ann Rheum Dis. Aug;81(8):-. doi: 10./annrheumdis--. Epub Apr 25.I SomaScan 04/27/ Dayon L, et al. Proteomics of human biological fluids for biomarker discoveries: technical advances and recent applications Expert Rev Proteomics 19 2 131-151 https://www.doi.org/10./.. 35,466,824 Biomarkers/metabolism *Body Fluids/metabolism Humans Proteome/metabolism *Proteomics/methods Automation Ms biofluid biomarker cohort human mass spectrometry plasma proteomics INTRODUCTION: Biological fluids are routine samples for diagnostic testing and monitoring. Blood samples are typically measured because of their moderate invasive collection and high information content on health and disease. Several body fluids, such as cerebrospinal fluid (CSF), are also studied and suited to specific pathologies. Over the last two decades, proteomics has quested to identify protein biomarkers but with limited success. Recent technologies and refined pipelines have accelerated the profiling of human biological fluids. AREAS COVERED: We review proteomic technologies for the identification of biomarkers. These are based on antibodies/aptamers arrays or mass spectrometry (MS), but new ones are emerging. Advances in scalability and throughput have allowed to better design studies and cope with the limited sample size that has until now prevailed due to technological constraints. With these enablers, plasma/serum, CSF, saliva, tears, urine, and milk proteomes have been further profiled; we provide a non-exhaustive picture of some recent highlights (mainly covering literature from the last 5 years in the Scopus database) using MS-based proteomics. EXPERT OPINION: While proteomics has been in the shadow of genomics for years, proteomic tools and methodologies have reached certain maturity. They are now better suited to discover innovative and robust biofluid biomarkers. Dayon, Loic Cominetti, Ornella Affolter, Michael eng Research Support, Non-U.S. Gov't Review England Expert Rev Proteomics. Feb;19(2):131-151. doi: 10./... Epub May 5.I SomaScan 04/26/ Wu BS, et al. Identifying causal genes for stroke via integrating the proteome and transcriptome from brain and blood J Transl Med 20 1 181 https://www.doi.org/10./s-022--9 35,449,099 Bayes Theorem Brain/metabolism Genetic Predisposition to Disease *Genome-Wide Association Study Humans Polymorphism, Single Nucleotide/genetics Proteome/genetics/metabolism *Stroke/complications Transcriptome/genetics Bayesian colocalization Mendelian randomization Proteome-wide association study Stroke Transcriptome-wide association study BACKGROUND: Genome-wide association studies (GWAS) have revealed numerous loci associated with stroke. However, the underlying mechanisms at these loci in the pathogenesis of stroke and effective stroke drug targets are elusive. Therefore, we aimed to identify causal genes in the pathogenesis of stroke and its subtypes. METHODS: Utilizing multidimensional high-throughput data generated, we integrated proteome-wide association study (PWAS), transcriptome-wide association study (TWAS), Mendelian randomization (MR), and Bayesian colocalization analysis to prioritize genes that contribute to stroke and its subtypes risk via affecting their expression and protein abundance in brain and blood. RESULTS: Our integrative analysis revealed that ICA1L was associated with small-vessel stroke (SVS), according to robust evidence at both protein and transcriptional levels based on brain-derived data. We also identified NBEAL1 that was causally related to SVS via its cis-regulated brain expression level. In blood, we identified 5 genes (MMP12, SCARF1, ABO, F11, and CKAP2) that had causal relationships with stroke and stroke subtypes. CONCLUSIONS: Together, via using an integrative analysis to deal with multidimensional data, we prioritized causal genes in the pathogenesis of SVS, which offered hints for future biological and therapeutic studies. Wu, Bang-Sheng Chen, Shu-Fen Huang, Shu-Yi Ou, Ya-Nan Deng, Yue-Ting Chen, Shi-Dong Dong, Qiang Yu, Jin-Tai eng Research Support, Non-U.S. Gov't England J Transl Med. Apr 21;20(1):181. doi: 10./s-022--9.I SomaScan 04/23/ Hoppe JE, et al. Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D J Cyst Fibros epub ahead of print https://www.doi.org/10./j.jcf..03.012 35,440,409 CFTR modulation Extrapulmonary Inflammation Proteomics Foundation, outside the submitted work, SMR reports grants, personal fees, non-financial support and other from Vertex Pharmaceuticals Inc., during the conduct of the study grants and personal fees from Novartis, grants and personal fees from Bayer, grants from Translate Bio, non-financial support from Proteostasis, grants, personal fees and non-financial support from Galapagos/Abbvie, grants, personal fees and other from Synedgen/Synspira, grants from Eloxx, grants and personal fees from Celtaxsys, grants, personal fees, non-financial support and other from Vertex Pharmaceuticals Inc, personal fees from Renovion, grants and personal fees from Arrowhead, grants and other from Ionis, grants from Astra Zenica, personal fees from Cystetic Medicines, personal fees from Arcturus, outside the submitted work EMD reports other from EvoEndoscopy (formerly Triple Endoscopy), outside the submitted work and is a consultant for Boehringer Ingelheim, not related to this work. SDS reports grants from the Cystic Fibrosis Foundation that funds the work under consideration, and grants from the Cystic Fibrosis Foundation and National Institutes of Health funding activities outside the submitted work. BDW, JKH and SLH have nothing to disclose. BACKGROUND: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment. METHODS: Blood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed. MEASUREMENTS AND MAIN RESULTS: Significant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight. CONCLUSIONS: Ivacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation. Hoppe, Jordana E Wagner, Brandie D Kirk Harris, J Rowe, Steven M Heltshe, Sonya L DeBoer, Emily M Sagel, Scott D eng P30 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ Netherlands J Cyst Fibros. Apr 16:S-(22)-3. doi: 10./j.jcf..03.012.I SomaScan 04/21/ Axelsson GT, et al. The Proteomic Profile of Interstitial Lung Abnormalities Am J Respir Crit Care Med 206 3 337-346 https://www.doi.org/10./rccm.-OC 35,438,610 Genetic Predisposition to Disease Humans Lung *Lung Diseases, Interstitial/epidemiology/genetics Prospective Studies Proteomics *Respiratory System Abnormalities Tomography, X-Ray Computed biomarkers idiopathic pulmonary fibrosis interstitial lung abnormalities interstitial lung disease Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility-Reykjavik) study (N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study (N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20-4.30]; P = 4.28 x 10(-67)), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13-2.77]; P = 8.01 x 10(-40)), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11-2.78]; P = 4.01 x 10(-36)) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning-based models with favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease. Axelsson, Gisli Thor Gudmundsson, Gunnar Pratte, Katherine A Aspelund, Thor Putman, Rachel K Sanders, Jason L Gudmundsson, Elias F Hatabu, Hiroto Gudmundsdottir, Valborg Gudjonsson, Alexander Hino, Takuya Hida, Tomoyuki Hobbs, Brian D Cho, Michael H Silverman, Edwin K Bowler, Russell P Launer, Lenore J Jennings, Lori L Hunninghake, Gary M Emilsson, Valur Gudnason, Vilmundur eng R01CA/NH/NIH HHS/ R01 HL/NH/NIH HHS/ U01 HL/NH/NIH HHS/ R01 HL/NH/NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ HHSNC/NH/NIH HHS/ R01 /NH/NIH HHS/ N01-AG-1-/NH/NIH HHS/ K08 HL/NH/NIH HHS/ 5U01CA-03/NH/NIH HHS/ R01 HL/NH/NIH HHS/ R01 HL/NH/NIH HHS/ P01 HL/NH/NIH HHS/ P50HL/HL/NHLBI NIH HHS/ R01 /NH/NIH HHS/ R01 /NH/NIH HHS/ R01 HL/NH/NIH HHS/ R21HL/HL/NHLBI NIH HHS/ K08 HL/NH/NIH HHS/ R01 HL/NH/NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ R01 HL/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. Aug 1;206(3):337-346. doi: 10./rccm.-OC.I SomaScan 04/20/ Chan KY, et al. Chemical Modifications for a Next Generation of Nucleic Acid Aptamers Chembiochem 23 15 e https://www.doi.org/10./cbic. 35,416,400 Antibodies *Aptamers, Nucleotide/metabolism Ligands *Nucleic Acids SELEX Aptamer Technique/methods Selex Xna aptamers chemical modifications nucleic acids In the past three decades, in vitro systematic evolution of ligands by exponential enrichment (SELEX) has yielded many aptamers for translational applications in both research and clinical settings. Despite their promise as an alternative to antibodies, the low success rate of SELEX ( approximately 30 %) has been a major bottleneck that hampers the further development of aptamers. One hurdle is the lack of chemical diversity in nucleic acids. To address this, the aptamer chemical repertoire has been extended by introducing exotic chemical groups, which provide novel binding functionalities. This review will focus on how modified aptamers can be selected and evolved, with illustration of some successful examples. In particular, unique chemistries are exemplified. Various strategies of incorporating modified building blocks into the standard SELEX protocol are highlighted, with a comparison of the differences between pre-SELEX and post-SELEX modifications. Nucleic acid aptamers with extended functionality evolved from non-natural chemistries will open up new vistas for function and application of nucleic acids. Chan, Kwing Yeung Kinghorn, Andrew Brian Hollenstein, Marcel Tanner, Julian Alexander eng Research Support, Non-U.S. Gov't Review Germany Chembiochem. Aug 3;23(15):e. doi: 10./cbic.. Epub Apr 29.I SomaScan 04/14/ Nandakumar M, et al. Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor protein response Diabetes Obes Metab 24 8 - https://www.doi.org/10./dom. 35,415,885 Case-Control Studies *Diabetes Mellitus, Type 2 *Fibroblast Growth Factors/metabolism Humans *Hypoglycemia/chemically induced/complications Iatrogenic Disease fibroblast growth factors hypoglycaemia proteomics type 2 diabetes INTRODUCTION: There is evidence that fibroblast growth factor (FGF) levels may be implicated in hypoglycaemia, with FGF19 being a potential contributor to insulin-independent pathways driving postprandial hypoglycaemia following bariatric surgery and basic FGF (FGF2) being elevated following mild hypoglycaemia occurring after the glucose tolerance test. However, their response following severe iatrogenic hypoglycaemia is unknown and therefore this pilot exploratory study was undertaken. METHODS: A case-control study of aged-matched type 2 diabetes (T2D; n = 23) and control (n = 23) subjects who underwent a hyperinsulinaemic clamp, initially to euglycaemia in T2D (5 mmol/L; 90 mg/dl), and then to hypoglycaemia (<2 mmol/L; <36 mg/dl) with subsequent follow-up time course to 24 h. FGF and FGF receptor proteins were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. RESULTS: At baseline, FGF12 (p = .006) was higher and FGF20 (p = .004) was lower in T2D versus controls. At hypoglycaemia, FGF7 was lower in T2D. Post-hypoglycaemic levels of FGF18, FGF19, FGF20 and FGF23 were lower while FGF12 and FGF16 were higher in T2D versus control at different time points. No differences between T2D and controls were seen for FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, FGF10, FGF21 or any of the FGF receptors. At 24 h post-hypoglycaemia, FGF20 (p = .01) differed between controls and T2D, while the levels for the other proteins measured returned to baseline. None of the FGF proteins altered from baseline to euglycaemia when clamped in T2D subjects. FGF23 negatively correlated with fasting blood glucose, but no FGFs correlated with body mass index in T2D. CONCLUSION: Severe transient hypoglycaemia modulated FGF7, 16, 19, 20 and 23 (known to be associated with diabetes), together with FGF18 and 12, not previously reported to be associated with diabetes but that may be important in the pathophysiology of hypoglycaemia; FGF20 remained low at 24 h. Taken together, these data suggest that recurrent hypoglycaemia may contribute to the development of complications through changes in FGF proteins. Nandakumar, Manjula Moin, Abu Saleh Md Ramanjaneya, Manjunath Qaissi, Ahmed Al Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng England Diabetes Obes Metab. Aug;24(8):-. doi: 10./dom.. Epub May 3.I SomaScan 04/14/ Nguyen KA, et al. Epidermal growth factor receptor signaling in precancerous keratinocytes promotes neighboring head and neck cancer squamous cell carcinoma cancer stem cell-like properties and phosphoinositide 3-kinase inhibitor insensitivity Mol Carcinog 61 7 664-676 https://www.doi.org/10./mc. 35,417,043 *Carcinoma, Squamous Cell/genetics Cell Line, Tumor ErbB Receptors/metabolism *Head and Neck Neoplasms/drug therapy Humans Keratinocytes/metabolism Neoplastic Stem Cells/pathology Phosphatidylinositol 3-Kinase/metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors *Precancerous Conditions Receptors, Fibroblast Growth Factor Squamous Cell Carcinoma of Head and Neck/drug therapy Tumor Microenvironment Egfr Hnscc Pi3k cancer stem cell resistance squamous cell carcinoma Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol consumption that induce a precancerous field," with phosphoinositide 3-kinase (PI3K) signaling being a common driver. However, the preclinical effectiveness of PI3K inhibitors has not necessarily translated to remarkable benefit in HNSCC patients. Thus, we sought to determine how precancerous keratinocytes influence HNSCC proliferation, cancer stem cell (CSC) maintenance, and response to PI3K inhibitors. We used the NOK keratinocyte cell line as a model of preneoplastic keratinocytes because it harbors two frequent genetic events in HNSCC, CDKN2A promoter methylation and TP53 mutation, but does not form tumors. NOK cell coculture or NOK cell-conditioned media promoted HNSCC proliferation, PI3K inhibitor resistance, and CSC phenotypes. SOMAscan-targeted proteomics determined the relative levels of > analytes in the media conditioned by NOK cells and HNSCC cells +/- PI3K inhibitor. These results demonstrated that NOK cells release abundant levels of ligands that activate epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR), two receptor tyrosine kinases with oncogenic activity. Inhibition of EGFR, but not FGFR, blunted PI3K inhibitor resistance and CSC phenotypes induced by NOK cells. Our results demonstrate that precancerous keratinocytes can directly support neighboring HNSCC by activating EGFR. Importantly, PI3K inhibitor sensitivity was not necessarily a cancer cell-intrinsic property, and the tumor microenvironment impacts therapeutic response and supports CSCs. Additionally, combined inhibition of EGFR with PI3K inhibitor diminished EGFR activation induced by PI3K inhibitor and potently inhibited cancer cell proliferation and CSC maintenance." Nguyen, Khoa A Keith, Madison J Keysar, Stephen B Hall, Spencer C Bimali, Anamol Jimeno, Antonio Wang, Xiao-Jing Young, Christian D eng P50 CA/CA/NCI NIH HHS/ R01 DE/DE/NIDCR NIH HHS/ I01 BX/BX/BLRD VA/ IK6 BX/BX/BLRD VA/ P30 CA/CA/NCI NIH HHS/ R01 DE/DE/NIDCR NIH HHS/ R01 DE/DE/NIDCR NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Mol Carcinog. Jul;61(7):664-676. doi: 10./mc.. Epub Apr 13.I SomaScan 04/14/ Aid M, et al. Ad26.COV2.S prevents upregulation of SARS-CoV-2 induced pathways of inflammation and thrombosis in hamsters and rhesus macaques PLoS Pathog 18 4 e https://www.doi.org/10./journal.ppat. 35,395,058 Ad26COVS1 Animals Antibodies, Neutralizing *covid-19 COVID-19 Vaccines Cricetinae Humans Inflammation Macaca mulatta SARS-CoV-2 Spike Glycoprotein, Coronavirus *Thrombosis Up-Regulation Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 WA1/ challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 WA1/ challenge in hamsters stimulates myeloid and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways, such that the mRNA expression profiles of vaccinated hamsters are comparable to uninfected animals. Using proteomics profiling, we validated these findings in rhesus macaques challenged with SARS-CoV-2 WA1/ or SARS-CoV-2 B.1.351. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses weeks following vaccination. These data provide insights into the molecular mechanisms of Ad26.COV2.S protection against severe COVID-19 in animal models. Aid, Malika Vidal, Samuel J Piedra-Mora, Cesar Ducat, Sarah Chan, Chi N Bondoc, Stephen Colarusso, Alessandro Starke, Carly E Nekorchuk, Michael Busman-Sahay, Kathleen Estes, Jacob D Martinot, Amanda J Barouch, Dan H eng P51 OD/OD/NIH HHS/ Research Support, Non-U.S. Gov't PLoS Pathog. Apr 8;18(4):e. doi: 10./journal.ppat.. eCollection Apr.I SomaScan 04/09/ Harbaum L, et al. Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension Am J Respir Crit Care Med 205 12 - https://www.doi.org/10./rccm.-OC 35,394,406 Blood Proteins/genetics Familial Primary Pulmonary Hypertension Humans *Hypertension, Pulmonary Netrins Pathology, Molecular Proteome *Pulmonary Arterial Hypertension Thrombospondins Mendelian randomization case-control studies genome protein quantitative trait loci Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis-pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH. Harbaum, Lars Rhodes, Christopher J Wharton, John Lawrie, Allan Karnes, Jason H Desai, Ankit A Nichols, William C Humbert, Marc Montani, David Girerd, Barbara Sitbon, Olivier Boehm, Mario Novoyatleva, Tatyana Schermuly, Ralph T Ghofrani, H Ardeschir Toshner, Mark Kiely, David G Howard, Luke S Swietlik, Emilia M Graf, Stefan Pietzner, Maik Morrell, Nicholas W Wilkins, Martin R eng R01HL/NIH/NHLBI/ R01 HL/HL/NHLBI NIH HHS/ FS/13/48//BHF_/British Heart Foundation/United Kingdom FS/15/59//BHF_/British Heart Foundation/United Kingdom R24 HL/HL/NHLBI NIH HHS/ SP/12/12//BHF_/British Heart Foundation/United Kingdom K01HL/NIH/NHLBI/ R01 HL/HL/NHLBI NIH HHS/ RE/18/4//BHF_/British Heart Foundation/United Kingdom R01 HL/HL/NHLBI NIH HHS/ MR/K/1/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom FS/18/52//BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. Jun 15;205(12):-. doi: 10./rccm.-OC.I SomaScan 04/09/ Dillon ST, et al. Patterns and Persistence of Perioperative Plasma and Cerebrospinal Fluid Neuroinflammatory Protein Biomarkers After Elective Orthopedic Surgery Using SOMAscan Anesth Analg epub ahead of print https://www.doi.org/10./ANE. 35,389,379 BACKGROUND: The neuroinflammatory response to surgery can be characterized by peripheral acute plasma protein changes in blood, but corresponding, persisting alterations in cerebrospinal fluid (CSF) proteins remain mostly unknown. Using the SOMAscan assay, we define acute and longer-term proteome changes associated with surgery in plasma and CSF. We hypothesized that biological pathways identified by these proteins would be in the categories of neuroinflammation and neuronal function and define neuroinflammatory proteome changes associated with surgery in older patients. METHODS: SOMAscan analyzed proteins in blood plasma (n = 14) and CSF (n = 15) samples from older patients enrolled in the Role of Inflammation after Surgery for Elders (RISE) study undergoing elective hip and knee replacement surgery with spinal anesthesia. Systems biology analysis identified biological pathways enriched among the surgery-associated differentially expressed proteins in plasma and CSF. RESULTS: Comparison of postoperative day 1 (POD1) to preoperative (PREOP) plasma protein levels identified 343 proteins with postsurgical changes (P 1.2). Comparing postoperative 1-month (PO1MO) plasma and CSF with PREOP identified 67 proteins in plasma and 79 proteins in CSF with altered levels (P 1.2). In plasma, 21 proteins, primarily linked to immune response and inflammation, were similarly changed at POD1 and PO1MO. Comparison of plasma to CSF at PO1MO identified 8 shared proteins. Comparison of plasma at POD1 to CSF at PO1MO identified a larger number, 15 proteins in common, most of which are regulated by interleukin-6 (IL-6) or transforming growth factor beta-1 (TGFB1) and linked to the inflammatory response. Of the 79 CSF PO1MO-specific proteins, many are involved in neuronal function and neuroinflammation. CONCLUSIONS: SOMAscan can characterize both short- and long-term surgery-induced protein alterations in plasma and CSF. Acute plasma protein changes at POD1 parallel changes in PO1MO CSF and suggest 15 potential biomarkers for longer-term neuroinflammation that warrant further investigation. Dillon, Simon T Otu, Hasan H Ngo, Long H Fong, Tamara G Vasunilashorn, Sarinnapha M Xie, Zhongcong Kunze, Lisa J Vlassakov, Kamen V Abdeen, Ayesha Lange, Jeffrey K Earp, Brandon E Cooper, Zara R Schmitt, Eva M Arnold, Steven E Hshieh, Tammy T Jones, Richard N Inouye, Sharon K Marcantonio, Edward R Libermann, Towia A eng R01 AG/AG/NIA NIH HHS/ R03 AG/AG/NIA NIH HHS/ K24 AG/AG/NIA NIH HHS/ K01 AG/AG/NIA NIH HHS/ P01 AG/AG/NIA NIH HHS/ R21 AG/AG/NIA NIH HHS/ R24 AG/AG/NIA NIH HHS/ Anesth Analg. Apr 7:10./ANE.. doi: 10./ANE..I SomaScan 04/08/ Williams SA, et al. A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk Sci Transl Med 14 639 eabj https://www.doi.org/10./scitranslmed.abj 35,385,337 Biomarkers *Cardiovascular Diseases *Heart Failure/drug therapy Humans *Myocardial Infarction/drug therapy Proteomics *Stroke/complications A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a universal" surrogate end point for cardiovascular risk." Williams, Stephen A Ostroff, Rachel Hinterberg, Michael A Coresh, Josef Ballantyne, Christie M Matsushita, Kunihiro Mueller, Christian E Walter, Joan Jonasson, Christian Holman, Rury R Shah, Svati H Sattar, Naveed Taylor, Roy Lean, Michael E Kato, Shintaro Shimokawa, Hiroaki Sakata, Yasuhiko Nochioka, Kotaro Parikh, Chirag R Coca, Steven G Omland, Torbjorn Chadwick, Jessica Astling, David Hagar, Yolanda Kureshi, Natasha Loupy, Kelsey Paterson, Clare Primus, Jeremy Simpson, Missy Trujillo, Nelson P Ganz, Peter eng R01 HL/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ R01 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sci Transl Med. Apr 6;14(639):eabj. doi: 10./scitranslmed.abj. Epub Apr 6.I SomaScan 04/07/ Hardy-Sosa A, et al. Diagnostic Accuracy of Blood-Based Biomarker Panels: A Systematic Review Front Aging Neurosci 14 https://www.doi.org/10./fnagi.. 35,360,215 Alzheimer's disease (AD) biomarker panel blood-based biomarker diagnosis preclinical AD commercial or financial relationships that could be construed as a potential conflict of interest. BACKGROUND: Because of high prevalence of Alzheimer's disease (AD) in low- and middle-income countries (LMICs), there is an urgent need for inexpensive and minimally invasive diagnostic tests to detect biomarkers in the earliest and asymptomatic stages of the disease. Blood-based biomarkers are predicted to have the most impact for use as a screening tool and predict the onset of AD, especially in LMICs. Furthermore, it has been suggested that panels of markers may perform better than single protein candidates. METHODS: Medline/Pubmed was searched to identify current relevant studies published from January to December . We included all full-text articles examining blood-based biomarkers as a set of protein markers or panels to aid in AD's early diagnosis, prognosis, and characterization. RESULTS: Seventy-six articles met the inclusion criteria for systematic review. Majority of the studies reported plasma and serum as the main source for biomarker determination in blood. Protein-based biomarker panels were reported to aid in AD diagnosis and prognosis with better accuracy than individual biomarkers. Conventional (amyloid-beta and tau) and neuroinflammatory biomarkers, such as amyloid beta-42, amyloid beta-40, total tau, phosphorylated tau-181, and other tau isoforms, were the most represented. We found the combination of amyloid beta-42/amyloid beta-40 ratio and APOEepsilon4 status to be most represented with high accuracy for predicting amyloid beta-positron emission tomography status. CONCLUSION: Assessment of Alzheimer's disease biomarkers in blood as a non-invasive and cost-effective alternative will potentially contribute to early diagnosis and improvement of therapeutic interventions. Given the heterogeneous nature of AD, combination of markers seems to perform better in the diagnosis and prognosis of the disease than individual biomarkers. Hardy-Sosa, Anette Leon-Arcia, Karen Llibre-Guerra, Jorge J Berlanga-Acosta, Jorge Baez, Saiyet de la C Guillen-Nieto, Gerardo Valdes-Sosa, Pedro A eng Switzerland Front Aging Neurosci. Mar 11;14:. doi: 10./fnagi... eCollection .I SomaScan 04/02/ Honey S, et al. Acceptability and experience of a personalised proteomic risk intervention for type 2 diabetes in primary care: qualitative interview study with patients and healthcare providers Prim Health Care Res Dev 23 e24 https://www.doi.org/10./S 35,361,303 *Diabetes Mellitus, Type 2/prevention & control Health Personnel Humans Primary Health Care Proteomics Qualitative Research behaviour change pre-diabetes proteomic risk assessment type 2 diabetes AIM: We explored the acceptability of a personalised proteomic risk intervention for patients at increased risk of type 2 diabetes and their healthcare providers, as well as their experience of participating in the delivery of proteomic-based risk feedback in UK primary care. BACKGROUND: Advances in proteomics now allow the provision of personalised proteomic risk reports, with the intention of achieving positive behaviour change. This technology has the potential to encourage behaviour change in people at risk of developing type 2 diabetes. METHODS: A semi-structured interview study was carried out with patients at risk of type 2 diabetes and their healthcare providers in primary care in the North of England. Participants (n = 17) and healthcare provider (n = 4) were interviewed either face to face or via . Data were analysed using thematic analysis. This qualitative study was nested within a single-arm pilot trial and undertaken in primary care. FINDINGS: The personalised proteomic risk intervention was generally acceptable and the experience was positive. The personalised nature of the report was welcomed, especially the way it provided a holistic approach to risks of organ damage and lifestyle factors. Insights were provided as to how this may change behaviour. Some participants reported difficulties in understanding the format of the presentation of risk and expressed surprise at receiving risk estimates for conditions other than type 2 diabetes. Personalised proteomic risk interventions have the potential to provide holistic and comprehensive assessments of risk factors and lifestyle factors which may lead to positive behaviour change. Honey, Stephanie Neal, Richard D Messenger, Michael Smith, Samuel G eng DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't England Prim Health Care Res Dev. Apr 1;23:e24. doi: 10./S.I SomaScan 04/02/ Liu S, et al. Translation of aptamers toward clinical diagnosis and commercialization Biosens Bioelectron 208 https://www.doi.org/10./j.bios.. 35,364,525 *Aptamers, Nucleotide *Biosensing Techniques Point-of-Care Testing SELEX Aptamer Technique Aptamer Aptasensor Clinical diagnostic Point-of-care test Translation The dominance of antibodies in diagnostics has gradually changed following the discovery of aptamers in the early s. Aptamers offer inherent advantages over traditional antibodies, including higher specificity, higher affinity, smaller size, greater stability, ease of manufacture, and low immunogenicity, rendering them the best candidates for point-of-care testing (POCT). In the past 20 years, the research community and pharmaceutical companies have made great efforts to promote the development of aptamer technology. Macugen(R) (pegaptanib) was the first aptamer drug approved by the US Food and Drug Administration (FDA), and various aptamer-based diagnostics show great promise in preclinical research and clinical trials. In this review, we introduce recent literature, ongoing clinical trials, commercial reagents of aptamer-based diagnostics, discuss the FDA regulatory mechanisms, and highlight the prospects and challenges in translating these studies into viable clinical diagnostic tools. Liu, Shan Xu, Yixin Jiang, Xin Tan, Hong Ying, Binwu eng Review England Biosens Bioelectron. Jul 15;208:. doi: 10./j.bios... Epub Mar 16.I SomaScan 04/02/ Osawa Y, et al. Plasma Growth and Differentiation Factor 15 Predict Longitudinal Changes in Bone Parameters in Women, but Not in Men J Gerontol A Biol Sci Med Sci 77 10 - https://www.doi.org/10./gerona/glac079 35,363,860 Aged Aged, 80 and over Bone Density/physiology *Bone Diseases, Metabolic *Calcium Female Growth Differentiation Factor 15 Humans Male Parathyroid Hormone Radius/physiology Tibia/diagnostic imaging/physiology Cortical bone Growth/differentiation factor 15 Osteopenia Sex difference Trabecular bone Bone fragility can progress with aging, but biomarkers to detect emerging osteopenia have not been fully elucidated. Growth/differentiation factor 15 (GDF-15) has pleiotropic roles in a broad range of age-related conditions, but its association with osteopenia is unknown. We examined the relationship between plasma GDF-15 levels and rate of change in bone parameters over 9 years of follow-up in 596 adults in the InCHIANTI study (baseline age, 65-94 years; women, 52.4%; mean follow-up, 7.0 +/- 3.0 years). Plasma GDF-15 concentrations were measured using the 1.3k HTS SOMAscan assay. Eight bone parameters were measured in the right tibia by peripheral quantitative computed tomography; total bone density, trabecular bone density, medullary plus trabecular bone density, cortical bone density, total bone area, cortical bone area, medullary bone area, and minimum moment of inertia (mMOI). We ran sex-specific linear mixed-effect models with random intercepts and slopes adjusted for age, age-squared, education, body mass index, the rate of change in weight, smoking, sedentary behavior, cross-sectional areas of calf muscles and fat, 25-hydroxyvitamin D, parathyroid hormone, calcium, diabetes mellitus, and follow-up time. We found a significant association of baseline GDF-15 x time" in models predicting cortical bone density and the mMOI in women, suggesting that the rates of decline in these bone parameters increased with higher GDF-15 (false discovery rate <0.05). Higher plasma levels GDF-15 predicted an accelerated decline in bone parameters in women, but was less associated in men. Furthermore studies are needed to understand the mechanisms underlying these sex differences." Osawa, Yusuke Tanaka, Toshiko Semba, Richard D Fantoni, Giovanna Moaddel, Ruin Candia, Julian Simonsick, Eleanor M Bandinelli, Stefania Ferrucci, Luigi eng R21 HL/HL/NHLBI NIH HHS/ R01 MD/MD/NIMHD NIH HHS/ 21K/JSPS/ 263MD/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't J Gerontol A Biol Sci Med Sci. Oct 6;77(10):-. doi: 10./gerona/glac079.I SomaScan 04/02/ Skuladottir AT, et al. A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome Nat Commun 13 1 https://www.doi.org/10./s-022--7 35,332,129 Anthropometry *Carpal Tunnel Syndrome/genetics Genetic Loci Genome-Wide Association Study Humans Phenotype Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 x 10(-24), OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS. Skuladottir, Astros Th Bjornsdottir, Gyda Ferkingstad, Egil Einarsson, Gudmundur Stefansdottir, Lilja Nawaz, Muhammad Sulaman Oddsson, Asmundur Olafsdottir, Thorunn A Saevarsdottir, Saedis Walters, G Bragi Magnusson, Sigurdur H Bjornsdottir, Anna Sveinsson, Olafur A Vikingsson, Arnor Hansen, Thomas Folkmann Jacobsen, Rikke Louise Erikstrup, Christian Schwinn, Michael Brunak, Soren Banasik, Karina Ostrowski, Sisse Rye Troelsen, Anders Henkel, Cecilie Pedersen, Ole Birger Jonsdottir, Ingileif Gudbjartsson, Daniel F Sulem, Patrick Thorgeirsson, Thorgeir E Stefansson, Hreinn Stefansson, Kari eng Meta-Analysis Research Support, Non-U.S. Gov't England Nat Commun. Mar 24;13(1):. doi: 10./s-022--7.I SomaScan 03/26/ Sobolev VV, et al. Proteomic Studies of Psoriasis Biomedicines 10 3 https://www.doi.org/10./biomedicines 35,327,421 Lc-ms/ms SOMAscan biomarkers comorbidities mass spectrometry predisposition proximity extension assay psoriasis risk factors In this review paper, we discuss the contribution of proteomic studies to the discovery of disease-specific biomarkers to monitor the disease and evaluate available treatment options for psoriasis. Psoriasis is one of the most prevalent skin disorders driven by a Th17-specific immune response. Although potential patients have a genetic predisposition to psoriasis, the etiology of the disease remains unknown. During the last two decades, proteomics became deeply integrated with psoriatic research. The data obtained in proteomic studies facilitated the discovery of novel mechanisms and the verification of many experimental hypotheses of the disease pathogenesis. The detailed data analysis revealed multiple differentially expressed proteins and significant changes in proteome associated with the disease and drug efficacy. In this respect, there is a need for proteomic studies to characterize the role of the disease-specific biomarkers in the pathogenesis of psoriasis, develop clinical applications to choose the most efficient treatment options and monitor the therapeutic response. Sobolev, Vladimir V Soboleva, Anna G Denisova, Elena V Pechatnikova, Eva A Dvoryankova, Eugenia Korsunskaya, Irina M Mezentsev, Alexandre eng Review Switzerland Biomedicines. Mar 7;10(3):619. doi: 10./biomedicines.I SomaScan 03/26/ Moin ASM, et al. Diagnostic and Prognostic Protein Biomarkers of beta-Cell Function in Type 2 Diabetes and Their Modulation with Glucose Normalization Metabolites 12 3 https://www.doi.org/10./metabo 35,323,639 biomarkers diagnostic euglycemia glucose variability prognostic type 2 diabetes Development of type-2 diabetes(T2D) is preceded by beta-cell dysfunction and loss. However, accurate measurement of beta-cell function remains elusive. Biomarkers have been reported to predict beta-cell functional decline but require validation. Therefore, we determined whether reported protein biomarkers could distinguish patients with T2D (onset < 10-years) from controls. A prospective, parallel study in T2D (n = 23) and controls (n = 23) was undertaken. In T2D subjects, insulin-induced blood glucose normalization from baseline 7.6 +/- 0.4 mmol/L (136.8 +/- 7.2 mg/dL) to 4.5 +/- 0.07 mmol/L (81 +/- 1.2 mg/dL) was maintained for 1-h. Controls were maintained at 4.9 +/- 0.1 mmol/L (88.2 +/- 1.8 mg/dL). Slow Off-rate Modified Aptamer (SOMA) -scan plasma protein measurement determined a 43-protein panel reported as diagnostic and/or prognostic for T2D. At baseline, 9 proteins were altered in T2D. Three of 13 prognostic/diagnostic proteins were lower in T2D: Adiponectin (p < 0.), Endocan (p < 0.05) and Mast/stem cell growth factor receptor-Kit (KIT) (p < 0.01). Two of 14 prognostic proteins [Cathepsin-D (p < 0.05) and Cadherin-E (p < 0.005)], and four of 16 diagnostic proteins [Kallikrein-4 (p = 0.001), Aminoacylase-1 (p = 0.001), Insulin-like growth factor-binding protein-4 (IGFBP4) (p < 0.05) and Reticulon-4 receptor (RTN4R) (p < 0.001)] were higher in T2D. Protein levels were unchanged following glucose normalization in T2D. Our results suggest that a focused biomarker panel may be useful for assessing beta-cell dysfunction and may complement clinical decision-making on insulin therapy. Unchanged post-glucose normalization levels indicate these are not acute-phase proteins or affected by glucose variability. Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Metabolites. Feb 22;12(3):196. doi: 10./metabo.I SomaScan 03/25/ Pala E, et al. Proteins and pathways in atrial fibrillation and atrial cardiomyopathy underlying cryptogenic stroke Int J Cardiol Heart Vasc 39 https://www.doi.org/10./j.ijcha.. 35,281,755 Atrial cardiomyopathy Atrial fibrillation Atrial function Biomarkers Cryptogenic stroke personal relationships that could have appeared to influence the work reported in this paper. BACKGROUND: Atrial fibrillation (AF) is one of the most prevalent causes of cryptogenic stroke. Also, apart from AF itself, structural and remodelling changes in the atria might be an underlying cause of cryptogenic stroke. We aimed to discover circulating proteins and reveal pathways altered in AF and atrial cardiomyopathy, measured by left atrial volume index (LAVI) and peak atrial longitudinal strain (PALS), in patients with cryptogenic stroke. METHODS: An aptamer array (including proteins) was measured in the blood of 20 cryptogenic stroke patients monitored during 28 days with a Holter device as a case-control study of the Crypto-AF cohort. Protein levels were compared between patients with (n = 10) and without AF (n = 10) after stroke, and the best candidates were tested in 111 patients from the same cohort (44 patients with AF and 67 without AF). In addition, in the first 20 patients, proteins were explored according to PALS and LAVI values. RESULTS: Forty-six proteins were differentially expressed in AF cases. Of those, four proteins were tested in a larger sample size. Only DPP7, presenting lower levels in AF patients, was further validated. Fifty-seven proteins correlated with LAVI, and 270 correlated with PALS. NT-proBNP was common in all the discovery analyses performed. Interestingly, many proteins and pathways were altered in patients with low PALS. CONCLUSIONS: Multiple proteins and pathways related to AF and atrial cardiomyopathy have been revealed. The role of DPP7 as a biomarker for stroke aetiology should be further explored. Moreover, the present study may be considered hypothesis-generating. Pala, Elena Pagola, Jorge Juega, Jesus Francisco-Pascual, Jaume Penalba, Anna Rodriguez, Maite De Lera Alfonso, Mercedes Arenillas, Juan F Cabezas, Juan Antonio Moniche, Francisco de Torres, Reyes Perez-Sanchez, Soledad Gonzalez-Alujas, Teresa Molina, Carlos A Bustamante, Alejandro Montaner, Joan eng Ireland Int J Cardiol Heart Vasc. Mar 7;39:. doi: 10./j.ijcha... eCollection Apr.I SomaScan 03/15/ Echouffo-Tcheugui JB, et al. Diabetes, GDF-15 and incident heart failure: the atherosclerosis risk in communities study Diabetologia 65 6 955-963 https://www.doi.org/10./s-022--6 35,275,240 Adult *Atherosclerosis/epidemiology Biomarkers *Diabetes Mellitus/epidemiology Female Growth Differentiation Factor 15 *Heart Failure/epidemiology/etiology Humans Male Middle Aged Risk Factors Growth differentiation factor-15 Heart failure Prediction Type 2 diabetes AIMS/HYPOTHESIS: Elevated circulating growth differentiation factor-15 (GDF-15), a marker of cellular stress, is associated with both heart failure (HF) and diabetes. However, it is unclear to what extent GDF-15 is associated with HF among individuals with and without diabetes. METHODS: We evaluated 10,570 participants free of HF at Visit 3 (-) of the Atherosclerosis Risk in Communities study. We used Cox regression to evaluate the joint associations of GDF-15 and diabetes with incident HF. Models were adjusted for traditional cardiovascular risk factors. RESULTS: Among a total of 10,570 individuals (mean age of 60.0 years, 54% women, 27% black adults), elevated GDF-15 (>/=75th percentile) was more common in people with diabetes compared with those without diabetes (32.8% vs 23.6%, p<0.). During 23 years of follow-up, there were incident HF events. GDF-15 (in quartiles) was independently associated with HF among those with and without diabetes, with a stronger association among individuals with diabetes (p-for-diabetes-GDF-15 interaction = 0.034): HR for highest vs lowest GDF-15 quartile (reference): 1.64 (95% CI 1.41, 1.91) among those without diabetes and 1.72 (95% CI 1.32, 2.23) among those with diabetes. Individuals with diabetes and elevated GDF-15 had the highest risk of incident HF (HR 2.46; 95% CI 1.99, 3.03). After accounting for HF risk factors, GDF-15 provided additional prognostic information among participants with diabetes (DeltaC statistic for model with vs model without GDF-15: +0.008, p = 0.001) and among those without diabetes (+0.006, p<0.). CONCLUSIONS/INTERPRETATION: In a community-based sample of US adults, GDF-15 provided complementary prognostic information on the HF risk, especially among individuals with diabetes. Echouffo-Tcheugui, Justin B Daya, Natalie Ndumele, Chiadi E Matsushita, Kunihiro Hoogeveen, Ron C Ballantyne, Christie M Coresh, Josef Shah, Amil M Selvin, Elizabeth eng R01 DK/DK/NIDDK NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ K24 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ K23 HL/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ K24 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Germany Diabetologia. Jun;65(6):955-963. doi: 10./s-022--6. Epub Mar 11.I SomaScan 03/12/ Stacey D, et al. Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus Nat Commun 13 1 https://www.doi.org/10./s-022--3 35,264,566 Antigens, CD/genetics Crosses, Genetic Endothelial Cells/metabolism Endothelial Protein C Receptor/genetics Humans Protein C/metabolism Receptors, Cell Surface/genetics *Thrombosis/genetics *Venous Thromboembolism/genetics Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations. Stacey, David Chen, Lingyan Stanczyk, Paulina J Howson, Joanna M M Mason, Amy M Burgess, Stephen MacDonald, Stephen Langdown, Jonathan McKinney, Harriett Downes, Kate Farahi, Neda Peters, James E Basu, Saonli Pankow, James S Tang, Weihong Pankratz, Nathan Sabater-Lleal, Maria de Vries, Paul S Smith, Nicholas L Gelinas, Amy D Schneider, Daniel J Janjic, Nebojsa Samani, Nilesh J Ye, Shu Summers, Charlotte Chilvers, Edwin R Danesh, John Paul, Dirk S eng MR/L/1/MRC_/Medical Research Council/United Kingdom BRC--/DH_/Department of Health/United Kingdom MR/P/1/MRC_/Medical Research Council/United Kingdom UL1 RR/RR/NCRR NIH HHS/ NIHR/DH_/Department of Health/United Kingdom R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ RG/18/13//BHF_/British Heart Foundation/United Kingdom R01 HL/HL/NHLBI NIH HHS/ RG/19/9//BHF_/British Heart Foundation/United Kingdom HHSNC/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ RG/16/4//BHF_/British Heart Foundation/United Kingdom R01 HL/HL/NHLBI NIH HHS/ MR/S/2/MRC_/Medical Research Council/United Kingdom RE/13/6//BHF_/British Heart Foundation/United Kingdom U01 HG/HG/NHGRI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ WT_/Wellcome Trust/United Kingdom HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ CSO_/Chief Scientist Office/United Kingdom R01 HL/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ RG/13/13//BHF_/British Heart Foundation/United Kingdom SP/19/2//BHF_/British Heart Foundation/United Kingdom England Nat Commun. Mar 9;13(1):. doi: 10./s-022--3.I SomaScan 03/11/ Vasunilashorn SM, et al. Proteome-Wide Analysis Using SOMAscan Identifies and Validates Chitinase-3-Like Protein 1 as a Risk and Disease Marker of Delirium Among Older Adults Undergoing Major Elective Surgery J Gerontol A Biol Sci Med Sci 77 3 484-493 https://www.doi.org/10./gerona/glaa326 35,239,952 Aged Biomarkers Case-Control Studies *Chitinase-3-Like Protein 1/genetics *Delirium/diagnosis/etiology Elective Surgical Procedures Humans Interleukin-6 *Postoperative Cognitive Complications/diagnosis/genetics Proteome Inflammation Postoperative Proteomics BACKGROUND: Delirium (an acute change in cognition) is a common, morbid, and costly syndrome seen primarily in aging adults. Despite increasing knowledge of its epidemiology, delirium remains a clinical diagnosis with no established biomarkers to guide diagnosis or management. Advances in proteomics now provide opportunities to identify novel markers of risk and disease progression for postoperative delirium and its associated long-term consequences (eg, long-term cognitive decline and Alzheimer's disease [AD]). METHODS: In a nested matched case-control study (18 delirium/no-delirium pairs) within the Successful Aging after Elective Surgery study (N = 556), we evaluated the association of plasma proteins preoperatively [PREOP] and on postoperative day 2 [POD2]) with delirium using SOMAscan. Generalized linear models were applied to enzyme-linked immunosorbant assay (ELISA) validation data of one protein across the full cohort. Multi-protein modeling included delirium biomarkers identified in prior work (C-reactive protein, interleukin-6 [IL6]). RESULTS: We identified chitinase-3-like-protein-1 (CHI3L1/YKL-40) as the sole delirium-associated protein in both a PREOP and a POD2 predictor model, a finding confirmed by ELISA. Multi-protein modeling found high PREOP CHI3L1/YKL-40 and POD2 IL6 increased the risk of delirium (relative risk [95% confidence interval] Quartile [Q]4 vs Q1: 2.4[1.2-5.0] and 2.1[1.1-4.1], respectively). CONCLUSIONS: Our identification of CHI3L1/YKL-40 in postoperative delirium parallels reports of CHI3L1/YKL-40 and its association with aging, mortality, and age-related conditions including AD onset and progression. This highlights the type 2 innate immune response, involving CHI3L1/YKL-40, as an underlying mechanism of postoperative delirium, a common, morbid, and costly syndrome that threatens the independence of older adults. Vasunilashorn, Sarinnapha M Dillon, Simon T Chan, Noel Y Fong, Tamara G Joseph, Marie Tripp, Bridget Xie, Zhongcong Ngo, Long H Lee, Chun Geun Elias, Jack A Otu, Hasan H Inouye, Sharon K Marcantonio, Edward R Libermann, Towia A eng R01 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ K24 AG/AG/NIA NIH HHS/ K01 AG/AG/NIA NIH HHS/ R21 AG/AG/NIA NIH HHS/ R21 AG/AG/NIA NIH HHS/ R03 AG/AG/NIA NIH HHS/ ALZ/Alzheimer's Association/ R01AG/AG/NIA NIH HHS/ R24 AG/AG/NIA NIH HHS/ P01 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Gerontol A Biol Sci Med Sci. Mar 3;77(3):484-493. doi: 10./gerona/glaa326.I SomaScan 03/04/ Ghanbari F, et al. Connecting Genomics and Proteomics to Identify Protein Biomarkers for Adult and Youth-Onset Type 2 Diabetes: A Two-Sample Mendelian Randomization Study Diabetes 71 6 - https://www.doi.org/10./db21- 35,234,851 Adolescent Adult Biomarkers Child *Diabetes Mellitus, Type 2/metabolism Genome-Wide Association Study Genomics Humans *Mendelian Randomization Analysis Polymorphism, Single Nucleotide Proteomics Type 2 diabetes shows an increasing prevalence in both adults and children. Identification of biomarkers for both youth and adult-onset type 2 diabetes is crucial for development of screening tools or drug targets. In this study, using two-sample Mendelian randomization (MR), we identified 22 circulating proteins causally linked to adult type 2 diabetes and 11 proteins with suggestive evidence for association with youth-onset type 2 diabetes. Among these, colocalization analysis further supported a role in type 2 diabetes for C-type mannose receptor 2 (MR odds ratio [OR] 0.85 [95% CI 0.79-0.92] per genetically predicted SD increase in protein level), MANS domain containing 4 (MR OR 0.90 [95% CI 0.88-0.92]), sodium/potassium-transporting ATPase subunit beta2 (MR OR 1.10 [95% CI 1.06-1.15]), endoplasmic reticulum oxidoreductase 1beta (MR OR 1.09 [95% CI 1.05-1.14]), spermatogenesis-associated protein 20 (MR OR 1.12 [95% CI 1.06-1.18]), haptoglobin (MR OR 0.96 [95% CI 0.94-0.98]), and alpha1-3-N-acetylgalactosaminyltransferase and alpha1-3-galactosyltransferase (MR OR 1.04 [95% CI 1.03-1.05]). Our findings support a causal role in type 2 diabetes for a set of circulating proteins, which represent promising type 2 diabetes drug targets. Ghanbari, Faegheh Yazdanpanah, Nahid Yazdanpanah, Mojgan Richards, J Brent Manousaki, Despoina eng Diabetes. Jun 1;71(6):-. doi: 10./db21-.I SomaScan 03/03/ Cummins TD, et al. Advances in proteomic profiling of pediatric kidney diseases Pediatr Nephrol 37 10 - https://www.doi.org/10./s-022--2 35,220,505 Adult Biomarkers Child Glomerular Filtration Rate Humans *Kidney Diseases/diagnosis Proteomics Renal Dialysis *Renal Insufficiency, Chronic Biomarker Chronic kidney disease Mass spectrometry Pediatric glomerular disease Proteomics conflicts of interest to declare. Chronic kidney disease (CKD) can progress to kidney failure and require dialysis or transplantation, while early diagnosis can alter the course of disease and lead to better outcomes in both pediatric and adult patients. Significant CKD comorbidities include the manifestation of cardiovascular disease, heart failure, coronary disease, and hypertension. The pathogenesis of chronic kidney diseases can present as subtle and especially difficult to distinguish between different glomerular pathologies. Early detection of adult and pediatric CKD and detailed mechanistic understanding of the kidney damage can be helpful in delaying or curtailing disease progression via precise intervention toward diagnosis and prognosis. Clinically, serum creatinine and albumin levels can be indicative of CKD, but often are a lagging indicator only significantly affected once kidney function has severely diminished. The evolution of proteomics and mass spectrometry technologies has begun to provide a powerful research tool in defining these mechanisms and identifying novel biomarkers of CKD. Many of the same challenges and advances in proteomics apply to adult and pediatric patient populations. Additionally, proteomic analysis of adult CKD patients can be transferred directly toward advancing our knowledge of pediatric CKD as well. In this review, we highlight applications of proteomics that have yielded such biomarkers as PLA2R, SEMA3B, and other markers of membranous nephropathy as well as KIM-1, MCP-1, and NGAL in lupus nephritis among other potential diagnostic and prognostic markers. The potential for improving the clinical toolkit toward better treatment of pediatric kidney diseases is significantly aided by current and future development of proteomic applications. Cummins, Timothy D Korte, Erik A Bhayana, Sagar Merchant, Michael L Barati, Michelle T Smoyer, William E Klein, Jon B eng R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review Germany Pediatr Nephrol. Oct;37(10):-. doi: 10./s-022--2. Epub Feb 26.I SomaScan 02/28/ Galbraith MD, et al. Specialized interferon action in COVID-19 Proc Natl Acad Sci U S A 119 11 https://www.doi.org/10./pnas. 35,217,532 Blood/*metabolism COVID-19/blood/*immunology Case-Control Studies Datasets as Topic Humans Inpatients Interferons/*blood *Proteome *Transcriptome Covid-19 CyTOF SARS-CoV-2 cytokine interferon Board for Eli Lilly. The impacts of interferon (IFN) signaling on COVID-19 pathology are multiple, with both protective and harmful effects being documented. We report here a multiomics investigation of systemic IFN signaling in hospitalized COVID-19 patients, defining the multiomics biosignatures associated with varying levels of 12 different type I, II, and III IFNs. The antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of IFNs, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage and platelet activation associate with high levels of IFNB1 and IFNA6. Seroconversion and time since hospitalization associate with a significant decrease in a specific subset of IFNs. Additionally, differential IFN subtype production is linked to distinct constellations of circulating myeloid and lymphoid immune cell types. Each IFN has a unique metabolic signature, with IFNG being the most associated with activation of the kynurenine pathway. IFNs also show differential relationships with clinical markers of poor prognosis and disease severity. For example, whereas IFNG has the strongest association with C-reactive protein and other immune markers of poor prognosis, IFNB1 associates with increased neutrophil to lymphocyte ratio, a marker of late severe disease. Altogether, these results reveal specialized IFN action in COVID-19, with potential diagnostic and therapeutic implications. Galbraith, Matthew D Kinning, Kohl T Sullivan, Kelly D Araya, Paula Smith, Keith P Granrath, Ross E Shaw, Jessica R Baxter, Ryan Jordan, Kimberly R Russell, Seth Dzieciatkowska, Monika Reisz, Julie A Gamboni, Fabia Cendali, Francesca Ghosh, Tusharkanti Guo, Kejun Wilson, Cara C Santiago, Mario L Monte, Andrew A Bennett, Tellen D Hansen, Kirk C Hsieh, Elena W Y D'Alessandro, Angelo Espinosa, Joaquin M eng K23 AR/AR/NIAMS NIH HHS/ P30 CA/CA/NCI NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R01 AI/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. Mar 15;119(11):e. doi: 10./pnas..I SomaScan 02/27/ Gallego-Fabrega C, et al. Biological Age Acceleration Is Lower in Women With Ischemic Stroke Compared to Men Stroke 53 7 - https://www.doi.org/10./STROKEAHA.121. 35,209,739 Acceleration Aging Child, Preschool DNA Methylation *Epigenesis, Genetic Female Genetic Markers Humans *Ischemic Stroke Male Proteomics ischemic stroke men women BACKGROUND: Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA. METHODS: We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing proteins. RESULTS: Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=-0.64, men=1.24, P=1.34x10(-2)); the same tendency was observed in the second cohort (women=-0.57, men=0.79, P=0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA (P<0.05), belonging to the immune effector process (P=1.54x10(-6)) and platelet degranulation (P<8.74x10(-6)) pathways. CONCLUSIONS: This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women. Gallego-Fabrega, Cristina Muino, Elena Cullell, Natalia Carcel-Marquez, Jara Lazcano, Uxue Soriano-Tarraga, Carolina Lledos, Miquel Llucia-Carol, Laia Aguilera-Simon, Ana Marin, Rebeca Prats-Sanchez, Luis Camps-Renom, Pol Delgado-Mederos, Raquel Martin-Campos, Jesus M Delgado, Pilar Marti-Fabregas, Joan Montaner, Joan Krupinski, Jerzy Jimenez-Conde, J Roquer, Jaume Fernandez-Cadenas, Israel eng Research Support, Non-U.S. Gov't Stroke. Jul;53(7):-. doi: 10./STROKEAHA.121.. Epub Feb 25.I SomaScan 02/26/ Steffen BT, et al. Proteomic profiling identifies novel proteins for genetic risk of severe COVID-19: the Atherosclerosis Risk in Communities Study Hum Mol Genet 31 14 - https://www.doi.org/10./hmg/ddac024 35,212,764 *COVID-19/genetics *Genetic Predisposition to Disease Genome-Wide Association Study Humans Proteomics Risk Factors BACKGROUND: Genome-wide association studies have identified six genetic variants associated with severe COVID-19, yet the mechanisms through which they may affect disease remains unclear. We investigated proteomic signatures related to COVID-19 risk variants rs (ABO), rs (OAS1/OAS2/OAS3), rs (DPP9), rs (TYK2), rs (IFNAR2) and rs (SLC6A20/LZTFL1/CCR9/FYCO1/CXCR6/XCR1) as well as their corresponding downstream pathways that may promote severe COVID-19 in risk allele carriers and their potential relevancies to other infection outcomes. METHODS: A DNA aptamer-based array measured plasma proteins among 11 471 participants. Linear regression estimated associations between the COVID-19 risk variants and proteins with correction for multiple comparisons, and canonical pathway analysis was conducted. Cox regression assessed associations between proteins identified in the main analysis and risk of incident hospitalized respiratory infections ( events) over a 20.7-year follow-up. RESULTS: The ABO variant rs was associated with 84 proteins in white participants with 24 replicated in Black participants. The TYK2 variant rs was associated with ICAM-1 and -5 in white participants with ICAM-5 replicated in Black participants. Of the 84 proteins identified in the main analysis, seven were significantly associated with incident hospitalized respiratory infections including Ephrin type-A receptor 4 (hazard ratio (HR): 0.87; P = 2.3 x 10-11) and von Willebrand factor type A (HR: 1.17; P = 1.6x10-13). CONCLUSIONS: Novel proteomics signatures and pathways for COVID-19-related risk variants TYK2 and ABO were identified. A subset of these proteins predicted greater risk of incident hospitalized pneumonia and respiratory infections. Further studies to examine these proteins in COVID-19 patients are warranted. Steffen, Brian T Pankow, James S Lutsey, Pamela L Demmer, Ryan T Misialek, Jeffrey R Guan, Weihua Cowan, Logan T Coresh, Josef Norby, Faye L Tang, Weihong eng T32 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Hum Mol Genet. Jul 21;31(14):-. doi: 10./hmg/ddac024.I SomaScan 02/26/ Lopez-Silva C, et al. Comparison of Aptamer-Based and Antibody-Based Assays for Protein Quantification in Chronic Kidney Disease Clin J Am Soc Nephrol 17 3 350-360 https://www.doi.org/10./CJN. 35,197,258 Biomarkers Cystatin C Female Glomerular Filtration Rate Humans Interleukin-8 Male Receptors, Tumor Necrosis Factor Receptors, Urokinase Plasminogen Activator *Renal Insufficiency *Renal Insufficiency, Chronic AASK (African American Study of Kidney Disease and Hypertension) antibodies biological assay chronic inflammation chronic kidney disease end-stage renal disease mortality BACKGROUND AND OBJECTIVES: Novel aptamer-based technologies can identify > analytes per sample, offering a high-throughput alternative to traditional immunoassays in biomarker discovery. However, the specificity for distinct proteins has not been thoroughly studied in the context of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We assessed the use of SOMAscan, an aptamer-based technology, for the quantification of eight immune activation biomarkers and cystatin C among 498 African American Study of Kidney Disease and Hypertension (AASK) participants using immunoassays as the gold standard. We evaluated correlations of serum proteins as measured by SOMAscan versus immunoassays with each other and with iothalamate-measured GFR. We then compared associations between proteins measurement with risks of incident kidney failure and all-cause mortality. RESULTS: Six biomarkers (IL-8, soluble TNF receptor superfamily member 1B [TNFRSF1B], cystatin C, soluble TNF receptor superfamily member 1A [TNFRSF1A], IL-6, and soluble urokinase-type plasminogen activator receptor [suPAR]) had non-negligible correlations (r=0.94, 0.93, 0.89, 0.85, 0.46, and 0.23, respectively) between SOMAscan and immunoassay measurements, and three (IL-10, IFN-gamma, and TNF-alpha) were uncorrelated (r=0.08, 0.07, and 0.02, respectively). Of the six biomarkers with non-negligible correlations, TNFRSF1B, cystatin C, TNFRSF1A, and suPAR were negatively correlated with measured GFR and associated with higher risk of kidney failure. IL-8, TNFRSF1B, cystatin C, TNFRSF1A, and suPAR were associated with a higher risk of mortality via both methods. On average, immunoassay measurements were more strongly associated with adverse outcomes than their SOMAscan counterparts. CONCLUSIONS: SOMAscan is an efficient and relatively reliable technique for quantifying IL-8, TNFRSF1B, cystatin C, and TNFRSF1A in CKD and detecting their potential associations with clinical outcomes. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/_02_23_CJN.mp3. Lopez-Silva, Carolina Surapaneni, Aditya Coresh, Josef Reiser, Jochen Parikh, Chirag R Obeid, Wassim Grams, Morgan E Chen, Teresa K eng U01 DK/DK/NIDDK NIH HHS/ P20 RR/RR/NCRR NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ K08 DK/DK/NIDDK NIH HHS/ M01 RR/RR/NCRR NIH HHS/ P20 RR/RR/NCRR NIH HHS/ K24 HL/HL/NHLBI NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ M01 RR/RR/NCRR NIH HHS/ UL1 RR/RR/NCRR NIH HHS/ K24 DK/DK/NIDDK NIH HHS/ M01 RR/RR/NCRR NIH HHS/ M01 RR/RR/NCRR NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Clin J Am Soc Nephrol. Mar;17(3):350-360. doi: 10./CJN.. Epub Feb 23.I SomaScan 02/25/ Schubert R, et al. Protein prediction for trait mapping in diverse populations PLoS One 17 2 e https://www.doi.org/10./journal.pone. 35,202,437 Atherosclerosis/ethnology/*genetics Female Gene Frequency *Genetic Association Studies Humans Male *Models, Genetic Pilot Projects Polymorphism, Single Nucleotide Proteins/*genetics Proteome/*genetics Quantitative Trait Loci Genetically regulated gene expression has helped elucidate the biological mechanisms underlying complex traits. Improved high-throughput technology allows similar interrogation of the genetically regulated proteome for understanding complex trait mechanisms. Here, we used the Trans-omics for Precision Medicine (TOPMed) Multi-omics pilot study, which comprises data from Multi-Ethnic Study of Atherosclerosis (MESA), to optimize genetic predictors of the plasma proteome for genetically regulated proteome-wide association studies (PWAS) in diverse populations. We built predictive models for protein abundances using data collected in TOPMed MESA, for which we have measured 1,305 proteins by a SOMAscan assay. We compared predictive models built via elastic net regression to models integrating posterior inclusion probabilities estimated by fine-mapping SNPs prior to elastic net. In order to investigate the transferability of predictive models across ancestries, we built protein prediction models in all four of the TOPMed MESA populations, African American (n = 183), Chinese (n = 71), European (n = 416), and Hispanic/Latino (n = 301), as well as in all populations combined. As expected, fine-mapping produced more significant protein prediction models, especially in African ancestries populations, potentially increasing opportunity for discovery. When we tested our TOPMed MESA models in the independent European INTERVAL study, fine-mapping improved cross-ancestries prediction for some proteins. Using GWAS summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study, which comprises approximately 50,000 Hispanic/Latinos, African Americans, Asians, Native Hawaiians, and Native Americans, we applied S-PrediXcan to perform PWAS for 28 complex traits. The most protein-trait associations were discovered, colocalized, and replicated in large independent GWAS using proteome prediction model training populations with similar ancestries to PAGE. At current training population sample sizes, performance between baseline and fine-mapped protein prediction models in PWAS was similar, highlighting the utility of elastic net. Our predictive models in diverse populations are publicly available for use in proteome mapping methods at https://doi.org/10./zenodo.. Schubert, Ryan Geoffroy, Elyse Gregga, Isabelle Mulford, Ashley J Aguet, Francois Ardlie, Kristin Gerszten, Robert Clish, Clary Van Den Berg, David Taylor, Kent D Durda, Peter Johnson, W Craig Cornell, Elaine Guo, Xiuqing Liu, Yongmei Tracy, Russell Conomos, Matthew Blackwell, Tom Papanicolaou, George Lappalainen, Tuuli Mikhaylova, Anna V Thornton, Timothy A Cho, Michael H Gignoux, Christopher R Lange, Leslie Lange, Ethan Rich, Stephen S Rotter, Jerome I Manichaikul, Ani Im, Hae Kyung Wheeler, Heather E eng R15 HG/HG/NHGRI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. Feb 24;17(2):e. doi: 10./journal.pone.. eCollection .I SomaScan 02/25/ Povero D, et al. Protein and miRNA profile of circulating extracellular vesicles in patients with primary sclerosing cholangitis Sci Rep 12 1 https://www.doi.org/10./s-022--0 35,194,091 Adult Aged Biomarkers/blood Cholangitis, Sclerosing/*diagnosis Extracellular Vesicles/*genetics/*metabolism Female Gene Expression Humans Interleukin-13 Receptor alpha1 Subunit/*genetics/*metabolism Liver Cirrhosis/diagnosis Male MicroRNAs/*genetics/*metabolism Middle Aged Young Adult Primary sclerosing cholangitis (PSC) is an idiopathic and heterogenous cholestatic liver disease characterized by chronic inflammation and fibrosis of the biliary tree. Currently, no effective therapies are available for this condition, whose incidence is rising. At present, specificity and sensitivity of current serum markers used to diagnose PSC are limited and often unreliable. In this study, we characterize circulating extracellular vesicles and provide supporting data on their potential use as novel surrogate biomarkers for PSC. EVs are membrane surrounded structures, 100- nm in size, released by cells under various conditions and which carry a variety of bioactive molecules, including small non-coding RNAs, lipids and proteins. In recent years, a large body of evidence has pointed to diagnostic implications of EVs and relative cargo in various human diseases. We isolated EVs from serum of well-characterized patients with PSC or control subjects by differential centrifugation and size-exclusion chromatography. A complete characterization identified elevated levels of circulating EVs in PSC patients compared to healthy control subjects ( vs. 500 Calcein-FITC + EVs/muL). Tissue and cell specificity of circulating EVs was assessed by identification of liver-specific markers and cholangiocyte marker CK-19. Further molecular characterization identified 282 proteins that were differentially regulated in PSC-derived compared to healthy control-EVs. Among those, IL-13Ra1 was the most significantly and differentially expressed protein in PSC-derived EVs and correlated with the degree of liver fibrosis. In addition to protein profiling, we performed a miRNA-sequencing analysis which identified 11 among established, liver-specific (e.g., miR-122 and miR-192) and novel miRNAs. One of the newly identified miRNAs, miR--3p, was significantly up-regulated fourfold in PSC-derived EVs compared to circulating EVs isolated from healthy controls. This study provides supporting evidence of the potential role of circulating EVs and associated protein and miRNA cargo as surrogate noninvasive and reliable biomarker for PSC. Povero, Davide Tameda, Masahiko Eguchi, Akiko Ren, Wenhua Kim, Jihoon Myers, Robert Goodman, Zachary D Harrison, Stephen A Sanyal, Arun J Bosch, Jaime Ohno-Machado, Lucila Feldstein, Ariel E eng Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. Feb 22;12(1):. doi: 10./s-022--0.I SomaScan 02/24/ Chen G, et al. Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis Arthritis Rheumatol 74 7 - https://www.doi.org/10./art. 35,189,047 *Arthritis, Juvenile/complications Biomarkers Humans *Lung Diseases/epidemiology *Macrophage Activation Syndrome Matrix Metalloproteinase 7 Proteome OBJECTIVE: Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high-mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA-LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA-LD. METHODS: We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA-LD, or other related diseases. We verified selected findings by enzyme-linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA-LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort. RESULTS: Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat-shock proteins and glycolytic enzymes. Interleukin-18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA-LD. We also identified an MAS-independent SJIA-LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM-5), matrix metalloproteinase 7 (MMP-7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM-5 and MMP-7 in the lungs of patients with SJIA-LD. The ability of ICAM-5 to distinguish SJIA-LD from systemic JIA/MAS was independently validated. CONCLUSION: Serum proteins support a systemic JIA-to-MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA-LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM-5, could aid in early detection and management of SJIA-LD. Chen, Guangbo Deutsch, Gail H Schulert, Grant S Zheng, Hong Jang, SoRi Trapnell, Bruce Lee, Pui Y Macaubas, Claudia Ho, Katherine Schneider, Corinne Saper, Vivian E de Jesus, Adriana Almeida Krasnow, Mark A Grom, Alexei Goldbach-Mansky, Raphaela Khatri, Purvesh Mellins, Elizabeth D Canna, Scott W eng R01 HD/HD/NICHD NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ U19 AI/AI/NIAID NIH HHS/ R01 AI/AI/NIAID NIH HHS/ U19 AI/AI/NIAID NIH HHS/ K22 AI/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Arthritis Rheumatol. Jul;74(7):-. doi: 10./art.. Epub May 31.I SomaScan 02/22/ Sacco K, et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19 Nat Med 28 5 - https://www.doi.org/10./s-022--3 35,177,862 *COVID-19/complications/genetics Child Humans SARS-CoV-2 Systemic Inflammatory Response Syndrome/genetics T-Lymphocytes Pediatric Coronavirus Disease (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-kappaB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy. Sacco, Keith Castagnoli, Riccardo Vakkilainen, Svetlana Liu, Can Delmonte, Ottavia M Oguz, Cihan Kaplan, Ian M Alehashemi, Sara Burbelo, Peter D Bhuyan, Farzana de Jesus, Adriana A Dobbs, Kerry Rosen, Lindsey B Cheng, Aristine Shaw, Elana Vakkilainen, Mikko S Pala, Francesca Lack, Justin Zhang, Yu Fink, Danielle L Oikonomou, Vasileios Snow, Andrew L Dalgard, Clifton L Chen, Jinguo Sellers, Brian A Montealegre Sanchez, Gina A Barron, Karyl Rey-Jurado, Emma Vial, Cecilia Poli, Maria Cecilia Licari, Amelia Montagna, Daniela Marseglia, Gian Luigi Licciardi, Francesco Ramenghi, Ugo Discepolo, Valentina Lo Vecchio, Andrea Guarino, Alfredo Eisenstein, Eli M Imberti, Luisa Sottini, Alessandra Biondi, Andrea Mato, Sayonara Gerstbacher, Dana Truong, Meng Stack, Michael A Magliocco, Mary Bosticardo, Marita Kawai, Tomoki Danielson, Jeffrey J Hulett, Tyler Askenazi, Manor Hu, Shaohui Cohen, Jeffrey I Su, Helen C Kuhns, Douglas B Lionakis, Michail S Snyder, Thomas M Holland, Steven M Goldbach-Mansky, Raphaela Tsang, John S Notarangelo, Luigi D eng ZIA AI/ImNIH/Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Nat Med. May;28(5):-. doi: 10./s-022--3. Epub Feb 17.I SomaScan 02/19/ Ding Z, et al. Proteomics technologies for cancer liquid biopsies Mol Cancer 21 1 53 https://www.doi.org/10./s-022--8 35,168,611 Early Detection of Cancer Humans Liquid Biopsy *Neoplasms/diagnosis/genetics Proteome/metabolism *Proteomics/methods Antibody arrays Aptamer Cancer liquid biopsy Mass spectrometry (MS) Proteomics Proximity extension assay (PEA) Reverse phase protein arrays (RPPA) declare no conflicts of interests and no competing interests of this work. Alterations in DNAs could not reveal what happened in proteins. The accumulated alterations of DNAs would change the manifestation of proteins. Therefore, as is the case in cancer liquid biopsies, deep proteome profiling will likely provide invaluable and clinically relevant information in real-time throughout all stages of cancer progression. However, due to the great complexity of proteomes in liquid biopsy samples and the limitations of proteomic technologies compared to high-plex sequencing technologies, proteomic discoveries have yet lagged behind their counterpart, genomic technologies. Therefore, novel protein technologies are in urgent demand to fulfill the goals set out for biomarker discovery in cancer liquid biopsies.Notably, conventional and innovative technologies are being rapidly developed for proteomic analysis in cancer liquid biopsies. These advances have greatly facilitated early detection, diagnosis, prognosis, and monitoring of cancer evolution, adapted or adopted in response to therapeutic interventions. In this paper, we review the high-plex proteomics technologies that are capable of measuring at least hundreds of proteins simultaneously from liquid biopsy samples, ranging from traditional technologies based on mass spectrometry (MS) and antibody/antigen arrays to innovative technologies based on aptamer, proximity extension assay (PEA), and reverse phase protein arrays (RPPA). Ding, Zhiyong Wang, Nan Ji, Ning Chen, Zhe-Sheng eng Research Support, Non-U.S. Gov't Review England Mol Cancer. Feb 15;21(1):53. doi: 10./s-022--8.I SomaScan 02/17/ Essone PN, et al. Creatine kinase-(MB) and hepcidin as candidate biomarkers for early diagnosis of pulmonary tuberculosis: a proof-of-concept study in Lambarene, Gabon Infection 50 4 897-905 https://www.doi.org/10./s-022--8 35,133,607 Biomarkers Creatine Kinase, MB Form Early Diagnosis Gabon Hepcidins Humans *Mycobacterium tuberculosis ROC Curve Sensitivity and Specificity *Tuberculosis/diagnosis *Tuberculosis, Pulmonary/diagnosis Creatine kinase-MB Diagnosis Hepcidin Tuberculosis BACKGROUND: The present study aimed to evaluate the diagnostic utility of creatine kinase-MB (CK-MB), hepcidin (HEPC), phospholipase A2 group IIA (PLa2G2A), and myosin-binding protein C (MYBPC1) for tuberculosis (TB). These four biomarkers are differentially regulated between quiescent Mycobacterium tuberculosis (Mtb) infected individuals (non-progressors to TB disease) and Mtb-infected TB disease progressors 6 months before the onset of symptoms. METHODS: We enrolled samples from patients experiencing moderate-to-severe pulmonary infections diseases including 23 TB cases confirmed by smear microscopy and culture, and 34 TB-negative cases. For each participant, the serum levels of the four biomarkers were measured using ELISA. RESULTS: The levels of CK-MB and HEPC were significantly reduced in patients with active TB disease. CK-MB median level was pg/ml (- pg/ml) in active TB cases and pg/ml (- pg/ml) in non-TB pulmonary diseases. Using the receiver operating characteristic curve (ROC) analysis, HEPC and CK-MB had the Area Under the Curve (AUC) of 79% (95% CI 67-91%) and 81% (95% CI 69-93%), respectively. Both markers correlated with TB diagnosis as a single marker. PLa2G2A and MYBPC1 with AUCs of 48% (95% CI 36-65%) and 62% (95% CI 48-76%) did not performed well as single biomarkers. The three markers'model (CK-MB-HEPC-PLa2G2A) had the highest diagnostic accuracy at 82% (95% CI 56-82%) after cross-validation. CONCLUSION: CK-MB and HEPC levels were statistically different between confirmed TB cases and non-TB cases. This study yields promising results for the rapid diagnosis of TB disease using a single marker or three biomarkers model. Essone, Paulin N Adegbite, Bayode R Mbadinga, Marien J M Mbouna, Armel V Lotola-Mougeni, Fabrice Alabi, Ayodele Edoa, Jean R Lell, Bertrand Alabi, Abraham S Adegnika, Ayola A Ramharter, Michael Siawaya, Joel F D Grobusch, Martin P Kremsner, Peter G Agnandji, Selidji T eng EDCTP-TMA-SF--VARSAF/European and Developing Countries Clinical Trials Partnership/ Germany Infection. Aug;50(4):897-905. doi: 10./s-022--8. Epub Feb 8.I SomaScan 02/09/ Schreiner C, et al. Placental proteins with predicted roles in fetal development decrease in premature infants Pediatr Res 92 5 - https://www.doi.org/10./s-022--y 35,132,128 Female Humans Infant, Newborn Pregnancy Fetal Blood Fetal Development *Infant, Premature Placenta/metabolism *Pregnancy Proteins BACKGROUND: Emerging evidence from animal experiments indicate that factors secreted by the placenta are critical for normal fetal organ development. Our objective was to characterize the umbilical vein and artery proteome in preterm infants and identify proteins that decrease in the neonatal circulation following delivery. METHODS: Cord blood at delivery and neonatal blood at 48-72 h of life was collected in 25 preterm infants. Plasma protein abundance was determined using the SomaLogic platform. RESULTS: When comparing protein levels of umbilical venous to arterial cord blood, 434 proteins were significantly higher indicating placental secretion into the fetal circulation. Moreover, when comparing neonatal blood to umbilical vein levels, 142 proteins were significantly lower. These proteins included Endoplasmic reticulum resident protein 29, CD59, Fibroblast growth factor 2 and Dynactin subunit 2, which are involved in brain development and prevention of brain damage as well as Fibroblast growth factor 1 which prevents lung fibrosis. CONCLUSIONS: The late second trimester human placenta secretes proteins into the fetal circulation which decrease following delivery. Many of these proteins are predicted to be important in the development of fetal organs. Further studies are needed to directly link placental proteins to organ development and poor outcomes in preterm infants. IMPACT: Prematurity remains a leading cause of morbidity and mortality requiring the development of novel treatments. Emerging evidence from animal studies suggest that factors secreted from the placenta may be critical in the development of the fetus. We report that the preterm human placenta secretes an array of proteins into the fetal circulation. Some of these proteins are predicted to be involved in the development of the brain and the lung. When born prematurely, infants are deprived of these placental proteins, which may contribute to their poor outcomes. Schreiner, Cynthia Powell, Theresa L Palmer, Claire Jansson, Thomas eng R21 HD/HD/NICHD NIH HHS/ Pediatr Res. Nov;92(5):-. doi: 10./s-022--y. Epub Feb 7.I SomaScan 02/09/ Mookherjee N, et al. Defining the effects of traffic-related air pollution on the human plasma proteome using an aptamer proteomic array: A dose-dependent increase in atherosclerosis-related proteins Environ Res 209 https://www.doi.org/10./j.envres.. 35,120,890 *Air Pollutants/analysis/toxicity *Air Pollution/adverse effects/analysis *Atherosclerosis/chemically induced/etiology/metabolism Humans Proteome Proteomics Random Allocation Vehicle Emissions/analysis/toxicity Air pollution Atherosclerosis Biomarkers Diesel exhaust BACKGROUND: Traffic-related air pollution (TRAP) is a critical risk factor and major contributor to respiratory and cardiovascular disease (CVD). The effects of TRAP beyond the lungs can be related to changes in circulatory proteins. However, such TRAP-mediated changes have not been defined in an unbiased manner using a controlled human model. OBJECTIVE: To detail global protein changes (the proteome) in plasma following exposure to inhaled diesel exhaust (DE), a paradigm of TRAP, using controlled human exposures. METHODS: In one protocol, ex-smokers and never-smokers were exposed to filtered air (FA) and DE (300 mug PM(2.5)/m(3)), on order-randomized days, for 2 h. In a second protocol, independent never-smoking participants were exposed to lower concentrations of DE (20, 50 or 150 mug PM(2.5)/m(3)) and FA, for 4 h, on order-randomized days. Each exposure was separated by 4 weeks of washout. Plasma samples obtained 24 h post-exposure from ex-smokers (n = 6) were first probed using Slow off-rate modified aptamer proteomic array. Plasma from never-smokers (n = 11) was used for independent assessment of proteins selected from the proteomics study by immunoblotting. RESULTS: Proteomics analyses revealed that DE significantly altered 342 proteins in plasma of ex-smokers (n = 6). The top 20 proteins therein were primarily associated with inflammation and CVD. Plasma from never-smokers (n = 11) was used for independent assessment of 6 proteins, amongst the top 10 proteins increased by DE in the proteomics study, for immunoblotting. The abundance of all six proteins (fractalkine, apolipoproteins (APOB and APOM), IL18R1, MIP-3 and MMP-12) was significantly increased by DE in plasma of these never-smokers. DE-mediated increase was shown to be concentration-dependent for fractalkine, APOB and MMP-12, all biomarkers of atherosclerosis, which correlated with plasma levels of IL-6, a subclinical marker of CVD, in independent participants. CONCLUSION: This investigation details changes in the human plasma proteome due to TRAP. We identify specific atherosclerosis-related proteins that increase concentration-dependently across a range of TRAP levels applicable worldwide. Mookherjee, Neeloffer Ryu, Min Hyung Hemshekhar, Mahadevappa Orach, Juma Spicer, Victor Carlsten, Christopher eng Netherlands Environ Res. Jun;209:. doi: 10./j.envres... Epub Feb 1.I SomaScan 02/06/ Bjornsdottir G, et al. Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology Nat Commun 13 1 634 https://www.doi.org/10./s-022--1 35,110,524 3' Untranslated Regions Bone and Bones/metabolism Genome-Wide Association Study Humans Intervertebral Disc/*metabolism Intervertebral Disc Degeneration/*genetics Intervertebral Disc Displacement/*genetics Sodium Sulfate Cotransporter/*genetics/*metabolism Sulfates/*metabolism Symporters/genetics/metabolism Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (OR(IDD) = 0.92, P = 1.6 x 10(-39); OR(dorsalgia) = 0.92, P = 7.2 x 10(-15)) is with a 3'UTR variant (rs-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 x 10(-11)); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes. Bjornsdottir, Gyda Stefansdottir, Lilja Thorleifsson, Gudmar Sulem, Patrick Norland, Kristjan Ferkingstad, Egil Oddsson, Asmundur Zink, Florian Lund, Sigrun H Nawaz, Muhammad S Bragi Walters, G Skuladottir, Astros Th Gudjonsson, Sigurjon A Einarsson, Gudmundur Halldorsson, Gisli H Bjarnadottir, Valgerdur Sveinbjornsson, Gardar Helgadottir, Anna Styrkarsdottir, Unnur Gudmundsson, Larus J Pedersen, Ole B Hansen, Thomas Folkmann Werge, Thomas Banasik, Karina Troelsen, Anders Skou, Soren T Thorner, Lise Wegner Erikstrup, Christian Nielsen, Kaspar Rene Mikkelsen, Susan Jonsdottir, Ingileif Bjornsson, Aron Olafsson, Ingvar H Ulfarsson, Elfar Blondal, Josep Vikingsson, Arnor Brunak, Soren Ostrowski, Sisse R Ullum, Henrik Thorsteinsdottir, Unnur Stefansson, Hreinn Gudbjartsson, Daniel F Thorgeirsson, Thorgeir E Stefansson, Kari eng Research Support, Non-U.S. Gov't England Nat Commun. Feb 2;13(1):634. doi: 10./s-022--1.I SomaScan 02/04/ Schunkert H, et al. Linking Genetics and Proteomics: Gene-Protein Associations Built on Diversity Circulation 145 5 371-374 https://www.doi.org/10./CIRCULATIONAHA.121. 35,100,019 Genome-Wide Association Study *Genomics Humans *Proteomics Editorials cardiovascular disease ethnic diversity genomics proteomics Schunkert, Heribert Mayr, Manuel eng SP/17/10//BHF_/British Heart Foundation/United Kingdom RG/16/14//BHF_/British Heart Foundation/United Kingdom CH/16/3//BHF_/British Heart Foundation/United Kingdom Comment Editorial Research Support, Non-U.S. Gov't Circulation. Feb;145(5):371-374. doi: 10./CIRCULATIONAHA.121.. Epub Jan 31.I SomaScan 02/01/ Vanarsa K, et al. Aptamer-Based Screen of Neuropsychiatric Lupus Cerebrospinal Fluid Reveals Potential Biomarkers That Overlap With the Choroid Plexus Transcriptome Arthritis Rheumatol 74 7 - https://www.doi.org/10./art. 35,099,126 *Biomarkers/cerebrospinal fluid Choroid Plexus/metabolism Complement C3/metabolism Humans Immunoglobulin M/metabolism Lipocalin-2/metabolism *Lupus Vasculitis, Central Nervous System/cerebrospinal fluid/diagnosis Macrophage Colony-Stimulating Factor/metabolism Proteomics Transcriptome OBJECTIVE: As no gold-standard diagnostic test exists for neuropsychiatric systemic lupus erythematosus (NPSLE), we undertook this study to execute a broad screen of NPSLE cerebrospinal fluid (CSF) using an aptamer-based platform. METHODS: CSF was obtained from NPSLE patients and subjected to proteomic assay using the aptamer-based screen. Potential biomarkers were identified and validated in independent NPSLE cohorts in comparison to other neurologic diseases. RESULTS: Forty proteins out of the 1,129 screened were found to be elevated in NPSLE CSF. Based on enzyme-linked immunosorbent assay validation, CSF levels of angiostatin, alpha2-macroglobulin, DAN, fibronectin, hepatocellular carcinoma clone 1, IgM, lipocalin 2, macrophage colony-stimulating factor (M-CSF), and serine protease inhibitor G1 were significantly elevated in a predominantly White NPSLE cohort (n = 24), compared to patients with other neurologic diseases (n = 54), with CSF IgM (area under the curve [AUC] 0.95) and M-CSF (AUC 0.91) being the most discriminatory proteins. In a second Hong Kong-based NPSLE cohort, CSF IgM (AUC 0.78) and lipocalin 2 (AUC 0.85) were the most discriminatory proteins. Several CSF proteins exhibited high diagnostic specificity for NPSLE in both cohorts. Elevated CSF complement C3 was associated with an acute confusional state. Eleven molecules elevated in NPSLE CSF exhibited concordant elevation in the choroid plexus, suggesting shared origins. CONCLUSION: Lipocalin 2, M-CSF, IgM, and complement C3 emerge as promising CSF biomarkers of NPSLE with diagnostic potential. Vanarsa, Kamala Sasidharan, Prashanth Duran, Valeria Gokaraju, Sirisha Nidhi, Malavika Titus, Anto Sam Crosslee Louis Sam Soomro, Sanam Stock, Ariel D Der, Evan Putterman, Chaim Greenberg, Benjamin Mok, Chi Chiu Hanly, John G Mohan, Chandra eng R01 AR/GF/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Arthritis Rheumatol. Jul;74(7):-. doi: 10./art.. Epub May 18.I SomaScan 02/01/ Emilsson V, et al. Coding and regulatory variants are associated with serum protein levels and disease Nat Commun 13 1 481 https://www.doi.org/10./s-022--6 35,079,000 Aged Blood Proteins/*genetics Disease/classification/*genetics Exome/*genetics Female *Genetic Predisposition to Disease *Genotype Humans Iceland Male *Polymorphism, Single Nucleotide Proteome/*metabolism Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to protein measurements in the serum of individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that independent exome array variants are associated with serum levels of proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases. Emilsson, Valur Gudmundsdottir, Valborg Gudjonsson, Alexander Jonmundsson, Thorarinn Jonsson, Brynjolfur G Karim, Mohd A Ilkov, Marjan Staley, James R Gudmundsson, Elias F Launer, Lenore J Lindeman, Jan H Morton, Nicholas M Aspelund, Thor Lamb, John R Jennings, Lori L Gudnason, Vilmundur eng N01AG/AG/NIA NIH HHS/ /WT_/Wellcome Trust/United Kingdom R01 AG/AG/NIA NIH HHS/ WT_/Wellcome Trust/United Kingdom HHSNC/DA/NIDA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. Jan 25;13(1):481. doi: 10./s-022--6.I SomaScan 01/27/ Gudjonsson A, et al. A genome-wide association study of serum proteins reveals shared loci with common diseases Nat Commun 13 1 480 https://www.doi.org/10./s-021--z 35,078,996 Aged Aged, 80 and over Blood Proteins/*genetics Cohort Studies Disease/classification/*genetics Female *Genetic Predisposition to Disease *Genome, Human Genome-Wide Association Study/*methods Humans Iceland Male *Polymorphism, Single Nucleotide *Quantitative Trait Loci With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein's genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease. Gudjonsson, Alexander Gudmundsdottir, Valborg Axelsson, Gisli T Gudmundsson, Elias F Jonsson, Brynjolfur G Launer, Lenore J Lamb, John R Jennings, Lori L Aspelund, Thor Emilsson, Valur Gudnason, Vilmundur eng HHSNC/DA/NIDA NIH HHS/ N01AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. Jan 25;13(1):480. doi: 10./s-021--z.I SomaScan 01/27/ Rhodes CJ, et al. Using the Plasma Proteome for Risk Stratifying Patients with Pulmonary Arterial Hypertension Am J Respir Crit Care Med 205 9 - https://www.doi.org/10./rccm.-OC 35,081,018 Area Under Curve Biomarkers Familial Primary Pulmonary Hypertension Humans Natriuretic Peptide, Brain Peptide Fragments Prognosis Proteome *Pulmonary Arterial Hypertension clinical outcomes Rationale: NT-proBNP (N-terminal pro-brain natriuretic peptide), a biomarker of cardiac origin, is used to risk stratify patients with pulmonary arterial hypertension (PAH). Its limitations include poor sensitivity to early vascular pathology. Other biomarkers of vascular or systemic origin may also be useful in the management of PAH. Objectives: Identify prognostic proteins in PAH that complement NT-proBNP and clinical risk scores. Methods: An aptamer-based assay (SomaScan version 4) targeting 4,152 proteins was used to measure plasma proteins in patients with idiopathic, heritable, or drug-induced PAH from the UK National Cohort of PAH (n = 357) and the French EFORT (Evaluation of Prognostic Factors and Therapeutic Targets in PAH) study (n = 79). Prognostic proteins were identified in discovery-replication analyses of UK samples. Proteins independent of 6-minute-walk distance and NT-proBNP entered least absolute shrinkage and selection operator modeling, and the best combination in a single score was evaluated against clinical targets in EFORT. Measurements and Main Results: Thirty-one proteins robustly informed prognosis independent of NT-proBNP and 6-minute-walk distance in the UK cohort. A weighted combination score of six proteins was validated at baseline (5-yr mortality; area under the curve [AUC], 0.73; 95% confidence interval [CI], 0.63-0.85) and follow-up in EFORT (AUC, 0.84; 95% CI, 0.75-0.94; P = 9.96 x 10(-6)). The protein score risk stratified patients independent of established clinical targets and risk equations. The addition of the six-protein model score to NT-proBNP improved prediction of 5-year outcomes from AUC 0.762 (0.702-0.821) to 0.818 (0.767-0.869) by receiver operating characteristic analysis (P = 0. for difference in AUC) in the UK replication and French samples combined. Conclusions: The plasma proteome informs prognosis beyond established factors in PAH and may provide a more sensitive measure of therapeutic response. Rhodes, Christopher J Wharton, John Swietlik, Emilia M Harbaum, Lars Girerd, Barbara Coghlan, J Gerry Lordan, James Church, Colin Pepke-Zaba, Joanna Toshner, Mark Wort, Stephen J Kiely, David G Condliffe, Robin Lawrie, Allan Graf, Stefan Montani, David Boucly, Athenais Sitbon, Olivier Humbert, Marc Howard, Luke S Morrell, Nicholas W Wilkins, Martin R eng FS/15/59//BHF_/British Heart Foundation/United Kingdom MR/K/1/MRC_/Medical Research Council/United Kingdom FS/13/48//BHF_/British Heart Foundation/United Kingdom FS/18/52//BHF_/British Heart Foundation/United Kingdom RE/18/4//BHF_/British Heart Foundation/United Kingdom SP/12/12//BHF_/British Heart Foundation/United Kingdom DH_/Department of Health/United Kingdom SP/18/10//BHF_/British Heart Foundation/United Kingdom Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. May 1;205(9):-. doi: 10./rccm.-OC.I SomaScan 01/27/ Sproull M, et al. Comparison of Proteomic Expression Profiles after Radiation Exposure across Four Different Species Radiat Res 197 4 315-323 https://www.doi.org/10./RADE-21-.1 35,073,400 Animals Biomarkers/metabolism Dose-Response Relationship, Radiation Histones Humans Mice Mice, Inbred C57BL *Proteomics *Radiation Exposure/adverse effects/analysis Swine Swine, Miniature There is a need to identify biomarkers of radiation exposure for use in development of circulating biodosimeters for radiation exposure and for clinical use as markers of radiation injury. Most research approaches for biomarker discovery rely on a single animal model. The current study sought to take advantage of a novel aptamer-based proteomic assay which has been validated for use in many species to characterize changes to the blood proteome after total-body irradiation (TBI) across four different mammalian species including humans. Plasma was collected from C57BL6 mice, Sinclair minipigs, and Rhesus non-human primates (NHPs) receiving a single dose of TBI at a range of 3.3 Gy to 4.22 Gy at 24 h postirradiation. NHP and minipig models were irradiated using a 60Co source at a dose rate of 0.6 Gy/min, the C57BL6 mouse model using an X-ray source at a dose rate of 2.28 Gy/min and clinical samples from a photon source at 10 cGy/min. Plasma was collected from human patients receiving a single dose of 2 Gy TBI collected 6 h postirradiation. Plasma was screened using the aptamer-based SomaLogic SomaScan(R) proteomic assay technology to evaluate changes in the expression of 1,310 protein analytes. Confirmatory analysis of protein expression of biomarker HIST1H1C, was completed using plasma from C57BL6 mice receiving a 2, 3.5 or 8 Gy TBI collected at days 1, 3, and 7 postirradiation by singleplex ELISA. Summary of key pathways with altered expression after radiation exposure across all four mammalian species was determined using Ingenuity Pathway Analysis (IPA). Detectable values were obtained for all 1,310 proteins in all samples included in the SomaScan assay. A subset panel of protein biomarkers which demonstrated significant (p < 0.05) changes in expression of at least 1.3-fold after radiation exposure were characterized for each species. IPA of significantly altered proteins yielded a variety of top disease and biofunction pathways across species with the organismal injury and abnormalities pathway held in common for all four species. The HIST1H1C protein was shown to be radiation responsive within the human, NHP and murine species within the SomaScan dataset and was shown to demonstrate dose dependent upregulation at 2, 3.5 and 8 Gy at 24 h postirradiation in a separate murine cohort by ELISA. The SomaScan proteomics platform is a useful screening tool to evaluate changes in biomarker expression across multiple mammalian species. In our study, we were able to identify a novel biomarker of radiation exposure, HIST1H1C, and characterize panels of radiation responsive proteins and functional proteomic pathways altered by radiation exposure across murine, minipig, NHP and human species. Our study demonstrates the efficacy of using a multispecies approach for biomarker discovery. Sproull, Mary Nishita, Denise Chang, Polly Moroni, Maria Citrin, Deborah Shankavaram, Uma Camphausen, Kevin eng Z99 CA/ImNIH/Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Radiat Res. Apr 1;197(4):315-323. doi: 10./RADE-21-.1.I SomaScan 01/25/ Todd JL, et al. Association of Circulating Proteins with Death or Lung Transplant in Patients with Idiopathic Pulmonary Fibrosis in the IPF-PRO Registry Cohort Lung 200 1 18-Nov https://www.doi.org/10./s-021--y 35,066,606 Cohort Studies Humans *Idiopathic Pulmonary Fibrosis *Lung Transplantation Proteomics Registries Biomarkers Interstitial lung diseases Observational study Proteomics RO, HM and SMP are employees of the Duke Clinical Research Institute, which was funded by Boehringer Ingelheim Pharmaceuticals, Inc to conduct this research. JR reports grants and personal fees from Boehringer Ingelheim and grants from Genentech, Galapagos, Syneos Health, Bellerophon Therapeutics, FibroGen, and the National Institutes of Health. JAL reports personal fees from Biogen, Boehringer Ingelheim, Galecto, Roche/Genentech and Veracyte. JAdA reports personal fees from Boehringer Ingelheim. MG reports personal fees, non-financial support, and other support from the France Foundation grants, non-financial support and other support from Boehringer Ingelheim and the Pulmonary Fibrosis Foundation and personal fees from Genentech. HH is on a speaker panel for Boehringer Ingelheim. IN reports personal fees from Boehringer Ingelheim, Genentech, and ImmuneWorks. JAB has no disclosures. KRF reports grants and personal fees from Boehringer Ingelheim and Roche/Genentech and personal fees from FibroGen, Sanofi, Genzyme, and Veracyte. TBL was an employee of Boehringer Ingelheim at the time this study was conducted. CH is an employee of Boehringer Ingelheim. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a variable clinical course. Biomarkers that predict patient outcomes are needed. We leveraged data from 300 patients in the multicenter IPF-PRO Registry to determine associations between circulating proteins and the composite outcome of respiratory death or lung transplant. Plasma collected at enrollment was analyzed using aptamer-based proteomics ( proteins). Over a median follow-up of 30.4 months, there were 76 respiratory deaths and 26 lung transplants. In unadjusted univariable analyses, 61 proteins were significantly associated with the outcome (hazard ratio > 2 or < 0.5, corrected p /= 0.90. Immunostaining was used to characterize the cellular localization of the new biomarker proteins in liver tissues. We identified nine proteins in the discovery cohort (n = 40 subjects) and five proteins in the validation cohort (n = 80 subjects) that individually or in combination predicted clinical PHT with AUROCs >/= 0.90. Merging the two cohorts, we found that semaphorin 6B (SEMA6B) alone and three other protein combinations (SEMA6B+secreted frizzle protein 3 [SFRP3], SEMA6B+COMM domain containing 7 [COMMD7], and vascular cell adhesion molecule 1 [VCAM1]+BMX nonreceptor tyrosine kinase [BMX]) had AUROCs >/= 0.90 in both cohorts, with high positive- and negative-predictive values. Immunostaining of the new protein biomarkers showed increased expression in hepatic endothelial cells, cholangiocytes, and immune cells within portal triads in BA livers with clinical PHT compared to healthy livers. Conclusion: Large-scale proteomics identified SEMA6B, SFRP3, COMMD7, BMX, and VCAM1 as biomarkers highly associated with clinical PHT in BA. The expression of the biomarkers in hepatic epithelial, endothelial, and immune cells support their potential role in the pathophysiology of PHT. Osborn, Julie Mourya, Reena Thanekar, Unmesha Su, Weizhe Fei, Lin Shivakumar, Pranavkumar Bezerra, Jorge A eng T32 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Hepatol Commun. May;6(5):995-. doi: 10./hep4.. Epub Dec 27.I SomaScan 12/29/ Rahman ML, et al. Proteomic analysis of serum in workers exposed to diesel engine exhaust Environ Mol Mutagen 63 1 18-28 https://www.doi.org/10./em. 34,894,159 *Air Pollutants, Occupational/analysis/toxicity Carbon/analysis/metabolism Cross-Sectional Studies Group IB Phospholipases A2/metabolism Humans Inflammation/metabolism *Occupational Exposure/adverse effects/analysis Proteomics RNA-Binding Proteins/analysis Vehicle Emissions/analysis/toxicity SOMAscan carcinogenesis diesel engine exhaust elemental carbon lung cancer Diesel engine exhaust (DEE) is classified as a Group 1 human carcinogen. Using a targeted proteomics approach, we aimed to identify proteins associated with DEE and characterize these markers to understand the mechanisms of DEE-induced carcinogenicity. In this cross-sectional molecular epidemiology study, we measured elemental carbon (EC) using a personal air monitor and quantified targeted proteins in the serum using the SOMAScan assay (SOMALogic) among 19 diesel exposed factory workers and 19 unexposed controls. We used linear regressions to identify proteins associated with DEE and examined their exposure-response relationship across levels of EC using linear trend tests. We further examined pathway enrichment of DEE-related proteins using MetaCore. Occupational exposure to DEE was associated with altered levels of 22 serum proteins (permutation p < .01). Of these, 13 proteins (CXCL11, HAPLN1, FLT4, CD40LG, PES1, IGHE.IGK..IGL, TNFSF9, PGD, NAGK, CCL25, CCL4L1, PDXK, and PLA2G1B) showed an exposure-response relationship with EC (p trend < .01), with serum levels of all but PLA2G1B declining with increasing air levels of EC. For instance, C-X-C Motif Chemokine Ligand 11 (CXCL11) showed the most significant association with DEE (beta = -0.25; permutation p = .), where mean serum levels were .1, .7, and .8 relative fluorescent units among the unexposed, lower exposed (median, range : 56.9, 40.2-62.1 mug/m(3) EC), and higher exposed (median, range of EC: 72.9, 66.9-107.7 mug/m(3) EC) groups, respectively (p trend = .). Pathway analysis suggested that these proteins are enriched in pathways related to inflammation and immune regulation. Our study suggests that DEE exposure is associated with altered serum proteins, which play a role in inflammation and immune regulation. Rahman, Mohammad L Bassig, Bryan A Dai, Yufei Hu, Wei Wong, Jason Y Y Blechter, Batel Hosgood, H Dean Ren, Danzhi Duan, Huawei Niu, Yong Xu, Jun Fu, Wei Meliefste, Kees Zhou, Baosen Yang, Jufang Ye, Meng Jia, Xiaowei Meng, Tao Bin, Ping Silverman, Debra T Vermeulen, Roel Rothman, Nathaniel Zheng, Yuxin Lan, Qing eng Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Environ Mol Mutagen. Jan;63(1):18-28. doi: 10./em.. Epub Dec 28.I SomaScan 12/12/ Katz DH, et al. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease Circulation 145 5 357-370 https://www.doi.org/10./CIRCULATIONAHA.121. 34,814,699 Adult Blacks Cardiovascular Diseases/*epidemiology/*genetics Female Genome-Wide Association Study/*methods Humans Male Proteome/*metabolism cardiovascular disease genetics proteomics race and ethnicity BACKGROUND: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. METHODS: Proteomic profiling of proteins was performed in Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count >/=5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). RESULTS: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8x10(-11). These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs-T, beta=0.61+/-0.05, P=3.27x10(-30)) and MMP-3 (beta=-0.60+/-0.05, P=1.67x10(-32)), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs-G, beta=0.34+/-0.04, P=1.34x10(-17)) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. CONCLUSIONS: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function. Katz, Daniel H Tahir, Usman A Bick, Alexander G Pampana, Akhil Ngo, Debby Benson, Mark D Yu, Zhi Robbins, Jeremy M Chen, Zsu-Zsu Cruz, Daniel E Deng, Shuliang Farrell, Laurie Sinha, Sumita Schmaier, Alec A Shen, Dongxiao Gao, Yan Hall, Michael E Correa, Adolfo Tracy, Russell P Durda, Peter Taylor, Kent D Liu, Yongmei Johnson, W Craig Guo, Xiuqing Yao, Jie Ida Chen, Yii-Der Manichaikul, Ani W Jain, Deepti Bouchard, Claude Sarzynski, Mark A Rich, Stephen S Rotter, Jerome I Wang, Thomas J Wilson, James G Natarajan, Pradeep Gerszten, Robert E (Trans-Omics for Precision Medicine) eng R01 NR/NR/NINR NIH HHS/ DP5 OD/OD/NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ F32 HL/HL/NHLBI NIH HHS/ K08 HL/HL/NHLBI NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ KL2 TR/TR/NCATS NIH HHS/ K08 HL/HL/NHLBI NIH HHS/ RF1 AG/AG/NIA NIH HHS/ K23 DK/DK/NIDDK NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. Feb;145(5):357-370. doi: 10./CIRCULATIONAHA.121.. Epub Nov 24.I SomaScan 11/25/ Schuppan D, et al. Liquid biomarkers for fibrotic NASH - progress in a complex field J Hepatol 76 1 7-May https://www.doi.org/10./j.jhep..11.005 34,801,249 Biomarkers Fibrosis Humans *Non-alcoholic Fatty Liver Disease/diagnosis Companion biomarker Nafld fibrogenesis liver biopsy liver fibrosis prediction serum marker arrangement or affiliation with any organization that may have a direct influence on their work. Please refer to the accompanying ICMJE disclosure forms for further details. Schuppan, Detlef Myneni, Sudharani Surabattula, Rambabu eng Comment Editorial Research Support, Non-U.S. Gov't Netherlands J Hepatol. Jan;76(1):5-7. doi: 10./j.jhep..11.005. Epub Nov 17.I SomaScan 11/22/ Chelliah SS, et al. Identification of blood-based biomarkers for diagnosis and prognosis of Parkinson's disease: A systematic review of proteomics studies Ageing Res Rev 73 https://www.doi.org/10./j.arr.. 34,798,300 Biomarkers Dopaminergic Neurons Humans *Parkinson Disease/diagnosis Prognosis Proteomics Apolipoprotein A-I Apolipoproteins Blood-based biomarkers Parkinson's disease Systematic review Parkinson's Disease (PD), a neurodegenerative disorder, is characterised by the loss of motor function and dopamine neurons. Therapeutic avenues remain a challenge due to lack of accuracy in early diagnosis, monitoring of disease progression and limited therapeutic options. Proteomic platforms have been utilised to discover biomarkers for numerous diseases, a tool that may benefit the diagnosis and monitoring of disease progression in PD patients. Therefore, this systematic review focuses on analysing blood-based candidate biomarkers (CB) identified via proteomics platforms for PD. This study systematically reviewed articles across six databases (EMBASE, Cochrane, Ovid Medline, Scopus, Science Direct and PubMed) published between and . Of the 504 articles identified, 12 controlled-PD studies were selected for further analysis. A total of 115 candidate biomarkers (CB) were identified across selected 12-controlled studies, of which 23 CB were found to be replicable in more than two cohorts. Using the PANTHER Go-Slim classification system and STRING network, the gene function and protein interactions between biomarkers were analysed. Our analysis highlights Apolipoprotein A-I (ApoA-I), which is essential in lipid metabolism, oxidative stress, and neuroprotection demonstrates high replicability across five cohorts with consistent downregulation across four cohorts. Since ApoA-I was highly replicable across blood fractions, proteomic platforms and continents, its relationship with cholesterol, statin and oxidative stress as PD biomarker, its role in the pathogenesis of PD is discussed in this paper. The present study identified ApoA-I as a potential biomarker via proteomics analysis of PD for the early diagnosis and prediction of disease progression. Chelliah, Shalini Sundramurthi Bhuvanendran, Saatheeyavaane Magalingam, Kasthuri Bai Kamarudin, Muhamad Noor Alfarizal Radhakrishnan, Ammu Kutty eng Research Support, Non-U.S. Gov't Review Systematic Review England Ageing Res Rev. Jan;73:. doi: 10./j.arr... Epub Nov 16.I SomaScan 11/20/ Yousri NA, et al. Proteome-wide associations with short- and long-term weight loss and regain after Roux-en-Y gastric bypass surgery Obesity (Silver Spring) 30 1 129-141 https://www.doi.org/10./oby. 34,796,696 Body Mass Index Follow-Up Studies *Gastric Bypass/methods Humans *Obesity, Morbid/complications/surgery Proteome Retrospective Studies Treatment Outcome Weight Loss OBJECTIVE: Gastric bypass surgery results in long-term weight loss. Small studies have examined protein changes during rapid weight loss (up to 1 or 2 years post surgery). This study tested whether short-term changes were maintained after 12 years. METHODS: A 12-year follow-up, protein-wide association study of 1,297 SomaLogic aptamer-based plasma proteins compared short- (2-year) and long-term (12-year) protein changes in 234 individuals who had gastric bypass surgery with 144 nonintervened individuals with severe obesity. RESULTS: There were 51 replicated 12-year protein changes that differed between the surgery and nonsurgery groups. Adjusting for change in BMI, only 12 proteins remained significant, suggesting that BMI change was the primary reason for most protein changes and not non-BMI-related surgical effects. Protein changes were related to BMI changes during both weight-loss and weight-regain periods. The significant proteins were associated primarily with lipid, uric acid, or resting energy expenditure clinical variables and metabolic pathways. Eight protein changes were associated with 12-year diabetes remission, including apolipoprotein M, sex hormone binding globulin, and adiponectin (p < 3.5 x 10(-5) ). CONCLUSIONS: This study showed that most short-term postsurgical changes in proteins were maintained at 12 years. Systemic protection pathways, including inflammation, complement, lipid, and adipocyte pathways, were related to the long-term benefits of gastric bypass surgery. Yousri, Noha A Engelke, Rudolf Sarwath, Hina McKinlay, Rodrick D Simper, Steven C Adams, Ted D Schmidt, Frank Suhre, Karsten Hunt, Steven C eng M01 RR/RR/NCRR NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Obesity (Silver Spring). Jan;30(1):129-141. doi: 10./oby.. Epub Nov 18.I SomaScan 11/20/ Yazdanpanah N, et al. Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study Diabetes Care 45 1 169-177 https://www.doi.org/10./dc21- 34,758,976 Biomarkers *Diabetes Mellitus, Type 1/genetics *Epstein-Barr Virus Infections Genome-Wide Association Study/methods Herpesvirus 4, Human Humans Mendelian Randomization Analysis/methods Polymorphism, Single Nucleotide OBJECTIVE: To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS: We used a large-scale two-sample MR study, using cis genetic determinants (protein quantitative trait loci [pQTL]) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 case subjects with type 1 diabetes and 15,743 control subjects. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL. RESULTS: We found that a genetically predicted SD increase in signal regulatory protein gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR odds ratio [OR] 1.66 [95% 1.36-2.03]; P = 7.1 x 10-7). The risk of type 1 diabetes increased almost twofold per genetically predicted standard deviation (SD) increase in interleukin-27 Epstein-Barr virus-induced 3 (IL27-EBI3) protein levels (MR OR 1.97 [95% CI 1.48-2.62]; P = 3.7 x 10-6). However, an SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR 0.84 [95% CI 0.77-0.90]; P = 6.1 x 10-6). Sensitivity analyses using MR methods testing for pleiotropy while including trans-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (P value MR-Egger intercept = 0.31), there was evidence of pleiotropy in MR-PRESSO (P value global test = 0.006). CONCLUSIONS: We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using an MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes. Yazdanpanah, Nahid Yazdanpanah, Mojgan Wang, Ye Forgetta, Vincenzo Pollak, Michael Polychronakos, Constantin Richards, J Brent Manousaki, Despoina eng Research Support, Non-U.S. Gov't Diabetes Care. Jan 1;45(1):169-177. doi: 10./dc21-.I SomaScan 11/12/ Corey KE, et al. ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD J Hepatol 76 1 25-33 https://www.doi.org/10./j.jhep..09.026 34,600,973 ADAMTS Proteins/*analysis Adult Area Under Curve Biomarkers/analysis Biopsy/methods/statistics & numerical data Case-Control Studies Cohort Studies Female Humans Liver Cirrhosis/blood/*diagnosis/pathology Logistic Models Male Massachusetts Middle Aged Non-alcoholic Fatty Liver Disease/*diagnosis/pathology Prospective Studies ROC Curve Adamtsl2 biomarker fibrosis non-alcoholic fatty liver disease non-alcoholic steatohepatitis proteomics of Novartis. KEC serves on the scientific advisory board for Novo Nordisk and BMS and has received grant funding from Boehringer-Ingelheim, BMS and Novartis. All other authors have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details. BACKGROUND & AIMS: Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and guide treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD. METHODS: We used aptamer-based proteomics to measure 4,783 proteins in 2 cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modeling-logistic regression assessed the ability of candidate proteins to classify fibrosis. RESULTS: From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n = 62) and B (n = 98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n = 71) and D (n = 84). The A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) protein accurately distinguished non-alcoholic fatty liver (NAFL)/non-alcoholic steatohepatitis (NASH) with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4, with AUROCs of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3), with AUROCs of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROCs 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROCs 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and fibrosis-4 score. CONCLUSION: The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis; they exhibited superior diagnostic performance compared to standard of care fibrosis scores. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in the blood which may identify fibrosis without the need for a liver biopsy. Corey, Kathleen E Pitts, Rebecca Lai, Michelle Loureiro, Joseph Masia, Ricard Osganian, Stephanie A Gustafson, Jenna L Hutter, Matthew M Gee, Denise W Meireles, Ozanan R Witkowski, Elan R Richards, Shola M Jacob, Jaison Finkel, Nancy Ngo, Debby Wang, Thomas J Gerszten, Robert E Ukomadu, Chinweike Jennings, Lori L eng P30 DK/DK/NIDDK NIH HHS/ R03 DK/DK/NIDDK NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Netherlands J Hepatol. Jan;76(1):25-33. doi: 10./j.jhep..09.026. Epub Oct 1.I SomaScan 10/04/ Yamaguchi Y, et al. The Plasma Proteome Fingerprint Associated with Circulating Carotenoids and Retinol in Older Adults J Nutr 152 1 40-48 https://www.doi.org/10./jn/nxab340 34,550,359 Carotenoids Lutein *Proteome Proteomics *Vitamin A Zeaxanthins beta Carotene carotene carotenoid cryptoxanthin lycopene protein retinol zeaxanthin BACKGROUND: Although diets rich in carotenoids are associated with reduced risks of cardiovascular disease, age-related macular degeneration, disability, and other adverse aging outcomes, the underlying biological mechanisms are not fully elucidated. OBJECTIVES: To characterize the plasma proteome fingerprint associated with circulating carotenoid and retinol concentrations in older adults. METHODS: In 728 adults >/=65 y participating in the Invecchiare in Chianti (InCHIANTI) Study, plasma alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene were measured using HPLC. The SOMAscan assay was used to measure plasma proteins. Multivariable linear regression models were used to examine the relationship of individual carotenoids and retinol with plasma proteins. A false discovery rate approach was used to deal with multiple comparisons using a q-value < 0.05. RESULTS: Plasma beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene were associated with 85, 39, 4, 2, and 5 plasma proteins, respectively, in multivariable linear regression models adjusting for potential confounders (q < 0.05). No proteins were associated with alpha-carotene or retinol. Two or more carotenoids were positively associated with ferritin, 6-phosphogluconate dehydrogenase (decarboxylating), hepcidin, thrombospondin-2, and choline/ethanolamine kinase. The proteins associated with circulating carotenoids were related to energy metabolism, sirtuin signaling, inflammation and oxidative stress, iron metabolism, proteostasis, innate immunity, and longevity. CONCLUSIONS: The plasma proteomic fingerprint associated with elevated circulating carotenoids in older adults provides insight into the mechanisms underlying the protective role of carotenoids on health. Yamaguchi, Yuko Zampino, Marta Tanaka, Toshiko Bandinelli, Stefania Moaddel, Ruin Fantoni, Giovanna Candia, Julian Ferrucci, Luigi Semba, Richard D eng R01 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Nutr. Jan 11;152(1):40-48. doi: 10./jn/nxab340.I SomaScan 09/23/ Gropler MRF, et al. Pediatric and adult dilated cardiomyopathy are distinguished by distinct biomarker profiles Pediatr Res 92 1 206-215 https://www.doi.org/10./s-021--x 34,404,929 Biomarkers *Cardiomyopathy, Dilated/diagnosis Humans Phenotype Prospective Studies BACKGROUND: Emerging evidence suggests that pediatric and adult dilated cardiomyopathy (DCM) represent distinct diseases. Few diagnostic tools exist for pediatric cardiologists to assess clinical status and prognosis. We hypothesized that pediatric DCM would have a unique biomarker profile compared to adult DCM and controls. METHODS: We utilized a DNA aptamer array (SOMAScan) to compare biomarker profiles between pediatric and adult DCM. We simultaneously measured plasma proteins and peptides from 39 healthy children (mean age 3 years, interquartile range (IQR) 1-14), 39 ambulatory subjects with pediatric DCM (mean age 2.7 years, IQR 1-13), and 40 ambulatory adults with DCM (mean age 53 years, IQR 46-63). RESULTS: Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics. We identified 20 plasma peptides and proteins that were increased in pediatric DCM compared to age- and sex-matched controls. Unbiased multidimensionality reduction analysis suggested previously unrecognized heterogeneity among pediatric DCM subjects. Biomarker profile analysis identified four subgroups of pediatric DCM with distinguishing clinical characteristics. CONCLUSIONS: These findings support the emerging concept that pediatric and adult DCM are distinct disease entities, signify the need to develop pediatric-specific biomarkers for disease prognostication, and challenge the paradigm that pediatric DCM should be viewed as a single disease. IMPACT: Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics and outcomes. Our findings suggest that pediatric DCM may be a heterogeneous disease with various sub-phenotypes, including differing biomarker profiles and clinical findings. These data provide prerequisite information for future prospective studies that validate the identified pediatric DCM biomarkers, address their diagnostic accuracy and prognostic significance, and explore the full extent of heterogeneity amongst pediatric DCM patients. Gropler, Melanie R F Lipshultz, Steven E Wilkinson, James D Towbin, Jeffrey A Colan, Steven D Canter, Charles E Lavine, Kory J Simpson, Kathleen E eng R01 HL/HL/NHLBI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Pediatr Res. Jul;92(1):206-215. doi: 10./s-021--x. Epub Aug 17.I SomaScan 08/19/ Lindbohm JV, et al. Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies Alzheimers Dement 18 4 612-624 https://www.doi.org/10./alz. 34,338,426 *Alzheimer Disease *Atherosclerosis/epidemiology Blood Proteins *Cognitive Dysfunction/epidemiology *Dementia/epidemiology Humans Prospective Studies tau Proteins cognitive decline cohort study dementia longitudinal study proteomics the hypothesis and study design and SomaLogic, Inc. provided expertise in plasma proteins and funded the SOMAscan assays. Joni V. Lindbohm and Pyry N. Sipila have received personal lecture fees from the University of Helsinki. Nina Mars reports no conflicts of interest. Keenan A. Walker reports personal lecture fee from the Boston University Medical Center and holds the Programming Chair at the National Academy of Neuropsychology. Eric J. Brunner reports Osaka University research capacity building grant paid to employer. Archana Singh-Manoux reports no conflicts of interest. Gill Livingston reports no conflicts of interest. Kalle Saksela reports no conflicts of interest. Jane E. Ferrie reports no conflicts of interest. Ruth C. Lovering reports personal lecture fees from the University College London, funding from a COST action grant, and is a member of the executive committee for the International Society of Biocuration (a voluntary role and no payment has been or will be made). Stephen A. Williams is employee of SomaLogic Inc., which has a commercial interest in the results and co-inventor on multiple patents for specific proteomic models of disease. None of these patents relate to dementia (the topic of the manuscript). Aroon D. Hingorani reports no conflicts of interest. Rebecca F. Gottesman reports personal lecture fees for speaking at University of Michigan grand rounds, University of Alabama McKnight lecture, and the American College of Cardiology conference. Rebecca F. Gottesman is the secretary for the American Neurological Association. Henrik Zetterberg reports that he has served on the scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Henrik Zetterberg is also the chair of the Alzheimer's Association Global Biomarker Standardization Consortium and the Alzheimer's Association Biolfluid-Based Biomarker Professional Interest Area. Mika Kivimaki reports no conflicts of interest. INTRODUCTION: Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20-year follow-ups. METHODS: In the Whitehall II prospective cohort study proteins were measured using SOMAscan technology. Cognitive performance was tested five times over 20 years. Linkage to electronic health records identified incident dementia. The results were replicated in the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: Fifteen non-amyloid/non-tau-related proteins were associated with cognitive decline and dementia, were consistently identified in both cohorts, and were not explained by known dementia risk factors. Levels of six of the proteins are modifiable by currently approved medications for other conditions. DISCUSSION: This study identified several plasma proteins in dementia-free people that are associated with long-term risk of cognitive decline and dementia. Lindbohm, Joni V Mars, Nina Walker, Keenan A Singh-Manoux, Archana Livingston, Gill Brunner, Eric J Sipila, Pyry N Saksela, Kalle Ferrie, Jane E Lovering, Ruth C Williams, Stephen A Hingorani, Aroon D Gottesman, Rebecca F Zetterberg, Henrik Kivimaki, Mika eng RG/16/11//BHF_/British Heart Foundation/United Kingdom UL1 RR/RR/NCRR NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ /Z/20/Z/WT_/Wellcome Trust/United Kingdom R01 HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ MR/R/1/MRC_/Medical Research Council/United Kingdom RG/13/2//BHF_/British Heart Foundation/United Kingdom HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ R56 AG/AG/NIA NIH HHS/ MR/S/1/MRC_/Medical Research Council/United Kingdom R01 HL/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ R01 AG/AG/NIA NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ K23 AG/AG/NIA NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ RF1 AG/AG/NIA NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ WT_/Wellcome Trust/United Kingdom K24 AG/AG/NIA NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Alzheimers Dement. Apr;18(4):612-624. doi: 10./alz.. Epub Aug 2.I SomaScan 08/03/ Mc Ardle A, et al. Identification and Evaluation of Serum Protein Biomarkers That Differentiate Psoriatic Arthritis From Rheumatoid Arthritis Arthritis Rheumatol 74 1 81-91 https://www.doi.org/10./art. 34,114,357 Adult Arthritis, Psoriatic/*blood/*diagnosis Arthritis, Rheumatoid/*blood/*diagnosis Biomarkers/blood Blood Proteins/*analysis Cross-Sectional Studies Diagnosis, Differential Female Humans Male Middle Aged OBJECTIVE: To identify serum protein biomarkers that might distinguish patients with early inflammatory arthritis (IA) with psoriatic arthritis (PsA) from those with rheumatoid arthritis (RA) and may be used to support appropriate early intervention. METHODS: The serum proteome of patients with PsA and patients with RA was interrogated using nano-liquid chromatography mass spectrometry (nano-LC-MS/MS) (n = 64 patients), an aptamer-based assay (SomaScan) targeting 1,129 proteins (n = 36 patients), and a multiplexed antibody assay (Luminex) for 48 proteins (n = 64 patients). Multiple reaction monitoring (MRM) assays were developed to evaluate the performance of putative markers using the discovery cohort (n = 60 patients) and subsequently an independent cohort of PsA and RA patients (n = 167). RESULTS: Multivariate machine learning analysis of the protein discovery data from the 3 platforms revealed that it was possible to differentiate PsA patients from RA patients with an area under the curve (AUC) of 0.94 for nano-LC-MS/MS, 0.69 for bead-based immunoassay measurements, and 0.73 for aptamer-based analysis. Subsequently, in the separate verification and evaluation studies, random forest models revealed that a subset of proteins measured by MRM could differentiate PsA and RA patients with AUCs of 0.79 and 0.85, respectively. CONCLUSION: We present a serum protein biomarker panel that can separate patients with early-onset IA with PsA from those with RA. With continued evaluation and refinement using additional and larger patient cohorts, including those with other arthropathies, we suggest that the panel identified here could contribute to improved clinical decision making. Mc Ardle, Angela Kwasnik, Anna Szentpetery, Agnes Hernandez, Belinda Parnell, Andrew de Jager, Wilco de Roock, Sytze FitzGerald, Oliver Pennington, Stephen R eng /FP7 Health/ Research Support, Non-U.S. Gov't Arthritis Rheumatol. Jan;74(1):81-91. doi: 10./art.. Epub Nov 23.I SomaScan 06/12/ Hinckley JD, et al. An Approach to Biomarker Discovery of Cannabis Use Utilizing Proteomic, Metabolomic, and Lipidomic Analyses Cannabis Cannabinoid Res 7 1 65-77 https://www.doi.org/10./can.. 33,998,853 Adult Analgesics Biomarkers Cannabinoid Receptor Agonists *Cannabis Chromatography, Liquid/methods Dronabinol/analysis Female *Hallucinogens Humans Lipidomics Lipids Male Proteomics Substance Abuse Detection/methods Tandem Mass Spectrometry Myc proto-oncogene cannabis markers Introduction: Relatively little is known about the molecular pathways influenced by cannabis use in humans. We used a multi-omics approach to examine protein, metabolomic, and lipid markers in plasma differentiating between cannabis users and nonusers to understand markers associated with cannabis use. Methods: Eight discordant twin pairs and four concordant twin pairs for cannabis use completed a blood draw, urine and plasma toxicology testing, and provided information about their past 30-day cannabis use and other substance use patterns. The 24 twins were all non-Hispanic whites. Sixty-six percent were female. Median age was 30 years. Fifteen participants reported that they had used cannabis in the last 30 days, including eight participants that used every day or almost every day (29-30 of 30 days). Of these 15 participants, plasma 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH) and total tetrahydrocannabinol (THC) concentrations were detectable in 12 participants. Among the eight heavy users" the amount of total THC (sum of THC and its metabolites) and plasma THC-COOH concentrations varied widely, with ranges of 13.1- ng/mL and 2.7-284 ng/mL, respectively. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay measured plasma THC-COOH, THC, and other cannabinoids and metabolites. Plasma THC-COOH was used as the primary measure. Expression levels of proteins were measured using SOMAScan assay, and 34 lipid mediators and 314 metabolites were measured with LC-MS/MS. Analyses examined associations between markers and THC-COOH levels with and without taking genetic relatedness into account. Results: Thirteen proteins, three metabolites, and two lipids were identified as associated with THC-COOH levels. Myc proto-oncogene was identified as associated with THC-COOH levels in both molecular insight and potential marker analyses. Five pathways (interleukin-6 production, T lymphocyte regulation, apoptosis, kinase signaling pathways, and nuclear factor kappa-light-chain-enhancer of activated B cells) were linked with molecules identified in these analyses. Conclusions: THC-COOH levels are associated with immune system-related pathways. This study presents a feasible approach to identify additional molecular markers associated with THC-COOH levels." Hinckley, Jesse D Saba, Laura Raymond, Kristen Bartels, Karsten Klawitter, Jost Christians, Uwe Hopfer, Christian eng P30 DA/DA/NIDA NIH HHS/ K24 DA/DA/NIDA NIH HHS/ Research Support, N.I.H., Extramural Twin Study Cannabis Cannabinoid Res. Feb;7(1):65-77. doi: 10./can... Epub Jun 19.I SomaScan 05/18/ Ghaemi MS, et al. Proteomic signatures predict preeclampsia in individual cohorts but not across cohorts - implications for clinical biomarker studies J Matern Fetal Neonatal Med 35 25 - https://www.doi.org/10./.. 33,653,202 Female Humans Pregnancy *Proteomics/methods *Pre-Eclampsia/diagnosis Proteome/metabolism Biomarkers Blood Proteins Biomarker gestational age preeclampsia proteomics BACKGROUND: Early identification of pregnant women at risk for preeclampsia (PE) is important, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analyses of plasma proteins feature prominently among molecular approaches used for risk prediction. However, derivation of protein signatures of sufficient predictive power has been challenging. The recent availability of platforms simultaneously assessing over plasma proteins offers broad examinations of the plasma proteome, which may enable the extraction of proteomic signatures with improved prognostic performance in prenatal care. OBJECTIVE: The primary aim of this study was to examine the generalizability of proteomic signatures predictive of PE in two cohorts of pregnant women whose plasma proteome was interrogated with the same highly multiplexed platform. Establishing generalizability, or lack thereof, is critical to devise strategies facilitating the development of clinically useful predictive tests. A second aim was to examine the generalizability of protein signatures predictive of gestational age (GA) in uncomplicated pregnancies in the same cohorts to contrast physiological and pathological pregnancy outcomes. STUDY DESIGN: Serial blood samples were collected during the first, second, and third trimesters in 18 women who developed PE and 18 women with uncomplicated pregnancies (Stanford cohort). The second cohort (Detroit), used for comparative analysis, consisted of 76 women with PE and 90 women with uncomplicated pregnancies. Multivariate analyses were applied to infer predictive and cohort-specific proteomic models, which were then tested in the alternate cohort. Gene ontology (GO) analysis was performed to identify biological processes that were over-represented among top-ranked proteins associated with PE. RESULTS: The model derived in the Stanford cohort was highly significant (p = 3.9E-15) and predictive (AUC = 0.96), but failed validation in the Detroit cohort (p = 9.7E-01, AUC = 0.50). Similarly, the model derived in the Detroit cohort was highly significant (p = 1.0E-21, AUC = 0.73), but failed validation in the Stanford cohort (p = 7.3E-02, AUC = 0.60). By contrast, proteomic models predicting GA were readily validated across the Stanford (p = 1.1E-454, R = 0.92) and Detroit cohorts (p = 1.1.E-92, R = 0.92) indicating that the proteomic assay performed well enough to infer a generalizable model across studied cohorts, which makes it less likely that technical aspects of the assay, including batch effects, accounted for observed differences. CONCLUSIONS: Results point to a broader issue relevant for proteomic and other omic discovery studies in patient cohorts suffering from a clinical syndrome, such as PE, driven by heterogeneous pathophysiologies. While novel technologies including highly multiplex proteomic arrays and adapted computational algorithms allow for novel discoveries for a particular study cohort, they may not readily generalize across cohorts. A likely reason is that the prevalence of pathophysiologic processes leading up to the same" clinical syndrome can be distributed differently in different and smaller-sized cohorts. Signatures derived in individual cohorts may simply capture different facets of the spectrum of pathophysiologic processes driving a syndrome. Our findings have important implications for the design of omic studies of a syndrome like PE. They highlight the need for performing such studies in diverse and well-phenotyped patient populations that are large enough to characterize subsets of patients with shared pathophysiologies to then derive subset-specific signatures of sufficient predictive power." Ghaemi, Mohammad S Tarca, Adi L Romero, Roberto Stanley, Natalie Fallahzadeh, Ramin Tanada, Athena Culos, Anthony Ando, Kazuo Han, Xiaoyuan Blumenfeld, Yair J Druzin, Maurice L El-Sayed, Yasser Y Gibbs, Ronald S Winn, Virginia D Contrepois, Kevin Ling, Xuefeng B Wong, Ronald J Shaw, Gary M Stevenson, David K Gaudilliere, Brice Aghaeepour, Nima Angst, Martin S eng R01 HL/HL/NHLBI NIH HHS/ R35 GM/GM/NIGMS NIH HHS/ England J Matern Fetal Neonatal Med. Dec;35(25):-. doi: 10./... Epub Mar 2.I SomaScan 03/04/ Banu K, et al. Prospects for the application of aptamer based assay platforms in pathogen detection Biocybernetics and Biomedical Engineering 42 3 934-949 https://www.doi.org/10./j.bbe..07.005 Aptamer SELEX Biosensor Microfluidics Flow-cytometry Aptamer-based diagnostics platforms for animal, human, plant and environmental pathogens are gaining importance as they are rapid, user-friendly, sensitive and selective. However, most of the aptamer-based platforms have not yet become commercially available. The increasing number of publications signifies the applications of aptamer-based platform and their potential. Herein, the present review is to describe, a brief overview of the development of various aptamer-based platforms and their applicability for the sensitive detection of pathogens. In this review, several aptamer-based platforms such as Enzyme linked immunosorbent assay (ELISA)-like assay, Apta blot, Apta Polymerase Chain Reaction (PCR), Apta array, Aptamer-based Lateral Flow Assays (LFA), Aptamer based fluorescence assay, Flowcytometry-based assay, Apta affinity chromatography, microfluidics-based platforms, and various aptasensor have been discussed. Most of the platforms are highlighted will encourage researchers to focus on developing pathogen detection platform for various applications. Banu, Kauser Mondal, Bhairab Rai, Bhawana Monica, N. Hanumegowda, Raju SomaScan Belkadi A, et al. Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population Cell Genomics epub ahead of print https://www.doi.org/10./j.xgen.. human gene knockouts metabolomics proteomics whole-genome sequencing consanguineous population drug target validation, drug target identification Summary Natural human knockouts of genes associated with desirable outcomes, such as PCSK9 with low levels of LDL-cholesterol, can lead to the discovery of new drug targets and treatments. Rare loss-of-function variants are more likely to be found in the homozygous state in consanguineous populations, and deep molecular phenotyping of blood samples from homozygous carriers can help to discriminate between silent and functional variants. Here, we combined whole-genome sequencing with proteomics and metabolomics for 2,935 individuals from the Qatar Biobank (QBB) to evaluate the power of this approach for finding genes of clinical and pharmaceutical interest. As proof-of-concept, we identified a homozygous carrier of a very rare PCSK9 variant with extremely low circulating PCSK9 levels and low LDL. Our study demonstrates that the chances of finding such variants are about 168 times higher in QBB compared with GnomAD and emphasizes the potential of consanguineous populations for drug discovery. Belkadi, Aziz Thareja, Gaurav Abbaszadeh, Fatemeh Badii, Ramin Fauman, Eric Albagha, Omar M. E. Suhre, Karsten SomaScan Curci D, et al. Proteome-Wide Analysis Using SOMAscan Identifies and Validates Epidermal Growth Factor as a Disease Marker of Collagenous Gastritis Gastro Hep Advances 1 5 689-702 https://www.doi.org/10./j.gastha..04.016 Collagenous Gastritis Proteomics Biomarker Epidermal Growth Factor Collagenous gastritis (CG) is a rare disorder characterized by increased subepithelial collagen deposition and inflammatory infiltrates. The mechanisms involved in CG pathogenesis are poorly understood, and no CG-associated biomarkers have been identified. This proteomics study identified serum biomarkers and pathogenic pathways to provide new knowledge about the pathobiology of CG, a disease reported in less than 100 patients. Curci, Debora Dillon, Simon T. Gu, Xuesong Winter, Harland Libermann, Towia A. SomaScan Ge Y-J, et al. Prioritization of drug targets for neurodegenerative diseases by integrating genetic and proteomic data from brain and blood Biological Psychiatry epub ahead of print https://www.doi.org/10./j.biopsych..11.002 drug discovery genetics Mendelian randomization neurodegenerative disease omics proteomics Background Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases. Methods We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci (pQTLs) identified from one GWAS with 376 individuals and another with 3,301, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated. Results Our analyses showed targeting BIN1, GRN, and RET levels in blood, as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce AD risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side-effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for PD. Among them, GPNMB was the most promising target for PD with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, MAPK3 in blood and DHRS11, FAM120B, SHMT1, TSFM in brain might affect MS risk. The risk of ALS might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain. Conclusions Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets. Ge, Yi-Jun Ou, Ya-Nan Deng, Yue-Ting Wu, Bang-Sheng Yang, Liu Zhang, Ya-Ru Chen, Shi-Dong Huang, Yu-Yuan Dong, Qiang Tan, Lan Yu, Jin-Tai SomaScan Lindbohm JV, et al. Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases Nature Aging 2 10 956-972 https://www.doi.org/10./s-022--x Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827_immune system- and blood–brain barrier-related biomarkers and identified 127_potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-_, tau and _-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n_=_339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88, P_=_0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases. Lindbohm, Joni V. Mars, Nina Sipilä, Pyry N. Singh-Manoux, Archana Runz, Heiko Livingston, Gill Seshadri, Sudha Xavier, Ramnik Hingorani, Aroon D. Ripatti, Samuli Kivimäki, Mika SomaScan Shuken SR, et al. Limited proteolysis–mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures Nature Aging 2 5 379-388 https://www.doi.org/10./s-022--x Cerebrospinal fluid (CSF) proteins and their structures have been implicated in aging and neurodegenerative diseases. In the present study, we used limited proteolysis–mass spectrometry (LiP–MS) to screen for new aging-associated changes in the CSF proteome using a modified analysis. We found 38 protein groups that change in abundance with aging, predominantly immunoglobulins of the IgM subclass. We discovered six high-confidence candidates that underwent structural changes with aging, of which Kng1, Itih2, Lp-PLA2 and 14-3-3 proteins have binding partners or chemical forms known previously to change in the brains of patients with Alzheimer’s disease. Orthogonal validation by western blotting identified that the LiP–MS hit Cd5l forms a covalent complex with IgM in mouse and human CSF, the abundance of which increases with aging. In human CSF, SOMAmer probe signals for all six LiP–MS hits were associated with cognitive function and/or biomarkers of neurodegeneration, especially 14-3-3 proteins YWHAB and YWHAZ. Together, our findings show that LiP–MS can uncover age-related structural changes in CSF with relevance to neurodegeneration. Shuken, Steven R. Rutledge, Jarod Iram, Tal Losada, Patricia Moran Wilson, Edward N. Andreasson, Katrin I. Leib, Ryan D. Wyss-Coray, Tony SomaScan Ferrannini E, et al. Differential Proteomics of Cardiovascular Risk and Coronary Artery Disease in Humans Front Cardiovasc Med 8 https://www.doi.org/10./fcvm.. 35,187,107 atrial myosin regulatory light chain 2 cardiovascular risk factors coronary artery disease protein shisa-3 homolog proteomics Sankyo outside the submitted work. SW is an employee and shareholder of SomaLogic Inc., Boulder, Colorado, USA. AMag reports personal fees from Bayer, Fresenius, and Novartis outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. BACKGROUND: Proteomics of atypical phenotypes may help unravel cardiovascular disease mechanisms. AIM: We aimed to prospectively screen the proteome of four types of individuals: with or without coronary artery disease (CAD), each with or without multiple risk factors. Associations with individual risk factors and circulating biomarkers were also tested to provide a functional context to the protein hits. MATERIALS AND METHODS: The CAPIRE study (ClinicalTrials.gov Identifier: NCT) is a cross-sectional study aimed at identifying possible new mechanisms promoting or protecting against atherothrombosis. Quantification (by aptamer technology), ranking (using partial least squares), and correlations (by multivariate regression) of ~ plasma proteins were performed in consecutive individuals aged 45-75 years, without previous cardiovascular disease, undergoing computed tomography angiography for suspected CAD, showing either >5/16 atherosclerotic segments (CAD(+)) or completely clean arteries (CAD(-)) and either = 1 risk factor (RF(+)) or >/=3 risk factors (RF(-)) (based on history, blood pressure, glycemia, lipids, and smoking). RESULTS: Of 544 individuals, 39% were atypical (93 CAD(+)/RF(-); 120 CAD(-)/RF(+)) and 61% typical (102 CAD(+)/RF(+); 229 CAD(-)/RF(-)). In the comparison with CAD(+)/RF(-) adjusted for sex and age, CAD(-)/RF(+) was associated with increased atrial myosin regulatory light chain 2 (MYO) and C-C motif chemokine-22 (C-C-22), and reduced protein shisa-3 homolog (PS-3) and platelet-activating factor acetylhydrolase (PAF-AH). Extending the analysis to the entire cohort, an additional 8 proteins were independently associated with CAD or RF; by logistic regression, the 12-protein panel alone discriminated the four groups with AUC(ROC)'s of 0.72-0.81 (overall p = 1.0e(-38)). Among them, insulin-like growth factor binding protein-3 is positively associated with RF, lower BMI, and HDL-cholesterol, renin with CAD higher glycated hemoglobin HbA(1c), and smoking. CONCLUSIONS: In a CCTA-based cohort, four proteins, involved in opposing vascular processes (healing vs. adverse remodeling), are specifically associated with low CAD burden in high CV-risk individuals (high MYO and C-C-22) and high CAD burden in low-risk subjects (high PS-3 and PAF-AH), in interaction with BMI, smoking, diabetes, HDL-cholesterol, and HbA(1c). These findings could contribute to a deeper understanding of the atherosclerotic process beyond traditional risk profile assessment and potentially constitute new treatment targets. Ferrannini, Ele Manca, Maria Laura Ferrannini, Giulia Andreotti, Felicita Andreini, Daniele Latini, Roberto Magnoni, Marco Williams, Stephen A Maseri, Attilio Maggioni, Aldo P eng Switzerland Front Cardiovasc Med. Feb 4;8:. doi: 10./fcvm... eCollection .I SomaScan 02/22/ Wu L, et al. Integrated Multi-Omics for Novel Aging Biomarkers and Antiaging Targets Biomolecules 12 1 https://www.doi.org/10./biom 35,053,186 Aging/genetics Biomarkers *Genomics/methods Humans Metabolomics/methods *Proteomics/methods aging aging biomarkers aging clock antiaging targets multi-omics Aging is closely related to the occurrence of human diseases; however, its exact biological mechanism is unclear. Advancements in high-throughput technology provide new opportunities for omics research to understand the pathological process of various complex human diseases. However, single-omics technologies only provide limited insights into the biological mechanisms of diseases. DNA, RNA, protein, metabolites, and microorganisms usually play complementary roles and perform certain biological functions together. In this review, we summarize multi-omics methods based on the most relevant biomarkers in single-omics to better understand molecular functions and disease causes. The integration of multi-omics technologies can systematically reveal the interactions among aging molecules from a multidimensional perspective. Our review provides new insights regarding the discovery of aging biomarkers, mechanism of aging, and identification of novel antiaging targets. Overall, data from genomics, transcriptomics, proteomics, metabolomics, integromics, microbiomics, and systems biology contribute to the identification of new candidate biomarkers for aging and novel targets for antiaging interventions. Wu, Lei Xie, Xinqiang Liang, Tingting Ma, Jun Yang, Lingshuang Yang, Juan Li, Longyan Xi, Yu Li, Haixin Zhang, Jumei Chen, Xuefeng Ding, Yu Wu, Qingping eng Research Support, Non-U.S. Gov't Review Switzerland Biomolecules. Dec 28;12(1):39. doi: 10./biom.I SomaScan 01/22/ Wu J, et al. Multi-omic analysis in injured humans: Patterns align with outcomes and treatment responses Cell Rep Med 2 12 https://www.doi.org/10./j.xcrm.. 35,028,617 Brain Injuries, Traumatic/*genetics/*therapy Cluster Analysis Cohort Studies *Genomics Humans Metabolome Plasma Proteome/metabolism Time Factors Treatment Outcome PAMPer trial endotype host response metabolomics multi-omics outcome proteomics systemic storm thawed plasma trauma Avita Medical and Spectral MD. M.D.N. holds an equity stake in Haima Therapeutics. He has received research support and/or honoraria from Haemonetics, Instrumentation Laboratories, and Janssen Pharmaceuticals. T.R.B. is a stakeholder in Immunetrics. Other authors declare no conflict of interests. Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A systemic storm" pattern with release of 1,061 markers, together with a pattern suggestive of the "massive consumption" of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses." Wu, Junru Vodovotz, Yoram Abdelhamid, Sultan Guyette, Francis X Yaffe, Michael B Gruen, Danielle S Cyr, Anthony Okonkwo, David O Kar, Upendra K Krishnamoorthi, Neha Voinchet, Robert G Billiar, Isabel M Yazer, Mark H Namas, Rami A Daley, Brian J Miller, Richard S Harbrecht, Brian G Claridge, Jeffrey A Phelan, Herbert A Zuckerbraun, Brian S Johansson, Par I Stensballe, Jakob Morrissey, James H Tracy, Russell P Wisniewski, Stephen R Neal, Matthew D Sperry, Jason L Billiar, Timothy R eng T32 GM/GM/NIGMS NIH HHS/ UM1 HL/HL/NHLBI NIH HHS/ R35 GM/GM/NIGMS NIH HHS/ R35 GM/GM/NIGMS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Cell Rep Med. Dec 21;2(12):. doi: 10./j.xcrm... eCollection Dec 21.I SomaScan 01/15/ Ghodsian N, et al. Blood Levels of the SMOC1 Hepatokine Are Not Causally Linked with Type 2 Diabetes: A Bidirectional Mendelian Randomization Study Nutrients 13 12 https://www.doi.org/10./nu 34,959,760 Blood Glucose/metabolism Body Mass Index Case-Control Studies Diabetes Mellitus, Type 2/blood/*genetics Fasting/blood Gene Expression/physiology Genome-Wide Association Study Glycated Hemoglobin A/metabolism Humans Insulin/blood Insulin Resistance/genetics Liver/metabolism Mendelian Randomization Analysis Non-alcoholic Fatty Liver Disease/blood/*genetics Osteonectin/*blood Polymorphism, Single Nucleotide Risk Factors Waist-Hip Ratio Mendelian randomization Smoc1 hepatokine type 2 diabetes research contracts from Pfizer, Ionis Pharmaceuticals and Silence Therapeutics. Hepatokines are liver-derived proteins that may influence metabolic pathways such as insulin sensitivity. Recently, Sparc-related modular calcium-binding protein 1 (SMOC1) was identified as glucose-responsive hepatokine that is dysregulated in the setting of non-alcoholic fatty liver disease (NAFLD). While SMOC1 may influence glucose-insulin homeostasis in rodents, it is unknown if SMOC1 is influenced by NAFLD in humans. It is also unknown if SMOC1 is causally associated with metabolic and disease traits in humans. Therefore, we aimed to determine the effect of NAFLD on SMOC1 gene expression in the liver and aimed to explore the potential causal associations of SMOC1 levels with NAFLD, T2D, and glycemic traits in humans. Using an RNA sequencing dataset from a cohort of 216 patients with NAFLD, we assessed SMOC1 expression levels across the NAFLD spectrum. We performed a series of bidirectional inverse-variance weighted Mendelian randomization (MR) analyses on blood SMOC1 levels using two sources of genome-wide association studies (GWAS) (Fenland study, n = 10,708 and INTERVAL study, n = ). We utilized GWAS summary statistics for NAFLD in cases and 770,180 controls, as well as publicly available GWAS for type 2 diabetes (T2D), body mass index (BMI), waist-to-hip ratio (WHR), fasting blood insulin (FBI), fasting blood glucose (FBG), homeostatic Model Assessment of Insulin Resistance (HOMA-B and HOMA-IR), and hemoglobin A1c (HbA1C). We found that SMOC1 expression showed no significant differences across NAFLD stages. We also identified that the top single-nucleotide polymorphism associated with blood SMOC1 levels, was associated with SMOC1 gene expression in the liver, but not in other tissues. Using MR, we did not find any evidence that genetically predicted NAFLD, T2D, and glycemic traits influenced SMOC1 levels. We also did not find evidence that blood SMOC1 levels were causally associated with T2D, NAFLD, and glycemic traits. In conclusion, the hepatokine SMOC1 does not appear to be modulated by the presence of NAFLD and may not regulate glucose-insulin homeostasis in humans. Results of this study suggest that blood factors regulating metabolism in rodents may not always translate to human biology. Ghodsian, Nooshin Gagnon, Eloi Bourgault, Jerome Gobeil, Emilie Manikpurage, Hasanga D Perrot, Nicolas Girard, Arnaud Mitchell, Patricia L Arsenault, Benoit J eng Switzerland Nutrients. Nov 24;13(12):. doi: 10./nu.I SomaScan 12/29/ Suzuki M, et al. Large-scale plasma proteomics can reveal distinct endotypes in chronic obstructive pulmonary disease and severe asthma Clin Transl Allergy 11 10 e https://www.doi.org/10./clt2. 34,962,717 Bpco Copd Epoc asma severa asthme severe endotipos endotypen endotypes exosomas exosome exosomen exosomes proteomic proteomics proteomica proteomique schweres Asthma severe asthma ______ ______ _______ ____ Masaru Suzuki has received lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, and GlaxoSmithKline. Satoshi Konno has received grants from AstraZeneca, Boehringer Ingelheim, KYORIN Pharmaceutical, Novartis, and Japan Allergy Foundation during the conduct of the study, and has received lecture fees from AstraZeneca and Boehringer Ingelheim. Masaharu Nishimura has received grants from AstraZeneca, Boehringer Ingelheim, KYORIN Pharmaceutical, and MSD during the conduct of the study. John J. Cole, Hironi Makita, and Hiroki Kimura have no relevant conflicts of interest. BACKGROUND: Chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma are heterogenous in nature and endotypes within are underpinned by complex biology. This study aimed to investigate the utility of proteomic profiling of plasma combined with bioinformatic mining, and to define molecular endotypes and expand our knowledge of the underlying biology in chronic respiratory diseases. METHODS: The plasma proteome was evaluated using an aptamer-based affinity proteomics platform (SOMAscan(R)), representing proteins in 34 subjects with stable COPD and 51 subjects with stable but severe asthma. For each disease, we evaluated a range of clinical/demographic characteristics including bronchodilator reversibility, blood eosinophilia levels, and smoking history. We applied modified bioinformatic approaches used in the evaluation of RNA transcriptomics. RESULTS: Subjects with COPD and severe asthma were distinguished from each other by 365 different protein abundancies, with differential pathway networks and upstream modulators. Furthermore, molecular endotypes within each disease could be defined. The protein groups that defined these endotypes had both known and novel biology including groups significantly enriched in exosomal markers derived from immune/inflammatory cells. Finally, we observed associations to clinical characteristics that previously have been under-explored. CONCLUSION: This investigational study evaluating the plasma proteome in clinically-phenotyped subjects with chronic airway diseases provides support that such a method can be used to define molecular endotypes and pathobiological mechanisms that underpins these endotypes. It provided new concepts about the complexity of molecular pathways that define these diseases. In the longer term, such information will help to refine treatment options for defined groups. Suzuki, Masaru Cole, John J Konno, Satoshi Makita, Hironi Kimura, Hiroki Nishimura, Masaharu Maciewicz, Rose A eng KYORIN Pharmaceutical/ Pfizer/ Boehringer Ingelheim/ Ministry of Health, Labor, and Welfare, Japan/ AstraZeneca/ Japan Allergy Foundation/ /Ministry of Education, Science, Culture and Sports of Japan/ /Ministry of Education, Science, Culture and Sports of Japan/ /Ministry of Education, Science, Culture and Sports of Japan/ England Clin Transl Allergy. Dec;11(10):e. doi: 10./clt2..I SomaScan 12/29/ Daniels JR, et al. Discovery of Novel Proteomic Biomarkers for the Prediction of Kidney Recovery from Dialysis-Dependent AKI Patients Kidney360 2 11 - https://www.doi.org/10./kid. 34,913,041 *Acute Kidney Injury/diagnosis Biomarkers/urine Humans Kidney/metabolism *Proteomics Renal Dialysis/methods BACKGROUND: AKI requiring dialysis (AKI-D) is associated with prolonged hospitalization, mortality, and progressive CKD among survivors. Previous studies have examined only select urine or serum biomarkers for predicting kidney recovery from AKI. METHODS: Serum samples collected on day 8 of randomized RRT from 72 patients enrolled in the Veteran's Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the SOMAscan proteomic platform to profile proteins in each sample. Of these patients, 38 recovered kidney function and dialysis was discontinued, whereas another 34 patients remained on dialysis by day 28. RESULTS: Differential serum levels of 119 proteins, with 53 higher and 66 lower, were detected in samples from patients who discontinued dialysis, compared with patients who remained on dialysis by day 28. Patients were classified into tertiles on the basis of SOMAscan protein measurements for the 25 proteins most differentially expressed. The association of serum levels of each protein with kidney recovery was further evaluated using logistic regression analysis. Higher serum levels of CXCL11, CXCL2/CXCL3, CD86, Wnt-7a, BTK, c-Myc, TIMP-3, CCL5, ghrelin, PDGF-C, survivin, CA2, IL-9, EGF, and neuregulin-1, and lower levels of soluble CXCL16, IL1RL1, stanniocalcin-1, IL-6, and FGF23 when classified in tertiles were significantly associated with better kidney recovery. This significant association persisted for each of these proteins after adjusting for potential confounding risk factors including age, sex, cardiovascular SOFA score, congestive heart failure, diabetes, modality of intensive dialysis treatment, cause of AKI, baseline serum creatinine, day 8 urine volume, and estimated 60-day mortality risk. CONCLUSIONS: These results suggest concerted changes between survival-related proteins and immune-regulatory chemokines in regulating angiogenesis, endothelial and epithelial remodeling, and kidney cell regeneration, illustrating potential mechanisms of kidney recovery. Thus, this study identifies potential novel predictive biomarkers of kidney recovery in patients with AKI-D. Daniels, Jaclyn R Ma, Jennie Z Cao, Zhijun Beger, Richard D Sun, Jinchun Schnackenberg, Laura Pence, Lisa Choudhury, Devasmita Palevsky, Paul M Portilla, Didier Yu, Li-Rong eng FD/ImFDA/Intramural FDA HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Kidney360. Nov 25;2(11):-. doi: 10./kid..I SomaScan 12/17/ Sayed N, et al. An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging Nat Aging 1 598-615 https://www.doi.org/10./s-021--y 34,888,528 While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes. Sayed, Nazish Huang, Yingxiang Nguyen, Khiem Krejciova-Rajaniemi, Zuzana Grawe, Anissa P Gao, Tianxiang Tibshirani, Robert Hastie, Trevor Alpert, Ayelet Cui, Lu Kuznetsova, Tatiana Rosenberg-Hasson, Yael Ostan, Rita Monti, Daniela Lehallier, Benoit Shen-Orr, Shai S Maecker, Holden T Dekker, Cornelia L Wyss-Coray, Tony Franceschi, Claudio Jojic, Vladimir Haddad, Francois Montoya, Jose G Wu, Joseph C Davis, Mark M Furman, David eng P30 AG/AG/NIA NIH HHS/ P30 AG/AG/NIA NIH HHS/ U19 AI/AI/NIAID NIH HHS/ U19 AI/AI/NIAID NIH HHS/ P50 AG/AG/NIA NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ UL1 RR/RR/NCRR NIH HHS/ K01 HL/HL/NHLBI NIH HHS/ Nat Aging. Jul;1:598-615. doi: 10./s-021--y. Epub Jul 12.I SomaScan 12/11/ De Miguel Z, et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin Nature 600 7,889 494-499 https://www.doi.org/10./s-021--x 34,880,498 *Alzheimer Disease/metabolism Animals Clusterin/genetics/metabolism *Encephalitis Endothelial Cells/metabolism Humans Mice Proteomics Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration(1). The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus(2-4), yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer's disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise. De Miguel, Zurine Khoury, Nathalie Betley, Michael J Lehallier, Benoit Willoughby, Drew Olsson, Niclas Yang, Andrew C Hahn, Oliver Lu, Nannan Vest, Ryan T Bonanno, Liana N Yerra, Lakshmi Zhang, Lichao Saw, Nay Lui Fairchild, J Kaci Lee, Davis Zhang, Hui McAlpine, Patrick L Contrepois, Kevin Shamloo, Mehrdad Elias, Joshua E Rando, Thomas A Wyss-Coray, Tony eng R01 AG/AG/NIA NIH HHS/ P30 AG/AG/NIA NIH HHS/ F32 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ P01 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Nature. Dec;600():494-499. doi: 10./s-021--x. Epub Dec 8.I SomaScan 12/10/ O'Neil LJ, et al. Proteomic Approaches to Defining Remission and the Risk of Relapse in Rheumatoid Arthritis Front Immunol 12 https://www.doi.org/10./fimmu.. 34,867,950 Adult Aged Antirheumatic Agents/therapeutic use Arthritis, Rheumatoid/*blood/*classification/drug therapy Biomarkers/blood Blood Proteins/*analysis Female Humans Male Middle Aged Proteomics Recurrence Remission Induction disease activity outcomes research rheumatoid arthritis treatment commercial or financial relationships that could be construed as a potential conflict of interest. OBJECTIVES: Patients with Rheumatoid Arthritis (RA) are increasingly achieving stable disease remission, yet the mechanisms that govern ongoing clinical disease and subsequent risk of future flare are not well understood. We sought to identify serum proteomic alterations that dictate clinically important features of stable RA, and couple broad-based proteomics with machine learning to predict future flare. METHODS: We studied baseline serum samples from a cohort of stable RA patients (RETRO, n = 130) in clinical remission (DAS28<2.6) and quantified serum proteins using the SOMAscan platform. Unsupervised hierarchical clustering and supervised classification were applied to identify proteomic-driven clusters and model biomarkers that were associated with future disease flare after 12 months of follow-up and RA medication withdrawal. Network analysis was used to define pathways that were enriched in proteomic datasets. RESULTS: We defined 4 proteomic clusters, with one cluster (Cluster 4) displaying a lower mean DAS28 score (p = 0.03), with DAS28 associating with humoral immune responses and complement activation. Clustering did not clearly predict future risk of flare, however an XGboost machine learning algorithm classified patients who relapsed with an AUC (area under the receiver operating characteristic curve) of 0.80 using only baseline serum proteomics. CONCLUSIONS: The serum proteome provides a rich dataset to understand stable RA and its clinical heterogeneity. Combining proteomics and machine learning may enable prediction of future RA disease flare in patients with RA who aim to withdrawal therapy. O'Neil, Liam J Hu, Pingzhao Liu, Qian Islam, Md Mohaiminul Spicer, Victor Rech, Juergen Hueber, Axel Anaparti, Vidyanand Smolik, Irene El-Gabalawy, Hani S Schett, Georg Wilkins, John A eng Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't Switzerland Front Immunol. Nov 18;12:. doi: 10./fimmu... eCollection .I SomaScan 12/07/ Ferkingstad E, et al. Large-scale integration of the plasma proteome with genetics and disease Nat Genet 53 12 - https://www.doi.org/10./s-021--w 34,857,953 Biomarkers/blood Blood Proteins/*genetics/metabolism Disease/*genetics Female Gene Frequency Genetic Variation Genome-Wide Association Study Humans Male Middle Aged Proteome/*genetics Quantitative Trait Loci The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development. Ferkingstad, Egil Sulem, Patrick Atlason, Bjarni A Sveinbjornsson, Gardar Magnusson, Magnus I Styrmisdottir, Edda L Gunnarsdottir, Kristbjorg Helgason, Agnar Oddsson, Asmundur Halldorsson, Bjarni V Jensson, Brynjar O Zink, Florian Halldorsson, Gisli H Masson, Gisli Arnadottir, Gudny A Katrinardottir, Hildigunnur Juliusson, Kristinn Magnusson, Magnus K Magnusson, Olafur Th Fridriksdottir, Run Saevarsdottir, Saedis Gudjonsson, Sigurjon A Stacey, Simon N Rognvaldsson, Solvi Eiriksdottir, Thjodbjorg Olafsdottir, Thorunn A Steinthorsdottir, Valgerdur Tragante, Vinicius Ulfarsson, Magnus O Stefansson, Hreinn Jonsdottir, Ingileif Holm, Hilma Rafnar, Thorunn Melsted, Pall Saemundsdottir, Jona Norddahl, Gudmundur L Lund, Sigrun H Gudbjartsson, Daniel F Thorsteinsdottir, Unnur Stefansson, Kari eng Nat Genet. Dec;53(12):-. doi: 10./s-021--w. Epub Dec 2.I SomaScan 12/04/ Dreyfuss JM, et al. High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control Nat Commun 12 1 https://www.doi.org/10./s-021--2 34,845,204 Animals Biomarkers/blood Blood Glucose/metabolism Body Mass Index Carrier Proteins/blood/genetics Diabetes Mellitus, Type 2/*blood/genetics/pathology/surgery Dipeptidases/blood/genetics Fasting/physiology *Gastric Bypass Gene Expression Regulation Glycated Hemoglobin A/genetics/metabolism Hepatocytes/metabolism/pathology Human Growth Hormone/blood/genetics Humans Insulin-Like Growth Factor Binding Protein 1/blood/genetics Insulin-Like Growth Factor Binding Protein 2/blood/genetics Liver/*metabolism/pathology *Metabolome Obesity/*blood/genetics/pathology/surgery Primary Cell Culture *Proteome Rats Retrospective Studies To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR's mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT. Dreyfuss, Jonathan M Yuchi, Yixing Dong, Xuehong Efthymiou, Vissarion Pan, Hui Simonson, Donald C Vernon, Ashley Halperin, Florencia Aryal, Pratik Konkar, Anish Sebastian, Yinong Higgs, Brandon W Grimsby, Joseph Rondinone, Cristina M Kasif, Simon Kahn, Barbara B Foster, Kathleen Seeley, Randy Goldfine, Allison Djordjilovic, Vera Patti, Mary Elizabeth eng RC1 DK/DK/NIDDK NIH HHS/ P01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R56 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. Nov 29;12(1):. doi: 10./s-021--2.I SomaScan 12/01/ Moin ASM, et al. Heat Shock-Related Protein Responses and Inflammatory Protein Changes Are Associated with Mild Prolonged Hypoglycemia Cells 10 11 https://www.doi.org/10./cells 34,831,332 Adult Biomarkers/metabolism Case-Control Studies Diabetes Mellitus, Type 2/blood/metabolism Dinoprost/analogs & derivatives/metabolism Female Heat-Shock Proteins/blood *Heat-Shock Response Humans Hypoglycemia/blood/*metabolism Inflammation/*metabolism Male Middle Aged Oxidative Stress Protein Interaction Mapping Proteins/*metabolism Ubiquitin-Conjugating Enzymes/metabolism heat shock proteins hypoglycemia inflammatory proteins type 2 diabetes Mild hypoglycemia is common in clinical practice. Severe hypoglycemia results in heat shock protein and associate co-chaperone changes. Whether mild prolonged hypoglycemia elicits a similar response with inflammatory and oxidative-stress responses compared with a severe hypoglycemic event is unclear; therefore, this pilot exploratory study was undertaken. We performed a case-control induced hypoglycemia clamp study, maintaining blood glucose at 2.8 mmol/L (50 mg/dL) for 1 h in 17 subjects (T2D (n = 10); controls (n = 7)). Blood sampling was performed at baseline, hypoglycemia, and 24 h; slow off-rate modified aptamer (SOMA)-scan plasma protein analysis of HSP-related proteins, inflammatory stress markers, and oxidative stress markers was performed. In total, 16 HSPs were analyzed. At baseline, TLR4:MD-2 complex was elevated (p = 0.01), whilst HSPA8 was lower (p < 0.05) in T2D. At hypoglycemia, UBE2N, STIP1, and UBE2L3 increased (all p < 0.05), whilst TLR4:MD-2 and HSPA8 decreased (p < 0.05) in T2D versus baseline. In follow-up after hypoglycemia, HSPs normalized to baseline by 24 h, except UBE2L3 (p < 0.05), which was decreased in controls versus baseline. Correlation of altered inflammatory markers with HSPs revealed the following: at baseline, TLR4:MD-2 correlated with CXCL10 (p < 0.01) and SIGLEC1 (p < 0.05) in controls; HSPA8 negatively correlated with IL5 (p < 0.05) in T2D. A negative correlation between urinary isoprostane 8-iso PGF2alpha, a marker of oxidative stress, and HSPA1A was seen at 24 h in T2D only (p < 0.05). In conclusion, the HSP changes seen for mild prolonged hypoglycemia were similar to those previously reported for a severe event. However, mild prolonged hypoglycemia appeared to elicit an increased inflammatory response that was associated with heat shock and related proteins. Moin, Abu Saleh Md Nandakumar, Manjula Kahal, Hassan Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Clinical Trial Switzerland Cells. Nov 10;10(11):. doi: 10./cells.I SomaScan 11/28/ Govender MA, et al. The Use of 'Omics for Diagnosing and Predicting Progression of Chronic Kidney Disease: A Scoping Review Front Genet 12 https://www.doi.org/10./fgene.. 34,819,944 Sub-Saharan Africa biomarkers chronic kidney disease diabetes diagnosis early detection hypertension 'omics commercial or financial relationships that could be construed as a potential conflict of interest. Globally, chronic kidney disease (CKD) contributes substantial morbidity and mortality. Recently, various 'omics platforms have provided insight into the molecular basis of kidney dysfunction. This scoping review is a synthesis of the current literature on the use of different 'omics platforms to identify biomarkers that could be used to detect early-stage CKD, predict disease progression, and identify pathways leading to CKD. This review includes 123 articles published from January to May , following a structured selection process. The most common type of 'omic platform was proteomics, appearing in 55 of the studies and two of these included a metabolomics component. Most studies (n = 91) reported on CKD associated with diabetes mellitus. Thirteen studies that provided information on the biomarkers associated with CKD and explored potential pathways involved in CKD are discussed. The biomarkers that are associated with risk or early detection of CKD are SNPs in the MYH9/APOL1 and UMOD genes, the proteomic CKD273 biomarker panel and metabolite pantothenic acid. Pantothenic acid and the CKD273 biomarker panel were also involved in predicting CKD progression. Retinoic acid pathway genes, UMOD, and pantothenic acid provided insight into potential pathways leading to CKD. The biomarkers were mainly used to detect CKD and predict progression in high-income, European ancestry populations, highlighting the need for representative 'omics research in other populations with disparate socio-economic strata, including Africans, since disease etiologies may differ across ethnic groups. To assess the transferability of findings, it is essential to do research in diverse populations. Govender, Melanie A Brandenburg, Jean-Tristan Fabian, June Ramsay, Michele eng Review Switzerland Front Genet. Nov 8;12:. doi: 10./fgene... eCollection .I SomaScan 11/26/ Pietzner M, et al. Synergistic insights into human health from aptamer- and antibody-based proteomic profiling Nat Commun 12 1 https://www.doi.org/10./s-021--0 34,819,519 Adult Alzheimer Disease/genetics Antibodies/metabolism Aptamers, Peptide/metabolism Cohort Studies Female Humans Male Membrane Glycoproteins/genetics Middle Aged Phenotype Protein Interaction Mapping Protein Interaction Maps/genetics Proteome/*genetics/metabolism Proteomics/*methods *Quantitative Trait Loci Receptors, Immunologic/genetics Affinity-based proteomics has enabled scalable quantification of thousands of protein targets in blood enhancing biomarker discovery, understanding of disease mechanisms, and genetic evaluation of drug targets in humans through protein quantitative trait loci (pQTLs). Here, we integrate two partly complementary techniques-the aptamer-based SomaScan((R)) v4 assay and the antibody-based Olink assays-to systematically assess phenotypic consequences of hundreds of pQTLs discovered for 871 protein targets across both platforms. We create a genetically anchored cross-platform proteome-phenome network comprising 547 protein-phenotype connections, 36.3% of which were only seen with one of the two platforms suggesting that both techniques capture distinct aspects of protein biology. We further highlight discordance of genetically predicted effect directions between assays, such as for PILRA and Alzheimer's disease. Our results showcase the synergistic nature of these technologies to better understand and identify disease mechanisms and provide a benchmark for future cross-platform discoveries. Pietzner, Maik Wheeler, Eleanor Carrasco-Zanini, Julia Kerrison, Nicola D Oerton, Erin Koprulu, Mine Luan, Jian'an Hingorani, Aroon D Williams, Steve A Wareham, Nicholas J Langenberg, Claudia eng MC_UU_/1/MRC_/Medical Research Council/United Kingdom MC_PC_/MRC_/Medical Research Council/United Kingdom AA/18/6//BHF_/British Heart Foundation/United Kingdom WT_/Wellcome Trust/United Kingdom MC_UU_/1/MRC_/Medical Research Council/United Kingdom MR/V/1/MRC_/Medical Research Council/United Kingdom Observational Study Research Support, Non-U.S. Gov't England Nat Commun. Nov 24;12(1):. doi: 10./s-021--0.I SomaScan 11/26/ Norby FL, et al. Proteomics and Risk of Atrial Fibrillation in Older Adults (From the Atherosclerosis Risk in Communities [ARIC] Study) Am J Cardiol 161 42-50 https://www.doi.org/10./j.amjcard..08.064 34,794,617 Atherosclerosis/*blood/complications/epidemiology Atrial Fibrillation/*blood/complications/epidemiology Biomarkers/blood Female Follow-Up Studies Humans Incidence Male Middle Aged Natriuretic Peptide, Brain/*blood Peptide Fragments/*blood Protein Precursors Proteomics/*methods Risk Assessment/*methods Risk Factors Time Factors United States/epidemiology Plasma proteomic profiling may aid in the discovery of novel biomarkers upstream of the development of atrial fibrillation (AF). We used data from the Atherosclerosis Risk in Communities study to examine the relation between large-scale proteomics and incident AF in a cohort of older-aged adults in the United States. We quantified 4,877 plasma proteins in Atherosclerosis Risk in Communities participants at visit 5 (-) using an aptamer-based proteomic profiling platform. We used Cox proportional hazards models to assess the association between protein levels and incident AF, and explored relation of selected protein biomarkers using annotated pathway analysis. Our study included 4,668 AF-free participants (mean age 75 +/- 5 years; 59% female; 20% Black race) with proteomic measures. A total of 585 participants developed AF over a mean follow-up of 5.7 +/- 1.7 years. After adjustment for clinical factors associated with AF, N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with the risk of incident AF (hazard ratio, 1.82; 95% CI, 1.68 to 1.98; p, 2.91 x 10(-45) per doubling of NT-proBNP). In addition, 36 other proteins were also significantly associated with incident AF after Bonferroni correction. We further adjusted for medication use and estimated glomerular filtration rate and found 17 proteins, including angiopoietin-2 and transgelin, that remained significantly associated with incident AF. Pathway analyses implicated the inhibition of matrix metalloproteases as the top canonical pathway in AF pathogenesis. In conclusion, using a large-scale proteomic platform, we identified both novel and established proteins associated with incident AF and explored mechanistic pathways of AF development. Norby, Faye L Tang, Weihong Pankow, James S Lutsey, Pamela L Alonso, Alvaro Steffan, Brian Chen, Lin Y Zhang, Michael Shippee, Nathan D Ballantyne, Christie M Boerwinkle, Eric Coresh, Josef Folsom, Aaron R eng 16EIA/AHA/American Heart Association-American Stroke Association/ HHSNC/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ K24 HL/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Cardiol. Dec 15;161:42-50. doi: 10./j.amjcard..08.064.I SomaScan 11/20/ Esefeld M, et al. The Proteomic Signature of Recombinant Growth Hormone in Recreational Athletes J Endocr Soc 5 12 bvab156 https://www.doi.org/10./jendso/bvab156 34,765,854 antidoping glucose metabolism human growth hormone proteomics OBJECTIVE: Administration of human growth hormone (hGH) is prohibited in competitive sport and its detection in an athlete's sample triggers an adverse analytical finding. However, the biological processes that are modulated by recombinant hGH are not well characterized and associated blood serum proteins may constitute new biomarkers for hGH misuse. METHODS: Thirty-five recreational athletes were enrolled in a study to investigate the time- and dose-dependent response of serum protein levels to recombinant hGH administration. Participants were randomly assigned to 4 groups, receiving 1 of 3 different doses of recombinant hGH or a placebo. Bio samples were collected at 22 time points over a period of 13 weeks, starting 4 weeks before treatment, during 3 weeks of treatment, and at 6 weeks' follow-up. A total of 749 serum samples were analyzed for protein markers using the SOMAscan proteomics platform. RESULTS: We identified 66 proteins that significantly associated with recombinant hGH administration and dosage, including well known hGH targets, such as IGF1, but also previously unknown hGH-related proteins (eg, protease inhibitors, WFIKKN1, and chemokines, CCL2). Network analysis revealed changes in specific biological pathways, mainly related to the immune system and glucose metabolism. CONCLUSION: Our analysis suggests that hGH administration affects biological processes more strongly than previously acknowledged. Some of the proteins were dysregulated even after hGH treatment and could potentially be developed into biomarkers for hGH misuse. Moreover, our findings suggest new roles for hGH-associated proteins in the etiology of hGH-related diseases and may indicate new risks that may be associated with hGH misuse. Esefeld, Max Pastor, Antoni de la Torre, Rafael Barroso, Osquel Aikin, Reid Sarwath, Hina Engelke, Rudolf Schmidt, Frank Suhre, Karsten eng J Endocr Soc. Nov 2;5(12):bvab156. doi: 10./jendso/bvab156. eCollection Dec 1.I SomaScan 11/13/ Helms L, et al. Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations JCI Insight 6 24 https://www.doi.org/10./jci.insight. 34,767,537 Acute Kidney Injury/etiology/*urine Adult Aged Angiotensin-Converting Enzyme 2/genetics Animals Apoptosis Bowman Capsule/cytology/virology COVID-19/complications/*urine Chlorocebus aethiops Female Gene Knockout Techniques Hospital Mortality Hospitalization Humans Kidney/metabolism/pathology/*virology Kidney Tubules, Proximal/metabolism/pathology/*virology Male Middle Aged Organoids/metabolism/*virology Podocytes/virology Polycystic Kidney Diseases Protein Kinase D2/genetics Proteome Receptors, Coronavirus/genetics Reproducibility of Results SARS-CoV-2/*pathogenicity Transcriptome Vero Cells Viral Tropism Virus Replication Covid-19 Genetic diseases Molecular pathology Nephrology iPS cells human kidney organoid differentiation and modeling of disease in this system (patent applications US 63/253,797 15/756,846 62/213,740 62/672,470 62/739,637 and PCT/US/). Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo-designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies. Helms, Louisa Marchiano, Silvia Stanaway, Ian B Hsiang, Tien-Ying Juliar, Benjamin A Saini, Shally Zhao, Yan Ting Khanna, Akshita Menon, Rajasree Alakwaa, Fadhl Mikacenic, Carmen Morrell, Eric D Wurfel, Mark M Kretzler, Matthias Harder, Jennifer L Murry, Charles E Himmelfarb, Jonathan Ruohola-Baker, Hannele Bhatraju, Pavan K Gale, Michael Jr Freedman, Benjamin S eng R21 AI/AI/NIAID NIH HHS/ P51 OD/OD/NIH HHS/ K23 DK/DK/NIDDK NIH HHS/ UH3 TR/TR/NCATS NIH HHS/ T90 DE/DE/NIDCR NIH HHS/ R24 HD/HD/NICHD NIH HHS/ F31 DK/DK/NIDDK NIH HHS/ U01 AI/AI/NIAID NIH HHS/ TL1 TR/TR/NCATS NIH HHS/ UC2 DK/DK/NIDDK NIH HHS/ UG3 TR/TR/NCATS NIH HHS/ UG3 TR/TR/NCATS NIH HHS/ K23 HL/HL/NHLBI NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. JCI Insight. Dec 22;6(24):e. doi: 10./jci.insight..I SomaScan 11/13/ Roberts JA, et al. A brain proteomic signature of incipient Alzheimer's disease in young APOE epsilon4 carriers identifies novel drug targets Sci Adv 7 46 eabi https://www.doi.org/10./sciadv.abi 34,757,788 Aptamer-based proteomics revealed differentially abundant proteins in Alzheimer's disease (AD) brains in the Baltimore Longitudinal Study of Aging and Religious Orders Study (mean age, 89 +/- 9 years). A subset of these proteins was also differentially abundant in the brains of young APOE epsilon4 carriers relative to noncarriers (mean age, 39 +/- 6 years). Several of these proteins represent targets of approved and experimental drugs for other indications and were validated using orthogonal methods in independent human brain tissue samples as well as in transgenic AD models. Using cell culture-based phenotypic assays, we showed that drugs targeting the cytokine transducer STAT3 and the Src family tyrosine kinases, YES1 and FYN, rescued molecular phenotypes relevant to AD pathogenesis. Our findings may accelerate the development of effective interventions targeting the earliest molecular triggers of AD. Roberts, Jackson A Varma, Vijay R An, Yang Varma, Sudhir Candia, Julian Fantoni, Giovanna Tiwari, Vinod Anerillas, Carlos Williamson, Andrew Saito, Atsushi Loeffler, Tina Schilcher, Irene Moaddel, Ruin Khadeer, Mohammed Lovett, Jacqueline Tanaka, Toshiko Pletnikova, Olga Troncoso, Juan C Bennett, David A Albert, Marilyn S Yu, Kaiwen Niu, Mingming Haroutunian, Vahram Zhang, Bin Peng, Junmin Croteau, Deborah L Resnick, Susan M Gorospe, Myriam Bohr, Vilhelm A Ferrucci, Luigi Thambisetty, Madhav eng P30 AG/AG/NIA NIH HHS/ P30 AG/AG/NIA NIH HHS/ RF1 AG/AG/NIA NIH HHS/ U01 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ P30 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ Sci Adv. Nov 12;7(46):eabi. doi: 10./sciadv.abi. Epub Nov 10.I SomaScan 11/11/ Singh K, et al. Ultrasensitive detection of blood biomarkers of Alzheimer's and Parkinson's diseases: a systematic review Biomark Med 15 17 - https://www.doi.org/10./bmm-- 34,743,546 Alzheimer Disease/*blood/*diagnosis Biomarkers/*blood Case-Control Studies Humans Longitudinal Studies Parkinson Disease/*blood/*diagnosis Publication Bias Publications Risk Alzheimer's disease Meso Scale Discovery Parkinson's disease Simoa SOMAscan biomarkers meta-analysis systematic review Purpose: Neurodegenerative disorders are a global health burden with costly and invasive diagnoses relying on brain imaging technology or CSF-based biomarkers. Therefore, considerable efforts to identify blood-biomarkers for Alzheimer's (AD) and Parkinson's diseases (PD) are ongoing. Objectives: This review evaluates the blood biomarkers for AD and PD for their diagnostic value. Methods: This study systematically reviewed articles published between July and February . Among papers, we selected 42 studies for a systematic review and 23 studies for meta-analysis. Results & conclusion: Our analysis highlights P-tau181, T-tau and Nfl as promising blood biomarkers for AD diagnosis. Nfl levels were consistently raised in 16 AD and three PD cohorts. P-tau181 and T-tau were also significantly increased in 12 and eight AD cohorts, respectively. Singh, Kailash Cheung, Bernard My Xu, Aimin eng Meta-Analysis Research Support, Non-U.S. Gov't Systematic Review England Biomark Med. Dec;15(17):-. doi: 10./bmm--. Epub Nov 8.I SomaScan 11/09/ Park YH, et al. Dysregulated expression levels of APH1B in peripheral blood are associated with brain atrophy and amyloid-beta deposition in Alzheimer's disease Alzheimers Res Ther 13 1 183 https://www.doi.org/10./s-021--z 34,732,252 *Alzheimer Disease/diagnostic imaging/genetics/pathology *Amyloid beta-Protein Precursor/metabolism Atrophy/pathology Brain/diagnostic imaging/pathology *Endopeptidases/genetics Genetic Predisposition to Disease Genome-Wide Association Study Humans *Membrane Proteins/genetics Transcriptome Alzheimer's disease Blood Expression Expression quantitative trait locus Imaging Transcriptome board. BACKGROUND: The interaction between the brain and periphery might play a crucial role in the development of Alzheimer's disease (AD). METHODS: Using blood transcriptomic profile data from two independent AD cohorts, we performed expression quantitative trait locus (cis-eQTL) analysis of 29 significant genetic loci from a recent large-scale genome-wide association study to investigate the effects of the AD genetic variants on gene expression levels and identify their potential target genes. We then performed differential gene expression analysis of identified AD target genes and linear regression analysis to evaluate the association of differentially expressed genes with neuroimaging biomarkers. RESULTS: A cis-eQTL analysis identified and replicated significant associations in seven genes (APH1B, BIN1, FCER1G, GATS, MS4A6A, RABEP1, TRIM4). APH1B expression levels in the blood increased in AD and were associated with entorhinal cortical thickness and global cortical amyloid-beta deposition. CONCLUSION: An integrative analysis of genetics, blood-based transcriptomic profiles, and imaging biomarkers suggests that APH1B expression levels in the blood might play a role in the pathogenesis of AD. Park, Young Ho Pyun, Jung-Min Hodges, Angela Jang, Jae-Won Bice, Paula J Kim, SangYun Saykin, Andrew J Nho, Kwangsik eng U01 AG/AG/NIA NIH HHS/ R01 LM/LM/NLM NIH HHS/ U01 AG/AG/NIA NIH HHS/ DH_/Department of Health/United Kingdom U01 AG/AG/NIA NIH HHS/ R03 AG/AG/NIA NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ R01 LM/LM/NLM NIH HHS/ P50 GM/GM/NIGMS NIH HHS/ K01 AG/AG/NIA NIH HHS/ CIHR/Canada Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Alzheimers Res Ther. Nov 3;13(1):183. doi: 10./s-021--z.I SomaScan 11/05/ Sivakumar P, et al. Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis Respir Res 22 1 273 https://www.doi.org/10./s-021--3 34,689,792 Biomarkers/blood Blood Proteins/*analysis Case-Control Studies *Gene Expression Profiling Humans Idiopathic Pulmonary Fibrosis/*blood/diagnosis/*genetics Lung/*chemistry *Proteome *Proteomics *Transcriptome Biomarkers Chemokines Extracellular matrix Idiopathic pulmonary fibrosis Mast cells BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need. Development of transformational therapies for IPF is challenging in part to due to lack of robust predictive biomarkers of prognosis and treatment response. Importantly, circulating biomarkers of IPF are limited and none are in clinical use. METHODS: We previously reported dysregulated pathways and new disease biomarkers in advanced IPF through RNA sequencing of lung tissues from a cohort of transplant-stage IPF patients (n = 36) in comparison to normal healthy donors (n = 19) and patients with acute lung injury (n = 11). Here we performed proteomic profiling of matching plasma samples from these cohorts through the Somascan- SomaLogics platform. RESULTS: Comparative analyses of lung transcriptomic and plasma proteomic signatures identified a set of 34 differentially expressed analytes (fold change (FC) >/= +/- 1.5, false discovery ratio (FDR) 75% of primary brain tumors. This includes anaplastic astrocytoma (grade III; AS), the most common and fatal glioblastoma multiforme (grade IV; GBM), and oligodendroglioma (ODG). We have generated patient-derived AS, GBM, and ODG cell models to study disease mechanisms and test patient-centered therapeutic strategies. We have used an aptamer-based high-throughput SOMAscan((R)) 1.3K assay to determine the proteomic profiles of different analytes. SOMAscan((R)) proteomes of AS and GBM self-organized into closely adjacent proteomes which were clearly distinct from ODG proteomes. GBM self-organized into four proteomic clusters of which SOMAscan((R)) cluster 4 proteome predicted a highly inter-connected proteomic network. Several up- and down-regulated proteins relevant to glioma were successfully validated in GBM cell isolates across different SOMAscan((R)) clusters and in corresponding GBM tissues. Slow off-rate modified aptamer proteomics is an attractive analytical tool for rapid proteomic stratification of different malignant gliomas and identified cluster-specific SOMAscan((R)) signatures and functionalities in patient GBM cells. Thanasupawat, Thatchawan Glogowska, Aleksandra Pascoe, Christopher Krishnan, Sai Nivedita Munir, Maliha Begum, Farhana Beiko, Jason Krcek, Jerry Del Bigio, Marc R Pitz, Marshall Shen, Yaoqing Spicer, Victor Coombs, Kevin M Wilkins, John Hombach-Klonisch, Sabine Klonisch, Thomas eng Switzerland Int J Mol Sci. Sep 3;22(17):. doi: 10./ijms.I SomaScan 09/11/ Ren X, et al. Evolving A RIG-I Antagonist: A Modified DNA Aptamer Mimics Viral RNA J Mol Biol 433 21 https://www.doi.org/10./j.jmb.. 34,487,794 Antigens, Viral/*chemistry/metabolism Aptamers, Nucleotide/*chemistry/metabolism Binding Sites Cloning, Molecular Crystallography, X-Ray DEAD Box Protein 58/*chemistry/genetics/metabolism Escherichia coli/genetics/metabolism Gene Expression Genetic Vectors/chemistry/metabolism Humans Immunologic Factors/*chemistry/metabolism Kinetics Models, Molecular Molecular Mimicry Mutation Nucleic Acid Conformation Protein Binding Protein Conformation, alpha-Helical Protein Conformation, beta-Strand Protein Interaction Domains and Motifs RNA, Viral/*chemistry/metabolism Receptors, Immunologic/*chemistry/genetics/metabolism Recombinant Proteins/chemistry/genetics/metabolism SELEX Aptamer Technique DNA structure in-vitro innate immunity molecular recognition nucleic acid folding Vertebrate organisms express a diversity of protein receptors that recognize and respond to the presence of pathogenic molecules, functioning as an early warning system for infection. As a result of mutation or dysregulated metabolism, these same innate immune receptors can be inappropriately activated, leading to inflammation and disease. One of the most important receptors for detection and response to RNA viruses is called RIG-I, and dysregulation of this protein is linked with a variety of disease states. Despite its central role in inflammatory responses, antagonists for RIG-I are underdeveloped. In this study, we use invitro selection from a pool of modified DNA aptamers to create a high affinity RIG-I antagonist. A high resolution crystal structure of the complex reveals molecular mimicry between the aptamer and the 5'-triphosphate terminus of viral ligands, which bind to the same amino acids within the CTD recognition platform of the RIG-I receptor. Our study suggests a powerful, generalizable strategy for generating immunomodulatory drugs and mechanistic tool compounds. Ren, Xiaoming Gelinas, Amy D Linehan, Melissa Iwasaki, Akiko Wang, Wenshuai Janjic, Nebojsa Pyle, Anna Marie eng Research Support, Non-U.S. Gov't Netherlands J Mol Biol. Oct 15;433(21):. doi: 10./j.jmb... Epub Sep 3.I SomaScan 09/07/ Berry J, et al. Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design Neurol Clin Pract 11 4 e472-e479 https://www.doi.org/10./CPJ. 34,476,128 OBJECTIVES: To identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes. METHODS: This is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration-approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale-Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported. RESULTS: The study is estimated to be completed in with an interim analysis planned. CONCLUSIONS: Findings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment. Berry, James Brooks, Benjamin Genge, Angela Heiman-Patterson, Terry Appel, Stanley Benatar, Michael Bowser, Robert Cudkowicz, Merit Gooch, Clifton Shefner, Jeremy Westra, Jurjen Agnese, Wendy Merrill, Charlotte Nelson, Sally Apple, Stephen eng Neurol Clin Pract. Aug;11(4):e472-e479. doi: 10./CPJ..I SomaScan 09/04/ Rhee J, et al. Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium Front Aging Neurosci 13 https://www.doi.org/10./fnagi.. 34,456,709 Il-6 Pde3a SOMAscan Timp-1 TruCulture cardiopulmonary bypass postoperative delirium proteomics commercial or financial relationships that could be construed as a potential conflict of interest. BACKGROUND: Postoperative delirium (POD) is an acute altered mental state commonly encountered after cardiac surgery. The pathophysiological mechanisms underlying POD remain unclear. We aimed to identify circulating proteins significantly altered after major cardiac surgery with cardiopulmonary bypass (CPB). We also aimed to enable inferences on associations with POD. METHODS: Serum and whole blood samples were collected before CPB (n = 16 patients; n = 8 with POD) and again from the same patients on postoperative day 1. All patients were clinically evaluated for POD on postoperative days 1-3. An aptamer-based proteomics platform (SOMAscan) was used to quantify serum protein abundance in patients with POD compared with non-POD controls. We also performed a lipopolysaccharide (LPS)-based in vitro functional analysis (TruCulture) on whole blood samples from patients with POD and non-POD controls to approximate surgical stress. Cytokine levels were determined using a Luminex immunoassay. RESULTS: Cardiac surgery with CPB resulted in a significant (p(adj) < 0.01) change in 48.8% (637 out of 1,305) of proteins detected by SOMAscan. Gene set enrichment showed that the most impacted biological processes involved myeloid cell activation. Specifically, activation and degranulation of neutrophils were the top five highest-scoring processes. Pathway analyses with the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that metabolic enzymes, particularly those of glycolysis, were elevated in serum concentration after surgery. Several proteins were significantly increased postoperatively in patients diagnosed with POD relative to the non-POD controls, with interleukin-6 (IL-6) showing the greatest fold-change. LPS stimulation of whole blood samples confirmed these findings. Linear regression analysis showed a highly significant correlation between Confusion Assessment Method (CAM) scores and CPB-mediated changes in cGMP-inhibited 3',5'-cyclic phosphodiesterase A (PDE3A). CONCLUSIONS: Cardiac surgery with CPB resulted in inflammasome changes accompanied by unexpected increases in metabolic pathways. In exploratory analyses, we found that POD was associated with changes in the expression level of various proteins, most notably IL-6 and PDE3A. This study and ongoing protein biomarker studies will likely help quantify risk or confirm the diagnosis for POD and increase understanding of its pathophysiological mechanisms. Rhee, James Kuznetsov, Alexandra McKay, Tina Lyons, Margaret Houstis, Nicholas Mekkonen, Jennifer Ethridge, Breanna Ibala, Reine Hahm, Eunice Gitlin, Jacob Guseh, J Sawalla Kitchen, Robert Rosenzweig, Anthony Shaefi, Shahzad Flaczyk, Adam Qu, Jason Akeju, Oluwaseun eng R01 DK/DK/NIDDK NIH HHS/ R35 HL/HL/NHLBI NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ R03 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ K08 GM/GM/NIGMS NIH HHS/ K08 HL/HL/NHLBI NIH HHS/ R21 EB/EB/NIBIB NIH HHS/ Switzerland Front Aging Neurosci. Aug 11;13:. doi: 10./fnagi... eCollection .I SomaScan 08/31/ Barros TT, et al. DNA Damage, n-3 Long-Chain PUFA Levels and Proteomic Profile in Brazilian Children and Adolescents Nutrients 13 8 https://www.doi.org/10./nu 34,444,642 Adolescent Brazil Child Class I Phosphatidylinositol 3-Kinases/blood Class Ia Phosphatidylinositol 3-Kinase/blood Cross-Sectional Studies Cyclin C/blood Cyclin-Dependent Kinase 8/blood *DNA Damage Docosahexaenoic Acids/*blood Eicosapentaenoic Acid/*blood Fatty Acids, Omega-3/*blood Female Humans Hydrolases/blood Inflammation/metabolism Male Protein Kinase C beta/blood Proteomics DNA damage adolescents fatty acids proteomic of the Nestle group. J.K. works for Vydiant, a for-profit company. S.M. is on the faculty of the Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteite Amsterdam. Fatty acids play a significant role in maintaining cellular and DNA protection and we previously found an inverse relationship between blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and DNA damage. The aim of this study was to explore differences in proteomic profiles, for 117 pro-inflammatory proteins, in two previously defined groups of individuals with different DNA damage and EPA and DHA levels. Healthy children and adolescents (n = 140) aged 9 to 13 years old in an urban area of Brazil were divided by k-means cluster test into two clusters of DNA damage (tail intensity) using the comet assay (cluster 1 = 5.9% +/- 1.2 and cluster 2 = 13.8% +/- 3.1) in our previous study. The cluster with higher DNA damage and lower levels of DHA (6.2 +/- 1.6 mg/dL; 5.4 +/- 1.3 mg/dL, p = 0.003) and EPA (0.6 +/- 0.2 mg/dL; 0.5 +/- 0.1 mg/dL, p < 0.001) presented increased expression of the proteins CDK8-CCNC, PIK3CA-PIK3R1, KYNU, and PRKCB, which are involved in pro-inflammatory pathways. Our findings support the hypothesis that low levels of n-3 long-chain PUFA may have a less protective role against DNA damage through expression of pro-inflammatory proteins, such as CDK8-CCNC, PIK3CA-PIK3R1, KYNU, and PRKCB. Barros, Tamiris Trevisan de Venancio, Vinicius de Paula Hernandes, Livia Cristina Antunes, Lusania Maria Greggi Hillesheim, Elaine Salomao, Roberta Garcia Mathias, Mariana Giaretta Coelho-Landell, Carolina Almeida Toffano, Roseli Borges Donega Almada, Maria Olimpia Ribeiro do Vale Camelo-Junior, Jose Simon Moco, Sofia Cominetti, Ornella Ued, Fabio da Veiga Kaput, Jim Monteiro, Jacqueline Pontes eng /-8/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo/ /-8/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ RDHS /Nestle Institute of Health Sciences/ Switzerland Nutrients. Jul 21;13(8):. doi: 10./nu.I SomaScan 08/28/ Ogundele M, et al. Validation of Chemokine Biomarkers in Duchenne Muscular Dystrophy Life (Basel) 11 8 https://www.doi.org/10./life 34,440,571 Becker muscular dystrophy Duchenne muscular dystrophy chemokines disease severity inflammatory biomarkers validation studies Duchenne muscular dystrophy (DMD) is a progressive muscle disease involving complex skeletal muscle pathogenesis. The pathogenesis is triggered by sarcolemma instability due to the lack of dystrophin protein expression, leading to Ca(2+) influx, muscle fiber apoptosis, inflammation, muscle necrosis, and fibrosis. Our lab recently used two high-throughput multiplexing techniques (e.g., SomaScan((R)) aptamer assay and tandem mass tag-(TMT) approach) and identified a series of serum protein biomarkers tied to different pathobiochemical pathways. In this study, we focused on validating the circulating levels of three proinflammatory chemokines (CCL2, CXCL10, and CCL18) that are believed to be involved in an early stage of muscle pathogenesis. We used highly specific and reproducible MSD ELISA assays and examined the association of these chemokines with DMD pathogenesis, age, disease severity, and response to glucocorticoid treatment. As expected, we confirmed that these three chemokines were significantly elevated in serum and muscle samples of DMD patients relative to age-matched healthy controls (p-value < 0.05, CCL18 was not significantly altered in muscle samples). These three chemokines were not significantly elevated in Becker muscular dystrophy (BMD) patients, a milder form of dystrophinopathy, when compared in a one-way ANOVA to a control group but remained significantly elevated in the age-matched DMD group (p < 0.05). CCL2 and CCL18 but not CXCL10 declined with age in DMD patients, whereas all three chemokines remained unchanged with age in BMD and controls. Only CCL2 showed significant association with time to climb four steps in the DMD group (r = 0.48, p = 0.038) and neared significant association with patients' reported outcome in the BMD group (r = 0.39, p = 0.058). Furthermore, CCL2 was found to be elevated in a serum of the mdx mouse model of DMD, relative to wild-type mouse model. This study suggests that CCL2 might be a suitable candidate biomarker for follow-up studies to demonstrate its physiological significance and clinical utility in DMD. Ogundele, Michael Zhang, Jesslyn S Goswami, Mansi V Barbieri, Marissa L Dang, Utkarsh J Novak, James S Hoffman, Eric P Nagaraju, Kanneboyina Cinrg-Dnhs Investigators Hathout, Yetrib eng R01 AR/AR/NIAMS NIH HHS/ P50HD/NH/NIH HHS/ W81XWH-16-1-/U.S. Department of Defense/ Switzerland Life (Basel). Aug 13;11(8):827. doi: 10./life.I SomaScan 08/28/ Pierson SK, et al. Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease Blood Adv 5 17 - https://www.doi.org/10./bloodadvances. 34,438,448 *Castleman Disease/drug therapy *Herpesvirus 8, Human Humans Interleukin-6 Proteomics Signal Transduction United States Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti-IL-6 therapy, siltuximab, is the only US Food and Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8-associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration. Pierson, Sheila K Shenoy, Sushila Oromendia, Ana B Gorzewski, Alexander M Langan Pai, Ruth-Anne Nabel, Christopher Shield Ruth, Jason R Parente, Sophia A T Arenas, Daniel J Guilfoyle, Mary Reddy, Manjula Weinblatt, Michael Shadick, Nancy Bower, Mark Pria, Alessia Dalla Masaki, Yasufumi Katz, Laura Mezey, Jason Beineke, Philip Lee, David Tendler, Craig Kambayashi, Taku Fossa, Alexander van Rhee, Frits Fajgenbaum, David C eng R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Blood Adv. Sep 14;5(17):-. doi: 10./bloodadvances..I SomaScan 08/27/ Kokelj S, et al. Smoking induces sex-specific changes in the small airway proteome Respir Res 22 1 234 https://www.doi.org/10./s-021--6 34,429,114 Cigarette Smoking/genetics/*metabolism/pathology Cohort Studies Female Humans Lung/*metabolism/pathology Male Middle Aged Proteomics/*methods *Sex Characteristics *Smokers Spirometry/methods Tobacco Smoking/*genetics/metabolism/pathology Copd Exhaled particles Inflammation Proteomics Respiratory tract lining fluid Small airways Smoking personal fees from PExA AB during the conduct of the study and was employed by PExA AB while writing the manuscript, but not during the planning and completion of the study. HKO and BG are full-time employees of AstraZeneca. INTRODUCTION: Cigarette smoke triggers many cellular and signaling responses in the lung and the resulting inflammation plays a central role in smoke-related lung diseases, such as COPD. We explored the effects of smoking on the small airway proteome in samples obtained by collection of exhaled particles with the aim to identify specific proteins dysregulated by smoking. METHODS: Exhaled particles were obtained from 38 current smokers, 47 former smokers and 22 healthy controls with the PExA method. 120 ng of sample was collected from individual subjects and analyzed with the SOMAscan proteomics platform. General linear model-based statistics were performed. RESULTS: Two hundred and three proteins were detected in at least half of 107 total samples. Active smoking exerted a significant impact on the protein composition of respiratory tract lining fluid (RTLF), with 81 proteins altered in current smokers compared to never smokers (p < 0.05, q < 0.124). Among the proteins most clearly discriminating between current and never smokers were sRAGE, FSTL3, SPOCK2 and protein S, all of them being less abundant in current smokers. Analysis stratified for sex unveiled sex differences with more pronounced proteomic alterations due to active smoking in females than males. Proteins whose abundance was altered by active smoking in women were to a larger extent related to the complement system. The small airway protein profile of former smokers appeared to be more similar to that observed in never smokers. CONCLUSIONS: The study shows that smoking has a strong impact on protein expression in the small airways, and that smoking affects men and women differently, suggesting PExA sampling combined with high sensitivity protein analysis offers a promising platform for early detection of COPD and identification of novel COPD drug targets. Kokelj, Spela Ostling, Jorgen Georgi, Benjamin Fromell, Karin Ekdahl, Kristina Nilsson Olsson, Henric K Olin, Anna-Carin eng -/Forskningsradet om Halsa, Arbetsliv och Valfard/ /Hjart-Lungfonden/ --5.1/Vetenskapsradet/ -/Linneuniversitetet/ England Respir Res. Aug 24;22(1):234. doi: 10./s-021--6.I SomaScan 08/26/ Bowker N, et al. Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region Diabetes 70 11 - https://www.doi.org/10./db21- 34,426,508 Adult Aged Cardiovascular Diseases/*blood Diabetes Mellitus, Type 2/*blood/genetics/metabolism Female Finland Gastric Inhibitory Polypeptide/*blood/genetics/metabolism *Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Genotype Humans Male Middle Aged Receptors, Gastrointestinal Hormone/genetics/*metabolism Risk Factors United Kingdom There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PP(coloc)] > 0.97; PP explained by the candidate variant [PP(explained)] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs; distance to E354 approximately 770 Kb; R (2) with E354 = 0.004; PP(coloc) > 0.99; PP(explained) = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354's association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs (R (2) with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials. Bowker, Nicholas Hansford, Robert Burgess, Stephen Foley, Christopher N Auyeung, Victoria P W Erzurumluoglu, A Mesut Stewart, Isobel D Wheeler, Eleanor Pietzner, Maik Gribble, Fiona Reimann, Frank Bhatnagar, Pallav Coghlan, Matthew P Wareham, Nicholas J Langenberg, Claudia eng MC_UU_/3/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom C864/A/CRUK_/Cancer Research UK/United Kingdom MC_PC_/MRC_/Medical Research Council/United Kingdom G/MRC_/Medical Research Council/United Kingdom /Z/14/Z/WT_/Wellcome Trust/United Kingdom G/MRC_/Medical Research Council/United Kingdom /CRUK_/Cancer Research UK/United Kingdom WT_/Wellcome Trust/United Kingdom MC_UU_/1/MRC_/Medical Research Council/United Kingdom MC_UU_/3/MRC_/Medical Research Council/United Kingdom /Z/14/Z/WT_/Wellcome Trust/United Kingdom MR/N/1/MRC_/Medical Research Council/United Kingdom MC_UU_/1/MRC_/Medical Research Council/United Kingdom MC_PC_/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Diabetes. Nov;70(11):-. doi: 10./db21-. Epub Aug 23.I SomaScan 08/25/ Snider JM, et al. Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality J Clin Invest 131 19 https://www.doi.org/10./JCI 34,428,181 Adolescent Adult Aged Aged, 80 and over COVID-19/*blood/*mortality Child Disease-Free Survival Female Group II Phospholipases A2/*blood Humans Male Middle Aged SARS-CoV-2/*metabolism Severity of Illness Index Survival Rate Covid-19 Cellular immune response Inflammation Molecular pathology officer of MicroRid Technologies Inc. There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality. Snider, Justin M You, Jeehyun Karen Wang, Xia Snider, Ashley J Hallmark, Brian Zec, Manja M Seeds, Michael C Sergeant, Susan Johnstone, Laurel Wang, Qiuming Sprissler, Ryan Carr, Tara F Lutrick, Karen Parthasarathy, Sairam Bime, Christian Zhang, Hao Helen Luberto, Chiara Kew, Richard R Hannun, Yusuf A Guerra, Stefano McCall, Charles E Yao, Guang Del Poeta, Maurizio Chilton, Floyd H eng I01 BX/BX/BLRD VA/ P30 ES/ES/NIEHS NIH HHS/ R01 AI/AI/NIAID NIH HHS/ P01 CA/CA/NCI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ R01 AI/AI/NIAID NIH HHS/ Clinical Trial Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Clin Invest. Oct 1;131(19):e. doi: 10./JCI.I SomaScan 08/25/ Kivimaki M, et al. Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies BMJ 374 n https://www.doi.org/10./bmj.n 34,407,988 Aged Aged, 80 and over Blood Proteins/analysis Dementia/blood/*epidemiology Europe/epidemiology Female Humans Incidence Male Neuropsychological Tests Occupational Diseases/blood/*epidemiology/psychology Occupations/*statistics & numerical data Proportional Hazards Models Prospective Studies Risk Factors Sedentary Behavior United Kingdom/epidemiology United States/epidemiology Workplace/*psychology OBJECTIVES: To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. DESIGN: Multicohort study with three sets of analyses. SETTING: United Kingdom, Europe, and the United States. PARTICIPANTS: Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. MAIN OUTCOME MEASURES: Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. RESULTS: During 1.8 million person years at risk, people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I(2)=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted beta -0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted beta -0.33, P<0.001), and peptidyl-glycine alpha-amidating monooxygenase (AMD, fully adjusted beta -0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD. CONCLUSIONS: The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms. Kivimaki, Mika Walker, Keenan A Pentti, Jaana Nyberg, Solja T Mars, Nina Vahtera, Jussi Suominen, Sakari B Lallukka, Tea Rahkonen, Ossi Pietilainen, Olli Koskinen, Aki Vaananen, Ari Kalsi, Jatinderpal K Goldberg, Marcel Zins, Marie Alfredsson, Lars Westerholm, Peter J M Knutsson, Anders Theorell, Tores Ervasti, Jenni Oksanen, Tuula Sipila, Pyry N Tabak, Adam G Ferrie, Jane E Williams, Stephen A Livingston, Gill Gottesman, Rebecca F Singh-Manoux, Archana Zetterberg, Henrik Lindbohm, Joni V eng MR/R/1/MRC_/Medical Research Council/United Kingdom MR/S/1/MRC_/Medical Research Council/United Kingdom P30 AG/AG/NIA NIH HHS/ Meta-Analysis Research Support, Non-U.S. Gov't England BMJ. Aug 18;374:n. doi: 10./bmj.n.I SomaScan 08/20/ Anisul M, et al. A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance Elife 10 https://www.doi.org/10./eLife. 34,402,426 2',5'-Oligoadenylate Synthetase/genetics COVID-19/genetics/immunology/physiopathology/*virology Cell Adhesion Molecules *Genome-Wide Association Study Humans Lectins, C-Type Proteome Receptors, Cell Surface SARS-CoV-2/*physiology Scavenger Receptors, Class A/genetics Severity of Illness Index fas Receptor/genetics Covid-19 apoptosis epidemiology genetic colocalization genetics genomics global health human mendelian randomization proteins partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. JS none, ES Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. ES is also a full-time employee of Bristol-Myers Squibb. MH Dr Holmes has consulted for Boehringer Ingelheim, and in adherence to the University of Oxford's Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies. JM JM is a full-time employee of Bristol-Myers Squibb and retains stock or stock options in Bristol-Myers Squibb. The author has no other competing interests to declare. TG TG received grants from Biogen and GlaxoSmithKline. The author has no other competing interests to declare. ID Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. ID also received travel costs within the last 36 months from Takeda for speaking at their Reverse Translation Symposium. The author has no other competing interests to declare. BACKGROUND: The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19. METHODS: To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets. RESULTS: Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 x 10(-4)), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. CONCLUSIONS: Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19. FUNDING: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_/4). JSh and GJW were funded by the Wellcome Trust Grant . This research was funded in part by the Wellcome Trust [Grant ]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Individuals who become infected with the virus that causes COVID-19 can experience a wide variety of symptoms. These can range from no symptoms or minor symptoms to severe illness and death. Key demographic factors, such as age, gender and race, are known to affect how susceptible an individual is to infection. However, molecular factors, such as unique gene mutations and gene expression levels can also have a major impact on patient responses by affecting the levels of proteins in the body. Proteins that are too abundant or too scarce may mean the difference between dying from or surviving COVID-19. Identifying the molecular factors in a host that affect how viruses can infect individuals, evade immune defences or trigger severe illness, could provide new ways to treat patients with COVID-19. Such factors are likely to remain constant, even when the virus mutates into new strains. Hence, insights would likely apply across all virus strains, including current strains, such as alpha and delta, and any new strains that may emerge in the future. Using such a 'natural experiment' approach, Karim et al. compared the genetic profiles of over 30,000 COVID-19 patients and a million healthy individuals. Nine proteins were found to have an impact on COVID-19 infection and disease severity. Four proteins were ranked as top priorities for potential treatment targets. One protein, called CD209 (also known as DC-SIGN), is involved in how the virus enters the host cells, and had one of the strongest associations with COVID-19. Two proteins, called IL-6R and FAS, were involved in the immune response and could be responsible for the immune over-activation often seen in severe COVID-19. Finally, one protein, called OAS1, formed part of the body's innate antiviral defence system and appeared to reduce susceptibility to COVID-19. Knowing more about the proteins that influence the severity of COVID-19 opens up new ways to predict, protect and treat patients who may have severe or fatal reactions to infection. Indeed, one of the identified proteins (IL-6R) had already been targeted in recent clinical trials with some encouraging results. Considering CD209 as a potential receptor for the virus could provide another avenue for therapeutics, similar to previously successful approaches to block the virus' known interaction with a receptor protein. Ultimately, this research could supply an entirely new set of treatment options to help combat the COVID-19 pandemic. eng Anisul, Mohd Shilts, Jarrod Schwartzentruber, Jeremy Hayhurst, James Buniello, Annalisa Shaikho Elhaj Mohammed, Elmutaz Zheng, Jie Holmes, Michael Ochoa, David Carmona, Miguel Maranville, Joseph Gaunt, Tom R Emilsson, Valur Gudnason, Vilmundur McDonagh, Ellen M Wright, Gavin J Ghoussaini, Maya Dunham, Ian eng Wellcome Trust/United Kingdom MC_UU_/4/MRC_/Medical Research Council/United Kingdom /WT_/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't England Elife. Aug 17;10:e. doi: 10./eLife..I SomaScan 08/18/ Slieker RC, et al. Distinct Molecular Signatures of Clinical Clusters in People With Type 2 Diabetes: An IMI-RHAPSODY Study Diabetes 70 11 - https://www.doi.org/10./db20- 34,376,475 Cluster Analysis Cohort Studies Cross-Sectional Studies Diabetes Mellitus, Type 2/*metabolism Humans Insulin Resistance Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (N = 12,828), metabolomic (N = 2,945), lipidomic (N = 2,593), and proteomic (N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease. Slieker, Roderick C Donnelly, Louise A Fitipaldi, Hugo Bouland, Gerard A Giordano, Giuseppe N Akerlund, Mikael Gerl, Mathias J Ahlqvist, Emma Ali, Ashfaq Dragan, Iulian Elders, Petra Festa, Andreas Hansen, Michael K van der Heijden, Amber A Mansour Aly, Dina Kim, Min Kuznetsov, Dmitry Mehl, Florence Klose, Christian Simons, Kai Pavo, Imre Pullen, Timothy J Suvitaival, Tommi Wretlind, Asger Rossing, Peter Lyssenko, Valeriya Legido Quigley, Cristina Groop, Leif Thorens, Bernard Franks, Paul W Ibberson, Mark Rutter, Guy A Beulens, Joline W J 't Hart, Leen M Pearson, Ewan R eng WT_/Wellcome Trust/United Kingdom /Z/13/Z/WT_/Wellcome Trust/United Kingdom WTAIA/WT_/Wellcome Trust/United Kingdom /Z/18/Z/WT_/Wellcome Trust/United Kingdom MR/R/1/MRC_/Medical Research Council/United Kingdom MR/J/1/MRC_/Medical Research Council/United Kingdom MR/L/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Diabetes. Nov;70(11):-. doi: 10./db20-. Epub Aug 10.I SomaScan 08/12/ Sullivan KD, et al. The COVIDome Explorer researcher portal Cell Rep 36 7 https://www.doi.org/10./j.celrep.. 34,348,131 Access to Information Adult COVID-19/*genetics/immunology/*metabolism Case-Control Studies Data Mining *Databases, Genetic Datasets as Topic Female Gene Expression Profiling Humans Male *Metabolome Metabolomics Middle Aged *Proteome Proteomics *Transcriptome Young Adult Covid-19 Crp Sars data portal immune system infection inflammation metabolism multi-omics serpins for Elly Lilly and has provided consulting services to Gilead Sciences Inc. J.M.E. also serves on the Cell Reports Advisory Board. The remaining authors declare no competing interests. COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. To expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients, including matched analysis of the whole-blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate herein the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide. Sullivan, Kelly Daniel Galbraith, Matthew Dominic Kinning, Kohl Thomas Bartsch, Kyle William Levinsky, Nik Caldwell Araya, Paula Smith, Keith Patrick Granrath, Ross Erich Shaw, Jessica Rose Baxter, Ryan Michael Jordan, Kimberly Rae Russell, Seth Aaron Dzieciatkowska, Monika Ewa Reisz, Julie Ann Gamboni, Fabia Cendali, Francesca Isabelle Ghosh, Tusharkanti Monte, Andrew Albert Bennett, Tellen Demeke Miller, Michael George Hsieh, Elena Wen-Yuan D'Alessandro, Angelo Hansen, Kirk Charles Espinosa, Joaquin Maximiliano eng R01 HL/HL/NHLBI NIH HHS/ RM1 GM/GM/NIGMS NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R01 AI/AI/NIAID NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ P30 CA/CA/NCI NIH HHS/ K23 AR/AR/NIAMS NIH HHS/ R35 GM/GM/NIGMS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R21 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell Rep. Aug 17;36(7):. doi: 10./j.celrep... Epub Jul 28.I SomaScan 08/05/ Liu RX, et al. Comparison of proteomic methods in evaluating biomarker-AKI associations in cardiac surgery patients Transl Res 238 49-62 https://www.doi.org/10./j.trsl..07.005 34,343,625 Acute Kidney Injury/*blood Aged Aged, 80 and over Aptamers, Peptide Biomarkers/*blood Blood Chemical Analysis/methods Blood Proteins/*analysis Cardiac Surgical Procedures/*adverse effects Female Humans Immunoassay/methods Male Middle Aged Preoperative Period Proteomics/*methods Although immunoassays are the most widely used protein measurement method, aptamer-based methods such as the SomaScan platform can quantify up to proteins per biosample, creating new opportunities for unbiased discovery. However, there is limited research comparing the consistency of biomarker-disease associations between immunoassay and aptamer-based platforms. In a substudy of the TRIBE-AKI cohort, preoperative and postoperative plasma samples from 294 patients with previous immunoassay measurements were analyzed using the SomaScan platform. Inter-platform Spearman correlations (r(s)) and biomarker-AKI associations were compared across 30 preoperative and 34 postoperative immunoassay-aptamer pairs. Possible factors contributing to inter-platform differences were examined including target protein characteristics, immunoassay, and SomaScan coefficients of variation, other assay characteristics, and sample storage time. The median r(s) was 0.54 (interquartile range [IQR] 0.34-0.83) in postoperative samples and 0.41 (IQR 0.21-0.69) in preoperative samples. We observed a trend of greater r(s) in biomarkers with greater concentrations; the Spearman correlation between the concentration of protein and the inter-platform correlation was 0.64 in preoperative pairs and 0.53 in postoperative pairs. Of proteins measured by immunoassays, we observed significant biomarker-AKI associations for 13 proteins preop and 24 postop; of all corresponding aptamers, 8 proteins preop and 12 postop. All proteins significantly associated with AKI as measured by SomaScan were also significantly associated with AKI as measured by immunoassay. All biomarker-AKI odds ratios were significantly different (P 0.50) inter-platform correlations. Although similar biomarker-disease associations were observed overall, biomarkers with high physiological concentrations tended to have the highest-confidence inter-platform operability in correlations and biomarker-disease associations. Aptamer assays provide excellent precision and an unprecedented coverage and promise for disease associations but interpretation of results should keep in mind a broad range of correlations with immunoassays. Liu, Richard X Thiessen-Philbrook, Heather R Vasan, Ramachandran S Coresh, Josef Ganz, Peter Bonventre, Joseph V Kimmel, Paul L Parikh, Chirag R eng R01 HL/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ RF1 AG/AG/NIA NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ UH3 DK/DK/NIDDK NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ N01HC/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ Comparative Study Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Transl Res. Dec;238:49-62. doi: 10./j.trsl..07.005. Epub Jul 31.I SomaScan 08/04/ Jimenez-Balado J, et al. New candidate blood biomarkers potentially associated with white matter hyperintensities progression Sci Rep 11 1 https://www.doi.org/10./s-021--w 34,253,757 Aged Biomarkers/*metabolism Blood-Brain Barrier/metabolism Humans Hypertension/*metabolism Magnetic Resonance Imaging Matrix Metalloproteinase 9/metabolism Middle Aged Neutral Ceramidase/genetics/metabolism Proto-Oncogene Proteins c-met/metabolism White Matter/*metabolism We aimed to discover blood biomarkers associated with longitudinal changes in white matter hyperintensities (WMH). This study was divided into a discovery phase and a replication phase. Subjects in both studies were patients with hypertension, aged 50-70, who underwent two magnetic resonance imaging (MRI) sessions and blood extractions over a 4-year follow-up period. In the discovery phase, we screened proteins in 12 subjects with WMH progression and in 12 matched control subjects. We found that 41 proteins were differentially expressed: 13 were upregulated and 28 were downregulated. We subsequently selected three biomarkers for replication in baseline and follow-up samples in 80 subjects with WMH progression and in 80 control subjects. The selected protein candidates for the replication were MMP9 (matrix metalloproteinase-9), which was higher in cases, MET (hepatocyte growth factor receptor) and ASAH2 (neutral ceramidase), which were both lower in cases of WMH progression. Baseline biomarker concentrations did not predict WMH progression. In contrast, patients with WMH progression presented a steeper decline in MET over time. Furthermore, cases showed higher MMP9 and lower ASAH2 levels than controls at the follow-up. These results indicate that MMP9, MET, and ASAH2 are potentially associated with the progression of WMH, and could therefore be interesting candidates to validate in future studies. Jimenez-Balado, Joan Pizarro, Jesus Riba-Llena, Iolanda Penalba, Anna Faura, Julia Pala, Elena Montaner, Joan Hernandez-Guillamon, Mar Delgado, Pilar eng Research Support, Non-U.S. Gov't England Sci Rep. Jul 12;11(1):. doi: 10./s-021--w.I SomaScan 07/14/ Moin ASM, et al. Soluble Neuropilin-1 Response to Hypoglycemia in Type 2 Diabetes: Increased Risk or Protection in SARS-CoV-2 Infection? Front Endocrinol (Lausanne) 12 https://www.doi.org/10./fendo.. 34,248,841 ADAM Proteins/*metabolism Aged Angiotensin-Converting Enzyme 2/*metabolism Angiotensins/metabolism Covid-19 Diabetes Mellitus, Type 2/*metabolism Female Glucose Clamp Technique Humans Hypoglycemia/*metabolism Male Membrane Proteins/*metabolism Middle Aged Neuropilin-1/*metabolism Protective Factors Renin/metabolism Risk Factors SARS-CoV-2 Semaphorin-3A/*metabolism Vascular Endothelial Growth Factor A/*metabolism ACE inhibitors Adam9 Neuropilin-1 type 2 diabetes commercial or financial relationships that could be construed as a potential conflict of interest. INTRODUCTION: Neuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection. METHODS: A case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(<40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins: renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9). RESULTS: Baseline RAS overactivity was present with REN elevated and AGT decreased in T2D (p<0.05); ACE2 was unchanged. Baseline sNRP1, VEGF and ADAM9 did not differ between T2D and controls and remained unchanged in response to hypoglycaemia. However, 4-hours post-hypoglycemia, sNRP1, VEGF and ADAM9 were elevated in T2D(p<0.05). SEMA3A was not different at baseline; at hypoglycemia, SEMA3A decreased in controls only. Post-hypoglycemia, SEMA3A levels were higher in T2D versus controls. sNRP1 did not correlate with ACE2, REN or AGT. T2D subjects stratified according to ACE inhibitor (ACEi) therapies showed no difference in sNRP1 levels at either glucose normalization or hypoglycaemia. CONCLUSION: Hypoglycemia potentiated both plasma sNRP1 level elevation and its ligands VEGF and SEMA3A, likely through an ADAM9-mediated mechanism that was not associated with RAS overactivity or ACEi therapy; however, whether this is protective or promotes increased risk for SARS-CoV-2 infection in T2D is unclear. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, identifier NCT. Moin, Abu Saleh Md Al-Qaissi, Ahmed Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Front Endocrinol (Lausanne). Jun 23;12:. doi: 10./fendo... eCollection .I SomaScan 07/13/ Moin ASM, et al. Type 2 Diabetes Coagulopathy Proteins May Conflict With Biomarkers Reflective of COVID-19 Severity Front Endocrinol (Lausanne) 12 https://www.doi.org/10./fendo.. 34,248,840 Aged Biomarkers/metabolism Blood Coagulation Blood Coagulation Factors/*metabolism COVID-19/*metabolism Case-Control Studies Complement Activation Diabetes Mellitus, Type 2/*metabolism Factor IX/metabolism Female Glucose Clamp Technique Heparin Cofactor II/metabolism Humans Hypoglycemia/*metabolism Kininogens/metabolism Male Middle Aged Peptides/metabolism Platelet Activation Platelet Factor 4/metabolism Prospective Studies Protein C/metabolism Proteomics SARS-CoV-2 Severity of Illness Index Thrombospondin 1/metabolism beta-Thromboglobulin/metabolism Covid-19 biomarkers hypoglycemia type 2 diabetes commercial or financial relationships that could be construed as a potential conflict of interest. OBJECTIVE: Detailed proteomic analysis in a cohort of patients with differing severity of COVID-19 disease identified biomarkers within the complement and coagulation cascades as biomarkers for disease severity has been reported; however, it is unclear if these proteins differ sufficiently from other conditions to be considered as biomarkers. METHODS: A prospective, parallel study in T2D (n = 23) and controls (n = 23). A hyperinsulinemic clamp was performed and normoglycemia induced in T2D [4.5 +/- 0.07 mmol/L (81 +/- 1.2 mg/dl)] for 1-h, following which blood glucose was decreased to 9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets. Gurinovich, Anastasia Song, Zeyuan Zhang, William Federico, Anthony Monti, Stefano Andersen, Stacy L Jennings, Lori L Glass, David J Barzilai, Nir Millman, Sofiya Perls, Thomas T Sebastiani, Paola eng R24 GM/GM/NIGMS NIH HHS/ U19 AG/AG/NIA NIH HHS/ U19-AG/AG/NIA NIH HHS/ T32 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ S10 OD/OD/NIH HHS/ P30 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ UH2AG/AG/NIA NIH HHS/ F31 DE/DE/NIDCR NIH HHS/ UH2 AG/AG/NIA NIH HHS/ U19 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ P30AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Switzerland Geroscience. Jun;43(3):-. doi: 10./s-021--4. Epub May 4.I SomaScan 05/06/ Han K, et al. Identification and Validation of Nutrient State-Dependent Serum Protein Mediators of Human CD4(+) T Cell Responsiveness Nutrients 13 5 https://www.doi.org/10./nu 33,924,911 Adult Aged Blood Proteins/*metabolism CD4-Positive T-Lymphocytes/*metabolism Cells, Cultured Fasting/*metabolism Female Humans Inflammation/*blood Male Middle Aged Nutrients/*blood Obesity/*blood Pilot Projects Reproducibility of Results Young Adult CD4+ T cell activation Igfbp1 Il1rl1 Mfge8 Pyy SOMAscan fasting integrative bioinformatics refeeding Intermittent fasting and fasting mimetic diets ameliorate inflammation. Similarly, serum extracted from fasted healthy and asthmatic subjects' blunt inflammation in vitro, implicating serum components in this immunomodulation. To identify the proteins orchestrating these effects, SOMAScan technology was employed to evaluate serum protein levels in healthy subjects following an overnight, 24-h fast and 3 h after refeeding. Partial least square discriminant analysis identified several serum proteins as potential candidates to confer feeding status immunomodulation. The characterization of recombinant IGFBP1 (elevated following 24 h of fasting) and PYY (elevated following refeeding) in primary human CD4(+) T cells found that they blunted and induced immune activation, respectively. Furthermore, integrated univariate serum protein analysis compared to RNA-seq analysis from peripheral blood mononuclear cells identified the induction of IL1RL1 and MFGE8 levels in refeeding compared to the 24-h fasting in the same study. Subsequent quantitation of these candidate proteins in lean versus obese individuals identified an inverse regulation of serum levels in the fasted subjects compared to the obese subjects. In parallel, IL1RL1 and MFGE8 supplementation promoted increased CD4(+) T responsiveness to T cell receptor activation. Together, these data show that caloric load-linked conditions evoke serological protein changes, which in turn confer biological effects on circulating CD4(+) T cell immune responsiveness. Han, Kim Singh, Komudi Rodman, Matthew J Hassanzadeh, Shahin Baumer, Yvonne Huffstutler, Rebecca D Chen, Jinguo Candia, Julian Cheung, Foo Stagliano, Katherine E R Pirooznia, Mehdi Powell-Wiley, Tiffany M Sack, Michael N eng Validation Study Switzerland Nutrients. Apr 28;13(5):. doi: 10./nu.I SomaScan 05/01/ Ramaswamy A, et al. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children Immunity 54 5 - e7 https://www.doi.org/10./j.immuni..04.003 33,891,889 Adolescent Alarmins/immunology Autoantibodies/immunology CD8-Positive T-Lymphocytes/immunology COVID-19/*immunology/*pathology Child Child, Preschool Cytotoxicity, Immunologic/genetics Endothelium/immunology/pathology Humans Killer Cells, Natural/immunology Myeloid Cells/immunology Plasma Cells/immunology Receptors, Antigen, T-Cell/genetics/immunology SARS-CoV-2/*immunology Severity of Illness Index Systemic Inflammatory Response Syndrome/*immunology/*pathology Mis-c SARS-CoV-2 Trbv11-2 alarmins cytotoxicity inflammation pediatric plasmablasts Squibb, Novartis, Sanofi, and Genentech. He has been a consultant for Bayer Pharmaceuticals, Bristol Myers Squibb, Compass Therapeutics, EMD Serono, Genentech, Juno Therapeutics, Novartis Pharmaceuticals, Proclara Biosciences, Sage Therapeutics, and Sanofi Genzyme. Further information regarding funding is available on: https://openpaymentsdata.cms.gov/physician//general-payments. N.K. reports personal fees from Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Indalo, Theravance, LifeMax, Three Lake Partners, RohBar in the last 36 months, and Equity in Pliant. N.K. is also a recipient of a grant from Veracyte and non-financial support from Miragen. All outside the submitted work In addition, N.K. has patents on New Therapies in Pulmonary Fibrosis and ARDS (unlicensed) and Peripheral Blood Gene Expression as biomarkers in IPF (licensed to biotech). S.H.K. receives consulting fees from Northrop Grumman. K.B.H. receives consulting fees from Prellis Biologics. B.S. is a former SomaLogic, Inc. (Boulder, CO, USA) employee and a company shareholder. All other authors declared that they have no competing interests. Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8(+) T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C. Ramaswamy, Anjali Brodsky, Nina N Sumida, Tomokazu S Comi, Michela Asashima, Hiromitsu Hoehn, Kenneth B Li, Ningshan Liu, Yunqing Shah, Aagam Ravindra, Neal G Bishai, Jason Khan, Alamzeb Lau, William Sellers, Brian Bansal, Neha Guerrerio, Pamela Unterman, Avraham Habet, Victoria Rice, Andrew J Catanzaro, Jason Chandnani, Harsha Lopez, Merrick Kaminski, Naftali Dela Cruz, Charles S Tsang, John S Wang, Zuoheng Yan, Xiting Kleinstein, Steven H van Dijk, David Pierce, Richard W Hafler, David A Lucas, Carrie L eng UL1 TR/TR/NCATS NIH HHS/ R21 AI/AI/NIAID NIH HHS/ R01 AI/AI/NIAID NIH HHS/ K08 HL/HL/NHLBI NIH HHS/ T32 AI/AI/NIAID NIH HHS/ R21 LM/LM/NLM NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Immunity. May 11;54(5):-.e7. doi: 10./j.immuni..04.003. Epub Apr 13.I SomaScan 04/24/ Renwick J, et al. Early Interleukin-22 and Neutrophil Proteins Are Correlated to Future Lung Damage in Children With Cystic Fibrosis Front Pediatr 9 https://www.doi.org/10./fped.. 33,869,115 biomarkers bronchoalveolar lavage cystic fibrosis neutrophils proteomics commercial or financial relationships that could be construed as a potential conflict of interest. Cystic Fibrosis (CF) lung damage begins early in life. Lung function decline is associated with pulmonary infections, neutrophil infiltration and inflammation. In CF, neutrophils have an altered phenotype. In this pilot study, we aimed to determine if signals of dysfunctional neutrophil responses were evident early in life and whether these signals may be associated with lung damage in later childhood. We examined the pulmonary protein profiles of 14 clinical stable infants and pre-school children with CF employing the aptamer-based affinity platform, SOMAscan(R). High resolution computed tomography (HRCT) was performed on all children after age 6 years and Brody score calculated. A Spearman's rank order correlation analysis and Benjamini-Hochberg adjustment was used to correlate protein concentrations in early life to Brody scores in later childhood. Early life concentrations of azurocidin and myeloperoxidase, were positively correlated with Brody score after age 6 (p = 0. and p = 0., respectively). Four other neutrophil associated proteins; Complement C3 (p = 0.), X-ray repair CCP 6 (p = 0.), C3a anaphylatoxin des Arginine (p = 0.) and cytokine receptor common subunit gamma (p = 0.) were all negatively correlated with Brody scores. Interestingly, patients with more severe lung damage after age 6 had significantly lower levels of IL-22 in early years of life (p = 0.). IL-22 has scarcely been reported to have implications in CF. Identification of early biomarkers that may predict more severe disease progression is particularly important for the future development of early therapeutic interventions in CF disease. We recommend further corroboration of these findings in prospective validation studies. Renwick, Julie Reece, Emma Walsh, Jamie Walsh, Ross Persaud, Thara O'Leary, Cathal Donnelly, Seamas C Greally, Peter eng Switzerland Front Pediatr. Mar 31;9:. doi: 10./fped... eCollection .I SomaScan 04/20/ Moin ASM, et al. Platelet Protein-Related Abnormalities in Response to Acute Hypoglycemia in Type 2 Diabetes Front Endocrinol (Lausanne) 12 https://www.doi.org/10./fendo.. 33,859,620 Aged Blood Platelet Disorders/*blood/*etiology Blood Platelets/*chemistry Blood Proteins/*analysis COVID-19/*blood/complications Case-Control Studies Diabetes Mellitus, Type 2/*blood/*complications Female Glucose Clamp Technique Humans Hypoglycemia/*blood/*complications Lipids/blood Male Middle Aged Platelet Activation Thromboembolism/blood/etiology Covid-19 SARS-CoV-2 obesity platelet type 2 diabetes commercial or financial relationships that could be construed as a potential conflict of interest. INTRODUCTION: Patients with severe COVID-19 infections have coagulation abnormalities indicative of a hypercoagulable state, with thromboembolic complications and increased mortality. Platelets are recognized as mediators of inflammation, releasing proinflammatory and prothrombotic factors, and are hyperactivated in COVID-19 infected patients. Activated platelets have also been reported in type 2 diabetes (T2D) patients, putting these patients at higher risk for thromboembolic complications of COVID-19 infection. METHODS: A case-control study of T2D (n=33) and control subjects (n=30) who underwent a hyperinsulinemic clamp to induce normoglycemia in T2D subjects: T2D: baseline glucose 7.5 +/- 0.3mmol/l (135.1 +/- 5.4mg/dl), reduced to 4.5 +/- 0.07mmol/l (81 +/- 1.2mg/dl) with 1-hour clamp; Controls: maintained at 5.1 +/- 0.1mmol/l (91.9 +/- 1.8mg/dl). Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was used to determine a panel of platelet proteins. RESULTS: Prothrombotic platelet proteins were elevated in T2D versus controls: platelet factor 4 (PF4, p<0.05); platelet glycoprotein VI (PGVI p<0.05); P-selectin (p<0.01) and plasminogen activator inhibitor I (PAI-1, p<0.01). In addition, the antithrombotic platelet-related proteins, plasmin (p<0.05) and heparin cofactor II (HCFII, p<0.05), were increased in T2D. Normalization of glucose in the T2D cohort had no effect on platelet protein levels. CONCLUSION: T2D patients have platelet hyperactivation, placing them at higher risk for thromboembolic events. When infected with COVID-19, this risk may be compounded, and their propensity for a more severe COVID-19 disease course increased. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT, identifier NCT. Moin, Abu Saleh Md Al-Qaissi, Ahmed Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Front Endocrinol (Lausanne). Mar 30;12:. doi: 10./fendo... eCollection .I SomaScan 04/17/ Gaziano L, et al. Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19 Nat Med 27 4 668-676 https://www.doi.org/10./s-021--z 33,837,377 Angiotensin-Converting Enzyme 2/genetics/physiology COVID-19/drug therapy/*genetics *Drug Repositioning Genome-Wide Association Study Humans Interleukin-10 Receptor beta Subunit/genetics/physiology Mendelian Randomization Analysis/*methods Quantitative Trait Loci Receptor, Interferon alpha-beta/genetics/physiology *SARS-CoV-2 Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 x 10(-6); IFNAR2, P = 9.8 x 10(-11) and IL-10RB, P = 2.3 x 10(-14)) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19. Gaziano, Liam Giambartolomei, Claudia Pereira, Alexandre C Gaulton, Anna Posner, Daniel C Swanson, Sonja A Ho, Yuk-Lam Iyengar, Sudha K Kosik, Nicole M Vujkovic, Marijana Gagnon, David R Bento, A Patricia Barrio-Hernandez, Inigo Ronnblom, Lars Hagberg, Niklas Lundtoft, Christian Langenberg, Claudia Pietzner, Maik Valentine, Dennis Gustincich, Stefano Tartaglia, Gian Gaetano Allara, Elias Surendran, Praveen Burgess, Stephen Zhao, Jing Hua Peters, James E Prins, Bram P Angelantonio, Emanuele Di Devineni, Poornima Shi, Yunling Lynch, Kristine E DuVall, Scott L Garcon, Helene Thomann, Lauren O Zhou, Jin J Gorman, Bryan R Huffman, Jennifer E O'Donnell, Christopher J Tsao, Philip S Beckham, Jean C Pyarajan, Saiju Muralidhar, Sumitra Huang, Grant D Ramoni, Rachel Beltrao, Pedro Danesh, John Hung, Adriana M Chang, Kyong-Mi Sun, Yan V Joseph, Jacob Leach, Andrew R Edwards, Todd L Cho, Kelly Gaziano, J Michael Butterworth, Adam S Casas, Juan P eng MR/L/1/MRC_/Medical Research Council/United Kingdom RG/13/13//BHF_/British Heart Foundation/United Kingdom MC_UU_/1/MRC_/Medical Research Council/United Kingdom /EC | EU Framework Programme for Research and Innovation H | H Priority Excellent Science | H Marie Sklodowska-Curie Actions (H Excellent Science - Marie Sklodowska-Curie Actions)/ I01 CX/CX/CSRD VA/ MR/S/2/MRC_/Medical Research Council/United Kingdom MC_UU_/7/MRC_/Medical Research Council/United Kingdom I01 BX/BX/BLRD VA/ /Z/16/Z/WT_/Wellcome Trust/United Kingdom MVP001/Department of Veteran Affairs/ RG/18/13//BHF_/British Heart Foundation/United Kingdom MVP035/Office of Research and Development, VA/ Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Nat Med. Apr;27(4):668-676. doi: 10./s-021--z. Epub Apr 9.I SomaScan 04/11/ Chen RY, et al. A Microbiota-Directed Food Intervention for Undernourished Children N Engl J Med 384 16 - https://www.doi.org/10./NEJMoa 33,826,814 Anthropometry Bangladesh Blood Proteins/analysis Body Weight *Dietary Supplements Feces/microbiology Female *Food, Formulated *Gastrointestinal Microbiome Growth Humans Infant *Infant Nutritional Physiological Phenomena Male Malnutrition/*diet therapy/microbiology Proteome Weight Gain BACKGROUND: More than 30 million children worldwide have moderate acute malnutrition. Current treatments have limited effectiveness, and much remains unknown about the pathogenesis of this condition. Children with moderate acute malnutrition have perturbed development of their gut microbiota. METHODS: In this study, we provided a microbiota-directed complementary food prototype (MDCF-2) or a ready-to-use supplementary food (RUSF) to 123 slum-dwelling Bangladeshi children with moderate acute malnutrition between the ages of 12 months and 18 months. The supplementation was given twice daily for 3 months, followed by 1 month of monitoring. We obtained weight-for-length, weight-for-age, and length-for-age z scores and mid-upper-arm circumference values at baseline and every 2 weeks during the intervention period and at 4 months. We compared the rate of change of these related phenotypes between baseline and 3 months and between baseline and 4 months. We also measured levels of proteins in plasma and 209 bacterial taxa in fecal samples. RESULTS: A total of 118 children (59 in each study group) completed the intervention. The rates of change in the weight-for-length and weight-for-age z scores are consistent with a benefit of MDCF-2 on growth over the course of the study, including the 1-month follow-up. Receipt of MDCF-2 was linked to the magnitude of change in levels of 70 plasma proteins and of 21 associated bacterial taxa that were positively correlated with the weight-for-length z score (P<0.001 for comparisons of both protein and bacterial taxa). These proteins included mediators of bone growth and neurodevelopment. CONCLUSIONS: These findings provide support for MDCF-2 as a dietary supplement for young children with moderate acute malnutrition and provide insight into mechanisms by which this targeted manipulation of microbiota components may be linked to growth. (Supported by the Bill and Melinda Gates Foundation and the National Institutes of Health; ClinicalTrials.gov number, NCT.). Chen, Robert Y Mostafa, Ishita Hibberd, Matthew C Das, Subhasish Mahfuz, Mustafa Naila, Nurun N Islam, M Munirul Huq, Sayeeda Alam, M Ashraful Zaman, Mahabub U Raman, Arjun S Webber, Daniel Zhou, Cyrus Sundaresan, Vinaik Ahsan, Kazi Meier, Martin F Barratt, Michael J Ahmed, Tahmeed Gordon, Jeffrey I eng R01 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ F30 DK/DK/NIDDK NIH HHS/ T32 GM/GM/NIGMS NIH HHS/ DK/DK/NIDDK NIH HHS/ Comparative Study Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't N Engl J Med. Apr 22;384(16):-. doi: 10./NEJMoa. Epub Apr 7.I SomaScan 04/08/ Larson A, et al. Plasma Proteomic Profiling in Hypertrophic Cardiomyopathy Patients before and after Surgical Myectomy Reveals Post-Procedural Reduction in Systemic Inflammation Int J Mol Sci 22 5 https://www.doi.org/10./ijms 33,804,404 Adult Aged Biomarkers/*blood Cardiac Surgical Procedures/*methods Cardiomyopathy, Hypertrophic/metabolism/pathology/*surgery Female Humans Inflammation/blood/*prevention & control Male Middle Aged Proteome/*analysis aptamer cardiovascular disease hypertrophic cardiomyopathy myectomy surgery proteomics design of the study in the collection, analyses, or interpretation of data in the writing of the manuscript, or in the decision to publish the results. Left Ventricular Outflow Tract (LVOT) obstruction occurs in approximately 70% of Hypertrophic Cardiomyopathy (HCM) patients and currently requires imaging or invasive testing for diagnosis, sometimes in conjunction with provocative physiological or pharmaceutical stimuli. To identify potential biomarkers of LVOT obstruction, we performed proteomics profiling of plasma proteins in 12 HCM patients with documented LVOT obstruction, referred for surgical myectomy. Plasma was collected at the surgical preoperative visit, approximately one month prior to surgery and then at the post-surgical visit, approximately 3 months later. Proteomic profiles were generated using the aptamer-based SOMAscan assay. Principal Component Analysis using the highest statistically significant proteins separated all preoperative samples from all postoperative samples. Further analysis revealed a set of 25 proteins that distinguished the preoperative and postoperative states with a paired t-test p-value of <0.01. Ingenuity Pathway analysis facilitated the generation of protein interaction networks and the elucidation of key upstream regulators of differentially expressed proteins, such as interferon-gamma, TGF-beta1, and TNF. Biological pathways affected by surgery included organ inflammation, migration, and motility of leukocytes, fibrosis, vasculogenesis, angiogenesis, acute coronary events, endothelial proliferation, eicosanoid metabolism, calcium flux, apoptosis, and morphology of the cardiovascular system. Our results indicate that surgical relief of dynamic outflow tract obstruction in HCM patients is associated with unique alterations in plasma proteomic profiles that likely reflect improvement in organ inflammation and physiological function. Larson, Amy Libermann, Towia A Bowditch, Heather Das, Gaurav Diakos, Nikolaos Huggins, Gordon S Rastegar, Hassan Chen, Frederick Y Rowin, Ethan J Maron, Martin S Chin, Michael T eng UL1 TR/TR/NCATS NIH HHS/ F32HL/NH/NIH HHS/ UL1TR/NH/NIH HHS/ 18IPA/American Heart Association/ Switzerland Int J Mol Sci. Mar 1;22(5):. doi: 10./ijms.I SomaScan 04/04/ Mills RJ, et al. BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection Cell 184 8 - e22 https://www.doi.org/10./j.cell..03.026 33,811,809 Angiotensin-Converting Enzyme 2/metabolism Animals COVID-19/*complications/drug therapy Cardiotonic Agents/*therapeutic use Cell Cycle Proteins/*antagonists & inhibitors/metabolism Cell Line Cytokines/metabolism Female Heart Diseases/*drug therapy/etiology Human Embryonic Stem Cells Humans Inflammation/complications/drug therapy Mice Mice, Inbred C57BL Quinazolinones/*therapeutic use Transcription Factors/*antagonists & inhibitors/metabolism Bromodomain and extraterminal family inhibitors Covid-19 drug discovery heart inflammation organoids co-inventors on patents relating to cardiac organoid maturation and cardiac therapeutics. J.E.H. is co-inventor on licensed patents for engineered heart muscle. R.J.M., E.R.P., D.M.T., B.G., and J.E.H. are co-founders, scientific advisors, and stockholders in Dynomics. D.M.T. and B.G. are employees of Dynomics. C.H., D.G., L.F., J.J., M.S., N.C.W.W., and E.K. are employees of Resverlogix. S.J.N. received honoraria and research support from Resverlogix. QIMR Berghofer Medical Research Institute filed a patent on the use of BETi. Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory cytokine-storm", a cocktail of interferon gamma, interleukin 1beta, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage." Mills, Richard J Humphrey, Sean J Fortuna, Patrick R J Lor, Mary Foster, Simon R Quaife-Ryan, Gregory A Johnston, Rebecca L Dumenil, Troy Bishop, Cameron Rudraraju, Rajeev Rawle, Daniel J Le, Thuy Zhao, Wei Lee, Leo Mackenzie-Kludas, Charley Mehdiabadi, Neda R Halliday, Christopher Gilham, Dean Fu, Li Nicholls, Stephen J Johansson, Jan Sweeney, Michael Wong, Norman C W Kulikowski, Ewelina Sokolowski, Kamil A Tse, Brian W C Devilee, Lynn Voges, Holly K Reynolds, Liam T Krumeich, Sophie Mathieson, Ellen Abu-Bonsrah, Dad Karavendzas, Kathy Griffen, Brendan Titmarsh, Drew Elliott, David A McMahon, James Suhrbier, Andreas Subbarao, Kanta Porrello, Enzo R Smyth, Mark J Engwerda, Christian R MacDonald, Kelli P A Bald, Tobias James, David E Hudson, James E eng Research Support, Non-U.S. Gov't Cell. Apr 15;184(8):-.e22. doi: 10./j.cell..03.026. Epub Mar 16.I SomaScan 04/04/ Huang J, et al. Advances in Aptamer-Based Biomarker Discovery Front Cell Dev Biol 9 https://www.doi.org/10./fcell.. 33,796,540 Cell-selex SOMAScan aptamer biomarker discovery human diseases commercial or financial relationships that could be construed as a potential conflict of interest. The discovery and identification of biomarkers promote the rational and fast development of medical diagnosis and therapeutics. Clinically, the application of ideal biomarkers still is limited due to the suboptimal technology in biomarker discovery. Aptamers are single-stranded deoxyribonucleic acid or ribonucleic acid molecules and can selectively bind to varied targets with high affinity and specificity. Compared with antibody, aptamers have desirable advantages, such as flexible design, easy synthesis and convenient modification with different functional groups. Currently, different aptamer-based technologies have been developed to facilitate biomarker discovery, especially CELL-SELEX and SOMAScan technology. CELL-SELEX technology is mainly used to identify cell membrane surface biomarkers of various cells. SOMAScan technology is an unbiased biomarker detection method that can analyze numerous and even thousands of proteins in complex biological samples at the same time. It has now become a large-scale multi-protein biomarker discovery platform. In this review, we introduce the aptamer-based biomarker discovery technologies, and summarize and highlight the discovered emerging biomarkers recently in several diseases. Huang, Jie Chen, Xinxin Fu, Xuekun Li, Zheng Huang, Yuhong Liang, Chao eng Review Switzerland Front Cell Dev Biol. Mar 16;9:. doi: 10./fcell... eCollection .I SomaScan 04/03/ Shi L, et al. Replication study of plasma proteins relating to Alzheimer's pathology Alzheimers Dement 17 9 - https://www.doi.org/10./alz. 33,792,144 Aged *Alzheimer Disease/blood/pathology Amyloid beta-Peptides/*blood Apolipoprotein E4/blood/genetics Biomarkers/*blood *Blood Proteins Cognitive Dysfunction/blood/pathology Europe Female Humans Male Middle Aged *Proteomics tau Proteins/*blood ATN framework Alzheimer's disease biomarker dementia network analysis plasma proteomics replication INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E epsilon4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis." Shi, Liu Winchester, Laura M Westwood, Sarah Baird, Alison L Anand, Sneha N Buckley, Noel J Hye, Abdul Ashton, Nicholas J Bos, Isabelle Vos, Stephanie J B Kate, Mara Ten Scheltens, Philip Teunissen, Charlotte E Vandenberghe, Rik Gabel, Silvy Meersmans, Karen Engelborghs, Sebastiaan De Roeck, Ellen E Sleegers, Kristel Frisoni, Giovanni B Blin, Olivier Richardson, Jill C Bordet, Regis Molinuevo, Jose L Rami, Lorena Wallin, Anders Kettunen, Petronella Tsolaki, Magda Verhey, Frans Lleo, Alberto Sala, Isabel Popp, Julius Peyratout, Gwendoline Martinez-Lage, Pablo Tainta, Mikel Johannsen, Peter Freund-Levi, Yvonne Frolich, Lutz Dobricic, Valerija Legido-Quigley, Cristina Barkhof, Frederik Andreasson, Ulf Blennow, Kaj Zetterberg, Henrik Streffer, Johannes Lill, Christina M Bertram, Lars Visser, Pieter Jelle Kolb, Hartmuth C Narayan, Vaibhav A Lovestone, Simon Nevado-Holgado, Alejo J eng DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't Alzheimers Dement. Sep;17(9):-. doi: 10./alz.. Epub Mar 31.I SomaScan 04/02/ Moaddel R, et al. Proteomics in aging research: A roadmap to clinical, translational research Aging Cell 20 4 e https://www.doi.org/10./acel. 33,730,416 Aging/*blood/genetics Animals Biomarkers/blood Gene Expression Regulation Geroscience/methods Humans Hypoxia-Inducible Factor 1, alpha Subunit/blood MAP Kinase Signaling System/*genetics Mitogen-Activated Protein Kinases/blood Prognosis Proteome/*metabolism Proteomics/*methods Translational Research, Biomedical/*methods aging geroscience human proteomics The identification of plasma proteins that systematically change with age and, independent of chronological age, predict accelerated decline of health is an expanding area of research. Circulating proteins are ideal translational omics" since they are final effectors of physiological pathways and because physicians are accustomed to use information of plasma proteins as biomarkers for diagnosis, prognosis, and tracking the effectiveness of treatments. Recent technological advancements, including mass spectrometry (MS)-based proteomics, multiplexed proteomic assay using modified aptamers (SOMAscan), and Proximity Extension Assay (PEA, O-Link), have allowed for the assessment of thousands of proteins in plasma or other biological matrices, which are potentially translatable into new clinical biomarkers and provide new clues about the mechanisms by which aging is associated with health deterioration and functional decline. We carried out a detailed literature search for proteomic studies performed in different matrices (plasma, serum, urine, saliva, tissues) and species using multiple platforms. Herein, we identified 232 proteins that were age-associated across studies. Enrichment analysis of the 232 age-associated proteins revealed metabolic pathways previously connected with biological aging both in animal models and in humans, most remarkably insulin-like growth factor (IGF) signaling, mitogen-activated protein kinases (MAPK), hypoxia-inducible factor 1 (HIF1), cytokine signaling, Forkhead Box O (FOXO) metabolic pathways, folate metabolism, advance glycation end products (AGE), and receptor AGE (RAGE) metabolic pathway. Information on these age-relevant proteins, likely expanded and validated in longitudinal studies and examined in mechanistic studies, will be essential for patient stratification and the development of new treatments aimed at improving health expectancy." Moaddel, Ruin Ubaida-Mohien, Ceereena Tanaka, Toshiko Lyashkov, Alexey Basisty, Nathan Schilling, Birgit Semba, Richard D Franceschi, Claudio Gorospe, Myriam Ferrucci, Luigi eng K99 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ U01 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Review England Aging Cell. Apr;20(4):e. doi: 10./acel.. Epub Mar 17.I SomaScan 03/18/ Galbraith MD, et al. Seroconversion stages COVID19 into distinct pathophysiological states Elife 10 https://www.doi.org/10./eLife. 33,724,185 Biomarkers COVID-19/*epidemiology/immunology/metabolism/*virology Comorbidity Complement Activation/immunology Complement System Proteins/immunology Hematopoiesis Homeostasis Hospitalization Humans Hypoalbuminemia Interferons/metabolism Models, Biological *SARS-CoV-2 *Seroconversion Seroepidemiologic Studies Signal Transduction Covid19 Sars antibodies complement cytokines human immunology inflammation interferons interests declared, KS is a co-inventor on two patents related to JAK inhibition in COVID19: U.S. Provisional Patent Application Serial No. 62/992,855 entitled 'JAK1 Inhibition For Modulation Of Overdrive Anti-Viral Response To COVID-19' U.S. Provisional Patent Application Serial No. 62/993,749 entitled 'Compounds and Methods for Inhibition or Modulation of Viral Hypercytokinemia'. JE Reviewing editor, eLife, is a co-inventor on two patents related to JAK inhibition in COVID19: U.S. Provisional Patent Application Serial No. 62/992,855 entitled 'JAK1 Inhibition For Modulation Of Overdrive Anti-Viral Response To COVID-19' U.S. Provisional Patent Application Serial No. 62/993,749 entitled 'Compounds and Methods for Inhibition or Modulation of Viral Hypercytokinemia'. COVID19 is a heterogeneous medical condition involving diverse underlying pathophysiological processes including hyperinflammation, endothelial damage, thrombotic microangiopathy, and end-organ damage. Limited knowledge about the molecular mechanisms driving these processes and lack of staging biomarkers hamper the ability to stratify patients for targeted therapeutics. We report here the results of a cross-sectional multi-omics analysis of hospitalized COVID19 patients revealing that seroconversion status associates with distinct underlying pathophysiological states. Low antibody titers associate with hyperactive T cells and NK cells, high levels of IFN alpha, gamma and lambda ligands, markers of systemic complement activation, and depletion of lymphocytes, neutrophils, and platelets. Upon seroconversion, all of these processes are attenuated, observing instead increases in B cell subsets, emergency hematopoiesis, increased D-dimer, and hypoalbuminemia. We propose that seroconversion status could potentially be used as a biosignature to stratify patients for therapeutic intervention and to inform analysis of clinical trial results in heterogenous patient populations. Galbraith, Matthew D Kinning, Kohl T Sullivan, Kelly D Baxter, Ryan Araya, Paula Jordan, Kimberly R Russell, Seth Smith, Keith P Granrath, Ross E Shaw, Jessica R Dzieciatkowska, Monika Ghosh, Tusharkanti Monte, Andrew A D'Alessandro, Angelo Hansen, Kirk C Benett, Tellen D Hsieh, Elena Wy Espinosa, Joaquin M eng RM1GM/GM/NIGMS NIH HHS/ R01 AI/AI/NIAID NIH HHS/ R01AI/National Institute of Allergy and Infectious Diseases/ R01HL/HL/NHLBI NIH HHS/ R01HL/HL/NHLBI NIH HHS/ 3R01AI-01S1/National Institute of Allergy and Infectious Diseases/ UL1TR/TR/NCATS NIH HHS/ R21HL/HL/NHLBI NIH HHS/ 3UL1TR-03S2/TR/NCATS NIH HHS/ R35GM/GM/NIGMS NIH HHS/ P30CA/CA/NCI NIH HHS/ R01AI/National Institute of Allergy and Infectious Diseases/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Elife. Mar 16;10:e. doi: 10./eLife..I SomaScan 03/17/ Moin ASM, et al. Vitamin D Association With Macrophage-Derived Cytokines in Polycystic Ovary Syndrome: An Enhanced Risk of COVID-19 Infection? Front Endocrinol (Lausanne) 12 https://www.doi.org/10./fendo.. 33,716,989 Adult Biomarkers/analysis Blood Proteins/analysis Body Mass Index COVID-19/complications/*epidemiology/immunology Cross-Sectional Studies Cytokines/*metabolism Female Humans Macrophage Activation Macrophages/chemistry/*metabolism Polycystic Ovary Syndrome/complications/*epidemiology/immunology Risk Assessment Tandem Mass Spectrometry Vitamin D/blood Vitamin D Deficiency/complications/*epidemiology COVID-19 risk factors cytokines macrophage polycystic ovary disease vitamin D commercial or financial relationships that could be construed as a potential conflict of interest. BACKGROUND: Women with polycystic ovary syndrome (PCOS) often have vitamin D deficiency, a known risk factor for severe COVID-19 disease. Alveolar macrophage-derived cytokines contribute to the inflammation underlying pulmonary disease in COVID-19. We sought to determine if basal macrophage activation, as a risk factor for COVID-19 infection, was present in PCOS and, if so, was further enhanced by vitamin D deficiency. METHODS: A cross-sectional study in 99 PCOS and 68 control women who presented sequentially. Plasma levels of a macrophage-derived cytokine panel were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. Vitamin D was measured by tandem mass spectroscopy. RESULTS: Vitamin D was lower in PCOS women (p<0.) and correlated negatively with body mass index (BMI) in PCOS (r=0.28, p=0.). Basal macrophage activation markers CXCL5, CD163 and MMP9 were elevated, whilst protective CD200 was decreased (p<0.05); changes in these variables were related to, and fully accounted for, by BMI. PCOS and control women were then stratified according to vitamin D concentration. Vitamin D deficiency was associated with decreased CD80 and IFN-gamma in PCOS and IL-12 in both groups (p<0.05). These factors, important in initiating and maintaining the immune response, were again accounted for by BMI. CONCLUSION: Basal macrophage activation was higher in PCOS with macrophage changes related with increased infection risk associating with vitamin D; all changes were BMI dependent, suggesting that obese PCOS with vitamin D deficiency may be at greater risk of more severe COVID-19 infection, but that it is obesity-related rather than an independent PCOS factor. Moin, Abu Saleh Md Sathyapalan, Thozhukat Butler, Alexandra E Atkin, Stephen L eng Switzerland Front Endocrinol (Lausanne). Feb 25;12:. doi: 10./fendo... eCollection .I SomaScan 03/16/ Moin ASM, et al. Metabolic consequences of obesity on the hypercoagulable state of polycystic ovary syndrome Sci Rep 11 1 https://www.doi.org/10./s-021--y 33,674,695 Adult Biomarkers/*blood Body Mass Index Female Humans Inflammation/metabolism Insulin Resistance Obesity/*metabolism Polycystic Ovary Syndrome/*metabolism Risk Factors Young Adult Polycystic ovary syndrome (PCOS) women have a hypercoagulable state; however, whether this is intrinsically due to PCOS or, alternatively, a consequence of its metabolic complications is unclear. We determined plasma coagulation pathway protein levels in PCOS (n = 146) and control (n = 97) women recruited to a PCOS biobank. Circulating levels of a panel of 18 clotting pathway proteins were determined by Slow Off-rate Modified Aptamer-scan plasma protein measurement. Cohorts were age matched, though PCOS had elevated body mass index (p < 0.001), insulin (p < 0.001) and C-reactive protein (CRP) (p < 0.). Eight pro-coagulation proteins were elevated in PCOS: plasminogen activator inhibitor-1 (p < 0.), fibrinogen (p < 0.01), fibrinogen gamma chain (p < 0.), fibronectin (p < 0.01), von Willebrand factor (p < 0.05), D-dimer (p < 0.), P-selectin (p < 0.05), and plasma kallikrein (p < 0.001). However, two anticoagulant proteins, vitamin K-dependent protein-S (p < 0.) and heparin cofactor-II (p < 0.001) were elevated and prothrombin was decreased (p < 0.05). CRP, as a marker of inflammation, and insulin resistance (HOMA-IR) correlated with 11 and 6 of the clotting proteins, respectively (p < 0.05). When matched for BMI < 25 (16 PCOS, 53 controls) HOMA-IR remained elevated (p < 0.05) and heparin cofactor-II was increased (p < 0.05). In a multivariate analysis accounting for inflammation, insulin resistance and BMI, there was no correlation of PCOS with any of the coagulation proteins. The hypercoagulable state in PCOS is not intrinsic to the disease as it can be fully accounted for by BMI, inflammation and insulin resistance. Moin, Abu Saleh Md Sathyapalan, Thozhukat Diboun, Ilhame Elrayess, Mohamed A Butler, Alexandra E Atkin, Stephen L eng England Sci Rep. Mar 5;11(1):. doi: 10./s-021--y.I SomaScan 03/07/ Hanff TC, et al. Quantitative Proteomic Analysis of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction JACC Basic Transl Sci 6 2 89-99 https://www.doi.org/10./j.jacbts..11.011 33,665,511 ApoM, apolipoprotein M CI, confidence interval CILP2, cartilage intermediate layer protein 2 DM, diabetes mellitus HFpEF, heart failure with preserved ejection fraction HR, hazard ratio LASSO, least absolute shrinkage and selection operator apolipoprotein M diabetes heart failure mediation analysis proteomics Cohen is supported by K23-HL. Dr. Javaheri is supported by K08-HL. Dr. Zamani is supported by grant K23-HL-. Dr. Chirinos is supported by a research grant from Bristol-Myers Squibb and by grants R01-HL - 01A1, R61-HL-, R01-AG, 1R01-HL, P01-HL, R03-HL-01, and R56-HL. Dr. Javaheri has been named co-inventor on the patent application for the use of fusion protein nanodiscs for the treatment of heart failure. Drs. Zhao, Walsh, Maranville, Wang, Adam, Ramirez-Valle, Schafer, Seiffert, Gordon, and Cvijic own stock in Bristol-Myers Squibb. Dr. Cappola has received research funding from Bristol-Myers Squibb. Dr. Zamani has consulted for Vyaire. Dr. Chirinos has been a consultant for Sanifit, Microsoft, Fukuda-Denshi, Bristol-Myers Squibb, OPKO Healthcare, Ironwood Pharmaceuticals, Pfizer, Akros Pharma, Merck, Bayer, JNJ, and Edwards Life Sciences and received research grants from National Institutes of Health, American College of Radiology Network, Fukuda Denshi, Bristol-Myers Squibb, and Microsoft, and has been named as inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of heart failure and preserved ejection fraction. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p < 0.001) of the association between DM and the risk of cardiovascular death, aborted cardiac arrest, and heart failure hospitalization. Hanff, Thomas C Cohen, Jordana B Zhao, Lei Javaheri, Ali Zamani, Payman Prenner, Stuart B Rietzschel, Ernst Jia, Yi Walsh, Alice Maranville, Joseph Wang, Zhaoqing Adam, Leonard Ramirez-Valle, Francisco Schafer, Peter Seiffert, Dietmar Gordon, David A Cvijic, Mary E Cappola, Thomas P Chirinos, Julio A eng K08 HL/HL/NHLBI NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ JACC Basic Transl Sci. Feb 10;6(2):89-99. doi: 10./j.jacbts..11.011. eCollection Feb.I SomaScan 03/06/ Zhou S, et al. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity Nat Med 27 4 659-667 https://www.doi.org/10./s-021--1 33,633,408 2',5'-Oligoadenylate Synthetase/genetics/*physiology Aged Aged, 80 and over Animals COVID-19/*etiology/genetics Case-Control Studies Female *Genetic Predisposition to Disease Humans Interleukin-10 Receptor beta Subunit/genetics Male Mendelian Randomization Analysis Middle Aged Neanderthals Protein Isoforms/physiology Quantitative Trait Loci *SARS-CoV-2 Severity of Illness Index Whites To identify circulating proteins influencing Coronavirus Disease (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 x 10(-8)), hospitalization (OR = 0.61, P = 8 x 10(-8)) and susceptibility (OR = 0.78, P = 8 x 10(-6)). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development. Zhou, Sirui Butler-Laporte, Guillaume Nakanishi, Tomoko Morrison, David R Afilalo, Jonathan Afilalo, Marc Laurent, Laetitia Pietzner, Maik Kerrison, Nicola Zhao, Kaiqiong Brunet-Ratnasingham, Elsa Henry, Danielle Kimchi, Nofar Afrasiabi, Zaman Rezk, Nardin Bouab, Meriem Petitjean, Louis Guzman, Charlotte Xue, Xiaoqing Tselios, Chris Vulesevic, Branka Adeleye, Olumide Abdullah, Tala Almamlouk, Noor Chen, Yiheng Chasse, Michael Durand, Madeleine Paterson, Clare Normark, Johan Frithiof, Robert Lipcsey, Miklos Hultstrom, Michael Greenwood, Celia M T Zeberg, Hugo Langenberg, Claudia Thysell, Elin Pollak, Michael Mooser, Vincent Forgetta, Vincenzo Kaufmann, Daniel E Richards, J Brent eng MC_UU_/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Nat Med. Apr;27(4):659-667. doi: 10./s-021--1. Epub Feb 25.I SomaScan 02/27/ Zaghlool SB, et al. Revealing the role of the human blood plasma proteome in obesity using genetic drivers Nat Commun 12 1 https://www.doi.org/10./s-021--4 33,627,659 Adult Aged Body Mass Index Female Humans Lipid Metabolism/genetics/physiology Male Mendelian Randomization Analysis Middle Aged Obesity/genetics/*metabolism Proteome/*metabolism Proteomics/methods Blood circulating proteins are confounded readouts of the biological processes that occur in different tissues and organs. Many proteins have been linked to complex disorders and are also under substantial genetic control. Here, we investigate the associations between over blood circulating proteins and body mass index (BMI) in three studies including over participants. We show that BMI is associated with widespread changes in the plasma proteome. We observe 152 replicated protein associations with BMI. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with LEPR/LEP, IGFBP1, and WFIKKN2, a protein-to-BMI relationship for AGER, DPT, and CTSA, and a BMI-to-protein relationship for another 21 proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets further elucidating the role of these proteins in obesity associated pathologies. Zaghlool, Shaza B Sharma, Sapna Molnar, Megan Matias-Garcia, Pamela R Elhadad, Mohamed A Waldenberger, Melanie Peters, Annette Rathmann, Wolfgang Graumann, Johannes Gieger, Christian Grallert, Harald Suhre, Karsten eng Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. Feb 24;12(1):. doi: 10./s-021--4.I SomaScan 02/26/ Hewitson L, et al. Blood biomarker discovery for autism spectrum disorder: A proteomic analysis PLoS One 16 2 e https://www.doi.org/10./journal.pone. 33,626,076 Algorithms Area Under Curve Autism Spectrum Disorder/*metabolism Biomarkers/metabolism Communication Humans Machine Learning Proteomics/*methods Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and social interaction and restricted, repetitive patterns of behavior, interests, or activities. Given the lack of specific pharmacological therapy for ASD and the clinical heterogeneity of the disorder, current biomarker research efforts are geared mainly toward identifying markers for determining ASD risk or for assisting with a diagnosis. A wide range of putative biological markers for ASD is currently being investigated. Proteomic analyses indicate that the levels of many proteins in plasma/serum are altered in ASD, suggesting that a panel of proteins may provide a blood biomarker for ASD. Serum samples from 76 boys with ASD and 78 typically developing (TD) boys, 18 months-8 years of age, were analyzed to identify possible early biological markers for ASD. Proteomic analysis of serum was performed using SomaLogic's SOMAScanTM assay 1.3K platform. A total of 1,125 proteins were analyzed. There were 86 downregulated proteins and 52 upregulated proteins in ASD (FDR < 0.05). Combining three different algorithms, we found a panel of 9 proteins that identified ASD with an area under the curve (AUC) = 0.+/-0., with specificity and sensitivity of 0.+/-0. and 0.835+/-0., respectively. All 9 proteins were significantly different in ASD compared with TD boys, and were significantly correlated with ASD severity as measured by ADOS total scores. Using machine learning methods, a panel of serum proteins was identified that may be useful as a blood biomarker for ASD in boys. Further verification of the protein biomarker panel with independent test sets is warranted. Hewitson, Laura Mathews, Jeremy A Devlin, Morgan Schutte, Claire Lee, Jeon German, Dwight C eng Research Support, Non-U.S. Gov't PLoS One. Feb 24;16(2):e. doi: 10./journal.pone.. eCollection .I SomaScan 02/25/ Ziemba M, et al. Biomarker-focused multi-drug combination therapy and repurposing trial in mdx mice PLoS One 16 2 e https://www.doi.org/10./journal.pone. 33,617,542 Aminoisobutyric Acids/therapeutic use Animals Biomarkers Disease Models, Animal Drug Repositioning Male Mice Mice, Inbred mdx Muscular Dystrophy, Animal/*drug therapy Muscular Dystrophy, Duchenne/*drug therapy Prednisolone/therapeutic use Pregnadienediols/therapeutic use Rituximab/therapeutic use Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFkB activation, mitochondrial dysfunction, and induction of TGFbeta fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, beta-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFkappaB and TGFbeta cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies. Ziemba, Michael Barkhouse, Molly Uaesoontrachoon, Kitipong Giri, Mamta Hathout, Yetrib Dang, Utkarsh J Gordish-Dressman, Heather Nagaraju, Kanneboyina Hoffman, Eric P eng Research Support, Non-U.S. Gov't PLoS One. Feb 22;16(2):e. doi: 10./journal.pone.. eCollection .I SomaScan 02/23/ Hernandez Cordero AI, et al. Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19 Hum Genet 140 6 969-979 https://www.doi.org/10./s-021--5 33,604,698 ABO Blood-Group System/metabolism Blood Proteins/*metabolism COVID-19/*epidemiology/metabolism/virology Cohort Studies *Genetic Predisposition to Disease Genome-Wide Association Study Humans Lung/*metabolism Mendelian Randomization Analysis *Polymorphism, Single Nucleotide *Quantitative Trait Loci Risk Factors SARS-CoV-2/*isolation & purification SARS-CoV-2 is responsible for the coronavirus disease (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We, therefore, used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n = 1,038) and eQTLGen (n = 31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n = 3,301) with COVID-19 loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). The expression of 18 genes in lung and/or blood co-localized with COVID-19 loci. Of these, 12 genes were in suggestive loci (P(GWAS) < 5 x 10(-05)). LZTFL1, SLC6A20, ABO, IL10RB and IFNAR2 and OAS1 had been previously associated with a heightened risk of COVID-19 (P(GWAS) < 5 x 10(-08)). We identified a causal association between OAS1 and COVID-19 GWAS. Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in the MR analysis; increased plasma levels were associated with an increased risk of COVID-19 and, in particular, severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigations. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19. Hernandez Cordero, Ana I Li, Xuan Milne, Stephen Yang, Chen Xi Bosse, Yohan Joubert, Philippe Timens, Wim van den Berge, Maarten Nickle, David Hao, Ke Sin, Don D eng Germany Hum Genet. Jun;140(6):969-979. doi: 10./s-021--5. Epub Feb 19.I SomaScan 02/20/ Skuladottir AT, et al. A meta-analysis uncovers the first sequence variant conferring risk of Bell's palsy Sci Rep 11 1 https://www.doi.org/10./s-021--w 33,602,968 Adult Aged Bell Palsy/*genetics Facial Muscles/pathology Facial Nerve/pathology Facial Paralysis/genetics Female Genome-Wide Association Study/methods Humans Inflammation/genetics Male Middle Aged Movement/physiology Prospective Studies Risk Bell's palsy is the most common cause of unilateral facial paralysis and is defined as an idiopathic and acute inability to control movements of the facial muscles on the affected side. While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. Reported heritability estimates of 4-14% suggest a genetic component in the etiology and an autosomal dominant inheritance has been proposed. Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell's palsy (rs-A; P = 6.79 x 10(-23), OR = 1.23; N(cases) = , N(controls) = 1,011,520). The variant also confers risk of intervertebral disc disorders (P = 2.99 x 10(-11), OR = 1.04) suggesting a common pathogenesis in part or a true pleiotropy. Skuladottir, Astros Th Bjornsdottir, Gyda Thorleifsson, Gudmar Walters, G Bragi Nawaz, Muhammad Sulaman Moore, Kristjan Helgi Swerford Olason, Pall I Thorgeirsson, Thorgeir E Sigurpalsdottir, Brynja Sveinbjornsson, Gardar Eggertsson, Hannes P Magnusson, Sigurdur H Oddsson, Asmundur Bjornsdottir, Anna Vikingsson, Arnor Sveinsson, Olafur A Hrafnsdottir, Maria G Sigurdardottir, Gudrun R Halldorsson, Bjarni V Hansen, Thomas Folkmann Paarup, Helene Erikstrup, Christian Nielsen, Kaspar Klokker, Mads Bruun, Mie Topholm Sorensen, Erik Banasik, Karina Burgdorf, Kristoffer S Pedersen, Ole Birger Ullum, Henrik Jonsdottir, Ingileif Stefansson, Hreinn Stefansson, Kari eng R01 DE/DE/NIDCR NIH HHS/ Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. Feb 18;11(1):. doi: 10./s-021--w.I SomaScan 02/20/ Germain A, et al. In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling Proteomes 9 1 https://www.doi.org/10./proteomes 33,572,894 Me/cfs SOMAscan(R) adherens junction diagnosis ephrin-Eph pathway glucose immune metabolism plasma proteomics Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease with worldwide prevalence and limited therapies exclusively aimed at treating symptoms. To gain insights into the molecular disruptions in ME/CFS, we utilized an aptamer-based technology that quantified unique human proteins, allowing us to obtain the largest proteomics dataset yet available for this disease, detecting highly abundant proteins as well as rare proteins over a nine-log dynamic range. We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the extracellular matrix, the immune system and cell-cell communication. Outputs of pathway and cluster analyses robustly highlight the ephrin pathway, which is involved in cell-cell signaling and regulation of an expansive variety of biological processes, including axon guidance, angiogenesis, epithelial cell migration, and immune response. Receiver Operating Characteristic (ROC) curve analyses distinguish the plasma proteomes of ME/CFS patients from controls with a high degree of accuracy (Area Under the Curve (AUC) > 0.85), and even higher when using protein ratios (AUC up to 0.95), that include some protein pairs with established biological relevance. Our results illustrate the promise of plasma proteomics for diagnosing and deciphering the molecular basis of ME/CFS. Germain, Arnaud Levine, Susan M Hanson, Maureen R eng U54 NS/NS/NINDS NIH HHS/ R01AI/National Institute of Allergy and Infectious Diseases/ Seed funds/Cornell University/ Switzerland Proteomes. Jan 29;9(1):6. doi: 10./proteomes.I SomaScan 02/13/ Richardson TG, et al. Evaluating the effects of cardiometabolic exposures on circulating proteins which may contribute to severe SARS-CoV-2 EBioMedicine 64 https://www.doi.org/10./j.ebiom.. 33,548,839 Biomarkers/blood Body Mass Index C-Reactive Protein/genetics/metabolism COVID-19/*blood/genetics Cardiovascular Diseases/*blood/genetics Female Genome-Wide Association Study Humans Interleukin-1/blood/genetics Interleukin-6/blood/genetics Male SARS-CoV-2/genetics/*metabolism Severity of Illness Index Cardiometabolic risk factors Circulating proteins Covid19 Mendelian randomization SARS-CoV-2 research, and in adherence to the University of Oxford's Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies. All other authors declare no conflicts of interest. BACKGROUND: Developing insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to overcome the global pandemic caused by coronavirus disease (covid-19). In this study, we have applied Mendelian randomization (MR) to systematically evaluate the effect of 10 cardiometabolic risk factors and genetic liability to lifetime smoking on 97 circulating host proteins postulated to either interact or contribute to the maladaptive host response of SARS-CoV-2. METHODS: We applied the inverse variance weighted (IVW) approach and several robust MR methods in a two-sample setting to systemically estimate the genetically predicted effect of each risk factor in turn on levels of each circulating protein. Multivariable MR was conducted to simultaneously evaluate the effects of multiple risk factors on the same protein. We also applied MR using cis-regulatory variants at the genomic location responsible for encoding these proteins to estimate whether their circulating levels may influence severe SARS-CoV-2. FINDINGS: In total, we identified evidence supporting 105 effects between risk factors and circulating proteins which were robust to multiple testing corrections and sensitivity analyzes. For example, body mass index provided evidence of an effect on 23 circulating proteins with a variety of functions, such as inflammatory markers c-reactive protein (IVW Beta=0.34 per standard deviation change, 95% CI=0.26 to 0.41, P = 2.19 x 10(-16)) and interleukin-1 receptor antagonist (IVW Beta=0.23, 95% CI=0.17 to 0.30, P = 9.04 x 10(-12)). Further analyzes using multivariable MR provided evidence that the effect of BMI on lowering immunoglobulin G, an antibody class involved in protection from infection, is substantially mediated by raised triglycerides levels (IVW Beta=-0.18, 95% CI=-0.25 to -0.12, P = 2.32 x 10(-08), proportion mediated=44.1%). The strongest evidence that any of the circulating proteins highlighted by our initial analysis influence severe SARS-CoV-2 was identified for soluble glycoprotein 130 (odds ratio=1.81, 95% CI=1.25 to 2.62, P = 0.002), a signal transductor for interleukin-6 type cytokines which are involved in inflammatory response. However, based on current case samples for severe SARS-CoV-2 we were unable to replicate findings in independent samples. INTERPRETATION: Our findings highlight several key proteins which are influenced by established exposures for disease. Future research to determine whether these circulating proteins mediate environmental effects onto risk of SARS-CoV-2 infection or covid-19 progression are warranted to help elucidate therapeutic strategies for severe covid-19 disease. FUNDING: The Medical Research Council, the Wellcome Trust, the British Heart Foundation and UK Research and Innovation. Richardson, Tom G Fang, Si Mitchell, Ruth E Holmes, Michael V Davey Smith, George eng MC_UU_/1/MRC_/Medical Research Council/United Kingdom MR/S/1/MRC_/Medical Research Council/United Kingdom Evaluation Study Netherlands EBioMedicine. Feb;64:. doi: 10./j.ebiom... Epub Feb 3.I SomaScan 02/07/ Matsuda K, et al. A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity J Clin Invest 131 5 https://www.doi.org/10./JCI 33,529,172 Adenoviruses, Human/*genetics/immunology/physiology Administration, Oral Adolescent Adult Antibodies, Neutralizing/blood Antibodies, Viral/blood Antigens, Viral/genetics Female *Genetic Vectors Hemagglutinin Glycoproteins, Influenza Virus/genetics/immunology Humans Immunity, Cellular Immunity, Humoral Immunity, Mucosal Influenza A Virus, H5N1 Subtype/genetics/immunology Influenza Vaccines/*administration & dosage/genetics/*immunology Influenza, Human/immunology/prevention & control Male Nasal Sprays Palatine Tonsil Virus Replication Virus Shedding Young Adult Adaptive immunity Beta cells Immunology Influenza Vaccines adenovirus type 4 SAR-CoV-2 vaccines and their use BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract-immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov NCT and NCT.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSNC). Matsuda, Kenta Migueles, Stephen A Huang, Jinghe Bolkhovitinov, Lyuba Stuccio, Sarah Griesman, Trevor Pullano, Alyssa A Kang, Byong H Ishida, Elise Zimmerman, Matthew Kashyap, Neena Martins, Kelly M Stadlbauer, Daniel Pederson, Jessica Patamawenu, Andy Wright, Nathaniel Shofner, Tulley Evans, Sean Liang, C Jason Candia, Julian Biancotto, Angelique Fantoni, Giovanna Poole, April Smith, Jon Alexander, Jeff Gurwith, Marc Krammer, Florian Connors, Mark eng HHSNC/AI/NIAID NIH HHS/ U19 AI/AI/NIAID NIH HHS/ Clinical Trial, Phase I Randomized Controlled Trial Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't J Clin Invest. Mar 1;131(5):e. doi: 10./JCI.I SomaScan 02/03/ Sebastiani P, et al. Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans Aging Cell 20 2 e https://www.doi.org/10./acel. 33,512,769 Aged Aged, 80 and over *Aging Blood Proteins/*metabolism Cellular Senescence Humans SomaLogic aging longevity protein senescence and stockholder of Regeneron Pharmaceuticals. Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians' offspring, and 65 age-matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified proteins that significantly differ between centenarians and their offspring and controls (FDR < 1%), and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with 2 independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age. The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence-associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence. Protein co-expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity. Sebastiani, Paola Federico, Anthony Morris, Melody Gurinovich, Anastasia Tanaka, Toshiko Chandler, Kevin B Andersen, Stacy L Denis, Gerald Costello, Catherine E Ferrucci, Luigi Jennings, Lori Glass, David J Monti, Stefano Perls, Thomas T eng F31 DE/DE/NIDCR NIH HHS/ S10-OD/NIH Office of the Director/ R24-GM/GM/NIGMS NIH HHS/ R01 AG/AG/NIA NIH HHS/ UH2 AG/AG/NIA NIH HHS/ U19 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Aging Cell. Feb;20(2):e. doi: 10./acel.. Epub Jan 29.I SomaScan 01/30/ AlGhatrif M, et al. Age-associated difference in circulating ACE2, the gateway for SARS-COV-2, in humans: results from the InCHIANTI study Geroscience 43 2 619-627 https://www.doi.org/10./s-020--w 33,462,706 Aged Angiotensin Receptor Antagonists Angiotensin-Converting Enzyme 2 Angiotensin-Converting Enzyme Inhibitors/therapeutic use *covid-19 Humans Italy/epidemiology *Peptidyl-Dipeptidase A SARS-CoV-2 Ace2 Aging Covid-19 Cardiovascular disease Levels of angiotensin-converting enzyme 2 (ACE2), the gateway for COVID-19 virus into the cells, have been implicated in worse COVID-19 outcomes associated with aging and cardiovascular disease (CVD). Data on age-associated differences in circulating ACE2 levels in humans and the role of CVD and medications is limited. We analyzed data from 967 participants of the InCHIANTI study, a community-dwelling cohort in the Chianti region, Italy. Relative abundance of ACE2 in plasma was assessed using a proteomics platform. CVD diagnoses, use of renin-angiotensin-aldosterone system (RAAS) antagonists: ACEi, ARBs, and aldosterone antagonists, were ascertained. Multiple linear analyses were performed to examine the independent association of ACE2 with age, CVD, and RAAS antagonist use. Age was independently associated with lower log (ACE2) in persons aged >/= 55 years (STD beta = - 0.12, p = 0.). ACEi treatment was also independently associated with significantly lower ACE2 levels, and ACE2 was inversely associated with weight, and positively associated with peripheral artery disease (PAD) status. There was a trend toward higher circulating ACE2 levels in hypertensive individuals, but it did not reach statistical significance. In a stratified analysis, the association between log (ACE2) and log (IL-6) was more evidenced in participants with PAD. Circulating ACE2 levels demonstrate curvilinear association with age, with older individuals beyond the sixth decade age having lower levels. ACEi was associated with greater circulating ACE2 levels. Interestingly, ACE2 was elevated in PAD and positively associated with inflammatory markers, suggesting compensatory upregulation in the setting of chronic inflammation. Further studies are needed to comprehensively characterize RAAS components with aging and disease, and assess its prognostic role in predicting COVID-19 outcomes. AlGhatrif, Majd Tanaka, Toshiko Moore, Ann Zenobia Bandinelli, Stefania Lakatta, Edward G Ferrucci, Luigi eng Research Support, N.I.H., Intramural Switzerland Geroscience. Apr;43(2):619-627. doi: 10./s-020--w. Epub Jan 18.I SomaScan 01/20/ Sharma R, et al. Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity J Clin Invest 131 2 https://www.doi.org/10./JCI 33,463,549 Adolescent Adult Aged Aged, 80 and over Alanine/blood Biomarkers/blood Child Child, Preschool Female Growth Differentiation Factor 15/blood Humans Hydroxybutyrates/blood Lactic Acid/blood MELAS Syndrome/*blood/genetics Male Middle Aged Mutation Severity of Illness Index Genetics Intermediary metabolism Metabolism Mitochondria Monogenic diseases Ret Hs6st1 sE-selectin integrated stress response creatine pyruvate 2-hydroxybutyrate alpha-hydroxybutyrate lactoyl-amino acids hydroxy-fatty acids hydroxy-acylcarnitines Mitochondrial disorders represent a large collection of rare syndromes that are difficult to manage both because we do not fully understand biochemical pathogenesis and because we currently lack facile markers of severity. The m.A>G variant is the most common heteroplasmic mitochondrial DNA mutation and underlies a spectrum of diseases, notably mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). To identify robust circulating markers of m.A>G disease, we first performed discovery proteomics, targeted metabolomics, and untargeted metabolomics on plasma from a deeply phenotyped cohort (102 patients, 32 controls). In a validation phase, we measured concentrations of prioritized metabolites in an independent cohort using distinct methods. We validated 20 analytes (1 protein, 19 metabolites) that distinguish patients with MELAS from controls. The collection includes classic (lactate, alanine) and more recently identified (GDF-15, alpha-hydroxybutyrate) mitochondrial markers. By mining untargeted mass-spectra we uncovered 3 less well-studied metabolite families: N-lactoyl-amino acids, beta-hydroxy acylcarnitines, and beta-hydroxy fatty acids. Many of these 20 analytes correlate strongly with established measures of severity, including Karnofsky status, and mechanistically, nearly all markers are attributable to an elevated NADH/NAD+ ratio, or NADH-reductive stress. Our work defines a panel of organelle function tests related to NADH-reductive stress that should enable classification and monitoring of mitochondrial disease. Sharma, Rohit Reinstadler, Bryn Engelstad, Kristin Skinner, Owen S Stackowitz, Erin Haller, Ronald G Clish, Clary B Pierce, Kerry Walker, Melissa A Fryer, Robert Oglesbee, Devin Mao, Xiangling Shungu, Dikoma C Khatri, Ashok Hirano, Michio De Vivo, Darryl C Mootha, Vamsi K eng F32 GM/GM/NIGMS NIH HHS/ P01 HD/HD/NICHD NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ Clinical Trial Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Clin Invest. Jan 19;131(2):e. doi: 10./JCI.I SomaScan 01/20/ Ngo LH, et al. Plasma protein expression profiles, cardiovascular disease, and religious struggles among South Asians in the MASALA study Sci Rep 11 1 961 https://www.doi.org/10./s-020--1 33,441,605 Aged Asian Americans/*psychology Biomarkers/blood/metabolism Blood Proteins/*metabolism Cardiovascular Diseases/*blood/*metabolism Case-Control Studies Cell Differentiation/physiology Female Humans Incidence Logistic Models Male Middle Aged Proteomics/methods Religion Risk Factors United States Blood protein concentrations are clinically useful, predictive biomarkers of cardiovascular disease (CVD). Despite a higher burden of CVD among U.S. South Asians, no CVD-related proteomics study has been conducted in this sub-population. The aim of this study is to investigate the associations between plasma protein levels and CVD incidence, and to assess the potential influence of religiosity/spirituality (R/S) on significant protein-CVD associations, in South Asians from the MASALA Study. We used a nested case-control design of 50 participants with incident CVD and 50 sex- and age-matched controls. Plasma samples were analyzed by SOMAscan for expression of proteins. Multivariable logistic regression models and model selection using Akaike Information Criteria were performed on the proteins and clinical covariates, with further effect modification analyses conducted to assess the influence of R/S measures on significant associations between proteins and incident CVD events. We identified 36 proteins that were significantly expressed differentially among CVD cases compared to matched controls. These proteins are involved in immune cell recruitment, atherosclerosis, endothelial cell differentiation, and vascularization. A final multivariable model found three proteins (Contactin-5 [CNTN5], Low affinity immunoglobulin gamma Fc region receptor II-a [FCGR2A], and Complement factor B [CFB]) associated with incident CVD after adjustment for diabetes (AUC = 0.82). Religious struggles that exacerbate the adverse impact of stressful life events, significantly modified the effect of Contactin-5 and Complement factor B on risk of CVD. Our research is this first assessment of the relationship between protein concentrations and risk of CVD in a South Asian sample. Further research is needed to understand patterns of proteomic profiles across diverse ethnic communities, and the influence of resources for resiliency on proteomic signatures and ultimately, risk of CVD. Ngo, Long H Austin Argentieri, M Dillon, Simon T Kent, Blake Victor Kanaya, Alka M Shields, Alexandra E Libermann, Towia A eng R01 HL/HL/NHLBI NIH HHS/ K24 HL/HL/NHLBI NIH HHS/ UL1 RR/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. Jan 13;11(1):961. doi: 10./s-020--1.I SomaScan 01/15/ Xu X, et al. Inhibition of the Complement Alternative Pathway by Chemically Modified DNA Aptamers That Bind with Picomolar Affinity to Factor B J Immunol 206 4 861-873 https://www.doi.org/10./jimmunol. 33,419,768 *Aptamers, Nucleotide/chemistry/immunology Complement C3/chemistry/immunology *Complement Factor B/chemistry/immunology *Complement Pathway, Alternative Humans The complement system is a conserved component of innate immunity that fulfills diverse roles in defense and homeostasis. Inappropriate activation of complement contributes to many inflammatory diseases, however, which has led to a renewed emphasis on development of therapeutic complement inhibitors. Activation of complement component C3 is required for amplification of complement and is achieved through two multisubunit proteases called C3 convertases. Of these, the alternative pathway (AP) C3 convertase is responsible for a majority of the C3 activation products in vivo, which renders it an attractive target for inhibitor discovery. In this study, we report the identification and characterization of two related slow off-rate modified DNA aptamers (SOMAmer) reagents that inhibit formation of the AP C3 convertase by binding to the proprotease, factor B (FB). These aptamers, known as SL (31 bases) and SL (29 bases), contain uniform substitutions of 5-(N-2-naphthylethylcarboxyamide)-2'-deoxyuridine for deoxythymidine. SL and SL bind FB with K (d) values of 49 and 88 pM, respectively, and inhibit activation of C3 and lysis of rabbit erythrocytes under AP-specific conditions. Cocrystal structures of SL (3.4 A) and SL (3.1 A) bound to human FB revealed that SL and SL recognize a site at the juncture of the CCP1, CCP3, and vWF domains of FB. Consistent with these structures and previously published information, these aptamers inhibited FB binding to C3b and blocked formation of the AP C3 convertase. Together, these results demonstrate potent AP inhibition by modified DNA aptamers and expand the pipeline of FB-binding molecules with favorable pharmacologic properties. Xu, Xin Zhang, Chi Denton, Dalton T O'Connell, Daniel Drolet, Daniel W Geisbrecht, Brian V eng R21 AI/AI/NIAID NIH HHS/ R21 NS/NS/NINDS NIH HHS/ Research Support, N.I.H., Extramural J Immunol. Feb 15;206(4):861-873. doi: 10./jimmunol.. Epub Jan 8.I SomaScan 01/10/ Abdel-Aziz MI, et al. Association of endopeptidases, involved in SARS-CoV-2 infection, with microbial aggravation in sputum of severe asthma Allergy 76 6 - https://www.doi.org/10./all. 33,411,967 *Asthma/diagnosis *covid-19 Endopeptidases Humans SARS-CoV-2 Sputum Abdel-Aziz, Mahmoud I Kermani, Nazanin Zounemat Neerincx, Anne H Vijverberg, Susanne J H Guo, Yike Howarth, Peter Dahlen, Sven-Erik Djukanovic, Ratko Sterk, Peter J Kraneveld, Aletta D Maitland-van der Zee, Anke H Chung, Kian Fan Adcock, Ian M eng /Innovative Medicines Initiative/ European Federation of Pharmaceutical Industries and Associations/ FP7/-/Seventh Framework Programme/ Letter Research Support, Non-U.S. Gov't Denmark Allergy. Jun;76(6):-. doi: 10./all.. Epub Jan 25.I SomaScan 01/08/ Ozen A, et al. Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease Nat Immunol 22 2 128-139 https://www.doi.org/10./s-020--z 33,398,182 Antibodies, Monoclonal, Humanized/adverse effects/pharmacokinetics/*therapeutic use Biomarkers/blood CD55 Antigens/deficiency/genetics Complement Activation/*drug effects Complement C5/*antagonists & inhibitors/metabolism Complement Inactivating Agents/adverse effects/pharmacokinetics/*therapeutic use Energy Metabolism/*drug effects Genetic Predisposition to Disease Humans Hypoproteinemia/*drug therapy/genetics/immunology/metabolism Immunity, Innate/*drug effects Mutation Phenotype Protein-Losing Enteropathies/*drug therapy/genetics/immunology/metabolism Treatment Outcome Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans. Ozen, Ahmet Kasap, Nurhan Vujkovic-Cvijin, Ivan Apps, Richard Cheung, Foo Karakoc-Aydiner, Elif Akkelle, Bilge Sari, Sinan Tutar, Engin Ozcay, Figen Uygun, Dilara Kocacik Islek, Ali Akgun, Gamze Selcuk, Merve Sezer, Oya Balci Zhang, Yu Kutluk, Gunsel Topal, Erdem Sayar, Ersin Celikel, Cigdem Houwen, Roderick H J Bingol, Aysen Ogulur, Ismail Eltan, Sevgi Bilgic Snow, Andrew L Lake, Camille Fantoni, Giovanna Alba, Camille Sellers, Brian Chauvin, Samuel D Dalgard, Clifton L Harari, Olivier Ni, Yan G Wang, Ming-Dauh Devalaraja-Narashimha, Kishor Subramanian, Poorani Ergelen, Rabia Artan, Reha Guner, Sukru Nail Dalgic, Buket Tsang, John Belkaid, Yasmine Ertem, Deniz Baris, Safa Lenardo, Michael J eng R01 GM/GM/NIGMS NIH HHS/ Z01 AI/ImNIH/Intramural NIH HHS/ Observational Study Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Nat Immunol. Feb;22(2):128-139. doi: 10./s-020--z. Epub Jan 4.I SomaScan 01/06/ Corlin L, et al. Proteomic Signatures of Lifestyle Risk Factors for Cardiovascular Disease: A Cross-Sectional Analysis of the Plasma Proteome in the Framingham Heart Study J Am Heart Assoc 10 1 e https://www.doi.org/10./JAHA.120. 33,372,532 *Alcohol Drinking/epidemiology/metabolism *Cardiovascular Diseases/blood/epidemiology/genetics Effect Modifier, Epidemiologic Exercise/*physiology Female Genome-Wide Association Study *Heart Disease Risk Factors Humans *Life Style Longitudinal Studies Male Middle Aged Mortality Proteomics/*methods Quantitative Trait Loci *Smoking/epidemiology/metabolism United States/epidemiology alcohol consumption lifestyle physical activity proteomics smoking Background Proteomic biomarkers related to cardiovascular disease risk factors may offer insights into the pathogenesis of cardiovascular disease. We investigated whether modifiable lifestyle risk factors for cardiovascular disease are associated with distinctive proteomic signatures. Methods and Results We analyzed circulating plasma proteomic biomarkers (assayed using the SomaLogic platform) in 897 FHS (Framingham Heart Study) Generation 3 participants (mean age 46+/-8 years; 56% women; discovery sample) and FOS (Framingham Offspring Study) participants (mean age 52 years; 54% women; validation sample). Participants were free of hypertension, diabetes mellitus, and clinical cardiovascular disease. We used linear mixed effects models (adjusting for age, sex, body mass index, and family structure) to relate levels of each inverse-log transformed protein to 3 lifestyle factors (ie, smoking, alcohol consumption, and physical activity). A Bonferroni-adjusted P value indicated statistical significance (based on number of proteins and traits tested, P<4.2x10(-6) in the discovery sample; P<6.85x10(-4) in the validation sample). We observed statistically significant associations of 60 proteins with smoking (37/40 top proteins validated in FOS), 30 proteins with alcohol consumption (23/30 proteins validated), and 5 proteins with physical activity (2/3 proteins associated with the physical activity index validated). We assessed the associations of protein concentrations with previously identified genetic variants (protein quantitative trait loci) linked to lifestyle-related disease traits in the genome-wide-association study catalogue. The protein quantitative trait loci were associated with coronary artery disease, inflammation, and age-related mortality. Conclusions Our cross-sectional study from a community-based sample elucidated distinctive sets of proteins associated with 3 key lifestyle factors. Corlin, Laura Liu, Chunyu Lin, Honghuang Leone, Dominick Yang, Qiong Ngo, Debby Levy, Daniel Cupples, L Adrienne Gerszten, Robert E Larson, Martin G Vasan, Ramachandran S eng P30 DK/DK/NIDDK NIH HHS/ N01HC/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ RF1 AG/AG/NIA NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ K12 HD/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England J Am Heart Assoc. Jan 5;10(1):e. doi: 10./JAHA.120.. Epub Dec 29.I SomaScan 12/30/ Idemoto K, et al. Platelet-derived growth factor BB: A potential diagnostic blood biomarker for differentiating bipolar disorder from major depressive disorder J Psychiatr Res 134 48-56 https://www.doi.org/10./j.jpsychires..12.051 33,360,224 Becaplermin Biomarkers *Bipolar Disorder/diagnosis/drug therapy Case-Control Studies Cross-Sectional Studies *Depressive Disorder, Major/diagnosis/drug therapy Humans Bipolar disorder Diagnostic biomarker Major depressive disorder Pdgf-bb Platelet-derived growth factor Sodium valproate Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case-control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD. Idemoto, Keita Ishima, Tamaki Niitsu, Tomihisa Hata, Tatsuki Yoshida, Sumiko Hattori, Kotaro Horai, Tadasu Otsuka, Ikuo Yamamori, Hidenaga Toda, Shigenobu Kameno, Yosuke Ota, Kiyomitsu Oda, Yasunori Kimura, Atsushi Hashimoto, Tasuku Mori, Norio Kikuchi, Mitsuru Minabe, Yoshio Hashimoto, Ryota Hishimoto, Akitoyo Nakagome, Kazuyuki Iyo, Masaomi Hashimoto, Kenji eng Multicenter Study Research Support, Non-U.S. Gov't England J Psychiatr Res. Feb;134:48-56. doi: 10./j.jpsychires..12.051. Epub Dec 21.I SomaScan 12/29/ Nounu A, et al. A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer Cancer Epidemiol Biomarkers Prev 30 3 564-575 https://www.doi.org/10./-.EPI-20- 33,318,029 Aspirin/pharmacology/*therapeutic use Colorectal Neoplasms/*drug therapy Humans Mendelian Randomization Analysis/*methods Proteomics/*methods Risk Factors BACKGROUND: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. METHODS: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). RESULTS: Altered expression was detected for 125/ proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively). CONCLUSIONS: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. IMPACT: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk. Nounu, Aayah Greenhough, Alexander Heesom, Kate J Richmond, Rebecca C Zheng, Jie Weinstein, Stephanie J Albanes, Demetrius Baron, John A Hopper, John L Figueiredo, Jane C Newcomb, Polly A Lindor, Noralane M Casey, Graham Platz, Elizabeth A Le Marchand, Loic Ulrich, Cornelia M Li, Christopher I van Duijnhoven, Franzel J B Gsur, Andrea Campbell, Peter T Moreno, Victor Vodicka, Pavel Vodickova, Ludmila Brenner, Hermann Chang-Claude, Jenny Hoffmeister, Michael Sakoda, Lori C Slattery, Martha L Schoen, Robert E Gunter, Marc J Castellvi-Bel, Sergi Kim, Hyeong Rok Kweon, Sun-Seog Chan, Andrew T Li, Li Zheng, Wei Bishop, D Timothy Buchanan, Daniel D Giles, Graham G Gruber, Stephen B Rennert, Gad Stadler, Zsofia K Harrison, Tabitha A Lin, Yi Keku, Temitope O Woods, Michael O Schafmayer, Clemens Van Guelpen, Bethany Gallinger, Steven Hampel, Heather Berndt, Sonja I Pharoah, Paul D P Lindblom, Annika Wolk, Alicja Wu, Anna H White, Emily Peters, Ulrike Drew, David A Scherer, Dominique Bermejo, Justo Lorenzo Williams, Ann C Relton, Caroline L eng R01 CA/CA/NCI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U10 CA/CA/NCI NIH HHS/ K05 CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ P30 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ P50 CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ R01 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ R35 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ P01 CA/CA/NCI NIH HHS/ P30 CA/CA/NCI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ P30 CA/CA/NCI NIH HHS/ U24 CA/CA/NCI NIH HHS/ P01 CA/CA/NCI NIH HHS/ S10 OD/OD/NIH HHS/ R01 CA/CA/NCI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R01 CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ /CRUK_/Cancer Research UK/United Kingdom R01 CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ HHSNC/WH/WHI NIH HHS/ MC_UU__2/MRC_/Medical Research Council/United Kingdom Z01 CP/ImNIH/Intramural NIH HHS/ U24 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ R21 CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ C/A/CRUK_/Cancer Research UK/United Kingdom R01 CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ P30 CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ P30 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ HHSNC/AG/NIA NIH HHS/ R01 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ P01 CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ UM1 CA/CA/NCI NIH HHS/ HHSNC/WH/WHI NIH HHS/ R01 CA/CA/NCI NIH HHS/ R03 CA/CA/NCI NIH HHS/ T32 ES/ES/NIEHS NIH HHS/ R01 CA/CA/NCI NIH HHS/ P30 CA/CA/NCI NIH HHS/ UM1 CA/CA/NCI NIH HHS/ K05 CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ WT_/Wellcome Trust/United Kingdom HHSNI/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ U01 CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ KL2 TR/TR/NCATS NIH HHS/ MR/R/1/MRC_/Medical Research Council/United Kingdom UM1 CA/CA/NCI NIH HHS/ K07 CA/CA/NCI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ /Z/19/Z/WT_/Wellcome Trust/United Kingdom U01 CA/CA/NCI NIH HHS/ R37 CA/CA/NCI NIH HHS/ HHSNC/WH/WHI NIH HHS/ HHSNC/WH/WHI NIH HHS/ R01 CA/CA/NCI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ U19 CA/CA/NCI NIH HHS/ U01 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Cancer Epidemiol Biomarkers Prev. Mar;30(3):564-575. doi: 10./-.EPI-20-. Epub Dec 14.I SomaScan 12/16/ Birkenbihl C, et al. ANMerge: A Comprehensive and Accessible Alzheimer's Disease Patient-Level Dataset J Alzheimers Dis 79 1 423-431 https://www.doi.org/10./JAD- 33,285,634 Aged Aged, 80 and over Alzheimer Disease/diagnostic imaging/genetics/metabolism/*physiopathology Cohort Studies *Datasets as Topic Female Gene Expression Profiling Genotype Humans Magnetic Resonance Imaging Male Proteomics AddNeuroMed Alzheimer's disease biomarkers cohort analysis data-driven science dataset dementia genome wide association studies multimodal (https://www.j-alz.com/manuscript-disclosures/20-r2 ). BACKGROUND: Accessible datasets are of fundamental importance to the advancement of Alzheimer's disease (AD) research. The AddNeuroMed consortium conducted a longitudinal observational cohort study with the aim to discover AD biomarkers. During this study, a broad selection of data modalities was measured including clinical assessments, magnetic resonance imaging, genotyping, transcriptomic profiling, and blood plasma proteomics. Some of the collected data were shared with third-party researchers. However, this data was incomplete, erroneous, and lacking in interoperability. OBJECTIVE: To provide the research community with an accessible, multimodal, patient-level AD cohort dataset. METHODS: We systematically addressed several limitations of the originally shared resources and provided additional unreleased data to enhance the dataset. RESULTS: In this work, we publish and describe ANMerge, a new version of the AddNeuroMed dataset. ANMerge includes multimodal data from 1,702 study participants and is accessible to the research community via a centralized portal. CONCLUSION: ANMerge is an information rich patient-level data resource that can serve as a discovery and validation cohort for data-driven AD research, such as, for example, machine learning and artificial intelligence approaches. Birkenbihl, Colin Westwood, Sarah Shi, Liu Nevado-Holgado, Alejo Westman, Eric Lovestone, Simon Hofmann-Apitius, Martin eng MC_PC_/MRC_/Medical Research Council/United Kingdom Department of Health (NIHR)/ Research Support, Non-U.S. Gov't Netherlands J Alzheimers Dis. ;79(1):423-431. doi: 10./JAD-.I SomaScan 12/09/ Suhre K, et al. Genetics meets proteomics: perspectives for large population-based studies Nat Rev Genet 22 1 19-37 https://www.doi.org/10./s-020--2 32,860,016 Biomarkers/analysis Blood Proteins/*analysis *Genome-Wide Association Study Humans Phenotype Proteome/*genetics *Proteomics Proteomic analysis of cells, tissues and body fluids has generated valuable insights into the complex processes influencing human biology. Proteins represent intermediate phenotypes for disease and provide insight into how genetic and non-genetic risk factors are mechanistically linked to clinical outcomes. Associations between protein levels and DNA sequence variants that colocalize with risk alleles for common diseases can expose disease-associated pathways, revealing novel drug targets and translational biomarkers. However, genome-wide, population-scale analyses of proteomic data are only now emerging. Here, we review current findings from studies of the plasma proteome and discuss their potential for advancing biomedical translation through the interpretation of genome-wide association analyses. We highlight the challenges faced by currently available technologies and provide perspectives relevant to their future application in large-scale biobank studies. Suhre, Karsten McCarthy, Mark I Schwenk, Jochen M eng Research Support, Non-U.S. Gov't Review England Nat Rev Genet. Jan;22(1):19-37. doi: 10./s-020--2. Epub Aug 28.I SomaScan 08/30/ O'Neil LJ, et al. Association of a Serum Protein Signature With Rheumatoid Arthritis Development Arthritis Rheumatol 73 1 78-88 https://www.doi.org/10./art. 32,770,634 Adolescent Adult Aged Anti-Citrullinated Protein Antibodies/immunology Arthritis, Rheumatoid/*blood/immunology *Asymptomatic Diseases Calreticulin/blood Disease Progression Female Humans *Indians, North American Interleukin-1/blood/immunology Lectins/blood Longitudinal Studies *Machine Learning Male Middle Aged *Proteomics Rheumatoid Factor/immunology Toll-Like Receptor 2/blood/immunology Tumor Necrosis Factor-alpha/blood/immunology Young Adult OBJECTIVE: The pathophysiologic events that precede the onset of rheumatoid arthritis (RA) remain incompletely understood. This study was undertaken to identify changes in the serum proteome that precede the onset of RA, with the aim of providing new insights into the pathogenic mechanisms that lead to its development. METHODS: In a cohort of first-degree relatives of Indigenous North American RA patients, the SomaScan proteomics platform was used to determine the levels of 1,307 proteins in multiple longitudinal serum samples from 17 individuals who were followed up prospectively to the time of disease onset. Proteomic signatures from this group of individuals (designated the progressor group) were compared to those in a group of individuals who were considered at risk of developing RA, stratified as either positive (n = 63) or negative (n = 47) for anti-citrullinated protein antibodies (ACPAs) (designated the at-risk group). Machine learning was used to identify a protein signature that could accurately classify those individuals at highest risk of future RA development. RESULTS: A preclinical proteomic signature that differentiated RA progressors from at-risk individuals, irrespective of ACPA status, was identified (area under the curve 0.913, accuracy 91.2%). Importantly, the predictive preclinical proteomic signature was present not only in serum samples obtained close to the onset of RA, but also in serum samples obtained a median of 30.9 months prior to onset. Network analysis implicated the activation of Toll-like receptor 2 and production of tumor necrosis factor and interleukin-1 as key events that precede RA progression. CONCLUSION: Alterations in the serum proteome in the preclinical phase of RA can emerge years prior to the onset of disease. Our findings suggest that the serum proteome provides a rich source of proteins serving both to classify at-risk individuals and to identify molecular pathways involved in the development of clinically detectable RA. O'Neil, Liam J Spicer, Victor Smolik, Irene Meng, Xiaobo Goel, Rishi R Anaparti, Vidyanand Wilkins, John El-Gabalawy, Hani S eng MOP /CIHR/Canada Research Support, Non-U.S. Gov't Arthritis Rheumatol. Jan;73(1):78-88. doi: 10./art.. Epub Nov 10.I SomaScan 08/10/ Fong TG, et al. Identification of Plasma Proteome Signatures Associated With Surgery Using SOMAscan Ann Surg 273 4 732-742 https://www.doi.org/10./SLA. 30,946,084 Aged Biomarkers/blood C-Reactive Protein/metabolism *Elective Surgical Procedures Enzyme-Linked Immunosorbent Assay Female Humans Length of Stay Male Postoperative Complications/*blood Proteome/*metabolism Proteomics/*methods OBJECTIVES: To characterize the proteomic signature of surgery in older adults and association with postoperative outcomes. SUMMARY OF BACKGROUND DATA: Circulating plasma proteins can reflect the physiological response to and clinical outcomes after surgery. METHODS: Blood plasma from older adults undergoing elective surgery was analyzed for proteins using SOMAscan. Surgery-associated proteins underwent Ingenuity Pathways Analysis. Selected surgery-associated proteins were independently validated using Luminex or enzyme-linked immunosorbent assay methods. Generalized linear models estimated correlations with postoperative outcomes. RESULTS: Plasma from a subcohort (n = 36) of the Successful Aging after Elective Surgery (SAGES) study was used for SOMAscan. Systems biology analysis of 110 proteins with Benjamini-Hochberg (BH) corrected P value =0.01 and an absolute foldchange (|FC|) >/=1.5 between postoperative day 2 (POD2) and preoperative (PREOP) identified functional pathways with major effects on pro-inflammatory proteins. Chitinase-3-like protein 1 (CHI3L1), C-reactive protein (CRP), and interleukin-6 (IL-6) were independently validated in separate validation cohorts from SAGES (n = 150 for CRP, IL-6; n = 126 for CHI3L1). Foldchange CHI3L1 and IL-6 were associated with increased postoperative complications [relative risk (RR) 1.50, 95% confidence interval (95% CI) 1.21-1.85 and RR 1.63, 95% CI 1.18-2.26, respectively], length of stay (RR 1.35, 95% CI 0.77-1.92 and RR 0.98, 95% CI 0.52-1.45), and risk of discharge to postacute facility (RR 1.15, 95% CI 1.04-1.26 and RR 1.11, 95% CI 1.04-1.18); POD2 and PREOP CRP difference was associated with discharge to postacute facility (RR 1.14, 95% CI 1.04-1.25). CONCLUSION: SOMAscan can identify novel and clinically relevant surgery-induced protein changes. Ultimately, proteomics may provide insights about pathways by which surgical stress contributes to postoperative outcomes. Fong, Tamara G Chan, Noel Y Dillon, Simon T Zhou, Wenxiao Tripp, Bridget Ngo, Long H Otu, Hasan H Inouye, Sharon K Vasunilashorn, Sarinnapha M Cooper, Zara Xie, Zhongcong Marcantonio, Edward R Libermann, Towia A eng R01 AG/AG/NIA NIH HHS/ R03 AG/AG/NIA NIH HHS/ K24 AG/AG/NIA NIH HHS/ K07 AG/AG/NIA NIH HHS/ K01 AG/AG/NIA NIH HHS/ T32 AT/AT/NCCIH NIH HHS/ P01 AG/AG/NIA NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ R21 AG/AG/NIA NIH HHS/ R24 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Ann Surg. Apr 1;273(4):732-742. doi: 10./SLA..I SomaScan 04/05/ Arthur L, et al. Cellular and plasma proteomic determinants of COVID-19 and non-COVID-19 pulmonary diseases relative to healthy aging Nature Aging 1 6 535-549 https://www.doi.org/10./s-021--x We examine the cellular and soluble determinants of coronavirus disease (COVID-19) relative to aging by performing mass cytometry in parallel with clinical blood testing and plasma proteomic profiling of ~4,700 proteins from 71 individuals with pulmonary disease and 148 healthy donors (25–80 years old). Distinct cell populations were associated with age (GZMK+CD8+ T cells and CD25low CD4+ T cells) and with COVID-19 (TBET_EOMES_ CD4+ T cells, HLA-DR+CD38+ CD8+ T cells and CD27+CD38+ B cells). A unique population of TBET+EOMES+ CD4+ T cells was associated with individuals with COVID-19 who experienced moderate, rather than severe or lethal, disease. Disease severity correlated with blood creatinine and urea nitrogen levels. Proteomics revealed a major impact of age on the disease-associated plasma signatures and highlighted the divergent contribution of hepatocyte and muscle secretomes to COVID-19 plasma proteins. Aging plasma was enriched in matrisome proteins and heart/aorta smooth muscle cell-specific proteins. These findings reveal age-specific and disease-specific changes associated with COVID-19, and potential soluble mediators of the physiological impact of COVID-19. Arthur, Laura Esaulova, Ekaterina Mogilenko, Denis A. Tsurinov, Petr Burdess, Samantha Laha, Anwesha Presti, Rachel Goetz, Brian Watson, Mark A. Goss, Charles W. Gurnett, Christina A. Mudd, Philip A. Beers, Courtney O’Halloran, Jane A. Artyomov, Maxim N. SomaScan Moin ASM, et al. Hypoglycemia-induced changes in complement pathways in type 2 diabetes Atherosclerosis Plus 46 35-45 https://www.doi.org/10./j.athplu..11.002 Hypoglycemia Type 2 diabetes Complement proteins Proteomics An association between hypoglycaemia and adverse cardiovascular events has been suggested from longitudinal and retrospective cohort studies. The complement pathway proteins in hypoglycemia are not well studied. Here, we hypothesized that these circulating proteins would be elevated in response to hypoglycemia in type 2 diabetes (T2D) through the inflammatory response. Moin, Abu Saleh Md Nandakumar, Manjula Diboun, Ilhame Al-Qaissi, Ahmed Sathyapalan, Thozhukat Atkin, Stephen L. Butler, Alexandra E. SomaScan Walker KA, et al. Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk Nature Aging 1 5 473-489 https://www.doi.org/10./s-021--0 The plasma proteomic changes that precede the onset of dementia could yield insights into disease biology and highlight new biomarkers and avenues for intervention. We quantified 4,877 plasma proteins in nondemented older adults in the Atherosclerosis Risk in Communities cohort and performed a proteome-wide association study of dementia risk over five years (n_=_4,110; 428 incident cases). Thirty-eight proteins were associated with incident dementia after Bonferroni correction. Of these, 16 were also associated with late-life dementia risk when measured in plasma collected nearly 20 years earlier, during mid-life. Two-sample Mendelian randomization causally implicated two dementia-associated proteins (SVEP1 and angiostatin) in Alzheimer’s disease. SVEP1, an immunologically relevant cellular adhesion protein, was found to be part of larger dementia-associated protein networks, and circulating levels were associated with atrophy in brain regions vulnerable to Alzheimer’s pathology. Pathway analyses for the broader set of dementia-associated proteins implicated immune, lipid, metabolic signaling and hemostasis pathways in dementia pathogenesis. Walker, Keenan A. Chen, Jingsha Zhang, Jingning Fornage, Myriam Yang, Yunju Zhou, Linda Grams, Morgan E. Tin, Adrienne Daya, Natalie Hoogeveen, Ron C. Wu, Aozhou Sullivan, Kevin J. Ganz, Peter Zeger, Scott L. Gudmundsson, Elias F. Emilsson, Valur Launer, Lenore J. Jennings, Lori L. Gudnason, Vilmundur Chatterjee, Nilanjan Gottesman, Rebecca F. Mosley, Thomas H. Boerwinkle, Eric Ballantyne, Christie M. Coresh, Josef SomaScan Morani F, et al. Functional Network Profiles in ARSACS Disclosed by Aptamer-Based Proteomic Technology Front Neurol 11 https://www.doi.org/10./fneur.. 33,584,503 Arsacs SomaLogic technology engulfment of cells neuroinflammation proteomic analysis sacsin synaptogenesis commercial or financial relationships that could be construed as a potential conflict of interest. Although the genetic basis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been uncovered, our poor understanding of disease mechanisms requires new light on functional pathways and modifying factors to improve early diagnostic strategies and offer alternative treatment options in a rare condition with no cure. Investigation of the pathologic state combining disease models and quantitative omic approach might improve biomarkers discovery with possible implications in patients' diagnoses. In this study, we analyzed proteomics data obtained using the SomaLogic technology, comparing cell lysates from ARSACS patients and from a SACS KO SH-SY5Y neuroblastoma cell model. Single-stranded deoxyoligonucleotides, selected in vitro from large random libraries, bound and quantified molecular targets related to the neuroinflammation signaling pathway and to neuronal development. Changes in protein levels were further analyzed by bioinformatics and network approaches to identify biomarkers of ARSACS and functional pathways impaired in the disease. We identified novel significantly dysregulated biological processes related to neuroinflammation, synaptogenesis, and engulfment of cells in patients and in KO cells compared with controls. Among the differential expressed proteins found in this work, we identified several proteins encoded by genes already known to be mutated in other forms of neurodegeneration. This finding suggests that common dysfunctional networks could be therapeutic targets for future investigations. Morani, Federica Doccini, Stefano Chiorino, Giovanna Fattori, Fabiana Galatolo, Daniele Sciarrillo, Elisa Gemignani, Federica Zuchner, Stephan Bertini, Enrico Silvio Santorelli, Filippo Maria eng Switzerland Front Neurol. Jan 27;11:. doi: 10./fneur... eCollection .I SomaScan 02/16/ Oyama Y, et al. Intense light as anticoagulant therapy in humans PLoS One 15 12 e https://www.doi.org/10./journal.pone. 33,382,840 Animals Blood Coagulation/*physiology Blood Platelets/*metabolism Humans Light Male Mice Myocardial Ischemia/blood/*metabolism Myocardial Reperfusion Injury/blood/*metabolism Period Circadian Proteins/genetics/*metabolism *Phototherapy Platelet Aggregation/physiology Proteomics Blood coagulation is central to myocardial ischemia and reperfusion (IR) injury. Studies on the light elicited circadian rhythm protein Period 2 (PER2) using whole body Per2-/- mice found deficient platelet function and reduced clotting which would be expected to protect from myocardial IR-injury. In contrast, intense light induction of PER2 protected from myocardial IR-injury while Per2 deficiency was detrimental. Based on these conflicting data, we sought to evaluate the role of platelet specific PER2 in coagulation and myocardial ischemia and reperfusion injury. We demonstrated that platelets from mice with tissue-specific deletion of Per2 in the megakaryocyte lineage (Per2loxP/loxP-PF4-CRE) significantly clot faster than platelets from control mice. We further found increases in infarct sizes or plasma troponin levels in Per2loxP/loxP-PF4-CRE mice when compared to controls. As intense light increases PER2 protein in human tissues, we also performed translational studies and tested the effects of intense light therapy on coagulation in healthy human subjects. Our human studies revealed that intense light therapy repressed procoagulant pathways in human plasma samples and significantly reduced the clot rate. Based on these results we conclude that intense light elicited PER2 has an inhibitory function on platelet aggregation in mice. Further, we suggest intense light as a novel therapy to prevent or treat clotting in a clinical setting. Oyama, Yoshimasa Shuff, Sydney Davizon-Castillo, Pavel Clendenen, Nathan Eckle, Tobias eng R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. Dec 31;15(12):e. doi: 10./journal.pone.. eCollection .I SomaScan 01/01/ Narasimhan A, et al. Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform Cancers (Basel) 12 12 https://www.doi.org/10./cancers 33,334,063 biomarkers cachexia humans neoplasms pancreatic adenocarcinoma paracrine communication proteome weight loss Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured ~ plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC >/= |1.5|, p = 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1; Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity (r >/= |0.50|, p 1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis. Ngo, Debby Wen, Donghai Gao, Yan Keyes, Michelle J Drury, Erika R Katz, Dan H Benson, Mark D Sinha, Sumita Shen, Dongxiao Farrell, Laurie A Peterson, Bennet D Friedman, David J Elmariah, Sammy Young, Bessie A Smith, J Gustav Yang, Qiong Vasan, Ramachandran S Larson, Martin G Correa, Adolfo Humphreys, Benjamin D Wang, Thomas J Pollak, Martin R Wilson, James G Gerszten, Robert E Rhee, Eugene P eng HHSNC/HL/NHLBI NIH HHS/ R01 NR/NR/NINR NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNI/MD/NIMHD NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ 75ND/HL/NHLBI NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ HHSNI/HB/NHLBI NIH HHS/ K08 HL/HL/NHLBI NIH HHS/ T32 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Proc Natl Acad Sci U S A. Oct 6;117(40):-. doi: 10./pnas.. Epub Sep 21.I SomaScan 09/23/ Ganz P, et al. Proteomics for personalized cardiovascular risk assessment: in pursuit of the Holy Grail Eur Heart J 41 41 - https://www.doi.org/10./eurheartj/ehaa661 32,901,246 *Cardiovascular Diseases Heart Disease Risk Factors Humans Plasma Primary Prevention *Proteomics Risk Factors Ganz, Peter Deo, Rajat Dubin, Ruth F eng U01 DK/DK/NIDDK NIH HHS/ Comment Editorial Research Support, N.I.H., Extramural England Eur Heart J. Nov 1;41(41):-. doi: 10./eurheartj/ehaa661.I SomaScan 09/10/ Lee SJ, et al. Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight Proc Natl Acad Sci U S A 117 38 - https://www.doi.org/10./pnas. 32,900,939 Activin Receptors, Type II/genetics/metabolism Activins/*metabolism Animals Bone Resorption/*metabolism Female Male Mice Mice, Inbred C57BL Mice, Knockout Muscle, Skeletal/*metabolism Muscular Atrophy/metabolism *Myostatin/genetics/metabolism Signal Transduction *Space Flight activin bone microgravity myostatin skeletal muscle Among the physiological consequences of extended spaceflight are loss of skeletal muscle and bone mass. One signaling pathway that plays an important role in maintaining muscle and bone homeostasis is that regulated by the secreted signaling proteins, myostatin (MSTN) and activin A. Here, we used both genetic and pharmacological approaches to investigate the effect of targeting MSTN/activin A signaling in mice that were sent to the International Space Station. Wild type mice lost significant muscle and bone mass during the 33 d spent in microgravity. Muscle weights of Mstn(-/-) mice, which are about twice those of wild type mice, were largely maintained during spaceflight. Systemic inhibition of MSTN/activin A signaling using a soluble form of the activin type IIB receptor (ACVR2B), which can bind each of these ligands, led to dramatic increases in both muscle and bone mass, with effects being comparable in ground and flight mice. Exposure to microgravity and treatment with the soluble receptor each led to alterations in numerous signaling pathways, which were reflected in changes in levels of key signaling components in the blood as well as their RNA expression levels in muscle and bone. These findings have implications for therapeutic strategies to combat the concomitant muscle and bone loss occurring in people afflicted with disuse atrophy on Earth as well as in astronauts in space, especially during prolonged missions. Lee, Se-Jin Lehar, Adam Meir, Jessica U Koch, Christina Morgan, Andrew Warren, Lara E Rydzik, Renata Youngstrom, Daniel W Chandok, Harshpreet George, Joshy Gogain, Joseph Michaud, Michael Stoklasek, Thomas A Liu, Yewei Germain-Lee, Emily L eng R01 AG/AG/NIA NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. Sep 22;117(38):-. doi: 10./pnas.. Epub Sep 8.I SomaScan 09/10/ Chan MY, et al. Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics Circulation 142 15 - https://www.doi.org/10./CIRCULATIONAHA.119. 32,885,678 Aged Aged, 80 and over Animals Blood Proteins/*biosynthesis Female *Gene Expression Profiling *Gene Expression Regulation *Heart Failure/blood/genetics Humans Male Mice Middle Aged *Myocardial Infarction/blood/complications *Proteomics *Single-Cell Analysis heart failure myocardial infarction proteomics transcriptome BACKGROUND: Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery. METHODS: We used aptamer-based affinity-capture plasma proteomics to measure plasma proteins at 1 month post-MI in a New Zealand cohort (CDCS [Coronary Disease Cohort Study]) including 181 patients post-MI who were subsequently hospitalized for HF in comparison with 250 patients post-MI who remained event free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially coregulated in post-MI HF using weighted gene co-expression network analysis. A Singapore cohort (IMMACULATE [Improving Outcomes in Myocardial Infarction through Reversal of Cardiac Remodelling]) of 223 patients post-MI, of which 33 patients were hospitalized for HF (median follow-up, 2.0 years), was used for further candidate enrichment of plasma proteins by using Fisher meta-analysis, resampling-based statistical testing, and machine learning. We then cross-referenced differentially expressed proteins with their differentially expressed genes from single-cell transcriptomes of nonmyocyte cardiac cells isolated from a murine MI model, and single-cell and single-nucleus transcriptomes of cardiac myocytes from murine HF models and human patients with HF. RESULTS: In the CDCS cohort, 212 differentially expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. Weighted gene co-expression network analysis prioritized 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF in comparison with event-free controls (data set 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (data set 2), whereas single-cell transcriptomes identified 15 gene-protein candidates (data set 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly enriched proteins that were common to all 3 data sets included well-established biomarkers of post-MI HF: N-terminal B-type natriuretic peptide and troponin T, and newly emergent biomarkers, angiopoietin-2, thrombospondin-2, latent transforming growth factor-beta binding protein-4, and follistatin-related protein-3, as well. CONCLUSIONS: Large-scale human plasma proteomics, cross-referenced to unbiased cardiac transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation. Chan, Mark Y Efthymios, Motakis Tan, Sock Hwee Pickering, John W Troughton, Richard Pemberton, Christopher Ho, Hee-Hwa Prabath, Joseph-Francis Drum, Chester L Ling, Lieng Hsi Soo, Wern-Miin Chai, Siang-Chew Fong, Alan Oon, Yen-Yee Loh, Joshua P Lee, Chi-Hang Foo, Roger S Y Ackers-Johnson, Matthew Andrew Pilbrow, Anna Richards, A Mark eng Clinical Trial Multicenter Study Research Support, Non-U.S. Gov't Circulation. Oct 13;142(15):-. doi: 10./CIRCULATIONAHA.119.. Epub Sep 4.I SomaScan 09/05/ Moin ASM, et al. Renin-Angiotensin System overactivation in polycystic ovary syndrome, a risk for SARS-CoV-2 infection? Metabol Open 7 https://www.doi.org/10./j.metop.. 32,838,280 ACE2 protein Angiotensinogen Polycystic ovary syndrome Renin BACKGROUND: The SARS-CoV-2 coronavirus gains entry to target cells via the angiotensin-converting enzyme 2 (ACE2) receptor present on cells in blood vessels, lungs, heart, intestines, and kidneys. Renin-Angiotensin System (RAS) overactivity has also been described in metabolic syndrome, type 2 diabetes (T2D) and obesity, conditions shared by women with polycystic ovary syndrome (PCOS) We hypothesized that RAS overactivity may be present in PCOS. METHODS: We determined plasma levels of RAS-related proteins in a cohort of age matched control women (n = 97) and women with PCOS (n = 146). Plasma levels of RAS-related proteins (ACE2, Renin and Angiotensinogen (AGT)) were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. RESULTS: PCOS women had a higher BMI (p < 0.001), systolic (p < 0.) and diastolic (p < 0.05) blood pressure, waist circumference (p < 0.), testosterone (p < 0.), free androgen index (p < 0.) and CRP (p < 0.). Renin was elevated in PCOS (p < 0.05) and angiotensinogen was lower in PCOS (p < 0.05), indicating overactivity of the RAS system in PCOS. ACE2 levels were lower in PCOS (p < 0.05), suggesting that PCOS women are at risk for development of hypertension. CONCLUSION: RAS proteins levels differed between PCOS and control women, suggesting that the insulin resistance inherent in PCOS may predispose these women to more severe COVID-19 infection. Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng England Metabol Open. Sep;7:. doi: 10./j.metop... Epub Aug 18.I SomaScan 08/25/ Shi L, et al. Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology J Alzheimers Dis 77 3 - https://www.doi.org/10./JAD- 32,831,200 Aged Alzheimer Disease/*blood/genetics/*pathology Biomarkers/blood Female Gene Expression HEK293 Cells Humans Intercellular Signaling Peptides and Proteins/biosynthesis/*blood/genetics Male Middle Aged ATN framework Dickkopf-1 SomaScan Wnt signaling replication (https://www.j-alz.com/manuscript-disclosures/20-r3). BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E varepsilon4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo. Shi, Liu Winchester, Laura M Liu, Benjamine Y Killick, Richard Ribe, Elena M Westwood, Sarah Baird, Alison L Buckley, Noel J Hong, Shengjun Dobricic, Valerija Kilpert, Fabian Franke, Andre Kiddle, Steven Sattlecker, Martina Dobson, Richard Cuadrado, Antonio Hye, Abdul Ashton, Nicholas J Morgan, Angharad R Bos, Isabelle Vos, Stephanie J B Ten Kate, Mara Scheltens, Philip Vandenberghe, Rik Gabel, Silvy Meersmans, Karen Engelborghs, Sebastiaan De Roeck, Ellen E Sleegers, Kristel Frisoni, Giovanni B Blin, Olivier Richardson, Jill C Bordet, Regis Molinuevo, Jose L Rami, Lorena Wallin, Anders Kettunen, Petronella Tsolaki, Magda Verhey, Frans Lleo, Alberto Alcolea, Daniel Popp, Julius Peyratout, Gwendoline Martinez-Lage, Pablo Tainta, Mikel Johannsen, Peter Teunissen, Charlotte E Freund-Levi, Yvonne Frolich, Lutz Legido-Quigley, Cristina Barkhof, Frederik Blennow, Kaj Rasmussen, Katrine Laura Nordestgaard, Borge Gronne Frikke-Schmidt, Ruth Nielsen, Sune Fallgaard Soininen, Hilkka Vellas, Bruno Kloszewska, Iwona Mecocci, Patrizia Zetterberg, Henrik Morgan, B Paul Streffer, Johannes Visser, Pieter Jelle Bertram, Lars Nevado-Holgado, Alejo J Lovestone, Simon eng MR/L/1/MRC_/Medical Research Council/United Kingdom MC_PC_/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom MC_PC_/MRC_/Medical Research Council/United Kingdom MR/L/2/MRC_/Medical Research Council/United Kingdom 171/ALZS_/Alzheimer's Society/United Kingdom Multicenter Study Research Support, Non-U.S. Gov't Netherlands J Alzheimers Dis. ;77(3):-. doi: 10./JAD-.I SomaScan 08/25/ Begic E, et al. Increased Levels of Coagulation Factor XI in Plasma Are Related to Alzheimer's Disease Diagnosis J Alzheimers Dis 77 1 375-386 https://www.doi.org/10./JAD- 32,804,133 Aged Aged, 80 and over Alzheimer Disease/*blood/*diagnosis Biomarkers/blood Cohort Studies *Databases, Factual Factor XI/*metabolism Female Humans Male Alzheimer's disease biomarkers blood coagulation blood coagulation factor xi cognitive impairment BACKGROUND: Alzheimer's disease is a complex disorder of unclear etiology that develops in the elderly population. It is a debilitating, progressive neurodegeneration for which disease-modifying therapies do not exist. Previous studies have suggested that, for a subset of patients, dysregulation in hemostasis might be one of the molecular mechanisms that ultimately leads to the development of neurodegeneration resulting in cognitive decline that represents the most prominent symptomatic characteristic of Alzheimer's disease. OBJECTIVE: To examine a relationship between factors that are part of coagulation and anticoagulation pathways with cognitive decline that develops during Alzheimer's disease. METHODS: SOMAscan assay was used to measure levels of coagulation/anticoagulation factors V, VII, IX, X, Xa, XI, antithrombin III, protein S, protein C, and activated protein C in plasma samples obtained from three groups of subjects: 1) subjects with stable cognitively healthy function, 2) subjects with stable mild cognitive impairment, and 3) subjects diagnosed with probable Alzheimer's disease. RESULTS: Our results show that protein levels of coagulation factor XI are significantly increased in patients who are diagnosed with probable Alzheimer's disease compared with cognitively healthy subjects or patients diagnosed with mild cognitive impairment. Furthermore, our results demonstrate that significant predictors of Alzheimer's-type diagnosis are factors IX and XI-an increase in both factors is associated with a reduction in cognitive function. CONCLUSION: Our study justifies further investigations of biological pathways involving coagulation/anticoagulation factors in relation to dementia, including dementia resulting from Alzheimer's-type neurodegeneration. Begic, Edin Hadzidedic, Suncica Obradovic, Slobodan Begic, Zijo Causevic, Mirsada eng Netherlands J Alzheimers Dis. ;77(1):375-386. doi: 10./JAD-.I SomaScan 08/18/ Sathyan S, et al. Plasma proteomic profile of frailty Aging Cell 19 9 e https://www.doi.org/10./acel. 32,762,010 Aged Female Frail Elderly/*statistics & numerical data Frailty/*genetics Humans Plasma/*metabolism Proteomics/*methods SomaScan(R) assay aging cumulative frailty score frailty frailty prediction proteomics Frailty is a state of decreased physiological reserve and increased vulnerability to adverse outcomes in aging, and is characterized by dysregulation across various biological pathways. Frailty may manifest biologically as alteration in protein expression, possibly regulated at genetic, transcriptional and epigenetic levels. In this study, we examined the proteomic profile associated with frailty defined by an established cumulative frailty index (FI). Using the SomaScan((R)) assay, proteins were measured in plasma, of which 55 were positively associated and 88 were negatively associated with the FI. The proteins most strongly associated with frailty were fatty acid-binding proteins, including fatty acid-binding protein (FABP) (p = 1.96 x 10(-19) ) and FABPA (p = 8.10 x 10(-16) ), leptin (p = 1.43 x 10(-14) ), and ANTR2 (p = 7.95 x 10(-20) ). Pathway analysis with the top 143 frailty-associated proteins revealed enrichment for proteins in pathways related to lipid metabolism, musculoskeletal development and function, cell-to-cell signaling and interaction, cellular assembly, and organization. Frailty prediction model constructed with elastic net regression utilizing 110 proteins demonstrated a correlation between predicted frailty and observed frailty (r = 0.57, p < 2.2 x 10(-16) ). Predicted frailty was also more strongly correlated with chronological age (r = 0.54, p < 2.2 x 10(-16) ) than observed frailty (r = 0.37, p = 1.2 x 10(-15) ). This study identified novel proteins and pathways related to frailty that may offer improved frailty phenotyping and prediction. Sathyan, Sanish Ayers, Emmeline Gao, Tina Milman, Sofiya Barzilai, Nir Verghese, Joe eng R01 AG/AG/NIA NIH HHS/ P30AG/The Nathan Shock Center of Excellence for the Biology of Aging/International K23AG/AG/NIA NIH HHS/ R01AG/AG/NIA NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R01AG/AG/NIA NIH HHS/ R01AG/AG/NIA NIH HHS/ R01AG/AG/NIA NIH HHS/ P30 AG/AG/NIA NIH HHS/ P01AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Aging Cell. Sep;19(9):e. doi: 10./acel.. Epub Aug 6.I SomaScan 08/08/ Glover K, et al. ZIKV Infection Induces DNA Damage Response and Alters the Proteome of Gastrointestinal Cells Viruses 12 7 https://www.doi.org/10./v 32,708,879 Caco-2 Cells/metabolism/virology *DNA Damage Gastrointestinal Tract/metabolism/*virology Gene Expression Regulation, Viral Humans Proteome/*metabolism Zika Virus Infection/metabolism/*pathology SomaScan aptamers bioinformatics dysregulated proteins flavivirus gastrointestinal disease proteomics design of the study in the collection, analyses, or interpretation of data in the writing of the manuscript, or in the decision to publish the results. The zika virus (ZIKV) is a neurotropic virus that causes congenital abnormalities in babies when they are infected in utero. Some studies have reported these congenital abnormalities result from ZIKV attacking neural progenitor cells within the brain which differentiate into neurons, oligodendrocytes, and astrocytes. Each of these glial cells play important roles during development of the fetal brain. In addition to ZIKV-induced congenital abnormalities, infected patients experience gastrointestinal complications. There are presently no reports investigating the role of this virus at the proteomic level in gastrointestinal associated cells, so we conducted an in vitro proteomic study of ZIKV-induced changes in Caco-2, a colon-derived human cell line which is known to be permissive to ZIKV infection. We used SomaScan, a new aptamer-based proteomic tool to identify host proteins that are dysregulated during ZIKV infection at 12, 24, and 48 h post-infection. Bioinformatic analyses predicted that dysregulation of differentially-regulated host proteins results in various gastrointestinal diseases. Validation of the clinical relevance of these promising protein targets will add to the existing knowledge of ZIKV biology. These potential proteins may be useful targets towards the development of therapeutic interventions. Glover, Kathleen Coombs, Kevin M eng Research Support, Non-U.S. Gov't Switzerland Viruses. Jul 17;12(7):771. doi: 10./v.I SomaScan 07/28/ Norman KC, et al. Identification of a unique temporal signature in blood and BAL associated with IPF progression Sci Rep 10 1 https://www.doi.org/10./s-020--w 32,694,604 Aged Biomarkers/blood/*metabolism Blood Proteins Bronchoalveolar Lavage Fluid Disease Progression Disease Susceptibility Female Gene Expression Humans Idiopathic Pulmonary Fibrosis/etiology/*metabolism/pathology Male Middle Aged Protein Interaction Mapping Proteomics/methods Idiopathic pulmonary fibrosis (IPF) is a progressive and heterogeneous interstitial lung disease of unknown origin with a low survival rate. There are few treatment options available due to the fact that mechanisms underlying disease progression are not well understood, likely because they arise from dysregulation of complex signaling networks spanning multiple tissue compartments. To better characterize these networks, we used systems-focused data-driven modeling approaches to identify cross-tissue compartment (blood and bronchoalveolar lavage) and temporal proteomic signatures that differentiated IPF progressors and non-progressors. Partial least squares discriminant analysis identified a signature of 54 baseline (week 0) blood and lung proteins that differentiated IPF progression status by the end of 80 weeks of follow-up with 100% cross-validation accuracy. Overall we observed heterogeneous protein expression patterns in progressors compared to more homogenous signatures in non-progressors, and found that non-progressors were enriched for proteomic processes involving regulation of the immune/defense response. We also identified a temporal signature of blood proteins that was significantly different at early and late progressor time points (p < 0.), but not present in non-progressors. Overall, this approach can be used to generate new hypothesis for mechanisms associated with IPF progression and could readily be translated to other complex and heterogeneous diseases. Norman, Katy C O'Dwyer, David N Salisbury, Margaret L DiLillo, Katarina M Lama, Vibha N Xia, Meng Gurczynski, Stephen J White, Eric S Flaherty, Kevin R Martinez, Fernando J Murray, Susan Moore, Bethany B Arnold, Kelly B eng K23 HL/HL/NHLBI NIH HHS/ R00 HL/HL/NHLBI NIH HHS/ L30 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R35 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. Jul 21;10(1):. doi: 10./s-020--w.I SomaScan 07/23/ Yang J, et al. Impact of Kidney Function on the Blood Proteome and on Protein Cardiovascular Risk Biomarkers in Patients With Stable Coronary Heart Disease J Am Heart Assoc 9 15 e https://www.doi.org/10./JAHA.120. 32,696,702 Aged Biomarkers/*blood Cohort Studies Coronary Disease/*blood/complications Female *Glomerular Filtration Rate Heart Disease Risk Factors Humans Male Middle Aged *Proteome Renal Insufficiency, Chronic/*blood/complications cardiovascular disease chronic kidney disease proteomics Background Chronic kidney disease (CKD) confers increased cardiovascular risk, not fully explained by traditional factors. Proteins regulate biological processes and inform the risk of diseases. Thus, in 938 patients with stable coronary heart disease from the Heart and Soul cohort, we quantified plasma proteins using modified aptamers (SOMAscan) to: (1) discern how reduced glomerular filtration influences the circulating proteome, (2) learn of the importance of kidney function to the prognostic information contained in recently identified protein cardiovascular risk biomarkers, and (3) identify novel and even unique cardiovascular risk biomarkers among individuals with CKD. Methods and Results Plasma protein levels were correlated to estimated glomerular filtration rate (eGFR) using Spearman-rank correlation coefficients. Cox proportional hazard models were used to estimate the association between individual protein levels and the risk of the cardiovascular outcome (first among myocardial infarction, stroke, heart failure hospitalization, or mortality). Seven hundred and nine (67.3%) plasma proteins correlated with eGFR at P<0.05 (rho 0.06-0.74); 218 (20.7%) proteins correlated with eGFR moderately or strongly (rho 0.2-0.74). Among the previously identified 196 protein cardiovascular biomarkers, just 87 remained prognostic after correction for eGFR. Among patients with CKD (eGFR <60 mL/min per 1.73 m(2)), we identified 21 protein cardiovascular risk biomarkers of which 8 are unique to CKD. Conclusions CKD broadly alters the composition of the circulating proteome. We describe protein biomarkers capable of predicting cardiovascular risk independently of glomerular filtration, and those that are prognostic of cardiovascular risk specifically in patients with CKD and even unique to patients with CKD. Yang, Joseph Brody, Edward N Murthy, Ashwin C Mehler, Robert E Weiss, Sophie J DeLisle, Robert K Ostroff, Rachel Williams, Stephen A Ganz, Peter eng R01 HL/HL/NHLBI NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ R01 AG/AG/NIA NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England J Am Heart Assoc. Aug 4;9(15):e. doi: 10./JAHA.120.. Epub Jul 22.I SomaScan 07/23/ Xing J, et al. Evaluation of a novel blood microsampling device for clinical trial sample collection and protein biomarker analysis Bioanalysis 12 13 919-935 https://www.doi.org/10./bio-- 32,686,955 Adult Biomarkers/blood Blood Proteins/*analysis Covid-19 Clinical Trials as Topic Coronavirus Infections/blood Enzyme-Linked Immunosorbent Assay Female Hemolysis Humans Male Middle Aged Pandemics Phlebotomy/*instrumentation Pneumonia, Viral/blood Proteomics/instrumentation Young Adult Dbs SomaScan Tap Vams biomarkers microsampling patient-centric sampling proteomics sampling device Aim: Evaluation of a novel microsampling device for its use in clinical sample collection and biomarker analysis. Methodology: Matching samples were collected from 16 healthy donors (ten females, six males; age 42 +/- 20) via K2EDTA touch activated phlebotomy (TAP) device and phlebotomy. The protein profile differences between sampling groups was evaluated using aptamer-based proteomic assay SomaScan and selected ELISA. Conclusion: Somascan signal concordance between phlebotomy- and TAP-generated samples was studied and comparability of protein abundances between these blood sample collection methods was demonstrated. Statistically significant correlation in selected ELISA assays also confirmed the TAP device applicability to the quantitative analysis of protein biomarkers in clinical trials. Xing, Jinming Loureiro, Joseph Patel, Michael T Mikhailov, Dmitri Gusev, Arkady I eng Evaluation Study England Bioanalysis. Jul;12(13):919-935. doi: 10./bio--. Epub Jul 20.I SomaScan 07/21/ Kemp PR, et al. Metabolic profiling shows pre-existing mitochondrial dysfunction contributes to muscle loss in a model of ICU-acquired weakness J Cachexia Sarcopenia Muscle 11 5 - https://www.doi.org/10./jcsm. 32,677,363 Aged *Hand Strength Humans Intensive Care Units Male Middle Aged *Mitochondria Quadriceps Muscle Stroke Volume *Ventricular Function, Left Aortic surgery Cortisol Metabolomics Mitochondrial dysfunction Muscle wasting grants, personal fees, and non-financial support from GSK, personal fees from BI, personal fees from Silence therapeutics, personal fees from Cell catapult, outside the submitted work all other authors have no conflicts of interest. BACKGROUND: Surgery can lead to significant muscle loss, which increases recovery time and associates with increased mortality. Muscle loss is not uniform, with some patients losing significant muscle mass and others losing relatively little, and is likely to be accompanied by marked changes in circulating metabolites and proteins. Determining these changes may help understand the variability and identify novel therapeutic approaches or markers of muscle wasting. METHODS: To determine the association between muscle loss and circulating metabolites, we studied 20 male patients (median age, 70.5, interquartile range, 62.5-75) undergoing aortic surgery. Muscle mass was determined before and 7 days after surgery and blood samples were taken before surgery, and 1, 3, and 7 days after surgery. The circulating metabolome and proteome were determined using commercial services (Metabolon and SomaLogic). RESULTS: Ten patients lost more than 10% of the cross-sectional area of the rectus femoris (RF(CSA) ) and were defined as wasting. Metabolomic analysis showed that 557 circulating metabolites were altered following surgery (q < 0.05) in the whole cohort and 104 differed between wasting and non-wasting patients (q < 0.05). Weighted genome co-expression network analysis, identified clusters of metabolites, both before and after surgery, that associated with muscle mass and function (r = -0.72, p = 6 x 10(-4) with RF(CSA) on Day 0, P = 3 x 10(-4) with RF(CSA) on Day 7 and r = -0.73, P = 5 x 10(-4) with hand-grip strength on Day 7). These clusters were mainly composed of acyl carnitines and dicarboxylates indicating that pre-existing mitochondrial dysfunction contributes to muscle loss following surgery. Surgery elevated cortisol to the same extent in wasting and non-wasting patients, but the cortisol:cortisone ratio was higher in the wasting patients (Day 3 P = 0.043 and Day 7 P = 0.016). Wasting patients also showed a greater increase in circulating nucleotides 3 days after surgery. Comparison of the metabolome with inflammatory markers identified by SOMAscan(R) showed that pre-surgical mitochondrial dysfunction was associated with growth differentiation factor 15 (GDF-15) (r = 0.79, P = 2 x 10(-4) ) and that GDF-15, interleukin (IL)-8), C-C motif chemokine 23 (CCL-23), and IL-15 receptor subunit alpha (IL-15RA) contributed to metabolic changes in response to surgery. CONCLUSIONS: We show that pre-existing mitochondrial dysfunction and reduced cortisol inactivation contribute to muscle loss following surgery. The data also implicate GDF-15 and IL-15RA in mitochondrial dysfunction. Kemp, Paul R Paul, Richard Hinken, Aaron C Neil, David Russell, Alan Griffiths, Mark J eng DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't Germany J Cachexia Sarcopenia Muscle. Oct;11(5):-. doi: 10./jcsm.. Epub Jul 16.I SomaScan 07/18/ Elskens JP, et al. Chemical Modification of Aptamers for Increased Binding Affinity in Diagnostic Applications: Current Status and Future Prospects Int J Mol Sci 21 12 https://www.doi.org/10./ijms 32,630,547 Aptamers, Nucleotide/*chemistry/*therapeutic use Humans Ligands Pathology, Molecular/methods SELEX Aptamer Technique/*methods/trends Selex aptamer chemical modifications diagnostic applications enhanced binding affinity Aptamers are short single stranded DNA or RNA oligonucleotides that can recognize analytes with extraordinary target selectivity and affinity. Despite their promising properties and diagnostic potential, the number of commercial applications remains scarce. In order to endow them with novel recognition motifs and enhanced properties, chemical modification of aptamers has been pursued. This review focuses on chemical modifications, aimed at increasing the binding affinity for the aptamer's target either in a non-covalent or covalent fashion, hereby improving their application potential in a diagnostic context. An overview of current methodologies will be given, thereby distinguishing between pre- and post-SELEX (Systematic Evolution of Ligands by Exponential Enrichment) modifications. Elskens, Jan P Elskens, Joke M Madder, Annemieke eng 1SN/Fonds Wetenschappelijk Onderzoek/ GN/Fonds Wetenschappelijk Onderzoek/ Review Switzerland Int J Mol Sci. Jun 25;21(12):. doi: 10./ijms.I SomaScan 07/08/ Dong L, et al. Aptamer based proteomic pilot study reveals a urine signature indicative of pediatric urinary tract infections PLoS One 15 7 e https://www.doi.org/10./journal.pone. 32,628,701 Adolescent Aptamers, Nucleotide/*chemistry Biomarkers/urine Child Child, Preschool Female Humans Male Pilot Projects Prospective Studies Proteomics/*methods *Support Vector Machine Urinalysis/*methods Urinary Tract Infections/*diagnosis/urine OBJECTIVE: Current urinary tract infection (UTI) diagnostic strategies that rely on leukocyte esterase have limited accuracy. We performed an aptamer-based proteomics pilot study to identify urine protein levels that could differentiate a culture proven UTI from culture negative samples, regardless of pyuria status. METHODS: We analyzed urine from 16 children with UTIs, 8 children with culture negative pyuria and 8 children with negative urine culture and no pyuria. The urine levels of 1,310 proteins were quantified using the Somascan platform and normalized to urine creatinine. Machine learning with support vector machine (SVM)-based feature selection was performed to determine the combination of urine biomarkers that optimized diagnostic accuracy. RESULTS: Eight candidate urine protein biomarkers met filtering criteria. B-cell lymphoma protein, C-X-C motif chemokine 6, C-X-C motif chemokine 13, cathepsin S, heat shock 70kDA protein 1A, mitogen activated protein kinase, protein E7 HPV18 and transgelin. AUCs ranged from 0.91 to 0.95. The best prediction was achieved by the SVMs with radial basis function kernel. CONCLUSIONS: Biomarkers panel can be identified by the emerging technologies of aptamer-based proteomics and machine learning that offer the potential to increase UTI diagnostic accuracy, thereby limiting unneeded antibiotics. Dong, Liang Watson, Joshua Cao, Sha Arregui, Samuel Saxena, Vijay Ketz, John Awol, Abduselam K Cohen, Daniel M Caterino, Jeffrey M Hains, David S Schwaderer, Andrew L eng R01 AG/AG/NIA NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study PLoS One. Jul 6;15(7):e. doi: 10./journal.pone.. eCollection .I SomaScan 07/07/ Guseh JS, et al. An expanded repertoire of intensity-dependent exercise-responsive plasma proteins tied to loci of human disease risk Sci Rep 10 1 https://www.doi.org/10./s-020--0 32,616,758 Adult Blood Pressure Blood Proteins/*metabolism Coronary Artery Disease/etiology/prevention & control Exercise/*physiology Female Genetic Loci Genome-Wide Association Study Humans Male *Proteomics Quantitative Trait Loci Risk Young Adult Routine endurance exercise confers numerous health benefits, and high intensity exercise may accelerate and magnify many of these benefits. To date, explanatory molecular mechanisms and the influence of exercise intensity remain poorly understood. Circulating factors are hypothesized to transduce some of the systemic effects of exercise. We sought to examine the role of exercise and exercise intensity on the human plasma proteome. We employed an aptamer-based method to examine 1,305 plasma proteins in 12 participants before and after exercise at two physiologically defined intensities (moderate and high) to determine the proteomic response. We demonstrate that the human plasma proteome is responsive to acute exercise in an intensity-dependent manner with enrichment analysis suggesting functional biological differences between the moderate and high intensity doses. Through integration of available genetic data, we estimate the effects of acute exercise on exercise-associated traits and find proteomic responses that may contribute to observed clinical effects on coronary artery disease and blood pressure regulation. In sum, we provide supportive evidence that moderate and high intensity exercise elicit different signaling responses, that exercise may act in part non-cell autonomously through circulating plasma proteins, and that plasma protein dynamics can simulate some the beneficial and adverse effects of acute exercise. Guseh, J Sawalla Churchill, Timothy W Yeri, Ashish Lo, Claire Brown, Marcel Houstis, Nicholas E Aragam, Krishna G Lieberman, Daniel E Rosenzweig, Anthony Baggish, Aaron L eng R01AG/NH/NIH HHS/ 16SFRN/AHA/American Heart Association-American Stroke Association/ R01 HL/NH/NIH HHS/ HL/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. Jul 2;10(1):. doi: 10./s-020--0.I SomaScan 07/04/ Dang UJ, et al. Serum biomarkers associated with baseline clinical severity in young steroid-naive Duchenne muscular dystrophy boys Hum Mol Genet 29 15 - https://www.doi.org/10./hmg/ddaa132 32,592,467 Biomarkers/*blood Child Child, Preschool Dystrophin/*blood Humans Male Muscular Dystrophy, Duchenne/*blood/drug therapy/pathology Oligonucleotides Phenotype Pregnadienediols/administration & dosage Severity of Illness Index Steroids/metabolism Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin in muscle, and while all patients share the primary gene and biochemical defect, there is considerable patient-patient variability in clinical symptoms. We sought to develop multivariate models of serum protein biomarkers that explained observed variation, using functional outcome measures as proxies for severity. Serum samples from 39 steroid-naive DMD boys 4 to <7 years enrolled into a clinical trial of vamorolone were studied (NCT). Four assessments of gross motor function were carried out for each participant over a 6-week interval, and their mean was used as response for biomarker models. Weighted correlation network analysis was used for unsupervised clustering of proteins quantified using SOMAscan(R) aptamer profiling to define highly representative and connected proteins. Multivariate models of biomarkers were obtained for time to stand performance (strength phenotype; 17 proteins) and 6 min walk performance (endurance phenotype; 17 proteins) including some shared proteins. Identified proteins were tested with associations of mRNA expression with histological severity of muscle from dystrophinopathy patients (n = 28) and normal controls (n = 6). Strong associations predictive of both clinical and histological severity were found for ERBB4 (reductions in both blood and muscle with increasing severity), SOD1 (reductions in muscle and increases in blood with increasing severity) and CNTF (decreased levels in blood and muscle with increasing severity). We show that performance of DMD boys was effectively modeled with serum proteins, proximal strength associated with growth and remodeling pathways and muscle endurance centered on TGFbeta and fibrosis pathways in muscle. Dang, Utkarsh J Ziemba, Michael Clemens, Paula R Hathout, Yetrib Conklin, Laurie S Hoffman, Eric P eng R44 NS/NS/NINDS NIH HHS/ Clinical Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Hum Mol Genet. Aug 29;29(15):-. doi: 10./hmg/ddaa132.I SomaScan 06/28/ Ferrannini E, et al. Mechanisms of Sodium-Glucose Cotransporter 2 Inhibition: Insights From Large-Scale Proteomics Diabetes Care 43 9 - https://www.doi.org/10./dc20- 32,527,800 Aged Benzhydryl Compounds/*pharmacology Biomarkers/analysis/blood Blood Proteins/drug effects/metabolism Female Glucose/metabolism Glucosides/*pharmacology Humans Hypoglycemic Agents/pharmacology Male Middle Aged Prospective Studies Proteome/analysis/*drug effects/metabolism Proteomics/methods Signal Transduction/drug effects Sodium-Glucose Transporter 2 Inhibitors/*pharmacology OBJECTIVE: To assess the effects of empagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics. RESEARCH DESIGN AND METHODS: Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate-corrected P < 0.05) was discerned through Ingenuity Pathway Analysis. RESULTS: Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid-binding protein 3 and 4 [FABPA], neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and beta2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration. CONCLUSIONS: SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design. Ferrannini, Ele Murthy, Ashwin C Lee, Yong-Ho Muscelli, Elza Weiss, Sophie Ostroff, Rachel M Sattar, Naveed Williams, Stephen A Ganz, Peter eng Research Support, Non-U.S. Gov't Diabetes Care. Sep;43(9):-. doi: 10./dc20-. Epub Jun 11.I SomaScan 06/13/ George MJ, et al. Novel Insights Into the Effects of Interleukin 6 Antagonism in Non-ST-Segment-Elevation Myocardial Infarction Employing the SOMAscan Proteomics Platform J Am Heart Assoc 9 12 e https://www.doi.org/10./JAHA.119. 32,515,246 Acute-Phase Proteins Aged Antibodies, Monoclonal, Humanized/*therapeutic use Aptamers, Nucleotide Blood Proteins/*metabolism Carrier Proteins/blood Chemokines, CC/blood Female Follow-Up Studies Hepcidins/blood High-Throughput Screening Assays Humans Insulin-Like Growth Factor Binding Protein 4/blood Male Membrane Glycoproteins/blood Middle Aged Myeloblastin/blood Non-ST Elevated Myocardial Infarction/blood/diagnosis/*drug therapy Norway *Proteome *Proteomics Randomized Controlled Trials as Topic Receptors, Interleukin-6/*antagonists & inhibitors Time Factors Treatment Outcome inflammation interleukin myocardial infarction proteomics Background Interleukin 6 concentration is associated with myocardial injury, heart failure, and mortality after myocardial infarction. In the Norwegian tocilizumab non-ST-segment-elevation myocardial infarction trial, the first randomized trial of interleukin 6 blockade in myocardial infarction, concentration of both C-reactive protein and troponin T were reduced in the active treatment arm. In this follow-up study, an aptamer-based proteomic approach was employed to discover additional plasma proteins modulated by tocilizumab treatment to gain novel insights into the effects of this therapeutic approach. Methods and Results Plasma from percutaneous coronary intervention-treated patients, 24 in the active intervention and 24 in the placebo-control arm, drawn 48 hours postrandomization were randomly selected for analysis with the SOMAscan assay. Employing slow off-rate aptamers, the relative abundance of circulating proteins was measured. Proteins identified as being significantly different between groups were subsequently measured by enzyme immunoassay in the whole trial cohort (117 patients) at all time points (days 1-3 [7 time points] and 3 and 6 months). Five proteins identified by the SOMAscan assay, and subsequently confirmed by enzyme immunoassay, were significantly altered by tocilizumab administration. The acute-phase proteins lipopolysaccharide-binding protein, hepcidin, and insulin-like growth factor-binding protein 4 were all reduced during the hospitalization phase, as was the monocyte chemoattractant C-C motif chemokine ligand 23. Proteinase 3, released primarily from neutrophils, was significantly elevated. Conclusions Employing the SOMAscan aptamer-based proteomics platform, 5 proteins were newly identified that are modulated by interleukin 6 antagonism and may mediate the therapeutic effects of tocilizumab in non-ST-segment-elevation myocardial infarction. George, Marc J Kleveland, Ola Garcia-Hernandez, Jorge Palmen, Jutta Lovering, Ruth Wiseth, Rune Aukrust, Pal Engmann, Jorgen Damas, Jan Kristian Hingorani, Aroon D Gullestad, Lars Casas, Juan P Ueland, Thor eng DH_/Department of Health/United Kingdom WT_/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't England J Am Heart Assoc. Jun 16;9(12):e. doi: 10./JAHA.119.. Epub Jun 9.I SomaScan 06/10/ Valsesia A, et al. Integrative phenotyping of glycemic responders upon clinical weight loss using multi-omics Sci Rep 10 1 https://www.doi.org/10./s-020--8 32,514,005 Adipose Tissue/*metabolism Area Under Curve Body Composition Diet, Reducing Down-Regulation Fatty Acid Elongases/genetics/metabolism *Genomics Humans Intra-Abdominal Fat/physiology Ketone Bodies/*blood Lipids/analysis Phenotype *Proteomics ROC Curve Weight Loss/*physiology Weight loss aims to improve glycemic control in obese but strong variability is observed. Using a multi-omics approach, we investigated differences between 174 responders and 201 non-responders, that had lost >8% body weight following a low-caloric diet (LCD, 800 kcal/d for 8 weeks). The two groups were comparable at baseline for body composition, glycemic control, adipose tissue transcriptomics and plasma ketone bodies. But they differed significantly in their response to LCD, including improvements in visceral fat, overall insulin resistance (IR) and tissue-specific IR. Transcriptomics analyses found down-regulation in key lipogenic genes (e.g. SCD, ELOVL5) in responders relative to non-responders; metabolomics showed increase in ketone bodies; while proteomics revealed differences in lipoproteins. Findings were consistent between genders; with women displaying smaller improvements owing to a better baseline metabolic condition. Integrative analyses identified a plasma omics model that was able to predict non-responders with strong performance (on a testing dataset, the Receiving Operating Curve Area Under the Curve (ROC AUC) was 75% with 95% Confidence Intervals (CI) [67%, 83%]). This model was based on baseline parameters without the need for intrusive measurements and outperformed clinical models (p = 0., with a +14% difference on the ROC AUCs). Our approach document differences between responders and non-responders, with strong contributions from liver and adipose tissues. Differences may be due to de novo lipogenesis, keto-metabolism and lipoprotein metabolism. These findings are useful for clinical practice to better characterize non-responders both prior and during weight loss. Valsesia, Armand Chakrabarti, Anirikh Hager, Jorg Langin, Dominique Saris, Wim H M Astrup, Arne Blaak, Ellen E Viguerie, Nathalie Masoodi, Mojgan eng Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't England Sci Rep. Jun 8;10(1):. doi: 10./s-020--8.I SomaScan 06/10/ Rashid MU, et al. Zika virus dysregulates human Sertoli cell proteins involved in spermatogenesis with little effect on tight junctions PLoS Negl Trop Dis 14 6 e https://www.doi.org/10./journal.pntd. 32,511,241 Animals Chlorocebus aethiops Humans Male Proteomics Semen/virology Sertoli Cells/*immunology/virology Signal Transduction *Spermatogenesis Tight Junctions/*immunology/virology Vero Cells Virus Replication Zika Virus Zika Virus Infection/*immunology Zika virus (ZIKV), a neglected tropical disease until its re-emergence in , causes microcephaly in infants and Guillain-Barre syndrome in adults. Its re-emergence and spread to more than 80 countries led the World Health Organization in to declare a Public Health Emergency. ZIKV is mainly transmitted by mosquitos, but can persist in infected human male semen for prolonged periods and may be sexually transmitted. Testicular Sertoli cells support ZIKV replication and may be a reservoir for persistent ZIKV infection. Electrical impedance analyses indicated ZIKV infection rapidly disrupted Vero cell monolayers but had little effect upon human Sertoli cells (HSerC). We determined ZIKV-induced proteomic changes in HSerC using an aptamer-based multiplexed technique (SOMAscan) targeting > human proteins. ZIKV infection caused differential expression of 299 proteins during three different time points, including 5 days after infection. Dysregulated proteins are involved in different bio-functions, including cell death and survival, cell cycle, maintenance of cellular function, cell signaling, cellular assembly, morphology, movement, molecular transport, and immune response. Many signaling pathways important for maintenance of HSerC function and spermatogenesis were highly dysregulated. These included IL-6, IGF1, EGF, NF-kappaB, PPAR, ERK/MAPK, and growth hormone signaling. Down-regulation of the PPAR signaling pathway might impact cellular energy supplies. Upstream molecule analysis also indicated microRNAs involved in germ cell development were downregulated by infection. Overall, this study leads to a better understanding of Sertoli cellular mechanisms used by ZIKV during persistent infection and possible ZIKV impacts on spermatogenesis. Rashid, Mahamud-Ur Zahedi-Amiri, Ali Glover, Kathleen K M Gao, Ang Nickol, Michaela E Kindrachuk, Jason Wilkins, John A Coombs, Kevin M eng 950-/CIHR/Canada Research Support, Non-U.S. Gov't PLoS Negl Trop Dis. Jun 8;14(6):e. doi: 10./journal.pntd.. eCollection Jun.I SomaScan 06/09/ Ruffieux H, et al. A fully joint Bayesian quantitative trait locus mapping of human protein abundance in plasma PLoS Comput Biol 16 6 e https://www.doi.org/10./journal.pcbi. 32,492,067 *Bayes Theorem Biomarkers/blood Blood Proteins/*genetics Genome-Wide Association Study Humans *Quantitative Trait Loci Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which >80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synthetic data emulating the real data show how LOCUS borrows strength across correlated protein levels and markers on a genome-wide scale to effectively increase statistical power. Notably, 15% of the pQTLs uncovered by LOCUS would be missed by the univariate approach, including several trans and pleiotropic hits with successful independent validation. Finally, the analysis of extensive clinical data from the two cohorts indicates that the genetically-driven proteins identified by LOCUS are enriched in associations with low-grade inflammation, insulin resistance and dyslipidemia and might therefore act as endophenotypes for metabolic diseases. While considerations on the clinical role of the pQTLs are beyond the scope of our work, these findings generate useful hypotheses to be explored in future research; all results are accessible online from our searchable database. Thanks to its efficient variational Bayes implementation, LOCUS can analyze jointly thousands of traits and millions of markers. Its applicability goes beyond pQTL studies, opening new perspectives for large-scale genome-wide association and QTL analyses. Diet, Obesity and Genes (DiOGenes) trial registration number: NCT. Ruffieux, Helene Carayol, Jerome Popescu, Radu Harper, Mary-Ellen Dent, Robert Saris, Wim H M Astrup, Arne Hager, Jorg Davison, Anthony C Valsesia, Armand eng MC_UU_/10/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't PLoS Comput Biol. Jun 3;16(6):e. doi: 10./journal.pcbi.. eCollection Jun.I SomaScan 06/04/ Demidowich AP, et al. Colchicine's effects on metabolic and inflammatory molecules in adults with obesity and metabolic syndrome: results from a pilot randomized controlled trial Int J Obes (Lond) 44 8 - https://www.doi.org/10./s-020--3 32,461,554 Adult Anti-Inflammatory Agents/pharmacology/*therapeutic use Betacoronavirus/drug effects C-Reactive Protein Covid-19 Colchicine/pharmacology/*therapeutic use Coronavirus Infections/drug therapy/*immunology Double-Blind Method Female Humans Interleukin-6 Male Metabolic Syndrome/*complications/drug therapy/*immunology Middle Aged Obesity/complications/drug therapy/*immunology Pandemics Pilot Projects Pneumonia, Viral/drug therapy/*immunology SARS-CoV-2 Treatment Outcome Young Adult OBJECTIVE: Recent clinical trials have demonstrated that colchicine may have metabolic and cardiovascular and benefits in at-risk patients; however, the mechanisms through which colchicine may improve outcomes are still unclear. We sought to examine colchicine's effects on circulating inflammatory and metabolic molecules in adults with obesity and metabolic syndrome (MetS). METHODS: Blood samples were collected pre- and post-intervention during a double-blind randomized controlled trial in which 40 adults with obesity and MetS were randomized to colchicine 0.6 mg or placebo twice-daily for 3 months. Serum samples were analyzed for circulating factors using the SomaScan Platform. The Benjamini-Hochberg procedure was used to adjust the false discovery rate (FDR) for multiple testing. RESULTS: At baseline, age (48.0 +/- 13.8 vs. 44.7 +/- 10.3 years) and BMI (39.8 +/- 6.4 vs. 41.8 +/- 8.2 kg/m(2)) were not different between groups. After controlling for the FDR, 34 molecules were significantly changed by colchicine. Colchicine decreased concentrations of multiple inflammatory molecules, including C-reactive protein, interleukin 6, and resistin, in addition to vascular-related proteins (e.g., oxidized low-density lipoprotein receptor, phosphodiesterase 5A). Conversely, relative to placebo, colchicine significantly increased concentrations of eight molecules including secreted factors associated with metabolism and anti-thrombosis. CONCLUSIONS: In adults with obesity, colchicine significantly affected concentrations of proteins involved in the innate immune system, endothelial function and atherosclerosis, uncovering new mechanisms behind its cardiometabolic effects. Further research is warranted to investigate whether colchicine's IL-6 suppressive effects may be beneficial in COVID-19. Demidowich, Andrew P Levine, Jordan A Apps, Richard Cheung, Foo K Chen, Jinguo Fantoni, Giovanna Patel, Tushar P Yanovski, Jack A eng ZIA HD/ImNIH/Intramural NIH HHS/ Randomized Controlled Trial England Int J Obes (Lond). Aug;44(8):-. doi: 10./s-020--3. Epub May 27.I SomaScan 05/29/ Walker ME, et al. Proteomic and Metabolomic Correlates of Healthy Dietary Patterns: The Framingham Heart Study Nutrients 12 5 https://www.doi.org/10./nu 32,438,708 Cross-Sectional Studies Diet Surveys Diet, Healthy/*statistics & numerical data Diet, Mediterranean/*statistics & numerical data Dietary Approaches To Stop Hypertension/*statistics & numerical data Eating/*physiology Female Humans Linear Models Longitudinal Studies Male *Metabolome Metabolomics Middle Aged Proteome/*analysis Proteomics biomarker diet quality dietary patterns metabolomic proteomic Data on proteomic and metabolomic signatures of healthy dietary patterns are limited. We evaluated the cross-sectional association of serum proteomic and metabolomic markers with three dietary patterns: the Alternative Healthy Eating Index (AHEI), the Dietary Approaches to Stop Hypertension (DASH) diet; and a Mediterranean-style (MDS) diet. We examined participants from the Framingham Offspring Study (mean age; 55 years; 52% women) who had complete proteomic (n = ) and metabolomic (n = ) data; using food frequency questionnaires to derive dietary pattern indices. Proteins and metabolites were quantified using the SomaScan platform and liquid chromatography/tandem mass spectrometry; respectively. We used multivariable-adjusted linear regression models to relate each dietary pattern index (independent variables) to each proteomic and metabolomic marker (dependent variables). Of the proteins; 103 were associated with at least one dietary pattern (48 with AHEI; 83 with DASH; and 8 with MDS; all false discovery rate [FDR] =15 vs OAHI<15) trained on SomaScan protein measures alone performed robustly, achieving 76% accuracy in a validation dataset. CONCLUSIONS: Multiplex protein assays offer diagnostic potential and provide new insights into the biological basis of sleep disordered breathing. Ambati, Aditya Ju, Yo-El Lin, Ling Olesen, Alexander N Koch, Henriette Hedou, Julien Jacques Leary, Eileen B Sempere, Vicente Peris Mignot, Emmanuel Taheri, Shahrad eng K23 NS/NS/NINDS NIH HHS/ KL2 RR/RR/NCRR NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ KL2 TR/TR/NCATS NIH HHS/ KL2 TR/TR/NCATS NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Sleep. Nov 12;43(11):zsaa086. doi: 10./sleep/zsaa086.I SomaScan 05/06/ Stanley S, et al. Comprehensive aptamer-based screening identifies a spectrum of urinary biomarkers of lupus nephritis across ethnicities Nat Commun 11 1 https://www.doi.org/10./s-020--3 32,366,845 Activated-Leukocyte Cell Adhesion Molecule/urine Adult African Americans/statistics & numerical data Aptamers, Peptide/*metabolism Asians/statistics & numerical data Biomarkers/*urine E-Selectin/analysis Female Humans Lupus Nephritis/*diagnosis/ethnology/urine Properdin/urine Proteins/*analysis Sensitivity and Specificity Vascular Cell Adhesion Molecule-1/urine Whites/statistics & numerical data Young Adult Emerging urinary biomarkers continue to show promise in evaluating lupus nephritis (LN). Here, we screen urine from active LN patients for proteins using an aptamer-based platform, followed by ELISA validation in two independent cohorts comprised of 127 inactive lupus, 107 active LN, 67 active non-renal lupus patients and 74 healthy controls, of three different ethnicities. Urine proteins that best distinguish active LN from inactive disease are ALCAM, PF-4, properdin, and VCAM-1 among African-Americans, sE-selectin, VCAM-1, BFL-1 and Hemopexin among Caucasians, and ALCAM, VCAM-1, TFPI and PF-4 among Asians. Most of these correlate significantly with disease activity indices in the respective ethnic groups, and surpass conventional metrics in identifying active LN, with better sensitivity, and negative/positive predictive values. Several elevated urinary molecules are also expressed within the kidneys in LN, based on single-cell RNAseq analysis. Longitudinal studies are warranted to assess the utility of these biomarkers in tracking lupus nephritis. Stanley, Samantha Vanarsa, Kamala Soliman, Samar Habazi, Deena Pedroza, Claudia Gidley, Gabriel Zhang, Ting Mohan, Shree Der, Evan Suryawanshi, Hemant Tuschl, Thomas Buyon, Jill Putterman, Chaim Mok, Chi Chiu Petri, Michelle Saxena, Ramesh Mohan, Chandra eng R01 AR/AR/NIAMS NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural England Nat Commun. May 4;11(1):. doi: 10./s-020--3.I SomaScan 05/06/ Harwardt MIE, et al. Single-Molecule Super-Resolution Microscopy Reveals Heteromeric Complexes of MET and EGFR upon Ligand Activation Int J Mol Sci 21 8 https://www.doi.org/10./ijms 32,316,583 Cell Line, Tumor Cell Membrane/*metabolism Epidermal Growth Factor/pharmacology ErbB Receptors/metabolism HeLa Cells Hepatocyte Growth Factor/pharmacology Humans Ligands Multiprotein Complexes/metabolism Proto-Oncogene Proteins c-met/*metabolism Signal Transduction Single Molecule Imaging/*methods DNA-paint Egfr Met receptor cross-interaction receptor tyrosine kinases single-molecule localization microscopy single-particle tracking Receptor tyrosine kinases (RTKs) orchestrate cell motility and differentiation. Deregulated RTKs may promote cancer and are prime targets for specific inhibitors. Increasing evidence indicates that resistance to inhibitor treatment involves receptor cross-interactions circumventing inhibition of one RTK by activating alternative signaling pathways. Here, we used single-molecule super-resolution microscopy to simultaneously visualize single MET and epidermal growth factor receptor (EGFR) clusters in two cancer cell lines, HeLa and BT-20, in fixed and living cells. We found heteromeric receptor clusters of EGFR and MET in both cell types, promoted by ligand activation. Single-protein tracking experiments in living cells revealed that both MET and EGFR respond to their cognate as well as non-cognate ligands by slower diffusion. In summary, for the first time, we present static as well as dynamic evidence of the presence of heteromeric clusters of MET and EGFR on the cell membrane that correlates with the relative surface expression levels of the two receptors. Harwardt, Marie-Lena I E Schroder, Mark S Li, Yunqing Malkusch, Sebastian Freund, Petra Gupta, Shashi Janjic, Nebojsa Strauss, Sebastian Jungmann, Ralf Dietz, Marina S Heilemann, Mike eng /Volkswagen Foundation/ SFB/Deutsche Forschungsgemeinschaft/ Ub-Net/Hessisches Ministerium fur Wissenschaft und Kunst/ DynaMem/Hessisches Ministerium fur Wissenschaft und Kunst/ Switzerland Int J Mol Sci. Apr 17;21(8):. doi: 10./ijms.I SomaScan 04/23/ Chirinos JA, et al. Reduced Apolipoprotein M and Adverse Outcomes Across the Spectrum of Human Heart Failure Circulation 141 18 - https://www.doi.org/10./CIRCULATIONAHA.119. 32,237,898 Aged Apolipoproteins M/*blood Biomarkers/blood Down-Regulation Female Heart Failure/*blood/diagnosis/mortality/therapy Humans Lipoproteins, HDL/blood Lysophospholipids/blood Male Middle Aged Prognosis *Proteome Proteomics Randomized Controlled Trials as Topic Registries Risk Assessment Risk Factors Sphingosine/analogs & derivatives/blood Time Factors United States apolipoproteins M heart failure lipoproteins, HDL sphingosine-1-phosphate survival BACKGROUND: Apo (apolipoprotein) M mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). Apo M exerts anti-inflammatory and cardioprotective effects in animal models. METHODS: In a subset of PHFS (Penn Heart Failure Study) participants (n=297), we measured apo M by Enzyme-Linked ImmunoSorbent Assay (ELISA). We also measured total S1P by liquid chromatography-mass spectrometry and isolated HDL particles to test the association between apo M and HDL-associated S1P. We confirmed the relationship between apo M and outcomes using modified aptamer-based apo M measurements among adults in the PHFS and 2 independent cohorts: the Washington University Heart Failure Registry (n=173) and a subset of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial; n=218). Last, we examined the relationship between apo M and approximately other proteins (SomaScan assay) to identify biological pathways associated with apo M in heart failure. RESULTS: In the PHFS, apo M was inversely associated with the risk of death (standardized hazard ratio, 0.56 [95% CI, 0.51-0.61]; P<0.) and the composite of death/ventricular assist device implantation/heart transplantation (standardized hazard ratio, 0.62 [95% CI, 0.58-0.67]; P<0.). This relationship was independent of HDL cholesterol or apo AI levels. Apo M remained associated with death (hazard ratio, 0.78 [95% CI, 0.69-0.88]; P<0.) and the composite of death/ventricular assist device/heart transplantation (hazard ratio, 0.85 [95% CI, 0.76-0.94]; P=0.001) in models that adjusted for multiple confounders. This association was present in both heart failure with reduced and preserved ejection fraction and was replicated in the Washington University cohort and a cohort with heart failure with preserved ejection fraction only (TOPCAT). The S1P and apo M content of isolated HDL particles strongly correlated (R=0.81, P<0.). The top canonical pathways associated with apo M were inflammation (negative association), the coagulation system (negative association), and liver X receptor/retinoid X receptor activation (positive association). The relationship with inflammation was validated with multiple inflammatory markers measured with independent assays. CONCLUSIONS: Reduced circulating apo M is independently associated with adverse outcomes across the spectrum of human heart failure. Further research is needed to assess whether the apo M/S1P axis is a suitable therapeutic target in heart failure. Chirinos, Julio A Zhao, Lei Jia, Yi Frej, Cecilia Adamo, Luigi Mann, Douglas Shewale, Swapnil V Millar, John S Rader, Daniel J French, Benjamin Brandimarto, Jeff Margulies, Kenneth B Parks, John S Wang, Zhaoqing Seiffert, Dietmar A Fang, James Sweitzer, Nancy Chistoffersen, Christina Dahlback, Bjorn Car, Bruce D Gordon, David A Cappola, Thomas P Javaheri, Ali eng U10 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ P01 HL/HL/NHLBI NIH HHS/ RC2 HL/HL/NHLBI NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R61 HL/HL/NHLBI NIH HHS/ R56 HL/HL/NHLBI NIH HHS/ R01 AG/AG/NIA NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ K08 HL/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. May 5;141(18):-. doi: 10./CIRCULATIONAHA.119.. Epub Apr 2.I SomaScan 04/03/ Wolk SK, et al. Modified nucleotides may have enhanced early RNA catalysis Proc Natl Acad Sci U S A 117 15 - https://www.doi.org/10./pnas. 32,229,566 Evolution, Molecular RNA/genetics/metabolism RNA, Catalytic/genetics/*metabolism Ribonucleotides/*metabolism RNA world catalytic RNA modified nucleotides The modern version of the RNA World Hypothesis begins with activated ribonucleotides condensing (nonenzymatically) to make RNA molecules, some of which possess (perhaps slight) catalytic activity. We propose that noncanonical ribonucleotides, which would have been inevitable under prebiotic conditions, might decrease the RNA length required to have useful catalytic function by allowing short RNAs to possess a more versatile collection of folded motifs. We argue that modified versions of the standard bases, some with features that resemble cofactors, could have facilitated that first moment in which early RNA molecules with catalytic capability began their evolutionary path toward self-replication. Wolk, Steven K Mayfield, Wesley S Gelinas, Amy D Astling, David Guillot, Jessica Brody, Edward N Janjic, Nebojsa Gold, Larry eng Proc Natl Acad Sci U S A. Apr 14;117(15):-. doi: 10./pnas.. Epub Mar 30.I SomaScan 04/02/ Sher AA, et al. Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome Cells 9 4 https://www.doi.org/10./cells 32,225,060 Astrocytes/*cytology/drug effects/*metabolism Astrocytoma/genetics/pathology *Autophagy/drug effects Biomarkers, Tumor/metabolism Cell Line, Tumor Cell Survival/drug effects Cytokines/metabolism Gene Expression Regulation, Neoplastic/drug effects Humans Macrolides/pharmacology Microtubule-Associated Proteins/metabolism Proteome/*metabolism Sequestosome-1 Protein/metabolism Sirolimus/pharmacology BafilomycinA1 Rapamycin aptamers autophagy bioinformatics cell responses Autophagy is a key cellular process that involves constituent degradation and recycling during cellular development and homeostasis. Autophagy also plays key roles in antimicrobial host defense and numerous pathogenic organisms have developed strategies to take advantage of and/or modulate cellular autophagy. Several pharmacologic compounds, such as BafilomycinA1, an autophagy inducer, and Rapamycin, an autophagy inhibitor, have been used to modulate autophagy, and their effects upon notable autophagy markers, such as LC3 protein lipidation and Sequestosome-1/p62 alterations are well defined. We sought to understand whether such autophagy modulators have a more global effect upon host cells and used a recently developed aptamer-based proteomic platform (SOMAscan((R))) to examine U-251 astrocytic cell proteins after the cells were treated with each compound. These analyses, and complementary cytokine array analyses of culture supernatants after drug treatment, revealed substantial perturbations in the U-251 astrocyte cellular proteome. Several proteins, including cathepsins, which have a role in autophagy, were differentially dysregulated by the two drugs as might be expected. Many proteins, not previously known to be involved in autophagy, were significantly dysregulated by the compounds, and several, including lactadherin and granulins, were up-regulated by both drugs. These data indicate that these two compounds, routinely used to help dissect cellular autophagy, have much more profound effects upon cellular proteins. Sher, Affan Ali Gao, Ang Coombs, Kevin M eng Research Support, Non-U.S. Gov't Switzerland Cells. Mar 26;9(4):805. doi: 10./cells.I SomaScan 04/01/ Arenas DJ, et al. Increased mTOR activation in idiopathic multicentric Castleman disease Blood 135 19 - https://www.doi.org/10./blood. 32,206,779 Adolescent Adult Aged Biomarkers, Tumor/*metabolism Case-Control Studies Castleman Disease/metabolism/*pathology Child Child, Preschool Cohort Studies Female Follow-Up Studies *Gene Expression Regulation, Neoplastic Humans Infant Interleukin-6/*metabolism Male Middle Aged Prognosis Proteome/*analysis/metabolism Ribosomal Protein S6 Kinases/*metabolism Signal Transduction TOR Serine-Threonine Kinases/*metabolism Young Adult Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood hematologic disorder characterized by lymphadenopathy, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. Interleukin-6 (IL-6) inhibition effectively treats approximately one-third of patients. Limited options exist for nonresponders, because the etiology, dysregulated cell types, and signaling pathways are unknown. We previously reported 3 anti-IL-6 nonresponders with increased mTOR activation who responded to mTOR inhibition with sirolimus. We investigated mTOR signaling in tissue and serum proteomes from iMCD patients and controls. mTOR activation was increased in the interfollicular space of iMCD lymph nodes (N = 26) compared with control lymph nodes by immunohistochemistry (IHC) for pS6, p4EBP1, and p70S6K, known effectors and readouts of mTORC1 activation. IHC for pS6 also revealed increased mTOR activation in iMCD compared with Hodgkin lymphoma, systemic lupus erythematosus, and reactive lymph nodes, suggesting that the mTOR activation in iMCD is not just a product of lymphoproliferation/inflammatory lymphadenopathy. Further, the degree of mTOR activation in iMCD was comparable to autoimmune lymphoproliferative syndrome, a disease driven by mTOR hyperactivation that responds to sirolimus treatment. Gene set enrichment analysis of serum proteomic data from iMCD patients (n = 88) and controls (n = 42) showed significantly enriched mTORC1 signaling. Finally, functional studies revealed increased baseline mTOR pathway activation in peripheral monocytes and T cells from iMCD remission samples compared with healthy controls. IL-6 stimulation augmented mTOR activation in iMCD patients, which was abrogated with JAK1/2 inhibition. These findings support mTOR activation as a novel therapeutic target for iMCD, which is being investigated through a trial of sirolimus (NCT). Arenas, Daniel J Floess, Katherine Kobrin, Dale Pai, Ruth-Anne Langan Srkalovic, Maya B Tamakloe, Mark-Avery Rasheed, Rozena Ziglar, Jasira Khor, Johnson Parente, Sophia A T Pierson, Sheila K Martinez, Daniel Wertheim, Gerald B Kambayashi, Taku Baur, Joseph Teachey, David T Fajgenbaum, David C eng R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Blood. May 7;135(19):-. doi: 10./blood..I SomaScan 03/25/ Shainker SA, et al. Placenta accreta spectrum: biomarker discovery using plasma proteomics Am J Obstet Gynecol 223 3 433 e1-433 e14 https://www.doi.org/10./j.ajog..03.019 32,199,927 Adult Biomarkers/blood Case-Control Studies Female Humans Placenta Accreta/*blood Pregnancy Pregnancy Trimester, Third *Prenatal Diagnosis Proteomics Vascular Endothelial Growth Factors/*blood antithrombin III diagnosis placenta accreta spectrum placentation plasma protein soluble Tie2 soluble VEGF receptor 2 BACKGROUND: Many cases of placenta accreta spectrum are not diagnosed antenatally, despite identified risk factors and improved imaging methods. Identification of plasma protein biomarkers could further improve the antenatal diagnosis of placenta accreta spectrum . OBJECTIVE: The purpose of this study was to determine if women with placenta accreta spectrum have a distinct plasma protein profile compared with control subjects. STUDY DESIGN: We obtained plasma samples before delivery from 16 participants with placenta accreta spectrum and 10 control subjects with similar gestational ages (35.1 vs 35.5 weeks gestation, respectively). We analyzed plasma samples with an aptamer-based proteomics platform for alterations in unique proteins. Heat maps of the most differentially expressed proteins (T test, P<.01) were generated with matrix visualization and analysis software. Principal component analysis was performed with the use of all proteins and the top 21 dysregulated proteins. We then confirmed dysregulated proteins using enzyme-linked immunosorbent assay and report significant differences between placenta accreta spectrum and control cases (Wilcoxon-rank sum test, P<.05). RESULTS: Many of the top 50 proteins that significantly dysregulated in participants with placenta accreta spectrum were inflammatory cytokines, factors that regulate vascular remodeling, and extracellular matrix proteins that regulate invasion. Placenta accreta spectrum, with the use of the top 21 proteins, distinctly separated the placenta accreta spectrum cases from control cases (P<.01). Using enzyme-linked immunosorbent assay, we confirmed 4 proteins that were dysregulated in placenta accreta spectrum compared with control cases: median antithrombin III concentrations (240.4 vs 150.3 mg/mL; P=.002), median plasminogen activator inhibitor 1 concentrations (4.1 vs 7.1 ng/mL; P<.001), soluble Tie2 (13.5 vs 10.4 ng/mL; P=.02), soluble vascular endothelial growth factor receptor 2 (9.0 vs 5.9 ng/mL; P=.003). CONCLUSION: Participants with placenta accreta spectrum had a unique and distinct plasma protein signature. Shainker, Scott A Silver, Robert M Modest, Anna M Hacker, Michele R Hecht, Jonathan L Salahuddin, Saira Dillon, Simon T Ciampa, Erin J D'Alton, Mary E Otu, Hasan H Abuhamad, Alfred Z Einerson, Brett D Branch, D Ware Wylie, Blair J Libermann, Towia A Karumanchi, S Ananth eng Evaluation Study Research Support, Non-U.S. Gov't Am J Obstet Gynecol. Sep;223(3):433.e1-433.e14. doi: 10./j.ajog..03.019. Epub Mar 19.I SomaScan 03/23/ Guerrero CLH, et al. Proteomic profiling of HTLV-1 carriers and ATL patients reveals sTNFR2 as a novel diagnostic biomarker for acute ATL Blood Adv 4 6 - https://www.doi.org/10./bloodadvances. 32,196,559 Adult Cytokines Flow Cytometry *Human T-lymphotropic virus 1/genetics Humans *Leukemia-Lymphoma, Adult T-Cell/diagnosis Proteomics Receptors, Tumor Necrosis Factor, Type II Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type 1 (HTLV-1)-associated T-cell malignancy with generally poor prognosis. Although only approximately 5% of HTLV-1 carriers progress to ATL, early diagnosis is challenging because of the lack of ATL biomarkers. In this study, we analyzed blood plasma profiles of asymptomatic HTLV-1 carriers (ACs); untreated ATL patients, including acute, lymphoma, smoldering, and chronic types; and ATL patients in remission. Through SOMAscan, expression levels of plasma proteins were analyzed in 85 samples (AC, n = 40; ATL, n = 40; remission, n = 5). Using gene set enrichment analysis and gene ontology, overrepresented pathways in ATL vs AC included angiogenesis, inflammation by cytokines and chemokines, interleukin-6 (IL-6)/JAK/STAT3, and notch signaling. In selecting candidate biomarkers, we focused on soluble tumor necrosis factor 2 (sTNFR2) because of its active role in enriched pathways, extreme significance (Welch's t test P 0.90), and novelty in ATL research. Quantification of sTNFR2 in 102 plasma samples (AC, n = 30; ATL, n = 68; remission, n = 4) using enzyme-linked immunosorbent assay showed remarkable elevations in acute ATL, at least 10 times those of AC samples, and return of sTNFR2 to AC state levels after achieving remission. Flow cytometry and immunostaining validated the expression of TNFR2 in ATL cells. No correlation between sIL-2 and sTNFR2 levels in acute ATL was found, suggesting the possibility of sTNFR2 as an independent biomarker. Our findings represent the first extensive blood-based proteomic analysis of ATL, suggesting the potential clinical utility of sTNFR2 in diagnosing acute ATL. Guerrero, Carmina Louise Hugo Yamashita, Yoshiko Miyara, Megumi Imaizumi, Naoki Kato, Megumi Sakihama, Shugo Hayashi, Masaki Miyagi, Takashi Karimata, Kaori Uchihara, Junnosuke Ohshiro, Kazuiku Todoroki, Junpei Nakachi, Sawako Morishima, Satoko Karube, Kennosuke Tanaka, Yuetsu Masuzaki, Hiroaki Fukushima, Takuya eng Research Support, Non-U.S. Gov't Blood Adv. Mar 24;4(6):-. doi: 10./bloodadvances..I SomaScan 03/21/ Kahal H, et al. Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects Sci Rep 10 1 https://www.doi.org/10./s-020--z 32,179,763 Adult Biomarkers/blood Blood Glucose C-Reactive Protein Case-Control Studies Diabetes Mellitus, Type 2/diagnosis/*drug therapy Female Humans Hypoglycemia/diagnosis/*etiology Hypoglycemic Agents/*adverse effects Inflammation Male Middle Aged *Oxidative Stress Time Factors Intensive diabetes control has been associated with increased mortality in type 2 diabetes (T2DM); this has been suggested to be due to increased hypoglycemia. We measured hypoglycemia-induced changes in endothelial parameters, oxidative stress markers and inflammation at baseline and after a 24-hour period in type 2 diabetic (T2DM) subjects versus age-matched controls. Case-control study: 10 T2DM and 8 control subjects. Blood glucose was reduced from 5 (90 mg/dl) to hypoglycemic levels of 2.8 mmol/L (50 mg/dl) for 1 hour by incremental hyperinsulinemic clamps using baseline and 24 hour samples. Measures of endothelial parameters, oxidative stress and inflammation at baseline and at 24-hours post hypoglycemia were performed: proteomic (Somalogic) analysis for inflammatory markers complemented by C-reactive protein (hsCRP) measurement, and proteomic markers and urinary isoprostanes for oxidative measures, together with endothelial function. Between baseline and 24 -hours after hypoglycemia, 15 of 140 inflammatory proteins differed in T2DM whilst only 1 of 140 differed in controls; all returned to baseline at 24-hours. However, elevated hsCRP levels were seen at 24-hours in T2DM (2.4 mg/L (1.2-5.4) vs. 3.9 mg/L (1.8-6.1), Baseline vs 24-hours, P < 0.05). In patients with T2DM, between baseline and 24-hour after hypoglycemia, only one of 15 oxidative stress proteins differed and this was not seen in controls. An increase (P = 0.016) from baseline (73.4 ng/mL) to 24 hours after hypoglycemia (91.7 ng/mL) was seen for urinary isoprostanes. Hypoglycemia resulted in inflammatory and oxidative stress markers being elevated in T2DM subjects but not controls 24-hours after the event. Kahal, Hassan Halama, Anna Aburima, Ahmed Bhagwat, Aditya M Butler, Alexandra E Graumann, Johannes Suhre, Karsten Sathyapalan, Thozhukat Atkin, Stephen L eng Research Support, Non-U.S. Gov't England Sci Rep. Mar 16;10(1):. doi: 10./s-020--z.I SomaScan 03/18/ Apps R, et al. Multimodal immune phenotyping of maternal peripheral blood in normal human pregnancy JCI Insight 5 7 https://www.doi.org/10./jci.insight. 32,163,376 Adolescent Adult Biomarkers/blood Female *Gestational Age Humans Immunophenotyping Leukocytes/*immunology/metabolism Middle Aged Pregnancy/blood/*immunology Pregnancy Trimester, First/blood/*immunology Cellular immune response Immunology Obstetrics/gynecology Proteomics Reproductive Biology exists. Changes in maternal immunity during pregnancy can result in an altered immune state, and as a natural perturbation, this provides an opportunity to understand functional interactions of the immune system in vivo. We report characterization of maternal peripheral immune phenotypes for 33 longitudinally sampled normal pregnancies, using clinical measurements of complete blood counts and major immune cell populations, as well as high parameter flow cytometry for 30 leukocyte antigens characterizing 79 cell populations, and monitoring of serum proteins using the SomaLogic platform. Cellular analyses characterized transient changes in T cell polarization and more persistent alterations in T and B cell subset frequencies and activation. Serum proteomic analysis identified a potentially novel set of 7 proteins that are predictive of gestational age: DDR1, PLAU, MRC1, ACP5, ROBO2, IGF2R, and GNS. We further show that gestational age can be predicted from the parameters obtained by complete blood count tests and clinical flow cytometry characterizing 5 major immune cell populations. Inferring gestational age from this routine clinical phenotyping data could be useful in resource-limited settings that lack obstetric ultrasound. Overall, both the cellular and proteomic analyses validate previously reported phenotypic immunological changes of pregnancy and uncover potentially new alterations and predictive markers. Apps, Richard Kotliarov, Yuri Cheung, Foo Han, Kyu Lee Chen, Jinguo Biancotto, Angelique Babyak, Ashley Zhou, Huizhi Shi, Rongye Barnhart, Lisa Osgood, Sharon M Belkaid, Yasmine Holland, Steven M Tsang, John S Zerbe, Christa S eng Clinical Trial Research Support, N.I.H., Intramural JCI Insight. Apr 9;5(7):e. doi: 10./jci.insight..I SomaScan 03/13/ Osawa Y, et al. Plasma proteomic signature of the risk of developing mobility disability: A 9-year follow-up Aging Cell 19 4 e https://www.doi.org/10./acel. 32,157,804 Aged Aged, 80 and over Biomarkers/blood Cathepsins/*blood Disabled Persons/*psychology Female Follow-Up Studies Growth Differentiation Factor 15/*blood Humans Middle Aged *Proteomics Risk Factors Thrombospondins/*blood Walking/*psychology cathepsin S growth/differentiation factor 15 mobility disability proteomics thrombospondin-2 INTRODUCTION: Mobility disability is a powerful indicator of poor health in older adults. The biological and pathophysiological mechanism underlying the development of mobility disability remains unknown. This study conducted a data-driven discovery phase investigation to identify plasma proteins that predict the incidence of mobility disability in community-dwelling older adults without mobility disability at baseline. METHODS: We investigated 660 women and men, aged 71.9 +/- 6.0 (60-94) years, who participated in the Invecchiare in Chianti, Aging in the Chianti Area" study and completed the 400-m walk at fast pace (400-m walk) at enrollment. Median follow-up time was 8.57 [interquartile, 3.20-9.08] years. SOMAscan technology was used to measure 1,301 plasma proteins at enrollment. The incident of mobility disability was defined as inability to complete the 400-m walk. Protein-specific Cox proportional hazard model was adjusted for sex, age, and other important covariates. RESULTS: Plasma levels of 75 proteins predicted mobility disability (p < .05). Significant proteins were enriched for the KEGG "PI3K-Akt signaling," "phagosomes," and "cytokine-cytokine receptor interaction" pathways. After multiple comparison adjustment, plasma cathepsin S (CTSS; hazard ratio [HR] 1.33, 95% CI: 1.17, 1.51, q = 0.007), growth/differentiation factor 15 (GDF15; HR: 1.45, 95% CI: 1.23, 1.72, q = 0.007), and thrombospondin-2 (THBS2; HR: 1.44, 95% CI: 1.22, 1.69, q = 0.007) remained significantly associated with high risk of losing mobility. CONCLUSION: CTSS, GDF15, and THBS2 are novel blood biomarkers associated with new mobility disability in community-dwelling individuals. Overall, our analysis suggests that cellular senescence and inflammation should be targeted for prevention of mobility disability." Osawa, Yusuke Semba, Richard D Fantoni, Giovanna Candia, Julian Biancotto, Angelique Tanaka, Toshiko Bandinelli, Stefania Ferrucci, Luigi eng R01HL/The National Institutes of Health/International R01 AG/AG/NIA NIH HHS/ R01AG/The National Institutes of Health/International R21HL/The National Institutes of Health/International 263MD/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural England Aging Cell. Apr;19(4):e. doi: 10./acel.. Epub Mar 10.I SomaScan 03/12/ Smith MA, et al. Using the circulating proteome to assess type I interferon activity in systemic lupus erythematosus Sci Rep 10 1 https://www.doi.org/10./s-020--9 32,157,125 Antibodies, Monoclonal, Humanized/*pharmacology Autoantibodies/*blood Biomarkers/*blood Gene Expression Profiling Humans Interferon Type I/*metabolism Lupus Erythematosus, Systemic/*blood/drug therapy/genetics Proteome/*analysis Severity of Illness Index Type I interferon (IFN) drives pathology in systemic lupus erythematosus (SLE) and can be tracked via IFN-inducible transcripts in blood. Here, we examined whether measurement of circulating proteins, which enter the bloodstream from inflamed tissues, also offers insight into global IFN activity. Using a novel protocol we generated 1,132 aptamer-based protein measurements from anti-dsDNA(pos) SLE blood samples and derived an IFN protein signature (IFNPS) that approximates the IFN 21-gene signature (IFNGS). Of 82 patients with SLE, IFNPS was elevated for 89% of IFNGS-high patients (49/55) and 26% of IFNGS-low patients (7/27). IFNGS-high/IFNPS-high patients exhibited activated NK, CD4, and CD8 T cells, while IFNPS-high only patients did not. IFNPS correlated with global disease activity in lymphopenic and non-lymphopenic patients and decreased following type I IFN neutralisation with anifrolumab in the SLE phase IIb study, MUSE. In summary, we developed a protein signature that reflects IFNGS and identifies a new subset of patients with SLE who have IFN activity. Smith, Michael A Chiang, Chia-Chien Zerrouki, Kamelia Rahman, Saifur White, Wendy I Streicher, Katie Rees, William A Schiffenbauer, Adam Rider, Lisa G Miller, Frederick W Manna, Zerai Hasni, Sarfaraz Kaplan, Mariana J Siegel, Richard Sinibaldi, Dominic Sanjuan, Miguel A Casey, Kerry A eng Research Support, Non-U.S. Gov't England Sci Rep. Mar 10;10(1):. doi: 10./s-020--9.I SomaScan 03/12/ Ferrannini G, et al. Coronary Artery Disease and Type 2 Diabetes: A Proteomic Study Diabetes Care 43 4 843-851 https://www.doi.org/10./dc19- 31,988,066 Aged Cohort Studies Computed Tomography Angiography Coronary Angiography/methods Coronary Artery Disease/diagnosis/epidemiology/*metabolism Diabetes Mellitus, Type 2/complications/diagnosis/epidemiology/*metabolism Diabetic Angiopathies/diagnosis/epidemiology/metabolism Female Humans Male Middle Aged Prevalence Proteome/*analysis/metabolism *Proteomics/methods Risk Factors Tomography, X-Ray Computed/methods OBJECTIVE: Coronary artery disease (CAD) is a major challenge in patients with type 2 diabetes (T2D). Coronary computed tomography angiography (CCTA) provides a detailed anatomic map of the coronary circulation. Proteomics are increasingly used to improve diagnostic and therapeutic algorithms. We hypothesized that the protein panel is differentially associated with T2D and CAD. RESEARCH DESIGN AND METHODS: In CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation-a cohort of 528 individuals with no previous cardiovascular event undergoing CCTA), participants were grouped into CAD(-) (clean coronaries) and CAD(+) (diffuse lumen narrowing or plaques). Plasma proteins were screened by aptamer analysis. Two-way partial least squares was used to simultaneously rank proteins by diabetes status and CAD. RESULTS: Though CAD(+) was more prevalent among participants with T2D (HbA(1c) 6.7 +/- 1.1%) than those without diabetes (56 vs. 30%, P < 0.), CCTA-based atherosclerosis burden did not differ. Of the 20 top-ranking proteins, 15 were associated with both T2D and CAD, and 3 (osteomodulin, cartilage intermediate-layer protein 15, and HTRA1) were selectively associated with T2D only and 2 (epidermal growth factor receptor and contactin-1) with CAD only. Elevated renin and GDF15, and lower adiponectin, were independently associated with both T2D and CAD. In multivariate analysis adjusting for the Framingham risk panel, patients with T2D were protected" from CAD if female (P = 0.007), younger (P = 0.021), and with lower renin levels (P = 0.02). CONCLUSIONS: We concluded that 1) CAD severity and quality do not differ between participants with T2D and without diabetes; 2) renin, GDF15, and adiponectin are shared markers by T2D and CAD; 3) several proteins are specifically associated with T2D or CAD; and 4) in T2D, lower renin levels may protect against CAD." Ferrannini, Giulia Manca, Maria Laura Magnoni, Marco Andreotti, Felicita Andreini, Daniele Latini, Roberto Maseri, Attilio Maggioni, Aldo P Ostroff, Rachel M Williams, Stephen A Ferrannini, Ele eng Research Support, Non-U.S. Gov't Diabetes Care. Apr;43(4):843-851. doi: 10./dc19-. Epub Jan 27.I SomaScan 01/29/ Celik H, et al. Highly multiplexed proteomic assessment of human bone marrow in acute myeloid leukemia Blood Adv 4 2 367-379 https://www.doi.org/10./bloodadvances. 31,985,806 Bone Marrow/*pathology Case-Control Studies Cellular Microenvironment Chemokines/analysis Chemokines, CC/metabolism Cytokines/analysis Gene Expression Regulation, Leukemic Humans Interleukin-8/metabolism Leukemia, Myeloid, Acute/*pathology Neoplasm Proteins/analysis Proteomics/*methods Acute myeloid leukemia (AML) is a genetically heterogeneous disease that is characterized by abnormal clonal proliferation of myeloid progenitor cells found predominantly within the bone marrow (BM) and blood. Recent studies suggest that genetic and phenotypic alterations in the BM microenvironment support leukemogenesis and allow leukemic cells to survive and evade chemotherapy-induced death. However, despite substantial evidence indicating the role of tumor-host interactions in AML pathogenesis, little is known about the complex microenvironment of the BM. To address this, we performed novel proteomic profiling of the noncellular compartment of the BM microenvironment in patients with AML (n = 10) and age- and sex-matched healthy control subjects (n = 10) using an aptamer-based, highly multiplexed, affinity proteomics platform (SOMAscan). We show that proteomic assessment of blood or RNA-sequencing of BM are suboptimal alternate screening strategies to determine the true proteomic composition of the extracellular soluble compartment of AML patient BM. Proteomic analysis revealed that 168 proteins significantly differed in abundance, with 91 upregulated and 77 downregulated in leukemic BM. A highly connected signaling network of cytokines and chemokines, including IL-8, was found to be the most prominent proteomic signature associated with AML in the BM microenvironment. We report the first description of significantly elevated levels of the myelosuppressive chemokine CCL23 (myeloid progenitor inhibitory factor-1) in both AML and myelodysplastic syndrome patients and perform functional experiments supportive of a role in the suppression of normal hematopoiesis. This unique paired RNA-sequencing and proteomics data set provides innovative mechanistic insights into AML and healthy aging and should serve as a useful public resource. Celik, Haydar Lindblad, Katherine E Popescu, Bogdan Gui, Gege Goswami, Meghali Valdez, Janet DeStefano, Christin Lai, Catherine Thompson, Julie Ghannam, Jack Y Fantoni, Giovanna Biancotto, Angelique Candia, Julian Cheung, Foo Sukumar, Gauthaman Dalgard, Clifton L Smith, Richard H Larochelle, Andre Dillon, Laura W Hourigan, Christopher S eng ZIA HL/Intramural NIH HHS/ Blood Adv. Jan 28;4(2):367-379. doi: 10./bloodadvances..I SomaScan 01/28/ Arjaans S, et al. Early angiogenic proteins associated with high risk for bronchopulmonary dysplasia and pulmonary hypertension in preterm infants Am J Physiol Lung Cell Mol Physiol 318 4 L644-L654 https://www.doi.org/10./ajplung.. 31,967,847 Adult Angiogenic Proteins/*metabolism Biomarkers/metabolism Bronchopulmonary Dysplasia/*etiology/*metabolism Female Gestational Age Humans Hypertension, Pulmonary/*etiology/*metabolism Infant, Extremely Premature/*metabolism Lung/metabolism Male Prospective Studies Proteomics/methods Vascular Diseases/metabolism SOMAmer angiogenesis aptamers biomarkers bronchopulmonary dysplasia lung development proteomics pulmonary hypertension related to this current work: laboratory research grants from United Therapeutics, Shire Pharmaceuticals, and Actelion. None of the other authors has any conflicts of interest, financial or otherwise, to disclose. Early pulmonary vascular disease in preterm infants is associated with the subsequent development of bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH); however, mechanisms that contribute to or identify infants with increased susceptibility for BPD and/or PH are incompletely understood. Therefore, we tested if changes in circulating angiogenic peptides during the first week of life are associated with the later development of BPD and/or PH. We further sought to determine alternate peptides and related signaling pathways with the risk for BPD or PH. We prospectively enrolled infants with gestational age <34 wk and collected blood samples during their first week of life. BPD and PH were assessed at 36 wk postmenstrual age. Samples were assayed for each of the 1,121 peptides included in the SOMAscan scan technology, with subsequent pathway analysis. Of 102 infants in the study, 82 had BPD, and 13 had PH. Multiple angiogenic proteins (PF-4, VEGF121, ANG-1, bone morphogenetic protein 10 [BMP10], hepatocyte growth factor (HGF), ANG-2) were associated with the subsequent diagnosis of BPD; and FGF-19, PF-4, connective tissue activating peptide (CTAP)-III, and PDGF-AA levels were associated with BPD severity. Early increases in BMP10 was strongly associated with the late risk for BPD and PH. We found that early alterations of circulating angiogenic peptides and others were associated with the subsequent development of BPD. We further identified peptides that were associated with BPD severity and BPD-associated PH, including BMP10. We speculate that proteomic biomarkers during the first week of life may identify infants at risk for BPD and/or PH to enhance care and research. Arjaans, Sanne Wagner, Brandie D Mourani, Peter M Mandell, Erica W Poindexter, Brenda B Berger, Rolf M F Abman, Steven H eng K23 RR/RR/NCRR NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Observational Study Research Support, N.I.H., Extramural Am J Physiol Lung Cell Mol Physiol. Apr 1;318(4):L644-L654. doi: 10./ajplung... Epub Jan 22.I SomaScan 01/23/ Tala JA, et al. Protein biomarkers for incident deep venous thrombosis in critically ill adolescents: An exploratory study Pediatr Blood Cancer 67 4 e https://www.doi.org/10./pbc. 31,904,170 Adolescent Biomarkers/*blood *Critical Illness Female Follow-Up Studies Humans Incidence Intensive Care Units Male Prognosis Prospective Studies Proteins/*analysis Risk Factors United States/epidemiology Venous Thrombosis/blood/*diagnosis/epidemiology adolescents biomarkers bleeding deep venous thrombosis proteins BACKGROUND: There are no tests to identify critically ill children at high risk of deep venous thrombosis (DVT). In this exploratory study, we aimed to identify proteins that are associated with incident DVT in critically ill adolescents. PROCEDURE: Plasma samples were obtained from critically ill adolescents within 24 hours after initiation of cardiopulmonary support. The adolescents were followed with ultrasound to detect the development of DVT of the lower extremity and clinically for bleeding. Thrombin-antithrombin complex and prothrombin fragment 1+2 were measured using immunosorbent assays, whereas procoagulation and anticoagulation factors were measured using multiplex assays. Plasma samples were also analyzed using SOMAscan, an aptamer-based capture assay. The associations between DVT and the log-transformed level of the proteins were assessed using logistic regression adjusting for the presence of femoral venous catheter and severity of illness. Associations were expressed as odds ratio (OR) for every log-fold increase in level of the protein with 95% confidence interval (CI). RESULTS: Plasma from 59 critically ill adolescents, of whom 9 developed incident DVT, was analyzed. The median age of the adolescents was 15.1 years (interquartile range, 14.0-16.7 years). Higher levels of thrombin-antithrombin complex (OR: 31.54; 95% CI: 2.09-475.92) and lower levels of factor XIII (OR: 0.03; 95% CI: 0.002-0.44) were associated with DVT. CD36, MIC-1, and EpoR were marginally associated with DVT. Only factor XIII was associated with clinically relevant bleeding (OR: 0.27; 95% CI: 0.08-0.97). CONCLUSIONS: We identified candidate protein biomarkers for incident DVT. We plan to validate our findings in adequately powered studies. Tala, Joana A Polikoff, Lee A Pinto, Matthew G Li, Simon Trakas, Erin Miksa, Michael Gertz, Shira Faustino, Edward Vincent S eng 14CRP/AHA/American Heart Association-American Stroke Association/ Multicenter Study Research Support, Non-U.S. Gov't Pediatr Blood Cancer. Apr;67(4):e. doi: 10./pbc.. Epub Jan 6.I SomaScan 01/07/ Zaghlool SB, et al. Epigenetics meets proteomics in an epigenome-wide association study with circulating blood plasma protein traits Nat Commun 11 1 15 https://www.doi.org/10./s-019--w 31,900,413 Adult Aged Aged, 80 and over Blood Proteins/*genetics Chemokine CXCL10/genetics Cohort Studies CpG Islands DNA Methylation Epigenome Epigenomics Female GPI-Linked Proteins/genetics Germany Humans Inflammation/*genetics Intracellular Signaling Peptides and Proteins/genetics Male Middle Aged Proteomics Receptors, IgG/genetics DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation. Zaghlool, Shaza B Kuhnel, Brigitte Elhadad, Mohamed A Kader, Sara Halama, Anna Thareja, Gaurav Engelke, Rudolf Sarwath, Hina Al-Dous, Eman K Mohamoud, Yasmin A Meitinger, Thomas Wilson, Rory Strauch, Konstantin Peters, Annette Mook-Kanamori, Dennis O Graumann, Johannes Malek, Joel A Gieger, Christian Waldenberger, Melanie Suhre, Karsten eng Research Support, Non-U.S. Gov't England Nat Commun. Jan 3;11(1):15. doi: 10./s-019--w.I SomaScan 01/05/ Almufleh A, et al. Biomarker discovery in cardiac allograft vasculopathy using targeted aptamer proteomics Clin Transplant 34 1 e https://www.doi.org/10./ctr. 31,815,308 Allografts Biomarkers Coronary Angiography *Coronary Artery Disease/diagnosis/etiology Female *Heart Transplantation/adverse effects Humans Male Middle Aged Prospective Studies Proteomics aptamer proteomic profiling cardiac allograft vasculopathy serum biomarkers Cardiac allograft vasculopathy (CAV) limits long-term survival after heart transplantation. Non-invasive evaluation is challenging, and currently, there is no validated biomarker for CAV diagnosis or prognostication. To identify potential candidate CAV biomarkers, we utilized the Slow Off-rate Modified Aptamer (SOMAscan) assay, which evaluates over serum proteins, including many relevant to biological pathways in CAV. We evaluated three heart transplant patient groups according to angiographic ISHLT CAV grade: CAV(1-2) (mild-moderate CAV), CAV(3) (severe CAV), and CAV(0) (normal control). SOMAscan assays were performed and proteins quantitated. Comparisons of proteins between study groups were performed using one-way ANOVA (false discovery rate q-value < 0.10). Thirty-one patients (12 mild-moderate CAV, 9 severe CAV, 10 controls) were included: 81% male, median age 57 years and median 1.1 years post-transplant. Compared to controls, patients with mild-moderate CAV had similar characteristics, while patients with severe CAV had longer time from transplant and increased allosensitization. Statistical/bioinformatics analysis identified 14 novel biomarkers for CAV, including 4 specific for mild-moderate CAV. These proteins demonstrated important actions including apoptosis, inflammation, and platelet/coagulation activation. Upon preliminary receiver operating characteristics curve analysis, our protein biomarkers showed moderate-to-high discriminative ability for CAV (area under curve: 0.72 to 0.94). These candidate biomarkers are being validated in prospective studies. Almufleh, Aws Zhang, Liyong Mielniczuk, Lisa M Stadnick, Ellamae Davies, Ross A Du, Qiujiang Rayner, Katey Liu, Peter P Chih, Sharon eng CIHR/Canada Research Support, Non-U.S. Gov't Denmark Clin Transplant. Jan;34(1):e. doi: 10./ctr.. Epub Dec 30.I SomaScan 12/10/ Shubin NJ, et al. Serum Protein Changes in Pediatric Sepsis Patients Identified With an Aptamer-Based Multiplexed Proteomic Approach Crit Care Med 48 1 e48-e57 https://www.doi.org/10./CCM. 31,714,400 Aptamers, Peptide Blood Proteins/*analysis Child Cohort Studies Humans Proteomics/*methods Retrospective Studies Sepsis/*blood/*diagnosis/genetics OBJECTIVES: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death and disability among children worldwide. Identifying sepsis in pediatric patients is difficult and can lead to treatment delay. Our objective was to assess the host proteomic response to infection utilizing an aptamer-based multiplexed proteomics approach to identify novel serum protein changes that might help distinguish between pediatric sepsis and infection-negative systemic inflammation and hence can potentially improve sensitivity and specificity of the diagnosis of sepsis over current clinical criteria approaches. DESIGN: Retrospective, observational cohort study. SETTING: PICU and cardiac ICU, Seattle Children's Hospital, Seattle, WA. PATIENTS: A cohort of 40 children with clinically overt sepsis and 30 children immediately postcardiopulmonary bypass surgery (infection-negative systemic inflammation control subjects) was recruited. Children with sepsis had a confirmed or suspected infection, two or more systemic inflammatory response syndrome criteria, and at least cardiovascular and/or pulmonary organ dysfunction. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum samples from 35 of the sepsis and 28 of the bypass surgery subjects were available for screening with an aptamer-based proteomic platform that measures 1,305 proteins to search for large-scale serum protein expression pattern changes in sepsis. A total of 111 proteins were significantly differentially expressed between the sepsis and control groups, using the linear models for microarray data (linear modeling) and Boruta (decision trees) R packages, with 55 being previously identified in sepsis patients. Weighted gene correlation network analysis helped identify 76 proteins that correlated highly with clinical sepsis traits, 27 of which had not been previously reported in sepsis. CONCLUSIONS: The serum protein changes identified with the aptamer-based multiplexed proteomics approach used in this study can be useful to distinguish between sepsis and noninfectious systemic inflammation. Shubin, Nicholas J Navalkar, Krupa Sampson, Dayle Yager, Thomas D Cermelli, Silvia Seldon, Therese Sullivan, Erin Zimmerman, Jerry J Permut, Lester C Piliponsky, Adrian M eng Observational Study Crit Care Med. Jan;48(1):e48-e57. doi: 10./CCM..I SomaScan 11/13/ Leonard A, et al. Atopic Dermatitis Endotypes Based on Allergen Sensitization, Reactivity to Staphylococcus aureus Antigens, and Underlying Systemic Inflammation J Allergy Clin Immunol Pract 8 1 236-247 e3 https://www.doi.org/10./j.jaip..08.013 31,430,591 Allergens *Dermatitis, Atopic/diagnosis Humans Inflammation Proteomics *Staphylococcus aureus Allergy Atopic dermatitis BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory disease with significant local and systemic inflammation and barrier disruption. AD is associated with increased risk of allergen sensitization and skin colonization by Staphylococcus aureus. The heterogeneity of AD is unknown, and its complexity suggests its subdivision into several endotypes. OBJECTIVE: To evaluate allergy-driven endotypic differences in patients with AD and identify proteomic signatures to distinguish between inflammatory responses. To perform proteomic profiling of allergen sensitivity, antibody levels to S aureus antigens, and circulating inflammatory mediators to characterize AD subsets in 76 subjects with moderate to severe AD and 39 healthy controls (HCs). METHODS: Sera were collected from 76 subjects with moderate to severe AD and 39 HCs with no history of skin disease. Serum was tested for levels of total serum immunoglobulin E (IgE) and allergen-specific IgE using a panel of 119 allergens as well as IgE antibodies against S aureus antigens, and was profiled for more than proteins by SOMAscan to detect differential expression of inflammatory mediators. RESULTS: Total serum IgE levels were significantly (P < .001) elevated in subjects with AD versus controls. A greater percentage of subjects with AD were allergic compared with HCs, and patients with AD tested positive to a greater number of allergens than did HCs. IgE was upregulated across 4 allergen subsets (food, perennial, seasonal, and mixed), and each allergen subset was associated with a distinct inflammatory signature marked by a specific suite of upregulated proteins. Finally, IgE antibodies against S aureus toxic shock syndrome toxin-1 were significantly upregulated in subjects with seasonal allergy (P = .) and perennial allergy (P = .). CONCLUSIONS: Overall, this study addresses the heterogeneity of AD by characterizing subsets of AD on the basis of allergen sensitization. It also demonstrates the differential systemic inflammation and S aureus-specific antibody responses associated with the allergenic endotypes. These unique proteomic signatures may be valuable for precise disease characterization and subsequent personalized treatment. Leonard, Alexandra Wang, Jingya Yu, Li Liu, Hao Estrada, Yeriel Greenlees, Lydia McPhee, Roderick Ruzin, Alexey Guttman-Yassky, Emma Howell, Michael D eng Research Support, Non-U.S. Gov't J Allergy Clin Immunol Pract. Jan;8(1):236-247.e3. doi: 10./j.jaip..08.013. Epub Aug 17.I SomaScan 08/21/ Semba RD, et al. Elevated Plasma Growth and Differentiation Factor 15 Is Associated With Slower Gait Speed and Lower Physical Performance in Healthy Community-Dwelling Adults J Gerontol A Biol Sci Med Sci 75 1 175-180 https://www.doi.org/10./gerona/glz071 30,874,790 Adult Aged Aged, 80 and over Aging/*physiology Biomarkers/blood Female Follow-Up Studies Gait/*physiology Geriatric Assessment/*methods Growth Differentiation Factor 15/*blood Healthy Volunteers Humans *Independent Living Male Middle Aged Physical Functional Performance Prospective Studies Sarcopenia/*blood/epidemiology/physiopathology Walking Speed/*physiology Young Adult Aging Growth and differentiation factor 15 Physical performance Sarcopenia Skeletal muscle BACKGROUND: Growth and differentiation factor 15 (GDF-15) has been associated with obesity, muscle wasting, and cachexia. The receptor for GDF-15 was recently identified in the brainstem and regulates food intake and metabolism. The relationship of plasma GDF-15 with the age-associated decline of muscle mass and strength, gait speed, and physical performance in adults has not been well characterized. METHODS: Plasma GDF-15, grip strength, 6-m gait speed, 400-m walking test time, lower extremity physical performance score, appendicular lean mass, and fat mass were measured in 194 healthy adult participants, aged 22-93 years, of the Baltimore Longitudinal Study of Aging. RESULTS: Plasma GDF-15 concentrations increased with age (p < .001) and were higher in whites compared with blacks and Asians (p = .04). Adults with higher plasma GDF-15 had slower 6-m gait speed, longer 400-m walking time, and lower physical performance score in multivariable analyses adjusting for age and race. Plasma GDF-15 was not associated with grip strength, appendicular lean mass, or fat mass. CONCLUSIONS: Elevated plasma GDF-15 is associated with slower gait speed, higher 400-m walking time, and lower physical performance in very healthy community-dwelling adults. The relationship between plasma GDF-15 and sarcopenia-related outcomes may be stronger in the population not selected to be healthy, and this hypothesis should be tested in a representative population. Semba, Richard D Gonzalez-Freire, Marta Tanaka, Toshiko Biancotto, Angelique Zhang, Pingbo Shardell, Michelle Moaddel, Ruin Ferrucci, Luigi eng R01 AG/AG/NIA NIH HHS/ R01 EY/EY/NEI NIH HHS/ R01 AG/AG/NIA NIH HHS/ R56 AG/AG/NIA NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural J Gerontol A Biol Sci Med Sci. Jan 1;75(1):175-180. doi: 10./gerona/glz071.I SomaScan 03/16/ King JD, et al. Joint Fluid Proteome after Anterior Cruciate Ligament Rupture Reflects an Acute Posttraumatic Inflammatory and Chondrodegenerative State Cartilage 11 3 329-337 https://www.doi.org/10./ 30,033,738 Adolescent Anterior Cruciate Ligament/metabolism Anterior Cruciate Ligament Injuries/*metabolism Arthrocentesis Biomarkers/metabolism Cytokines/metabolism Female Humans Inflammation Knee Joint/*metabolism Male Osteoarthritis, Knee/*metabolism Proteome/*metabolism Proteomics Randomized Controlled Trials as Topic Rupture/metabolism Signal Transduction/genetics Synovial Fluid/*metabolism Young Adult anterior cruciate ligament biomarker osteoarthritis pathway analysis proteome conflicts of interest with respect to the research, authorship, and/or publication of this article. OBJECTIVE: The purpose of this study was to evaluate changes in the synovial fluid proteome following acute anterior cruciate ligament (ACL) injury. DESIGN: This study represents a secondary analysis of synovial fluid samples collected from the placebo group of a previous randomized trial. Arthrocentesis was performed twice on 6 patients with an isolated acute ACL tear at a mean of 6 and 14 days postinjury. Synovial fluid was analyzed by a highly multiplexed assay of proteins (SOMAscan version 3, SomaLogic, Inc., Boulder, CO). Pathway analysis using DAVID was performed; genes included met 3 criteria: significant change between the 2 study time points using a paired t test, significant change between the 2 study time points using a Mann-Whitney nonparametric test, and significant Benjamini post hoc analysis. RESULTS: Fifteen analytes demonstrated significant increases between time points. Five of the 15 have been previously associated with the onset and/or severity of rheumatoid arthritis, including apoliopoprotein E and isoform E3, vascular cell adhesion protein 1, interleukin-34, and cell surface glycoprotein CD200 receptor 1. Chondrodegenerative enzymes and products of cartilage degeneration all increased over time following injury: MMP-1 (P = 0.08, standardized response mean [SRM] = 1.00), MMP-3 (P = 0.05, SRM = 0.90), ADAM12 (P = 0.03, SRM = 1.31), aggrecan (P = 0.08, SRM = 1.13), and CTX-II (P = 0.07, SRM = 0.56). Notable pathways that were differentially expressed following injury were the cytokine-cytokine receptor interaction and osteoclast differentiation pathways. CONCLUSIONS: The proteomic results and pathway analysis demonstrated a pattern of cartilage degeneration, not only consistent with previous findings but also changes consistent with an inflammatory arthritogenic process post-ACL injury. King, John D Rowland, Grant Villasante Tezanos, Alejandro G Warwick, James Kraus, Virginia B Lattermann, Christian Jacobs, Cale A eng K23 AR/AR/NIAMS NIH HHS/ R24 HD/HD/NICHD NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cartilage. Jul;11(3):329-337. doi: 10./. Epub Jul 22.I SomaScan 07/24/ Cuvelliez M, et al. Circulating proteomic signature of early death in heart failure patients with reduced ejection fraction Sci Rep 9 1 https://www.doi.org/10./s-019--1 31,844,116 Cardiovascular System/metabolism Cause of Death Extracellular Matrix/metabolism Female Heart Failure/*blood/metabolism/*mortality Humans Male Middle Aged Proteome/*metabolism Proteomics/methods Risk Factors Heart failure (HF) remains a main cause of mortality worldwide. Risk stratification of patients with systolic chronic HF is critical to identify those who may benefit from advanced HF therapies. The aim of this study is to identify plasmatic proteins that could predict the early death (within 3 years) of HF patients with reduced ejection fraction hospitalized in CHRU de Lille. The subproteome targeted by an aptamer-based technology, the Slow Off-rate Modified Aptamer (SOMA) scan assay of proteins, was profiled in blood samples from 168 HF patients, and 203 proteins were significantly modulated between patients who died of cardiovascular death and patients who were alive after 3 years of HF evaluation (Wilcoxon test, FDR 5%). A molecular network was built using these 203 proteins, and the resulting network contained molecules assigned to 34 clusters annotated to biological pathways by Gene Ontology. This network model highlighted extracellular matrix organization as the main mechanism involved in early death in HF patients. In parallel, an adaptive Least Absolute Shrinkage and Selection Operator (LASSO) was performed on these 203 proteins, and six proteins were selected as candidates to predict early death in HF patients: complement C3, cathepsin S and F107B were decreased and MAPK5, MMP1 and MMP7 increased in patients who died of cardiovascular causes compared with patients living 3 years after HF evaluation. This proteomic signature of 6 circulating plasma proteins allows the identification of systolic HF patients with a risk of early death. Cuvelliez, Marie Vandewalle, Vincent Brunin, Maxime Beseme, Olivia Hulot, Audrey de Groote, Pascal Amouyel, Philippe Bauters, Christophe Marot, Guillemette Pinet, Florence eng Research Support, Non-U.S. Gov't England Sci Rep. Dec 16;9(1):. doi: 10./s-019--1.I SomaScan 12/18/ Shubin AV, et al. Blood proteome profiling using aptamer-based technology for rejection biomarker discovery in transplantation Sci Data 6 1 314 https://www.doi.org/10./s-019--y 31,819,064 *Aptamers, Nucleotide Biomarkers/blood Blood Proteins/*analysis Graft Rejection/blood/*diagnosis Humans *Proteome Proteomics/*methods *Transplantation Face transplantation is a promising solution for patients with devastating facial injuries who lack other satisfactory treatment options. At the same time, this type of transplantation is accompanied with high risks of acute transplant rejection. The limitations of traditional skin biopsy and the need to frequently monitor the condition of face transplant call for less invasive biomarkers to better diagnose and treat acute rejection. Discovery of peripheral serum proteins accurately reflecting the transplant status would represent a reasonable solution to meet this demand. However, to date, there is no clinical data available to address the feasibility of this approach. In this study, we used the next generation aptamer-based SOMAscan proteomics platform to profile proteins of peripheral blood serum in twenty-four samples taken from 6 patients during no-rejection, nonsevere rejection, and severe rejection episodes. Also, we provide a detailed description of biosample processing and all steps to generate and analyze the SOMAscan dataset with hope it will assist in performing biomarker discovery in other transplantation centers using this platform. Shubin, Andrey V Kollar, Branislav Dillon, Simon T Pomahac, Bohdan Libermann, Towia A Riella, Leonardo V eng W81XWH-16-1-/U.S. Department of Health & Human Services | Office of the Assistant Secretary for Health (OASH)/International P30 CA/CA/NCI NIH HHS/ Dataset Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Sci Data. Dec 9;6(1):314. doi: 10./s-019--y.I SomaScan 12/11/ Emilsson V, et al. Predicting health and life span with the deep plasma proteome Nat Med 25 12 - https://www.doi.org/10./s-019--y 31,806,904 Aging/*blood/genetics Humans Longevity/*genetics Proteome/*genetics Emilsson, Valur Gudnason, Vilmundur Jennings, Lori L eng Nat Med. Dec;25(12):-. doi: 10./s-019--y.I SomaScan 12/07/ Lehallier B, et al. Undulating changes in human plasma proteome profiles across the lifespan Nat Med 25 12 - https://www.doi.org/10./s-019--2 31,806,903 Adolescent Adult Aged Aged, 80 and over Aging/*blood/genetics Animals Blood Proteins/*genetics Chronic Disease Female Humans Longevity/*genetics Male Mice Middle Aged Proteome/*genetics Risk Factors Young Adult Aging is a predominant risk factor for several chronic diseases that limit healthspan(1). Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues(2-10), which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases. Lehallier, Benoit Gate, David Schaum, Nicholas Nanasi, Tibor Lee, Song Eun Yousef, Hanadie Moran Losada, Patricia Berdnik, Daniela Keller, Andreas Verghese, Joe Sathyan, Sanish Franceschi, Claudio Milman, Sofiya Barzilai, Nir Wyss-Coray, Tony eng RG/13/13//BHF_/British Heart Foundation/United Kingdom K99 NS/NS/NINDS NIH HHS/ R01 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ DP1 AG/AG/NIA NIH HHS/ P30 AG/AG/NIA NIH HHS/ T32 AG/AG/NIA NIH HHS/ F32 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ P50 AG/AG/NIA NIH HHS/ K23 AG/AG/NIA NIH HHS/ R00 NS/NS/NINDS NIH HHS/ RG/18/13//BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Med. Dec;25(12):-. doi: 10./s-019--2. Epub Dec 5.I SomaScan 12/07/ Williams SA, et al. Plasma protein patterns as comprehensive indicators of health Nat Med 25 12 - https://www.doi.org/10./s-019--2 31,792,462 Adipose Tissue/metabolism Blood Proteins/*genetics Body Composition/*genetics/physiology *Exercise Female Humans Intra-Abdominal Fat/metabolism Life Style Liver/metabolism Male *Precision Medicine Risk Factors Proteins are effector molecules that mediate the functions of genes(1,2) and modulate comorbidities(3-10), behaviors and drug treatments(11). They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning(12-16) coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check. Williams, Stephen A Kivimaki, Mika Langenberg, Claudia Hingorani, Aroon D Casas, J P Bouchard, Claude Jonasson, Christian Sarzynski, Mark A Shipley, Martin J Alexander, Leigh Ash, Jessica Bauer, Tim Chadwick, Jessica Datta, Gargi DeLisle, Robert Kirk Hagar, Yolanda Hinterberg, Michael Ostroff, Rachel Weiss, Sophie Ganz, Peter Wareham, Nicholas J eng MR/R/1/MRC_/Medical Research Council/United Kingdom MC_UU_/1/MRC_/Medical Research Council/United Kingdom RF1 AG/AG/NIA NIH HHS/ MR/S/1/MRC_/Medical Research Council/United Kingdom R01 HL/HL/NHLBI NIH HHS/ R01 AG/AG/NIA NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ RG/10/12//BHF_/British Heart Foundation/United Kingdom SP/13/6//BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Med. Dec;25(12):-. doi: 10./s-019--2. Epub Dec 2.I SomaScan 12/04/ Graumann J, et al. Multi-platform Affinity Proteomics Identify Proteins Linked to Metastasis and Immune Suppression in Ovarian Cancer Plasma Front Oncol 9 https://www.doi.org/10./fonc.. 31,737,572 SOMAscan aptamer assay Spint2 affinity proteomics metastasis ovarian carcinoma proximity extension assay (PEA) A central reason behind the poor clinical outcome of patients with high-grade serous carcinoma (HGSC) of the ovary is the difficulty in reliably detecting early occurrence or recurrence of this malignancy. Biomarkers that provide reliable diagnosis of this disease are therefore urgently needed. Systematic proteomic methods that identify HGSC-associated molecules may provide such biomarkers. We applied the antibody-based proximity extension assay (PEA) platform (Olink) for the identification of proteins that are upregulated in the plasma of OC patients. Using binders targeting 368 different plasma proteins, we compared 20 plasma samples from HGSC patients (OC-plasma) with 20 plasma samples from individuals with non-malignant gynecologic disorders (N-plasma). We identified 176 proteins with significantly higher levels in OC-plasma compared to N-plasma by PEA (p < 0.05 by U-test; Benjamini-Hochberg corrected), which are mainly implicated in immune regulation and metastasis-associated processes, such as matrix remodeling, adhesion, migration and proliferation. A number of these proteins have not been reported in previous studies, such as BCAM, CDH6, DDR1, N2DL-2 (ULBP2), SPINT2, and WISP-1 (CCN4). Of these SPINT2, a protease inhibitor mainly derived from tumor cells within the HGSC microenvironment, showed the highest significance (p < 2 x 10(-7)) similar to the previously described IL-6 and PVRL4 (NECTIN4) proteins. Results were validated by means of the aptamer-based 1.3 k SOMAscan proteomic platform, which revealed a high inter-platform correlation with a median Spearman rho of 0.62. Likewise, ELISA confirmed the PEA data for 10 out of 12 proteins analyzed, including SPINT2. These findings suggest that in contrast to other entities SPINT2 does not act as a tumor suppressor in HGSC. This is supported by data from the PRECOG and KM-Plotter meta-analysis databases, which point to a tumor-type-specific inverse association of SPINT2 gene expression with survival. Our data also demonstrate that both the PEA and SOMAscan affinity proteomics platforms bear considerable potential for the unbiased discovery of novel disease-associated biomarkers. Graumann, Johannes Finkernagel, Florian Reinartz, Silke Stief, Thomas Brodje, Dorte Renz, Harald Jansen, Julia M Wagner, Uwe Worzfeld, Thomas Pogge von Strandmann, Elke Muller, Rolf eng Switzerland Front Oncol. Nov 1;9:. doi: 10./fonc... eCollection .I SomaScan 11/19/ Coombs KM, et al. Aptamer Profiling of A549 Cells Infected with Low-Pathogenicity and High-Pathogenicity Influenza Viruses Viruses 11 11 https://www.doi.org/10./v 31,694,171 A549 Cells/metabolism/*virology Aptamers, Nucleotide/*analysis Cell Line Humans Influenza A Virus, H1N1 Subtype/pathogenicity Influenza A Virus, H5N1 Subtype/pathogenicity Influenza A Virus, H7N9 Subtype/pathogenicity Influenza A virus/*pathogenicity Proteome Proteomics/methods Virulence RNA virus infection SOMAScan(R) aptamers emerging viruses proteomics Influenza A viruses (IAVs) are important animal and human emerging and re-emerging pathogens that are responsible for yearly seasonal epidemics and sporadic pandemics. IAVs cause a wide range of clinical illnesses, from relatively mild infections by seasonal strains, to acute respiratory distress during infections with highly pathogenic avian IAVs (HPAI). For this study, we infected A549 human lung cells with lab prototype A/PR/8/34 (H1N1) (PR8), a seasonal H1N1 (RV733), the pandemic H1N1 (pdm09), or with two avian strains, an H5N1 HPAI strain or an H7N9 strain that has low pathogenicity in birds but high pathogenicity in humans. We used a newly-developed aptamer-based multiplexed technique (SOMAscan((R))) to examine > human lung cell proteins affected by the different IAV strains, and identified more than 500 significantly dysregulated cellular proteins. Our analyses indicated that the avian strains induced more profound changes in the A549 global proteome compared to all tested low-pathogenicity H1N1 strains. The PR8 strain induced a general activation, primarily by upregulating many immune molecules, the seasonal RV733 and pdm09 strains had minimal effect upon assayed molecules, and the avian strains induced significant downregulation, primarily in antimicrobial response, cardiovascular and post-translational modification systems. Coombs, Kevin M Simon, Philippe F McLeish, Nigel J Zahedi-Amiri, Ali Kobasa, Darwyn eng MOP-/CIHR/Canada Research Support, Non-U.S. Gov't Switzerland Viruses. Nov 5;11(11):. doi: 10./v.I SomaScan 11/07/ Alexaki A, et al. Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies Sci Rep 9 1 https://www.doi.org/10./s-019--2 31,664,102 *Codon Factor IX/*chemistry/*genetics Genetic Code *Genetic Therapy HEK293 Cells Humans *Protein Biosynthesis Protein Conformation Synonymous codons occur with different frequencies in different organisms, a phenomenon termed codon usage bias. Codon optimization, a common term for a variety of approaches used widely by the biopharmaceutical industry, involves synonymous substitutions to increase protein expression. It had long been presumed that synonymous variants, which, by definition, do not alter the primary amino acid sequence, have no effect on protein structure and function. However, a critical mass of reports suggests that synonymous codon variations may impact protein conformation. To investigate the impact of synonymous codons usage on protein expression and function, we designed an optimized coagulation factor IX (FIX) variant and used multiple methods to compare its properties to the wild-type FIX upon expression in HEK293T cells. We found that the two variants differ in their conformation, even when controlling for the difference in expression levels. Using ribosome profiling, we identified robust changes in the translational kinetics of the two variants and were able to identify a region in the gene that may have a role in altering the conformation of the protein. Our data have direct implications for codon optimization strategies, for production of recombinant proteins and gene therapies. Alexaki, Aikaterini Hettiarachchi, Gaya K Athey, John C Katneni, Upendra K Simhadri, Vijaya Hamasaki-Katagiri, Nobuko Nanavaty, Puja Lin, Brian Takeda, Kazuyo Freedberg, Daron Monroe, Dougald McGill, Joseph R Peters, Robert Kames, Jacob M Holcomb, David D Hunt, Ryan C Sauna, Zuben E Gelinas, Amy Janjic, Nebojsa DiCuccio, Michael Bar, Haim Komar, Anton A Kimchi-Sarfaty, Chava eng R15 HL/HL/NHLBI NIH HHS/ HL/U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/International Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. England Sci Rep. Oct 29;9(1):. doi: 10./s-019--2.I SomaScan 10/31/ Kukova LZ, et al. Comparison of Urine and Plasma Biomarker Concentrations Measured by Aptamer-Based versus Immunoassay Methods in Cardiac Surgery Patients J Appl Lab Med 4 3 331-342 https://www.doi.org/10./jalm.. 31,659,071 Aged Biomarkers/*blood/*urine Cardiac Surgical Procedures Comorbidity Female Heart Diseases/*blood/diagnosis/surgery/*urine Humans Immunoassay/*methods/*standards Male Middle Aged BACKGROUND: Protein detection assays are invaluable tools in the field of biomarker discovery. However, only immunoassays are widely used and can measure 10-20 analytes per biosample. The novel SOMAmer-based assay uses nucleotide aptamer technology to measure over analytes per biosample. We compared the SOMAmer-based platform to traditional approaches to quantify analytes in a clinical setting with paired samples before and after cardiac surgery. METHODS: In a substudy of the Translational Research Investigating Biomarker Endpoints in Acute Kidney Injury cohort, 54 individuals with acute kidney injury after cardiac surgery were identified. Preoperative and postoperative plasma and urine samples that had been previously evaluated for biomarker concentrations via immunoassays were analyzed via SOMAmer-based assay. RESULTS: Spearman correlations were estimated when >50% of biomarker values were within detectable ranges by immunoassay (plasma biomarkers: preoperative, 26/33; postoperative, 31/33; urine biomarkers: preoperative, 13/16; postoperative, 16/16). Overall, 27% of reportable plasma preoperative biomarkers displayed correlations >/=0.75 between immunoassay and SOMAmer measurements; 23% displayed correlations of 0.50-0.75, and 50% displayed correlations /=0.75, 16% displayed correlations 0.50-0.75, and 42% displayed correlations <0.50. In urine, these values were 19%, 25%, and 56%, respectively. CONCLUSIONS: In cardiac surgery patients, the SOMAmer-based assay detects proteins with moderate to strong correlation to current immunoassay methods. The correlations in urine are weaker than those in plasma. SOMAmer-based assay technology should be further evaluated in multiple settings as a high-throughput screening tool for biomarker discovery. Kukova, Lidiya Z Mansour, Sherry G Coca, Steven G de Fontnouvelle, Christina A Thiessen-Philbrook, Heather R Shlipak, Michael G El-Khoury, Joe M Parikh, Chirag R eng K24 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural England J Appl Lab Med. Nov;4(3):331-342. doi: 10./jalm... Epub May 28.I SomaScan 10/30/ Ochsner UA, et al. Targeting Unique Epitopes on Highly Similar Proteins GDF-11 and GDF-8 with Modified DNA Aptamers Biochemistry 58 46 - https://www.doi.org/10./acs.biochem.9b 31,638,376 Amino Acid Sequence Aptamers, Nucleotide/*chemistry Base Sequence Binding Sites Bone Morphogenetic Proteins/*analysis Epitopes/analysis Growth Differentiation Factors/*analysis Humans Indicators and Reagents Myostatin/*analysis Recombinant Proteins/analysis SELEX Aptamer Technique The mature forms of the TGF-beta family members GDF-11 and GDF-8 are highly similar 25 kDa homodimers with 90% amino acid sequence identity and 99% similarity. Cross-reactivity of GDF-11 and GDF-8 binding reagents is common, making it difficult to attribute distinct roles of these two proteins in biology. We report the selection of GDF-11 and GDF-8 specific SOMAmer (Slow Off-rate Modified Aptamer) reagents aided by a combination of positive selection for one protein coupled with counter-selection against the other. We identified GDF-11 specific SOMAmer reagents from four modified DNA libraries that showed a high affinity (K(d) range 0.05-1.2 nM) for GDF-11 but did not bind to GDF-8 (K(d) > 1 muM). Conversely, we identified one SOMAmer reagent for GDF-8 from one of the modified libraries that demonstrated excellent affinity (K(d) = 0.23 nM) and specificity. In contrast, standard protocols that utilized only positive selection produced binding reagents with similar affinity for both proteins. High affinity and specificity were efficiently encoded in minimal sequences of 21 nucleotides for GDF-11 and 24 nucleotides for GDF-8. Further characterization in pull-down, competition, sandwich-binding, and kinetic studies revealed robust binding under a wide range of buffer and assay conditions. For highly similar proteins like GDF-11 and GDF-8, our method of selection coupled with counter-selection was essential for identification of high-affinity, specific reagents that have the potential to elucidate the fundamental distinction of these growth factors in biology. Ochsner, Urs A Green, Louis S Rice, Taylor P Olivas, Edgar Janjic, Nebojsa Katilius, Evaldas eng Biochemistry. Nov 19;58(46):-. doi: 10./acs.biochem.9b. Epub Nov 7.I SomaScan 10/23/ Tin A, et al. Reproducibility and Variability of Protein Analytes Measured Using a Multiplexed Modified Aptamer Assay J Appl Lab Med 4 1 30-39 https://www.doi.org/10./jalm.. 31,639,705 Aged Atherosclerosis/*blood/diagnosis Blood Proteins/*analysis Equipment Design Female Glomerular Filtration Rate/physiology Humans Male Middle Aged Prospective Studies Proteomics/*instrumentation Reproducibility of Results BACKGROUND: There is growing interest in the use of multiplexed aptamer-based assays for large-scale proteomic studies. However, the analytic, short- and long-term variation of the measured proteins is largely uncharacterized. METHODS: We quantified plasma protein analytes from 42 participants in the Atherosclerosis Risk in Communities (ARIC) Study in split samples and at multiple visits using a multiplexed modified aptamer assay. We calculated the CV, Spearman correlation, and intraclass correlation (ICC) between split samples and evaluated the short-term (4-9 weeks) and long-term (approximately 20 years) variability using paired t-tests with log-transformed protein concentrations and Bonferroni-corrected significance thresholds. We performed principal component (PC) analysis of protein analyte concentrations and evaluated their associations with age, sex, race, and estimated glomerular filtration rate (eGFR). RESULTS: The mean baseline age was 57 years at the first visit, 43% of participants were male and 57% were white. Among protein analytes that passed quality control, half (n = ) had CVs 0.89, and ICCs > 0.96 among the split samples. Over the short term, only 1 analyte had a statistically significant difference between the 2 time points, whereas, over approximately 20 years, 866 analytes (23.4%) had statistically significant differences (P < 1.4 x 10(-5), 681 increased, 185 decreased). PC1 had high correlations with age (-0.73) and eGFR (0.60). PC2 had moderate correlation with male sex (0.18) and white race (0.31). CONCLUSIONS: Multiplexed modified aptamer technology can assay thousands of proteins with excellent precision. Our results support the potential for large-scale studies of the plasma proteome over the lifespan. Tin, Adrienne Yu, Bing Ma, Jianzhong Masushita, Kunihiro Daya, Natalie Hoogeveen, Ron C Ballantyne, Christie M Couper, David Rebholz, Casey M Grams, Morgan E Alonso, Alvaro Mosley, Thomas Heiss, Gerardo Ganz, Peter Selvin, Elizabeth Boerwinkle, Eric Coresh, Josef eng HHSNC/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ K01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England J Appl Lab Med. Jul;4(1):30-39. doi: 10./jalm... Epub Jan 22.I SomaScan 10/23/ Posavi M, et al. Characterization of Parkinson's disease using blood-based biomarkers: A multicohort proteomic analysis PLoS Med 16 10 e https://www.doi.org/10./journal.pmed. 31,603,904 Aged Algorithms Amidohydrolases/blood Biomarkers/*blood Carrier Proteins/blood Disease Progression Extracellular Matrix Proteins/blood Female Humans Longitudinal Studies Male Middle Aged Neurodegenerative Diseases Osteopontin/blood Parkinson Disease/*blood Proportional Hazards Models Proteoglycans/blood *Proteomics Reproducibility of Results BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disease affecting about 5 million people worldwide with no disease-modifying therapies. We sought blood-based biomarkers in order to provide molecular characterization of individuals with PD for diagnostic confirmation and prediction of progression. METHODS AND FINDINGS: In 141 plasma samples (96 PD, 45 neurologically normal control [NC] individuals; 45.4% female, mean age 70.0 years) from a longitudinally followed Discovery Cohort based at the University of Pennsylvania (UPenn), we measured levels of 1,129 proteins using an aptamer-based platform. We modeled protein plasma concentration (log10 of relative fluorescence units [RFUs]) as the effect of treatment group (PD versus NC), age at plasma collection, sex, and the levodopa equivalent daily dose (LEDD), deriving first-pass candidate protein biomarkers based on p-value for PD versus NC. These candidate proteins were then ranked by Stability Selection. We confirmed findings from our Discovery Cohort in a Replication Cohort of 317 individuals (215 PD, 102 NC; 47.9% female, mean age 66.7 years) from the multisite, longitudinally followed National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) Cohort. Analytical approach in the Replication Cohort mirrored the approach in the Discovery Cohort: each protein plasma concentration (log10 of RFU) was modeled as the effect of group (PD versus NC), age at plasma collection, sex, clinical site, and batch. Of the top 10 proteins from the Discovery Cohort ranked by Stability Selection, four associations were replicated in the Replication Cohort. These blood-based biomarkers were bone sialoprotein (BSP, Discovery false discovery rate [FDR]-corrected p = 2.82 x 10-2, Replication FDR-corrected p = 1.03 x 10-4), osteomodulin (OMD, Discovery FDR-corrected p = 2.14 x 10-2, Replication FDR-corrected p = 9.14 x 10-5), aminoacylase-1 (ACY1, Discovery FDR-corrected p = 1.86 x 10-3, Replication FDR-corrected p = 2.18 x 10-2), and growth hormone receptor (GHR, Discovery FDR-corrected p = 3.49 x 10-4, Replication FDR-corrected p = 2.97 x 10-3). Measures of these proteins were not significantly affected by differences in sample handling, and they did not change comparing plasma samples from 10 PD participants sampled both on versus off dopaminergic medication. Plasma measures of OMD, ACY1, and GHR differed in PD versus NC but did not differ between individuals with amyotrophic lateral sclerosis (ALS, n = 59) versus NC. In the Discovery Cohort, individuals with baseline levels of GHR and ACY1 in the lowest tertile were more likely to progress to mild cognitive impairment (MCI) or dementia in Cox proportional hazards analyses adjusting for age, sex, and disease duration (hazard ratio [HR] 2.27 [95% CI 1.04-5.0, p = 0.04] for GHR, and HR 3.0 [95% CI 1.24-7.0, p = 0.014] for ACY1). GHR's association with cognitive decline was confirmed in the Replication Cohort (HR 3.6 [95% CI 1.20-11.1, p = 0.02]). The main limitations of this study were its reliance on the aptamer-based platform for protein measurement and limited follow-up time available for some cohorts. CONCLUSIONS: In this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD. Posavi, Marijan Diaz-Ortiz, Maria Liu, Benjamine Swanson, Christine R Skrinak, R Tyler Hernandez-Con, Pilar Amado, Defne A Fullard, Michelle Rick, Jacqueline Siderowf, Andrew Weintraub, Daniel McCluskey, Leo Trojanowski, John Q Dewey, Richard B Jr Huang, Xuemei Chen-Plotkin, Alice S eng P30 AG/AG/NIA NIH HHS/ U01 NS/NS/NINDS NIH HHS/ T32 AG/AG/NIA NIH HHS/ U24 NS/NS/NINDS NIH HHS/ P50 NS/NS/NINDS NIH HHS/ R01 NS/NS/NINDS NIH HHS/ U19 AG/AG/NIA NIH HHS/ U01 NS/NS/NINDS NIH HHS/ U01 NS/NS/NINDS NIH HHS/ U01 NS/NS/NINDS NIH HHS/ U01 NS/NS/NINDS NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS Med. Oct 11;16(10):e. doi: 10./journal.pmed.. eCollection Oct.I SomaScan 10/12/ Finkernagel F, et al. Dual-platform affinity proteomics identifies links between the recurrence of ovarian carcinoma and proteins released into the tumor microenvironment Theranostics 9 22 - https://www.doi.org/10./thno. 31,588,238 Ascites/metabolism/pathology Biomarkers, Tumor/analysis/metabolism Blood Proteins/analysis Cystadenocarcinoma, Serous/metabolism/mortality/*pathology Extracellular Vesicles/metabolism/pathology Female Humans Kaplan-Meier Estimate Ovarian Neoplasms/metabolism/mortality/*pathology Proteomics/*methods Recurrence *Tumor Microenvironment The peritoneal fluid (ascites), replete with abundant tumor-promoting factors and extracellular vesicles (EVs) reflecting the tumor secretome, plays an essential role in ovarian high-grade serous carcinoma (HGSC) metastasis and immune suppression. A comprehensive picture of mediators impacting HGSC progression is, however, not available. Methods: Proteins in ascites from HGSC patients were quantified by the aptamer-based SOMAscan affinity proteomic platform. SOMAscan data were analyzed by bioinformatic methods to reveal clinically relevant links and functional connections, and were validated using the antibody-based proximity extension assay (PEA) Olink platform. Mass spectrometry was used to identify proteins in extracellular microvesicles released by HGSC cells. Results: Consistent with the clinical features of HGSC, 779 proteins in ascites identified by SOMAscan clustered into groups associated either with metastasis and a short relapse-free survival (RFS), or with immune regulation and a favorable RFS. In total, 346 proteins were linked to OC recurrence in either direction. Reanalysis of 214 of these proteins by PEA revealed an excellent median Spearman inter-platform correlation of rho=0.82 for the 46 positively RFS-associated proteins in both datasets. Intriguingly, many proteins strongly associated with clinical outcome were constituents of extracellular vesicles. These include proteins either linked to a poor RFS, such as HSPA1A, BCAM and DKK1, or associated with a favorable outcome, such as the protein kinase LCK. Finally, based on these data we defined two protein signatures that clearly classify short-term and long-term relapse-free survivors. Conclusion: The ascites secretome points to metastasis-promoting events and an anti-tumor response as the major determinants of the clinical outcome of HGSC. Relevant proteins include both bone fide secreted and vesicle-encapsulated polypeptides, many of which have previously not been linked to HGSC recurrence. Besides a deeper understanding of the HGSC microenvironment our data provide novel potential tools for HGSC patient stratification. Furthermore, the first large-scale inter-platform validation of SOMAscan and PEA will be invaluable for other studies using these affinity proteomics platforms. Finkernagel, Florian Reinartz, Silke Schuldner, Maximiliane Malz, Alexandra Jansen, Julia M Wagner, Uwe Worzfeld, Thomas Graumann, Johannes von Strandmann, Elke Pogge Muller, Rolf eng Research Support, Non-U.S. Gov't Australia Theranostics. Aug 22;9(22):-. doi: 10./thno.. eCollection .I SomaScan 10/08/ Aguado BA, et al. Transcatheter aortic valve replacements alter circulating serum factors to mediate myofibroblast deactivation Sci Transl Med 11 509 https://www.doi.org/10./scitranslmed.aav 31,511,425 Aortic Valve/drug effects/metabolism/pathology Cell Cycle Female Humans Hydrogels/pharmacology Inflammation Mediators/metabolism MAP Kinase Signaling System Male Myofibroblasts/metabolism/*pathology Phenotype Reproducibility of Results Serum/*metabolism Sex Characteristics Signal Transduction/drug effects *Transcatheter Aortic Valve Replacement Transcriptome/drug effects/genetics The transcatheter aortic valve replacement (TAVR) procedure has emerged as a minimally invasive treatment for patients with aortic valve stenosis (AVS). However, alterations in serum factor composition and biological activity after TAVR remain unknown. Here, we quantified the systemic inflammatory effects of the TAVR procedure and hypothesized that alterations in serum factor composition would modulate valve and cardiac fibrosis. Serum samples were obtained from patients with AVS immediately before their TAVR procedure (pre-TAVR) and about 1 month afterward (post-TAVR). Aptamer-based proteomic profiling revealed alterations in post-TAVR serum composition, and ontological analysis identified inflammatory macrophage factors implicated in myofibroblast activation and deactivation. Hydrogel biomaterials used as valve matrix mimics demonstrated that post-TAVR serum reduced myofibroblast activation of valvular interstitial cells relative to pre-TAVR serum from the same patient. Transcriptomics and curated network analysis revealed a shift in myofibroblast phenotype from pre-TAVR to post-TAVR and identified p38 MAPK signaling as one pathway involved in pre-TAVR-mediated myofibroblast activation. Post-TAVR serum deactivated valve and cardiac myofibroblasts initially exposed to pre-TAVR serum to a quiescent fibroblast phenotype. Our in vitro deactivation data correlated with patient disease severity measured via echocardiography and multimorbidity scores, and correlations were dependent on hydrogel stiffness. Sex differences in cellular responses to male and female sera were also observed and may corroborate clinical observations regarding sex-specific TAVR outcomes. Together, alterations in serum composition after TAVR may lead to an antifibrotic fibroblast phenotype, which suggests earlier interventions may be beneficial for patients with advanced AVS to prevent further disease progression. Aguado, Brian A Schuetze, Katherine B Grim, Joseph C Walker, Cierra J Cox, Anne C Ceccato, Tova L Tan, Aik-Choon Sucharov, Carmen C Leinwand, Leslie A Taylor, Matthew R G McKinsey, Timothy A Anseth, Kristi S eng R01 GM/GM/NIGMS NIH HHS/ 16SFRN/AHA/American Heart Association-American Stroke Association/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R00 HL/HL/NHLBI NIH HHS/ R01 DE/DE/NIDCR NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ F32 HL/HL/NHLBI NIH HHS/ K99 HL/HL/NHLBI NIH HHS/ F31 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R21 AR/AR/NIAMS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ T32 GM/GM/NIGMS NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Sci Transl Med. Sep 11;11(509):eaav. doi: 10./scitranslmed.aav.I SomaScan 09/13/ Teumer A, et al. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria Nat Commun 10 1 https://www.doi.org/10./s-019--0 31,511,532 Albuminuria/*genetics Animals *Chromosome Mapping Creatinine/urine Diabetes Mellitus/genetics/urine Drosophila melanogaster/genetics Gene Expression Regulation Genetic Loci Genetic Predisposition to Disease *Genome-Wide Association Study Humans *Meta-Analysis as Topic Phenomics Risk Factors Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria. Teumer, Alexander Li, Yong Ghasemi, Sahar Prins, Bram P Wuttke, Matthias Hermle, Tobias Giri, Ayush Sieber, Karsten B Qiu, Chengxiang Kirsten, Holger Tin, Adrienne Chu, Audrey Y Bansal, Nisha Feitosa, Mary F Wang, Lihua Chai, Jin-Fang Cocca, Massimiliano Fuchsberger, Christian Gorski, Mathias Hoppmann, Anselm Horn, Katrin Li, Man Marten, Jonathan Noce, Damia Nutile, Teresa Sedaghat, Sanaz Sveinbjornsson, Gardar Tayo, Bamidele O van der Most, Peter J Xu, Yizhe Yu, Zhi Gerstner, Lea Arnlov, Johan Bakker, Stephan J L Baptista, Daniela Biggs, Mary L Boerwinkle, Eric Brenner, Hermann Burkhardt, Ralph Carroll, Robert J Chee, Miao-Li Chee, Miao-Ling Chen, Mengmeng Cheng, Ching-Yu Cook, James P Coresh, Josef Corre, Tanguy Danesh, John de Borst, Martin H De Grandi, Alessandro de Mutsert, Renee de Vries, Aiko P J Degenhardt, Frauke Dittrich, Katalin Divers, Jasmin Eckardt, Kai-Uwe Ehret, Georg Endlich, Karlhans Felix, Janine F Franco, Oscar H Franke, Andre Freedman, Barry I Freitag-Wolf, Sandra Gansevoort, Ron T Giedraitis, Vilmantas Gogele, Martin Grundner-Culemann, Franziska Gudbjartsson, Daniel F Gudnason, Vilmundur Hamet, Pavel Harris, Tamara B Hicks, Andrew A Holm, Hilma Foo, Valencia Hui Xian Hwang, Shih-Jen Ikram, M Arfan Ingelsson, Erik Jaddoe, Vincent W V Jakobsdottir, Johanna Josyula, Navya Shilpa Jung, Bettina Kahonen, Mika Khor, Chiea-Chuen Kiess, Wieland Koenig, Wolfgang Korner, Antje Kovacs, Peter Kramer, Holly Kramer, Bernhard K Kronenberg, Florian Lange, Leslie A Langefeld, Carl D Lee, Jeannette Jen-Mai Lehtimaki, Terho Lieb, Wolfgang Lim, Su-Chi Lind, Lars Lindgren, Cecilia M Liu, Jianjun Loeffler, Markus Lyytikainen, Leo-Pekka Mahajan, Anubha Maranville, Joseph C Mascalzoni, Deborah McMullen, Barbara Meisinger, Christa Meitinger, Thomas Miliku, Kozeta Mook-Kanamori, Dennis O Muller-Nurasyid, Martina Mychaleckyj, Josyf C Nauck, Matthias Nikus, Kjell Ning, Boting Noordam, Raymond Connell, Jeffrey O' Olafsson, Isleifur Palmer, Nicholette D Peters, Annette Podgornaia, Anna I Ponte, Belen Poulain, Tanja Pramstaller, Peter P Rabelink, Ton J Raffield, Laura M Reilly, Dermot F Rettig, Rainer Rheinberger, Myriam Rice, Kenneth M Rivadeneira, Fernando Runz, Heiko Ryan, Kathleen A Sabanayagam, Charumathi Saum, Kai-Uwe Schottker, Ben Shaffer, Christian M Shi, Yuan Smith, Albert V Strauch, Konstantin Stumvoll, Michael Sun, Benjamin B Szymczak, Silke Tai, E-Shyong Tan, Nicholas Y Q Taylor, Kent D Teren, Andrej Tham, Yih-Chung Thiery, Joachim Thio, Chris H L Thomsen, Hauke Thorsteinsdottir, Unnur Tonjes, Anke Tremblay, Johanne Uitterlinden, Andre G van der Harst, Pim Verweij, Niek Vogelezang, Suzanne Volker, Uwe Waldenberger, Melanie Wang, Chaolong Wilson, Otis D Wong, Charlene Wong, Tien-Yin Yang, Qiong Yasuda, Masayuki Akilesh, Shreeram Bochud, Murielle Boger, Carsten A Devuyst, Olivier Edwards, Todd L Ho, Kevin Morris, Andrew P Parsa, Afshin Pendergrass, Sarah A Psaty, Bruce M Rotter, Jerome I Stefansson, Kari Wilson, James G Susztak, Katalin Snieder, Harold Heid, Iris M Scholz, Markus Butterworth, Adam S Hung, Adriana M Pattaro, Cristian Kottgen, Anna eng MC_PC_/MRC_/Medical Research Council/United Kingdom R01 HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ K12 HD/HD/NICHD NIH HHS/ I01 BX/BX/BLRD VA/ P30 DK/DK/NIDDK NIH HHS/ MC_QA/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't England Nat Commun. Sep 11;10(1):. doi: 10./s-019--0.I SomaScan 09/13/ Shi L, et al. Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay Alzheimers Dement 15 11 - https://www.doi.org/10./j.jalz..06. 31,495,601 Age Factors Aged *Alzheimer Disease/genetics/metabolism Amyloid/*metabolism Apolipoprotein E4/genetics/metabolism Biomarkers/*blood Brain/*metabolism Europe Female Humans Male Middle Aged *Proteomics Amyloid beta Causal relationship Plasma proteomics Replication SOMAscan assay Tau INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) epsilon4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition. Shi, Liu Westwood, Sarah Baird, Alison L Winchester, Laura Dobricic, Valerija Kilpert, Fabian Hong, Shengjun Franke, Andre Hye, Abdul Ashton, Nicholas J Morgan, Angharad R Bos, Isabelle Vos, Stephanie J B Buckley, Noel J Kate, Mara Ten Scheltens, Philip Vandenberghe, Rik Gabel, Silvy Meersmans, Karen Engelborghs, Sebastiaan De Roeck, Ellen E Sleegers, Kristel Frisoni, Giovanni B Blin, Olivier Richardson, Jill C Bordet, Regis Molinuevo, Jose L Rami, Lorena Wallin, Anders Kettunen, Petronella Tsolaki, Magda Verhey, Frans Lleo, Alberto Alcolea, Daniel Popp, Julius Peyratout, Gwendoline Martinez-Lage, Pablo Tainta, Mikel Johannsen, Peter Teunissen, Charlotte E Freund-Levi, Yvonne Frolich, Lutz Legido-Quigley, Cristina Barkhof, Frederik Blennow, Kaj Zetterberg, Henrik Baker, Susan Morgan, B Paul Streffer, Johannes Visser, Pieter Jelle Bertram, Lars Lovestone, Simon Nevado-Holgado, Alejo J eng MC_PC_/MRC_/Medical Research Council/United Kingdom MR/L/2/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Alzheimers Dement. Nov;15(11):-. doi: 10./j.jalz..06.. Epub Sep 5.I SomaScan 09/10/ Grover M, et al. Proteomics in gastroparesis: unique and overlapping protein signatures in diabetic and idiopathic gastroparesis Am J Physiol Gastrointest Liver Physiol 317 5 G716-G726 https://www.doi.org/10./ajpgi.. 31,482,734 Adult Aged Complement C2/genetics/metabolism Diabetes Complications/*genetics/metabolism/physiopathology Endothelial Cells/metabolism Female Fibroblasts/metabolism Gastric Emptying Gastroparesis/etiology/*genetics/metabolism/physiopathology Humans Macrophages/metabolism Male Middle Aged Prostaglandin-Endoperoxide Synthases/genetics/metabolism Protein Kinase C/genetics/metabolism Proteome/*genetics/metabolism diabetes immune cells inflammation macrophages Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected P < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, Role of Macrophages, Fibroblasts and Endothelial Cells" was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 x 10(-9); IG FDR = 6.3 x 10(-12)]. In DG, properdin expression correlated with GCSI bloating (r = -0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C-zeta type, and complement C2 correlated with 4 h gastric retention (r = -0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis.NEW & NOTEWORTHY This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis." Grover, Madhusudan Dasari, Surendra Bernard, Cheryl E Chikkamenahalli, Lakshmikanth L Yates, Katherine P Pasricha, Pankaj J Sarosiek, Irene McCallum, Richard Koch, Kenneth L Abell, Thomas L Kuo, Braden Shulman, Robert J Gibbons, Simon J McKenzie, Travis J Kellogg, Todd A Kendrick, Michael L Tonascia, James Hamilton, Frank A Parkman, Henry P Farrugia, Gianrico eng U24 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ K23 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ R03 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Am J Physiol Gastrointest Liver Physiol. Nov 1;317(5):G716-G726. doi: 10./ajpgi... Epub Sep 4.I SomaScan 09/05/ Daniels JR, et al. Stability of the Human Plasma Proteome to Pre-analytical Variability as Assessed by an Aptamer-Based Approach J Proteome Res 18 10 - https://www.doi.org/10./acs.jproteome.9b 31,442,052 Adult Aptamers, Peptide Blood Preservation/methods Blood Specimen Collection/methods Complement Activation Healthy Volunteers Humans Plasma/*chemistry *Protein Stability Proteome/analysis Proteomics/*methods aptamer technology biomarkers human blood plasma pre-analytical variability proteomics quality assessment Variable processing and storage of whole blood and/or plasma are potential confounders in biomarker development and clinical assays. The goal of the study was to investigate how pre-analytical variables impact the human plasma proteome. Whole blood obtained from 16 apparently healthy individuals was collected in six EDTA tubes and processed randomly under six pre-analytical variable conditions including blood storage at 0 degrees C or RT for 6 h (B6h0C or B6hRT) before processing to plasma, plasma storage at 4 degrees C or RT for 24 h (P24h4C or P24hRT), low centrifugal force at x g, (Lowxg), and immediate processing to plasma under x g (control) followed by plasma storage at -80 degrees C. An aptamer-based proteomic assay was performed to identify significantly changed proteins (fold change >/=1.2, P < 0.05, and false discovery rate < 0.05) relative to the control from a total of proteins assayed. Pre-analytical conditions Lowxg and B6h0C resulted in the most plasma proteome changes with 200 and 148 proteins significantly changed, respectively. Only 36 proteins were changed under B6hRT. Conditions P24h4C and P24hRT yielded changes of 28 and 75 proteins, respectively. The complement system was activated in vitro under the conditions B6hRT, P24h4C, and P24hRT. The results suggest that particular pre-analytical variables should be controlled for clinical measurement of specific biomarkers. Daniels, Jaclyn R Cao, Zhijun Maisha, Mackean Schnackenberg, Laura K Sun, Jinchun Pence, Lisa Schmitt, Thomas C Kamlage, Beate Rogstad, Sarah Beger, Richard D Yu, Li-Rong eng FD/ImFDA/Intramural FDA HHS/ Research Support, Non-U.S. Gov't J Proteome Res. Oct 4;18(10):-. doi: 10./acs.jproteome.9b. Epub Sep 12.I SomaScan 08/24/ Hathout Y, et al. Disease-specific and glucocorticoid-responsive serum biomarkers for Duchenne Muscular Dystrophy Sci Rep 9 1 https://www.doi.org/10./s-019--9 31,434,957 Biomarkers/*blood Blood Proteins/*metabolism Case-Control Studies Cell Adhesion Molecules/metabolism Child Child, Preschool Cross-Sectional Studies Extracellular Matrix Proteins/metabolism Glucocorticoids/*therapeutic use Humans Muscular Dystrophy, Duchenne/*drug therapy/pathology Extensive biomarker discoveries for DMD have occurred in the past 7 years, and a vast array of these biomarkers were confirmed in independent cohorts and across different laboratories. In these previous studies, glucocorticoids and age were two major confounding variables. In this new study, using SomaScan technology and focusing on a subset of young DMD patients who were not yet treated with glucocorticoids, we identified 108 elevated and 70 decreased proteins in DMD relative to age matched healthy controls (p value < 0.05 after adjusting for multiple testing). The majority of the elevated proteins were muscle centric followed by cell adhesion, extracellular matrix proteins and a few pro-inflammatory proteins. The majority of decreased proteins were of cell adhesion, however, some had to do with cell differentiation and growth factors. Subsequent treatment of this group of DMD patients with glucocorticoids affected two major groups of pharmacodynamic biomarkers. The first group consisted of 80 serum proteins that were not associated with DMD and either decreased or increased following treatment with glucocorticoids, and therefore were reflective of a broader effect of glucocorticoids. The second group consisted of 17 serum proteins that were associated with DMD and these tended to normalize under treatment, thus reflecting physiologic effects of glucocorticoid treatment in DMD. In summary, we have identified a variety of circulating protein biomarkers that reflect the complex nature of DMD pathogenesis and response to glucocorticoids. Hathout, Yetrib Liang, Chen Ogundele, Michael Xu, Ganggang Tawalbeh, Shefa M Dang, Utkarsh J Hoffman, Eric P Gordish-Dressman, Heather Conklin, Laurie S van den Anker, John N Clemens, Paula R Mah, Jean K Henricson, Erik McDonald, Craig eng U54HD/U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/International Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Sci Rep. Aug 21;9(1):. doi: 10./s-019--9.I SomaScan 08/23/ Hok AHYS, et al. Guidelines for CSF Processing and Biobanking: Impact on the Identification and Development of Optimal CSF Protein Biomarkers Methods Mol Biol 27-50 https://www.doi.org/10./978-1---0_2 31,432,404 *Biological Specimen Banks Biomarkers/cerebrospinal fluid Blood/metabolism *Cerebrospinal Fluid Cerebrospinal Fluid Proteins/*metabolism Early Diagnosis Freezing Humans Immunoassay Nervous System Diseases/*cerebrospinal fluid/diagnosis Protein Stability Proteome/genetics/*metabolism Proteomics Reproducibility of Results Serum/chemistry/metabolism Specimen Handling/*standards Workflow Biobanking Biomarkers Csf Guidelines Neurology Pre-analytical confounding factors Reproducibility Stability The field of neurological diseases strongly needs biomarkers for early diagnosis and optimal stratification of patients in clinical trials or to monitor disease progression. Cerebrospinal fluid (CSF) is one of the main sources for the identification of novel protein biomarkers for neurological diseases. Despite the enormous efforts employed to identify novel CSF biomarkers, the high variability observed across different studies has hampered their validation and implementation in clinical practice. Such variability is partly caused by the effect of different pre-analytical confounding factors on protein stability, highlighting the importance to develop and comply with standardized operating procedures. In this chapter, we describe the international consensus pre-analytical guidelines for CSF processing and biobanking that have been established during the last decade, with a special focus on the influence of pre-analytical confounders on the global CSF proteome. In addition, we provide novel results on the influence of different delayed storage and freeze/thaw conditions on the CSF proteome using two novel large multiplex protein arrays (SOMAscan and Olink). Compliance to consensus guidelines will likely facilitate the successful development and implementation of CSF protein biomarkers in both research and clinical settings, ultimately facilitating the successful development of disease-modifying therapies. Hok-A-Hin, Yanaika S Willemse, Eline A J Teunissen, Charlotte E Del Campo, Marta eng Methods Mol Biol. ;:27-50. doi: 10./978-1---0_2.I SomaScan 08/23/ Simats A, et al. Application of an Aptamer-Based Proteomics Assay (SOMAscan) in Rat Cerebrospinal Fluid Methods Mol Biol 221-231 https://www.doi.org/10./978-1---0_13 31,432,415 Animals Aptamers, Nucleotide Biomarkers/*cerebrospinal fluid/metabolism Cerebrospinal Fluid Proteins/*analysis/metabolism Humans Oligonucleotide Array Sequence Analysis Proteome/*metabolism Proteomics/*methods Rats Software Aptamer Csf Multiplex Proteome Rat SOMAscan The exploration of the cerebrospinal fluid (CSF) through proteomics techniques might help in the search of molecular biomarkers relevant to neurological pathologies. Aiming this, we describe here a commercially available multiplexed proteomics technology based on the use of modified aptamers (SOMAscan assay). From our experience in exploring the rat CSF proteome, we detail the basic principles of this oligonucleotide-based proteomics approach, as well as the main data-processing steps to obtain relative quantitative values for proteins that could discriminate among different brain conditions, as an attempt in the search of neurological biomarkers. Finally, we give some tips on performing the SOMAscan assay and key recommendations on the verification analyses of the resulting candidate biomarkers. Simats, Alba Ramiro, Laura Montaner, Joan Garcia-Berrocoso, Teresa eng Research Support, Non-U.S. Gov't Methods Mol Biol. ;:221-231. doi: 10./978-1---0_13.I SomaScan 08/23/ Deterding RR, et al. Pulmonary Aptamer Signatures in Children's Interstitial and Diffuse Lung Disease Am J Respir Crit Care Med 200 12 - https://www.doi.org/10./rccm.-OC 31,409,098 Biomarkers/metabolism Bronchoalveolar Lavage Fluid/*chemistry Case-Control Studies Child Child, Preschool Diagnosis, Differential Female Humans Hyperplasia Infant Lung Diseases, Interstitial/*diagnosis/*metabolism Male Neuroendocrine Cells/pathology Proteomics neuroendocrine pediatric surfactant Rationale: Biomarker signatures are needed in children with children's interstitial and diffuse lung disease (chILD) to improve diagnostic approaches, increase our understanding of disease pathogenesis, monitor disease progression, and develop new treatment strategies. Proteomic technology using SOMAmer (Slow Off-rate Modified Aptamer) nucleic acid-based protein-binding reagents allows for biomarker discovery.Objectives: We hypothesized that proteins and protein pathways in BAL fluid (BALF) would distinguish children with neuroendocrine cell hyperplasia of infancy (NEHI), surfactant dysfunction mutations, and other chILD diagnoses and control subjects.Methods: BALF was collected for clinical indications and banked in patients with chILD and disease control subjects using standardized protocols over 10 years. BALF supernatant was analyzed using an aptamer assay to measure 1,129 protein levels. Protein levels were compared between groups using an ANOVA and adjusted for multiple comparisons using false discovery rate. Proteins were classified into pathways. Hierarchical clustering was used to define endotypes in the group of children with NEHI.Measurements and Main Results: After correcting for multiple testing, children with NEHI (n = 22) had 202 aptamers that were significantly different (P < 0.05) in BALF compared with control subjects (n = 9). Children with surfactant mutation (n = 8) had 51 aptamers significantly different (P < 0.05) in BALF compared with control subjects (n = 9). Proteins associated with pulmonary fibrosis and inflammation were associated with the surfactant dysfunction group but not the NEHI group. Using hierarchical clustering analysis, two distinct NEHI endotypes were identified.Conclusions: Distinct proteins and protein pathways can be determined from BALF of children with chILD, and these hold promise to further our understanding of chILD. Deterding, Robin R Wagner, Brandie D Harris, J Kirk DeBoer, Emily M eng UL1 TR/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. Dec 15;200(12):-. doi: 10./rccm.-OC.I SomaScan 08/15/ Fajgenbaum DC, et al. Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease J Clin Invest 129 10 - https://www.doi.org/10./JCI 31,408,438 Adolescent Adult *Castleman Disease/drug therapy/metabolism/pathology Female Humans Interleukin-6/*metabolism Male Middle Aged Phosphatidylinositol 3-Kinases/*metabolism Proteomics Proto-Oncogene Proteins c-akt/*metabolism Signal Transduction/*drug effects Sirolimus/*pharmacology TOR Serine-Threonine Kinases/*metabolism Cytokines Hematology Immunology Lymphomas Janssen Pharmaceuticals. TSU is a coinventor on US patent 10,001,483 B2, assigned to the U.S. Government, with a portion of royalties going to employee-inventors under PL 99-502. TSU has research support through Cooperative Research and Development Agreements with the National Cancer Institute, Celgene Corporation, and Merck, and through a clinical trial agreement from Roche and the Fred Hutchinson Cancer Research Center. BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype. METHODS: We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus. RESULTS: Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months. CONCLUSION: This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT). FUNDING: Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute. Fajgenbaum, David C Langan, Ruth-Anne Japp, Alberto Sada Partridge, Helen L Pierson, Sheila K Singh, Amrit Arenas, Daniel J Ruth, Jason R Nabel, Christopher S Stone, Katie Okumura, Mariko Schwarer, Anthony Jose, Fabio Freire Hamerschlak, Nelson Wertheim, Gerald B Jordan, Michael B Cohen, Adam D Krymskaya, Vera Rubenstein, Arthur Betts, Michael R Kambayashi, Taku van Rhee, Frits Uldrick, Thomas S eng R01 HL/HL/NHLBI NIH HHS/ ZIA BC/ImNIH/Intramural NIH HHS/ Case Reports Research Support, Non-U.S. Gov't J Clin Invest. Aug 13;129(10):-. doi: 10./JCI.I SomaScan 08/14/ Sebastiani P, et al. A serum protein signature of APOE genotypes in centenarians Aging Cell 18 6 e https://www.doi.org/10./acel. 31,385,390 Adult Aged Aged, 80 and over Alzheimer Disease/blood/*genetics/metabolism Apolipoproteins E/blood/*genetics/metabolism Cohort Studies Female Fluorescence Genotype Humans Male Middle Aged Prospective Studies Proteomics Young Adult Apoe SomaLogic centenarian cognitive function genotypes protein The discovery of treatments to prevent or delay dementia and Alzheimer's disease is a priority. The gene APOE is associated with cognitive change and late-onset Alzheimer's disease, and epidemiological studies have provided strong evidence that the e(2) allele of APOE has a neuroprotective effect, it is associated with increased longevity and an extended healthy lifespan in centenarians. In this study, we correlated APOE genotype data of 222 participants of the New England Centenarian Study, including 75 centenarians, 82 centenarian offspring, and 65 controls, comprising 55 carriers of APOE e(2) , with aptamer-based serum proteomics (SomaLogic technology) of 4,785 human proteins corresponding to 4,137 genes. We discovered a signature of 16 proteins that associated with different APOE genotypes and replicated the signature in three independent studies. We also show that the protein signature tracks with gene expression profiles in brains of late-onset Alzheimer's disease versus healthy controls. Finally, we show that seven of these proteins correlate with cognitive function patterns in longitudinally collected data. This analysis in particular suggests that Baculoviral IAP repeat containing two (BIRC2) is a novel biomarker of neuroprotection that associates with the neuroprotective allele of APOE. Therefore, targeting APOE e(2) molecularly may preserve cognitive function. Sebastiani, Paola Monti, Stefano Morris, Melody Gurinovich, Anastasia Toshiko, Tanaka Andersen, Stacy L Sweigart, Benjamin Ferrucci, Luigi Jennings, Lori L Glass, David J Perls, Thomas T eng ICS110.1/RF97.71/Italian Ministry of Health/International R21 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ Novartis Institute for Biomedical Research (NIBR)/International UH2 AG/AG/NIA NIH HHS/ U19 AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Aging Cell. Dec;18(6):e. doi: 10./acel.. Epub Aug 5.I SomaScan 08/07/ Malekzadeh A, et al. Plasma proteome in multiple sclerosis disease progression Ann Clin Transl Neurol 6 9 - https://www.doi.org/10./acn3.771 31,364,818 Adult Biomarkers/blood Brain/*diagnostic imaging Disease Progression Female Humans Magnetic Resonance Imaging Male Middle Aged Multiple Sclerosis, Chronic Progressive/diagnostic imaging/*metabolism Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging/*metabolism Prognosis Proteome/*metabolism BACKGROUND: The pathophysiology of multiple sclerosis disease progression remains undetermined. The aim of this study was to identify differences in plasma proteome during different stages of MS disease progression. METHODS: We used a multiplex aptamer proteomics platform (Somalogic) for sensitive detection of proteins in plasma. MS patients were selected and categorized based on baseline and a 4-year follow-up EDSS (delta EDSS) scores; relapse-onset (RO) slow progression (n = 31), RO with rapid progression (n = 29), primary progressive (n = 30), and healthy controls (n = 20). The relation of baseline plasma protein levels with delta EDSS and different MRI progression parameters were assessed using linear regression models. RESULTS: Regression analyses of plasma proteins with delta EDSS showed six significant associations. Strong associations were found for the proteins LGLAS8 (P = 7.64 x 10(-5) , q = 0.06), CCL3 (P = 0., q = 0.06), and RGMA (P = 0., q = 0.09). In addition, associations of plasma proteins were found with percentage brain volume for C3 (P = 2,08 x 10(-9) , q = 1,70 x 10(-6) ), FGF9 (P = 3,42 x 10(-9) , q = 1,70 x 10(-6) ), and EHMT2 (P = 0., q = 0.01). Most of the significant markers were associated with cell-cell and cell-extracellular matrix adhesion, immune system communication, immune system activation, and complement pathways. CONCLUSIONS: Our results revealed eight novel biomarkers related to clinical and radiological progression in MS. These results indicate that changes in immune system, complement pathway and ECM remodeling proteins contribute to MS progression and may therefore be further explored for use in prognosis of MS. Malekzadeh, Arjan Leurs, Cyra van Wieringen, Wessel Steenwijk, Martijn D Schoonheim, Menno M Amann, Michael Naegelin, Yvonne Kuhle, Jens Killestein, Joep Teunissen, Charlotte E eng 14-358e/Dutch MS Research Foundation/International PA /Primary Progressive MS Alliance/International Research Support, Non-U.S. Gov't Ann Clin Transl Neurol. Sep;6(9):-. doi: 10./acn3.771. Epub Jul 31.I SomaScan 08/01/ Tsujikawa LM, et al. Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism Clin Epigenetics 11 1 102 https://www.doi.org/10./s-019--z 31,300,040 Cardiovascular Diseases/*drug therapy/metabolism Cell Adhesion/drug effects Cell Adhesion Molecules/genetics Cell Cycle Proteins/antagonists & inhibitors/*metabolism Cell Line Clinical Trials, Phase II as Topic Epigenesis, Genetic/drug effects Gene Expression Profiling Gene Expression Regulation/drug effects Human Umbilical Vein Endothelial Cells Humans Proteomics/methods Quinazolinones/*administration & dosage/pharmacology THP-1 Cells Transcription Factors/antagonists & inhibitors/*metabolism Vasculitis/*drug therapy/genetics Adhesion Apabetalone Atherosclerosis Brd4 Bromodomain Cvd Diabetes Epigenetics Huvec THP-1 monocytes Vascular inflammation endothelium company. BACKGROUND: Apabetalone (RVX-208) is a bromodomain and extraterminal protein inhibitor (BETi) that in phase II trials reduced the relative risk (RR) of major adverse cardiac events (MACE) in patients with cardiovascular disease (CVD) by 44% and in diabetic CVD patients by 57% on top of statins. A phase III trial, BETonMACE, is currently assessing apabetalone's ability to reduce MACE in statin-treated post-acute coronary syndrome type 2 diabetic CVD patients with low high-density lipoprotein C. The leading cause of MACE is atherosclerosis, driven by dysfunctional lipid metabolism and chronic vascular inflammation (VI). In vitro studies have implicated the BET protein BRD4 as an epigenetic driver of inflammation and atherogenesis, suggesting that BETi may be clinically effective in combating VI. Here, we assessed apabetalone's ability to regulate inflammation-driven gene expression and cell adhesion in vitro and investigated the mechanism by which apabetalone suppresses expression. The clinical impact of apabetalone on mediators of VI was assessed with proteomic analysis of phase II CVD patient plasma. RESULTS: In vitro, apabetalone prevented inflammatory (TNFalpha, LPS, or IL-1beta) induction of key factors that drive endothelial activation, monocyte recruitment, adhesion, and plaque destabilization. BRD4 abundance on inflammatory and adhesion gene promoters and enhancers was reduced by apabetalone. BRD2-4 degradation by MZ-1 also prevented TNFalpha-induced transcription of monocyte and endothelial cell adhesion molecules and inflammatory mediators, confirming BET-dependent regulation. Transcriptional regulation by apabetalone translated into a reduction in monocyte adhesion to an endothelial monolayer. In a phase II trial, apabetalone treatment reduced the abundance of multiple VI mediators in the plasma of CVD patients (SOMAscan(R) 1.3 k). These proteins correlate with CVD risk and include adhesion molecules, cytokines, and metalloproteinases. Ingenuity(R) Pathway Analysis (IPA(R)) predicted that apabetalone inhibits pro-atherogenic regulators and pathways and prevents disease states arising from leukocyte recruitment. CONCLUSIONS: Apabetalone suppressed gene expression of VI mediators in monocytes and endothelial cells by inhibiting BET-dependent transcription induced by multiple inflammatory stimuli. In CVD patients, apabetalone treatment reduced circulating levels of VI mediators, an outcome conducive with atherosclerotic plaque stabilization and MACE reduction. Inhibition of inflammatory and adhesion molecule gene expression by apabetalone is predicted to contribute to MACE reduction in the phase III BETonMACE trial. Tsujikawa, Laura M Fu, Li Das, Shovon Halliday, Christopher Rakai, Brooke D Stotz, Stephanie C Sarsons, Christopher D Gilham, Dean Daze, Emily Wasiak, Sylwia Studer, Deborah Rinker, Kristina D Sweeney, Michael Johansson, Jan O Wong, Norman C W Kulikowski, Ewelina eng Research Support, Non-U.S. Gov't Germany Clin Epigenetics. Jul 12;11(1):102. doi: 10./s-019--z.I SomaScan 07/14/ Frottin F, et al. The nucleolus functions as a phase-separated protein quality control compartment Science 365 6,451 342-347 https://www.doi.org/10./science.aaw 31,296,649 Cell Nucleolus/*metabolism HEK293 Cells HSP70 Heat-Shock Proteins/metabolism Humans Nuclear Proteins/*chemistry Nucleophosmin Phase Transition *Protein Folding Proteome Tissue Culture Techniques The nuclear proteome is rich in stress-sensitive proteins, which suggests that effective protein quality control mechanisms are in place to ensure conformational maintenance. We investigated the role of the nucleolus in this process. In mammalian tissue culture cells under stress conditions, misfolded proteins entered the granular component (GC) phase of the nucleolus. Transient associations with nucleolar proteins such as NPM1 conferred low mobility to misfolded proteins within the liquid-like GC phase, avoiding irreversible aggregation. Refolding and extraction of proteins from the nucleolus during recovery from stress was Hsp70-dependent. The capacity of the nucleolus to store misfolded proteins was limited, and prolonged stress led to a transition of the nucleolar matrix from liquid-like to solid, with loss of reversibility and dysfunction in quality control. Thus, we suggest that the nucleolus has chaperone-like properties and can promote nuclear protein maintenance under stress. Frottin, F Schueder, F Tiwary, S Gupta, R Korner, R Schlichthaerle, T Cox, J Jungmann, R Hartl, F U Hipp, M S eng Research Support, Non-U.S. Gov't Science. Jul 26;365():342-347. doi: 10./science.aaw. Epub Jul 11.I SomaScan 07/13/ Gehrig JL, et al. Effects of microbiota-directed foods in gnotobiotic animals and undernourished children Science 365 6,449 https://www.doi.org/10./science.aau 31,296,738 Animals Bangladesh Blood Proteins/analysis Child Nutrition Disorders/*diet therapy/metabolism/*microbiology Child, Preschool *Gastrointestinal Microbiome *Germ-Free Life *Host Microbial Interactions Humans Infant *Infant Nutritional Physiological Phenomena To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF that changes the abundances of targeted bacteria and increases plasma biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function in children with MAM. Gehrig, Jeanette L Venkatesh, Siddarth Chang, Hao-Wei Hibberd, Matthew C Kung, Vanderlene L Cheng, Jiye Chen, Robert Y Subramanian, Sathish Cowardin, Carrie A Meier, Martin F O'Donnell, David Talcott, Michael Spears, Larry D Semenkovich, Clay F Henrissat, Bernard Giannone, Richard J Hettich, Robert L Ilkayeva, Olga Muehlbauer, Michael Newgard, Christopher B Sawyer, Christopher Head, Richard D Rodionov, Dmitry A Arzamasov, Aleksandr A Leyn, Semen A Osterman, Andrei L Hossain, Md Iqbal Islam, Munirul Choudhury, Nuzhat Sarker, Shafiqul Alam Huq, Sayeeda Mahmud, Imteaz Mostafa, Ishita Mahfuz, Mustafa Barratt, Michael J Ahmed, Tahmeed Gordon, Jeffrey I eng P30 AR/AR/NIAMS NIH HHS/ P30 AR/AR/NIAMS NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ T32 GM/GM/NIGMS NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ P30 CA/CA/NCI NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Science. Jul 12;365():eaau. doi: 10./science.aau.I SomaScan 07/13/ Shimada YJ, et al. Application of Proteomics Profiling for Biomarker Discovery in Hypertrophic Cardiomyopathy J Cardiovasc Transl Res 12 6 569-579 https://www.doi.org/10./s-019--z 31,278,493 Aged Biomarkers/blood Blood Proteins/*analysis Cardiomyopathy, Hypertrophic/*blood/diagnosis Case-Control Studies Female High-Throughput Screening Assays Humans Least-Squares Analysis Male Middle Aged Predictive Value of Tests Protein Interaction Maps *Proteomics Biomarker discovery Hypertrophic cardiomyopathy Proteomics member of MyoKardia. The other authors have no conflict of interest related to this article. High-throughput proteomics profiling has never been applied to discover biomarkers in patients with hypertrophic cardiomyopathy (HCM). The objective was to identify plasma protein biomarkers that can distinguish HCM from controls. We performed a case-control study of patients with HCM (n = 15) and controls (n = 22). We carried out plasma proteomics profiling of proteins using the SOMAscan assay. We used the sparse partial least squares discriminant analysis to identify 50 most discriminant proteins. We also determined the area under the curve (AUC) of the receiver operating characteristic curve using the Monte Carlo cross validation with balanced subsampling. The average AUC was 0.94 (95% confidence interval, 0.82-1.00) and the discriminative accuracy was 89%. In HCM, 13 out of the 50 proteins correlated with troponin I and 12 with New York Heart Association class. Proteomics profiling can be used to elucidate protein biomarkers that distinguish HCM from controls. Shimada, Yuichi J Hasegawa, Kohei Kochav, Stephanie M Mohajer, Pouya Jung, Jeeyoun Maurer, Mathew S Reilly, Muredach P Fifer, Michael A eng 18CDA/AHA/American Heart Association-American Stroke Association/ UL1 TR/TR/NCATS NIH HHS/ Research Support, Non-U.S. Gov't J Cardiovasc Transl Res. Dec;12(6):569-579. doi: 10./s-019--z. Epub Jul 5.I SomaScan 07/07/ Suhre K, et al. Fine-Mapping of the Human Blood Plasma N-Glycome onto Its Proteome Metabolites 9 7 https://www.doi.org/10./metabo 31,247,951 Hilic-uplc N-glycosylation SOMAscan aptamers glycomics population study proteomics Ivo Ugrina and Gordan Lauc are working for or have stakes in Genos Ltd., a private company specialized in glycomics analyses. The other authors have nothing to disclose. The funders had no role in the design of the study in the collection, analyses, or interpretation of data in the writing of the manuscript or in the decision to publish the results. The statements made herein are solely the responsibility of the authors. Most human proteins are glycosylated. Attachment of complex oligosaccharides to the polypeptide part of these proteins is an integral part of their structure and function and plays a central role in many complex disorders. One approach towards deciphering this human glycan code is to study natural variation in experimentally well characterized samples and cohorts. High-throughput capable large-scale methods that allow for the comprehensive determination of blood circulating proteins and their glycans have been recently developed, but so far, no study has investigated the link between both traits. Here we map for the first time the blood plasma proteome to its matching N-glycome by correlating the levels of blood circulating proteins with 113 N-glycan traits, determined in 344 samples from individuals of Arab, South-Asian, and Filipino descent, and then replicate our findings in 46 subjects of European ancestry. We report protein-specific N-glycosylation patterns, including a correlation of core fucosylated structures with immunoglobulin G (IgG) levels, and of trisialylated, trigalactosylated, and triantennary structures with heparin cofactor 2 (SERPIND2). Our study reveals a detailed picture of protein N-glycosylation and suggests new avenues for the investigation of its role and function in the associated complex disorders. Suhre, Karsten Trbojevic-Akmacic, Irena Ugrina, Ivo Mook-Kanamori, Dennis O Spector, Tim Graumann, Johannes Lauc, Gordan Falchi, Mario eng Biomedical Research Program' funds at Weill Cornell Medicine in Qatar/Qatar Foundation/ Switzerland Metabolites. Jun 26;9(7):122. doi: 10./metabo.I SomaScan 06/30/ Xie Z, et al. Neutrophil activation in systemic capillary leak syndrome (Clarkson disease) J Cell Mol Med 23 8 - https://www.doi.org/10./jcmm. 31,210,423 Adult Blood Proteins/*genetics Capillary Leak Syndrome/*blood/genetics/pathology Endothelial Cells Endothelium, Vascular/metabolism Female Humans Male Middle Aged Neutrophil Activation/*genetics Neutrophils/metabolism *Proteomics neutrophils proteomics vascular leak Systemic capillary leak syndrome (SCLS; Clarkson disease) is a rare orphan disorder characterized by transient yet recurrent episodes of hypotension and peripheral oedema due to diffuse vascular leakage of fluids and proteins into soft tissues. Humoral mediators, cellular responses and genetic features accounting for the clinical phenotype of SCLS are virtually unknown. Here, we searched for factors altered in acute SCLS plasma relative to matched convalescent samples using multiplexed aptamer-based proteomic screening. Relative amounts of 612 proteins were changed greater than twofold and 81 proteins were changed at least threefold. Among the most enriched proteins in acute SCLS plasma were neutrophil granule components including bactericidal permeability inducing protein, myeloperoxidase and matrix metalloproteinase 8. Neutrophils isolated from blood of subjects with SCLS or healthy controls responded similarly to routine pro-inflammatory mediators. However, acute SCLS sera activated neutrophils relative to remission sera. Activated neutrophil supernatants increased permeability of endothelial cells from both controls and SCLS subjects equivalently. Our results suggest systemic neutrophil degranulation during SCLS acute flares, which may contribute to the clinical manifestations of acute vascular leak. Xie, Zhihui Kuhns, Douglas B Gu, Xuesong Otu, Hasan H Libermann, Towia A Gallin, John I Parikh, Samir M Druey, Kirk M eng Research Support, N.I.H., Intramural England J Cell Mol Med. Aug;23(8):-. doi: 10./jcmm.. Epub Jun 18.I SomaScan 06/19/ Tarca AL, et al. The prediction of early preeclampsia: Results from a longitudinal proteomics study PLoS One 14 6 e https://www.doi.org/10./journal.pone. 31,163,045 Adult Female Humans Longitudinal Studies *Models, Biological Pre-Eclampsia/*blood Predictive Value of Tests Pregnancy Pregnancy Proteins/*blood *Proteomics OBJECTIVES: To identify maternal plasma protein markers for early preeclampsia (delivery <34 weeks of gestation) and to determine whether the prediction performance is affected by disease severity and presence of placental lesions consistent with maternal vascular malperfusion (MVM) among cases. STUDY DESIGN: This longitudinal case-control study included 90 patients with a normal pregnancy and 33 patients with early preeclampsia. Two to six maternal plasma samples were collected throughout gestation from each woman. The abundance of 1,125 proteins was measured using high-affinity aptamer-based proteomic assays, and data were modeled using linear mixed-effects models. After data transformation into multiples of the mean values for gestational age, parsimonious linear discriminant analysis risk models were fit for each gestational-age interval (8-16, 16.1-22, 22.1-28, 28.1-32 weeks). Proteomic profiles of early preeclampsia cases were also compared to those of a combined set of controls and late preeclampsia cases (n = 76) reported previously. Prediction performance was estimated via bootstrap. RESULTS: We found that 1) multi-protein models at 16.1-22 weeks of gestation predicted early preeclampsia with a sensitivity of 71% at a false-positive rate (FPR) of 10%. High abundance of matrix metalloproteinase-7 and glycoprotein IIbIIIa complex were the most reliable predictors at this gestational age; 2) at 22.1-28 weeks of gestation, lower abundance of placental growth factor (PlGF) and vascular endothelial growth factor A, isoform 121 (VEGF-121), as well as elevated sialic acid binding immunoglobulin-like lectin 6 (siglec-6) and activin-A, were the best predictors of the subsequent development of early preeclampsia (81% sensitivity, FPR = 10%); 3) at 28.1-32 weeks of gestation, the sensitivity of multi-protein models was 85% (FPR = 10%) with the best predictors being activated leukocyte cell adhesion molecule, siglec-6, and VEGF-121; 4) the increase in siglec-6, activin-A, and VEGF-121 at 22.1-28 weeks of gestation differentiated women who subsequently developed early preeclampsia from those who had a normal pregnancy or developed late preeclampsia (sensitivity 77%, FPR = 10%); 5) the sensitivity of risk models was higher for early preeclampsia with placental MVM lesions than for the entire early preeclampsia group (90% versus 71% at 16.1-22 weeks; 87% versus 81% at 22.1-28 weeks; and 90% versus 85% at 28.1-32 weeks, all FPR = 10%); and 6) the sensitivity of prediction models was higher for severe early preeclampsia than for the entire early preeclampsia group (84% versus 71% at 16.1-22 weeks). CONCLUSION: We have presented herein a catalogue of proteome changes in maternal plasma proteome that precede the diagnosis of preeclampsia and can distinguish among early and late phenotypes. The sensitivity of maternal plasma protein models for early preeclampsia is higher in women with underlying vascular placental disease and in those with a severe phenotype. Tarca, Adi L Romero, Roberto Benshalom-Tirosh, Neta Than, Nandor Gabor Gudicha, Dereje W Done, Bogdan Pacora, Percy Chaiworapongsa, Tinnakorn Panaitescu, Bogdan Tirosh, Dan Gomez-Lopez, Nardhy Draghici, Sorin Hassan, Sonia S Erez, Offer eng HHSNC/HD/NICHD NIH HHS/ Clinical Trial Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't PLoS One. Jun 4;14(6):e. doi: 10./journal.pone.. eCollection .I SomaScan 06/05/ Huang G, et al. Circulating Biomarkers of Testosterone's Anabolic Effects on Fat-Free Mass J Clin Endocrinol Metab 104 9 -78 https://www.doi.org/10./jc.- 31,120,518 BACKGROUND: Biomarkers that predict response to anabolic therapies could expedite the development of function promoting anabolic drugs. This study aimed to identify serum biomarkers that are responsive to testosterone administration and associated with increases in fat-free mass (FFM). METHODS: Serum samples were obtained from the 5alpha-Reductase Trial, a randomized trial that compared the effects of graded doses of testosterone enanthate for 20-weeks in healthy men randomized to placebo or dutasteride (dual SRD5A inhibitor). Testosterone's effects on FFM or strength measures did not differ between placebo vs dutasteride groups. Accordingly, 54 subjects treated with testosterone plus placebo were included in the Discovery Cohort, and 48 randomized to dutasteride were included in the Validation Cohort. biomarkers were evaluated using pre-specified criteria. RESULTS: In the Discovery Cohort, testosterone administration increased PRO-C3 and PRO-C6 levels in a dose- and concentration-dependent manner; increases in these biomarkers from baseline to week-12 were associated with changes in FFM from baseline to week-20 (PRO-C3: r2=0.437, p<0.001; PRO-C6: r2=0.434, p<0.001). Changes in PRO-C3 and PRO-C6 levels were significantly associated with changes in chest press strength (PRO-C3: r2=0.394, p<0.001; PRO-C6: r2=0.530, p<0.001). In the SOMAscan, changes in insulin-like growth factor binding protein-6 (IGFBP6) and Glypican 3 (GPC3) were associated with changes in total and free testosterone levels and FFM. These findings were replicated in the Validation Cohort. CONCLUSION: PRO-C3, PRO-C6, IGFBP6 and GPC3 fulfilled the pre-specified criteria for biomarkers of testosterone-induced muscle anabolism: changes in these biomarkers were associated with changes in total and free testosterone concentrations and with testosterone-induced gains in FFM. Huang, Grace Rocha, Guilherme V Pencina, Karol M Cox, Karen Krishnan, Venkatesh Henriksen, Kim Mitchell, Peter Sissons, Sean E Li, Zhuoying Nedergaard, Anders F Karsdal, Morten A Sun, Shu Storer, Thomas W Basaria, Shehzad Bhasin, Shalender eng K08 HL/HL/NHLBI NIH HHS/ R01 HD/HD/NICHD NIH HHS/ J Clin Endocrinol Metab. May 23;104(9):-78. doi: 10./jc.-.I SomaScan 05/24/ Gordin D, et al. Characterization of Glycolytic Enzymes and Pyruvate Kinase M2 in Type 1 and 2 Diabetic Nephropathy Diabetes Care 42 7 - https://www.doi.org/10./dc18- 31,076,418 Aged Aged, 80 and over Autopsy Biomarkers/blood Case-Control Studies Cohort Studies Diabetes Mellitus, Type 1/blood/*complications/metabolism/pathology Diabetes Mellitus, Type 2/blood/*complications/metabolism/pathology Diabetic Nephropathies/blood/*metabolism/pathology Disease Progression Enzymes/analysis/*metabolism Female Glomerular Filtration Rate Glucose/*metabolism Humans Kidney/metabolism/pathology/physiopathology Kidney Glomerulus/metabolism/pathology/physiopathology Male Metabolic Networks and Pathways/physiology Metabolomics/methods Middle Aged Mitochondria/metabolism Proteomics/methods Pyruvate Kinase/*metabolism Renal Insufficiency, Chronic/complications/metabolism/pathology/physiopathology OBJECTIVE: Elevated glycolytic enzymes in renal glomeruli correlated with preservation of renal function in the Medalist Study, individuals with >/=50 years of type 1 diabetes. Specifically, pyruvate kinase M2 (PKM2) activation protected insulin-deficient diabetic mice from hyperglycemia-induced glomerular pathology. This study aims to extend these findings in a separate cohort of individuals with type 1 and type 2 diabetes and discover new circulatory biomarkers for renal protection through proteomics and metabolomics of Medalists' plasma. We hypothesize that increased glycolytic flux and improved mitochondrial biogenesis will halt the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS: Immunoblots analyzed selected glycolytic and mitochondrial enzymes in postmortem glomeruli of non-Medalists with type 1 diabetes (n = 15), type 2 diabetes (n = 19), and no diabetes (n = 5). Plasma proteomic (SOMAscan) (n = 180) and metabolomic screens (n = 214) of Medalists with and without stage 3b chronic kidney disease (CKD) were conducted and significant markers validated by ELISA. RESULTS: Glycolytic (PKM1, PKM2, and ENO1) and mitochondrial (MTCO2) enzymes were significantly elevated in glomeruli of CKD- versus CKD+ individuals with type 2 diabetes. Medalists' plasma PKM2 correlated with estimated glomerular filtration rate (r (2) = 0.077; P = 0.). Several glucose and mitochondrial enzymes in circulation were upregulated with corresponding downregulation of toxic metabolites in CKD-protected Medalists. Amyloid precursor protein was also significantly upregulated, tumor necrosis factor receptors downregulated, and both confirmed by ELISA. CONCLUSIONS: Elevation of enzymes involved in the metabolism of intracellular free glucose and its metabolites in renal glomeruli is connected to preserving kidney function in both type 1 and type 2 diabetes. The renal profile of elevated glycolytic enzymes and reduced toxic glucose metabolites is reflected in the circulation, supporting their use as biomarkers for endogenous renal protective factors in people with diabetes. Gordin, Daniel Shah, Hetal Shinjo, Takanori St-Louis, Ronald Qi, Weier Park, Kyoungmin Paniagua, Samantha M Pober, David M Wu, I-Hsien Bahnam, Vanessa Brissett, Megan J Tinsley, Liane J Dreyfuss, Jonathan M Pan, Hui Dong, Yutong Niewczas, Monika A Amenta, Peter Sadowski, Thorsten Kannt, Aimo Keenan, Hillary A King, George L eng DP3 DK/DK/NIDDK NIH HHS/ T32 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R24 DK/DK/NIDDK NIH HHS/ DP3 DK/DK/NIDDK NIH HHS/ UL1 RR/RR/NCRR NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Diabetes Care. Jul;42(7):-. doi: 10./dc18-. Epub May 10.I SomaScan 05/12/ Wells QS, et al. Accelerating Biomarker Discovery Through Electronic Health Records, Automated Biobanking, and Proteomics J Am Coll Cardiol 73 17 - https://www.doi.org/10./j.jacc..01.074 31,047,008 Academic Medical Centers Acceleration Aged Automation/*methods Biological Specimen Banks/organization & administration Biomarkers/blood Cohort Studies Electronic Health Records/*organization & administration Female Heart Failure/*blood/diagnosis Humans Male Middle Aged Proportional Hazards Models Prospective Studies Proteomics/*organization & administration Reproducibility of Results Risk Assessment Sensitivity and Specificity Thrombospondins/*blood biomarkers electronic health records heart failure proteomics BACKGROUND: Circulating biomarkers can facilitate diagnosis and risk stratification for complex conditions such as heart failure (HF). Newer molecular platforms can accelerate biomarker discovery, but they require significant resources for data and sample acquisition. OBJECTIVES: The purpose of this study was to test a pragmatic biomarker discovery strategy integrating automated clinical biobanking with proteomics. METHODS: Using the electronic health record, the authors identified patients with and without HF, retrieved their discarded plasma samples, and screened these specimens using a DNA aptamer-based proteomic platform (1,129 proteins). Candidate biomarkers were validated in 3 different prospective cohorts. RESULTS: In an automated manner, plasma samples from 1,315 patients (31% with HF) were collected. Proteomic analysis of a 96-patient subset identified 9 candidate biomarkers (p < 4.42 x 10(-5)). Two proteins, angiopoietin-2 and thrombospondin-2, were associated with HF in 3 separate validation cohorts. In an emergency department-based registry of 852 dyspneic patients, the 2 biomarkers improved discrimination of acute HF compared with a clinical score (p < 0.) or clinical score plus B-type natriuretic peptide (p = 0.02). In a community-based cohort (n = 768), both biomarkers predicted incident HF independent of traditional risk factors and N-terminal pro-B-type natriuretic peptide (hazard ratio per SD increment: 1.35 [95% confidence interval: 1.14 to 1.61; p = 0.] for angiopoietin-2, and 1.37 [95% confidence interval: 1.06 to 1.79; p = 0.02] for thrombospondin-2). Among 30 advanced HF patients, concentrations of both biomarkers declined (80% to 84%) following cardiac transplant (p < 0.001 for both). CONCLUSIONS: A novel strategy integrating electronic health records, discarded clinical specimens, and proteomics identified 2 biomarkers that robustly predict HF across diverse clinical settings. This approach could accelerate biomarker discovery for many diseases. Wells, Quinn S Gupta, Deepak K Smith, J Gustav Collins, Sean P Storrow, Alan B Ferguson, Jane Smith, Maya Landenhed Pulley, Jill M Collier, Sarah Wang, Xiaoming Roden, Dan M Gerszten, Robert E Wang, Thomas J eng S10 OD/OD/NIH HHS/ K23 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ K12 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Am Coll Cardiol. May 7;73(17):-. doi: 10./j.jacc..01.074.I SomaScan 05/03/ Niewczas MA, et al. A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes Nat Med 25 5 805-813 https://www.doi.org/10./s-019--5 31,011,203 Adult Aged Biomarkers/blood Blood Proteins/genetics/metabolism Cohort Studies Diabetes Mellitus, Type 1/blood/complications/genetics Diabetes Mellitus, Type 2/blood/complications/genetics Diabetic Nephropathies/*blood/*etiology/genetics Disease Progression Female Humans Inflammation Mediators/blood Kidney Failure, Chronic/*blood/*etiology/genetics Male Middle Aged Prognosis Prospective Studies Proteomics Receptors, Tumor Necrosis Factor/blood/genetics Risk Factors Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease. Niewczas, Monika A Pavkov, Meda E Skupien, Jan Smiles, Adam Md Dom, Zaipul I Wilson, Jonathan M Park, Jihwan Nair, Viji Schlafly, Andrew Saulnier, Pierre-Jean Satake, Eiichiro Simeone, Christopher A Shah, Hetal Qiu, Chengxiang Looker, Helen C Fiorina, Paolo Ware, Carl F Sun, Jennifer K Doria, Alessandro Kretzler, Matthias Susztak, Katalin Duffin, Kevin L Nelson, Robert G Krolewski, Andrzej S eng DP3 DK/DK/NIDDK NIH HHS/ DP3 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Med. May;25(5):805-813. doi: 10./s-019--5. Epub Apr 22.I SomaScan 04/24/ Zahedi-Amiri A, et al. Influenza a virus-triggered autophagy decreases the pluripotency of human-induced pluripotent stem cells Cell Death Dis 10 5 337 https://www.doi.org/10./s-019--4 31,000,695 A549 Cells *Autophagy/drug effects Cell Differentiation Embryonic Development Humans Induced Pluripotent Stem Cells/cytology/*metabolism/virology Influenza A virus/*physiology Macrolides/pharmacology Metabolic Networks and Pathways Nanog Homeobox Protein/metabolism Proteome/analysis Proteomics SOXB1 Transcription Factors/metabolism Sirolimus/pharmacology Virus Replication Maternal influenza infection during pregnancy was reported multiple times as the possible cause of many defects and congenital anomalies. Apart from several cases of influenza-related miscarriage during various trimesters of pregnancy, some epidemiological data suggest a link between maternal influenza infection and genetic abnormalities in offspring. However, there are no reports yet describing how maternal influenza alters cellular pathways at early stages of development to result in congenital defects in the fetus. In the present study, using proteomic approaches, we utilized human-induced pluripotent stem cells (hiPSCs) for modeling intrablastocyst infection with influenza virus to not only investigate the vulnerability and responses of pluripotent stem cells to this virus but also to determine the possible impacts of influenza on pluripotency and signaling pathways controlling differentiation and embryogenesis. Our data indicated viral protein production in influenza A virus (IAV)-infected hiPSCs. However, viral replication was restricted in these cells, but cell viability and pluripotency were negatively affected. These events occurred simultaneously with an excessive level of IAV-induced autophagy as well as cytopathic effects. Quantitative SOMAscan screening also indicated that changes in the proteome of hiPSCs corresponded to abnormal differentiation in these cells. Taken together, our results showed that IAV-modulated reduction in hiPSC pluripotency is associated with significant activation of autophagy. Further investigations are required to explore the role of IAV-induced autophagy in leading pluripotent stem cells toward abnormal differentiation and impaired development in early stages of embryogenesis. Zahedi-Amiri, Ali Sequiera, Glen L Dhingra, Sanjiv Coombs, Kevin M eng MOP-/CIHR/Canada MOP-/CIHR/Canada Research Support, Non-U.S. Gov't England Cell Death Dis. Apr 18;10(5):337. doi: 10./s-019--4.I SomaScan 04/20/ Penn-Nicholson A, et al. Discovery and validation of a prognostic proteomic signature for tuberculosis progression: A prospective cohort study PLoS Med 16 4 e https://www.doi.org/10./journal.pmed. 30,990,820 Adolescent Biomarkers/analysis/*blood/metabolism Child Cohort Studies Diagnostic Tests, Routine/methods Disease Progression Female Humans Longitudinal Studies Male Point-of-Care Testing Prognosis Prospective Studies Proteome/*analysis/metabolism Proteomics Tuberculosis/blood/*diagnosis/pathology BACKGROUND: A nonsputum blood test capable of predicting progression of healthy individuals to active tuberculosis (TB) before clinical symptoms manifest would allow targeted treatment to curb transmission. We aimed to develop a proteomic biomarker of risk of TB progression for ultimate translation into a point-of-care diagnostic. METHODS AND FINDINGS: Proteomic TB risk signatures were discovered in a longitudinal cohort of 6,363 Mycobacterium tuberculosis-infected, HIV-negative South African adolescents aged 12-18 years (68% female) who participated in the Adolescent Cohort Study (ACS) between July 6, and April 23, , through either active (every 6 months) or passive follow-up over 2 years. Forty-six individuals developed microbiologically confirmed TB disease within 2 years of follow-up and were selected as progressors; 106 nonprogressors, who remained healthy, were matched to progressors. Over 3,000 human proteins were quantified in plasma with a highly multiplexed proteomic assay (SOMAscan). Three hundred sixty-one proteins of differential abundance between progressors and nonprogressors were identified. A 5-protein signature, TB Risk Model 5 (TRM5), was discovered in the ACS training set and verified by blind prediction in the ACS test set. Poor performance on samples 13-24 months before TB diagnosis motivated discovery of a second 3-protein signature, 3-protein pair-ratio (3PR) developed using an orthogonal strategy on the full ACS subcohort. Prognostic performance of both signatures was validated in an independent cohort of 1,948 HIV-negative household TB contacts from The Gambia (aged 15-60 years, 66% female), longitudinally followed up for 2 years between March 5, and October 21, , sampled at baseline, month 6, and month 18. Amongst these contacts, 34 individuals progressed to microbiologically confirmed TB disease and were included as progressors, and 115 nonprogressors were included as controls. Prognostic performance of the TRM5 signature in the ACS training set was excellent within 6 months of TB diagnosis (area under the receiver operating characteristic curve [AUC] 0.96 [95% confidence interval, 0.93-0.99]) and 6-12 months (AUC 0.76 [0.65-0.87]) before TB diagnosis. TRM5 validated with an AUC of 0.66 (0.56-0.75) within 1 year of TB diagnosis in the Gambian validation cohort. The 3PR signature yielded an AUC of 0.89 (0.84-0.95) within 6 months of TB diagnosis and 0.72 (0.64-0.81) 7-12 months before TB diagnosis in the entire South African discovery cohort and validated with an AUC of 0.65 (0.55-0.75) within 1 year of TB diagnosis in the Gambian validation cohort. Signature validation may have been limited by a systematic shift in signal magnitudes generated by differences between the validation assay when compared to the discovery assay. Further validation, especially in cohorts from non-African countries, is necessary to determine how generalizable signature performance is. CONCLUSIONS: Both proteomic TB risk signatures predicted progression to incident TB within a year of diagnosis. To our knowledge, these are the first validated prognostic proteomic signatures. Neither meet the minimum criteria as defined in the WHO Target Product Profile for a progression test. More work is required to develop such a test for practical identification of individuals for investigation of incipient, subclinical, or active TB disease for appropriate treatment and care. Penn-Nicholson, Adam Hraha, Thomas Thompson, Ethan G Sterling, David Mbandi, Stanley Kimbung Wall, Kirsten M Fisher, Michelle Suliman, Sara Shankar, Smitha Hanekom, Willem A Janjic, Nebojsa Hatherill, Mark Kaufmann, Stefan H E Sutherland, Jayne Walzl, Gerhard De Groote, Mary Ann Ochsner, Urs Zak, Daniel E Scriba, Thomas J eng U01 AI/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study PLoS Med. Apr 16;16(4):e. doi: 10./journal.pmed.. eCollection Apr.I SomaScan 04/17/ Sher AA, et al. Zika Virus Infection Disrupts Astrocytic Proteins Involved in Synapse Control and Axon Guidance Front Microbiol 10 596 https://www.doi.org/10./fmicb.. 30,984,137 RNA virus infection SOMAScan aptamers astrocytic dysregulation proteomics virus-host interaction The first human Zika virus (ZIKV) outbreak was reported in Micronesia in , followed by one in Brazil in . Recent studies have reported cases in Europe, Oceania and Latin America. In , ZIKV transmission was also reported in the US and the World Health Organization declared it a Public Health Emergency of International Concern. Because various neurological conditions are associated with ZIKV, such as microcephaly, Guillain-Barre syndrome, and other disorders of both the central and peripheral nervous systems, including encephalopathy, (meningo)encephalitis and myelitis, and because of the lack of reliable patient diagnosis, numerous ongoing studies seek to understand molecular mechanisms underlying ZIKV pathogenesis. Astrocytes are one of the most abundant cells in the CNS. They control axonal guidance, synaptic signaling, neurotransmitter trafficking and maintenance of neurons, and are targeted by ZIKV. In this study, we used a newly developed multiplexed aptamer-based technique (SOMAScan) to examine > human astrocyte cell proteins. We identified almost 300 astrocyte proteins significantly dysregulated by ZIKV infection that span diverse functions and signaling pathways, including protein translation, synaptic control, cell migration and differentiation. Sher, Affan A Glover, Kathleen K M Coombs, Kevin M eng Switzerland Front Microbiol. Mar 26;10:596. doi: 10./fmicb... eCollection .I SomaScan 04/16/ Mulla CM, et al. Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia Obes Surg 29 7 - https://www.doi.org/10./s-019--0 30,976,983 Adult Bariatric Surgery/*adverse effects Blood Glucose/metabolism Blood Proteins/analysis/metabolism Case-Control Studies Female Fibroblast Growth Factors/*blood Gastric Bypass/adverse effects Gastrointestinal Hormones/blood Glucagon-Like Peptide 1/blood Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors Humans Hypoglycemia/*blood/diet therapy/drug therapy/*etiology Male Meals Middle Aged Obesity, Morbid/blood/*surgery Peptide Fragments/therapeutic use Postoperative Complications/*blood/diet therapy/drug therapy Proteome/analysis Proteomics Up-Regulation Bile acids Fgf-19 Gastric bypass Hypoglycemia Pharmaceuticals, has received investigator-initiated grant support from Janssen Pharmaceuticals, Medimmune, Sanofi, Astra-Zeneca, Jenesis, and Nuclea, has been a site investigator for XOMA, and acknowledges clinical trial research trial product support from Ethicon, Covidien, NovoNordisk, Nestle, and Dexcom within the past 5 years. Dr. Patti and Dr. Goldfine disclose a patent application for plasma proteins contributing to hypoglycemia. Dr. Mulla, Dr. Dreyfuss, Dr. Houten, Dr. Pan, Dr. Pober, Dr. Wewer Albrechtsen, Dr. Svane, Dr. Schmidt, Dr. Holst, Dr. Craig and Dr. McLaughlin declare no potential competing interests. BACKGROUND: Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB. METHODS: Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics. RESULTS: The top-ranking differentially abundant protein at 120 min after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally derived hormone regulated by bile acid-FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean + SEM, +/- 141 vs. 428 +/- 45, P < 0.001, FDR < 0.01). FGF-19 ELISA confirmed 3.5-fold higher concentrations in PBH versus asymptomatic (360 +/- 70 vs. 103 +/- 18, P = 0.025). To explore potential links between increased FGF-19 and GLP-1, residual samples from other human studies in which GLP-1 was modulated were assayed. FGF-19 levels did not change in response to infusion of GLP-1 and PYY in overweight/obese individuals. Infusion of the GLP-1 receptor antagonist exendin 9-39 in recently operated asymptomatic post-RYGB did not alter FGF-19 levels after mixed meal. By contrast, GLP-1 receptor antagonist infusion yielded a significant increase in FGF-19 levels after oral glucose in individuals with PBH. While plasma bile acids did not differ between PBH and asymptomatic post-RYGB, these data suggest unique interrelationships between GLP-1 and FGF-19 in PBH. CONCLUSIONS: Taken together, these data support FGF-19 as a potential contributor to insulin-independent pathways driving postprandial hypoglycemia in PBH. Mulla, Christopher M Goldfine, Allison B Dreyfuss, Jonathan M Houten, Sander Pan, Hui Pober, David M Wewer Albrechtsen, Nicolai J Svane, Maria S Schmidt, Julie B Holst, Jens Juul Craig, Colleen M McLaughlin, Tracey L Patti, Mary-Elizabeth eng L30 TR/TR/NCATS NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ KL2 TR/TR/NCATS NIH HHS/ RC1 DK/DK/NIDDK NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ R56 DK/DK/NIDDK NIH HHS/ R44 DK/DK/NIDDK NIH HHS/ T32 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Obes Surg. Jul;29(7):-. doi: 10./s-019--0.I SomaScan 04/13/ Bar-Or D, et al. Stress Hyperglycemia in Critically Ill Patients: Insight Into Possible Molecular Pathways Front Med (Lausanne) 6 54 https://www.doi.org/10./fmed.. 30,972,338 Warburg effect dipeptidyl peptidase IV glycolysis hyperglycemia oxidative phosphorylation sepsis Severe sepsis, systemic inflammatory response syndrome (SIRS), and traumatic brain injury are frequently associated with hyperglycemia in non-diabetic patients. In patients suffering from any of these conditions, hyperglycemia at admission to an intensive care unit (ICU) is directly correlated with increased mortality or morbidity. Although there was initial enthusiasm for insulin treatment to blood glucose levels below 110 mg/dL in these patients, recent understanding suggests that the potential for hypoglycemic complications make this approach potentially dangerous. More moderate glucose control seems to be more beneficial than the aggressive glucose lowering initially suggested. An important publication has shown that hyperlactatemia accompanying hyperglycemia could be the real culprit in bad outcomes. This suggests that coupling moderate glucose lowering with therapeutic agents which might treat the underlying metabolic disturbances in these conditions may be a better strategy. The key metabolic disturbance in these three conditions seems to be persistent glycolysis as an energy source even in the presence of adequate tissue oxygenation (the Warburg Effect). We look at recent advances in understanding aerobic glycolysis and possibly the action of DPP4 on incretins resulting in insulin dysregulation and suggest key metabolic pathways involved in hyperglycemia regulation. Bar-Or, David Rael, Leonard T Madayag, Robert M Banton, Kaysie L Tanner, Allen 2nd Acuna, David L Lieser, Mark J Marshall, Gary T Mains, Charles W Brody, Edward eng Switzerland Front Med (Lausanne). Mar 27;6:54. doi: 10./fmed... eCollection .I SomaScan 04/12/ Xiong H, et al. Cancer protein biomarker discovery based on nucleic acid aptamers Int J Biol Macromol 132 190-202 https://www.doi.org/10./j.ijbiomac..03.165 30,926,499 Animals Aptamers, Nucleotide/metabolism Biomarkers, Tumor/*metabolism Cell Membrane/metabolism Humans Neoplasm Proteins/*metabolism SELEX Aptamer Technique/*methods Cancer biomarker Nucleic acid aptamer Protein Identification of biomarkers is essential for diagnosis, targeted therapy and prognosis evaluation of diseases, especially cancers. Currently, the number of ideal clinical biomarkers is still limited partially because of lacking efficient methods in biomarker discovery. Nucleic acid aptamers are artificial single-stranded DNA or RNA sequences that can selectively bind to various targets with high specificity and affinity. Moreover, aptamers possess desirable advantages, including easy synthesis, convenient modification, relative chemical stability and low immunogenicity. Recently, different aptamer-based strategies have been developed to facilitate the discovery of biomarkers. Based on cell-SELEX technology, the selected aptamers can be used to identify cell-surface protein biomarkers of different cancer cells. SOMAscan can analyze thousands of proteins of different biological samples, which becomes a multiplexed protein biomarker discovery platform. Additionally, secreted protein biomarkers can be discovered by aptamers screened through secretome SELEX. In order to facilitate the identification of target proteins, several covalent cross-linking strategies have been developed, such as aptamer-based affinity labeling (ABAL), DNA-templated aptamer and protein-aptamer template (PAT). In this review, we mainly highlight the emerging nucleic acid aptamer-based biomarker discovery strategies and demonstrate their unique technological advantages in discovering cancer biomarkers. The challenges and perspectives of aptamer-based methods are also discussed. Xiong, Hongjie Yan, Jianhua Cai, Shundong He, Qunye Peng, Dongming Liu, Zhenbao Liu, Yanfei eng Review Netherlands Int J Biol Macromol. Jul 1;132:190-202. doi: 10./j.ijbiomac..03.165. Epub Mar 26.I SomaScan 03/31/ Helfand BT, et al. A Novel Proteomics Approach to Identify Serum and Urinary Biomarkers and Pathways that Associate with Lower Urinary Tract Symptoms in Men and Women: Pilot Results of the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) Study Urology 129 35-42 https://www.doi.org/10./j.urology..03.014 30,922,973 Adult Aged Biomarkers/blood/urine Cohort Studies Feasibility Studies Female Humans Lower Urinary Tract Symptoms/*blood/diagnosis/*urine Male Middle Aged Pilot Projects *Proteomics Symptom Assessment OBJECTIVES: To assess the feasibility of a novel proteomics approach to identify biomarkers associated with lower urinary tract symptoms (LUTS) within serum and urine, because many clinical factors contribute to LUTS in men and women. These factors confound clinicians' abilities to reliably evaluate and treat LUTS. Previous studies identified candidate LUTS biomarkers, but none are clinically utilized. METHODS: Eighteen male and 18 female symptoms of lower urinary tract dysfunction research network (LURN) observational cohort study participants with LUTS (measured on the LUTS Tool questionnaire) were randomly selected. Twelve male and 12 female controls with minimal or no LUTS were recruited and matched for clinico-demographic characteristics. The SomaScan Assay (SomaLogic) was used to measure the abundance of proteins contained within urine and serum. Statistical analyses were performed to evaluate reproducibility of assays, compare protein abundances, and estimate effect size. RESULTS: SomaScan assay results were more reproducible in serum than in urine. Within serum, there were many more differentially abundant proteins between cases and controls in males than in females. An enrichment/pathway analysis of the affected proteins in male and female subjects demonstrated that the enriched Gene Ontology processes were related to prostate morphogenesis in men and growth and inflammation in women. CONCLUSION: The pilot study results support that the etiology and pathophysiologic mechanisms underlying LUTS may be sex-specific. While further studies involving larger numbers of subjects are warranted, our results support the feasibility of a novel proteomic approach to identify biomarkers for diagnostic classification of LUTS. Helfand, Brian T Andreev, Victor P Siddiqui, Nazema Y Liu, Gang Erickson, Bradley A Helmuth, Margaret E Lutgendorf, Susan K Lai, H Henry Kirkali, Ziya eng U01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ K23 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U24 DK/DK/NIDDK NIH HHS/ K12 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ Observational Study Urology. Jul;129:35-42. doi: 10./j.urology..03.014. Epub Mar 25.I SomaScan 03/30/ Bodewes ILA, et al. Fatigue in Sjogren's Syndrome: A Search for Biomarkers and Treatment Targets Front Immunol 10 312 https://www.doi.org/10./fimmu.. 30,863,411 Adult Aged Biomarkers/blood/*metabolism Blood Proteins/*metabolism Fatigue/diagnosis/*metabolism/therapy Female Humans Interferons/blood/metabolism Male Middle Aged Proteome/*metabolism Proteomics/*methods ROC Curve Signal Transduction Sjogren's Syndrome/diagnosis/*metabolism/therapy Up-Regulation Young Adult SOMAscan Sjogren's syndrome fatigue interferon proteomics Background: Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease, where patients often suffer from fatigue. Biological pathways underlying fatigue are unknown. In this study aptamer-based SOMAscan technology is used to identify potential biomarkers and treatment targets for fatigue in pSS. Methods: SOMAscan(R) Assay 1.3k was performed on serum samples of healthy controls (HCs) and pSS patients characterized for interferon upregulation and fatigue. Differentially expressed proteins (DEPs) between pSS patients and HC or fatigued and non-fatigued pSS patients were validated and discriminatory capacity of markers was tested using independent technology. Results: Serum concentrations of over 1,300 proteins were compared between 63 pSS patients and 20 HCs resulting in 58 upregulated and 46 downregulated proteins. Additionally, serum concentrations of 30 interferon positive (IFNpos) and 30 interferon negative (IFNneg) pSS patients were compared resulting in 25 upregulated and 13 downregulated proteins. ELISAs were performed for several DEPs between pSS patients and HCs or IFNpos and IFNneg all showing a good correlation between protein levels measured by ELISA and relative fluorescence units (RFU) measured by the SOMAscan. Comparing 22 fatigued and 23 non-fatigued pSS patients, 16 serum proteins were differentially expressed, of which 14 were upregulated and 2 were downregulated. Top upregulated DEPs included neuroactive synaptosomal-associated protein 25 (SNAP-25), alpha-enolase (ENO1) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). Furthermore, the proinflammatory mediator IL36a and several complement factors were upregulated in fatigued compared to non-fatigued pSS patients. ROC analysis indicated that DEPs showed good capacity to discriminate fatigued and non-fatigued pSS patients. Conclusion: In this study we validated the use of aptamer-based proteomics and identified a novel set of proteins which were able to distinguish fatigued from non-fatigued pSS patients and identified a so-called fatigue signature."" Bodewes, Iris L A van der Spek, Peter J Leon, Leticia G Wijkhuijs, Annemarie J M van Helden-Meeuwsen, Cornelia G Tas, Liselotte Schreurs, Marco W J van Daele, Paul L A Katsikis, Peter D Versnel, Marjan A eng Research Support, Non-U.S. Gov't Switzerland Front Immunol. Feb 26;10:312. doi: 10./fimmu... eCollection .I SomaScan 03/14/ Ko D, et al. Proteomics Profiling and Risk of New-Onset Atrial Fibrillation: Framingham Heart Study J Am Heart Assoc 8 6 e https://www.doi.org/10./JAHA.118. 30,841,775 Atrial Fibrillation/blood/*epidemiology/genetics Biomarkers/blood Blood Proteins/genetics/*metabolism Female Follow-Up Studies *Forecasting Genome-Wide Association Study/*methods Humans Incidence Longitudinal Studies Male Middle Aged Polymorphism, Genetic Prospective Studies Proteomics/*methods Risk Factors United States/epidemiology atrial fibrillation biomarker proteomics risk Background Prior studies relating proteomics markers to incident AF screened for limited numbers of proteins. Methods and Results We performed proteomics assays among participants from the Framingham Heart Study Offspring attending their fifth examination. Plasma protein levels (n=) were measured by the SOMAscan proteomic profiling platform. We used robust inference for the Cox proportional hazards model to relate each protein level with incident AF. In addition, we examined the association between AF-related genetic loci and levels of proteins associated with AF. Our study included participants (mean age 55+/-10 years, 54% women) who had proteomic profiles measured. A total of 349 participants developed AF during follow-up (mean follow-up 18.3 years). We observed that 8 proteins were significantly associated with incident AF after adjusting for age, sex, technical covariates, and correction for multiple testing ( P<0.05/=3.6x10(-5)). After additional adjustments for clinical factors associated with AF, ADAMTS13 and N-terminal pro-B-type natriuretic peptide remained significantly associated with the risk of incident AF (hazard ratio, 0.78; 95% CI, 0.70-0.88; and 1.44; 95% CI, 1.22-1.70, respectively; P<3.6x10(-5) for both). None of the 8 proteins were encoded by genes at AF-related genetic loci previously identified by genome-wide association studies. Conclusions We identified 8 proteins associated with risk of incident AF after adjustment for age and sex; 2 proteins were associated with AF after adjustment for AF risk factors. Future studies are needed to replicate our findings, identify whether the markers are mechanistically related to AF development, and whether they are clinically useful for identification of future AF risk. Ko, Darae Benson, Mark D Ngo, Debby Yang, Qiong Larson, Martin G Wang, Thomas J Trinquart, Ludovic McManus, David D Lubitz, Steven A Ellinor, Patrick T Vasan, Ramachandran S Gerszten, Robert E Benjamin, Emelia J Lin, Honghuang eng UL1 TR/TR/NCATS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ K08 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ K24 HL/HL/NHLBI NIH HHS/ UH3 TR/TR/NCATS NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ HHSNI/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England J Am Heart Assoc. Mar 19;8(6):e. doi: 10./JAHA.118..I SomaScan 03/08/ Roh JD, et al. Activin type II receptor signaling in cardiac aging and heart failure Sci Transl Med 11 482 https://www.doi.org/10./scitranslmed.aau 30,842,316 Activin Receptors, Type II/*metabolism Activins/blood Adult Aged Aged, 80 and over Aging/blood/*metabolism Animals Constriction, Pathologic Disease Models, Animal Follistatin-Related Proteins/metabolism Frailty Heart Failure/blood/*metabolism/pathology/physiopathology Heart Ventricles/pathology/physiopathology Humans Ligands Male Mice, Inbred C57BL Middle Aged Myocardium/*metabolism/*pathology Myocytes, Cardiac/metabolism Pressure Proteasome Endopeptidase Complex/metabolism Proteolysis Rats Sarcoplasmic Reticulum Calcium-Transporting ATPases Severity of Illness Index *Signal Transduction Systole Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF. Roh, Jason D Hobson, Ryan Chaudhari, Vinita Quintero, Pablo Yeri, Ashish Benson, Mark Xiao, Chunyang Zlotoff, Daniel Bezzerides, Vassilios Houstis, Nicholas Platt, Colin Damilano, Federico Lindman, Brian R Elmariah, Sammy Biersmith, Michael Lee, Se-Jin Seidman, Christine E Seidman, Jonathan G Gerszten, Robert E Lach-Trifilieff, Estelle Glass, David J Rosenzweig, Anthony eng R01 AG/AG/NIA NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ UH3 TR/TR/NCATS NIH HHS/ 14FTF/AHA_/American Heart Association-American Stroke Association/ UH2 TR/TR/NCATS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ K08 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sci Transl Med. Mar 6;11(482):eaau. doi: 10./scitranslmed.aau.I SomaScan 03/08/ Begic E, et al. SOMAscan-based proteomic measurements of plasma brain natriuretic peptide are decreased in mild cognitive impairment and in Alzheimer's dementia patients PLoS One 14 2 e https://www.doi.org/10./journal.pone. 30,763,368 Aged Aged, 80 and over Alzheimer Disease/*blood Biomarkers/blood Cognitive Dysfunction/*blood Female Humans Male Natriuretic Peptide, Brain/*blood Proteomics Alzheimer's disease represents the most common age-related neurodegenerative disorder and a leading cause of progressive cognitive impairment. Predicting cognitive decline is challenging but would be invaluable in an increasingly aging population which also experiences a rising cardiovascular risk. In order to examine whether plasma measurements of one of the established biomarkers of heart failure, brain natriuretic peptide (BNP), reflect a decline in cognitive function, associated with Alzheimer's disease neurodegeneration, BNP levels were analysed, by using a novel assay called a SOMAscan, in 1. cognitively healthy, control subjects; 2. subjects with mild cognitive impairment, and 3. subjects with Alzheimer's disease. The results of our study show that the levels of the BNP were significantly different between the three types of diagnoses (p < 0.05), whereby subjects with mild cognitive impairment had the lowest mean BNP value, and healthy subjects had the highest BNP value. Importantly, our results show that the levels of the BNP are influenced by the presence of at least one APOE4 allele in the healthy (p < 0.05) and in the Alzheimer's disease groups of subjects (p < 0.1). As the levels of the BNP appear to be independent of the APOE4 genotype in subjects with mild cognitive impairment, the results of our study support inclusion of measurements of plasma levels of the BNP in the list of the core Alzheimer's disease biomarkers for identification of the mild cognitive impairment group of patients. In addition, the results of our study warrant further investigations into molecular links between Alzheimer's disease-type cognitive decline and cardiovascular disorders. Begic, Edin Hadzidedic, Suncica Kulaglic, Ajla Ramic-Brkic, Belma Begic, Zijo Causevic, Mirsada eng Research Support, Non-U.S. Gov't PLoS One. Feb 14;14(2):e. doi: 10./journal.pone.. eCollection .I SomaScan 02/15/ Lynch AM, et al. Proteomic Profiles in Advanced Age-Related Macular Degeneration Using an Aptamer-Based Proteomic Technology Transl Vis Sci Technol 8 1 14 https://www.doi.org/10./tvst.8.1.14 30,697,465 aptamer-based technologies geographic atrophy neovascular AMD proteomics PURPOSE: To explore top-ranked plasma proteins related to neovascular age-related macular degeneration (AMD) and geographic atrophy (GA), and explore pathways related to neovascular AMD and GA. METHODS: We conducted a pilot study of patients with neovascular AMD (n = 10), GA (n = 10), and age-matched cataract controls (n = 10) who were recruited into an AMD registry. We measured proteins in ethylenediaminetetraacetic acid plasma samples using an aptamer-based proteomic technology. Relative concentrations of each of proteins were log (base 2) transformed and compared between cases of neovascular AMD and GA versus controls using linear regression. Pathway analysis was conducted using pathways downloaded from Reactome. RESULTS: In this pilot study, higher levels of vinculin and lower levels of CD177 were found in patients with neovascular AMD compared with controls. Neuregulin-4 was higher and soluble intercellular adhesion molecule-1 was lower in patients with GA compared with controls. For neovascular AMD, cargo trafficking to the periciliary membrane, fibroblast growth factor receptor 3b ligand binding and activation, and vascular endothelial growth factor-related pathways were in the top ranked pathways. The top-ranked pathways for GA included several related to ErbB4 signaling. CONCLUSIONS: We found different proteins and different pathways associated with neovascular AMD and GA. Vinculin and some of the top-ranked pathways have been previously associated with AMD, whereas others have not been described. TRANSLATIONAL RELEVANCE: Biomarkers identified in plasma likely reflect systemic alterations in protein expression and may improve our understanding of the mechanisms leading to AMD. Lynch, Anne M Wagner, Brandie D Weiss, Sophie J Wall, Kirsten M Palestine, Alan G Mathias, Marc T Siringo, Frank S Cathcart, Jennifer N Patnaik, Jennifer L Drolet, Daniel W Janjic, Nebojsa Mandava, Naresh eng Transl Vis Sci Technol. Jan 25;8(1):14. doi: 10./tvst.8.1.14. eCollection Jan.I SomaScan 01/31/ Lukjanenko L, et al. Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors Cell Stem Cell 24 3 433-446 e7 https://www.doi.org/10./j.stem..12.014 30,686,765 Adipocytes/cytology/*metabolism Adipogenesis Aging/*metabolism Animals CCN Intercellular Signaling Proteins/deficiency/*metabolism Cells, Cultured Humans Mice Mice, Inbred C57BL Mice, Knockout Muscle, Skeletal/cytology/*metabolism Proto-Oncogene Proteins/deficiency/*metabolism Stem Cells/cytology/*metabolism Ccn4 Wisp1 aging fibro-adipogenic progenitors matricellular signaling muscle stem cells regeneration satellite cell skeletal muscle stem cell niche or were employees of the Nestle Institute of Health Sciences / Nestec S.A., Switzerland. L.L. and J.N.F. are inventors of patent WOA1 assigned to Nestec S.A. Research on age-related regenerative failure of skeletal muscle has extensively focused on the phenotypes of muscle stem cells (MuSCs). In contrast, the impact of aging on regulatory cells in the MuSC niche remains largely unexplored. Here, we demonstrate that aging impairs the function of mouse fibro-adipogenic progenitors (FAPs) and thereby indirectly affects the myogenic potential of MuSCs. Using transcriptomic profiling, we identify WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as a FAP-derived matricellular signal that is lost during aging. WISP1 is required for efficient muscle regeneration and controls the expansion and asymmetric commitment of MuSCs through Akt signaling. Transplantation of young FAPs or systemic treatment with WISP1 restores the myogenic capacity of MuSCs in aged mice and rescues skeletal muscle regeneration. Our work establishes that loss of WISP1 from FAPs contributes to MuSC dysfunction in aged skeletal muscles and demonstrates that this mechanism can be targeted to rejuvenate myogenesis. Lukjanenko, Laura Karaz, Sonia Stuelsatz, Pascal Gurriaran-Rodriguez, Uxia Michaud, Joris Dammone, Gabriele Sizzano, Federico Mashinchian, Omid Ancel, Sara Migliavacca, Eugenia Liot, Sophie Jacot, Guillaume Metairon, Sylviane Raymond, Frederic Descombes, Patrick Palini, Alessio Chazaud, Benedicte Rudnicki, Michael A Bentzinger, C Florian Feige, Jerome N eng R01 AR/AR/NIAMS NIH HHS/ FDN-/CIHR/Canada Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell Stem Cell. Mar 7;24(3):433-446.e7. doi: 10./j.stem..12.014. Epub Jan 24.I SomaScan 01/29/ Hemnes AR, et al. Human PAH is characterized by a pattern of lipid-related insulin resistance JCI Insight 4 1 https://www.doi.org/10./jci.insight. 30,626,738 Cardiology Hypertension Insulin Proteomics Pulmonology Therapeutics, and Complexa. MEP has served as a consultant to Gilead. CJR has served as consultant to Actelion and United Therapeutics. BACKGROUND: Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose- and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. METHODS: Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. RESULTS: PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulin-sensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages. CONCLUSIONS: IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium- and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH. FUNDING: NIH DK, HL, UL1 RR-01, UL1 TR-06, DK, P01 HL-01A1, and UL1 TR; American Heart Association 13FTF. Hemnes, Anna R Luther, J Matthew Rhodes, Christopher J Burgess, Jason P Carlson, James Fan, Run Fessel, Joshua P Fortune, Niki Gerszten, Robert E Halliday, Stephen J Hekmat, Rezzan Howard, Luke Newman, John H Niswender, Kevin D Pugh, Meredith E Robbins, Ivan M Sheng, Quanhu Shibao, Cyndya A Shyr, Yu Sumner, Susan Talati, Megha Wharton, John Wilkins, Martin R Ye, Fei Yu, Chang West, James Brittain, Evan L eng UL1 TR/TR/NCATS NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ P60 DK/DK/NIDDK NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ FS/15/59//BHF_/British Heart Foundation/United Kingdom K08 HL/HL/NHLBI NIH HHS/ UL1 RR/RR/NCRR NIH HHS/ P01 HL/HL/NHLBI NIH HHS/ JCI Insight. Jan 10;4(1):e. doi: 10./jci.insight..I SomaScan 01/11/ Glover KKM, et al. Vero Cell Proteomic Changes Induced by Zika Virus Infection Proteomics 19 4 e https://www.doi.org/10./pmic. 30,578,658 Animals Chlorocebus aethiops *Proteomics Vero Cells Virus Replication Zika Virus/*physiology Zika Virus Infection/*metabolism RNA virus infection SOMAScan aptamers proteomics The re-emergence and the recent spread of the Zika virus (ZIKV) has raised significant global concerns due to lack of information in patient diagnosis and management. Thus, in addition to gaining more basic information about ZIKV biology, appropriate interventions and management strategies are being sought to control ZIKV-associated diseases and its spread. This study's objective is to identify host cell proteins that are significantly dysregulated during ZIKV infection. SOMAScan, a novel aptamer-based assay, is used to simultaneously screen > host proteins to detect ZIKV-induced host protein dysregulation at multiple time points during infection. A total of 125 Vero cell host proteins, including cytokines such as CXCL11 and CCL5, interferon stimulated gene 15, and translation initiation factors EIF5A and EIF4G2, are significantly dysregulated after ZIKV infection. Bioinformatic analyses of 77 host proteins, that are significantly dysregulated >/=1.25-fold, identify several activated biological processes, including the JAK/STAT, Tec kinase, and complement cascade pathways. Glover, Kathleen K M Gao, Ang Zahedi-Amiri, Ali Coombs, Kevin M eng CIHR/Canada Research Support, Non-U.S. Gov't Germany Proteomics. Feb;19(4):e. doi: 10./pmic.. Epub Jan 23.I SomaScan 12/24/ Mysona D, et al. A combined score of clinical factors and serum proteins can predict time to recurrence in high grade serous ovarian cancer Gynecol Oncol 152 3 574-580 https://www.doi.org/10./j.ygyno..12.015 30,578,005 Cystadenocarcinoma, Serous/*blood/pathology/surgery Cytoreduction Surgical Procedures Disease-Free Survival Female Humans Middle Aged Neoplasm Grading Neoplasm Proteins/*blood Neoplasm Recurrence, Local/*blood/pathology Ovarian Neoplasms/*blood/pathology/surgery Predictive Value of Tests Progression-Free Survival Prospective Studies Biomarkers Ovarian neoplasm Prognosis Serum proteomics OBJECTIVE: To investigate the utility of a combined panel of protein biomarkers and clinical factors to predict recurrence in serous ovarian cancer patients. METHODS: Women at Augusta University diagnosed with ovarian cancer were enrolled between and (n_=_71). Blood was drawn at enrollment and follow-up visits. Patient serum collected at remission was analyzed using the SOMAscan array (n_=_35) to measure levels of proteins. The best 26 proteins were confirmed using Luminex assays in the same 35 patients and in an additional 36 patients (n(total)_=_71) as orthogonal validation. The data from these 26 proteins was combined with clinical factors using an elastic net multivariate model to find an optimized combination predictive of progression-free survival (PFS). RESULTS: Of the 26 proteins, Brain Derived Neurotrophic Factor and Platelet Derived Growth Factor molecules were significant for predicting PFS on both univariate and multivariate analyses. All 26 proteins were combined with clinical factors using the elastic net algorithm. Ten components were determined to predict PFS (HR of 6.55, p-value 1.12_x_10(-6), CI 2.57-16.71). This model was named the serous high grade ovarian cancer (SHOC) score. CONCLUSION: The SHOC score can predict patient prognosis in remission. This tool will hopefully lead to early intervention and consolidation therapy strategies in remission patients destined to recur. Mysona, David Pyrzak, Adam Purohit, Sharad Zhi, Wenbo Sharma, Ashok Tran, Lynn Tran, Paul Bai, Shan Rungruang, Bunja Ghamande, Sharad She, Jin-Xiong eng F30 DK/DK/NIDDK NIH HHS/ Observational Study Research Support, Non-U.S. Gov't Gynecol Oncol. Mar;152(3):574-580. doi: 10./j.ygyno..12.015. Epub Dec 18.I SomaScan 12/24/ Ghaemi MS, et al. Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy Bioinformatics 35 1 95-103 https://www.doi.org/10./bioinformatics/bty537 30,561,547 Computational Biology Female Humans *Metabolome *Microbiota *Pregnancy *Proteome *Transcriptome MOTIVATION: Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia. RESULTS: We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified. AVAILABILITY AND IMPLEMENTATION: Datasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. Ghaemi, Mohammad Sajjad DiGiulio, Daniel B Contrepois, Kevin Callahan, Benjamin Ngo, Thuy T M Lee-McMullen, Brittany Lehallier, Benoit Robaczewska, Anna Mcilwain, David Rosenberg-Hasson, Yael Wong, Ronald J Quaintance, Cecele Culos, Anthony Stanley, Natalie Tanada, Athena Tsai, Amy Gaudilliere, Dyani Ganio, Edward Han, Xiaoyuan Ando, Kazuo McNeil, Leslie Tingle, Martha Wise, Paul Maric, Ivana Sirota, Marina Wyss-Coray, Tony Winn, Virginia D Druzin, Maurice L Gibbs, Ronald Darmstadt, Gary L Lewis, David B Partovi Nia, Vahid Agard, Bruno Tibshirani, Robert Nolan, Garry Snyder, Michael P Relman, David A Quake, Stephen R Shaw, Gary M Stevenson, David K Angst, Martin S Gaudilliere, Brice Aghaeepour, Nima eng K01 LM/LM/NLM NIH HHS/ CIHR /CIHR/Canada U19 AI/AI/NIAID NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ K12 HL/HL/NHLBI NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Bioinformatics. Jan 1;35(1):95-103. doi: 10./bioinformatics/bty537.I SomaScan 12/19/ Masvekar R, et al. Cerebrospinal fluid biomarkers link toxic astrogliosis and microglial activation to multiple sclerosis severity Mult Scler Relat Disord 28 34-43 https://www.doi.org/10./j.msard..11.032 30,553,167 Adolescent Adult Aged Astrocytes/metabolism Biomarkers/cerebrospinal fluid Cell Culture Techniques Cells, Cultured Cluster Analysis Female Gliosis/*cerebrospinal fluid Humans Male Microglia/metabolism Middle Aged Multiple Sclerosis/*cerebrospinal fluid Prospective Studies Severity of Illness Index Young Adult CNS tissue destruction CSF biomarkers MS severity Microglial activation Multiple sclerosis Toxic astrogliosis BACKGROUND: Once multiple sclerosis (MS) reaches the progressive stage, immunomodulatory treatments have limited efficacy. This suggests that processes other than activation of innate immunity may at least partially underlie disability progression during late stages of MS. Pathology identified these alternative processes as aberrant activation of astrocytes and microglia, and subsequent degeneration of oligodendrocytes and neurons. However, we mostly lack biomarkers that could measure central nervous system (CNS) cell-specific intrathecal processes in living subjects. This prevents differentiating pathogenic processes from an epiphenomenon. Therefore, we sought to develop biomarkers of CNS cell-specific processes and link them to disability progression in MS. METHODS: In a blinded manner, we measured over proteins in the cerebrospinal fluid (CSF) of 431 patients with neuroimmunological diseases and healthy volunteers using modified DNA-aptamers (SOMAscan(R)). We defined CNS cell type-enriched clusters using variable cluster analysis, combined with in vitro modeling. Differences between diagnostic categories were identified in the training cohort (n_=_217) and their correlation to disability measures were assessed; results were validated in an independent validation cohort (n_=_214). RESULTS: Astrocyte cluster 8 (MMP7, SERPINA3, GZMA and CLIC1) and microglial cluster 2 (DSG2 and TNFRSF25) were reproducibly elevated in MS and had a significant and reproducible correlation with MS severity suggesting their pathogenic role. In vitro studies demonstrated that proteins of astrocyte cluster 8 are noticeably released upon stimulation with proinflammatory stimuli and overlap with the phenotype of recently described neuro-toxic (A1) astrocytes. CONCLUSION: Microglial activation and toxic astrogliosis are associated with MS disease process and may partake in CNS tissue destruction. This hypothesis should be tested in new clinical trials. Masvekar, Ruturaj Wu, Tianxia Kosa, Peter Barbour, Christopher Fossati, Valentina Bielekova, Bibiana eng ZIA NS-11/Intramural NIH HHS/ Clinical Trial Netherlands Mult Scler Relat Disord. Feb;28:34-43. doi: 10./j.msard..11.032. Epub Dec 5.I SomaScan 12/16/ Halama A, et al. Metabolic and proteomic signatures of hypoglycaemia in type 2 diabetes Diabetes Obes Metab 21 4 909-919 https://www.doi.org/10./dom. 30,525,282 Adult Amino Acids/metabolism Bile Acids and Salts/metabolism Blood Glucose/metabolism Case-Control Studies Diabetes Mellitus, Type 2/*metabolism Fatty Acids/metabolism Female Glucose Clamp Technique Healthy Volunteers Humans Hypoglycemia/*metabolism Inflammation/metabolism Lipid Metabolism Male *Metabolomics Middle Aged *Proteomics Steroids/metabolism clinical physiology glucose metabolism hypoglycaemia type 2 diabetes AIMS: To determine the biochemical changes that underlie hypoglycaemia in a healthy control group and in people with type 2 diabetes (T2D). MATERIALS AND METHODS: We report a hypoglycaemic clamp study in seven healthy controls and 10 people with T2D. Blood was withdrawn at four time points: at baseline after an overnight fast; after clamping to euglycaemia at 5 mmol/L; after clamping to hypoglycaemia at 2.8 mmol/L; and 24 hours later, after overnight fast. Deep molecular phenotyping using non-targeted metabolomics and the SomaLogic aptamer-based proteomics platform was performed on collected samples. RESULTS: A total of 955 metabolites and proteins were identified, with significant alterations in >90 molecules. A number of metabolites significantly increased during hypoglycaemia, but only cortisol, adenosine-3',5'-cyclic monophosphate (cyclic AMP), and pregnenolone sulphate, were independent of insulin. By contrast, identified protein changes were triggered by hypoglycaemia rather than insulin. The T2D group had significantly higher levels of fatty acids including 10-nonadecenoate, linolenate and dihomo-linoleate during hypoglycaemia compared with the control group. Molecules contributing to cardiovascular complications such as fatty-acid-binding protein-3 and pregnenolone sulphate were altered in the participants with T2D during hypoglycaemia. Almost all molecules returned to baseline at 24 hours. CONCLUSIONS: The present study provides a comprehensive description of molecular events that are triggered by insulin-induced hypoglycaemia. We identified deregulated pathways in T2D that may play a role in the pathophysiology of hypoglycaemia-induced cardiovascular complications. Halama, Anna Kahal, Hassan Bhagwat, Aditya M Zierer, Jonas Sathyapalan, Thozhukat Graumann, Johannes Suhre, Karsten Atkin, Stephen L eng Research Support, Non-U.S. Gov't England Diabetes Obes Metab. Apr;21(4):909-919. doi: 10./dom.. Epub Dec 27.I SomaScan 12/14/ Wu D, et al. Osteitis is associated with dysregulated pro-osteoblastic activity in patients with nasal polyps Laryngoscope 129 3 E102-E109 https://www.doi.org/10./lary. 30,537,181 Adult Bone Morphogenetic Proteins/*metabolism Case-Control Studies Down-Regulation Female Humans Male Middle Aged Nasal Polyps/*metabolism Osteitis/*metabolism Osteoblasts/*metabolism Prospective Studies Rhinitis/*metabolism Signal Transduction Sinusitis/*metabolism Osteitis bone morphogenetic protein pathway chronic rhinosinusitis nasal polyps OBJECTIVES/HYPOTHESIS: The overlying inflammatory mucosa plays a crucial role in the initiation of osteitis; however, the molecular mechanism is unclear. The objective of this study was to explore the bone morphogenetic protein (BMP) pathway and to correlate the expression of key signaling molecules with the degree of osteitis in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). STUDY DESIGN: Prospective experimental analysis. METHODS: This was an institutional review board-approved study in which mucosal samples were obtained from sites of osteitis in CRSwNP and compared to nonosteitic healthy controls (n = 10/group). Protein expression of key BMP pathway was quantified by aptamer-based protein array and confirmed by a set of selected mRNA analyses. Degree of osteitis was assessed using both Kennedy Osteitis Score and Global Osteitis Score (GOS). RESULTS: Pro-osteoblastic expression of BMP7 (fold change [FC] = -1.18, P = .017) and BMP9 (FC = -1.32, P = .023), their receptors, BMP receptor type-1A (BMPR1A) (FC = -2.56, P = .005) and BMP receptor type-2 (FC = -1.28, P = .022), and two enhancers of BMP signaling pathway, the repulsive guidance molecule domain family member B (FC = -1.13, P = .008) and the chordin-like protein 1 (FC = -1.18, P = .027), were all significantly downregulated in CRSwNP. Conversely, the pro-osteoclastic factor, tartrate-resistant acid phosphatase type 5 (ACP5) (FC = 2.36, P = .001), was significantly increased in CRSwNP. GOS was inversely correlated with levels of BMP7 (r = -0.684, P = .005) and BMPR1A (r = -0.864, P = .005) and positively correlated with levels of ACP5 (r = 0.815, P = .004). The FCs among the proteins studied significantly and positively correlated with the FCs of their mRNA expression (r = 0.908, P = .002). CONCLUSIONS: Downregulated pro-osteoblastic mucosal BMP signaling is strongly and significantly associated with increased osteitis in CRSwNP. LEVEL OF EVIDENCE: NA Laryngoscope, 129:E102-E109, . Wu, Dawei Nocera, Angela L Mueller, Sarina K Finn, Kristen Libermann, Towia A Bleier, Benjamin S eng Laryngoscope. Mar;129(3):E102-E109. doi: 10./lary.. Epub Dec 11.I SomaScan 12/12/ Desai VG, et al. Candidate early predictive plasma protein markers of doxorubicin-induced chronic cardiotoxicity in B6C3F(1) mice Toxicol Appl Pharmacol 363 164-173 https://www.doi.org/10./j.taap..11.016 30,517,846 Administration, Intravenous Animals Antibiotics, Antineoplastic/*toxicity Biomarkers/blood Cardiotoxicity/*blood/etiology/prevention & control Dexrazoxane/administration & dosage Doxorubicin/administration & dosage/*toxicity Heart/drug effects Male Mice Myocardium/pathology Protective Agents/administration & dosage Proteome/analysis/drug effects Proteomics Receptor, Notch1/blood Risk Assessment/methods von Willebrand Factor/analysis Biomarkers Cardiotoxicity Dexrazoxane Doxorubicin Mouse Plasma SOMAscan Proteomic Assay Cardiotoxicity is a serious adverse effect of doxorubicin (DOX) treatment in cancer patients. Currently, there is a lack of sensitive biomarkers to predict the risk of DOX-induced cardiotoxicity. Using SOMAmer-based proteomic technology, proteins were profiled to identify potential early biomarkers of cardiotoxicity in plasma from male B6C3F(1) mice given a weekly intravenous dose of 3_mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8_weeks (6, 9, 12, 18, or 24_mg/kg cumulative DOX doses, respectively). Also, a group of mice received the cardio-protectant, dexrazoxane (DXZ; 60_mg/kg; intraperitoneal) 30_min before a weekly DOX or SAL dose. Proteomic analysis in plasma collected a week after the last dose showed a significant >/=1.2-fold change in level of 18 proteins in DOX-treated mice compared to SAL-treated counterparts during 8-week exposure. Of these, neurogenic locus notch homolog protein 1 (NOTCH1), von Willebrand factor (vWF), mitochondrial glutamate carrier 2, Wnt inhibitory factor 1, legumain, and mannan-binding lectin serine protease 1 were increased in plasma at 6_mg/kg cumulative DOX dose, prior to the release of myocardial injury marker, cardiac troponin I at 12_mg/kg and higher cumulative doses. These six proteins also remained significantly elevated following myocardial injury or pathology at 24_mg/kg. Pretreatment of mice with DXZ significantly attenuated DOX-induced elevated levels of only NOTCH1 and vWF with mitigation of cardiotoxicity. This suggests NOTCH1 and vWF as candidate early biomarkers of DOX cardiotoxicity, which may help in addressing a clinically important question of identifying cancer patients at risk for cardiotoxicity. Desai, Varsha G Lee, Taewon Moland, Carrie L Vijay, Vikrant Han, Tao Lewis, Sherry M Herman, Eugene H Fuscoe, James C eng Research Support, U.S. Gov't, P.H.S. Toxicol Appl Pharmacol. Jan 15;363:164-173. doi: 10./j.taap..11.016. Epub Dec 2.I SomaScan 12/06/ Mueller SK, et al. Noninvasive exosomal proteomic biosignatures, including cystatin SN, peroxiredoxin-5, and glycoprotein VI, accurately predict chronic rhinosinusitis with nasal polyps Int Forum Allergy Rhinol 9 2 177-186 https://www.doi.org/10./alr. 30,485,711 Adult Chronic Disease Exosomes/*metabolism Female Humans Male Middle Aged Nasal Polyps/*diagnosis Peroxiredoxins/*metabolism Platelet Membrane Glycoproteins/*metabolism Predictive Value of Tests Prognosis Proteome Rhinitis/*diagnosis Salivary Cystatins/*metabolism Sinusitis/*diagnosis Transcriptome Young Adult and platelet glycoprotein VI biosignature chronic rhinosinusitis cystatin-SN exosome mucus nasal polyps peroxiredoxin-5 proteomics BACKGROUND: Exosomes are secreted epithelial-derived vesicles that contain a conserved protein array representative of their parent cell. Exosomes may be reproducibly and noninvasively purified from nasal mucus. The exosomal proteome can be quantified using SOMAscan(TM) , a highly multiplexed, aptamer-based proteomic platform. The purpose of this study was to determine whether chronic rhinosinusitis with nasal polyps (CRSwNP) has a unique predictive exosomal proteomic biosignature. METHODS: Exosomes were isolated from whole mucus sampled from control and CRSwNP patients (n = 20 per group) by differential ultracentrifugation. The SOMAscan(TM) platform was used to simultaneously quantify biologically relevant human proteins. Matched tissue and whole mucus proteomes were also analyzed. Differential protein expression and discriminatory power were calculated using the unweighted pair group method with arithmetic-mean and principal component analysis, respectively. Bioinformatic analysis was performed using Ingenuity Pathway, MetaCore, and GeneMANIA analyses. RESULTS: The exosomal proteome demonstrated 123 significantly (p < 0.05) differentially regulated proteins in CRSwNP relative to control. Eighty of these proteins overlapped with the matched CRSwNP tissue proteome as compared with only 4 among matched whole mucus samples. Forty-three significantly dysregulated pathway networks overlapped between the exosomal and tissue proteome in CRSwNP as compared with only 3 among matched whole mucus samples. The best-performing protein set (cystatin-SN, peroxiredoxin-5, and glycoprotein VI) achieved an area under the curve (AUC) value of up to 99%. CONCLUSION: Our data contribute a significant advance in the development of a reproducible, noninvasive, serial, and quantitative liquid biopsy" for rhinosinusitis. The exosomal proteomic approach has revealed a unique biosignature associated with CRSwNP, which outperforms whole mucus sampling, and thus provides a method of noninvasive disease detection and proposes new potential therapeutic targets." Mueller, Sarina K Nocera, Angela L Dillon, Simon T Gu, Xuesong Wendler, Olaf Otu, Hasan H Libermann, Towia A Bleier, Benjamin S eng Int Forum Allergy Rhinol. Feb;9(2):177-186. doi: 10./alr.. Epub Nov 28.I SomaScan 11/30/ Di Narzo AF, et al. High-Throughput Identification of the Plasma Proteomic Signature of Inflammatory Bowel Disease J Crohns Colitis 13 4 462-471 https://www.doi.org/10./ecco-jcc/jjy190 30,445,421 C-Reactive Protein/metabolism Case-Control Studies Colitis, Ulcerative/*blood/genetics/metabolism Crohn Disease/*blood/genetics/metabolism Databases, Genetic Humans Intestinal Mucosa/metabolism Proteome/genetics/*metabolism Proteomics/*methods RNA, Messenger/*blood/metabolism Severity of Illness Index *Transcriptome Proteomics differential expression analysis inflammatory bowel disease proteomic quantitative trait loci BACKGROUND: The molecular aetiology of inflammatory bowel disease [IBD] and its two subtypes, ulcerative colitis [UC] and Crohn's disease [CD], have been carefully investigated at genome and transcriptome levels. Recent advances in high-throughput proteome quantification has enabled comprehensive large-scale plasma proteomics studies of IBD. METHODS: The study used two cohorts: [1] The CERTIFI-cohort: 42 samples from the CERTIFI trial of anti-TNFalpha-refractory CD patients; [2] the PROgECT-UNITI-HCs cohort: 46 UC samples of the PROgECT study, 84 CD samples of the UNITI I and UNITI II studies, and 72 healthy controls recruited in Mount Sinai Hospital, New York, USA. The plasma proteome for these two cohorts was quantified using high-throughput platforms. RESULTS: For the PROgECT-UNITI-HCs cohort, we measured a total of proteins. Of these, 493 proteins showed different plasma levels in IBD patients to the plasma levels in controls at 10% false discovery rate [FDR], among which 11 proteins had a fold change greater than 2. The proteins upregulated in IBD were associated with immunity functionality, whereas the proteins downregulated in IBD were associated with nutrition and metabolism. The proteomic profiles were very similar between UC and CD. In the CERTIFI cohort, proteins were measured, and it was found that the plasma protein level had little correlation with the blood or intestine transcriptomes. CONCLUSIONS: We report the largest proteomics study to date on IBD and controls. A large proportion of plasma proteins are altered in IBD, which provides insights into the disease aetiology and indicates a potential for biomarker discovery. Di Narzo, Antonio F Brodmerkel, Carrie Telesco, Shannon E Argmann, Carmen Peters, Lauren A Li, Katherine Kidd, Brian Dudley, Joel Cho, Judy Schadt, Eric E Kasarskis, Andrew Dobrin, Radu Hao, Ke eng S10 OD/OD/NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ U24 DK/DK/NIDDK NIH HHS/ England J Crohns Colitis. Mar 30;13(4):462-471. doi: 10./ecco-jcc/jjy190.I SomaScan 11/18/ Nocera AL, et al. Exosome swarms eliminate airway pathogens and provide passive epithelial immunoprotection through nitric oxide J Allergy Clin Immunol 143 4 - e1 https://www.doi.org/10./j.jaci..08.046 30,442,371 Exosomes/*immunology Humans Immunity, Innate/*immunology Nasal Mucosa/*immunology/metabolism Nitric Oxide/metabolism Nitric Oxide Synthase Type II/metabolism Pseudomonas Infections/immunology Cd81 Exosome epithelium innate immunity nitric oxide proteomics sinonasal mucus BACKGROUND: Nasal mucosa-derived exosomes (NMDEs) harbor immunodefensive proteins and are capable of rapid interepithelial protein transfer. OBJECTIVES: We sought to determine whether mucosal exposure to inhaled pathogens stimulates a defensive swarm of microbiocidal exosomes, which also donate their antimicrobial cargo to adjacent epithelial cells. METHODS: We performed an institutional review board-approved study of healthy NMDE secretion after Toll-like receptor (TLR) 4 stimulation by LPS (12.5 mug/mL) in the presence of TLR4 inhibitors. Interepithelial transfer of exosomal nitric oxide (NO) synthase and nitric oxide was measured by using ELISAs and NO activity assays. Exosomal antimicrobial assays were performed with Pseudomonas aeruginosa. Proteomic analyses were performed by using SOMAscan. RESULTS: In vivo and in vitro LPS exposure induced a 2-fold increase in NMDE secretion along with a 2-fold increase in exosomal inducible nitric oxide synthase expression and function through TLR4 and inhibitor of nuclear factor kappaB kinase activation. LPS stimulation increased exosomal microbiocidal activity against P aeruginosa by almost 2 orders of magnitude. LPS-stimulated exosomes induced a 4-fold increase in NO production within autologous epithelial cells with protein transfer within 5 minutes of contact. Pathway analysis of the NMDE proteome revealed 44 additional proteins associated with NO signaling and innate immune function. CONCLUSIONS: We provide direct in vivo evidence for a novel exosome-mediated innate immunosurveillance and defense mechanism of the human upper airway. These findings have implications for lower airway innate immunity, delivery of airway therapeutics, and host microbiome regulation. Nocera, Angela L Mueller, Sarina K Stephan, Jules R Hing, Loretta Seifert, Philip Han, Xue Lin, Derrick T Amiji, Mansoor M Libermann, Towia Bleier, Benjamin S eng P30 EY/EY/NEI NIH HHS/ Research Support, N.I.H., Extramural J Allergy Clin Immunol. Apr;143(4):-.e1. doi: 10./j.jaci..08.046. Epub Nov 12.I SomaScan 11/18/ DeBoer EM, et al. Novel Application of Aptamer Proteomic Analysis in Cystic Fibrosis Bronchoalveolar Lavage Fluid Proteomics Clin Appl 13 3 e https://www.doi.org/10./prca. 30,431,231 Adolescent Aptamers, Nucleotide/*metabolism *Bronchoalveolar Lavage Fluid Case-Control Studies Child Child, Preschool Cystic Fibrosis/*metabolism Female Humans Infant Male Proteomics/*methods Young Adult Pseudomonas aeruginosa inflammation pediatrics PURPOSE: Biomarkers are needed in cystic fibrosis (CF) to understand disease progression, assess response to therapy, and enrich enrollment for clinical trials. Aptamer-based proteomics have proven useful in blood samples. The aim is to evaluate proteins in bronchoalveolar lavage fluid (BALF) in CF children compared to controls and identify endotypes during CF exacerbations. EXPERIMENTAL DESIGN: BALF is collected clinically from 50 patients with CF and nine disease controls, processed, and stored per protocol. BALF supernatants are analyzed for proteins by aptamer approach (SOMAscan proteomics platform). Proteins are compared across groups and used for pathway analysis. Endotypes are identified within the CF group. RESULTS: CF BALF has increased concentrations of neutrophil elastase, myeloperoxidase, and decreased concentration of protein folding and host defense proteins. Pathways that distinguished CF subjects included interferon gamma signaling, membrane trafficking, and phospholipid metabolism. In the CF group, unbiased analysis of proteins identified two distinct endotypes that differed based on BALF white blood cell and neutrophil counts and detection of CF pathogens. CONCLUSIONS AND CLINICAL RELEVANCE: Proteomic analysis of the CF airway demonstrates a complex environment of proteins and pathways. This work provides evidence that aptamer-based proteomics can differentiate between groups and can determine endotypes within CF. DeBoer, Emily M Wagner, Brandie D Popler, Jonathan Harris, Jonathan Kirk Zemanick, Edith T Accurso, Frank J Sagel, Scott D Deterding, Robin R eng UL1 TR/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Germany Proteomics Clin Appl. May;13(3):e. doi: 10./prca.. Epub Jan 3.I SomaScan 11/16/ Mahendra A, et al. Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA-Sequencing Arthritis Rheumatol 71 4 529-541 https://www.doi.org/10./art. 30,407,753 Arthritis, Rheumatoid/blood/*genetics/*immunology Autoantibodies/*genetics/immunology B-Lymphocytes/*immunology Cytokines/blood/immunology ErbB Receptors/blood/immunology Humans Leukocytes, Mononuclear/immunology Receptors, Interleukin-15/blood/immunology Sequence Analysis, RNA Signal Transduction/immunology Transcriptome/*immunology OBJECTIVE: To obtain the comprehensive transcriptome profile of human citrulline-specific B cells from patients with rheumatoid arthritis (RA). METHODS: Citrulline- and hemagglutinin-specific B cells were sorted by flow cytometry using peptide-streptavidin conjugates from the peripheral blood of RA patients and healthy individuals. The transcriptome profile of the sorted cells was obtained by RNA-sequencing, and expression of key protein molecules was evaluated by aptamer-based SOMAscan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays. RESULTS: Citrulline-specific B cells, in comparison to citrulline-negative B cells, from patients with RA differentially expressed the interleukin-15 receptor alpha (IL-15Ralpha) gene as well as genes related to protein citrullination and cyclic AMP signaling. In analyses of an independent cohort of cyclic citrullinated peptide-seropositive RA patients, the expression of IL-15Ralpha protein was enriched in citrulline-specific B cells from the patients' peripheral blood, and surprisingly, all B cells from RA patients were capable of producing the epidermal growth factor ligand amphiregulin (AREG). Production of AREG directly led to increased migration and proliferation of fibroblast-like synoviocytes, and, in combination with anti-citrullinated protein antibodies, led to the increased differentiation of osteoclasts. CONCLUSION: To the best of our knowledge, this is the first study to document the whole transcriptome profile of autoreactive B cells in any autoimmune disease. These data identify several genes and pathways that may be targeted by repurposing several US Food and Drug Administration-approved drugs, and could serve as the foundation for the comparative assessment of B cell profiles in other autoimmune diseases. Mahendra, Ankit Yang, Xingyu Abnouf, Shaza Adolacion, Jay R T Park, Daechan Soomro, Sanam Roszik, Jason Coarfa, Cristian Romain, Gabrielle Wanzeck, Keith Bridges, S Louis Jr Aggarwal, Amita Qiu, Peng Agarwal, Sandeep K Mohan, Chandra Varadarajan, Navin eng RP/Cancer Prevention and Research Institute of Texas/International CA/ Department of Defense/International R01 CA/CA/NCI NIH HHS/ RP/Cancer Prevention and Research Institute of Texas/International E-/Welch Foundation/International /National Science Foundation/International /Melanoma Research Alliance/International Evaluation Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Arthritis Rheumatol. Apr;71(4):529-541. doi: 10./art.. Epub Feb 23.I SomaScan 11/09/ Michelsen TM, et al. The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4-vessel sampling FASEB J 33 2 - https://www.doi.org/10./fj.R 30,335,547 Adult Cohort Studies Female Fetal Development Fetus/*metabolism Humans *Maternal-Fetal Exchange Placenta/*metabolism Pregnancy Pregnancy Proteins/*metabolism Protein Interaction Maps Proteome/*analysis Specimen Handling/*methods placental physiology pregnancy proteins proteomics trophoblast We sought to identify proteins secreted by the human placenta into the maternal and fetal circulations. Blood samples from the maternal radial artery and uterine vein and umbilical artery and vein were obtained during cesarean section in 35 healthy women with term pregnancy. Slow off-rate modified aptamer (SOMA) protein-binding technology was used to quantify known proteins. The uteroplacental and umbilical venoarterial concentration differences were calculated. Thirty-four proteins were significantly secreted by the placenta into the maternal circulation, including placental growth factor, growth/differentiation factor 15, and matrix metalloproteinase 12. There were 341 proteins significantly secreted by the placenta into the fetal circulation. Only 7 proteins were secreted into both the fetal and maternal circulations, suggesting a distinct directionality in placental protein release. We examined changes across gestation in the proteins found to be significantly secreted by the placenta into the maternal circulation using serial blood samples from healthy women. Among the 34 proteins secreted into the maternal circulation, 8 changed significantly across gestation. The identified profiles of secreted placental proteins will allow us to identify novel minimally invasive biomarkers for human placental function across gestation and discover previously unknown proteins secreted by the human placenta that regulate maternal physiology and fetal development.-Michelsen, T. M., Henriksen, T., Reinhold, D., Powell, T. L., Jansson, T. The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4-vessel sampling. Michelsen, Trond M Henriksen, Tore Reinhold, Dominik Powell, Theresa L Jansson, Thomas eng Research Support, Non-U.S. Gov't FASEB J. Feb;33(2):-. doi: 10./fj.R. Epub Oct 18.I SomaScan 10/20/ Liang X, et al. Assessing the Genetic Correlations Between Blood Plasma Proteins and Osteoporosis: A Polygenic Risk Score Analysis Calcif Tissue Int 104 2 171-181 https://www.doi.org/10./s-018--4 30,306,195 Absorptiometry, Photon Adult Aged Blood Proteins/analysis/*genetics Bone Density/*genetics Female Femur Neck/anatomy & histology/diagnostic imaging Genetic Predisposition to Disease/ethnology Genome-Wide Association Study Genotype Humans Male Middle Aged Multifactorial Inheritance/*genetics Organ Size Osteoporosis/blood/epidemiology/*genetics Polymorphism, Single Nucleotide Radius/anatomy & histology/diagnostic imaging Research Design Risk Factors Spine/anatomy & histology/diagnostic imaging Whites/genetics/statistics & numerical data Blood plasma proteins Osteoporosis Polygenic risk score analysis Miao Ding, Bolun Cheng, Shiqiang Cheng, Mei Ma, Lu Zhang, Hui Shen, Qing Tian, Xiong Guo, Feng Zhang, and Hong-Wen Deng declare that they have no conflicts of interest. Osteoporosis is a common metabolic bone disease. The impact of global blood plasma proteins on the risk of osteoporosis remains elusive now. We performed a large-scale polygenic risk score (PRS) analysis to evaluate the potential effects of blood plasma proteins on the development of osteoporosis in Caucasians, including 558 males and females. Bone mineral density (BMD) and bone areas at ulna & radius, hip, and spine were measured using Hologic W DXA. BMD/bone areas values were adjusted for age, sex, height, and weight as covariates. Genome-wide SNP genotyping of Caucasian subjects was performed using Affymetrix Human SNP Array 6.0. The 267 blood plasma proteins-associated SNP loci and their genetic effects were obtained from recently published genome-wide association study (GWAS) using a highly multiplexed aptamer-based affinity proteomics platform. The polygenetic risk score (PRS) of study subjects for each blood plasma protein was calculated from the genotypes data of the Caucasian subjects by PLINK software. Pearson correlation analysis of individual PRS values and BMD/bone area value was performed using R. Additionally, gender-specific analysis also was performed by Pearson correlation analysis. 267 blood plasma proteins were analyzed in this study. For BMD, we observed association signals between 41 proteins and BMD, mainly including whole body total BMD versus Factor H (p value = 9.00 x 10(-3)), whole body total BMD versus BGH3 (p value = 1.40 x 10(-2)), spine total BMD versus IGF-I (p value = 2.15 x 10(-2)), and spine total BMD versus SAP (p value = 3.90 x 10(-2)). As for bone areas, association evidence was observed between 45 blood plasma proteins and bone areas, such as ferritin versus spine area (p value = 1.90 x 10(-2)), C4 versus hip area (p value = 1.25 x 10(-2)), and hemoglobin versus right ulna and radius area (p value = 2.70 x 10(-2)). Our study results suggest the modest impact of blood plasma proteins on the variations of BMD/bone areas, and identify several candidate blood plasma proteins for osteoporosis. Liang, Xiao Du, Yanan Wen, Yan Liu, Li Li, Ping Zhao, Yan Ding, Miao Cheng, Bolun Cheng, Shiqiang Ma, Mei Zhang, Lu Shen, Hui Tian, Qing Guo, Xiong Zhang, Feng Deng, Hong-Wen eng R01 MH/MH/NIMH NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ R01 GM/GM/NIGMS NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ U19 AG/AG/NIA NIH HHS/ P20 GM/GM/NIGMS NIH HHS/ R01 MH/MH/NIMH NIH HHS/ R01 MH/MH/NIMH NIH HHS/ R01 EB/EB/NIBIB NIH HHS/ R01 EB/EB/NIBIB NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Calcif Tissue Int. Feb;104(2):171-181. doi: 10./s-018--4. Epub Oct 10.I SomaScan 10/12/ Foulkes AC, et al. A Framework for Multi-Omic Prediction of Treatment Response to Biologic Therapy for Psoriasis J Invest Dermatol 139 1 100-107 https://www.doi.org/10./j.jid..04.041 30,030,151 Adult Biological Therapy/*methods Etanercept/*therapeutic use Female Follow-Up Studies *Gene Expression Regulation Humans Immunosuppressive Agents/therapeutic use Male Pilot Projects Prognosis Prospective Studies Psoriasis/*drug therapy/genetics/metabolism RNA, Messenger/*genetics Skin Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (i.e., PSORT) study, we evaluated a comprehensive array of omics platforms across three time points and multiple tissues in a pilot investigation of 10 patients with severe psoriasis, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used RNA sequencing to analyze mRNA and small RNA transcriptome in blood, lesional and nonlesional skin, and the SOMAscan platform to investigate the serum proteome. Using an integrative systems biology approach, we identified signals of treatment response in genes and pathways associated with TNF signaling, psoriasis pathology, and the major histocompatibility complex region. We found association between clinical response and TNF-regulated genes in blood and skin. Using a combination of differential expression testing, upstream regulator analysis, clustering techniques, and predictive modeling, we show that baseline samples are indicative of patient response to biologic therapies, including signals in blood, which have traditionally been considered unreliable for inference in dermatology. In conclusion, our pilot study provides both an analytical framework and empirical basis to estimate power for larger studies, specifically the ongoing PSORT study, which we show as powered for biomarker discovery and patient stratification. Foulkes, Amy C Watson, David S Carr, Daniel F Kenny, John G Slidel, Timothy Parslew, Richard Pirmohamed, Munir Anders, Simon Reynolds, Nick J Griffiths, Christopher E M Warren, Richard B Barnes, Michael R eng R13 AR/AR/NIAMS NIH HHS/ MR//1/MRC_/Medical Research Council/United Kingdom MR/L/1/MRC_/Medical Research Council/United Kingdom MR/N/1/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom MR/L/1/MRC_/Medical Research Council/United Kingdom Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Invest Dermatol. Jan;139(1):100-107. doi: 10./j.jid..04.041. Epub Jul 17.I SomaScan 07/22/ Datta G, et al. Balanced Event Prediction Through Sampled Survival Analysis Systems Medicine 2 1 28-38 https://www.doi.org/10./sysm.. Abstract Class imbalance can present a major issue in time-to-event analyses for instances where the number of individuals diagnosed with a disease are far outnumbered by those who remain undiagnosed within a specified time frame. An example of this is the incidence rate of myocardial infarction (MI) among patients with stable coronary heart disease, where MI events are typically sparse over the course of a study. This imbalance may result in inaccurate risk predictions for individuals who are more likely to be having an MI event. In this study, we combine sampling with the Cox proportional hazards model in a cross-validation framework to balance predictive performance. This approach leverages advantages provided by classification tools and the statistical power of survival models in examining time-to-event data. To demonstrate the effectiveness of this modeling approach, we use high-dimensional proteomic data (obtained using the SOMAScan? assay) to identify patients likely to experience an MI event within 4 years of a blood draw. In our data set, 8.1% of patients experienced an MI within 4 years, making this a severely class-imbalanced data set. Cox proportional hazards elastic net regression models were developed using sampling techniques, allowing us to identify and select features that more accurately identify individuals at higher risk of MI. The resulting Cox elastic net regression models created on the sampled data (both upsampled and downsampled) were superior to three other competing models: elastic net logistic regression and support vector machine models developed on downsampled data, and a Cox proportional hazards elastic net developed on the full data. These results, and additional simulation results, demonstrate the effectiveness of combining sampling with survival analysis techniques for improved predictive performance in a biomedical application. Class imbalance can present a major issue in time-to-event analyses for instances where the number of individuals diagnosed with a disease are far outnumbered by those who remain undiagnosed within a specified time frame. An example of this is the incidence rate of myocardial infarction (MI) among patients with stable coronary heart disease, where MI events are typically sparse over the course of a study. This imbalance may result in inaccurate risk predictions for individuals who are more likely to be having an MI event. In this study, we combine sampling with the Cox proportional hazards model in a cross-validation framework to balance predictive performance. This approach leverages advantages provided by classification tools and the statistical power of survival models in examining time-to-event data. To demonstrate the effectiveness of this modeling approach, we use high-dimensional proteomic data (obtained using the SOMAScan? assay) to identify patients likely to experience an MI event within 4 years of a blood draw. In our data set, 8.1% of patients experienced an MI within 4 years, making this a severely class-imbalanced data set. Cox proportional hazards elastic net regression models were developed using sampling techniques, allowing us to identify and select features that more accurately identify individuals at higher risk of MI. The resulting Cox elastic net regression models created on the sampled data (both upsampled and downsampled) were superior to three other competing models: elastic net logistic regression and support vector machine models developed on downsampled data, and a Cox proportional hazards elastic net developed on the full data. These results, and additional simulation results, demonstrate the effectiveness of combining sampling with survival analysis techniques for improved predictive performance in a biomedical application. Datta, Gargi Alexander, Leigh E. Hinterberg, Michael A. Hagar, Yolanda SomaScan Jung YJ, et al. Clinical Validation of a Protein Biomarker Panel for Non-Small Cell Lung Cancer J Korean Med Sci 33 53 e342 https://www.doi.org/10./jkms..33.e342 30,595,683 Adult Aged Area Under Curve Biomarkers, Tumor/*blood Blood Proteins/*metabolism Carcinoma, Non-Small-Cell Lung/*diagnosis/pathology Female Humans Lung Neoplasms/*diagnosis/pathology Male Middle Aged Neoplasm Staging ROC Curve Republic of Korea Sensitivity and Specificity Smoking Aptamer Computed Tomography Lung Cancer Screening Lung Nodule conflict: Kim Y, Jung JH, and Seok M are employees of Aptamer Sciences Inc. Although the present study used AptoDetectTM-Lung, a product of Aptamer Sciences Inc., the 3 co-researchers did not involve study design and data analysis that made any biased influence. The whole study was free from conflicts of interest. These facts do not alter the authors' adherence to Journal Korean Medical Science policies on the sharing of data and material. Jung YJ, Oh IJ, Lee W, Park CK, Lim JH, Kim YC, Kim WS, and Choi CM have no conflict of interest to disclose. We validated the diagnostic performance of a previously developed blood-based 7-protein biomarker panel, AptoDetect-Lung (Aptamer Sciences Inc., Pohang, Korea) using modified aptamer-based proteomic technology for lung cancer detection. Non-small cell lung cancer (NSCLC), 200 patients and benign nodule controls, 200 participants were enrolled. In a high-risk population corresponding to >/= 55 years of age and >/= 30 pack-years, the diagnostic performance was improved, showing 73.3% sensitivity and 90.5% specificity with an area under the curve of 0.88. AptoDetect-Lung (Aptamer Sciences Inc.) offers the best validated performance to discriminate NSCLC from benign nodule controls in a high-risk population and could play a complementary role in lung cancer screening. Jung, Young Ju Oh, In-Jae Kim, Youndong Jung, Jong Ha Seok, Minkyoung Lee, Woochang Park, Cheol Kyu Lim, Jung-Hwan Kim, Young-Chul Kim, Woo-Sung Choi, Chang-Min eng Korea (South) J Korean Med Sci. Dec 13;33(53):e342. doi: 10./jkms..33.e342. eCollection Dec 31.I SomaScan 01/01/ Mosley JD, et al. Probing the Virtual Proteome to Identify Novel Disease Biomarkers Circulation 138 22 - https://www.doi.org/10./CIRCULATIONAHA.118. 30,571,344 Adult Aged Aged, 80 and over Biomarkers/*blood Carotid Artery Diseases/*diagnosis/genetics Female *Genome-Wide Association Study Genotype Humans Lectins, C-Type/analysis Male Middle Aged Odds Ratio Phenotype Polymorphism, Single Nucleotide Proteome/*analysis Proteomics Receptor, Platelet-Derived Growth Factor beta/blood atherosclerosis biomarkers electronic health records BACKGROUND: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. METHODS: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmo Diet and Cancer Study; n=651). RESULTS: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-beta predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-beta. CONCLUSIONS: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases." Mosley, Jonathan D Benson, Mark D Smith, J Gustav Melander, Olle Ngo, Debby Shaffer, Christian M Ferguson, Jane F Herzig, Matthew S McCarty, Catherine A Chute, Christopher G Jarvik, Gail P Gordon, Adam S Palmer, Melody R Crosslin, David R Larson, Eric B Carrell, David S Kullo, Iftikhar J Pacheco, Jennifer A Peissig, Peggy L Brilliant, Murray H Kitchner, Terrie E Linneman, James G Namjou, Bahram Williams, Marc S Ritchie, Marylyn D Borthwick, Kenneth M Kiryluk, Krzysztof Mentch, Frank D Sleiman, Patrick M Karlson, Elizabeth W Verma, Shefali S Zhu, Yineng Vasan, Ramachandran S Yang, Qiong Denny, Josh C Roden, Dan M Gerszten, Robert E Wang, Thomas J eng U01 HG/HG/NHGRI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ R01 LM/LM/NLM NIH HHS/ S10 RR/RR/NCRR NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ 16FTF/AHA/American Heart Association-American Stroke Association/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ P30 EY/EY/NEI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ P50 GM/GM/NIGMS NIH HHS/ P30 CA/CA/NCI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ U01 HG/HG/NHGRI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. Nov 27;138(22):-. doi: 10./CIRCULATIONAHA.118..I SomaScan 12/21/ Dubin RF, et al. Proteomic analysis of heart failure hospitalization among patients with chronic kidney disease: The Heart and Soul Study PLoS One 13 12 e https://www.doi.org/10./journal.pone. 30,557,359 Aged Aged, 80 and over Angiopoietin-2/blood Biomarkers/blood Extracellular Matrix Proteins/blood Female Glomerular Filtration Rate Heart Failure/blood/*diagnosis/etiology/therapy Hospitalization/statistics & numerical data Humans Male Middle Aged Prognosis Proteomics Receptor, Notch1/blood Renal Insufficiency, Chronic/blood/*complications Risk Assessment Tartrate-Resistant Acid Phosphatase/blood BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk for heart failure (HF). We aimed to investigate differences in proteins associated with HF hospitalizations among patients with and without CKD in the Heart and Soul Study. METHODS AND RESULTS: We measured unique plasma proteins from baseline samples of 974 participants in The Heart and Soul Study who were followed for HF hospitalization over a median of 7 years. We sequentially applied forest regression and Cox survival analyses to select prognostic proteins. Among participants with CKD, four proteins were associated with HF at Bonferroni-level significance (p<2.5x10(-4)): Angiopoietin-2 (HR[95%CI] 1.45[1.33, 1.59]), Spondin-1 (HR[95%CI] 1.13 [1.06, 1.20]), tartrate-resistant acid phosphatase type 5 (HR[95%CI] 0.65[0.53, 0.78]) and neurogenis locus notch homolog protein 1 (NOTCH1) (HR[95%CI] 0.67[0.55, 0.80]). These associations persisted at p<0.01 after adjustment for age, estimated glomerular filtration and history of HF. CKD was a significant interaction term in the associations of NOTCH1 and Spondin-1 with HF. Pathway analysis showed a trend for higher representation of the Cardiac Hypertrophy and Complement/Coagulation pathways among proteins prognostic of HF in the CKD sub-group. CONCLUSIONS: These results suggest that markers of heart failure differ between patients with and without CKD. Further research is needed to validate novel markers in cohorts of patients with CKD and adjudicated HF events. Dubin, Ruth F Whooley, Mary Pico, Alexander Ganz, Peter Schiller, Nelson B Meyer, Craig eng R01 HL/HL/NHLBI NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. Dec 17;13(12):e. doi: 10./journal.pone.. eCollection .I SomaScan 12/18/ Bridel C, et al. No Plasmatic Proteomic Signature at Clinical Disease Onset Associated With 11 Year Clinical, Cognitive and MRI Outcomes in Relapsing-Remitting Multiple Sclerosis Patients Front Mol Neurosci 11 371 https://www.doi.org/10./fnmol.. 30,429,773 Mri cognition multiple sclerosis prognosis proteomics Background: The clinical course of relapsing-remitting multiple sclerosis (RRMS) is highly heterogeneous and prognostic biomarkers at time of diagnosis are lacking. Objective: We investigated the predictive value of the plasma proteome at time of diagnosis in RRMS patients. Methods: The plasma proteome was interrogated using a novel aptamer-based proteomics platform, which allows to measure the levels of a predefined set of proteins. Results: In 67 clinically and radiologically well characterized RRMS patients, we found no association between the plasma proteome at diagnosis and clinical, cognitive or MRI outcomes after 11 years. Conclusions: Proteomics studies on cerebrospinal fluid may be better suited to identify prognostic biomarkers in early RRMS. Bridel, Claire Eijlers, Anand J C van Wieringen, Wessel N Koel-Simmelink, Marleen Leurs, Cyra E Schoonheim, Menno M Killestein, Joep Teunissen, Charlotte E eng Switzerland Front Mol Neurosci. Oct 31;11:371. doi: 10./fnmol... eCollection .I SomaScan 11/16/ Conklin LS, et al. Serum biomarkers of glucocorticoid response and safety in anti-neutrophil cytoplasmic antibody-associated vasculitis and juvenile dermatomyositis Steroids 140 159-166 https://www.doi.org/10./j.steroids..10.008 30,352,204 Adolescent Adult Aged Aged, 80 and over Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/*blood/*drug therapy Biomarkers/blood Child Child, Preschool Dermatomyositis/*blood/*drug therapy Female Glucocorticoids/*adverse effects/*pharmacology/therapeutic use Humans Male Middle Aged Proteomics *Safety Treatment Outcome Young Adult Anti-inflammatory Biomarker Glucocorticoids Juvenile dermatomyositis Vasculitis BioPharma. KN, and EPH are co-founders of ReveraGen and own founder shares. LSC, JMD, JvdA own stock options of ReveraGen. Glucocorticoids are standard of care for many chronic inflammatory conditions, including juvenile dermatomyositis (JDM) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We sought to define pharmacodynamic biomarkers of therapeutic efficacy and safety concerns of glucocorticoid treatment for these two disorders. Previous proteomic profiling of patients with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease (IBD) treated with glucocorticoids identified candidate biomarkers for efficacy and safety concerns of glucocorticoids. Serial serum samples from patients with AAV (n_=_30) and JDM (n_=_12) were obtained during active disease, and after treatment with glucocorticoids. For AAV, 8 of 11 biomarkers of the anti-inflammatory response to glucocorticoids were validated (P-value proteins. In the present study, we performed SOMAscan analysis of plasma samples and validated the measurements by comparison with selected biomarkers. We compared concentrations of SOMAscan-measured prostate specific antigen (PSA) between males and females, and validated SOMAscan concentrations of fibroblast growth factor 23 (FGF23), FGF receptor 1 (FGFR1), and FGFR4 using Enzyme-Linked immunosorbent assay (ELISA). The median (25th and 75th percentile) SOMAscan PSA level in males and females was .7 (.4 to .5) and 547.8 (521.8 to 993.4) relative fluorescence units (p = 0.002), respectively, suggesting biological plausibility. Pearson correlation between SOMAscan and ELISA was high for FGF23 (R = 0.95, p < 0.001) and FGFR4 (R = 0.69, p < 0.001), indicating significant positive correlation, while a weak correlation was found for FGFR1 (R = 0.13, p = 0.16). In conclusion, there is a good to near-perfect correlation between SOMAscan and standard immunoassays for FGF23 and FGFR4, but not for FGFR1. This technology may be useful to simultaneously measure a large number of plasma proteins in ESRD, and identify clinically important prognostic markers to predict outcomes. Han, Zhongji Xiao, Zhousheng Kalantar-Zadeh, Kamyar Moradi, Hamid Shafi, Tariq Waikar, Sushrut S Quarles, L Darryl Yu, Zhi Tin, Adrienne Coresh, Josef Kovesdy, Csaba P eng IK2 CX/CX/CSRD VA/ Switzerland Diagnostics (Basel). Oct 8;8(4):71. doi: 10./diagnostics.I SomaScan 10/10/ Kollar B, et al. Increased levels of circulating MMP3 correlate with severe rejection in face transplantation Sci Rep 8 1 https://www.doi.org/10./s-018--7 30,297,859 Acute Disease Adult Biomarkers/blood Biopsy Cluster Analysis Facial Transplantation/*adverse effects Female Graft Rejection/*blood Humans Male Matrix Metalloproteinase 3/*blood Middle Aged Reproducibility of Results Up-Regulation Face transplantation is a viable treatment option for carefully selected patients with devastating injuries to the face. However, acute rejection episodes occur in more than 80% of recipients in the first postoperative year. Unfortunately, neither a correlation between histological grades of rejection and anti-rejection treatment nor systemic surrogate markers of rejection in face transplantation are established in clinical routine. Therefore, we utilized next generation aptamer-based SOMAscan proteomics platform for non-invasive rejection biomarker discovery. Longitudinal serum samples from face transplant recipients with long-term follow-up were included in this study. From the 1,310 proteins analyzed by SOMAscan, a 5-protein signature (MMP3, ACY1, IL1R2, SERPINA4, CPB2) was able to discriminate severe rejection from both no-rejection and nonsevere rejection samples. Technical validation on ELISA platform showed high correlation with the SOMAscan data for the MMP3 protein (r(s) = 0.99). Additionally, MMP3 levels were significantly increased during severe rejection as compared to no-rejection (p = 0.) and nonsevere rejection (p = 0.) episodes. Pathway analyses revealed significant activation of the metallopeptidase activity during severe face transplant rejection. This pilot study demonstrates the feasibility of SOMAscan to identify non-invasive candidate biomarkers of rejection in face transplantation. Further validation in a larger independent patient cohort is needed. Kollar, Branislav Shubin, Andrey Borges, Thiago J Tasigiorgos, Sotirios Win, Thet Su Lian, Christine G Dillon, Simon T Gu, Xuesong Wyrobnik, Iris Murphy, George F Pomahac, Bohdan Libermann, Towia A Riella, Leonardo V eng P30 CA/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. England Sci Rep. Oct 8;8(1):. doi: 10./s-018--7.I SomaScan 10/10/ Patel V, et al. Aptamer-based search for correlates of plasma and serum water T(2): implications for early metabolic dysregulation and metabolic syndrome Biomark Res 6 28 https://www.doi.org/10./s-018--x 30,237,882 Classification and regression tree analysis Glucokinase regulatory protein Hepatocyte growth factor Insulin resistance Metabolic syndrome Nuclear magnetic resonance relaxometry Random forests Receptor tyrosine kinase FLT3 SOMAscan aptamer assay Transverse relaxation time constant of the University of North Texas Health Science Center, Fort Worth (Protocol -205). All enrolled subjects gave prior consent to participate by signing an IRB-approved consent form, after being made aware of benefits and risks of participation.Not applicable.The University of North Texas Health Science Center, Fort Worth has pending patent applications for the use of plasma and serum water T2 for metabolic health screening, with D.P.C as an inventor.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. BACKGROUND: Metabolic syndrome is a cluster of abnormalities that increases the risk for type 2 diabetes and atherosclerosis. Plasma and serum water T(2) from benchtop nuclear magnetic resonance relaxometry are early, global and practical biomarkers for metabolic syndrome and its underlying abnormalities. In a prior study, water T(2) was analyzed against ~ 130 strategically selected proteins and metabolites to identify associations with insulin resistance, inflammation and dyslipidemia. In the current study, the analysis was broadened ten-fold using a modified aptamer (SOMAmer) library, enabling an unbiased search for new proteins correlated with water T(2) and thus, metabolic health. METHODS: Water T(2) measurements were recorded using fasting plasma and serum from non-diabetic human subjects. In parallel, plasma samples were analyzed using a SOMAscan assay that employed modified DNA aptamers to determine the relative concentrations of proteins. A multi-step statistical analysis was performed to identify the biomarkers most predictive of water T(2). The steps included Spearman rank correlation, followed by principal components analysis with variable clustering, random forests for biomarker selection, and regression trees for biomarker ranking. RESULTS: The multi-step analysis unveiled five new proteins most predictive of water T(2): hepatocyte growth factor, receptor tyrosine kinase FLT3, bone sialoprotein 2, glucokinase regulatory protein and endothelial cell-specific molecule 1. Three of the five strongest predictors of water T(2) have been previously implicated in cardiometabolic diseases. Hepatocyte growth factor has been associated with incident type 2 diabetes, and endothelial cell specific molecule 1, with atherosclerosis in subjects with diabetes. Glucokinase regulatory protein plays a critical role in hepatic glucose uptake and metabolism and is a drug target for type 2 diabetes. By contrast, receptor tyrosine kinase FLT3 and bone sialoprotein 2 have not been previously associated with metabolic conditions. In addition to the five most predictive biomarkers, the analysis unveiled other strong correlates of water T(2) that would not have been identified in a hypothesis-driven biomarker search. CONCLUSIONS: The identification of new proteins associated with water T(2) demonstrates the value of this approach to biomarker discovery. It provides new insights into the metabolic significance of water T(2) and the pathophysiology of metabolic syndrome. Patel, Vipulkumar Dwivedi, Alok K Deodhar, Sneha Mishra, Ina Cistola, David P eng England Biomark Res. Sep 17;6:28. doi: 10./s-018--x. eCollection .I SomaScan 09/22/ Santos-Parker JR, et al. Habitual aerobic exercise and circulating proteomic patterns in healthy adults: relation to indicators of healthspan J Appl Physiol () 125 5 - https://www.doi.org/10./japplphysiol.. 30,236,049 Adult Aged Aging/*blood Biomarkers Exercise/*physiology Female Healthy Aging/*blood Humans Male Middle Aged *Proteome Young Adult SomaLogic blood pressure inflammation weighted correlation network analysis Habitual aerobic exercise enhances physiological function and reduces risk of morbidity and mortality throughout life, but the underlying molecular mechanisms are largely unknown. The circulating proteome reflects the intricate network of physiological processes maintaining homeostasis and may provide insight into the molecular transducers of the health benefits of physical activity. In this exploratory study, we assessed the plasma proteome (SOMAscan proteomic assay; 1,129 proteins) of healthy sedentary or aerobic exercise-trained young women and young and older men ( n = 47). Using weighted correlation network analysis to identify clusters of highly co-expressed proteins, we characterized 10 distinct plasma proteomic modules (patterns). In healthy young (24 +/- 1 yr) men and women, 4 modules were associated with aerobic exercise status and 1 with participant sex. In healthy young and older (64 +/- 2 yr) men, 5 modules differed with age, but 2 of these were partially preserved at young adult levels in older men who exercised; among all men, 4 modules were associated with exercise status, including 3 of the 4 identified in young adults. Exercise-linked proteomic patterns were related to pathways involved in wound healing, regulation of apoptosis, glucose-insulin and cellular stress signaling, and inflammation/immune responses. Importantly, several of the exercise-related modules were associated with physiological and clinical indicators of healthspan, including diastolic blood pressure, insulin resistance, maximal aerobic capacity, and vascular endothelial function. Overall, these findings provide initial insight into circulating proteomic patterns modulated by habitual aerobic exercise in healthy young and older adults, the biological processes involved, and their relation to indicators of healthspan. NEW & NOTEWORTHY This is the first study to assess the relation between plasma proteomic patterns and aerobic exercise status in healthy adults. Weighted correlation network analysis identified 10 distinct proteomic modules, including 5 patterns specific for exercise status. Additionally, 5 modules differed with aging in men, two of which were preserved in older exercising men. Exercise-associated modules included proteins related to inflammation, stress pathways, and immune function and correlated with clinical and physiological indicators of healthspan. Santos-Parker, Jessica R Santos-Parker, Keli S McQueen, Matthew B Martens, Christopher R Seals, Douglas R eng R37 AG/AG/NIA NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ T32 AG/AG/NIA NIH HHS/ Comparative Study Research Support, N.I.H., Extramural J Appl Physiol (). Nov 1;125(5):-. doi: 10./japplphysiol... Epub Sep 20.I SomaScan 09/22/ Conklin LS, et al. Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug Pharmacol Res 136 140-150 https://www.doi.org/10./j.phrs..09.007 30,219,580 Administration, Oral Anti-Inflammatory Agents/blood/*pharmacology/*therapeutic use Biomarkers/blood Blood Glucose/analysis Child Child, Preschool Humans Hydrocortisone/blood Insulin/blood Male Muscular Dystrophy, Duchenne/*drug therapy/metabolism Pregnadienediols/blood/*pharmacology/*therapeutic use We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes. Conklin, Laurie S Damsker, Jesse M Hoffman, Eric P Jusko, William J Mavroudis, Panteleimon D Schwartz, Benjamin D Mengle-Gaw, Laurel J Smith, Edward C Mah, Jean K Guglieri, Michela Nevo, Yoram Kuntz, Nancy McDonald, Craig M Tulinius, Mar Ryan, Monique M Webster, Richard Castro, Diana Finkel, Richard S Smith, Andrea L Morgenroth, Lauren P Arrieta, Adrienne Shimony, Maya Jaros, Mark Shale, Phil McCall, John M Hathout, Yetrib Nagaraju, Kanneboyina van den Anker, John Ward, Leanne M Ahmet, Alexandra Cornish, Michaelyn R Clemens, Paula R eng R44 NS/NS/NINDS NIH HHS/ U34 AR/AR/NIAMS NIH HHS/ U54 HD/HD/NICHD NIH HHS/ U54 HD/HD/NICHD NIH HHS/ P50 HD/HD/NICHD NIH HHS/ Clinical Trial, Phase II Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Netherlands Pharmacol Res. Oct;136:140-150. doi: 10./j.phrs..09.007. Epub Sep 13.I SomaScan 09/17/ Coca SG Scanning" into the Future: The Promise of SOMAScan Technology for Kidney Disease" Kidney Int Rep 3 5 - https://www.doi.org/10./j.ekir..06.009 30,197,965 Coca, Steven G eng R01 HL/HL/NHLBI NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Editorial Kidney Int Rep. Jun 30;3(5):-. doi: 10./j.ekir..06.009. eCollection Sep.I SomaScan 09/11/ Yu LR, et al. Aptamer-Based Proteomics Identifies Mortality-Associated Serum Biomarkers in Dialysis-Dependent AKI Patients Kidney Int Rep 3 5 - https://www.doi.org/10./j.ekir..04.012 30,197,987 acute kidney injury aptamers biomarkers INTRODUCTION: Currently, no effective therapies exist to reduce the high mortality associated with dialysis-dependent acute kidney injury (AKI-D). Serum biomarkers may be useful in understanding the pathophysiological processes involved with AKI and the severity of injury, and point to novel therapeutic targets. METHODS: Study day 1 serum samples from 100 patients and day 8 samples from 107 patients enrolled in the Veteran's Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the slow off-rate modified aptamers scan proteomic platform to profile proteins in each sample. Patients in each cohort were classified into tertiles based on baseline biomarker measurements. Cox regression analyses were performed to examine the relationships between serum levels of each biomarker and mortality. RESULTS: Changes in the serum levels of 54 proteins, 33 of which increased and 21 of which decreased, were detected when comparing samples of patients who died in the first 8 days versus patients who survived >8 days. Among the 33 proteins that increased, higher serum levels of fibroblast growth factor-23 (FGF23), tissue plasminogen activator (tPA), neutrophil collagenase (matrix metalloproteinase-8), and soluble urokinase plasminogen activator receptor, when stratified by tertiles, were associated with higher mortality. The association with mortality persisted for each of these proteins after adjusting for other potential risk factors, including age, sex, cardiovascular sequential organ failure assessment score, congestive heart failure, and presence of diabetes. Upper tertile levels of FGF23, tPA, and interleukin-6 on day 8 were associated with increased mortality; however, FGF23 barely lost significance after multivariable adjustment. CONCLUSIONS: Our results underscore an emerging proteomics tool capable of identifying low-abundance serum proteins important not only in the pathogenesis of AKI-D, but which is also helpful in discriminating AKI-D patients with high mortality. Yu, Li-Rong Sun, Jinchun Daniels, Jaclyn R Cao, Zhijun Schnackenberg, Laura Choudhury, Devasmita Palevsky, Paul M Ma, Jennie Z Beger, Richard D Portilla, Didier eng R01 DK/DK/NIDDK NIH HHS/ Y01 DK/DK/NIDDK NIH HHS/ Kidney Int Rep. May 3;3(5):-. doi: 10./j.ekir..04.012. eCollection Sep.I SomaScan 09/11/ Moore RP, et al. Improving probes for super-resolution Nat Methods 15 9 659-660 https://www.doi.org/10./s-018--1 30,171,240 *DNA Microscopy, Fluorescence *Oligonucleotides Moore, Regan P Legant, Wesley R eng Comment Nat Methods. Sep;15(9):659-660. doi: 10./s-018--1.I SomaScan 09/02/ Curran AM, et al. A proteomic signature that reflects pancreatic beta-cell function PLoS One 13 8 e https://www.doi.org/10./journal.pone. 30,161,145 Adult Area Under Curve Body Mass Index Calcineurin/metabolism Cell Line Female Glucose Tolerance Test Humans Insulin Secretion/drug effects Insulin-Secreting Cells/cytology/*metabolism Interleukin-17/genetics/metabolism/pharmacology Linear Models Male Metabolic Networks and Pathways Proteome/*metabolism *Proteomics ROC Curve Young Adult beta-Endorphin/metabolism AIM: Proteomics has the potential to enhance early identification of beta-cell dysfunction, in conjunction with monitoring the various stages of type 2 diabetes onset. The most routine method of assessing pancreatic beta-cell function is an oral glucose tolerance test, however this method is time consuming and carries a participant burden. The objectives of this research were to identify protein signatures and pathways related to pancreatic beta-cell function in fasting blood samples. METHODS: Beta-cell function measures were calculated for MECHE study participants who completed an oral glucose tolerance test and had proteomic data (n = 100). Information on 1,129 protein levels was obtained using the SOMAscan assay. Receiver operating characteristic curves were used to assess discriminatory ability of proteins of interest. Subsequent in vitro experiments were performed using the BRIN-BD11 pancreatic beta-cell line. Replication of findings were achieved in a second human cohort where possible. RESULTS: Twenty-two proteins measured by aptamer technology were significantly associated with beta-cell function/HOMA-IR while 17 proteins were significantly associated with the disposition index (p 2-fold change (p < 0.01) using western blots conclusively demonstrated that inflammatory cytokines alter the expression of APPs differentially. For example, the abundance of cathepsin S was enhanced by only IFN-gamma, whereas lipocalin-2 was increased by IL-17 alone. Abundance of elafin increased in presence of IL-17 or TNF, but decreased in response to IFN-gamma. Whereas the abundance of cathepsin V decreased following stimulation with IL-17, TNF and IFN-gamma. The results of this study demonstrate that inflammatory cytokines alter the expression of APPs disparately. This suggests that the composition of the inflammatory cytokine milieu may influence APPs abundance and thus alter the processes required for infection control and regulation of inflammation in the lungs. Altieri, Anthony Piyadasa, Hadeesha Recksiedler, Breann Spicer, Victor Mookherjee, Neeloffer eng Switzerland Vaccines (Basel). Aug 7;6(3):51. doi: 10./vaccines.I SomaScan 08/09/ Emilsson V, et al. Co-regulatory networks of human serum proteins link genetics to disease Science 361 6,404 769-773 https://www.doi.org/10./science.aaq 30,072,576 Aptamers, Nucleotide Blood Proteins/*analysis/*genetics Cardiovascular Diseases/*genetics Genetic Predisposition to Disease Genetic Variation Humans Iceland Metabolic Diseases/*genetics Metabolic Networks and Pathways Proteome/*analysis/*genetics Proteomics/*methods Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, proteins covering most predicted extracellular proteins were measured in the serum of Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states. Emilsson, Valur Ilkov, Marjan Lamb, John R Finkel, Nancy Gudmundsson, Elias F Pitts, Rebecca Hoover, Heather Gudmundsdottir, Valborg Horman, Shane R Aspelund, Thor Shu, Le Trifonov, Vladimir Sigurdsson, Sigurdur Manolescu, Andrei Zhu, Jun Olafsson, Orn Jakobsdottir, Johanna Lesley, Scott A To, Jeremy Zhang, Jia Harris, Tamara B Launer, Lenore J Zhang, Bin Eiriksdottir, Gudny Yang, Xia Orth, Anthony P Jennings, Lori L Gudnason, Vilmundur eng N01AG/AG/NIA NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ HHSNC/DA/NIDA NIH HHS/ Z99 AG/ImNIH/Intramural NIH HHS/ Z01 AG-02/ImNIH/Intramural NIH HHS/ Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Science. Aug 24;361():769-773. doi: 10./science.aaq. Epub Aug 2.I SomaScan 08/04/ Tasaki S, et al. Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission Nat Commun 9 1 https://www.doi.org/10./s-018--4 30,013,029 Antibodies, Monoclonal, Humanized/therapeutic use Antirheumatic Agents/*therapeutic use Arthritis, Rheumatoid/*drug therapy/genetics/immunology/pathology Biomarkers, Pharmacological/blood Blood Proteins/*genetics/immunology Case-Control Studies Cell Count Gene Expression Regulation Humans Infliximab/therapeutic use Lymphocytes/drug effects/immunology/pathology Methotrexate/*therapeutic use Monocytes/drug effects/immunology/pathology Neutrophils/drug effects/immunology/pathology Proteomics/methods Remission Induction Severity of Illness Index *Transcriptome Treatment Outcome Sustained clinical remission (CR) without drug treatment has not been achieved in patients with rheumatoid arthritis (RA). This implies a substantial difference between CR and the healthy state, but it has yet to be quantified. We report a longitudinal monitoring of the drug response at multi-omics levels in the peripheral blood of patients with RA. Our data reveal that drug treatments alter the molecular profile closer to that of HCs at the transcriptome, serum proteome, and immunophenotype level. Patient follow-up suggests that the molecular profile after drug treatments is associated with long-term stable CR. In addition, we identify molecular signatures that are resistant to drug treatments. These signatures are associated with RA independently of known disease severity indexes and are largely explained by the imbalance of neutrophils, monocytes, and lymphocytes. This high-dimensional phenotyping provides a quantitative measure of molecular remission and illustrates a multi-omics approach to understanding drug response. Tasaki, Shinya Suzuki, Katsuya Kassai, Yoshiaki Takeshita, Masaru Murota, Atsuko Kondo, Yasushi Ando, Tatsuya Nakayama, Yusuke Okuzono, Yuumi Takiguchi, Maiko Kurisu, Rina Miyazaki, Takahiro Yoshimoto, Keiko Yasuoka, Hidekata Yamaoka, Kunihiro Morita, Rimpei Yoshimura, Akihiko Toyoshiba, Hiroyoshi Takeuchi, Tsutomu eng England Nat Commun. Jul 16;9(1):. doi: 10./s-018--4.I SomaScan 07/18/ Jalal D, et al. Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease J Am Heart Assoc 7 14 https://www.doi.org/10./JAHA.117. 30,006,493 Adult Aged Brachial Artery/diagnostic imaging/physiopathology Case-Control Studies Cell-Derived Microparticles/*metabolism Complement Activation Complement C4a/metabolism Complement C5a/metabolism Complement Factor B/*metabolism Complement Factor D/*metabolism Complement Membrane Attack Complex/metabolism *Complement Pathway, Alternative Complement System Proteins/metabolism Endothelial Cells Endothelium, Vascular/*physiopathology Female Glomerular Filtration Rate Humans Kidney Transplantation Male Middle Aged Pilot Projects Proteomics Renal Insufficiency, Chronic/*metabolism/physiopathology/surgery Severity of Illness Index Vasodilation Microparticles complement activation chronic kidney disease BACKGROUND: Endothelial microparticles are associated with chronic kidney disease (CKD) and complement activation. We hypothesized that the complement pathway is activated in patients with CKD via endothelial microparticles and that complement activation correlates with endothelial dysfunction in CKD. METHODS AND RESULTS: We analyzed complement data of 30 healthy subjects, 30 patients with stage III/IV CKD, and 30 renal transplant recipients with stage III/IV CKD, evaluating the potential correlation of complement fragments with brachial artery flow-mediated dilation, Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and urinary albumin/creatinine ratio. Endothelial microparticles were characterized via proteomic analysis and compared between study groups. Complement fragment Ba was significantly increased in CKD and post-kidney transplant CKD. Plasma Ba levels correlated significantly with lower brachial artery flow-mediated dilation, lower Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and higher urinary albumin/creatinine ratio. Factor D levels were significantly higher in the plasma microparticles of patients with CKD versus healthy controls. Plasma microparticles isolated from patients with CKD and containing factor D activated the alternative pathway in vitro. CONCLUSION: The alternative complement pathway is activated in CKD and correlates with endothelial dysfunction and markers of CKD. Future studies are needed to evaluate whether endothelial microparticles with increased factor D play a pathologic role in CKD-associated vascular disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT. Jalal, Diana Renner, Brandon Laskowski, Jennifer Stites, Erik Cooper, James Valente, Karissa You, Zhiying Perrenoud, Loni Le Quintrec, Moglie Muhamed, Ismaeel Christians, Uwe Klawitter, Jelena Lindorfer, Margaret A Taylor, Ronald P Holers, V Michael Thurman, Joshua M eng R01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England J Am Heart Assoc. Jul 13;7(14):e. doi: 10./JAHA.117..I SomaScan 07/15/ Tanaka T, et al. Plasma proteomic signature of age in healthy humans Aging Cell 17 5 e https://www.doi.org/10./acel. 29,992,704 Adult Aged Aged, 80 and over Aging/*blood Female *Health Humans Male Middle Aged Molecular Sequence Annotation *Proteomics Reproducibility of Results Young Adult *aging *aptamers *healthy aging *humans *plasma To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and women, 22-93 years old, who were disease- and treatment-free and had no physical and cognitive impairment. Using a p /= 0.4) for 91% of proteins. These results demonstrate the feasibility of SOMAscan for analyses of archived plasma samples. Kim, Claire H Tworoger, Shelley S Stampfer, Meir J Dillon, Simon T Gu, Xuesong Sawyer, Sherilyn J Chan, Andrew T Libermann, Towia A Eliassen, A Heather eng UM1 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ P30 CA/CA/NCI NIH HHS/ T32 CA/CA/NCI NIH HHS/ R01 CA/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. May 30;8(1):. doi: 10./s-018--w.I SomaScan 06/01/ Ciampa E, et al. Cerebrospinal Fluid Protein Changes in Preeclampsia Hypertension 72 1 219-226 https://www.doi.org/10./HYPERTENSIONAHA.118. 29,844,151 Adult Biomarkers/cerebrospinal fluid Cerebrospinal Fluid Proteins/*cerebrospinal fluid Enzyme-Linked Immunosorbent Assay Female Humans Pre-Eclampsia/*cerebrospinal fluid Pregnancy Prognosis Proteomics/*methods activin brain cerebrospinal fluid proteins hypertension preeclampsia proteomics The molecular mechanisms underlying seizure susceptibility in preeclampsia are unknown. We hypothesized that altered expression of distinct proteins in the cerebrospinal fluid (CSF) may reflect pathophysiological changes in the central nervous system that contribute to the neurological manifestations of severe preeclampsia. We obtained CSF samples from 13 patients with preeclampsia and 14 control patients during spinal anesthesia before delivery and analyzed them by SOMAscan, an aptamer-based proteomics platform for alterations in protein levels. Ingenuity Pathway Analysis was conducted to highlight relationships between preeclampsia-specific proteins found to be significantly altered. For 2 of the target proteins, we validated the difference in CSF concentrations by ELISA. SOMAscan revealed 82 proteins, whose expression levels were significantly different (P<0.05) in CSF from patients with preeclampsia versus controls. Principal component analysis achieved perfect separation of the preeclampsia and control groups in 2 dimensions. The differentially expressed proteins converge around 4 signaling molecules: TGF-beta (transforming growth factor-beta), VEGFA (vascular endothelial growth factor A), angiotensinogen, and IL-6 (interleukin-6). Within the TGF-beta pathway, upregulation of activin A (301.6+/-47.4 versus 151.6+/-20.5 pg/mL; P=0.) and follistatin-related gene (+/-347 versus +/-188 pg/mL; P<0.) in preeclampsia was confirmed by ELISA. In summary, signaling pathways important for vascular remodeling, inflammation, and neuronal growth, signaling, and electrophysiology were well represented among the proteins found to be altered in CSF in patients with preeclampsia. Ciampa, Erin Li, Yunping Dillon, Simon Lecarpentier, Edouard Sorabella, Laura Libermann, Towia A Karumanchi, S Ananth Hess, Philip E eng Research Support, Non-U.S. Gov't Hypertension. Jul;72(1):219-226. doi: 10./HYPERTENSIONAHA.118.. Epub May 29.I SomaScan 05/31/ Depner CM, et al. Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome Proc Natl Acad Sci U S A 115 23 E-E https://www.doi.org/10./pnas. 29,784,788 Adult Circadian Clocks Circadian Rhythm/physiology Eating/*physiology Healthy Volunteers Humans Male Melatonin/metabolism Plasma/chemistry/metabolism Proteome/*metabolism Sleep/*physiology Wakefulness/physiology Work Schedule Tolerance/physiology circadian rhythm eating at night peripheral clocks personalized medicine shift work Philips Inc. and Somalogics, Inc. K.P.W. has received grants/research support from CurAegis Technologies (formerly known as Torvec, Inc.), Philips Inc., and Somalogics, Inc. K.P.W. has received consulting fees or has served as a paid member of the scientific advisory boards for CurAegis Technologies, the NIH, and Circadian Therapeutics. K.P.W. has received speaker honoraria from the American Academy of Sleep Medicine, the American College of Chest Physicians, the American Diabetes Association, The Obesity Society, and Philips, Inc. K.P.W. holds stock options for CurAegis Technologies. Proteomics holds great promise for understanding human physiology, developing health biomarkers, and precision medicine. However, how much the plasma proteome varies with time of day and is regulated by the master circadian suprachiasmatic nucleus brain clock, assessed here by the melatonin rhythm, is largely unknown. Here, we assessed 24-h time-of-day patterns of human plasma proteins in six healthy men during daytime food intake and nighttime sleep in phase with the endogenous circadian clock (i.e., circadian alignment) versus daytime sleep and nighttime food intake out of phase with the endogenous circadian clock (i.e., circadian misalignment induced by simulated nightshift work). We identified 24-h time-of-day patterns in 573 of 1,129 proteins analyzed, with 30 proteins showing strong regulation by the circadian cycle. Relative to circadian alignment, the average abundance and/or 24-h time-of-day patterns of 127 proteins were altered during circadian misalignment. Altered proteins were associated with biological pathways involved in immune function, metabolism, and cancer. Of the 30 circadian-regulated proteins, the majority peaked between hours and hours, and these 30 proteins were associated with basic pathways involved in extracellular matrix organization, tyrosine kinase signaling, and signaling by receptor tyrosine-protein kinase erbB-2. Furthermore, circadian misalignment altered multiple proteins known to regulate glucose homeostasis and/or energy metabolism, with implications for altered metabolic physiology. Our findings demonstrate the circadian clock, the behavioral wake-sleep/food intake-fasting cycle, and interactions between these processes regulate 24-h time-of-day patterns of human plasma proteins and help identify mechanisms of circadian misalignment that may contribute to metabolic dysregulation. Depner, Christopher M Melanson, Edward L McHill, Andrew W Wright, Kenneth P Jr eng P30 DK/DK/NIDDK NIH HHS/ F32 DK/DK/NIDDK NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R21 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. Jun 5;115(23):E-E. doi: 10./pnas.. Epub May 21.I SomaScan 05/23/ Simats A, et al. Characterization of the rat cerebrospinal fluid proteome following acute cerebral ischemia using an aptamer-based proteomic technology Sci Rep 8 1 https://www.doi.org/10./s-018--3 29,784,938 Acute Disease Animals Aptamers, Nucleotide/*genetics Biomarkers/*cerebrospinal fluid Brain/*metabolism/pathology Brain Ischemia/*cerebrospinal fluid/genetics/pathology Humans Male Proteome/*analysis Proteomics/*methods Rats Rats, Wistar Stroke/*cerebrospinal fluid/genetics/pathology The limited accessibility to the brain has turned the cerebrospinal fluid (CSF) into a valuable source that may contribute to the complete understanding of the stroke pathophysiology. Here we have described the CSF proteome in the hyper-acute phase of cerebral ischemia by performing an aptamer-based proteomic assay (SOMAscan) in CSF samples collected before and 30 min after male Wistar rats had undergone a 90 min Middle Cerebral Artery Occlusion (MCAO) or sham-surgery. Proteomic results indicated that cerebral ischemia acutely increased the CSF levels of 716 proteins, mostly overrepresented in leukocyte chemotaxis and neuronal death processes. Seven promising candidates were further evaluated in rat plasma and brain (CKB, CaMK2A, CaMK2B, CaMK2D, PDXP, AREG, CMPK). The 3 CaMK2 family-members and CMPK early decreased in the infarcted brain area and, together with AREG, co-localized with neurons. Conversely, CKB levels remained consistent after the insult and specifically matched with astrocytes. Further exploration of these candidates in human plasma revealed the potential of CKB and CMPK to diagnose stroke, while CaMK2B and CMPK resulted feasible biomarkers of functional stroke outcome. Our findings provided insights into the CSF proteome following cerebral ischemia and identified new outstanding proteins that might be further considered as potential biomarkers of stroke. Simats, Alba Garcia-Berrocoso, Teresa Ramiro, Laura Giralt, Dolors Gill, Natalia Penalba, Anna Bustamante, Alejandro Rosell, Anna Montaner, Joan eng Research Support, Non-U.S. Gov't England Sci Rep. May 21;8(1):. doi: 10./s-018--3.I SomaScan 05/23/ Spitali P, et al. Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies J Cachexia Sarcopenia Muscle 9 4 715-726 https://www.doi.org/10./jcsm. 29,682,908 Adult Aged Biomarkers Computational Biology/methods Cross-Sectional Studies Disease Progression Follow-Up Studies Humans Middle Aged Muscle, Skeletal/diagnostic imaging/pathology/physiopathology Muscular Dystrophy, Duchenne/*diagnosis Proteome Proteomics/methods Young Adult Becker muscular dystrophy Biomarker Duchenne muscular dystrophy Longitudinal analysis Proteomics Sarcopenia BACKGROUND: Analysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs. METHODS: A large-scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo (31) P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross-sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4 years to allow monitoring of individual disease trajectories based on yearly visits. RESULTS: Cross-sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over-representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development. CONCLUSIONS: Serum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression. Spitali, Pietro Hettne, Kristina Tsonaka, Roula Charrout, Mohammed van den Bergen, Janneke Koeks, Zaida Kan, Hermien E Hooijmans, Melissa T Roos, Andreas Straub, Volker Muntoni, Francesco Al-Khalili-Szigyarto, Cristina Koel-Simmelink, Marleen J A Teunissen, Charlotte E Lochmuller, Hanns Niks, Erik H Aartsma-Rus, Annemieke eng Department of Health/United Kingdom Research Support, Non-U.S. Gov't Germany J Cachexia Sarcopenia Muscle. Aug;9(4):715-726. doi: 10./jcsm.. Epub Apr 16.I SomaScan 04/24/ Pierson SK, et al. Plasma proteomics identifies a 'chemokine storm' in idiopathic multicentric Castleman disease Am J Hematol 93 7 902-912 https://www.doi.org/10./ajh. 29,675,946 Adult Antibodies, Monoclonal/therapeutic use Castleman Disease/blood/*etiology Chemokine CXCL13/metabolism Chemokines/*metabolism Female Humans Interleukin-6/immunology Male Middle Aged Plasma/*chemistry Proteomics/*methods Up-Regulation Human Herpesvirus-8 (HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a poorly understood disease involving polyclonal lymphoproliferation with dysmorphic germinal centers, constitutional symptoms, and multi-organ failure. Patients can experience thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly, and normal immunoglobulin levels, - iMCD-TAFRO. Others experience thrombocytosis, milder effusions, and hypergammaglobulinemia, -iMCD-Not Otherwise Specified (iMCD-NOS). Though the etiology is unknown in both subtypes, iMCD symptoms and disease progression are believed to be driven by a cytokine storm, often including interleukin-6 (IL-6). However, approximately two-thirds of patients do not respond to anti-IL-6 therapy; alternative drivers and signaling pathways are not known for anti-IL-6 nonresponders. To identify potential mediators of iMCD pathogenesis, we quantified proteins in 13 plasma samples from six iMCD patients during flare and remission. The acute phase reactant NPS-PLA2 was the only significantly increased protein (P = .017); chemokines and complement were significantly enriched pathways. Chemokines represented the greatest proportion of upregulated cytokines, suggesting that iMCD involves a chemokine storm. The chemokine CXCL13, which is essential in homing B cells to germinal centers, was the most upregulated cytokine across all patients (log2 fold-change = 3.22). Expression of CXCL13 was also significantly increased in iMCD lymph node germinal centers compared to controls in a stromal meshwork pattern. We observed distinct proteomic profiles between the two iMCD-TAFRO patients, who both failed anti-IL-6-therapy, and the four iMCD-NOS patients, in whom all three treated with anti-IL-6-therapy responded, suggesting that differing mechanisms may exist. This study reveals proteomic differences between flare and remission and the potential to molecularly define iMCD subgroups. Pierson, Sheila K Stonestrom, Aaron J Shilling, Dustin Ruth, Jason Nabel, Christopher S Singh, Amrit Ren, Yue Stone, Katie Li, Hongzhe van Rhee, Frits Fajgenbaum, David C eng Research Support, Non-U.S. Gov't Am J Hematol. Jul;93(7):902-912. doi: 10./ajh.. Epub May 16.I SomaScan 04/21/ Jin P, et al. Plasma from some cancer patients inhibits adenoviral Ad5f35 vector transduction of dendritic cells Cytotherapy 20 5 728-739 https://www.doi.org/10./j.jcyt..03.001 29,655,599 Adenoviridae/*genetics Adult Aged Cytokines/metabolism Dendritic Cells/*metabolism Female Gene Expression Regulation Genetic Vectors/*metabolism Humans Middle Aged Monocytes/cytology/metabolism Neoplasms/*blood Plasma/*metabolism Principal Component Analysis Receptor, ErbB-2/metabolism Tissue Donors *Transduction, Genetic adHER2/neu cancer immunotherapy dendritic cells (DCs) BACKGROUND: Pooled AB serum is often used as a media supplement for cell culture but it has the potential to transmit infectious diseases. To avoid this risk, we used autologous plasma as a media supplement for manufacturing dendritic cells (DCs) for cancer immunotherapy. We noticed inconsistencies in the DCs and investigated their nature and cause. METHODS: Adenovirus human epidural growth factor receptor 2 (adHER2/neu) DCs for 21 patients were manufactured from autologous peripheral blood monocytes that were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 for 3 days, transduced with Ad5f35HER2ECTM and then treated with lipopolysaccharide and interferon (IFN)-gamma for 1 day. The cells were cultured in RPMI- supplemented with either 10% heat inactivated autologous or AB plasma. RESULTS: Twenty-eight adHER2/neu DCs were manufactured for 21 patients using autologous plasma and 68 were manufactured for 20 of those patients using AB plasma. The expression of human epidural growth factor receptor 2 (HER2/neu) was less for DCs manufactured with autologous plasma (70.3 +/- 33.3% versus 86.1 +/- 22.8%; P <0.01). Manufacturing adHER2/neu DCs using monocytes from three healthy subjects and plasma from one patient with low HER2/neu expression (18%) resulted in low HER2/neu expression by all three DCs (13%, 16% and 23%). Analysis of the levels of proteins in eight plasma samples associated with low HER2/neu expression and in 12 associated with high HER2/neu expression revealed that the levels of 14 predicted HER2/neu transduction efficiency. CONCLUSION: The manufacture of adHER2/neu DC using autologous plasma as a media supplement resulted in inconsistent HER2/neu expression. It is likely that variability in the levels of multiple proteins in autologous plasma contributed to low HER2/neu expression. Jin, Ping Chen, Wenjing Ren, Jiaqiang Chen, Steven Wood, Lauren Zhao, Yingdong Remaley, Alan Pham, Chauha Lian, Sheena Liu, Shutong Liu, Hui Highfill, Steven Berzofsky, Jay A Stroncek, David F eng ZIA CL-09/Intramural NIH HHS/ ZIA CL-09/Intramural NIH HHS/ Research Support, N.I.H., Intramural England Cytotherapy. May;20(5):728-739. doi: 10./j.jcyt..03.001. Epub Apr 11.I SomaScan 04/16/ Hess AL, et al. Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study Genes Nutr 13 7 https://www.doi.org/10./s-018--3 29,619,113 Angiopoietin-like protein 3 Lipid metabolism Lipoprotein lipase Liver markers Liver steatosis Protein quantitative trait locus Single nucleotide polymorphisms countries, confirming that the study protocol was in accordance with the Declaration of Helsinki.Not applicable.AA is an advisor to or a member of advisory boards for a number of food and pharmaceutical producers: Basic Research, USA Beachbody, USA BioCare Copenhagen, Denmark Crossfit, USA Dutch Beer Institute, Netherlands Feast Kitchen A/S, Denmark Gelesis, USA Groupe Ethique et Sante, France McCain Foods Limited, USA Nestle Research Center, Switzerland Novo Nordisk, Denmark Pfizer, Germany Saniona, Denmark Sanofi-Aventis, Germany S-Biotek, Denmark Scandinavian Airlines System, Denmark TetraPak, Sweden Weight Watchers, USA and from Zaluvida, Switzerland. AA does not own stock in, or have other ownership interests in, any of the companies to which he provides scientific advice, or in any nutrition company other than those companies whose stock is held by various mutual fund retirement accounts. Recent research at the University of Copenhagen, Denmark, has been funded by unrestricted grants from or contracts with DC-Ingredients, Denmark Danish Dairy Foundation Global Dairy Platform and Gelesis AS, USA. AA receives payment as associate editor of The American Journal of Clinical Nutrition and as a member of the editorial committee of Annual Review of Nutrition. AA is a recipient of honoraria as speaker for a wide range of Danish and international concerns and of royalties from textbooks and from popular diet and cookery books. AA is a co-inventor of a number of patents, including Methods of inducing weight loss, treating obesity and preventing weight gain (licensee Gelesis, USA) and Biomarkers for predicting degree of weight loss (licensee Nestec SA, CH), owned by the University of Copenhagen, in accordance with Danish law. AA is a co-founder and co-owner of the University of Copenhagen spin-out companies Mobile Fitness A/S, Personalized Weight Management Research Consortium ApS (Gluco-diet.dk), and Flaxslim ApS, where he is also a member of the board. AA is not an advocate or activist for specific diets and is not strongly committed to any specific diet, e.g., veganism, Atkins diet, gluten-free diet, high animal protein diet, or dietary supplements. AV, JC, and JH are full-time employees at Nestle Institute of Health Sciences. The remaining authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3), a liver-derived protein, plays an important role in the lipid and lipoprotein metabolism. Using data available from the DiOGenes study, we assessed the link with clinical improvements (weight, plasma lipid, and insulin levels) and changes in liver markers, alanine aminotransferase, aspartate aminotransferase (AST), adiponectin, fetuin A and B, and cytokeratin 18 (CK-18), upon low-calorie diet (LCD) intervention. We also examined the role of genetic variation in determining the level of circulating ANGPTL3 and the relation between the identified genetic markers and markers of hepatic steatosis. METHODS: DiOGenes is a multicenter, controlled dietary intervention where obese participants followed an 8-week LCD (800 kcal/day, using a meal replacement product). Plasma ANGPTL3 and liver markers were measured using the SomaLogic (Boulder, CO) platform. Protein quantitative trait locus (pQTL) analyses assessed the link between more than four million common variants and the level of circulating ANGPTL3 at baseline and changes in levels during the LCD intervention. RESULTS: Changes in ANGPTL3 during weight loss showed only marginal association with changes in triglycerides (nominal p = 0.02) and insulin (p = 0.04); these results did not remain significant after correcting for multiple testing. However, significant association (after multiple-testing correction) were observed between changes in ANGPTL3 and AST during weight loss (p = 0.004) and between ANGPTL3 and CK-18 (baseline p = 1.03 x 10(-7), during weight loss p = 1.47 x 10(-13)). Our pQTL study identified two loci significantly associated with changes in ANGPTL3. One of these loci (the APOA4-APOA5-ZNF259-BUD13 gene cluster) also displayed significant association with changes in CK-18 levels during weight loss (p = 0.007). CONCLUSION: We clarify the link between circulating levels of ANGPTL3 and specific markers of liver function. We demonstrate that changes in ANGPLT3 and CK-18 during LCD are under genetic control from trans-acting variants. Our results suggest an extended function of ANGPTL3 in the inflammatory state of liver steatosis and toward liver metabolic processes. Hess, Anne Lundby Carayol, Jerome Blaedel, Trine Hager, Jorg Di Cara, Alessandro Astrup, Arne Saris, Wim H M Larsen, Lesli Hingstrup Valsesia, Armand eng Germany Genes Nutr. Apr 2;13:7. doi: 10./s-018--3. eCollection .I SomaScan 04/06/ Duo J, et al. Slow Off-Rate Modified Aptamer (SOMAmer) as a Novel Reagent in Immunoassay Development for Accurate Soluble Glypican-3 Quantification in Clinical Samples Anal Chem 90 8 - https://www.doi.org/10./acs.analchem.7b 29,605,994 Aptamers, Nucleotide/*chemistry Carcinoma, Hepatocellular/*diagnosis Chromatography, Liquid Glypicans/*analysis Humans *Immunoassay Liver Neoplasms/*diagnosis Recombinant Proteins/analysis Solubility Tandem Mass Spectrometry Accurate quantification of soluble glypican-3 in clinical samples using immunoassays is challenging, because of the lack of appropriate antibody reagents to provide a full spectrum measurement of all potential soluble glypican-3 fragments in vivo. Glypican-3 SOMAmer (slow off-rate modified aptamer) is a novel reagent that binds, with high affinity, to a far distinct epitope of glypican-3, when compared to all available antibody reagents generated in-house. This paper describes an integrated analytical approach to rational selection of key reagents based on molecular characterization by epitope mapping, with the focus on our work using a SOMAmer as a new reagent to address development challenges with traditional antibody reagents for the soluble glypican-3 immunoassay. A qualified SOMAmer-based assay was developed and used for soluble glypican-3 quantification in hepatocellular carcinoma (HCC) patient samples. The assay demonstrated good sensitivity, accuracy, and precision. Data correlated with those obtained using the traditional antibody-based assay were used to confirm the clinically relevant soluble glypican-3 forms in vivo. This result was reinforced by a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay quantifying signature peptides generated from trypsin digestion. The work presented here offers an integrated strategy for qualifying aptamers as an alternative affinity platform for immunoassay reagents that can enable speedy assay development, especially when traditional antibody reagents cannot meet assay requirements. Duo, Jia Chiriac, Camelia Huang, Richard Y-C Mehl, John Chen, Guodong Tymiak, Adrienne Sabbatini, Peter Pillutla, Renuka Zhang, Yan eng Anal Chem. Apr 17;90(8):-. doi: 10./acs.analchem.7b. Epub Apr 6.I SomaScan 04/03/ Katilius E, et al. Sperm cell purification from mock forensic swabs using SOMAmer affinity reagents Forensic Sci Int Genet 35 13-Sep https://www.doi.org/10./j.fsigen..03.011 29,609,058 Cell Separation DNA/*isolation & purification DNA Fingerprinting Epithelial Cells/cytology Female Forensic Genetics Humans Indicators and Reagents Male Specimen Handling/instrumentation Spermatozoa/*cytology Affinity reagents Cell elution DNA typing Detergents Forensic science Selex SOMAmers Sex offenses Sperm purification We have demonstrated a proof of concept with affinity-based purification of sperm cells from mock forensic samples using SOMAmer reagents, DNA-based affinity reagents developed by SomaLogic, Inc. SOMAmer reagents were selected in vitro using whole-cell SELEX to bind specifically with intact, detergent-treated sperm cells. Successful separation of sperm from epithelial cells and their debris was demonstrated using buccal swabs with added semen. Primarily male DNA profiles were generated from sperm cells eluted from the types of cotton swabs typically used for rape kit evidence collection. The quality of sperm DNA isolated from samples purified using SOMAmers is comparable to existing commercially available differential extraction-based methods at higher sperm concentrations. This purification method is simple, offers relatively rapid (<2hr) sperm purification, and can potentially be automated using robotic workstations. This work serves as proof of concept that demonstrates the first use of SOMAmer reagents as affinity ligands to bind sperm cells. With further development, this technique can potentially be used for high-throughput sexual assault forensic casework. Katilius, Evaldas Carmel, Andrew B Koss, Heidi O'Connell, Dan Smith, Breanna C Sanders, Glenn M LaBerge, Greggory S eng Research Support, U.S. Gov't, Non-P.H.S. Netherlands Forensic Sci Int Genet. Jul;35:9-13. doi: 10./j.fsigen..03.011. Epub Mar 27.I SomaScan 04/03/ McGarrah RW, et al. Integrative Omics: Harnessing the Proteome to Maximize the Potential of the Genome Circulation 137 11 - https://www.doi.org/10./CIRCULATIONAHA.117. 29,530,892 *Cardiovascular Diseases Genomics Humans *Proteome Proteomics Risk Factors Editorials biomarkers cardiovascular diseases genetics genome-wide association study McGarrah, Robert W Shah, Svati H eng Comment Editorial Circulation. Mar 13;137(11):-. doi: 10./CIRCULATIONAHA.117..I SomaScan 03/14/ Parolo S, et al. Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy PLoS One 13 3 e https://www.doi.org/10./journal.pone. 29,529,088 Case-Control Studies Female Gene Expression Regulation Humans Male Muscle, Skeletal/metabolism Muscular Dystrophy, Duchenne/diagnosis/genetics/*metabolism *Protein Interaction Mapping *Protein Interaction Maps *Proteome *Proteomics/methods Signal Transduction Workflow Although the genetic basis of Duchenne muscular dystrophy has been known for almost thirty years, the cellular and molecular mechanisms characterizing the disease are not completely understood and an efficacious treatment remains to be developed. In this study we analyzed proteomics data obtained with the SomaLogic technology from blood serum of a cohort of patients and matched healthy subjects. We developed a workflow based on biomarker identification and network-based pathway analysis that allowed us to describe different deregulated pathways. In addition to muscle-related functions, we identified other biological processes such as apoptosis, signaling in the immune system and neurotrophin signaling as significantly modulated in patients compared with controls. Moreover, our network-based analysis identified the involvement of FoxO transcription factors as putative regulators of different pathways. On the whole, this study provided a global view of the molecular processes involved in Duchenne muscular dystrophy that are decipherable from serum proteome. Parolo, Silvia Marchetti, Luca Lauria, Mario Misselbeck, Karla Scott-Boyer, Marie-Pier Caberlotto, Laura Priami, Corrado eng Research Support, Non-U.S. Gov't PLoS One. Mar 12;13(3):e. doi: 10./journal.pone.. eCollection .I SomaScan 03/13/ Lam MPY, et al. Harnessing the Power of Proteomics to Assess Drug Safety and Guide Clinical Trials Circulation 137 10 - https://www.doi.org/10./CIRCULATIONAHA.117. 29,506,994 Biomarkers Early Diagnosis *Proteomics *Quinolines Editorials clinical trials drugs proteomics Assessing drug safety and efficacy is costly, and many promising candidates can present unwanted side effects. Can new developments in proteomic biomarkers help provide timely monitoring of efficacy and protect participant safety? In this issue, Williams et al. tackled this question with a retrospective study on whether patients treated with torcetrapib in the ILLUMINATE trial showed signs of increased cardiovascular risks early in the trial. Lam, Maggie P Y Ge, Ying eng R00 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Comment Editorial Research Support, N.I.H., Extramural Circulation. Mar 6;137(10):-. doi: 10./CIRCULATIONAHA.117..I SomaScan 03/07/ Zhang W, et al. Proteomic analysis reveals distinctive protein profiles involved in CD8(+) T cell-mediated murine autoimmune cholangitis Cell Mol Immunol 15 8 756-767 https://www.doi.org/10./cmi..149 29,375,127 Adoptive Transfer Analysis of Variance Animals Autoimmune Diseases/blood/*immunology Blood Proteins/*analysis CD8-Positive T-Lymphocytes/*immunology/*metabolism Cholangitis/blood/*immunology Disease Models, Animal Female Liver/metabolism Mice Mice, Inbred C57BL Natural Killer T-Cells/metabolism Proteomics/*methods Receptor, Transforming Growth Factor-beta Type II/metabolism Spleen/metabolism Cd8 autoimmune cholangitis dnTGFbetaRII mice proteomic analysis Autoimmune cholangitis arises from abnormal innate and adaptive immune responses in the liver, and T cells are critical drivers in this process. However, little is known about the regulation of their functional behavior during disease development. We previously reported that mice with T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type II (dnTGFbetaRII) spontaneously develop an autoimmune cholangitis that resembles human primary biliary cholangitis (PBC). Adoptive transfer of CD8(+) but not CD4(+) T cells into Rag1(-/-) mice reproduced the disease, demonstrating a critical role for CD8(+) T cells in PBC pathogenesis. Herein, we used SOMAscan technology to perform proteomic analysis of serum samples from dnTGFbetaRII and B6 control mice at different ages. In addition, we analyzed CD8 protein profiles after adoptive transfer of splenic CD8(+) cells into Rag1(-/-) recipients. The use of the unique SOMAscan aptamer technology revealed critical and distinct profiles of CD8 cells, which are key to biliary mediation. In total, 254 proteins were significantly increased while 216 proteins were significantly decreased in recipient hepatic CD8(+) cells compared to donor splenic CD8(+) cells. In contrast to donor splenic CD8(+) cells, recipient hepatic CD8(+) cells expressed distinct profiles for proteins involved in chemokine signaling, focal adhesion, T cell receptor and natural killer cell-mediated cytotoxicity pathways. Zhang, Weici Zhang, Ren Zhang, Jun Sun, Ying Leung, Patrick Sc Yang, Guo-Xiang Shuai, Zongwen Ridgway, William M Gershwin, M Eric eng P30 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural China Cell Mol Immunol. Aug;15(8):756-767. doi: 10./cmi..149. Epub Jan 29.I SomaScan 01/30/ Xie Z, et al. Adrenomedullin surges are linked to acute episodes of the systemic capillary leak syndrome (Clarkson disease) J Leukoc Biol 103 4 749-759 https://www.doi.org/10./JLB.5A-324R 29,360,169 Acute Disease Adrenomedullin/*metabolism Aged Biomarkers/*metabolism Capillary Leak Syndrome/metabolism/*pathology Case-Control Studies Cells, Cultured Endothelium, Vascular/metabolism/*pathology Female Gene Expression Profiling Gene Expression Regulation Humans Leukocytes, Mononuclear/metabolism/*pathology Male Middle Aged Monocytes/metabolism/*pathology adrenomedullin angiogenesis endothelium vascular leak BACKGROUND: Systemic Capillary Leak Syndrome (SCLS) is an extremely rare and life-threatening vascular disorder of unknown etiology. SCLS is characterized by abrupt and transient episodes of hypotensive shock and edema due to plasma leakage into peripheral tissues. The disorder has garnered attention recently because its initial presentation resembles more common vascular disorders including systemic anaphylaxis, sepsis, and acute infections with the Ebola/Marburg family of filoviruses. Although approximately 70-85% of patients with SCLS have a concurrent monoclonal gammopathy of unknown significance (MGUS), any contribution of the paraprotein to acute flares is unknown. PROCEDURE: To identify circulating factors that might trigger acute SCLS crises, we profiled transcriptomes of paired peripheral blood mononuclear cell fractions obtained from patients during acute attacks and convalescent intervals by microarray. RESULTS: This study uncovered 61 genes that were significantly up- or downregulated more than 2.5-fold in acute samples relative to respective baselines. One of the most upregulated genes was ADM, which encodes the vasoactive peptide adrenomedullin. A stable ADM protein surrogate (pro-ADM) was markedly elevated in SCLS acute sera compared to remission samples or sera from healthy controls. Monocytes and endothelial cells (ECs) from SCLS subjects expressed significantly more ADM in response to proinflammatory stimuli compared to healthy control cells. Application of ADM to ECs elicited protective effects on vascular barrier function, suggesting a feedback protective mechanism in SCLS. CONCLUSIONS: Since ADM has established hypotensive effects, differentiating between these dual actions of ADM is crucial for therapeutic applications aimed at more common diseases associated with increased ADM levels. Xie, Zhihui Chen, Wei-Sheng Yin, Yuzhi Chan, Eunice C Terai, Kaoru Long, Lauren M Myers, Timothy G Dudek, Arkadiusz Z Druey, Kirk M eng ZIA AI-08/Intramural NIH HHS/ Research Support, N.I.H., Intramural J Leukoc Biol. Apr;103(4):749-759. doi: 10./JLB.5A-324R. Epub Jan 23.I SomaScan 01/24/ Zaghlool SB, et al. Deep molecular phenotypes link complex disorders and physiological insult to CpG methylation Hum Mol Genet 27 6 - https://www.doi.org/10./hmg/ddy006 29,325,019 Basic Helix-Loop-Helix Transcription Factors/genetics Carrier Proteins/genetics Computational Biology/methods *CpG Islands *DNA Methylation Epigenesis, Genetic Female Genetic Association Studies/methods Genome, Human Genome-Wide Association Study/methods Glucose Metabolism Disorders/*genetics Humans Lipids/blood Male Metabolome Obesity/*genetics Repressor Proteins/genetics Tobacco Smoking/*genetics Epigenetic regulation of cellular function provides a mechanism for rapid organismal adaptation to changes in health, lifestyle and environment. Associations of cytosine-guanine di-nucleotide (CpG) methylation with clinical endpoints that overlap with metabolic phenotypes suggest a regulatory role for these CpG sites in the body's response to disease or environmental stress. We previously identified 20 CpG sites in an epigenome-wide association study (EWAS) with metabolomics that were also associated in recent EWASs with diabetes-, obesity-, and smoking-related endpoints. To elucidate the molecular pathways that connect these potentially regulatory CpG sites to the associated disease or lifestyle factors, we conducted a multi-omics association study including mass-spectrometry-based metabolites in plasma, urine and saliva, 225 NMR-based lipid and metabolite measures in blood, blood-circulating proteins using aptamer technology, 113 plasma protein N-glycans and 60 IgG-glyans, using 359 samples from the multi-ethnic Qatar Metabolomics Study on Diabetes (QMDiab). We report 138 multi-omics associations at these CpG sites, including diabetes biomarkers at the diabetes-associated TXNIP locus, and smoking-specific metabolites and proteins at multiple smoking-associated loci, including AHRR. Mendelian randomization suggests a causal effect of metabolite levels on methylation of obesity-associated CpG sites, i.e. of glycerophospholipid PC(O-36: 5), glycine and a very low-density lipoprotein (VLDL-A) on the methylation of the obesity-associated CpG loci DHCR24, MYO5C and CPT1A, respectively. Taken together, our study suggests that multi-omics-associated CpG methylation can provide functional read-outs for the underlying regulatory response mechanisms to disease or environmental insults. Zaghlool, Shaza B Mook-Kanamori, Dennis O Kader, Sara Stephan, Nisha Halama, Anna Engelke, Rudolf Sarwath, Hina Al-Dous, Eman K Mohamoud, Yasmin A Roemisch-Margl, Werner Adamski, Jerzy Kastenmuller, Gabi Friedrich, Nele Visconti, Alessia Tsai, Pei-Chien Spector, Tim Bell, Jordana T Falchi, Mario Wahl, Annika Waldenberger, Melanie Peters, Annette Gieger, Christian Pezer, Marija Lauc, Gordan Graumann, Johannes Malek, Joel A Suhre, Karsten eng Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't England Hum Mol Genet. Mar 15;27(6):-. doi: 10./hmg/ddy006.I SomaScan 01/13/ Christensson A, et al. The Impact of the Glomerular Filtration Rate on the Human Plasma Proteome Proteomics Clin Appl 12 3 e https://www.doi.org/10./prca. 29,281,176 Aged Blood Proteins/*metabolism Female *Glomerular Filtration Rate Humans Male Middle Aged *Proteomics Sex Characteristics PURPOSE: The application of proteomics in chronic kidney disease (CKD) can potentially uncover biomarkers and pathways that are predictive of disease. EXPERIMENTAL DESIGN: Within this context, this study examines the relationship between the human plasma proteome and glomerular filtration rate (GFR) as measured by iohexol clearance in a cohort from Sweden (n = 389; GFR range: 8-100 mL min(-1) /1.73 m(2) ). A total of proteins are quantified using a modified aptamer assay. RESULTS: A large proportion of the proteome is associated with GFR, reinforcing the concept that CKD affects multiple physiological systems (individual protein-GFR correlations listed here). Of these, cystatin C shows the most significant correlation with GFR (rho = -0.85, p = 1.2 x 10(-97) ), establishing strong validation for the use of this biomarker in CKD diagnostics. Among the other highly significant protein markers are insulin-like growth factor-binding protein 6, neuroblastoma suppressor of tumorigenicity 1, follistatin-related protein 3, trefoil factor 3, and beta-2 microglobulin. These proteins may indicate an imbalance in homeostasis across a variety of cellular processes, which may be underlying renal dysfunction. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, this study represents the most extensive characterization of the plasma proteome and its relation to GFR to date, and suggests the diagnostic and prognostic value of proteomics for CKD across all stages. Christensson, Anders Ash, Jessica A DeLisle, Robert K Gaspar, Fraser W Ostroff, Rachel Grubb, Anders Lindstrom, Veronica Bruun, Laila Williams, Steve A eng Research Support, Non-U.S. Gov't Germany Proteomics Clin Appl. May;12(3):e. doi: 10./prca.. Epub Jan 31.I SomaScan 12/28/ Aghaeepour N, et al. A proteomic clock of human pregnancy Am J Obstet Gynecol 218 3 347 e1-347 e14 https://www.doi.org/10./j.ajog..12.208 29,277,631 Adult Algorithms Biomarkers/blood CD4-Positive T-Lymphocytes/metabolism Female Gene Ontology *Gestational Age Glypicans/blood Granulins/blood Humans Janus Kinases/blood Models, Theoretical Placental Lactogen/blood Postpartum Period/*blood Predictive Value of Tests Pregnancy/*blood Pregnancy Trimesters/*blood Proteome/*metabolism STAT Transcription Factors/blood STAT5 Transcription Factor/blood Signal Transduction Janus kinase/signal transducer and activator of transcription Luminex Somalogic T cell alpha-fetoprotein antibody aptamer chrionic somatomammotropin hormore cross-validation elastic net gestational age glypican 3 granulins macrophage colony-stimulating factor 1 receptor plasma protein polymeric immunoglobulin receptor pregnancy prolactin proteome protooncogene tyrosine-protein kinase receptor Ret somamer BACKGROUND: Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable because it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome. OBJECTIVE: The recent availability of a highly multiplexed platform affording the simultaneous measurement of plasma proteins opens the door for a more explorative approach. The major aim of this study was to examine whether analysis of plasma collected during gestation of term pregnancy would allow identifying a set of proteins that tightly track gestational age. Establishing precisely timed plasma proteomic changes during term pregnancy is a critical step in identifying deviations from regular patterns caused by fetal and maternal maladaptations. A second aim was to gain insight into functional attributes of identified proteins and link such attributes to relevant immunological changes. STUDY DESIGN: Pregnant women participated in this longitudinal study. In 2 subsequent sets of 21 (training cohort) and 10 (validation cohort) women, specific blood specimens were collected during the first (7-14 weeks), second (15-20 weeks), and third (24-32 weeks) trimesters and 6 weeks postpartum for analysis with a highly multiplexed aptamer-based platform. An elastic net algorithm was applied to infer a proteomic model predicting gestational age. A bootstrapping procedure and piecewise regression analysis was used to extract the minimum number of proteins required for predicting gestational age without compromising predictive power. Gene ontology analysis was applied to infer enrichment of molecular functions among proteins included in the proteomic model. Changes in abundance of proteins with such functions were linked to immune features predictive of gestational age at the time of sampling in pregnancies delivering at term. RESULTS: An independently validated model consisting of 74 proteins strongly predicted gestational age (P = 3.8 x 10(-14), R = 0.97). The model could be reduced to 8 proteins without losing its predictive power (P = 1.7 x 10(-3), R = 0.91). The 3 top ranked proteins were glypican 3, chorionic somatomammotropin hormone, and granulins. Proteins activating the Janus kinase and signal transducer and activator of transcription pathway were enriched in the proteomic model, chorionic somatomammotropin hormone being the top-ranked protein. Abundance of chorionic somatomammotropin hormone strongly correlated with signal transducer and activator of transcription-5 signaling activity in CD4 T cells, the endogenous cell-signaling event most predictive of gestational age. CONCLUSION: Results indicate that precisely timed changes in the plasma proteome during term pregnancy mirror a proteomic clock. Importantly, the combined use of several plasma proteins was required for accurate prediction. The exciting promise of such a clock is that deviations from its regular chronological profile may assist in the early diagnoses of pregnancy-related pathologies, and point to underlying pathophysiology. Functional analysis of the proteomic model generated the novel hypothesis that chrionic somatomammotropin hormone may critically regulate T-cell function during pregnancy. Aghaeepour, Nima Lehallier, Benoit Baca, Quentin Ganio, Ed A Wong, Ronald J Ghaemi, Mohammad S Culos, Anthony El-Sayed, Yasser Y Blumenfeld, Yair J Druzin, Maurice L Winn, Virginia D Gibbs, Ronald S Tibshirani, Rob Shaw, Gary M Stevenson, David K Gaudilliere, Brice Angst, Martin S eng Research Support, Non-U.S. Gov't Validation Study Am J Obstet Gynecol. Mar;218(3):347.e1-347.e14. doi: 10./j.ajog..12.208. Epub Dec 24.I SomaScan 12/27/ Benson MD, et al. Genetic Architecture of the Cardiovascular Risk Proteome Circulation 137 11 - https://www.doi.org/10./CIRCULATIONAHA.117. 29,258,991 Aged Apolipoproteins E/genetics/metabolism Blood Proteins/*genetics/metabolism Cardiovascular Diseases/blood/diagnosis/*genetics Databases, Genetic Female Gene Expression Profiling Genetic Predisposition to Disease *Genetic Variation Genome-Wide Association Study Hep G2 Cells Heredity Humans Male Mendelian Randomization Analysis Middle Aged Phenotype Protein Phosphatase 2C/genetics/metabolism Quantitative Trait Loci Risk Factors Apoe cardiovascular genomics genome-wide analysis proteomics systems biology exists. BACKGROUND: We recently identified 156 proteins in human plasma that were each associated with the net Framingham Cardiovascular Disease Risk Score using an aptamer-based proteomic platform in Framingham Heart Study Offspring participants. Here we hypothesized that performing genome-wide association studies and exome array analyses on the levels of each of these 156 proteins might identify genetic determinants of risk-associated circulating factors and provide insights into early cardiovascular pathophysiology. METHODS: We studied the association of genetic variants with the plasma levels of each of the 156 Framingham Cardiovascular Disease Risk Score-associated proteins using linear mixed-effects models in 2 population-based cohorts. We performed discovery analyses on plasma samples from 759 participants of the Framingham Heart Study Offspring cohort, an observational study of the offspring of the original Framingham Heart Study and their spouses, and validated these findings in plasma samples from participants of the MDCS (Malmo Diet and Cancer Study). To evaluate the utility of this strategy in identifying new biological pathways relevant to cardiovascular disease pathophysiology, we performed studies in a cell-model system to experimentally validate the functional significance of an especially novel genetic association with circulating apolipoprotein E levels. RESULTS: We identified 120 locus-protein associations in genome-wide analyses and 41 associations in exome array analyses, the majority of which have not been described previously. These loci explained up to 66% of interindividual plasma protein-level variation and, on average, accounted for 3 times the amount of variation explained by common clinical factors, such as age, sex, and diabetes mellitus status. We described overlap among many of these loci and cardiovascular disease genetic risk variants. Finally, we experimentally validated a novel association between circulating apolipoprotein E levels and the transcription factor phosphatase 1G. Knockdown of phosphatase 1G in a human liver cell model resulted in decreased apolipoprotein E transcription and apolipoprotein E protein levels in cultured supernatants. CONCLUSIONS: We identified dozens of novel genetic determinants of proteins associated with the Framingham Cardiovascular Disease Risk Score and experimentally validated a new role for phosphatase 1G in lipoprotein biology. Further, genome-wide and exome array data for each protein have been made publicly available as a resource for cardiovascular disease research. Benson, Mark D Yang, Qiong Ngo, Debby Zhu, Yineng Shen, Dongxiao Farrell, Laurie A Sinha, Sumita Keyes, Michelle J Vasan, Ramachandran S Larson, Martin G Smith, J Gustav Wang, Thomas J Gerszten, Robert E eng P30 DK/DK/NIDDK NIH HHS/ N01 HC/HC/NHLBI NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ K01 GM/GM/NIGMS NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study Circulation. Mar 13;137(11):-. doi: 10./CIRCULATIONAHA.117.. Epub Dec 19.I SomaScan 12/21/ Jacob J, et al. Application of Large-Scale Aptamer-Based Proteomic Profiling to Planned Myocardial Infarctions Circulation 137 12 - https://www.doi.org/10./CIRCULATIONAHA.117. 29,222,138 Ablation Techniques *Aptamers, Nucleotide Biomarkers/blood Blood Proteins/genetics/*metabolism Cardiomyopathy, Hypertrophic/*blood/genetics/pathology/surgery Case-Control Studies Feasibility Studies High-Throughput Screening Assays Humans Myocardium/*metabolism/pathology Predictive Value of Tests Prognosis Proteomics/*methods Reproducibility of Results ST Elevation Myocardial Infarction/*blood/genetics/pathology Time Factors cardiovascular disease myocardial infarction proteins BACKGROUND: Emerging proteomic technologies using novel affinity-based reagents allow for efficient multiplexing with high-sample throughput. To identify early biomarkers of myocardial injury, we recently applied an aptamer-based proteomic profiling platform that measures proteins to samples from patients undergoing septal alcohol ablation for hypertrophic cardiomyopathy, a human model of planned myocardial injury. Here, we examined the scalability of this approach using a markedly expanded platform to study a far broader range of human proteins in the context of myocardial injury. METHODS: We applied a highly multiplexed, expanded proteomic technique that uses single-stranded DNA aptamers to assay human proteins ( distinct human gene targets) to derivation and validation cohorts of planned myocardial injury, individuals with spontaneous myocardial infarction, and at-risk controls. RESULTS: We found 376 target proteins that significantly changed in the blood after planned myocardial injury in a derivation cohort (n=20; P<1.05E-05, 1-way repeated measures analysis of variance, Bonferroni threshold). Two hundred forty-seven of these proteins were validated in an independent planned myocardial injury cohort (n=15; P90% were directionally consistent and reached nominal significance in the validation cohort. Among the validated proteins that were increased within 1 hour after planned myocardial injury, 29 were also elevated in patients with spontaneous myocardial infarction (n=63; P<6.17E-04). Many of the novel markers identified in our study are intracellular proteins not previously identified in the peripheral circulation or have functional roles relevant to myocardial injury. For example, the cardiac LIM protein, cysteine- and glycine-rich protein 3, is thought to mediate cardiac mechanotransduction and stress responses, whereas the mitochondrial ATP synthase F(0) subunit component is a vasoactive peptide on its release from cells. Last, we performed aptamer-affinity enrichment coupled with mass spectrometry to technically verify aptamer specificity for a subset of the new biomarkers. CONCLUSIONS: Our results demonstrate the feasibility of large-scale aptamer multiplexing at a level that has not previously been reported and with sample throughput that greatly exceeds other existing proteomic methods. The expanded aptamer-based proteomic platform provides a unique opportunity for biomarker and pathway discovery after myocardial injury. Jacob, Jaison Ngo, Debby Finkel, Nancy Pitts, Rebecca Gleim, Scott Benson, Mark D Keyes, Michelle J Farrell, Laurie A Morgan, Thomas Jennings, Lori L Gerszten, Robert E eng P30 DK/DK/NIDDK NIH HHS/ T32 HL/HL/NHLBI NIH HHS/ K01 GM/GM/NIGMS NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Comparative Study Research Support, N.I.H., Extramural Validation Study Circulation. Mar 20;137(12):-. doi: 10./CIRCULATIONAHA.117.. Epub Dec 8.I SomaScan 12/10/ Wang X, et al. Chemotherapy-induced differential cell cycle arrest in B-cell lymphomas affects their sensitivity to Wee1 inhibition Haematologica 103 3 466-476 https://www.doi.org/10./haematol.. 29,217,775 Animals Antineoplastic Agents/pharmacology Apoptosis/drug effects Cell Cycle Checkpoints/*drug effects Cell Cycle Proteins/*antagonists & inhibitors Cells, Cultured Cytarabine/pharmacology DNA Damage/drug effects Doxorubicin/pharmacology Drug Synergism Humans Lymphoma, B-Cell/drug therapy/*pathology Mice Nuclear Proteins/*antagonists & inhibitors Protein-Tyrosine Kinases/*antagonists & inhibitors Chemotherapeutic agents, e.g., cytarabine and doxorubicin, cause DNA damage. However, it remains unknown whether such agents differentially regulate cell cycle arrest in distinct types of B-cell lymphomas, and whether this phenotype can be exploited for developing new therapies. We treated various types of B cells, including primary and B lymphoma cells, with cytarabine or doxorubicin, and determined DNA damage responses, cell cycle regulation and sensitivity to a Wee1 inhibitor. We found that cyclin A2/B1 upregulation appears to be an intrinsic programmed response to DNA damage; however, different types of B cells arrest in distinct phases of the cell cycle. The Wee1 inhibitor significantly enhanced the apoptosis of G2 phase-arrested B-cell lymphomas by inducing premature entry into mitosis and mitotic catastrophe, whereas it did not affect G1/S-phase-arrested lymphomas. Cytarabine-induced G1-arrest can be converted to G2-arrest by doxorubicin treatment in certain B-cell lymphomas, which correlates with newly acquired sensitivity to the Wee1 inhibitor. Consequently, the Wee1 inhibitor together with cytarabine or doxorubicin inhibited tumor growth in vitro and in vivo more effectively, providing a potential new therapy for treating B-cell lymphomas. We propose that the differential cell cycle arrest can be exploited to enhance the chemosensitivity of B-cell lymphomas. Wang, Xiaoguang Chen, Zhangguo Mishra, Ameet K Silva, Alexa Ren, Wenhua Pan, Zenggang Wang, Jing H eng R01 CA/CA/NCI NIH HHS/ Italy Haematologica. Mar;103(3):466-476. doi: 10./haematol... Epub Dec 7.I SomaScan 12/09/ Pannerec A, et al. Vitamin B12 deficiency and impaired expression of amnionless during aging J Cachexia Sarcopenia Muscle 9 1 41-52 https://www.doi.org/10./jcsm. 29,159,972 Adult Aged Aged, 80 and over Aging Animals Biomarkers/*blood Female Humans Longitudinal Studies Male Membrane Proteins Methylmalonic Acid/*blood Middle Aged Proteins/*metabolism Rats Rats, Wistar Vitamin B 12/*blood Vitamin B 12 Deficiency/*physiopathology Amnionless Cobalamin Frailty Methylmalonic acid Sarcopenia Vitamin B12 BACKGROUND: Physical frailty and loss of mobility in elderly individuals lead to reduced independence, quality of life, and increased mortality. Vitamin B12 deficiency has been linked to several age-related chronic diseases, including in the musculo-skeletal system, where vitamin B12 deficiency is generally believed to be linked to poor nutritional intake. In the present study, we asked whether aging and frailty associate with altered vitamin B12 homeostasis in humans and investigated the underlying molecular mechanisms using preclinical models. METHODS: We analysed a subset of the Singapore Longitudinal Aging Study and stratified 238 participants based on age and Fried frailty criteria. Levels of methyl-malonic acid (MMA), a marker for vitamin B12 deficiency, and amnionless, the vitamin B12 co-receptor that anchors the vitamin B12 transport complex to the membrane of epithelial cells, were measured in plasma. In addition, vitamin B12 levels and the molecular mechanisms of vitamin B12 uptake and excretion were analysed in ileum, kidney, liver, and blood using a rat model of natural aging where nutritional intake is fully controlled. RESULTS: We demonstrate that aging and frailty are associated with a higher prevalence of functional vitamin B12 deficiency that can be detected by increased levels of MMA in blood (rho = 0.25; P = 0.). The decline in circulating vitamin B12 levels is recapitulated in a rat model of natural aging where food composition and intake are stable. At the molecular level, these perturbations involve altered expression of amnionless in the ileum and kidney. Interestingly, we demonstrate that amnionless can be detected in serum where its levels increase during aging in both rodents and human (P = 3.3e-07 and 9.2e-07, respectively). Blood amnionless levels negatively correlate with vitamin B12 in rats (r(2) = 0.305; P = 0.) and positively correlate with the vitamin B12 deficiency marker MMA in humans (rho = 0.22; P = 0.). CONCLUSIONS: Our results demonstrate that aging and frailty cause intrinsic vitamin B12 deficiencies, which can occur independently of nutritional intake. Mechanistically, vitamin B12 deficiency involves the physio-pathological decline of both the intestinal uptake and the renal reabsorption system for vitamin B12. Finally, amnionless is a novel biomarker which can detect perturbed vitamin B12 bioavailability during aging and physical frailty. Pannerec, Alice Migliavacca, Eugenia De Castro, Antonio Michaud, Joris Karaz, Sonia Goulet, Laurence Rezzi, Serge Ng, Tze Pin Bosco, Nabil Larbi, Anis Feige, Jerome N eng Germany J Cachexia Sarcopenia Muscle. Feb;9(1):41-52. doi: 10./jcsm.. Epub Nov 21.I SomaScan 11/22/ Thrush AB, et al. Diet-resistant obesity is characterized by a distinct plasma proteomic signature and impaired muscle fiber metabolism Int J Obes (Lond) 42 3 353-362 https://www.doi.org/10./ijo..286 29,151,592 Biomarkers/blood Blood Proteins/analysis/*metabolism Case-Control Studies Diet Exosomes/metabolism Female Humans Middle Aged Muscle Fibers, Skeletal/*metabolism Muscle, Skeletal/metabolism/physiopathology *Obesity/blood/diet therapy/epidemiology/metabolism Proteome/analysis/*metabolism Treatment Failure BACKGROUND/OBJECTIVES: Inter-individual variability in weight loss during obesity treatment is complex and poorly understood. Here we use whole body and tissue approaches to investigate fuel oxidation characteristics in skeletal muscle fibers, cells and distinct circulating protein biomarkers before and after a high fat meal (HFM) challenge in those who lost the most (obese diet-sensitive; ODS) vs the least (obese diet-resistant; ODR) amount of weight in a highly controlled weight management program. SUBJECTS/METHODS: In 20 weight stable-matched ODS and ODR women who previously completed a standardized clinical weight loss program, we analyzed whole-body energetics and metabolic parameters in vastus lateralis biopsies and plasma samples that were obtained in the fasting state and 6 h after a defined HFM, equivalent to 35% of total daily energy requirements. RESULTS: At baseline (fasting) and post-HFM, muscle fatty acid oxidation and maximal oxidative phosphorylation were significantly greater in ODS vs ODR, as was reactive oxygen species emission. Plasma proteomics of proteins pre and 1, 2, 5 and 6 h after the HFM demonstrated distinct group and interaction differences. Group differences identified S-formyl glutathione hydratase, heat shock 70 kDA protein 1A/B (HSP72), and eukaryotic translation initiation factor 5 (eIF5) to be higher in ODS vs ODR. Group-time differences included aryl hydrocarbon interacting protein (AIP), peptidylpropyl isomerase D (PPID) and tyrosine protein-kinase Fgr, which increased in ODR vs ODS over time. HSP72 levels correlated with muscle oxidation and citrate synthase activity. These proteins circulate in exosomes; exosomes isolated from ODS plasma increased resting, leak and maximal respiration rates in C2C12 myotubes by 58%, 21% and 51%, respectively, vs those isolated from ODR plasma. CONCLUSIONS: Findings demonstrate distinct muscle metabolism and plasma proteomics in fasting and post-HFM states corresponding in diet-sensitive vs diet-resistant obese women. Thrush, A B Antoun, G Nikpay, M Patten, D A DeVlugt, C Mauger, J-F Beauchamp, B L Lau, P Reshke, R Doucet, E Imbeault, P Boushel, R Gibbings, D Hager, J Valsesia, A Slack, R S Al-Dirbashi, O Y Dent, R McPherson, R Harper, M-E eng MOP/CIHR/Canada MOP/CIHR/Canada Research Support, Non-U.S. Gov't England Int J Obes (Lond). Mar;42(3):353-362. doi: 10./ijo..286. Epub Nov 20.I SomaScan 11/21/ Vilar-Gomez E, et al. Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers J Hepatol 68 2 305-315 https://www.doi.org/10./j.jhep..11.013 29,154,965 Biomarkers/*blood Decision Support Techniques Humans *Liver Cirrhosis/blood/diagnosis/etiology *Non-alcoholic Fatty Liver Disease/blood/complications/diagnosis Prognosis Apri Fib-4 Nafld Nash The correct identification of patients at increased risk of non-alcoholic steatohepatitis (NASH) and advanced fibrosis is a critical step in the assessment of non-alcoholic fatty liver disease (NAFLD). Since liver biopsy is invasive, expensive and prone to sampling error, several clinical prediction rules and blood-based biomarkers have been developed as attractive and affordable alternatives for identification of patients at high risk of NASH and advanced fibrosis. Current biomarkers constitute predictive models (e.g. NAFLD fibrosis score, FIB-4 index and BARD score) or direct measures of inflammation (e.g. circulating keratin 18 fragments), or fibrosis (e.g. FibroTest(R), ELF or Pro-C3 tests). In the clinical setting, biomarkers may discriminate between patients with NASH or advanced fibrosis, predict dynamic changes in NASH/fibrosis over time, and provide long-term prognostic information. Although clinically useful, current biomarker predictions may be influenced by hepatic and extrahepatic conditions (e.g. age, patient comorbidities, and fibrosis or NASH prevalence), which may lead to inaccurate estimates in small subsamples of patients. No highly sensitive and specific tests are available to differentiate NASH from simple steatosis. However, diagnostic accuracy can be improved by combining blood biomarkers. NAFLD fibrosis score and FIB-4 index are both cost-effective and highly sensitive tools to exclude patients with advanced fibrosis. Moreover, their higher scores may identify patients at higher risk of non-liver- and liver-related morbidity and mortality. More expensive tests such as FibroTest or ELF are more specific for detection of patients with significant and advanced fibrosis. Recent efforts have concentrated on omics" approaches for developing and validating novel biomarkers. Herein, we describe currently available clinical prediction rules and blood-based biomarkers for identifying NASH and advanced fibrosis in patients with NAFLD, discussing their advantages and disadvantages, as well as their potential clinical utility for predicting dynamic changes over time and identifying patients at increased risk of adverse outcomes." Vilar-Gomez, Eduardo Chalasani, Naga eng Review Netherlands J Hepatol. Feb;68(2):305-315. doi: 10./j.jhep..11.013. Epub Dec 2.I SomaScan 11/21/ Wermuth PJ, et al. Identification of novel systemic sclerosis biomarkers employing aptamer proteomic analysis Rheumatology (Oxford) 57 10 - https://www.doi.org/10./rheumatology/kex404 29,140,474 Biomarkers/analysis Humans Proteomics/*methods Scleroderma, Systemic/*diagnosis There is an important unmet need for clinically validated non-invasive biomarkers for SSc diagnosis, assessment of disease activity, extent of internal organ involvement, therapeutic response and prognosis. There is also an unmet need for biomarkers to accurately differentiate primary RP from recent onset RP evolving into SSc. The lack of sensitive and specific biomarkers for SSc and SSc-associated RP is a limitation for the optimal clinical management of these patients. The development of highly sensitive and specific proteomic analysis employing aptamers and the expansion in the number of proteins that can be specifically identified by aptamer proteomics have opened new horizons for biomarker discovery. Here, we review the background and rationale for aptamer proteomic analysis for the identification of novel non-invasive biomarkers for SSc and recent onset RP evolving into SSc. Large scale application of aptamer proteomic platforms for this purpose will be of substantial value for the precision and personalized medical care of SSc patients. These studies will be placed in context by comparison with proteomic biomarker studies performed for other rheumatological inflammatory and autoimmune diseases. Wermuth, Peter J Piera-Velazquez, Sonsoles Jimenez, Sergio A eng Review England Rheumatology (Oxford). Oct 1;57(10):-. doi: 10./rheumatology/kex404.I SomaScan 11/16/ Forster K, et al. Early Identification of Bronchopulmonary Dysplasia Using Novel Biomarkers by Proteomic Screening Am J Respir Crit Care Med 197 8 - https://www.doi.org/10./rccm.-LE 29,053,024 Age Factors Biomarkers/*blood Bronchopulmonary Dysplasia/*blood/*diagnosis *Early Diagnosis Female Gestational Age Humans Infant, Newborn Infant, Premature/*blood Male Proteomics/*methods Forster, Kai Sass, Steffen Ehrhardt, Harald Mous, Daphne S Rottier, Robbert J Oak, Prajakta Schulze, Andreas Flemmer, Andreas W Gronbach, Judith Hubener, Christoph Desai, Tushar Eickelberg, Oliver Theis, Fabian J Hilgendorff, Anne eng Comparative Study Letter Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. Apr 15;197(8):-. doi: 10./rccm.-LE.I SomaScan 10/21/ Williams SA, et al. Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib Circulation 137 10 999- https://www.doi.org/10./CIRCULATIONAHA.117. 28,974,520 Aged Aldosterone/metabolism Anticholesteremic Agents/*adverse effects/therapeutic use Biomarkers, Pharmacological Case-Control Studies Cholesterol Ester Transfer Proteins/antagonists & inhibitors Drug-Related Side Effects and Adverse Reactions/*metabolism/mortality Early Diagnosis Female Heart Failure/etiology/*metabolism/mortality Humans Male Middle Aged Myocardial Infarction/etiology/*metabolism/mortality Prognosis Prospective Studies Proteomics Quinolines/*adverse effects/therapeutic use Stroke/etiology/*metabolism/mortality Survival Analysis aptamers biomarkers peptides precision medicine prescription drugs proteins BACKGROUND: Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics. METHODS: A nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death. RESULTS: Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk. CONCLUSIONS: Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT. Williams, Stephen A Murthy, Ashwin C DeLisle, Robert K Hyde, Craig Malarstig, Anders Ostroff, Rachel Weiss, Sophie J Segal, Mark R Ganz, Peter eng R01 AG/AG/NIA NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. Mar 6;137(10):999-. doi: 10./CIRCULATIONAHA.117.. Epub Oct 3.I SomaScan 10/05/ Hussein AI, et al. Serum proteomic assessment of the progression of fracture healing J Orthop Res 36 4 - https://www.doi.org/10./jor. 28,971,515 Animals Biomarkers/*blood Bone and Bones/pathology Femoral Fractures/diagnostic imaging/pathology *Fracture Healing Male Mice, Inbred C57BL *Proteome Radiography animal models: preclinical studies fracture healing microarray serum biomarkers A targeted proteomic analysis of murine serum over a 35-day course of fracture healing was carried out to determine if serum proteomic changes could be used to monitor the biological progression of fracture healing. Transverse, closed femoral fractures where generated and stabilized with intramedullary fixation. A single stranded DNA aptamer-based multiplexed proteomic approach was used to assay 1,310 proteins. The transcriptomic profiles for genes matching the 1,310 proteins were obtained by microarray analysis of callus mRNA. Of the 1,310 proteins analyzed, 850 proteins showed significant differences among the time points (p-value <0.05). Ontology assessment associated these proteins with osteoblasts, monocyte/macrophage lineages, mesenchymal stem cell lines, hepatic tissues, and lymphocytes. Temporal clustering of these data identified proteins associated with inflammation, cartilage formation and bone remodeling stages of healing. VEGF, Wnt, and TGF-betasignaling pathways were restricted to the period of cartilage formation. Comparison of the proteomic and transcriptomic profiles showed that 87.5% of proteins in serum had concordant expression to their mRNA expression in the callus, while 12.5% of the protein and mRNA expression patterns were discordant. The discordant proteins that were elevated in the serum but down regulated in callus mRNA expression were related to clotting functions, allograft rejection, and complement function. While proteins down regulated in the serum and elevated in callus mRNA were associated with osteoblast function, NF-kb, and activin signaling. These data show the serum proteome may be used to monitor the different biological stages of fracture healing and have translational potential in assessing human fracture healing. (c) Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:-, . Hussein, Amira I Mancini, Christian Lybrand, Kyle E Cooke, Margaret E Matheny, Heather E Hogue, Brenna L Tornetta, Paul 3rd Gerstenfeld, Louis C eng R01 AR/AR/NIAMS NIH HHS/ R21 AR/AR/NIAMS NIH HHS/ TL1 TR/TR/NCATS NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural J Orthop Res. Apr;36(4):-. doi: 10./jor.. Epub Nov 22.I SomaScan 10/04/ Silkoff PE, et al. Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study J Allergy Clin Immunol 141 4 - https://www.doi.org/10./j.jaci..06.027 28,734,844 Adolescent Adult Aged Anti-Inflammatory Agents/*therapeutic use Antibodies, Monoclonal/*therapeutic use Asthma/diagnosis/*drug therapy/immunology/*virology Disease Progression Double-Blind Method Female Healthy Volunteers Humans Male Middle Aged Picornaviridae Infections/*complications/drug therapy/immunology *Rhinovirus Severity of Illness Index Toll-Like Receptor 3/*antagonists & inhibitors Treatment Outcome Young Adult Asthma Toll-like receptor 3 inflammation viral infection BACKGROUND: Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. OBJECTIVE: We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO, on experimental HRV-16 inoculation in healthy subjects and asthmatic patients. METHODS: In this double-blind, multicenter, randomized, parallel-group study in North America and Europe, healthy subjects and patients with mild-to-moderate stable asthma received single or multiple doses of CNTO or placebo, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV(1) during 10 days after inoculation. RESULTS: In asthmatic patients (n = 63) CNTO provided no protection against FEV(1) decrease (least squares mean: CNTO [n = 30] = -7.08% [SE, 8.15%]; placebo [n = 25] = -5.98% [SE, 8.56%]) or symptoms after inoculation. In healthy subjects (n = 12) CNTO versus placebo significantly attenuated upper (P = .03) and lower (P = .02) airway symptom scores, with area-under-the-curve increases of 9.1 (15.1) versus 34.9 (17.6) and 13.0 (18.4) versus 50.4 (25.9) for the CNTO (n = 8) and placebo (n = 4) groups, respectively, after inoculation. All of the severe and 4 of the nonserious asthma exacerbations occurred while receiving CNTO. CONCLUSION: In summary, CNTO was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought for this high unmet medical need. Silkoff, Philip E Flavin, Susan Gordon, Robert Loza, Mathew J Sterk, Peter J Lutter, Rene Diamant, Zuzana Turner, Ronald B Lipworth, Brian J Proud, David Singh, Dave Eich, Andreas Backer, Vibeke Gern, James E Herzmann, Christian Halperin, Scott A Mensinga, Tjeert T Del Vecchio, Alfred M Branigan, Patrick San Mateo, Lani Baribaud, Frederic Barnathan, Elliot S Johnston, Sebastian L eng G/MRC_/Medical Research Council/United Kingdom Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't J Allergy Clin Immunol. Apr;141(4):-. doi: 10./j.jaci..06.027. Epub Jul 20.I SomaScan 07/25/ Wagner BD, et al. Proteomic Profiles Associated with Early Echocardiogram Evidence of Pulmonary Vascular Disease in Preterm Infants Am J Respir Crit Care Med 197 3 394-397 https://www.doi.org/10./rccm.-LE 28,650,220 Biomarkers/blood Bronchopulmonary Dysplasia/*blood/diagnostic imaging/physiopathology Cohort Studies Echocardiography, Doppler/*methods Female Follow-Up Studies Humans Hypertension, Pulmonary/*blood/diagnostic imaging/physiopathology Infant, Newborn *Infant, Premature Male Prospective Studies Proteomics Risk Assessment Vascular Diseases/*blood/diagnostic imaging Wagner, Brandie D Babinec, Ana E Carpenter, Charlie Gonzalez, Samantha O'Brien, Grace Rollock, Kara Williamson, Kayla Mourani, Peter M Abman, Steven H eng R01 HL/HL/NHLBI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ K23 RR/RR/NCRR NIH HHS/ R25 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ Observational Study Research Support, N.I.H., Extramural Am J Respir Crit Care Med. Feb 1;197(3):394-397. doi: 10./rccm.-LE.I SomaScan 06/27/ Rossios C, et al. Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma J Allergy Clin Immunol 141 2 560-570 https://www.doi.org/10./j.jaci..02.045 28,528,200 Adult Animals Asthma/*immunology/pathology Eosinophils/immunology/pathology Female *Gene Expression Profiling Humans Male Mice Middle Aged Neutrophils/immunology/pathology Receptors, Interleukin-1/*immunology Sputum/*immunology Th2 Cells/immunology/pathology Up-Regulation/*immunology C-reactive protein IL-1alpha IL-1beta IL-33 receptor Severe asthma T(h)2 eosinophil exhaled nitric oxide inflammasome neutrophil BACKGROUND: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1beta protein levels, whereas eosinophilic asthma was associated with an IL-13-induced T(H)2 signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma. CONCLUSION: IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. T(H)2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA. Rossios, Christos Pavlidis, Stelios Hoda, Uruj Kuo, Chih-Hsi Wiegman, Coen Russell, Kirsty Sun, Kai Loza, Matthew J Baribaud, Frederic Durham, Andrew L Ojo, Oluwaseun Lutter, Rene Rowe, Anthony Bansal, Aruna Auffray, Charles Sousa, Ana Corfield, Julie Djukanovic, Ratko Guo, Yike Sterk, Peter J Chung, Kian Fan Adcock, Ian M (U-BIOPRED) eng G/MRC_/Medical Research Council/United Kingdom Department of Health/United Kingdom Clinical Trial Multicenter Study Research Support, Non-U.S. Gov't J Allergy Clin Immunol. Feb;141(2):560-570. doi: 10./j.jaci..02.045. Epub May 18.I SomaScan 05/22/ Oller Moreno S, et al. The differential plasma proteome of obese and overweight individuals undergoing a nutritional weight loss and maintenance intervention Proteomics Clin Appl 12 1 https://www.doi.org/10./prca. 28,371,297 Adiponectin/blood/genetics Adult Biomarkers/blood Blood Proteins/*genetics/metabolism Body Mass Index C-Reactive Protein/genetics/metabolism Diet, Reducing/methods Female Humans *Insulin Resistance Leukocyte L1 Antigen Complex/blood/genetics Longitudinal Studies Male Middle Aged Obesity/blood/*diet therapy/genetics/pathology Pregnancy Proteins/blood/genetics Proteoglycans/blood/genetics Proteome/*genetics/metabolism Serum Amyloid A Protein/genetics/metabolism Sex Hormone-Binding Globulin/genetics/metabolism Tandem Mass Spectrometry Weight Loss/physiology Weight Reduction Programs/*methods Biomarker Diabetes Large-scale study Mass spectrometry Obesity PURPOSE: The nutritional intervention program DiOGenes" focuses on how obesity can be prevented and treated from a dietary perspective. We generated differential plasma proteome profiles in the DiOGenes cohort to identify proteins associated with weight loss and maintenance and explore their relation to body mass index, fat mass, insulin resistance, and sensitivity. EXPERIMENTAL DESIGN: Relative protein quantification was obtained at baseline and after combined weight loss/maintenance phases using isobaric tagging and MS/MS. A Welch t-test determined proteins differentially present after intervention. Protein relationships with clinical variables were explored using univariate linear models, considering collection center, gender and age as confounding factors. RESULTS: Four hundred and seventy three subjects were measured at baseline and end of the intervention; 39 proteins were longitudinally differential. Proteins with largest changes were sex hormone-binding globulin, adiponectin, C-reactive protein, calprotectin, serum amyloid A, and proteoglycan 4 (PRG4), whose association with obesity and weight loss is known. We identified new putative biomarkers for weight loss/maintenance. Correlation between PRG4 and proline-rich acidic protein 1 variation and Matsuda insulin sensitivity increment was showed. CONCLUSION AND CLINICAL RELEVANCE: MS-based proteomic analysis of a large cohort of non-diabetic overweight and obese individuals concomitantly identified known and novel proteins associated with weight loss and maintenance." Oller Moreno, Sergio Cominetti, Ornella Nunez Galindo, Antonio Irincheeva, Irina Corthesy, John Astrup, Arne Saris, Wim H M Hager, Jorg Kussmann, Martin Dayon, Loic eng Clinical Trial Multicenter Study Research Support, Non-U.S. Gov't Germany Proteomics Clin Appl. Jan;12(1). doi: 10./prca.. Epub May 15.I SomaScan 04/04/ Carayol J, et al. Protein quantitative trait locus study in obesity during weight-loss identifies a leptin regulator Nat Commun 8 1 https://www.doi.org/10./s-017--z 29,234,017 Adolescent Adult *Body Mass Index Female Gene Regulatory Networks Humans Leptin/*genetics/metabolism Male Middle Aged Obesity/diet therapy/*genetics/metabolism Polynucleotide Adenylyltransferase Proteins/genetics/*metabolism Proteomics/methods *Quantitative Trait Loci Regulatory Elements, Transcriptional Weight Loss/genetics Young Adult Thousands of genetic variants have been associated with complex traits through genome-wide association studies. However, the functional variants or mechanistic consequences remain elusive. Intermediate traits such as gene expression or protein levels are good proxies of the metabolic state of an organism. Proteome analysis especially can provide new insights into the molecular mechanisms of complex traits like obesity. The role of genetic variation in determining protein level variation has not been assessed in obesity. To address this, we design a large-scale protein quantitative trait locus (pQTL) analysis based on a set of proteins from 494 obese subjects before and after a weight loss intervention. This reveals 55 BMI-associated cis-pQTLs and trans-pQTLs at baseline and 3 trans-pQTLs after the intervention. We provide evidence for distinct genetic mechanisms regulating BMI-associated proteins before and after weight loss. Finally, by functional analysis, we identify and validate FAM46A as a trans regulator for leptin. Carayol, Jerome Chabert, Christian Di Cara, Alessandro Armenise, Claudia Lefebvre, Gregory Langin, Dominique Viguerie, Nathalie Metairon, Sylviane Saris, Wim H M Astrup, Arne Descombes, Patrick Valsesia, Armand Hager, Jorg eng Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't England Nat Commun. Dec 12;8(1):. doi: 10./s-017--z.I SomaScan 12/14/ Coghlan RF, et al. A degradation fragment of type X collagen is a real-time marker for bone growth velocity Sci Transl Med 9 419 https://www.doi.org/10./scitranslmed.aan 29,212,713 Adult Animals Bone Development/*physiology Collagen Type X/*metabolism Enzyme-Linked Immunosorbent Assay Female Fracture Healing/*physiology Humans Male Mice Young Adult Despite its importance as a key parameter of child health and development, growth velocity is difficult to determine in real time because skeletal growth is slow and clinical tools to accurately detect very small increments of growth do not exist. We report discovery of a marker for skeletal growth in infants and children. The intact trimeric noncollagenous 1 (NC1) domain of type X collagen, the marker we designated as CXM for Collagen X Marker, is a degradation by-product of endochondral ossification that is released into the circulation in proportion to overall growth plate activity. This marker corresponds to the rate of linear bone growth at time of measurement. Serum concentrations of CXM plotted against age show a pattern similar to well-established height growth velocity curves and correlate with height growth velocity calculated from incremental height measurements in this study. The CXM marker is stable once collected and can be accurately assayed in serum, plasma, and dried blood spots. CXM testing may be useful for monitoring growth in the pediatric population, especially responses of infants and children with genetic and acquired growth disorders to interventions that target the underlying growth disturbances. The utility of CXM may potentially extend to managing other conditions such as fracture healing, scoliosis, arthritis, or cancer. Coghlan, Ryan F Oberdorf, Jon A Sienko, Susan Aiona, Michael D Boston, Bruce A Connelly, Kara J Bahney, Chelsea LaRouche, Jeremie Almubarak, Sarah M Coleman, Daniel T Girkontaite, Irute von der Mark, Klaus Lunstrum, Gregory P Horton, William A eng Sci Transl Med. Dec 6;9(419):eaan. doi: 10./scitranslmed.aan.I SomaScan 12/08/ Skarke C, et al. A Pilot Characterization of the Human Chronobiome Sci Rep 7 1 https://www.doi.org/10./s-017--6 29,215,023 Adult Blood Pressure Blood Proteins/metabolism *Circadian Rhythm Heart Rate Humans Hydrocortisone/metabolism Male *Metabolome *Microbiota Mouth/metabolism Pilot Projects *Proteome Saliva/metabolism Time Factors *Transcriptome Physiological function, disease expression and drug effects vary by time-of-day. Clock disruption in mice results in cardio-metabolic, immunological and neurological dysfunction; circadian misalignment using forced desynchrony increases cardiovascular risk factors in humans. Here we integrated data from remote sensors, physiological and multi-omics analyses to assess the feasibility of detecting time dependent signals - the chronobiome - despite the noise" attributable to the behavioral differences of free-living human volunteers. The majority (62%) of sensor readouts showed time-specific variability including the expected variation in blood pressure, heart rate, and cortisol. While variance in the multi-omics is dominated by inter-individual differences, temporal patterns are evident in the metabolome (5.4% in plasma, 5.6% in saliva) and in several genera of the oral microbiome. This demonstrates, despite a small sample size and limited sampling, the feasibility of characterizing at scale the human chronobiome "in the wild". Such reference data at scale are a prerequisite to detect and mechanistically interpret discordant data derived from patients with temporal patterns of disease expression, to develop time-specific therapeutic strategies and to refine existing treatments." Skarke, Carsten Lahens, Nicholas F Rhoades, Seth D Campbell, Amy Bittinger, Kyle Bailey, Aubrey Hoffmann, Christian Olson, Randal S Chen, Lihong Yang, Guangrui Price, Thomas S Moore, Jason H Bushman, Frederic D Greene, Casey S Grant, Gregory R Weljie, Aalim M FitzGerald, Garret A eng P30 ES/ES/NIEHS NIH HHS/ UL1 RR/RR/NCRR NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. Dec 7;7(1):. doi: 10./s-017--6.I SomaScan 12/08/ Lertudomphonwanit C, et al. Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia Sci Transl Med 9 417 https://www.doi.org/10./scitranslmed.aan 29,167,395 Animals Biliary Atresia/*metabolism/pathology Biomarkers/metabolism Cholestasis/metabolism/pathology Disease Models, Animal Humans Matrix Metalloproteinase 7/genetics/*metabolism Proteomics/*methods Biliary atresia is a progressive infantile cholangiopathy of complex pathogenesis. Although early diagnosis and surgery are the best predictors of treatment response, current diagnostic approaches are imprecise and time-consuming. We used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia and other cholestatic syndromes (serving as disease controls) to identify biomarkers of disease. In a discovery cohort of 70 subjects, the lead biomarker was matrix metalloproteinase-7 (MMP-7), which retained high distinguishing features for biliary atresia in two validation cohorts. Notably, the diagnostic performance reached 95% when MMP-7 was combined with gamma-glutamyltranspeptidase (GGT), a marker of cholestasis. Using human tissue and an experimental model of biliary atresia, we found that MMP-7 is primarily expressed by cholangiocytes, released upon epithelial injury, and promotes the experimental disease phenotype. Thus, we propose that serum MMP-7 (alone or in combination with GGT) is a diagnostic biomarker for biliary atresia and may serve as a therapeutic target. Lertudomphonwanit, Chatmanee Mourya, Reena Fei, Lin Zhang, Yue Gutta, Sridevi Yang, Li Bove, Kevin E Shivakumar, Pranavkumar Bezerra, Jorge A eng P30 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ R01 DK/DK/NIDDK NIH HHS/ U01 DK/DK/NIDDK NIH HHS/ Sci Transl Med. Nov 22;9(417):eaan. doi: 10./scitranslmed.aan.I SomaScan 11/24/ Scriba TJ, et al. Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease PLoS Pathog 13 11 e https://www.doi.org/10./journal.ppat. 29,145,483 Adolescent Child Disease Progression Humans Inflammation/complications/immunology/therapy *Mycobacterium tuberculosis T-Lymphocytes/*immunology Tuberculosis/*microbiology/*therapy Vaccines/therapeutic use Our understanding of mechanisms underlying progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease in humans remains limited. To define such mechanisms, we followed M. tuberculosis-infected adolescents longitudinally. Blood samples from forty-four adolescents who ultimately developed tuberculosis disease (progressors") were compared with those from 106 matched controls, who remained healthy during two years of follow up. We performed longitudinal whole blood transcriptomic analyses by RNA sequencing and plasma proteome analyses using multiplexed slow off-rate modified DNA aptamers. Tuberculosis progression was associated with sequential modulation of immunological processes. Type I/II interferon signalling and complement cascade were elevated 18 months before tuberculosis disease diagnosis, while changes in myeloid inflammation, lymphoid, monocyte and neutrophil gene modules occurred more proximally to tuberculosis disease. Analysis of gene expression in purified T cells also revealed early suppression of Th17 responses in progressors, relative to M. tuberculosis-infected controls. This was confirmed in an independent adult cohort who received BCG re-vaccination; transcript expression of interferon response genes in blood prior to BCG administration was associated with suppression of IL-17 expression by BCG-specific CD4 T cells 3 weeks post-vaccination. Our findings provide a timeline to the different immunological stages of disease progression which comprise sequential inflammatory dynamics and immune alterations that precede disease manifestations and diagnosis of tuberculosis disease. These findings have important implications for developing diagnostics, vaccination and host-directed therapies for tuberculosis. TRIAL REGISTRATION: Clincialtrials.gov, NCT." Scriba, Thomas J Penn-Nicholson, Adam Shankar, Smitha Hraha, Tom Thompson, Ethan G Sterling, David Nemes, Elisa Darboe, Fatoumatta Suliman, Sara Amon, Lynn M Mahomed, Hassan Erasmus, Mzwandile Whatney, Wendy Johnson, John L Boom, W Henry Hatherill, Mark Valvo, Joe De Groote, Mary Ann Ochsner, Urs A Aderem, Alan Hanekom, Willem A Zak, Daniel E eng D43 TW/TW/FIC NIH HHS/ N01AI/AI/NIAID NIH HHS/ R01 AI/AI/NIAID NIH HHS/ N01AI/AI/NIAID NIH HHS/ U19 AI/AI/NIAID NIH HHS/ Clinical Trial PLoS Pathog. Nov 16;13(11):e. doi: 10./journal.ppat.. eCollection Nov.I SomaScan 11/18/ Habiel DM, et al. Divergent roles for Clusterin in Lung Injury and Repair Sci Rep 7 1 https://www.doi.org/10./s-017--5 29,133,960 Aged Animals Apoptosis Bleomycin/adverse effects Case-Control Studies Cell Line Clusterin/blood/genetics/*metabolism Cytoplasm/metabolism DNA Breaks, Double-Stranded DNA Mismatch Repair Datasets as Topic Disease Models, Animal Epithelial Cells/pathology Extracellular Space/metabolism Female Fibrosis Gene Expression Profiling Gene Knockdown Techniques Humans Idiopathic Pulmonary Fibrosis/blood/chemically induced/genetics/*pathology Lung/drug effects/*pathology Male Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Pulmonary Disease, Chronic Obstructive/blood/*pathology RNA, Small Interfering/metabolism Respiratory Mucosa/cytology/pathology Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted epithelial cell apoptosis whereas intracellular Clusterin maintained epithelium viability during lung repair. Unlike normal and COPD lungs, IPF lungs were characterized by significantly increased extracellular Clusterin whereas the inverse was evident for intracellular Clusterin. In vitro and in vivo studies demonstrated that extracellular Clusterin promoted epithelial cell apoptosis while intercellular Clusterin modulated the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1. The fibrotic response in Clusterin deficient (CLU-/-) mice persisted after bleomycin and it was associated with increased DNA damage, reduced DNA repair responses, and elevated cellular senescence. Remarkably, this pattern mirrored that observed in IPF lung tissues. Together, our results show that cellular localization of Clusterin leads to divergent effects on epithelial cell regeneration and lung repair during fibrosis. Habiel, David M Camelo, Ana Espindola, Milena Burwell, Timothy Hanna, Richard Miranda, Elena Carruthers, Alan Bell, Matthew Coelho, Ana Lucia Liu, Hao Pilataxi, Fernanda Clarke, Lori Grant, Ethan Lewis, Arthur Moore, Bethany Knight, Darryl A Hogaboam, Cory M Murray, Lynne A eng R01 HL/HL/NHLBI NIH HHS/ RC2 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. Nov 13;7(1):. doi: 10./s-017--5.I SomaScan 11/15/ Sullivan KD, et al. Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation Sci Rep 7 1 https://www.doi.org/10./s-017--3 29,093,484 Adolescent Adult Child Child, Preschool Chronic Disease Complement System Proteins/analysis Cytokines/blood Down Syndrome/*blood/complications Female Humans Infant Inflammation/*blood/complications Male Proteome/*analysis Receptors, Growth Factor/blood Trisomy Young Adult Trisomy 21 (T21) causes Down syndrome (DS), but the mechanisms by which T21 produces the different disease spectrum observed in people with DS are unknown. We recently identified an activated interferon response associated with T21 in human cells of different origins, consistent with overexpression of the four interferon receptors encoded on chromosome 21, and proposed that DS could be understood partially as an interferonopathy. However, the impact of T21 on systemic signaling cascades in living individuals with DS is undefined. To address this knowledge gap, we employed proteomics approaches to analyze blood samples from 263 individuals, 165 of them with DS, leading to the identification of dozens of proteins that are consistently deregulated by T21. Most prominent among these proteins are numerous factors involved in immune control, the complement cascade, and growth factor signaling. Importantly, people with DS display higher levels of many pro-inflammatory cytokines (e.g. IL-6, MCP-1, IL-22, TNF-alpha) and pronounced complement consumption, resembling changes seen in type I interferonopathies and other autoinflammatory conditions. Therefore, these results are consistent with the hypothesis that increased interferon signaling caused by T21 leads to chronic immune dysregulation, and justify investigations to define the therapeutic value of immune-modulatory strategies in DS. Sullivan, Kelly D Evans, Donald Pandey, Ahwan Hraha, Thomas H Smith, Keith P Markham, Neil Rachubinski, Angela L Wolter-Warmerdam, Kristine Hickey, Francis Espinosa, Joaquin M Blumenthal, Thomas eng Research Support, Non-U.S. Gov't England Sci Rep. Nov 1;7(1):. doi: 10./s-017--3.I SomaScan 11/03/ Candia J, et al. Assessment of Variability in the SOMAscan Assay Sci Rep 7 1 https://www.doi.org/10./s-017--5 29,079,756 Adult Aptamers, Nucleotide/*metabolism Blood Proteins/*metabolism Calibration Female Humans Male Middle Aged Proteomics/*methods Reproducibility of Results SOMAscan is an aptamer-based proteomics assay capable of measuring 1,305 human protein analytes in serum, plasma, and other biological matrices with high sensitivity and specificity. In this work, we present a comprehensive meta-analysis of performance based on multiple serum and plasma runs using the current 1.3 k assay, as well as the previous 1.1 k version. We discuss normalization procedures and examine different strategies to minimize intra- and interplate nuisance effects. We implement a meta-analysis based on calibrator samples to characterize the coefficient of variation and signal-over-background intensity of each protein analyte. By incorporating coefficient of variation estimates into a theoretical model of statistical variability, we also provide a framework to enable rigorous statistical tests of significance in intervention studies and clinical trials, as well as quality control within and across laboratories. Furthermore, we investigate the stability of healthy subject baselines and determine the set of analytes that exhibit biologically stable baselines after technical variability is factored in. This work is accompanied by an interactive web-based tool, an initiative with the potential to become the cornerstone of a regularly updated, high quality repository with data sharing, reproducibility, and reusability as ultimate goals. Candia, Julian Cheung, Foo Kotliarov, Yuri Fantoni, Giovanna Sellers, Brian Griesman, Trevor Huang, Jinghe Stuccio, Sarah Zingone, Adriana Ryan, Brid M Tsang, John S Biancotto, Angelique eng Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural England Sci Rep. Oct 27;7(1):. doi: 10./s-017--5.I SomaScan 10/29/ Barbour C, et al. Molecular-based diagnosis of multiple sclerosis and its progressive stage Ann Neurol 82 5 795-812 https://www.doi.org/10./ana. 29,059,494 Adolescent Adult Aged Biomarkers/cerebrospinal fluid Case-Control Studies Cell Line Cerebrospinal Fluid Proteins/*metabolism Diagnosis, Differential Female Humans Male Middle Aged Multiple Sclerosis, Chronic Progressive/*cerebrospinal fluid/*diagnosis Multiple Sclerosis, Relapsing-Remitting/*cerebrospinal fluid/*diagnosis Young Adult OBJECTIVE: Biomarkers aid diagnosis, allow inexpensive screening of therapies, and guide selection of patient-specific therapeutic regimens in most internal medicine disciplines. In contrast, neurology lacks validated measurements of the physiological status, or dysfunction(s) of cells of the central nervous system (CNS). Accordingly, patients with chronic neurological diseases are often treated with a single disease-modifying therapy without understanding patient-specific drivers of disability. Therefore, using multiple sclerosis (MS) as an example of a complex polygenic neurological disease, we sought to determine whether cerebrospinal fluid (CSF) biomarkers are intraindividually stable, cell type-, disease- and/or process-specific, and responsive to therapeutic intervention. METHODS: We used statistical learning in a modeling cohort (n = 225) to develop diagnostic classifiers from DNA-aptamer-based measurements of 1,128 CSF proteins. An independent validation cohort (n = 85) assessed the reliability of derived classifiers. The biological interpretation resulted from in vitro modeling of primary or stem cell-derived human CNS cells and cell lines. RESULTS: The classifier that differentiates MS from CNS diseases that mimic MS clinically, pathophysiologically, and on imaging achieved a validated area under the receiver operating characteristic curve (AUROC) of 0.98, whereas the classifier that differentiates relapsing-remitting from progressive MS achieved a validated AUROC of 0.91. No classifiers could differentiate primary progressive from secondary progressive MS better than random guessing. Treatment-induced changes in biomarkers greatly exceeded intraindividual and technical variabilities of the assay. INTERPRETATION: CNS biological processes reflected by CSF biomarkers are robust, stable, disease specific, or even disease stage specific. This opens opportunities for broad utilization of CSF biomarkers in drug development and precision medicine for CNS disorders. Ann Neurol ;82:795-812. Barbour, Christopher Kosa, Peter Komori, Mika Tanigawa, Makoto Masvekar, Ruturaj Wu, Tianxia Johnson, Kory Douvaras, Panagiotis Fossati, Valentina Herbst, Ronald Wang, Yue Tan, Keith Greenwood, Mark Bielekova, Bibiana eng Z99 NS/Intramural NIH HHS/ ZIA NS-02/Intramural NIH HHS/ Ann Neurol. Nov;82(5):795-812. doi: 10./ana..I SomaScan 10/24/ Ali A, et al. Efficacy of individualised diets in patients with irritable bowel syndrome: a randomised controlled trial BMJ Open Gastroenterol 4 1 e https://www.doi.org/10./bmjgast-- 29,018,540 Dietary Factors Irritable Bowel Syndrome Quality Of Life BACKGROUND: Patients with irritable bowel syndrome (IBS) are often placed on diets guided by food intolerance assays, although these have not been validated. We assessed the effects of individualised diets in patients with IBS guided by a leucocyte activation test. METHODS: This is a parallel-group, double-blind, randomised controlled trial of 58 adults with IBS seen at an academic health centre in Northeast USA. Peripheral venous blood was analysed using a leucocyte activation test; individual foods were reported to produce positive or negative results. Participants were randomised to a 4-week diet with either individualised guidance to eliminate foods with positive assay results and allow foods with negative assay results (intervention), or with individualised guidance, matched in rigour and complexity, to eliminate foods with negative assay results and allow foods with positive assay results (comparison). The primary outcome was between-group differences in the IBS Global Improvement Scale (GIS). Secondary outcomes included reductions in IBS Symptom Severity Scale (SSS) scores and increases in IBS Adequate Relief (AR) and Quality of Life (QOL) scores. An aptamer-based proteomic analysis was conducted in strong responders. RESULTS: The intervention group had significantly greater increases in mean GIS score after 4 weeks (0.86 vs comparison; 95% CI 0.05 to 1.67; p=0.04) and 8 weeks (1.22 vs comparison; 95% CI 0.22 to 2.22; p=0.02). The intervention group also had significantly greater reductions in mean SSS score at 4 weeks (-61.78 vs comparison; 95% CI -4.43 to -119.14; p=0.04) and 8 weeks (-66.42 vs comparison; 95% CI -5.75 to -127.09; p=0.03). There were no significant differences between intervention and comparison groups in mean AR or QOL scores. A reduction in neutrophil elastase concentration was associated with reduced symptoms. CONCLUSIONS: Elimination diets guided by leucocyte activation tests reduced symptoms. These findings could lead to insights into the pathophysiology of IBS. TRIAL REGISTRATION NUMBER: NCT. Ali, Ather Weiss, Theresa R McKee, Douglas Scherban, Alisa Khan, Sumiya Fields, Maxine R Apollo, Damian Mehal, Wajahat Z eng UL1 TR/TR/NCATS NIH HHS/ England BMJ Open Gastroenterol. Sep 20;4(1):e. doi: 10./bmjgast--. eCollection .I SomaScan 10/12/ Ren X, et al. Structural basis for IL-1alpha recognition by a modified DNA aptamer that specifically inhibits IL-1alpha signaling Nat Commun 8 1 810 https://www.doi.org/10./s-017--2 28,993,621 Aptamers, Nucleotide/*chemistry/metabolism/*pharmacology Binding, Competitive Crystallography, X-Ray Deoxyuridine/chemistry Human Umbilical Vein Endothelial Cells Humans Hydrophobic and Hydrophilic Interactions Interleukin-1alpha/*chemistry/genetics/*metabolism Interleukin-1beta/metabolism Models, Molecular Receptors, Interleukin-1/metabolism SELEX Aptamer Technique Signal Transduction/drug effects IL-1alpha is an essential cytokine that contributes to inflammatory responses and is implicated in various forms of pathogenesis and cancer. Here we report a naphthyl modified DNA aptamer that specifically binds IL-1alpha and inhibits its signaling pathway. By solving the crystal structure of the IL-1alpha/aptamer, we provide a high-resolution structure of this critical cytokine and we reveal its functional interaction interface with high-affinity ligands. The non-helical aptamer, which represents a highly compact nucleic acid structure, contains a wealth of new conformational features, including an unknown form of G-quadruplex. The IL-1alpha/aptamer interface is composed of unusual polar and hydrophobic elements, along with an elaborate hydrogen bonding network that is mediated by sodium ion. IL-1alpha uses the same interface to interact with both the aptamer and its cognate receptor IL-1RI, thereby suggesting a novel route to immunomodulatory therapeutics.The cytokine interleukin 1alpha (IL-1alpha) plays an important role in inflammatory processes. Here the authors use SELEX to generate a modified DNA aptamer which specifically binds IL-1alpha, present the structure of the IL-1alpha/aptamer complex and show that this aptamer inhibits the IL-1alpha signaling pathway. Ren, Xiaoming Gelinas, Amy D von Carlowitz, Ira Janjic, Nebojsa Pyle, Anna Marie eng P41 GM/GM/NIGMS NIH HHS/ S10 RR/RR/NCRR NIH HHS/ HHMI/Howard Hughes Medical Institute/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Nat Commun. Oct 9;8(1):810. doi: 10./s-017--2.I SomaScan 10/11/ Spitsin S, et al. Antiinflammatory effects of aprepitant coadministration with cART regimen containing ritonavir in HIV-infected adults JCI Insight 2 19 https://www.doi.org/10./jci.insight. 28,978,797 Adult Aged Anti-HIV Agents/administration & dosage/adverse effects/blood/*therapeutic use Anti-Inflammatory Agents/administration & dosage/adverse effects/blood/*therapeutic use Aprepitant/administration & dosage/adverse effects/blood/*therapeutic use Drug Administration Schedule Drug Therapy, Combination Female HIV Infections/blood/*drug therapy/virology Humans Inflammation Mediators/metabolism Male Middle Aged Ritonavir/*therapeutic use Viral Load BACKGROUND: HIV-infected individuals, even well controlled with combined antiretroviral therapy (cART), have systemic inflammation and comorbidities. Substance P (SP) is an undecapeptide, which mediates neurotransmission and inflammation through its cognate neurokinin 1 receptor (NK1R). Plasma SP levels are elevated in HIV-infected individuals. The FDA-approved antiemetic aprepitant, an NK1R antagonist, has anti-HIV effects and antiinflammatory actions. We evaluated the safety, pharmacokinetics, and antiinflammatory properties of aprepitant in HIV-positive individuals receiving cART. METHODS: We conducted a phase 1B study of 12 HIV-positive individuals on a ritonavir-containing regimen (HIV viral load less than 40 copies/ml and CD4 > 400 cells/mul). Participants received open-label aprepitant 375 mg per day for 28 days and were followed for an additional 30 days. Changes in plasma levels of proinflammatory markers were assessed using flow cytometry, ELISA, luminex, and SOMAscan assays. RESULTS: The mean peak aprepitant plasma concentration was 30.7 +/- 15.3 mug/ml at day 14 and 23.3 +/- 12.3 mug/ml at day 28. Aprepitant treatment resulted in decreased plasma SP levels and affected 176 plasma proteins (56 after FDR) and several metabolic pathways, including inflammation and lipid metabolism. No change in soluble CD163 was observed. Aprepitant treatment was associated with a moderate increases in total and HDL cholesterol and affected select hematologic and metabolic markers, which returned to baseline levels 30 days after aprepitant treatment was stopped. There were 12 mild and 10 moderate adverse events (AE). CONCLUSIONS: Aprepitant is safe and well tolerated. The antiinflammatory properties of aprepitant make it a possible adjunctive therapy for comorbid conditions associated with HIV infection. TRIAL REGISTRATION: ClinicalTrials.gov (NCT). FUNDING: This research was funded by NIH UO1 MH, P30 MH, and PO1 MH. Spitsin, Sergei Tebas, Pablo Barrett, Jeffrey S Pappa, Vasiliki Kim, Deborah Taylor, Deanne Evans, Dwight L Douglas, Steven D eng P01 MH/MH/NIMH NIH HHS/ P30 MH/MH/NIMH NIH HHS/ U01 MH/MH/NIMH NIH HHS/ UM1 AI/AI/NIAID NIH HHS/ Clinical Trial, Phase I Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't JCI Insight. Oct 5;2(19):e. doi: 10./jci.insight..I SomaScan 10/06/ Gupta S, et al. Pharmacokinetic Properties of DNA Aptamers with Base Modifications Nucleic Acid Ther 27 6 345-353 https://www.doi.org/10./nat.. 28,961,063 Animals Aptamers, Nucleotide/administration & dosage/blood/*chemistry/*pharmacokinetics Base Sequence Drug Design Hydrophobic and Hydrophilic Interactions Ligands Linear Models Male Polyethylene Glycols/*chemistry/metabolism Rats Rats, Sprague-Dawley SELEX Aptamer Technique/methods Statistics, Nonparametric Uracil/*chemistry/metabolism aptamer pharmacokinetics modified nucleotides plasma clearance side chains N.J. are employees and stakeholders of SomaLogic, Inc. T.S., M.H., and Y.I. are employees and stakeholders of Otsuka Pharmaceutical Co., Ltd. The addition of novel side chains at the 5-position of uracil is an effective means to increase chemical diversity of aptamers and hence the success rate for discovery of high-affinity ligands to protein targets. Such modifications also increase nuclease resistance, which is useful in a range of applications, especially for therapeutics. In this study, we assess the impact of these side chains on plasma pharmacokinetics of modified aptamers conjugated to a 40 kDa polyethylene glycol. We show that clearance from plasma depends on relative hydrophobicity: side chains with a negative cLogP (more hydrophilic) result in slower plasma clearance compared with side chains with a positive cLogP (more hydrophobic). We show that clearance increases with the number of side chains in sequences of >/=28 synthons, but this effect is dramatically diminished in shorter sequences. These results serve as a guide for the design of new therapeutic aptamers with diversity-enhancing side chains. Gupta, Shashi Drolet, Daniel W Wolk, Steven K Waugh, Sheela M Rohloff, John C Carter, Jeffery D Mayfield, Wesley S Otis, Matthew R Fowler, Catherine R Suzuki, Tomoki Hirota, Masao Ishikawa, Yuichi Schneider, Daniel J Janjic, Nebojsa eng Nucleic Acid Ther. Dec;27(6):345-353. doi: 10./nat... Epub Sep 29.I SomaScan 09/30/ Welton JL, et al. Cerebrospinal fluid extracellular vesicle enrichment for protein biomarker discovery in neurological disease; multiple sclerosis J Extracell Vesicles 6 1 https://www.doi.org/10./.. 28,959,386 Extracellular vesicles biomarkers cerebrospinal fluid multiple sclerosis proteomics size exclusion chromatography The discovery of disease biomarkers, along with the use of liquid biopsies" as a minimally invasive source of biomarkers, continues to be of great interest. In inflammatory diseases of the central nervous system (CNS), cerebrospinal fluid (CSF) is the most obvious biofluid source. Extracellular vesicles (EVs) are also present in CSF and are thought to be potential "biomarker treasure chests". However, isolating these CSF-derived EVs remains challenging. This small-scale pilot study developed and tested a protocol to enrich for CSF-EVs, both in relapsing remitting multiple sclerosis (RRMS) CSF and controls. These were subsequently compared, using an aptamer based proteomics array, SOMAscan. EVs were enriched from RRMS patient (n = 4) and non-demyelinating control (idiopathic intracranial hypertension (IIH) (n = 3)) CSF using precipitation and mini size-exclusion chromatography (SEC). EV-enriched fractions were selected using pre-defined EV characteristics, including increased levels of tetraspanins. EVs and paired CSF were analysed by SOMAscan, providing relative abundance data for proteins. CSF-EVs were characterised, revealing exosome-like features: rich in tetraspanins CD9 and CD81, size ~100 nm, and exosome-like morphology by TEM. Sufficient quantities of, SOMAscan compatible, EV material was obtained from 5 ml CSF for proteomics analysis. Overall, 348 and 580 proteins were identified in CSF-EVs and CSF, respectively, of which 50 were found to be significantly (t-test) and exclusively enriched in RRMS CSF-EVs. Selected proteins, Plasma kallikrein and Apolipoprotein-E4, were further validated by western blot and appeared increased in CSF-EVs compared to CSF. Functional enrichment analysis of the 50 enriched proteins revealed strong associations with biological processes relating to MS pathology and also extracellular regions, consistent with EV enrichment. This pilot study demonstrates practicality for EV enrichment in CSF derived from patients with MS and controls, allowing detailed analysis of protein profiles that may offer opportunities to identify novel biomarkers and therapeutic approaches in CNS inflammatory diseases." Welton, Joanne L Loveless, Samantha Stone, Timothy von Ruhland, Chris Robertson, Neil P Clayton, Aled eng MR/L/1/MRC_/Medical Research Council/United Kingdom J Extracell Vesicles. Sep 3;6(1):. doi: 10./... eCollection .I SomaScan 09/30/ Curran AM, et al. Sexual Dimorphism, Age, and Fat Mass Are Key Phenotypic Drivers of Proteomic Signatures J Proteome Res 16 11 - https://www.doi.org/10./acs.jproteome.7b 28,950,061 Adipose Tissue Age Factors Female Humans Male *Phenotype Proteomics/*methods Sex Characteristics age biomarker fat mass pathway phenotype protein proteomics sex Validated protein biomarkers are needed for assessing health trajectories, predicting and subclassifying disease, and optimizing diagnostic and therapeutic clinical decision-making. The sensitivity, specificity, accuracy, and precision of single or combinations of protein biomarkers may be altered by differences in physiological states limiting the ability to translate research results to clinically useful diagnostic tests. Aptamer based affinity assays were used to test whether low abundant serum proteins differed based on age, sex, and fat mass in a healthy population of 94 males and 102 females from the MECHE cohort. The findings were replicated in 217 healthy male and 377 healthy female participants in the DiOGenes consortium. Of the proteins in the panel, 141, 51, and 112 proteins (adjusted p < 0.1) were identified in the MECHE cohort and significantly replicated in DiOGenes for sexual dimorphism, age, and fat mass, respectively. Pathway analysis classified a subset of proteins from the 3 phenotypes to the complement and coagulation cascades pathways and to immune and coagulation processes. These results demonstrated that specific proteins were statistically associated with dichotomous (male vs female) and continuous phenotypes (age, fat mass), which may influence the identification and use of biomarkers of clinical utility for health diagnosis and therapeutic strategies. Curran, Aoife M Fogarty Draper, Colleen Scott-Boyer, Marie-Pier Valsesia, Armand Roche, Helen M Ryan, Miriam F Gibney, Michael J Kutmon, Martina Evelo, Chris T Coort, Susan L Astrup, Arne Saris, Wim H Brennan, Lorraine Kaput, Jim eng Research Support, Non-U.S. Gov't J Proteome Res. Nov 3;16(11):-. doi: 10./acs.jproteome.7b. Epub Oct 4.I SomaScan 09/28/ Oak P, et al. Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease EMBO Mol Med 9 11 - https://www.doi.org/10./emmm. 28,923,828 Animals Animals, Newborn Cells, Cultured Chronic Disease Fibroblasts/cytology/metabolism Haploinsufficiency Human Umbilical Vein Endothelial Cells Humans Infant, Newborn Lung/metabolism Lung Diseases/metabolism/*pathology/prevention & control Mice Mice, Inbred C57BL Oxygen/metabolism Platelet-Derived Growth Factor/*metabolism/pharmacology/therapeutic use Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors/genetics/metabolism Respiration, Artificial Signal Transduction/drug effects Vascular Endothelial Growth Factor A/metabolism PDGF-Ralpha Vegf-a bronchopulmonary dysplasia neonatal chronic lung disease transforming growth factor-beta Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O(2)). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Ralpha gene in preterms with nCLD and directly test the effect of PDGF-Ralpha haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O(2) In the context of MV-O(2), attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-Ralpha-dependent reduction in lung VEGF-A. TGF-beta contributes to the PDGF-Ralpha-dependent decrease in myofibroblast function. Remarkably, endotracheal treatment with exogenous PDGF-A rescues both the lung defects in haploinsufficient mice undergoing MV-O(2) Overall, our results establish attenuated PDGF signaling as an important driver of nCLD pathology with provision of PDGF-A as a protective strategy for newborns undergoing MV-O(2). Oak, Prajakta Pritzke, Tina Thiel, Isabella Koschlig, Markus Mous, Daphne S Windhorst, Anita Jain, Noopur Eickelberg, Oliver Foerster, Kai Schulze, Andreas Goepel, Wolfgang Reicherzer, Tobias Ehrhardt, Harald Rottier, Robbert J Ahnert, Peter Gortner, Ludwig Desai, Tushar J Hilgendorff, Anne eng Research Support, Non-U.S. Gov't England EMBO Mol Med. Nov;9(11):-. doi: 10./emmm..I SomaScan 09/20/ Aghaeepour N, et al. An immune clock of human pregnancy Sci Immunol 2 15 https://www.doi.org/10./sciimmunol.aan 28,864,494 The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies. Aghaeepour, Nima Ganio, Edward A Mcilwain, David Tsai, Amy S Tingle, Martha Van Gassen, Sofie Gaudilliere, Dyani K Baca, Quentin McNeil, Leslie Okada, Robin Ghaemi, Mohammad S Furman, David Wong, Ronald J Winn, Virginia D Druzin, Maurice L El-Sayed, Yaser Y Quaintance, Cecele Gibbs, Ronald Darmstadt, Gary L Shaw, Gary M Stevenson, David K Tibshirani, Robert Nolan, Garry P Lewis, David B Angst, Martin S Gaudilliere, Brice eng K23 GM/GM/NIGMS NIH HHS/ U19 AI/AI/NIAID NIH HHS/ Sci Immunol. Sep 1;2(15):eaan. doi: 10./sciimmunol.aan.I SomaScan 09/03/ Belongie KJ, et al. Identification of novel biomarkers to monitor beta-cell function and enable early detection of type 2 diabetes risk PLoS One 12 8 e https://www.doi.org/10./journal.pone. 28,846,711 Adult Biomarkers/blood Blood Glucose/*metabolism Case-Control Studies Cross-Sectional Studies Diabetes Mellitus, Type 2/blood/*diagnosis Early Diagnosis Female Glucose Clamp Technique Glucose Intolerance/*blood Glucose Tolerance Test Humans Insulin/blood Insulin Resistance/*physiology Insulin-Secreting Cells/*metabolism Male Middle Aged Risk Factors A decline in beta-cell function is a prerequisite for the development of type 2 diabetes, yet the level of beta-cell function in individuals at risk of the condition is rarely measured. This is due, in part, to the fact that current methods for assessing beta-cell function are inaccurate, prone to error, labor-intensive, or affected by glucose-lowering therapy. The aim of the current study was to identify novel circulating biomarkers to monitor beta-cell function and to identify individuals at high risk of developing beta-cell dysfunction. In a nested case-control study from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort (n = ), proteomics and miRNA profiling were performed on fasting plasma samples from 43 individuals who progressed to impaired glucose tolerance (IGT) and 43 controls who maintained normal glucose tolerance (NGT) over three years. Groups were matched at baseline for age, gender, body mass index (BMI), insulin sensitivity (euglycemic clamp) and beta-cell glucose sensitivity (mathematical modeling). Proteomic profiling was performed using the SomaLogic platform (Colorado, USA); miRNA expression was performed using a modified RT-PCR protocol (Regulus Therapeutics, California, USA). Results showed differentially expressed proteins and miRNAs including some with known links to type 2 diabetes, such as adiponectin, but also novel biomarkers and pathways. In cross sectional analysis at year 3, the top differentially expressed biomarkers in people with IGT/ reduced beta-cell glucose sensitivity were adiponectin, alpha1-antitrypsin (known to regulate adiponectin levels), endocan, miR-181a, miR-342, and miR-323. At baseline, adiponectin, cathepsin D and NCAM.L1 (proteins expressed by pancreatic beta-cells) were significantly lower in those that progressed to IGT. Many of the novel prognostic biomarker candidates were within the epithelial-mesenchymal transition (EMT) pathway: for example, Noggin, DLL4 and miR-181a. Further validation studies are required in additional clinical cohorts and in patients with type 2 diabetes, but these results identify novel pathways and biomarkers that may have utility in monitoring beta-cell function and/ or predicting future decline, allowing more targeted efforts to prevent and intercept type 2 diabetes. Belongie, Kirstine J Ferrannini, Ele Johnson, Kjell Andrade-Gordon, Patricia Hansen, Michael K Petrie, John R eng PLoS One. Aug 28;12(8):e. doi: 10./journal.pone.. eCollection .I SomaScan 08/29/ Fitzgibbons TP, et al. Activation of Inflammatory and Pro-Thrombotic Pathways in Acute Stress Cardiomyopathy Front Cardiovasc Med 4 49 https://www.doi.org/10./fcvm.. 28,824,923 acute myocardial infarction coagulation inflammation stress cardiomyopathy women Stress cardiomyopathy (SCM) is a unique cardiac disorder that more often occurs in women. SCM presents in a similar fashion as acute myocardial infarction (AMI), with chest pain, ECG changes, and congestive heart failure. The primary distinguishing feature is the absence of thrombotic coronary occlusion in SCM. How this reduction in cardiac function occurs in the absence of coronary occlusion remains unknown. Therefore, we tested the hypothesis that a targeted proteomic comparison of patients with acute SCM and AMI might identify relevant mechanistic differences. Blood was drawn in normal controls (n = 6), women with AMI (n = 12), or women with acute SCM (n = 15). Two-week follow-up samples were available in AMI (n = 4) and SCM patients (n = 11). Relative concentrations of 1,310 serum proteins were measured in each of the 48 samples using the SOMAscan assay. Women with AMI had greater myocyte necrosis, as reflected by a higher peak troponin I concentration (AMI 32.03 +/- 29.46 vs. SCM 2.68 +/- 2.6 ng/ml, p < 0.05). AMI and SCM patients had equivalent reductions in left ventricular ejection fraction [LVEF (%) 39 +/- 12 vs. 37 +/- 12, p = 0.479]. In follow-up, women with SCM had a greater improvement in cardiac function [LVEF (%) 60 +/- 7 vs. 45 +/- 13, p 1; q < 0.05) between AMI and SCM in the acute or recovery phase. However, when we compared normal controls to patients with AMI, there was differential expression of 35 proteins. When we compared normal controls to patients with SCM, 45 proteins were differentially expressed. In comparison to normal controls, biological processes such as complement, coagulation, and inflammation were activated in both AMI and SCM. There were four proteins that showed a non-significant trend to be increased in acute SCM vs. AMI (netrin-1, follistatin-like 3, kallikrein 7, kynureninase). Despite a lesser degree of myocardial necrosis than AMI, SCM is characterized by a similar activation of inflammatory, complement, and coagulation pathways. These findings may explain reported thromboembolic complications in the short term and elevated risk of mortality in the long term of SCM. Fitzgibbons, Timothy P Edwards, Yvonne J K Shaw, Peter Iskandar, Aline Ahmed, Mohamed Bote, Josiah Shah, Tejen Sinha, Sumita Gerszten, Robert E Keaney, John F Jr Zile, Michael R Aurigemma, Gerard P eng Switzerland Front Cardiovasc Med. Aug 3;4:49. doi: 10./fcvm... eCollection .I SomaScan 08/22/ Anderson J, et al. Interleukin 1 Receptor-Like 1 Protein (ST2) is a Potential Biomarker for Cardiomyopathy in Duchenne Muscular Dystrophy Pediatr Cardiol 38 8 - https://www.doi.org/10./s-017--9 28,821,969 Adolescent Adult Biomarkers/*blood Cardiomyopathies/*blood/etiology Case-Control Studies Enzyme-Linked Immunosorbent Assay Humans Interleukin-1 Receptor-Like 1 Protein/*blood Linear Models Male Muscular Dystrophy, Duchenne/blood/*complications Stroke Volume Young Adult Biomarkers Cardiomyopathy Duchenne muscular dystrophy ST2 interest. Haeri Seol declares that she has no conflict of interest. Heather Gordish-Dressman declares that she has no conflict of interest. Yetrib Hathout declares that he has no conflict of interest. Christopher Spurney declares that he has no conflict of interest. Duchenne muscular dystrophy (DMD) is a rare, fatal X-linked disorder characterized by the lack of dystrophin, a key sarcolemma muscle protein. Cardiac failure is a significant cause of death in DMD subjects. The purpose of our research was to identify potential cardiac serum biomarkers associated with DMD cardiomyopathy. This is an observational, case-controlled study using subjects from the CINRG DMD natural history study with cardiomyopathy (ejection fraction (EF) <55%; shortening fraction (SF) /= 55%; SF >/= 28%) compared to normal healthy volunteer subjects. The DMD with cardiomyopathy group had significantly lower average EF and SF (EF = 45 +/- 10/SF = 25 +/- 2%) than the DMD without cardiomyopathy group (EF = 58 +/- 5% and SF = 32 +/- 3%; p < 0.01). Among a selected set of potential biomarkers for cardiomyopathy (MMP9, BNP, GAL3, CRP, LEP, TNC, TLR4 and ST2) we validated ST2 as significantly elevated in the serum of DMD cardiomyopathy group (35,798 +/- pg/mL) compared to normal controls ( +/- pg/mL; p < 0.01; n = 6). Matrix metallopeptidase 9 (MMP9) levels were found significantly increased in both DMD groups compared to controls (p < 0.01). No significant differences were seen in BNP, GAL3, CRP, LEP, TNC or TLR4 levels. Increased ST2 levels were found in serum of DMD subjects compared to healthy volunteers and further elevated in DMD subjects with cardiomyopathy. Future studies correlating cardiomyopathy with ST2 levels may allow for improved non-invasive monitoring of cardiac disease in DMD subjects. Anderson, Julia Seol, Haeri Gordish-Dressman, Heather Hathout, Yetrib Spurney, Christopher F eng W81XWH-09-1-/US Dept of Defense/ R01AR/NH/NIH HHS/ U54 HD/HD/NICHD NIH HHS/ 1R01AR/NH/NIH HHS/ U54 MD/MD/NIMHD NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ UL1 RR/RR/NCRR NIH HHS/ G12RR/NH/NIH HHS/ G12 RR/RR/NCRR NIH HHS/ H133B/US Dept of Education/ NIDDR/ UL1RR/NH/NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ U54 RR/RR/NCRR NIH HHS/ U54HD/NH/NIH HHS/ UL1RR/NH/NIH HHS/ R24HD/NH/NIH HHS/ U54RR/NH/NIH HHS/ U54 HD/HD/NICHD NIH HHS/ UL1 RR/RR/NCRR NIH HHS/ R24 HD/HD/NICHD NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ H133B/US Dept of Education/ NIDDR/ R01 AR/AR/NIAMS NIH HHS/ Observational Study Pediatr Cardiol. Dec;38(8):-. doi: 10./s-017--9. Epub Aug 18.I SomaScan 08/20/ De Groote MA, et al. Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis J Clin Microbiol 55 10 - https://www.doi.org/10./JCM.-17 28,794,177 Antigens, Bacterial/blood Biomarkers/blood Blood Proteins/*analysis Complement C9/*metabolism Fructose-Bisphosphate Aldolase/*blood Gelsolin/*blood Humans Mycobacterium tuberculosis/genetics/immunology Proteoglycans/*blood Proteomics Sensitivity and Specificity Serpins/*blood Tuberculosis, Pulmonary/*diagnosis/microbiology aptamer biomarker tuberculosis New non-sputum biomarker tests for active tuberculosis (TB) diagnostics are of the highest priority for global TB control. We performed in-depth proteomic analysis using the 4,000-plex SOMAscan assay on 1,470 serum samples from seven countries where TB is endemic. All samples were from patients with symptoms and signs suggestive of active pulmonary TB that were systematically confirmed or ruled out for TB by culture and clinical follow-up. HIV coinfection was present in 34% of samples, and 25% were sputum smear negative. Serum protein biomarkers were identified by stability selection using L1-regularized logistic regression and by Kolmogorov-Smirnov (KS) statistics. A naive Bayes classifier using six host response markers (HR6 model), including SYWC, kallistatin, complement C9, gelsolin, testican-2, and aldolase C, performed well in a training set (area under the sensitivity-specificity curve [AUC] of 0.94) and in a blinded verification set (AUC of 0.92) to distinguish TB and non-TB samples. Differential expression was also highly significant (P < 10(-20)) for previously described TB markers, such as IP-10, LBP, FCG3B, and TSP4, and for many novel proteins not previously associated with TB. Proteins with the largest median fold changes were SAA (serum amyloid protein A), NPS-PLA2 (secreted phospholipase A2), and CA6 (carbonic anhydrase 6). Target product profiles (TPPs) for a non-sputum biomarker test to diagnose active TB for treatment initiation (TPP#1) and for a community-based triage or referral test (TPP#2) have been published by the WHO. With 90% sensitivity and 80% specificity, the HR6 model fell short of TPP#1 but reached TPP#2 performance criteria. In conclusion, we identified and validated a six-marker signature for active TB that warrants diagnostic development on a patient-near platform. De Groote, Mary A Sterling, David G Hraha, Thomas Russell, Theresa M Green, Louis S Wall, Kirsten Kraemer, Stephan Ostroff, Rachel Janjic, Nebojsa Ochsner, Urs A eng Research Support, Non-U.S. Gov't J Clin Microbiol. Oct;55(10):-. doi: 10./JCM.-17. Epub Aug 9.I SomaScan 08/11/ Russell TM, et al. Potential of High-Affinity, Slow Off-Rate Modified Aptamer Reagents for Mycobacterium tuberculosis Proteins as Tools for Infection Models and Diagnostic Applications J Clin Microbiol 55 10 - https://www.doi.org/10./JCM.-17 28,794,178 Acyltransferases/*analysis Antigens, Bacterial/*analysis/immunology Aptamers, Peptide/*metabolism Bacterial Proteins/analysis/*blood/*urine Humans Immunologic Tests/methods Mycobacterium tuberculosis/*immunology Protein Binding/physiology Tuberculosis, Pulmonary/*diagnosis/microbiology Mycobacterium tuberculosis aptamer biomarker immunodiagnostics proteomics Direct pathogen detection in blood to diagnose active tuberculosis (TB) has been difficult due to low levels of circulating antigens or due to the lack of specific, high-affinity binding reagents and reliable assays with adequate sensitivity. We sought to determine whether slow off-rate modified aptamer (SOMAmer) reagents with subnanomolar affinity for Mycobacterium tuberculosis proteins (antigens 85A, 85B, 85C, GroES, GroEL2, DnaK, CFP10, KAD, CFP2, RplL, and Tpx) could be useful to diagnose tuberculosis. When incorporated into the multiplexed, array-based proteomic SOMAscan assay, limits of detection reached the subpicomolar range in 40% serum. Binding to native M. tuberculosis proteins was confirmed by using M. tuberculosis culture filtrate proteins and fractions from infected macrophages and via affinity capture assays and subsequent mass spectrometry. Comparison of serum from culture-positive pulmonary TB patients and TB suspects systematically ruled out for TB revealed small but statistically significant (P < 0.) differences in the median M. tuberculosis signals and in specific pathogen markers, such as antigen 85B. Samples where many M. tuberculosis aptamers produced high signals were rare exceptions. In concentrated, protein-normalized urine from TB patients and non-TB controls, the CFP10 (EsxB) SOMAmer yielded the most significant differential signals (P < 0.), particularly in TB patients with HIV coinfection. In conclusion, direct M. tuberculosis antigen detection proved difficult even with a sensitive method such as SOMAscan, likely due to their very low, subpicomolar abundance. The observed differences between cases and controls had limited diagnostic utility in serum and urine, but further evaluation of M. tuberculosis SOMAmers using other platforms and sample types is warranted. Russell, Theresa M Green, Louis S Rice, Taylor Kruh-Garcia, Nicole A Dobos, Karen De Groote, Mary A Hraha, Thomas Sterling, David G Janjic, Nebojsa Ochsner, Urs A eng Research Support, Non-U.S. Gov't J Clin Microbiol. Oct;55(10):-. doi: 10./JCM.-17. Epub Aug 9.I SomaScan 08/11/ Siddharth J, et al. Aging and sarcopenia associate with specific interactions between gut microbes, serum biomarkers and host physiology in rats Aging (Albany NY) 9 7 - https://www.doi.org/10./aging. 28,783,713 Aging/*physiology Animals Bacteria/classification Biomarkers/blood *Gastrointestinal Microbiome/physiology Genome, Bacterial Genomics Host-Pathogen Interactions Rats *Sarcopenia aging lipidomics microbiome muscle physiology proteomics sarcopenia Sciences SA. The microbiome has been demonstrated to play an integral role in the maintenance of many aspects of health that are also associated with aging. In order to identify areas of potential exploration and intervention, we simultaneously characterized age-related alterations in gut microbiome, muscle physiology and serum proteomic and lipidomic profiles in aged rats to define an integrated signature of the aging phenotype. We demonstrate that aging skews the composition of the gut microbiome, in particular by altering the Sutterella to Barneseilla ratio, and alters the metabolic potential of intestinal bacteria. Age-related changes of the gut microbiome were associated with the physiological decline of musculoskeletal function, and with molecular markers of nutrient processing/availability, and inflammatory/immune status in aged versus adult rats. Altogether, our study highlights that aging leads to a complex interplay between the microbiome and host physiology, and provides candidate microbial species to target physical and metabolic decline during aging by modulating gut microbial ecology. Siddharth, Jay Chakrabarti, Anirikh Pannerec, Alice Karaz, Sonia Morin-Rivron, Delphine Masoodi, Mojgan Feige, Jerome N Parkinson, Scott James eng Research Support, Non-U.S. Gov't Aging (Albany NY). Jul 17;9(7):-. doi: 10./aging..I SomaScan 08/08/ Erez O, et al. The prediction of late-onset preeclampsia: Results from a longitudinal proteomics study PLoS One 12 7 e https://www.doi.org/10./journal.pone. 28,738,067 Biomarkers/blood/metabolism Case-Control Studies Female Gestational Age Humans Longitudinal Studies Placenta Growth Factor/blood/metabolism Pre-Eclampsia/blood/*etiology/*metabolism Pregnancy Pregnancy Proteins/metabolism Prospective Studies Proteome/*metabolism Proteomics/methods Risk Factors Signal Transduction/physiology Vascular Endothelial Growth Factor A/blood/metabolism BACKGROUND: Late-onset preeclampsia is the most prevalent phenotype of this syndrome; nevertheless, only a few biomarkers for its early diagnosis have been reported. We sought to correct this deficiency using a high through-put proteomic platform. METHODS: A case-control longitudinal study was conducted, including 90 patients with normal pregnancies and 76 patients with late-onset preeclampsia (diagnosed at >/=34 weeks of gestation). Maternal plasma samples were collected throughout gestation (normal pregnancy: 2-6 samples per patient, median of 2; late-onset preeclampsia: 2-6, median of 5). The abundance of 1,125 proteins was measured using an aptamers-based proteomics technique. Protein abundance in normal pregnancies was modeled using linear mixed-effects models to estimate mean abundance as a function of gestational age. Data was then expressed as multiples of-the-mean (MoM) values in normal pregnancies. Multi-marker prediction models were built using data from one of five gestational age intervals (8-16, 16.1-22, 22.1-28, 28.1-32, 32.1-36 weeks of gestation). The predictive performance of the best combination of proteins was compared to placental growth factor (PIGF) using bootstrap. RESULTS: 1) At 8-16 weeks of gestation, the best prediction model included only one protein, matrix metalloproteinase 7 (MMP-7), that had a sensitivity of 69% at a false positive rate (FPR) of 20% (AUC = 0.76); 2) at 16.1-22 weeks of gestation, MMP-7 was the single best predictor of late-onset preeclampsia with a sensitivity of 70% at a FPR of 20% (AUC = 0.82); 3) after 22 weeks of gestation, PlGF was the best predictor of late-onset preeclampsia, identifying 1/3 to 1/2 of the patients destined to develop this syndrome (FPR = 20%); 4) 36 proteins were associated with late-onset preeclampsia in at least one interval of gestation (after adjustment for covariates); 5) several biological processes, such as positive regulation of vascular endothelial growth factor receptor signaling pathway, were perturbed; and 6) from 22.1 weeks of gestation onward, the set of proteins most predictive of severe preeclampsia was different from the set most predictive of the mild form of this syndrome. CONCLUSIONS: Elevated MMP-7 early in gestation (8-22 weeks) and low PlGF later in gestation (after 22 weeks) are the strongest predictors for the subsequent development of late-onset preeclampsia, suggesting that the optimal identification of patients at risk may involve a two-step diagnostic process. Erez, Offer Romero, Roberto Maymon, Eli Chaemsaithong, Piya Done, Bogdan Pacora, Percy Panaitescu, Bogdan Chaiworapongsa, Tinnakorn Hassan, Sonia S Tarca, Adi L eng HHSNC/HD/NICHD NIH HHS/ PLoS One. Jul 24;12(7):e. doi: 10./journal.pone.. eCollection .I SomaScan 07/25/ Sun HH, et al. Diagnosis and prognosis-review of biomarkers for mesothelioma Ann Transl Med 5 11 244 https://www.doi.org/10./atm..06.60 28,706,912 Mesothelioma asbestos biomarker diagnosis prognosis Malignant pleural mesothelioma (MPM) is an aggressive disease arising in pleural cell lining and is associated with asbestos exposure. Today, there is a rising incidence of MPM reaching 3,000 annual cases nationally, primarily from the large population occupationally exposed to asbestos between and . With a prolonged latency period, presenting clinically 10 to 40 years after exposure, MPM is often diagnosed in late stages and presents median survival time of less than 12 months. There is a serious need for improvement in prognostic and diagnostic tools for MPM. Recent investigation and discovery of various biomarkers has shown promise, including Osteopontin, Fibulin-3, Soluble Mesothelin-Related Proteins (SMRP), High Mobility Group Box 1 (HMGB1), micro-RNA's, peripheral blood-based markers, and Slow Off-rate Modified Aptamer (SOMAmer) proteomic assays. In this review, we explore these current major biomarkers and their prognostic and diagnostic potential, highlighting the most recent large studies and developments for each. While progress has been made in mesothelioma research, many questions remain unanswered. Increased international cooperation is necessary for improving validity of results for current biomarkers through repeated investigation and increasing cohort sizes, as well as for the continued search for new and better markers. Sun, Huan H Vaynblat, Allen Pass, Harvey I eng Review China Ann Transl Med. Jun;5(11):244. doi: 10./atm..06.60.I SomaScan 07/15/ Wang J, et al. Identification of unique proteomic signatures in allergic and non-allergic skin disease Clin Exp Allergy 47 11 - https://www.doi.org/10./cea. 28,703,865 Case-Control Studies Cluster Analysis Dermatitis, Atopic/*immunology/*metabolism Dermatitis, Contact/immunology/metabolism Female Humans Immunoglobulin E/blood/immunology Inflammation Mediators/blood/metabolism Male *Proteome *Proteomics/methods Skin Diseases/etiology/*metabolism atopic dermatitis biomarkers clinical immunology contact dermatitis dermatology psoriasis BACKGROUND: Atopic dermatitis (AD), psoriasis (PS), and contact dermatitis (CD) are common skin diseases, characterized by barrier disruption and systemic inflammation, with unique epidermal signatures and common inflammatory pathways identified by transcriptomic profiling. This study profiled proteomic signatures in serum from subjects with AD, PS, and CD compared with healthy controls (HC). OBJECTIVE: Identify unique proteomic signatures to distinguish between inflammatory diseases with similar epidermal disruption and overlapping epithelial inflammation. METHODS: Sera from 20 subjects with moderate to severe AD, 10 subjects with CD, 12 subjects with moderate to severe PS, 10 subjects with both AD and CD, and 10 HC with no history of skin disease was analysed using high-throughput proteomic analysis that detects expression of protein targets. Protein expression was compared between disease and HC, and across diseases for statistical significance (fold change>/=1.5 and false discovery rate0.40. RESULTS: There were 26 children included: mean age 11.3 years (SD 2.4 years), mean Brody Bronchiectasis score 0.65 (SD 0.83), mean airway count 14.3 (SD 5.7) per CT slice. Brody bronchiectasis change over 1 year ranged from -1.0 to 1.9 and airway count change over one year ranged from -7.7 to 13.5 airways per slice. Proteins related to inflammation and extracellular matrix degradation were associated with cross-sectional and longitudinal structural changes. CONCLUSIONS AND CLINICAL RELEVANCE: Imaging outcomes were more strongly correlated with circulating proteins than age or spirometry values. The unique SOMAscan proteomic platform identifies several novel proteins in blood that are associated with bronchiectasis and that may serve as clinically useful biomarkers in children with CF. DeBoer, Emily M Kroehl, Miranda E Wagner, Brandie D Accurso, Frank J Harris, J Kirk Lynch, David A Sagel, Scott D Deterding, Robin R eng KL2 TR/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Germany Proteomics Clin Appl. Sep;11(9-10). doi: 10./prca.. Epub May 29.I SomaScan 04/30/ Westwood S, et al. The influence of insulin resistance on cerebrospinal fluid and plasma biomarkers of Alzheimer's pathology Alzheimers Res Ther 9 1 31 https://www.doi.org/10./s-017--6 28,441,961 Alzheimer Disease/*blood/*cerebrospinal fluid Amyloid beta-Peptides/*blood/*cerebrospinal fluid Animals Apolipoprotein E4/*blood/*cerebrospinal fluid Biomarkers/blood/cerebrospinal fluid Humans *Insulin Resistance Male Middle Aged Reproducibility of Results Sensitivity and Specificity Alzheimer's disease Cerebrospinal fluid biomarkers Diabetes mellitus Insulin resistance Plasma biomarkers Proteomics BACKGROUND: Insulin resistance (IR) has previously been associated with an increased risk of developing Alzheimer's disease (AD), although the relationship between IR and AD is not yet clear. Here, we examined the influence of IR on AD using plasma and cerebrospinal fluid (CSF) biomarkers related to IR and AD in cognitively healthy men. We also aimed to characterise the shared protein signatures between IR and AD. METHODS: Fifty-eight cognitively healthy men, 28 IR and 30 non-IR (age and APOE epsilon4 matched), were drawn from the Metabolic Syndrome in Men study in Kuopio, Finland. CSF AD biomarkers (amyloid beta-peptide (Abeta), total tau and tau phosphorylated at the Thr181 epitope) were examined with respect to IR. Targeted proteomics using ELISA and Luminex xMAP assays were performed to assess the influence of IR on previously identified CSF and plasma protein biomarker candidates of AD pathology. Furthermore, CSF and plasma SOMAscan was performed to discover proteins that associate with IR and CSF AD biomarkers. RESULTS: CSF AD biomarkers did not differ between IR and non-IR groups, although plasma insulin correlated with CSF Abeta/tau across the whole cohort. In total, 200 CSF and 487 plasma proteins were differentially expressed between IR and non-IR subjects, and significantly enriched pathways, many of which have been previously implicated in AD, were identified. CSF and plasma proteins significantly associated with CSF AD biomarkers were also discovered, and those sensitive to both IR and AD were identified. CONCLUSIONS: These data indicate that IR is not directly related to the level of CSF AD pathology in cognitively healthy men. Proteins that associated with both AD and IR are potential markers indicative of shared pathology. Westwood, Sarah Liu, Benjamine Baird, Alison L Anand, Sneha Nevado-Holgado, Alejo J Newby, Danielle Pikkarainen, Maria Hallikainen, Merja Kuusisto, Johanna Streffer, Johannes R Novak, Gerald Blennow, Kaj Andreasson, Ulf Zetterberg, Henrik Smith, Ulf Laakso, Markku Soininen, Hilkka Lovestone, Simon eng G/MRC_/Medical Research Council/United Kingdom Review England Alzheimers Res Ther. Apr 26;9(1):31. doi: 10./s-017--6.I SomaScan 04/27/ O'Dwyer DN, et al. The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes Sci Rep 7 https://www.doi.org/10./srep 28,440,314 Adult Aged Aged, 80 and over *Blood Proteins/immunology/metabolism Female Humans *Idiopathic Pulmonary Fibrosis/blood/immunology Male Middle Aged *Proteome/immunology/metabolism Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial pneumonia. The disease pathophysiology is poorly understood and the etiology remains unclear. Recent advances have generated new therapies and improved knowledge of the natural history of IPF. These gains have been brokered by advances in technology and improved insight into the role of various genes in mediating disease, but gene expression and protein levels do not always correlate. Thus, in this paper we apply a novel large scale high throughput aptamer approach to identify more than proteins in the peripheral blood of well-characterized IPF patients and normal volunteers. We use systems biology approaches to identify a unique IPF proteome signature and give insight into biological processes driving IPF. We found IPF plasma to be altered and enriched for proteins involved in defense response, wound healing and protein phosphorylation when compared to normal human plasma. Analysis also revealed a minimal protein signature that differentiated IPF patients from normal controls, which may allow for accurate diagnosis of IPF based on easily-accessible peripheral blood. This report introduces large scale unbiased protein discovery analysis to IPF and describes distinct biological processes that further inform disease biology. O'Dwyer, David N Norman, Katy C Xia, Meng Huang, Yong Gurczynski, Stephen J Ashley, Shanna L White, Eric S Flaherty, Kevin R Martinez, Fernando J Murray, Susan Noth, Imre Arnold, Kelly B Moore, Bethany B eng UL1 TR/TR/NCATS NIH HHS/ K24 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ T32 AI/AI/NIAID NIH HHS/ Clinical Trial Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. Apr 25;7:. doi: 10./srep.I SomaScan 04/26/ Saleheen D, et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity Nature 544 7,649 235-239 https://www.doi.org/10./nature 28,406,212 1-Alkyl-2-acetylglycerophosphocholine Esterase/deficiency/genetics Apolipoprotein C-III/deficiency/genetics Cohort Studies *Consanguinity Coronary Disease/blood/genetics Cytochrome P450 Family 2/genetics *DNA Mutational Analysis Dietary Fats/pharmacology Exome/genetics Fasting/blood Female *Gene Deletion Gene Frequency Genes/*genetics Genetic Association Studies/*methods *Homozygote Humans Interleukin-8/blood Male Middle Aged Myocardial Infarction/blood/genetics Neuregulins/genetics Pakistan Pedigree *Phenotype Phosphoproteins/genetics Postprandial Period RNA Splice Sites/genetics Reverse Genetics/methods Sodium-Hydrogen Exchangers/genetics Triglycerides/blood A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans. Saleheen, Danish Natarajan, Pradeep Armean, Irina M Zhao, Wei Rasheed, Asif Khetarpal, Sumeet A Won, Hong-Hee Karczewski, Konrad J O'Donnell-Luria, Anne H Samocha, Kaitlin E Weisburd, Benjamin Gupta, Namrata Zaidi, Mozzam Samuel, Maria Imran, Atif Abbas, Shahid Majeed, Faisal Ishaq, Madiha Akhtar, Saba Trindade, Kevin Mucksavage, Megan Qamar, Nadeem Zaman, Khan Shah Yaqoob, Zia Saghir, Tahir Rizvi, Syed Nadeem Hasan Memon, Anis Hayyat Mallick, Nadeem Ishaq, Mohammad Rasheed, Syed Zahed Memon, Fazal-Ur-Rehman Mahmood, Khalid Ahmed, Naveeduddin Do, Ron Krauss, Ronald M MacArthur, Daniel G Gabriel, Stacey Lander, Eric S Daly, Mark J Frossard, Philippe Danesh, John Rader, Daniel J Kathiresan, Sekar eng P30 DK/DK/NIDDK NIH HHS/ RG/08/014//BHF_/British Heart Foundation/United Kingdom MR/PX/1/MRC_/Medical Research Council/United Kingdom R01 GM/GM/NIGMS NIH HHS/ MR/P/1/MRC_/Medical Research Council/United Kingdom U54 HG/HG/NHGRI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ MR/L/1/MRC_/Medical Research Council/United Kingdom Wellcome Trust/United Kingdom RG/16/4//BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Nature. Apr 12;544():235-239. doi: 10./nature.I SomaScan 04/14/ Asai A, et al. Paracrine signals regulate human liver organoid maturation from induced pluripotent stem cells Development 144 6 - https://www.doi.org/10./dev. 28,275,009 Animals Bile Acids and Salts/metabolism Biological Transport Biomarkers/metabolism *Cell Differentiation Cell Polarity Coculture Techniques Gene Expression Regulation Hepatocytes/cytology/ultrastructure Human Umbilical Vein Endothelial Cells/cytology/metabolism Humans Induced Pluripotent Stem Cells/*cytology/metabolism Liver/*cytology Mesenchymal Stem Cells/cytology/metabolism Mice Morphogenesis/genetics Organ Specificity/genetics Organoids/*cytology/metabolism *Paracrine Communication Proteins/analysis Abcb11 Hepatocyte differentiation Liver development Regeneration Tissue engineering A self-organizing organoid model provides a new approach to study the mechanism of human liver organogenesis. Previous animal models documented that simultaneous paracrine signaling and cell-to-cell surface contact regulate hepatocyte differentiation. To dissect the relative contributions of the paracrine effects, we first established a liver organoid using human induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) as previously reported. Time-lapse imaging showed that hepatic-specified endoderm iPSCs (HE-iPSCs) self-assembled into three-dimensional organoids, resulting in hepatic gene induction. Progressive differentiation was demonstrated by hepatic protein production after in vivo organoid transplantation. To assess the paracrine contributions, we employed a Transwell system in which HE-iPSCs were separately co-cultured with MSCs and/or HUVECs. Although the three-dimensional structure did not form, their soluble factors induced a hepatocyte-like phenotype in HE-iPSCs, resulting in the expression of bile salt export pump. In conclusion, the mesoderm-derived paracrine signals promote hepatocyte maturation in liver organoids, but organoid self-organization requires cell-to-cell surface contact. Our in vitro model demonstrates a novel approach to identify developmental paracrine signals regulating the differentiation of human hepatocytes. Asai, Akihiro Aihara, Eitaro Watson, Carey Mourya, Reena Mizuochi, Tatsuki Shivakumar, Pranavkumar Phelan, Kieran Mayhew, Christopher Helmrath, Michael Takebe, Takanori Wells, James Bezerra, Jorge A eng P30 DK/DK/NIDDK NIH HHS/ England Development. Mar 15;144(6):-. doi: 10./dev..I SomaScan 03/10/ Gawande BN, et al. Selection of DNA aptamers with two modified bases Proc Natl Acad Sci U S A 114 11 - https://www.doi.org/10./pnas. 28,265,062 *Aptamers, Nucleotide Cell Line, Tumor Deoxyribonucleases/metabolism Gene Library Humans Ligands PCSK9 Inhibitors Proprotein Convertase 9/chemistry/genetics *SELEX Aptamer Technique Pcsk9 Psma Selex SOMAmer modified aptamer SomaLogic, Inc. SOMAmer reagent is a registered trademark of SomaLogic, Inc. The nucleobases comprising DNA and RNA aptamers provide considerably less chemical diversity than protein-based ligands, limiting their versatility. The introduction of novel functional groups at just one of the four bases in modified aptamers has recently led to dramatic improvement in the success rate of identifying nucleic acid ligands to protein targets. Here we explore the benefits of additional enhancement in physicochemical diversity by selecting modified DNA aptamers that contain amino-acid-like modifications on both pyrimidine bases. Using proprotein convertase subtilisin/kexin type 9 as a representative protein target, we identify specific pairwise combinations of modifications that result in higher affinity, metabolic stability, and inhibitory potency compared with aptamers with single modifications. Such doubly modified aptamers are also more likely to be encoded in shorter sequences and occupy nonoverlapping epitopes more frequently than aptamers with single modifications. These highly modified DNA aptamers have broad utility in research, diagnostic, and therapeutic applications. Gawande, Bharat N Rohloff, John C Carter, Jeffrey D von Carlowitz, Ira Zhang, Chi Schneider, Daniel J Janjic, Nebojsa eng Proc Natl Acad Sci U S A. Mar 14;114(11):-. doi: 10./pnas.. Epub Mar 6.I SomaScan 03/08/ Wood GC, et al. A multi-component classifier for nonalcoholic fatty liver disease (NAFLD) based on genomic, proteomic, and phenomic data domains Sci Rep 7 https://www.doi.org/10./srep 28,266,614 Bariatric Surgery Biomarkers/*analysis *Decision Support Techniques Genomics/*methods Humans Non-alcoholic Fatty Liver Disease/*classification/*pathology Obesity/*complications/surgery Proteomics/*methods ROC Curve Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions that include steatohepatitis and fibrosis that are thought to emanate from hepatic steatosis. Few robust biomarkers or diagnostic tests have been developed for hepatic steatosis in the setting of obesity. We have developed a multi-component classifier for hepatic steatosis comprised of phenotypic, genomic, and proteomic variables using data from 576 adults with extreme obesity who underwent bariatric surgery and intra-operative liver biopsy. Using a 443 patient training set, protein biomarker discovery was performed using the highly multiplexed SOMAscan((R)) proteomic assay, a set of 19 clinical variables, and the steatosis predisposing PNPLA3 rs single nucleotide polymorphism genotype status. The most stable markers were selected using a stability selection algorithm with a L(1)-regularized logistic regression kernel and were then fitted with logistic regression models to classify steatosis, that were then tested against a 133 sample blinded verification set. The highest area under the ROC curve (AUC) for steatosis of PNPLA3 rs genotype, 8 proteins, or 19 phenotypic variables was 0.913, whereas the final classifier that included variables from all three domains had an AUC of 0.935. These data indicate that multi-domain modeling has better predictive power than comprehensive analysis of variables from a single domain. Wood, G Craig Chu, Xin Argyropoulos, George Benotti, Peter Rolston, David Mirshahi, Tooraj Petrick, Anthony Gabrielson, John Carey, David J DiStefano, Johanna K Still, Christopher D Gerhard, Glenn S eng R01 DK/DK/NIDDK NIH HHS/ Evaluation Study Research Support, N.I.H., Extramural England Sci Rep. Mar 7;7:. doi: 10./srep.I SomaScan 03/08/ Romero R, et al. The maternal plasma proteome changes as a function of gestational age in normal pregnancy: a longitudinal study Am J Obstet Gynecol 217 1 67 e1-67 e21 https://www.doi.org/10./j.ajog..02.037 28,263,753 Adult Biomarkers/blood Blood Proteins/*analysis Female *Gestational Age Humans Longitudinal Studies Pregnancy Pregnancy Complications/blood *Pregnancy Outcome Prospective Studies Proteome/*analysis Proteomics/methods C-C motif-28 aptamer biomarker carbonic anhydrase-6 dual-specificity mitogen-activated protein kinase kinase-4 glypican-3 high-throughput biology interleukin-1 receptor 4 placental growth factor pregnancy-associated plasma protein A prolactin proteins sialic acid-binding immunoglobulin-type lectin-6 OBJECTIVE: Pregnancy is accompanied by dramatic physiological changes in maternal plasma proteins. Characterization of the maternal plasma proteome in normal pregnancy is an essential step for understanding changes to predict pregnancy outcome. The objective of this study was to describe maternal plasma proteins that change in abundance with advancing gestational age and determine biological processes that are perturbed in normal pregnancy. STUDY DESIGN: A longitudinal study included 43 normal pregnancies that had a term delivery of an infant who was appropriate for gestational age without maternal or neonatal complications. For each pregnancy, 3 to 6 maternal plasma samples (median, 5) were profiled to measure the abundance of proteins using multiplex assays. Linear mixed-effects models with polynomial splines were used to model protein abundance as a function of gestational age, and the significance of the association was inferred via likelihood ratio tests. Proteins considered to be significantly changed were defined as having the following: (1) >1.5-fold change between 8 and 40 weeks of gestation; and (2) a false discovery rate-adjusted value of P < .1. Gene ontology enrichment analysis was used to identify biological processes overrepresented among the proteins that changed with advancing gestation. RESULTS: The following results were found: (1) Ten percent (112 of ) of the profiled proteins changed in abundance as a function of gestational age; (2) of the proteins analyzed, glypican-3, sialic acid-binding immunoglobulin-type lectin-6, placental growth factor, C-C motif-28, carbonic anhydrase 6, prolactin, interleukin-1 receptor 4, dual-specificity mitogen-activated protein kinase 4, and pregnancy-associated plasma protein-A had more than a 5-fold change in abundance across gestation (these 9 proteins are known to be involved in a wide range of both physiological and pathological processes, such as growth regulation, embryogenesis, angiogenesis immunoregulation, inflammation etc); and (3) biological processes associated with protein changes in normal pregnancy included defense response, defense response to bacteria, proteolysis, and leukocyte migration (false discovery rate, 10%). CONCLUSION: The plasma proteome of normal pregnancy demonstrates dramatic changes in both the magnitude of changes and the fraction of the proteins involved. Such information is important to understand the physiology of pregnancy and the development of biomarkers to differentiate normal vs abnormal pregnancy and determine the response to interventions. Romero, Roberto Erez, Offer Maymon, Eli Chaemsaithong, Piya Xu, Zhonghui Pacora, Percy Chaiworapongsa, Tinnakorn Done, Bogdan Hassan, Sonia S Tarca, Adi L eng HHSNC/HD/NICHD NIH HHS/ ZIA HD-26/Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Am J Obstet Gynecol. Jul;217(1):67.e1-67.e21. doi: 10./j.ajog..02.037. Epub Mar 3.I SomaScan 03/07/ Guiraud S, et al. Identification of serum protein biomarkers for utrophin based DMD therapy Sci Rep 7 https://www.doi.org/10./srep 28,252,048 Animals *Biomarkers *Blood Proteins Disease Models, Animal Enzyme-Linked Immunosorbent Assay Humans Mice Mice, Transgenic Muscular Dystrophy, Animal Muscular Dystrophy, Duchenne/blood/genetics/therapy Proteome Proteomics/methods Translational Research, Biomedical Utrophin/*blood/therapeutic use Despite promising therapeutic avenues, there is currently no effective treatment for Duchenne muscular dystrophy (DMD), a lethal monogenic disorder caused by the loss of the large cytoskeletal protein, dystrophin. A highly promising approach to therapy, applicable to all DMD patients irrespective to their genetic defect, is to modulate utrophin, a functional paralogue of dystrophin, able to compensate for the primary defects of DMD restoring sarcolemmal stability. One of the major difficulties in assessing the effectiveness of therapeutic strategies is to define appropriate outcome measures. In the present study, we utilised an aptamer based proteomics approach to profile 1,310 proteins in plasma of wild-type, mdx and Fiona (mdx overexpressing utrophin) mice. Comparison of the C57 and mdx sera revealed 83 proteins with statistically significant >2 fold changes in dystrophic serum abundance. A large majority of previously described biomarkers (ANP32B, THBS4, CAMK2A/B/D, CYCS, CAPNI) were normalised towards wild-type levels in Fiona animals. This work also identified potential mdx markers specific to increased utrophin (DUS3, TPI1) and highlights novel mdx biomarkers (GITR, MYBPC1, HSP60, SIRT2, SMAD3, CNTN1). We define a panel of putative protein mdx biomarkers to evaluate utrophin based strategies which may help to accelerate their translation to the clinic. Guiraud, Simon Edwards, Benjamin Squire, Sarah E Babbs, Arran Shah, Nandini Berg, Adam Chen, Huijia Davies, Kay E eng MR/N/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't England Sci Rep. Mar 2;7:. doi: 10./srep.I SomaScan 03/03/ Suhre K, et al. Connecting genetic risk to disease end points through the human blood plasma proteome Nat Commun 8 https://www.doi.org/10./ncomms 28,240,269 Alleles Blood Proteins/*metabolism Complement System Proteins/metabolism Drug Delivery Systems *Endpoint Determination Gene Regulatory Networks *Genetic Predisposition to Disease Genetic Variation Genome, Human Genome-Wide Association Study Glycoproteins/metabolism Heme/metabolism Humans Molecular Sequence Annotation Pharmacogenetics Protein Processing, Post-Translational/genetics Proteome/genetics/*metabolism Quantitative Trait Loci RNA Splicing/genetics RNA, Messenger/genetics/metabolism Reproducibility of Results Risk Factors Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence to map disease associations and translate them into clinical applications. However, although hundreds of genetic variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits are key in establishing functional links between GWAS-identified risk-variants and disease end points. Here we describe a GWAS using a highly multiplexed aptamer-based affinity proteomics platform. We quantify 539 associations between protein levels and gene variants (pQTLs) in a German cohort and replicate over half of them in an Arab and Asian cohort. Fifty-five of the replicated pQTLs are located in trans. Our associations overlap with 57 genetic risk loci for 42 unique disease end points. We integrate this information into a genome-proteome network and provide an interactive web-tool for interrogations. Our results provide a basis for novel approaches to pharmaceutical and diagnostic applications. Suhre, Karsten Arnold, Matthias Bhagwat, Aditya Mukund Cotton, Richard J Engelke, Rudolf Raffler, Johannes Sarwath, Hina Thareja, Gaurav Wahl, Annika DeLisle, Robert Kirk Gold, Larry Pezer, Marija Lauc, Gordan El-Din Selim, Mohammed A Mook-Kanamori, Dennis O Al-Dous, Eman K Mohamoud, Yasmin A Malek, Joel Strauch, Konstantin Grallert, Harald Peters, Annette Kastenmuller, Gabi Gieger, Christian Graumann, Johannes eng Research Support, Non-U.S. Gov't England Nat Commun. Feb 27;8:. doi: 10./ncomms.I SomaScan 02/28/ Trausch JJ, et al. Development and Characterization of an HPV Type-16 Specific Modified DNA Aptamer for the Improvement of Potency Assays Anal Chem 89 6 - https://www.doi.org/10./acs.analchem.6b 28,233,502 Antigen-Antibody Reactions Antigens, Viral/*immunology Aptamers, Nucleotide/chemical synthesis/chemistry/*immunology Enzyme-Linked Immunosorbent Assay Epitopes/*immunology Human papillomavirus 16/*immunology Humans Papillomavirus Vaccines/*immunology Measuring vaccine potency is critical for vaccine release and is often accomplished using antibody-based ELISAs. Antibodies can be associated with significant drawbacks that are often overlooked including lot-to-lot variability, problems with cell-line maintenance, limited stability, high cost, and long discovery lead times. Here, we address many of these issues through the development of an aptamer, known as a slow off-rate modified DNA aptamer (SOMAmer), which targets a vaccine antigen in the human papillomavirus (HPV) vaccine Gardasil. The aptamer, termed HPV-07, was selected to bind the Type 16 virus-like-particle (VLP) formed by the self-assembling capsid protein L1. It is capable of binding with high sensitivity (EC(50) of 0.1 to 0.4 mug/mL depending on assay format) while strongly discriminating against other VLP types. The aptamer competes for binding with the neutralizing antibody H16.V5, indicating at least partial recognition of a neutralizing and clinically relevant epitope. This makes it a useful reagent for measuring both potency and stability. When used in an ELISA format, the aptamer displays both high precision (intermediate precision of 6.3%) and a large linear range spanning from 25% to 200% of a typical formulation. To further exploit the advantages of aptamers, a simplified mix and read assay was also developed. This assay format offers significant time and resource reductions compared to a traditional ELISA. These results show aptamers are suitable reagents for biological potency assays, and we expect that their implementation could improve upon current assay formats. Trausch, Jeremiah J Shank-Retzlaff, Mary Verch, Thorsten eng Research Support, Non-U.S. Gov't Anal Chem. Mar 21;89(6):-. doi: 10./acs.analchem.6b. Epub Mar 8.I SomaScan 02/25/ van den Broek TJ, et al. The impact of micronutrient status on health: correlation network analysis to understand the role of micronutrients in metabolic-inflammatory processes regulating homeostasis and phenotypic flexibility Genes Nutr 12 5 https://www.doi.org/10./s-017--7 28,194,237 Carotenoids Glucose Inflammation Lipid Metabolic challenge test Phenotypic flexibility Systems biology Vitamins BACKGROUND: Vitamins and carotenoids are key micronutrients facilitating the maintenance of health, as evidenced by the increased risk of disease with low intake. Optimal phenotypic flexibility, i.e., the ability to respond to a physiological challenge, is an essential indicator of health status. Therefore, health can be measured by applying a challenge test and monitoring the response of relevant phenotypic processes. In this study, we assessed the correlation of three fat-soluble vitamins, (i.e., vitamin A or retinol, vitamin D(3), two homologues of vitamin E) and four carotenoids (i.e., alpha-carotene, beta-carotene, beta-cryptoxanthin, and lycopene), with characteristics of metabolic and inflammatory parameters at baseline and in response to a nutritional challenge test (NCT) in a group of 36 overweight and obese male subjects, using proteomics and metabolomics platforms. The phenotypic flexibility concept implies that health can be measured by the ability to adapt to a NCT, which may offer a more sensitive way to assess changes in health status of healthy subjects. RESULTS: Correlation analyses of results after overnight fasting revealed a rather evenly distributed network in a number of relatively strong correlations per micronutrient, with minor overlap between correlation profiles of each compound. Correlation analyses of challenge response profiles for metabolite and protein parameters with micronutrient status revealed a network that is more skewed towards alpha-carotene and gamma-tocopherol suggesting a more prominent role for these micronutrients in the maintenance of phenotypic flexibility. Comparison of the networks revealed that there is merely overlap of two parameters (inositol and oleic acid (C18:1)) affirming that there is a specific biomarker response profile upon NCT. CONCLUSIONS: Our study shows that applying the challenge test concept is able to reveal previously unidentified correlations between specific micronutrients and health-related processes, with potential relevance for maintenance of health that were not observed by correlating homeostatic measurements. This approach will contribute to insights on the influence of micronutrients on health and help to create efficient micronutrient intervention programs. van den Broek, Tim J Kremer, Bas H A Marcondes Rezende, Marisa Hoevenaars, Femke P M Weber, Peter Hoeller, Ulrich van Ommen, Ben Wopereis, Suzan eng Germany Genes Nutr. Feb 8;12:5. doi: 10./s-017--7. eCollection .I SomaScan 02/15/ Di Narzo AF, et al. High-Throughput Characterization of Blood Serum Proteomics of IBD Patients with Respect to Aging and Genetic Factors PLoS Genet 13 1 e https://www.doi.org/10./journal.pgen. 28,129,359 Adult Aging/*blood Biomarkers/blood Case-Control Studies Female *Genetic Predisposition to Disease Hepatocyte Growth Factor/blood High-Throughput Screening Assays Humans Inflammatory Bowel Diseases/*blood/epidemiology/genetics Male Middle Aged Polymorphism, Single Nucleotide Proteome/genetics/*metabolism Proto-Oncogene Proteins/blood Quantitative Trait Loci To date, no large scale, systematic description of the blood serum proteome has been performed in inflammatory bowel disease (IBD) patients. By using microarray technology, a more complete description of the blood proteome of IBD patients is feasible. It may help to achieve a better understanding of the disease. We analyzed blood serum profiles of proteins in IBD patients of European descent (84 Crohn's Disease (CD) subjects and 88 Ulcerative Colitis (UC) subjects) as well as 15 healthy control subjects, and linked protein variability to patient age (all cohorts) and genetic components (genotype data generated from CD patients). We discovered new, previously unreported aging-associated proteomic traits (such as serum Albumin level), confirmed previously reported results from different tissues (i.e., upregulation of APOE with aging), and found loss of regulation of MMP7 in CD patients. In carrying out a genome wide genotype-protein association study (proteomic Quantitative Trait Loci, pQTL) within the CD patients, we identified 41 distinct proteomic traits influenced by cis pQTLs (underlying SNPs are referred to as pSNPs). Significant overlaps between pQTLs and cis eQTLs corresponding to the same gene were observed and in some cases the QTL were related to inflammatory disease susceptibility. Importantly, we discovered that serum protein levels of MST1 (Macrophage Stimulating 1) were regulated by SNP rs (p = 5.96E-10, FDR<5%), an accepted GWAS locus for IBD. Filling the knowledge gap of molecular mechanisms between GWAS hits and disease susceptibility requires systematically dissecting the impact of the locus at the cell, mRNA expression, and protein levels. The technology and analysis tools that are now available for large-scale molecular studies can elucidate how alterations in the proteome driven by genetic polymorphisms cause or provide protection against disease. Herein, we demonstrated this directly by integrating proteomic and pQTLs with existing GWAS, mRNA expression, and eQTL datasets to provide insights into the biological processes underlying IBD and pinpoint causal genetic variants along with their downstream molecular consequences. Di Narzo, Antonio F Telesco, Shannon E Brodmerkel, Carrie Argmann, Carmen Peters, Lauren A Li, Katherine Kidd, Brian Dudley, Joel Cho, Judy Schadt, Eric E Kasarskis, Andrew Dobrin, Radu Hao, Ke eng Research Support, Non-U.S. Gov't PLoS Genet. Jan 27;13(1):e. doi: 10./journal.pgen.. eCollection Jan.I SomaScan 01/28/ Sasayama D, et al. Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome Hum Mol Genet 26 1 44-51 https://www.doi.org/10./hmg/ddw366 28,031,287 Biomarkers/*cerebrospinal fluid *Genome, Human Genome-Wide Association Study Humans Mental Disorders/cerebrospinal fluid/*genetics/pathology Phenotype Polymorphism, Single Nucleotide/*genetics Protein Array Analysis Proteome/*genetics Proteomics/methods Quantitative Trait Loci/*genetics Cerebrospinal fluid (CSF) is virtually the only one accessible source of proteins derived from the central nervous system (CNS) of living humans and possibly reflects the pathophysiology of a variety of neuropsychiatric diseases. However, little is known regarding the genetic basis of variation in protein levels of human CSF. We examined CSF levels of 1,126 proteins in 133 subjects and performed a genome-wide association analysis of 514,227 single nucleotide polymorphisms (SNPs) to detect protein quantitative trait loci (pQTLs). To be conservative, Spearman's correlation was used to identify an association between genotypes of SNPs and protein levels. A total of 421 cis and 25 trans SNP-protein pairs were significantly correlated at a false discovery rate (FDR) of less than 0.01 (nominal P < 7.66 x 10-9). Cis-only analysis revealed additional 580 SNP-protein pairs with FDR < 0.01 (nominal P < 2.13 x 10-5). pQTL SNPs were more likely, compared to non-pQTL SNPs, to be a disease/trait-associated variants identified by previous genome-wide association studies. The present findings suggest that genetic variations play an important role in the regulation of protein expression in the CNS. The obtained database may serve as a valuable resource to understand the genetic bases for CNS protein expression pattern in humans. Sasayama, Daimei Hattori, Kotaro Ogawa, Shintaro Yokota, Yuuki Matsumura, Ryo Teraishi, Toshiya Hori, Hiroaki Ota, Miho Yoshida, Sumiko Kunugi, Hiroshi eng Research Support, Non-U.S. Gov't England Hum Mol Genet. Jan 1;26(1):44-51. doi: 10./hmg/ddw366.I SomaScan 12/30/ Zyba SJ, et al. A moderate increase in dietary zinc reduces DNA strand breaks in leukocytes and alters plasma proteins without changing plasma zinc concentrations Am J Clin Nutr 105 2 343-351 https://www.doi.org/10./ajcn.116. 28,003,206 Adult Blood Proteins/*metabolism Body Composition Body Mass Index Cation Transport Proteins/blood DNA Damage/*drug effects Diet Edible Grain/chemistry *Food, Fortified Humans Leukocytes/drug effects/metabolism Male Metallothionein/blood Middle Aged Oxidative Stress/drug effects Phytic Acid/administration & dosage/blood Proteomics Young Adult Zinc/*administration & dosage/*blood DNA repair antioxidant inflammation zinc biomarkers zinc fortification BACKGROUND: Food fortification has been recommended to improve a population's micronutrient status. Biofortification techniques modestly elevate the zinc content of cereals, but few studies have reported a positive impact on functional indicators of zinc status. OBJECTIVE: We determined the impact of a modest increase in dietary zinc that was similar to that provided by biofortification programs on whole-body and cellular indicators of zinc status. DESIGN: Eighteen men participated in a 6-wk controlled consumption study of a low-zinc, rice-based diet. The diet contained 6 mg Zn/d for 2 wk and was followed by 10 mg Zn/d for 4 wk. To reduce zinc absorption, phytate was added to the diet during the initial period. Indicators of zinc homeostasis, including total absorbed zinc (TAZ), the exchangeable zinc pool (EZP), plasma and cellular zinc concentrations, zinc transporter gene expression, and other metabolic indicators (i.e., DNA damage, inflammation, and oxidative stress), were measured before and after each dietary-zinc period. RESULTS: TAZ increased with increased dietary zinc, but plasma zinc concentrations and EZP size were unchanged. Erythrocyte and leukocyte zinc concentrations and zinc transporter expressions were not altered. However, leukocyte DNA strand breaks decreased with increased dietary zinc, and the level of proteins involved in DNA repair and antioxidant and immune functions were restored after the dietary-zinc increase. CONCLUSIONS: A moderate 4-mg/d increase in dietary zinc, similar to that which would be expected from zinc-biofortified crops, improves zinc absorption but does not alter plasma zinc. The repair of DNA strand breaks improves, as do serum protein concentrations that are associated with the DNA repair process. This trial was registered at clinicaltrials.gov as NCT. Zyba, Sarah J Shenvi, Swapna V Killilea, David W Holland, Tai C Kim, Elijah Moy, Adrian Sutherland, Barbara Gildengorin, Virginia Shigenaga, Mark K King, Janet C eng Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Clin Nutr. Feb;105(2):343-351. doi: 10./ajcn.116.. Epub Dec 21.I SomaScan 12/23/ De Groote MA, et al. Highly Multiplexed Proteomic Analysis of Quantiferon Supernatants To Identify Biomarkers of Latent Tuberculosis Infection J Clin Microbiol 55 2 391-402 https://www.doi.org/10./JCM.-16 27,852,671 Adolescent Adult Biomarkers/*analysis Emigrants and Immigrants Enzyme-Linked Immunospot Assay/methods Female Humans Immunologic Factors/*analysis Interferon-gamma Release Tests/methods Latent Tuberculosis/*diagnosis Male Middle Aged Proteome/*analysis Proteomics/*methods Tuberculin Test/methods United States Young Adult biomarkers diagnosis immunity latent infection proteomics tuberculosis The tests for diagnosing latent tuberculosis infection (LTBI) are limited by a poor predictive value for identifying people at the highest risk for progressing to active tuberculosis (TB) and have various sensitivities and specificities in different populations. Identifying a more robust signature for LTBI is important for TB prevention and elimination. A pilot study was conducted with samples from immigrants to the United States that were screened for LTBI by the three commercially approved tests, namely, the tuberculin skin test (TST), the Quantiferon-TB Gold in-tube (QFT-GIT), and the T-SPOT.TB (T-SPOT). QFT-GIT supernatants from 13 people with concordant positive results and 26 people with concordant negative results were analyzed via the highly multiplexed SOMAscan proteomic assay. The proteins in the stimulated supernatants that distinguished LTBI from controls included interleukin-2 (IL-2), monocyte chemotactic protein 2 (MCP-2), interferon gamma inducible protein-10 (IP-10), interferon gamma (IFN-gamma), tumor necrosis factor superfamily member 14 (TNFSF14, also known as LIGHT), monokine induced by gamma interferon (MIG), and granzyme B (P <0.). In addition, antigen stimulation increased the expression of heparin-binding EGF-like growth factor (HB-EGF) and activin AB in LTBI samples. In nil tubes, LIGHT was the most significant marker (P <0.) and was elevated in LTBI subjects. Other prominent markers in nonstimulated QFT-GIT supernatants were the complement-3 components C3b, iC3b, and C3d, which were upregulated in LTBI and markedly decreased upon stimulation. We found known and novel proteins that warrant further studies for developing improved tests for LTBI, for predicting progression to active disease, and for discriminating LTBI from active TB. De Groote, Mary Ann Higgins, Michael Hraha, Thomas Wall, Kirsten Wilson, Michael L Sterling, David G Janjic, Nebojsa Reves, Randall Ochsner, Urs A Belknap, Robert eng J Clin Microbiol. Feb;55(2):391-402. doi: 10./JCM.-16. Epub Nov 16.I SomaScan 11/18/ Jung YJ, et al. Development of a Protein Biomarker Panel to Detect Non-Small-Cell Lung Cancer in Korea Clin Lung Cancer 18 2 e99-e107 https://www.doi.org/10./j.cllc..09.012 27,836,219 Adenocarcinoma/blood/*diagnosis Antigens, Neoplasm/blood Aptamers, Peptide/metabolism Area Under Curve Bayes Theorem Biomarkers, Tumor/*blood Carcinoma, Large Cell/blood/*diagnosis Carcinoma, Non-Small-Cell Lung/blood/*diagnosis Carcinoma, Squamous Cell/blood/*diagnosis Case-Control Studies Early Detection of Cancer Female Humans Keratin-19/blood Lung Neoplasms/blood/*diagnosis Male Middle Aged Neoplasm Staging Prognosis Proteomics/*methods Aptamer Biomarker Cyfra 21-1 Lung cancer screening Lung nodule BACKGROUND: Lung cancer screening using low-dose computed tomography reduces lung cancer mortality. However, the high false-positive rate, cost, and potential harms highlight the need for complementary biomarkers. We compared the diagnostic performance of modified aptamer-based protein biomarkers with Cyfra 21-1. PATIENTS AND METHODS: Participants included 100 patients diagnosed with lung cancer, and 100 control subjects from Asan Medical Center (Seoul, Korea). We investigated candidate biomarkers with new modified aptamer-based proteomic technology and developed a 7-protein panel that discriminates lung cancer from controls. A naive Bayesian classifier was trained using sera from 75 lung cancers and 75 controls. An independent set of 25 cases and 25 controls was used to verify performance of this classifier. The panel results were compared with Cyfra 21-1 to evaluate the diagnostic accuracy for lung nodules detected by computed tomography. RESULTS: We derived a 7-protein biomarker classifier from the initial train set comprising: EGFR1, MMP7, CA6, KIT, CRP, C9, and SERPINA3. This classifier distinguished lung cancer cases from controls with an area under the curve (AUC) of 0.82 in the train set and an AUC of 0.77 in the verification set. The 7-marker naive Bayesian classifier resulted in 91.7% specificity with 75.0% sensitivity for the subset of individuals with lung nodules. The AUC of the classifier for lung nodules was 0.88, whereas Cyfra 21-1 had an AUC of 0.72. CONCLUSION: We have developed a protein biomarker panel to identify lung cancers from controls with a high accuracy. This integrated noninvasive approach to the evaluation of lung nodules deserves further prospective validation among larger cohorts of patients with lung nodules in screening strategy. Jung, Young Ju Katilius, Evaldas Ostroff, Rachel M Kim, Youndong Seok, Minkyoung Lee, Sujin Jang, Seongsoo Kim, Woo Sung Choi, Chang-Min eng Comparative Study Research Support, Non-U.S. Gov't Clin Lung Cancer. Mar;18(2):e99-e107. doi: 10./j.cllc..09.012. Epub Oct 5.I SomaScan 11/12/ Billing AM, et al. Complementarity of SOMAscan to LC-MS/MS and RNA-seq for quantitative profiling of human embryonic and mesenchymal stem cells J Proteomics 150 86-97 https://www.doi.org/10./j.jprot..08.023 27,613,379 Adult Aptamers, Peptide/analysis/metabolism Biomarkers/metabolism Cells, Cultured Chromatography, Liquid Embryonic Stem Cells/*metabolism Gene Expression Profiling/*methods Genomics/methods Humans Male Mesenchymal Stem Cells/*metabolism Proteomics/*methods RNA/analysis *Sequence Analysis, RNA Tandem Mass Spectrometry/*methods Young Adult Embryonic stem cells Mesenchymal stem cells Quantitative LC-MS/MS RNA-seq SOMAscan assay Dynamic range limitations are challenging to proteomics, particularly in clinical samples. Affinity proteomics partially overcomes this, yet suffers from dependence on reagent quality. SOMAscan, an aptamer-based platform for over proteins, avoids that issue using nucleic acid binders. Targets include low expressed proteins not easily accessible by other approaches. Here we report on the potential of SOMAscan for the study of differently sourced mesenchymal stem cells (MSC) in comparison to LC-MS/MS and RNA sequencing. While targeting fewer analytes, SOMAscan displays high precision and dynamic range coverage, allowing quantification of proteins not measured by the other platforms. Expression between cell types (ESC and MSC) was compared across techniques and uncovered the expected large differences. Sourcing was investigated by comparing subtypes: bone marrow-derived, standard in clinical studies, and ESC-derived MSC, thought to hold similar potential but devoid of inter-donor variability and proliferating faster in vitro. We confirmed subtype-equivalency, as well as vesicle and extracellular matrix related processes in MSC. In contrast, the proliferative nature of ESC was captured less by SOMAscan, where nuclear proteins are underrepresented. The complementary of SOMAscan allowed the comprehensive exploration of CD markers and signaling molecules, not readily accessible otherwise and offering unprecedented potential in subtype characterization. SIGNIFICANCE: Mesenchymal stem cells (MSC) represent promising stem cell-derived therapeutics as indicated by their application in >500 clinical trials currently registered with the NIH. Tissue-derived MSC require invasive harvesting and imply donor-to-donor differences, to which embryonic stem cell (ESC)-derived MSC may provide an alternative and thus warrant thorough characterization. In continuation of our previous study where we compared in depth embryonic stem cells (ESC) and MSC from two sources (bone marrow and ESC-derived), we included the aptamer-based SOMAscan assay, complementing LC-MS/MS and RNA-seq data. Furthermore, SOMAscan, a targeted proteomics platform developed for analyzing clinical samples, has been benchmarked against established analytical platforms (LC-MS/MS and RNA-seq) using stem cell comparisons as a model. Billing, Anja M Ben Hamidane, Hisham Bhagwat, Aditya M Cotton, Richard J Dib, Shaima S Kumar, Pankaj Hayat, Shahina Goswami, Neha Suhre, Karsten Rafii, Arash Graumann, Johannes eng Netherlands J Proteomics. Jan 6;150:86-97. doi: 10./j.jprot..08.023. Epub Sep 6.I SomaScan 10/25/ Qiao Z, et al. Proteomic study of hepatocellular carcinoma using a novel modified aptamer-based array (SOMAscan) platform Biochim Biophys Acta Proteins Proteom 4 434-443 https://www.doi.org/10./j.bbapap..09.011 27,663,888 Aptamers, Nucleotide/*chemistry *Carcinoma, Hepatocellular/genetics/metabolism Female *Gene Expression Regulation, Neoplastic Humans *Liver Neoplasms/genetics/metabolism Male *Neoplasm Proteins/biosynthesis/genetics Oligonucleotide Array Sequence Analysis/*methods Hepatocellular carcinoma SOMAscan Vascular invasion Vascular invasion is a pathological hallmark of hepatocellular carcinoma (HCC), associated with poor prognosis; it is strongly related to the early recurrence and poor survival after curative resection. In order to determine the proteomic backgrounds of HCC carcinogenesis and vascular invasion, we employed a novel modified aptamer-based array (SOMAscan) platform. SOMAscan is based on the Slow Off-rate Modified Aptamers (SOMAmers), which rely on the natural 3D folding of single-stranded DNA-based protein affinity reagents. Currently, the expression level of proteins can be assessed quantitatively. Correlation matrix analysis showed that the overall proteomic features captured by SOMAscan differ between tumor and non-tumor tissues. Non-tumor tissues were shown to have more homogeneous proteome backgrounds than tumor tissues. A comparative study identified 68 proteins with differential expression between tumor and non-tumor tissues, together with eight proteins associated with vascular invasion. Gene Ontology analysis showed that the extracellular space and extracellular region proteins were predominantly detected. Network analysis revealed the linkage of seven proteins, AKT1, MDM2, PTEN, FGF1, MAPK8, PRKCB, and FN1, which were categorized as the components of Pathways in cancer" in pathway analysis. The results of SOMAscan analysis were not concordant with those obtained by western blotting; only the determined FN1 levels were concordant between the two platforms. We demonstrated that the proteome captured by SOMAscan includes the proteins relevant to carcinogenesis and vascular invasion in HCC. The identified proteins may serve as candidates for the future studies of disease mechanisms and clinical applications." Qiao, Zhiwei Pan, Xiaoqing Parlayan, Cuneyd Ojima, Hidenori Kondo, Tadashi eng Research Support, Non-U.S. Gov't Netherlands Biochim Biophys Acta Proteins Proteom. Apr;(4):434-443. doi: 10./j.bbapap..09.011. Epub Sep 20.I SomaScan 09/25/ Rice LM, et al. A Proteome-Derived Longitudinal Pharmacodynamic Biomarker for Diffuse Systemic Sclerosis Skin J Invest Dermatol 137 1 62-70 https://www.doi.org/10./j.jid..08.027 27,640,094 Adult Biomarkers/blood Case-Control Studies Cytokines/*metabolism Enzyme-Linked Immunosorbent Assay Female Humans Linear Models Longitudinal Studies Male Middle Aged Pharmacogenomic Testing Proteome/*metabolism Reproducibility of Results Scleroderma, Diffuse/*blood/drug therapy/physiopathology Severity of Illness Index In this study we systematically investigated alterations in the serum proteome of patients with diffuse cutaneous systemic sclerosis and identified differentially expressed proteins that correlated with disease severity. Our goal was to identify a combination of serum proteins that would provide a biological measure for the extent of skin disease and that could be combined into a longitudinal pharmacodynamic biomarker. We found that 16% of the sera proteins analyzed by SOMAscan aptamer technology, from two cohorts of patients with diffuse cutaneous systemic sclerosis, were identified as differentially regulated between diffuse cutaneous systemic sclerosis and controls and correlated with modified Rodnan skin score. This dataset showed tumor necrosis factor-alpha, IFN-gamma, transforming growth factor-beta, and IL-13 as potential upstream regulators of the serum protein patterns in the sera of patients with diffuse cutaneous systemic sclerosis. By ELISA, two analytes (ST2 and Spondin-1) best described longitudinal change in modified Rodnan skin score, using linear mixed models. This model was then validated in three independent cohorts. In this study we discovered a large array of proteins not previously associated with systemic sclerosis that provide insight into pathogenesis and potential targets for therapeutic intervention. Furthermore, we show that two of these proteins can be combined to form a robust longitudinal biomarker that might be used in clinical trials to assess changes in diffuse cutaneous systemic sclerosis skin disease over time. Rice, Lisa M Mantero, Julio C Stifano, Giuseppina Ziemek, Jessica Simms, Robert W Gordon, Jessica Domsic, Robyn Lafyatis, Robert eng UL1 TR/TR/NCATS NIH HHS/ P30 AR/AR/NIAMS NIH HHS/ P50 AR/AR/NIAMS NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Invest Dermatol. Jan;137(1):62-70. doi: 10./j.jid..08.027. Epub Sep 14.I SomaScan 09/19/ Escolano JM, et al. Selection of aptamers to Neisseria meningitidis and Streptococcus pneumoniae surface specific proteins and affinity assay using thin film AlN resonators Sensors and Actuators B: Chemical 246 591-596 https://www.doi.org/10./j.snb..02.098 Meningitis SOMAmer AlN gravimetric biosensor PavA FHbp The first steps in the development of an aptasensor for bacterial meningitis diagnosis in real time are described: slow off-rate modified aptamers (SOMAmer) selection, gravimetric sensor fabrication and functionalization of its active surface. SOMAmers polyclonal populations were generated to surface specific proteins PavA (S. pneumoniae) and FHbp (N. meningitidis) by systematic evolution of ligands by exponential enrichment method (SELEX). After eight rounds, they were tested by direct enzyme-linked oligonucleotide assays (ELONA) and by high frequency (1.4GHz) gravimetric sensors based on thin film AlN resonators operating in shear mode. The sensing surface of the resonators was functionalized using a silane-glutaraldehyde based protocol and the binding of PavA and FHbp was measured in real time. The SOMAmers polyclonal populations showing the best ELONA results have been also tested using gravimetric sensors and the binding to the protein functionalized surface was measured in real time showing positive results. These first steps towards the development of an aptasensor for the targeted bacteria demonstrate the potential of the method for sensitive, rapid, and cost effective detection of bacterial meningitis. Escolano, José M. Díaz-Durán, Bárbara DeMiguel-Ramos, Mario Olivares, Jimena Geday, Morten A. Iborra, Enrique SomaScan Tsim S, et al. Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma (DIAPHRAGM) study: protocol of a prospective, multicentre, observational study BMJ Open 6 11 e https://www.doi.org/10./bmjopen-- 27,884,852 Biomarkers, Tumor/blood Cross-Sectional Studies Extracellular Matrix Proteins/*blood GPI-Linked Proteins/*blood Humans Lung Neoplasms/*blood/*diagnostic imaging Magnetic Resonance Imaging Mesothelin Mesothelioma/*blood/*diagnostic imaging Mesothelioma, Malignant Prognosis Prospective Studies Proteomics/methods ROC Curve Research Design Scotland Biomarker Diagnosis Mesothelioma INTRODUCTION: Malignant pleural mesothelioma (MPM) is an asbestos-related cancer, which is difficult to diagnose. Thoracoscopy is frequently required but is not widely available. An accurate, non-invasive diagnostic biomarker would allow early specialist referral, limit diagnostic delays and maximise clinical trial access. Current markers offer insufficient sensitivity and are not routinely used. The SOMAmer proteomic classifier and fibulin-3 have recently demonstrated sensitivity and specificity exceeding 90% in retrospective studies. DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) is a suitably powered, multicentre, prospective observational study designed to determine whether these markers provide clinically useful diagnostic and prognostic information. METHODS AND ANALYSIS: Serum and plasma (for SOMAscan and fibulin-3, respectively) will be collected at presentation, prior to pleural biopsy/pleurodesis, from 83 to 120 patients with MPM, at least 480 patients with non-MPM pleural disease and 109 asbestos-exposed controls. Final numbers of MPM/non-MPM cases will depend on the incidence of MPM in the study population (estimated at 13-20%). Identical sampling and storage protocols will be used in 22 recruiting centres and histological confirmation sought in all cases. Markers will be measured using the SOMAscan proteomic assay (SomaLogic) and a commercially available fibulin-3 ELISA (USCN Life Science). The SE in the estimated sensitivity and specificity will be <5% for each marker and their performance will be compared with serum mesothelin. Blood levels will be compared with paired pleural fluid levels and MPM tumour volume (using MRI) in a nested substudy. The prognostic value of each marker will be assessed and a large bioresource created. ETHICS AND DISSEMINATION: The study has been approved by the West of Scotland Research Ethics Committee (Ref: 13/WS/). A Trial Management Group meets on a monthly basis. Results will be published in peer-reviewed journals, presented at international meetings and disseminated to patient groups. TRIAL REGISTRATION NUMBER: ISRCTN, Pre-results. Tsim, Selina Kelly, Caroline Alexander, Laura McCormick, Carol Thomson, Fiona Woodward, Rosie Foster, John E Stobo, David B Paul, Jim Maskell, Nick A Chalmers, Anthony Blyth, Kevin G eng ETM/285/CSO_/Chief Scientist Office/United Kingdom Multicenter Study Observational Study England BMJ Open. Nov 24;6(11):e. doi: 10./bmjopen--.I SomaScan 11/26/ Lynch AM, et al. The Relationship of Novel Plasma Proteins in the Early Neonatal Period With Retinopathy of Prematurity Invest Ophthalmol Vis Sci 57 11 - https://www.doi.org/10./iovs.16- 27,679,852 PURPOSE: Retinopathy of prematurity (ROP) is a vision-threatening disease associated with abnormal retinal vascular development. Proteins from the insulin-like growth factor pathway are related to ROP. However, there is a paucity of research on the role of other proteins in ROP. The aim of this study was to identify plasma proteins related to clinically significant ROP. METHODS: We measured plasma proteins in the early neonatal period in infants at risk for ROP using an aptamer-based proteomic technology. The primary aim of the study was to compare plasma protein concentrations in infants who did (n = 12) and did not (n = 23) subsequently develop clinically significant ROP using logistic regression. As a secondary aim, we examined patterns in the proteins across categories of clinically significant, low-grade, and no ROP groups. RESULTS: Lower levels of 16 proteins were associated with an increased risk of clinically significant ROP. In this group, superoxide dismutase (Mn), mitochondrial (MnSOD), and chordin-like protein 1 (CRDL1) were highly ranked. Other proteins in this group included: C-C motif chemokine 14 (HCC-1), prolactin, insulin-like growth factor-binding protein 7 (IGFBP-7), and eotaxin. Higher levels of 12 proteins were associated with a higher risk for ROP. Fibroblast growth factor 19 (FGF-19) was the top-ranked protein target followed by hepatocyte growth factor-like protein (MSP), luteinizing hormone (LH), cystatin M, plasminogen, and proprotein convertase subtilisin/kexin type 9 (PCSK9). We also noted different patterns in the trend of concentrations of proteins across the clinically significant, low-grade, and no ROP groups. CONCLUSIONS: We discovered plasma proteins with novel associations with clinically significant ROP (MnSOD, CRDL1, PCSK9), proteins with links to established ROP signaling pathways (IGFBP-7), and proteins such as MnSOD that may be a target for future therapeutic interventions. Lynch, Anne M Wagner, Brandie D Mandava, Naresh Palestine, Alan G Mourani, Peter M McCourt, Emily A Oliver, Scott C N Abman, Steven H eng R01 HL/HL/NHLBI NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ Invest Ophthalmol Vis Sci. Sep 1;57(11):-. doi: 10./iovs.16-.I SomaScan 09/30/ Heier CR, et al. Identification of Pathway-Specific Serum Biomarkers of Response to Glucocorticoid and Infliximab Treatment in Children with Inflammatory Bowel Disease Clin Transl Gastroenterol 7 9 e192 https://www.doi.org/10./ctg..49 27,628,422 OBJECTIVE: Serum biomarkers may serve to predict early response to therapy, identify relapse, and facilitate drug development in inflammatory bowel disease (IBD). Biomarkers are particularly important in children, in whom achieving early remission and minimizing procedures are especially beneficial. METHODS: We profiled protein and micro RNA (miRNA) in serum from patients pre- and post-therapy, to identify molecular markers of pharmacodynamic effect. Serum was obtained from children with IBD before and after treatment with either corticosteroids (prednisone; n=12) or anti-tumor necrosis factor-alpha biologic (infliximab; n=7). Over 1,100 serum proteins were assayed using aptamer-based SOMAscan proteomics, and 22 miRNAs analyzed by quantitative real time PCR. Concordance of longitudinal changes between the groups was used to identify markers responsive to treatment. Bioinformatic analysis was used to build insight into mechanisms of changes in response to treatment. RESULTS: We identified 18 proteins and three miRNAs responsive to both prednisone and infliximab. Eight markers that decreased are associated with inflammation and have gene promoters regulated by nuclear factor (NF)-kappaB. Several that increased are associated with resolving inflammation and tissue damage. We also identified six markers that appear to be steroid-specific, three of which have glucocorticoid receptor binding elements in their promoter region. CONCLUSIONS: Serum markers regulated by the inflammatory transcription factor NF-kappaB are potential candidates for pharmacodynamic biomarkers that, if correlated with later outcomes like endoscopic or histologic healing, could be used to monitor treatment, optimize dosing, and enhance drug development. The pharmacodynamic biomarkers identified here hold potential to improve both clinical care and drug development. Further studies are warranted to investigate these markers as early predictors of response, or possibly surrogate outcomes. Heier, Christopher R Fiorillo, Alyson A Chaisson, Ellen Gordish-Dressman, Heather Hathout, Yetrib Damsker, Jesse M Hoffman, Eric P Conklin, Laurie S eng K99 HL/HL/NHLBI NIH HHS/ L40 AR/AR/NIAMS NIH HHS/ R00 HL/HL/NHLBI NIH HHS/ Clin Transl Gastroenterol. Sep 15;7(9):e192. doi: 10./ctg..49.I SomaScan 09/16/ Hathout Y, et al. Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children Sci Rep 6 https://www.doi.org/10./srep 27,530,235 Adolescent Adrenal Cortex Hormones/adverse effects/blood/*therapeutic use Anti-Inflammatory Agents/adverse effects/*therapeutic use Biomarkers/blood Blood Proteins/metabolism Case-Control Studies Child Child, Preschool Cross-Sectional Studies Female Humans Inflammation Mediators/blood Inflammatory Bowel Diseases/*blood/*drug therapy Longitudinal Studies Male Muscular Dystrophy, Duchenne/*blood/*drug therapy Proteome/metabolism Corticosteroids are extensively used in pediatrics, yet the burden of side effects is significant. Availability of a simple, fast, and reliable biochemical read out of steroidal drug pharmacodynamics could enable a rapid and objective assessment of safety and efficacy of corticosteroids and aid development of corticosteroid replacement drugs. To identify potential corticosteroid responsive biomarkers we performed proteome profiling of serum samples from DMD and IBD patients with and without corticosteroid treatment using SOMAscan aptamer panel testing 1,129 proteins in <0.1 cc of sera. Ten pro-inflammatory proteins were elevated in untreated patients and suppressed by corticosteroids (MMP12, IL22RA2, CCL22, IGFBP2, FCER2, LY9, ITGa1/b1, LTa1/b2, ANGPT2 and FGG). These are candidate biomarkers for anti-inflammatory efficacy of corticosteroids. Known safety concerns were validated, including elevated non-fasting insulin (insulin resistance), and elevated angiotensinogen (salt retention). These were extended by new candidates for metabolism disturbances (leptin, afamin), stunting of growth (growth hormone binding protein), and connective tissue remodeling (MMP3). Significant suppression of multiple adrenal steroid hormones was also seen in treated children (reductions of 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol and testosterone). A panel of new pharmacodynamic biomarkers for corticosteroids in children was defined. Future studies will need to bridge specific biomarkers to mechanism of drug action, and specific clinical outcomes. Hathout, Yetrib Conklin, Laurie S Seol, Haeri Gordish-Dressman, Heather Brown, Kristy J Morgenroth, Lauren P Nagaraju, Kanneboyina Heier, Christopher R Damsker, Jesse M van den Anker, John N Henricson, Erik Clemens, Paula R Mah, Jean K McDonald, Craig Hoffman, Eric P eng R44 NS/NS/NINDS NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ R00 HL/HL/NHLBI NIH HHS/ L40 AR/AR/NIAMS NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ P50 AR/AR/NIAMS NIH HHS/ U54 HD/HD/NICHD NIH HHS/ K99 HL/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Sci Rep. Aug 17;6:. doi: 10./srep.I SomaScan 08/18/ Wu D, et al. Incorporation of Slow Off-Rate Modified Aptamers Reagents in Single Molecule Array Assays for Cytokine Detection with Ultrahigh Sensitivity Anal Chem 88 17 -9 https://www.doi.org/10./acs.analchem.6b 27,529,794 Antibodies/immunology Aptamers, Nucleotide/*chemistry Cytokines/*blood/immunology Enzyme-Linked Immunosorbent Assay Humans Indicators and Reagents/*chemistry Kinetics Slow off-rate modified aptamers (SOMAmers) are attractive protein recognition reagents due to their high binding affinities, stable chemical structures, easy production, and established selection process. Here, biotinylated SOMAmer reagents were incorporated into single molecule array (Simoa)-based assays in place of traditional detection antibodies for six cytokine targets. Optimization and validation were conducted for TNF-alpha as a demonstration using a capture antibody/detection-SOMAmer detection scheme to highlight the performance of this approach. The optimized assay has a broad dynamic range (>4 log10 units) and an ultralow detection limit of 0.67 fM (0.012 pg/mL). These results show comparable sensitivity to our antibody pair-based Simoa assays, and tens to thousands-fold enhancement in sensitivity compared with conventional ELISAs. High recovery percentages were observed in a spike-recovery test using human sera, demonstrating the feasibility of this novel Simoa assay in detecting TNF-alpha in clinically relevant samples. Detection SOMAmers were also used to detect other cytokines, such as IFN-gamma, IL-1beta, IL-2, IL-6, and IL-10, in human samples. Although not yet demonstrated, in principle it should be possible to eventually replace both the capture and detector antibodies with corresponding SOMAmer pairs in sandwich immunoassays. The combination of the ultrasensitive Simoa platform with the higher reliability of SOMAmer binding reagents will greatly benefit both biomarker discovery and disease diagnostic fields. Wu, Danlu Katilius, Evaldas Olivas, Edgar Dumont Milutinovic, Milena Walt, David R eng Letter Research Support, U.S. Gov't, Non-P.H.S. Anal Chem. Sep 6;88(17):-9. doi: 10./acs.analchem.6b. Epub Aug 23.I SomaScan 08/17/ Ashley SL, et al. Six-SOMAmer Index Relating to Immune, Protease and Angiogenic Functions Predicts Progression in IPF PLoS One 11 8 e https://www.doi.org/10./journal.pone. 27,490,795 Aged Area Under Curve Biomarkers/blood Cathepsins/metabolism Cysteine Endopeptidases/metabolism Disease Progression Disease-Free Survival Female Humans Idiopathic Pulmonary Fibrosis/immunology/metabolism/*pathology Inducible T-Cell Co-Stimulator Protein/metabolism Lectins/metabolism Logistic Models Male Middle Aged Peptide Hydrolases/*metabolism Proportional Hazards Models ROC Curve *Severity of Illness Index Smoking Vascular Endothelial Growth Factor Receptor-2/metabolism RATIONALE: Biomarkers in easily accessible compartments like peripheral blood that can predict disease progression in idiopathic pulmonary fibrosis (IPF) would be clinically useful regarding clinical trial participation or treatment decisions for patients. In this study, we used unbiased proteomics to identify relevant disease progression biomarkers in IPF. METHODS: Plasma from IPF patients was measured using an analyte slow off-rate modified aptamer (SOMAmer) array, and patient outcomes were followed over the next 80 weeks. Receiver operating characteristic (ROC) curves evaluated sensitivity and specificity for levels of each biomarker and estimated area under the curve (AUC) when prognostic biomarker thresholds were used to predict disease progression. Both logistic and Cox regression models advised biomarker selection for a composite disease progression index; index biomarkers were weighted via expected progression-free days lost during follow-up with a biomarker on the unfavorable side of the threshold. RESULTS: A six-analyte index, scaled 0 to 11, composed of markers of immune function, proteolysis and angiogenesis [high levels of ficolin-2 (FCN2), cathepsin-S (Cath-S), legumain (LGMN) and soluble vascular endothelial growth factor receptor 2 (VEGFsR2), but low levels of inducible T cell costimulator (ICOS) or trypsin 3 (TRY3)] predicted better progression-free survival in IPF with a ROC AUC of 0.91. An index score >/= 3 (group >/= 2) was strongly associated with IPF progression after adjustment for age, gender, smoking status, immunomodulation, forced vital capacity % predicted and diffusing capacity for carbon monoxide % predicted (HR 16.8, 95% CI 2.2-126.7, P = 0.006). CONCLUSION: This index, derived from the largest proteomic analysis of IPF plasma samples to date, could be useful for clinical decision making in IPF, and the identified analytes suggest biological processes that may promote disease progression. Ashley, Shanna L Xia, Meng Murray, Susan O'Dwyer, David N Grant, Ethan White, Eric S Flaherty, Kevin R Martinez, Fernando J Moore, Bethany B eng R01 HL/HL/NHLBI NIH HHS/ T32 AI/AI/NIAID NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ PLoS One. Aug 4;11(8):e. doi: 10./journal.pone.. eCollection .I SomaScan 08/05/ Gramolini A, et al. Identifying Low-Abundance Biomarkers: Aptamer-Based Proteomics Potentially Enables More Sensitive Detection in Cardiovascular Diseases Circulation 134 4 286-9 https://www.doi.org/10./CIRCULATIONAHA.116. 27,444,931 *Biomarkers Biomarkers, Tumor Cardiovascular Diseases/diagnosis Humans *Proteomics Editorials biomarkers cohort studies diagnosis prognosis proteomics Gramolini, Anthony Lau, Edward Liu, Peter P eng CIHR/Canada Comment Editorial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. Jul 26;134(4):286-9. doi: 10./CIRCULATIONAHA.116..I SomaScan 07/23/ Ngo D, et al. Aptamer-Based Proteomic Profiling Reveals Novel Candidate Biomarkers and Pathways in Cardiovascular Disease Circulation 134 4 270-85 https://www.doi.org/10./CIRCULATIONAHA.116. 27,444,932 Acute Coronary Syndrome/blood Adult Aptamers, Nucleotide/*metabolism Biomarkers/*blood Blood Proteins/*analysis Cardiomyopathy, Hypertrophic/*blood/complications Chromatography, Liquid DNA, Single-Stranded/metabolism Female Humans Longitudinal Studies Male Middle Aged Myocardial Infarction/*blood/etiology Phenotype Proteomics/*methods Reproducibility of Results Sensitivity and Specificity Tandem Mass Spectrometry aptamer, nucleotides cardiovascular diseases mass spectrometry myocardial infarction proteomics BACKGROUND: Single-stranded DNA aptamers are oligonucleotides of approximately 50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. Emerging DNA aptamer-based technologies may address limitations of existing proteomic techniques, including low sample throughput, which have hindered proteomic analyses of large cohorts. METHODS: To identify early biomarkers of myocardial injury, we applied an aptamer-based proteomic platform that measures proteins to a clinically relevant perturbational model of planned myocardial infarction (PMI), patients undergoing septal ablation for hypertrophic cardiomyopathy. Blood samples were obtained before and at 10 and 60 minutes after PMI, and protein changes were assessed by repeated-measures analysis of variance. The generalizability of our PMI findings was evaluated in a spontaneous myocardial infarction cohort (Wilcoxon rank-sum). We then tested the platform's ability to detect associations between proteins and Framingham Risk Score components in the Framingham Heart Study, performing regression analyses for each protein versus each clinical trait. RESULTS: We found 217 proteins that significantly changed in the peripheral vein blood after PMI in a derivation cohort (n=15; P<5.70E-5). Seventy-nine of these proteins were validated in an independent PMI cohort (n=15; P85% were directionally consistent and reached nominal significance. We detected many protein changes that are novel in the context of myocardial injury, including Dickkopf-related protein 4, a WNT pathway inhibitor (peak increase 124%, P=1.29E-15) and cripto, a growth factor important in cardiac development (peak increase 64%, P=1.74E-4). Among the 40 validated proteins that increased within 1 hour after PMI, 23 were also elevated in patients with spontaneous myocardial infarction (n=46; P low-abundance analytes with high sensitivity and high precision, applicable both to well-phenotyped perturbational studies and large human cohorts, as well. Ngo, Debby Sinha, Sumita Shen, Dongxiao Kuhn, Eric W Keyes, Michelle J Shi, Xu Benson, Mark D O'Sullivan, John F Keshishian, Hasmik Farrell, Laurie A Fifer, Michael A Vasan, Ramachandran S Sabatine, Marc S Larson, Martin G Carr, Steven A Wang, Thomas J Gerszten, Robert E eng U24 CA/CA/NCI NIH HHS/ R01HL//International T32 HL/HL/NHLBI NIH HHS/ K01 GM/GM/NIGMS NIH HHS/ HHSNC/HL/NHLBI NIH HHS/ R01 HL/HL/NHLBI NIH HHS/ N01HC/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Circulation. Jul 26;134(4):270-85. doi: 10./CIRCULATIONAHA.116..I SomaScan 07/23/ Gupta V, et al. An evaluation of an aptamer for use as an affinity reagent with MS: PCSK9 as an example protein Bioanalysis 8 15 - https://www.doi.org/10./bio-- 27,397,798 Antibodies, Immobilized/chemistry Antibodies, Monoclonal/chemistry Aptamers, Nucleotide/*chemistry Chromatography, Affinity/*methods Humans Magnets/chemistry Mass Spectrometry/*methods Proprotein Convertase 9/analysis/*blood Ms method development proteins BACKGROUND: For quantitative immunoaffinity IA-LC-MS, the utility of antibodies has been demonstrated many times but the utility of aptamers as affinity reagents is unproven. METHODS: Immunoaffinity reagents including a monoclonal antibody and an aptamer were coupled to magnetic beads and used as part of an enrichment strategy for PCSK9 quantitation in plasma. RESULTS: With limited method development, we have established a comparison of an anti-PCSK9 aptamer with an anti-PCSK9 monoclonal antibody. The background that results from a tryptic digest of affinity enrichment in plasma was demonstrated for each reagent using high-resolution full scan MS. The assay recovery was demonstrated for multiple concentrations of aptamer in plasma with different concentrations of PCSK9 protein. CONCLUSION: The aptamer achieved comparable enrichment to the antibody, but with lower peptide background, thus demonstrating the potential use of aptamers for IA-LC-MS. Gupta, Vinita Lassman, Michael E McAvoy, Thomas Lee, Anita Yh Chappell, Derek L Laterza, Omar F eng Comparative Study England Bioanalysis. Aug;8(15):-. doi: 10./bio--. Epub Jul 11.I SomaScan 07/12/ Lukjanenko L, et al. Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice Nat Med 22 8 897-905 https://www.doi.org/10./nm. 27,376,579 Aging/*metabolism Animals Blotting, Western Extracellular Matrix/metabolism Fibronectins/*genetics/metabolism Flow Cytometry Focal Adhesion Protein-Tyrosine Kinases/*metabolism Integrins/metabolism Mice Muscle, Skeletal/cytology/*metabolism Polymerase Chain Reaction Regeneration/*genetics *Stem Cell Niche p38 Mitogen-Activated Protein Kinases/*metabolism Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism. Lukjanenko, Laura Jung, M Juliane Hegde, Nagabhooshan Perruisseau-Carrier, Claire Migliavacca, Eugenia Rozo, Michelle Karaz, Sonia Jacot, Guillaume Schmidt, Manuel Li, Liangji Metairon, Sylviane Raymond, Frederic Lee, Umji Sizzano, Federico Wilson, David H Dumont, Nicolas A Palini, Alessio Fassler, Reinhard Steiner, Pascal Descombes, Patrick Rudnicki, Michael A Fan, Chen-Ming von Maltzahn, Julia Feige, Jerome N Bentzinger, C Florian eng F31 HD/HD/NICHD NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Med. Aug;22(8):897-905. doi: 10./nm.. Epub Jul 4.I SomaScan 07/05/ Welton JL, et al. Proteomics analysis of vesicles isolated from plasma and urine of prostate cancer patients using a multiplex, aptamer-based protein array J Extracell Vesicles 5 https://www.doi.org/10./jev.v5. 27,363,484 plasma protein array proteomics urine prostate Proteomics analysis of biofluid-derived vesicles holds enormous potential for discovering non-invasive disease markers. Obtaining vesicles of sufficient quality and quantity for profiling studies has, however, been a major problem, as samples are often replete with co-isolated material that can interfere with the identification of genuine low abundance, vesicle components. Here, we used a combination of ultracentrifugation and size-exclusion chromatography to isolate and analyse vesicles of plasma or urine origin. We describe a sample-handling workflow that gives reproducible, quality vesicle isolations sufficient for subsequent protein profiling. Using a semi-quantitative aptamer-based protein array, we identified around 1,000 proteins, of which almost 400 were present at comparable quantities in plasma versus urine vesicles. Significant differences were, however, apparent with elements like HSP90, integrin alphaVbeta5 and Contactin-1 more prevalent in urinary vesicles, while hepatocyte growth factor activator, prostate-specific antigen-antichymotrypsin complex and many others were more abundant in plasma vesicles. This was also applied to a small set of specimens collected from men with metastatic prostate cancer, highlighting several proteins with the potential to indicate treatment refractory disease. The study provides a practical platform for furthering protein profiling of vesicles in prostate cancer, and, hopefully, many other disease scenarios. Welton, Joanne Louise Brennan, Paul Gurney, Mark Webber, Jason Paul Spary, Lisa Kate Carton, David Gil Falcon-Perez, Juan Manuel Walton, Sean Peter Mason, Malcolm David Tabi, Zsuzsanna Clayton, Aled eng J Extracell Vesicles. Jun 29;5:. doi: 10./jev.v5.. eCollection .I SomaScan 07/02/ Ganz P, et al. Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients With Stable Coronary Heart Disease JAMA 315 23 -41 https://www.doi.org/10./jama.. 27,327,800 Aged Blood Proteins/*analysis Cause of Death Coronary Artery Disease/*blood Female Heart Failure/etiology Humans Male Myocardial Infarction/etiology Norway Prospective Studies Proteomics *Risk Assessment San Francisco Stroke/etiology IMPORTANCE: Precise stratification of cardiovascular risk in patients with coronary heart disease (CHD) is needed to inform treatment decisions. OBJECTIVE: To derive and validate a score to predict risk of cardiovascular outcomes among patients with CHD, using large-scale analysis of circulating proteins. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of participants with stable CHD. For the derivation cohort (Heart and Soul study), outpatients from San Francisco were enrolled from through and followed up through November (/= 2(8) and increased IL-6 and CXCL10 to healthy controls, we identified 162 differentially-expressed proteins between the two groups. This number greatly exceeds the number of DEPs identified in previous studies in human influenza patients. Most of the identified proteins were associated with the host immune response to infection, and changes in protein levels of 151 of the DEPs were significantly correlated with viral load. Most important, SOMAscan identified differentially expressed proteins heretofore not associated with respiratory influenza infection in humans. Our study is the first report for the use of SOMAscan to screen nasal secretions. It establishes a precedent for micro-proteomic quantification of proteins that reflect ongoing response to respiratory infection. Marion, Tony Elbahesh, Husni Thomas, Paul G DeVincenzo, John P Webby, Richard Schughart, Klaus eng HHSNC/AI/NIAID NIH HHS/ HHSNC/AI/NIAID NIH HHS/ HHSNC/PHS HHS/ HHSNC/PHS HHS/ Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. PLoS One. Apr 18;11(4):e. doi: 10./journal.pone.. eCollection .I SomaScan 04/19/ Hathout Y, et al. Clinical utility of serum biomarkers in Duchenne muscular dystrophy Clin Proteomics 13 9 https://www.doi.org/10./s-016--x 27,051,355 Biomarkers Clinical outcomes Duchenne muscular dystrophy Mass spectrometry Pharmacodynamic biomarkers Proteins SomaScan Surrogate biomarkers miRNA Assessments of disease progression and response to therapies in Duchenne muscular dystrophy (DMD) patients remain challenging. Current DMD patient assessments include complex physical tests and invasive procedures such as muscle biopsies, which are not suitable for young children. Defining alternative, less invasive and objective outcome measures to assess disease progression and response to therapy will aid drug development and clinical trials in DMD. In this review we highlight advances in development of non-invasive blood circulating biomarkers as a means to assess disease progression and response to therapies in DMD. Hathout, Yetrib Seol, Haeri Han, Meng Hsuan J Zhang, Aiping Brown, Kristy J Hoffman, Eric P eng U54 HD/HD/NICHD NIH HHS/ P30 HD/HD/NICHD NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ P50 AR/AR/NIAMS NIH HHS/ U54 HD/HD/NICHD NIH HHS/ Review England Clin Proteomics. Apr 5;13:9. doi: 10./s-016--x. eCollection .I SomaScan 04/07/ Gelinas AD, et al. Embracing proteins: structural themes in aptamer-protein complexes Curr Opin Struct Biol 36 122-32 https://www.doi.org/10./j.sbi..01.009 26,919,170 Aptamers, Nucleotide/*chemistry/metabolism Binding Sites Hydrophobic and Hydrophilic Interactions Ligands *Models, Molecular Nucleic Acid Conformation Nucleotide Motifs Protein Binding Protein Conformation Proteins/*chemistry/metabolism Structure-Activity Relationship Understanding the structural rules that govern specific, high-affinity binding characteristic of aptamer-protein interactions is important in view of the increasing use of aptamers across many applications. From the modest number of 16 aptamer-protein structures currently available, trends are emerging. The flexible phosphodiester backbone allows folding into precise three-dimensional structures using known nucleic acid motifs as scaffolds that orient specific functional groups for target recognition. Still, completely novel motifs essential for structure and function are found in modified aptamers with diversity-enhancing side chains. Aptamers and antibodies, two classes of macromolecules used as affinity reagents with entirely different backbones and composition, recognize protein epitopes of similar size and with comparably high shape complementarity. Gelinas, Amy D Davies, Douglas R Janjic, Nebojsa eng Review England Curr Opin Struct Biol. Feb;36:122-32. doi: 10./j.sbi..01.009. Epub Feb 24.I SomaScan 02/27/ Drolet DW, et al. Fit for the Eye: Aptamers in Ocular Disorders Nucleic Acid Ther 26 3 127-46 https://www.doi.org/10./nat.. 26,757,406 Aptamers, Nucleotide/*therapeutic use Eye Diseases/genetics/*therapy Humans Ligands Ophthalmology/*trends SELEX Aptamer Technique/*trends For any new class of therapeutics, there are certain types of indications that represent a natural fit. For nucleic acid ligands in general, and aptamers in particular, the eye has historically been an attractive site for therapeutic intervention. In this review, we recount the discovery and early development of three aptamers designated for use in ophthalmology, one approved (Macugen), and two in late-stage development (Fovista and Zimura). Every one of these molecules was originally intended for other indications. Key improvements in technology, specifically with regard to libraries used for in vitro selection and subsequent chemical optimization of aptamers, have played an important role in allowing the identification of development candidates with suitable properties. The lessons learned from the selection of these molecules are valuable for informing us about the many remaining opportunities for aptamer-based therapeutics in ophthalmology as well as for identifying additional indications for which aptamers as a class of therapeutics have distinct advantages. Drolet, Daniel W Green, Louis S Gold, Larry Janjic, Nebojsa eng Review Nucleic Acid Ther. Jun;26(3):127-46. doi: 10./nat... Epub Jan 12.I SomaScan 01/13/ Murota A, et al. Serum proteomic analysis identifies interleukin 16 as a biomarker for clinical response during early treatment of rheumatoid arthritis Cytokine 78 87-93 https://www.doi.org/10./j.cyto..12.002 26,700,586 Abatacept/therapeutic use Adult Aged Antibodies, Monoclonal, Humanized/therapeutic use Antirheumatic Agents/*therapeutic use Arthritis, Rheumatoid/*blood/*drug therapy Biomarkers/blood Blood Proteins/*analysis/immunology Blood Sedimentation Female Humans Infliximab/therapeutic use Interleukin-16/*blood Male Matrix Metalloproteinase 3/blood Methotrexate/therapeutic use Middle Aged *Proteomics Statistics as Topic Treatment Outcome Biomarker Interleukin-16 Proteomics Rheumatoid arthritis Serum protein OBJECTIVES: To conduct a comprehensive quantitative proteomics analysis of novel serum protein biomarkers based on synovitis status associated with matrix metalloproteinase-3 (MMP-3) and to determine the clinical significance of these biomarkers in rheumatoid arthritis (RA). METHODS: Patients with untreated RA (n=28), primary Sjogren's syndrome (pSS) (n=30), and healthy controls (HCs) (n=30) were enrolled for the screening assay. A total of serum proteins were analyzed using the SOMAscan assay. Serum levels of MMP-3 and interleukin (IL)-16 were measured using a latex turbidimetric immunoassay and ELISA at baseline and 12weeks after treatment with methotrexate (MTX) for MTX-naive RA patients (n=28) or with the biologics tocilizumab (TCZ) (n=7), abatacept (ABT) (n=11) or infliximab (n=22) for MTX-inadequate response (IR) RA patients. Correlation analysis was conducted using Spearman's rank correlation method. RESULTS: Proteomics showed that serum IL-16 levels were most positively correlated with those of MMP-3 (rho=0.51, p<0.01) and were significantly increased in patients with untreated active RA compared to HCs (p<0.01) or those with pSS (p<0.01). IL-16 levels decreased following treatment in both the MTX-naive and MTX-IR groups. Regarding clinical response, fluctuations in IL-16 levels were positively associated with changes in clinical indicators, particularly the Clinical Disease Activity Index (rho=0.89, p<0.01) in the TCZ and ABT-treated group. However, no similar correlation was noted in MMP-3 and acute phase reactants in any groups. CONCLUSIONS: IL-16 was a more effective clinical parameter than MMP-3, C-reactive protein, or erythrocyte sedimentation rate in both MTX-naive and MTX-IR RA patients. IL-16 might be a useful biomarker for evaluating clinical response in RA patients. Murota, Atsuko Suzuki, Katsuya Kassai, Yoshiaki Miyazaki, Takahiro Morita, Rimpei Kondo, Yasushi Takeshita, Masaru Niki, Yasuo Yoshimura, Akihiko Takeuchi, Tsutomu eng Research Support, Non-U.S. Gov't England Cytokine. Feb;78:87-93. doi: 10./j.cyto..12.002. Epub Dec 14.I SomaScan 12/25/ Sattlecker M, et al. Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer's Disease J Alzheimers Dis 49 4 -14 https://www.doi.org/10./JAD- 26,599,049 Aged Alzheimer Disease/*blood/*psychology Biomarkers/blood *Cognition/physiology Cognitive Dysfunction/blood/psychology Disease Progression Female Follow-Up Studies Humans Linear Models Longitudinal Studies Male Mental Status Schedule Neuropsychological Tests Alzheimer's disease cognitive decline complement cascade cytokine-cytokine receptor interaction plasma proteins Biomarkers of Alzheimer's disease (AD) progression are needed to support the development of urgently needed disease modifying drugs. We employed a SOMAscan assay for quantifying 1,001 proteins in blood samples from 90 AD subjects, 37 stable mild cognitive impaired (MCI) subjects, 39 MCI subjects converting to AD within a year and 69 controls at baseline and one year follow up. We used linear mixed effects models to identify proteins changing significantly over one year with the rate of cognitive decline, which was quantified as the reduction in Mini Mental State Examination (MMSE) scores. Additionally, we investigated proteins changing differently across disease groups and during the conversion from MCI to AD. We found that levels of proteins belonging to the complement cascade increase significantly in fast declining AD patients. Longitudinal changes in the complement cascade might be a surrogate biomarker for disease progression. We also found that members of the cytokine-cytokine receptor interaction pathway change during AD when compared to healthy aging subjects. Sattlecker, Martina Khondoker, Mizanur Proitsi, Petroula Williams, Stephen Soininen, Hilkka Kloszewska, Iwona Mecocci, Patrizia Tsolaki, Magda Vellas, Bruno Lovestone, Simon Dobson, Richard Jb eng 167/ALZS_/Alzheimer's Society/United Kingdom 171/ALZS_/Alzheimer's Society/United Kingdom G/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Netherlands J Alzheimers Dis. ;49(4):-14. doi: 10./JAD-.I SomaScan 11/26/ Hirota M, et al. Chemically Modified Interleukin-6 Aptamer Inhibits Development of Collagen-Induced Arthritis in Cynomolgus Monkeys Nucleic Acid Ther 26 1 https://www.doi.org/10./nat.. 26,579,954 Amino Acid Sequence Animals Aptamers, Peptide/*chemistry Arthritis, Experimental/chemically induced/*prevention & control Cells, Cultured Collagen/*adverse effects Female Humans Interleukin-6/*blood/chemistry Macaca fascicularis Molecular Sequence Data Phosphorylation STAT3 Transcription Factor/metabolism Sequence Homology, Amino Acid T-Lymphocytes/metabolism Interleukin-6 (IL-6) is a potent mediator of inflammatory and immune responses, and a validated target for therapeutic intervention of inflammatory diseases. Previous studies have shown that SL, a slow off-rate modified aptamer (SOMAmer) antagonist of IL-6, neutralizes IL-6 signaling in vitro. In the present study, we show that SL delays the onset and reduces the severity of rheumatoid symptoms in a collagen-induced arthritis model in cynomolgus monkeys. SL (1 and 10 mg/kg), administered q.i.d., delayed the progression of arthritis and the concomitant increase in serum IL-6 levels compared to the untreated control group. Furthermore, SL inhibited IL-6-induced STAT3 phosphorylation ex vivo in T lymphocytes from human blood and IL-6-induced C-reactive protein and serum amyloid A production in human primary hepatocytes. Importantly, SOMAmer treatment did not elicit an immune response, as evidenced by the absence of anti-SOMAmer antibodies in plasma of treated monkeys. These results demonstrate that SOMAmer antagonists of IL-6 may be attractive agents for the treatment of IL-6-mediated diseases, including rheumatoid arthritis. Hirota, Masao Murakami, Ikuo Ishikawa, Yuichi Suzuki, Tomoki Sumida, Shun-ichiro Ibaragi, Shigeru Kasai, Hayato Horai, Naoto Drolet, Daniel W Gupta, Shashi Janjic, Nebojsa Schneider, Daniel J eng Nucleic Acid Ther. Feb;26(1):10-9. doi: 10./nat... Epub Nov 18.I SomaScan 11/19/ Lynch AM, et al. The relationship of circulating proteins in early pregnancy with preterm birth Am J Obstet Gynecol 214 4 517 e1-517 e8 https://www.doi.org/10./j.ajog..11.001 26,576,488 Adult Biomarkers/blood Blood Proteins/*metabolism Case-Control Studies Cohort Studies Female Humans Logistic Models Pregnancy Pregnancy Trimester, First/*blood Premature Birth/*blood Proteomics coagulation cascade complement system early pregnancy preterm birth Hospital Colorado innovations grant to develop Kids Personalized Protein Signatures (KIPPS) panels for children using the SomaLogic technology. In addition she serves on the Joint Steering Committee for KIPPS. The other co-authors report no conflict of interest. BACKGROUND: Preterm birth (PTB) (< 37 completed weeks' gestation) is a pathological outcome of pregnancy and a major global health problem. Babies born preterm have an elevated risk for long-term adverse medical and neurodevelopmental sequelae. Substantial evidence implicates intrauterine infection and/or inflammation in PTB. However, these are often relatively late findings in the process, when PTB is inevitable. Identification of earlier markers of PTB may make successful intervention possible. Although select proteins, notably those related to the inflammatory pathways, have been associated with PTB, there has been a lack of research into the role of other protein pathways in the development of PTB. The purpose of this study was to investigate, using a previously described biomarker discovery approach, a subset of circulating proteins and their association with PTB focusing on samples from early pregnancy. OBJECTIVES: The objectives of the study were as follows: (1) to perform a large-scale biomarker discovery, utilizing an innovative platform to identify proteins associated with preterm birth in plasma taken between 10 and 15 weeks' gestation and, (2) to determine which protein pathways are most strongly associated with preterm birth. To address these aims, we measured proteins in a plasma sample from early pregnancy using a multiplexed aptamer-based proteomic technology developed in Colorado by SomaLogic. STUDY DESIGN: Using a nested case-control approach, we measured proteins at a single time point in early pregnancy in 41 women who subsequently delivered preterm and 88 women who had term uncomplicated deliveries. We measured proteins using a multiplexed aptamer-based proteomic technology developed by SomaLogic. Logistic regressions and random forests were used to compare protein levels. RESULTS: The complement factors B and H and the coagulation factors IX and IX ab were the highest-ranking proteins distinguishing cases of preterm birth from term controls. The top 3 pathways associated with preterm birth were the complement cascade, the immune system, and the clotting cascade. CONCLUSION: Using a discovery approach, these data provide further confirmation that there is an association of immune- and coagulation-related events in early pregnancy with preterm birth. Thus, plasma protein profiles at 10-15 weeks of gestation are related to the development of preterm birth later in pregnancy. Lynch, Anne M Wagner, Brandie D Deterding, Robin R Giclas, Patricia C Gibbs, Ronald S Janoff, Edward N Holers, V Michael Santoro, Nanette F eng K23 HD/HD/NICHD NIH HHS/ R21 HD/HD/NICHD NIH HHS/ 5 K23 HD-04/HD/NICHD NIH HHS/ R21 HD-01A1/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Obstet Gynecol. Apr;214(4):517.e1-517.e8. doi: 10./j.ajog..11.001. Epub Nov 11.I SomaScan 11/19/ McArdle A, et al. Developing clinically relevant biomarkers in inflammatory arthritis: A multiplatform approach for serum candidate protein discovery Proteomics Clin Appl 10 6 691-8 https://www.doi.org/10./prca. 26,332,844 Adult Arthritis, Psoriatic/blood/*diagnosis/pathology Arthritis, Rheumatoid/blood/*diagnosis/pathology Biomarkers/metabolism Blood Proteins/*metabolism Chromatography, Liquid Diagnosis, Differential Female Gene Expression Gene Expression Profiling Humans Immunoassay Male Middle Aged Tandem Mass Spectrometry Lc-ms/ms Luminex Multiplexing Psoriatic and Rhuematoid Arthritis SOMAscan PURPOSE: To identify candidate biomarkers that have the potential to distinguish between patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA) and explore the value of combining different protein discovery platforms for the development of a multiplexed protein biomarker panel. EXPERIMENTAL DESIGN: Serum samples from 32 patients (PsA; n = 16 and RA; n = 16) defined as active, early onset, and treatment naive were analyzed using unbiased label-free LC-MS/MS, a microsphere bead-based immunoassay (Luminex xMAP) and an aptamer-based assay (SOMAscan). RESULTS: LC-MS/MS was used to quantify 324 proteins, while the Luminex xMAP targeted 48 proteins and SOMAscan supported the measurement of proteins. The combined data from these techniques gave reproducible quantification of proteins in total. Of these, 42 (LC-MS/MS), 3 (Luminex xMAP), and 127 (SOMAscan) proteins were found to be differentially expressed between PsA and RA (p < 0.05). CONCLUSION AND CLINICAL RELEVANCE: Using three different and potentially complementary proteomic platforms we identified a total of 172 proteins that are differentially expressed in patients with PsA compared to RA. These proteins collectively represent candidates for inclusion in a protein signature that could be developed as a diagnostic test to discriminate patients with PsA from RA and therefore be of clinical utility. McArdle, Angela Qasim Butt, Aisha Szentpetery, Agnes de Jager, Wilco de Roock, Sytze FitzGerald, Oliver Pennington, Stephen R eng Research Support, Non-U.S. Gov't Germany Proteomics Clin Appl. Jun;10(6):691-8. doi: 10./prca.. Epub Nov 9.I SomaScan 09/04/ Gold L SELEX: How It Happened and Where It will Go J Mol Evol 81 6 140-3 https://www.doi.org/10./s-015--9 26,480,964 *Aptamers, Nucleotide History, 20th Century SELEX Aptamer Technique/*history United States Gold, Larry eng Autobiography Bibliography Historical Article Germany J Mol Evol. Dec;81(5-6):140-3. doi: 10./s-015--9. Epub Oct 20.I SomaScan 10/21/ Wolk SK, et al. Influence of 5-N-carboxamide modifications on the thermodynamic stability of oligonucleotides Nucleic Acids Res 43 19 -22 https://www.doi.org/10./nar/gkv981 26,438,535 Amides/chemistry Circular Dichroism Deoxyuridine/*analogs & derivatives Models, Molecular Nuclear Magnetic Resonance, Biomolecular Nucleic Acid Denaturation Nucleotide Motifs Oligonucleotides/*chemistry *Thermodynamics We have recently shown that the incorporation of modified nucleotides such as 5-N-carboxamide-deoxyuridines into random nucleic acid libraries improves success rates in SELEX experiments and facilitates the identification of ligands with slow off-rates. Here we report the impact of these modifications on the thermodynamic stability of both duplexes and intramolecular 'single-stranded' structures. Within duplexes, large, hydrophobic naphthyl groups were destabilizing relative to the all natural DNA duplex, while the hydrophilic groups exhibited somewhat improved duplex stability. All of the significant changes in stability were driven by opposing contributions from the enthalpic and entropic terms. In contrast, both benzyl and naphthyl modifications stabilized intramolecular single-stranded structures relative to their natural DNA analogs, consistent with the notion that intramolecular folding allows formation of novel, stabilizing hydrophobic interactions. Imino proton NMR data provided evidence that elements of the folded structure form at temperatures well below the Tm, with a melting transition that is distinctly less cooperative when compared to duplex DNA. Although there are no data to suggest that the unmodified DNA sequences fold into structures similar to their modified analogs, this still represents clear evidence that these modifications impart thermodynamic stability to the folded structure not achievable with unmodified DNA. Wolk, Steven K Shoemaker, Richard K Mayfield, Wes S Mestdagh, Andrew L Janjic, Nebojsa eng Research Support, Non-U.S. Gov't England Nucleic Acids Res. Oct 30;43(19):-22. doi: 10./nar/gkv981. Epub Oct 4.I SomaScan 10/07/ Olson KA, et al. Association of growth differentiation factor 11/8, putative anti-ageing factor, with cardiovascular outcomes and overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts Eur Heart J 36 48 -34 https://www.doi.org/10./eurheartj/ehv385 26,294,790 Age Factors Aged Bone Morphogenetic Proteins/*metabolism Coronary Disease/blood/mortality Female Growth Differentiation Factor 9/*metabolism Growth Differentiation Factors/*metabolism Heart Failure/blood/mortality Humans Hypertrophy, Left Ventricular/blood/*mortality Male Myocardial Ischemia/blood/*mortality Prognosis Prospective Studies Risk Factors Stroke/blood/mortality Ageing Cardiovascular outcomes Epidemiology Growth differentiation factor 11 and 8 Hypertrophy AIMS: Growth differentiation factor 11 and/or its homologue growth differentiation factor 8 (GDF11/8) reverses age-related cardiac hypertrophy and vascular ageing in mice. We investigated whether GDF11/8 associates with cardiovascular outcomes, left ventricular hypertrophy (LVH), or age in humans. METHODS AND RESULTS: We measured plasma GDF11/8 levels in 928 participants with stable ischaemic heart disease in the Heart and Soul study. We adjudicated heart failure hospitalization, stroke, myocardial infarction, death, and their composite endpoint. Left ventricular hypertrophy was evaluated by echocardiography. We used multivariable Cox proportional hazards models to compare rates of cardiovascular events and death across GDF11/8 quartiles and logistic regression models to evaluate the association between GDF11/8 and LVH. Four hundred and fifty participants (48.5%) experienced a cardiovascular event or death during 8.9 years of follow-up. The adjusted risk of the composite endpoint was lower in the highest compared with the lowest GDF11/8 quartile [hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.33-0.60; P < 0.001]. We replicated this relationship of GDF11/8 to adverse events in 971 participants in the HUNT3 cohort (adjusted HR, 0.34; 95% CI, 0.23-0.51; P < 0.001). Left ventricular hypertrophy was present in 368 participants (39.7%) at baseline. Participants in the highest quartile of GDF11/8 were less likely to have LVH than those in the lowest quartile (adjusted OR, 0.55; 95% CI, 0.35-0.86; P = 0.009). GDF11/8 levels were lower in older individuals (P < 0.001). CONCLUSION: In patients with stable ischaemic heart disease, higher GDF11/8 levels are associated with lower risk of cardiovascular events and death. Our findings suggest that GDF11/8 has similar cardioprotective properties in humans to those demonstrated in mice. Olson, Kristoff A Beatty, Alexis L Heidecker, Bettina Regan, Mathilda C Brody, Edward N Foreman, Trudi Kato, Shintaro Mehler, Robert E Singer, Britta S Hveem, Kristian Dalen, Havard Sterling, David G Lawn, Richard M Schiller, Nelson B Williams, Stephen A Whooley, Mary A Ganz, Peter eng KL2TR/TR/NCATS NIH HHS/ R01 H L/PHS HHS/ Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. England Eur Heart J. Dec 21;36(48):-34. doi: 10./eurheartj/ehv385. Epub Aug 20.I SomaScan 08/22/ Hathout Y Proteomic methods for biomarker discovery and validation. Are we there yet? Expert Rev Proteomics 12 4 329-31 https://www.doi.org/10./.. 26,186,709 *Biomarkers Chromatography, Liquid *Proteomics Tandem Mass Spectrometry SomaScan antibody bead arrays biomarkers biomarkers validation proteomics targeted mass spectrometry Noninvasive molecular biomarkers are becoming attractive tools to monitor disease progression, aid drug development programs and use as surrogate outcome measures in clinical trials. Cutting edge proteomic methods to assay biomarkers in body fluids have been developed in the past few years, but transitioning them to clinical practice has been slow and depends on the qualification of both the method and the biomarker. Hathout, Yetrib eng Editorial Validation Study England Expert Rev Proteomics. Aug;12(4):329-31. doi: 10./...I SomaScan 07/18/ Hattori K, et al. Increased cerebrospinal fluid fibrinogen in major depressive disorder Sci Rep 5 https://www.doi.org/10./srep 26,081,315 Brain/pathology Case-Control Studies Depressive Disorder, Major/*cerebrospinal fluid/diagnosis Diffusion Magnetic Resonance Imaging Female Fibrinogen/*cerebrospinal fluid Humans Male White Matter/pathology Major depressive disorder (MDD) presumably includes heterogeneous subgroups with differing pathologies. To obtain a marker reflecting such a subgroup, we analyzed the cerebrospinal fluid (CSF) levels of fibrinogen, which has been reported to be elevated in the plasma of patients with MDD. Three fibrinogen-related proteins were measured using aptamer-based analyses and CSF samples of 30 patients with MDD and 30 controls. The numbers of patients with an excessively high level (>99 percentile of the controls) was significantly increased (17 to 23%). Measurement reproducibility of these results was confirmed by an ELISA for fibrinogen (Pearson's r = 0.77). In an independent sample set from 36 patients and 30 controls, using the ELISA, results were similar (22%). When these two sample sets were combined, the number of patients with a high fibrinogen level was significantly increased (15/66; odds ratio 8.53; 95% confidence interval 1.9-39.1, p = 0.). By using diffusion tensor imaging, we found white matter tracts abnormalities in patients with a high fibrinogen level but not those patients with a normal fibrinogen level, compared with controls. Plasma fibrinogen levels were similar among the diagnostic groups. Our results point to a subgroup of MDD represented by increased CSF fibrinogen and white matter tract abnormalities. Hattori, Kotaro Ota, Miho Sasayama, Daimei Yoshida, Sumiko Matsumura, Ryo Miyakawa, Tomoko Yokota, Yuuki Yamaguchi, Shinobu Noda, Takamasa Teraishi, Toshiya Hori, Hiroaki Higuchi, Teruhiko Kohsaka, Shinichi Goto, Yu-ichi Kunugi, Hiroshi eng Research Support, Non-U.S. Gov't England Sci Rep. Jun 17;5:. doi: 10./srep.I SomaScan 06/18/ Kiddle SJ, et al. Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes Transl Psychiatry 5 6 e584 https://www.doi.org/10./tp..78 26,080,319 Aged Alzheimer Disease/*blood/pathology Asymptomatic Diseases Biomarkers/blood Brain/*pathology *Endophenotypes Entorhinal Cortex/pathology Female Humans Intracellular Signaling Peptides and Proteins/*blood MAP Kinase Kinase 4/*blood Male Middle Aged Neuropsychological Tests Organ Size Protein Serine-Threonine Kinases/*blood Twins/*genetics/psychology There is great interest in blood-based markers of Alzheimer's disease (AD), especially in its pre-symptomatic stages. Therefore, we aimed to identify plasma proteins whose levels associate with potential markers of pre-symptomatic AD. We also aimed to characterise confounding by genetics and the effect of genetics on blood proteins in general. Panel-based proteomics was performed using SOMAscan on plasma samples from TwinsUK subjects who are asymptomatic for AD, measuring the level of proteins. Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n = 195), and regional brain volumes (n = 34). Replication of proteins associated with regional brain volumes was performed in 254 individuals from the AddNeuroMed cohort. Across all the proteins measured, genetic factors were found to explain ~26% of the variability in blood protein levels on average. The plasma level of the mitogen-activated protein kinase (MAPK) MAPKAPK5 protein was found to positively associate with the 10-year change in CANTAB-PAL in both the individual and twin difference context. The plasma level of protein MAP2K4 was found to suggestively associate negatively (Q < 0.1) with the volume of the left entorhinal cortex. Future studies will be needed to assess the specificity of MAPKAPK5 and MAP2K4 to eventual conversion to AD. Kiddle, S J Steves, C J Mehta, M Simmons, A Xu, X Newhouse, S Sattlecker, M Ashton, N J Bazenet, C Killick, R Adnan, J Westman, E Nelson, S Soininen, H Kloszewska, I Mecocci, P Tsolaki, M Vellas, B Curtis, C Breen, G Williams, S C R Lovestone, S Spector, T D Dobson, R J B eng 171/ALZS_/Alzheimer's Society/United Kingdom MR/L/1/MRC_/Medical Research Council/United Kingdom /Z/08/Z/WT_/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't Transl Psychiatry. Jun 16;5(6):e584. doi: 10./tp..78.I SomaScan 06/17/ Hathout Y, et al. Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy Proc Natl Acad Sci U S A 112 23 -8 https://www.doi.org/10./pnas. 26,039,989 Adolescent Adult Biomarkers/*blood Blood Proteins/*metabolism Case-Control Studies Child Child, Preschool Cohort Studies Humans Male Muscular Dystrophy, Duchenne/*blood Young Adult SOMAmer SOMAscan biomarkers muscular dystrophy proteomics SomaLogic, Inc E.B., R.K.D., B.M., M.N., B.S., F.S., D.S., and S.W. are employees and stakeholders in SomaLogic, Inc. Y.M.K. has been affiliated with the Eli Lilly and Co. since October . Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases. Hathout, Yetrib Brody, Edward Clemens, Paula R Cripe, Linda DeLisle, Robert Kirk Furlong, Pat Gordish-Dressman, Heather Hache, Lauren Henricson, Erik Hoffman, Eric P Kobayashi, Yvonne Monique Lorts, Angela Mah, Jean K McDonald, Craig Mehler, Bob Nelson, Sally Nikrad, Malti Singer, Britta Steele, Fintan Sterling, David Sweeney, H Lee Williams, Steve Gold, Larry eng UL1RR/RR/NCRR NIH HHS/ U54 RR/RR/NCRR NIH HHS/ U54HD/HD/NICHD NIH HHS/ R01AR/AR/NIAMS NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ P50AR/AR/NIAMS NIH HHS/ P30 HD/HD/NICHD NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ R24HD/HD/NICHD NIH HHS/ UL1RR/RR/NCRR NIH HHS/ 2U54HD/HD/NICHD NIH HHS/ UL1 RR/RR/NCRR NIH HHS/ G12RR/RR/NCRR NIH HHS/ G12 RR/RR/NCRR NIH HHS/ U54 HD/HD/NICHD NIH HHS/ UL1 RR/RR/NCRR NIH HHS/ P30HD/HD/NICHD NIH HHS/ U54RR/RR/NCRR NIH HHS/ R24 HD/HD/NICHD NIH HHS/ U54 AR/AR/NIAMS NIH HHS/ UL1 TR/TR/NCATS NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ P50 AR/AR/NIAMS NIH HHS/ UL1TR/TR/NCATS NIH HHS/ R01 AR/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Proc Natl Acad Sci U S A. Jun 9;112(23):-8. doi: 10./pnas.. Epub May 26.I SomaScan 06/04/ Jarvis TC, et al. Non-helical DNA Triplex Forms a Unique Aptamer Scaffold for High Affinity Recognition of Nerve Growth Factor Structure 23 7 -304 https://www.doi.org/10./j.str..03.027 26,027,732 Amino Acid Sequence Base Sequence Binding Sites Crystallography, X-Ray DNA/*chemistry Humans Hydrophobic and Hydrophilic Interactions Molecular Sequence Data Nerve Growth Factor/*chemistry/physiology Protein Binding Protein Structure, Secondary SELEX Aptamer Technique Discerning the structural building blocks of macromolecules is essential for understanding their folding and function. For a new generation of modified nucleic acid ligands (called slow off-rate modified aptamers or SOMAmers), we previously observed essential functions of hydrophobic aromatic side chains in the context of well-known nucleic acid motifs. Here we report a 2.45-A resolution crystal structure of a SOMAmer complexed with nerve growth factor that lacks any known nucleic acid motifs, instead adopting a configuration akin to a triangular prism. The SOMAmer utilizes extensive hydrophobic stacking interactions, non-canonical base pairing and irregular purine glycosidic bond angles to adopt a completely non-helical, compact S-shaped structure. Aromatic side chains contribute to folding by creating an unprecedented intercalating zipper-like motif and a prominent hydrophobic core. The structure provides compelling rationale for potent inhibitory activity of the SOMAmer and adds entirely novel motifs to the repertoire of structural elements uniquely available to SOMAmers. Jarvis, Thale C Davies, Douglas R Hisaminato, Akihiko Resnicow, Daniel I Gupta, Shashi Waugh, Sheela M Nagabukuro, Akira Wadatsu, Takashi Hishigaki, Haretsugu Gawande, Bharat Zhang, Chi Wolk, Steven K Mayfield, Wesley S Nakaishi, Yuichiro Burgin, Alex B Stewart, Lance J Edwards, Thomas E Gelinas, Amy D Schneider, Daniel J Janjic, Nebojsa eng Structure. Jul 7;23(7):-304. doi: 10./j.str..03.027. Epub May 28.I SomaScan 06/02/ Eid C, et al. Rapid Slow Off-Rate Modified Aptamer (SOMAmer)-Based Detection of C-Reactive Protein Using Isotachophoresis and an Ionic Spacer Anal Chem 87 13 -43 https://www.doi.org/10./acs.analchem.5b 26,024,067 Aptamers, Nucleotide/*chemistry C-Reactive Protein/*analysis Ions *Isotachophoresis We present an on-chip electrophoretic assay for rapid protein detection with a SOMAmer (Slow Off-Rate Modified Aptamer) reagent. We used isotachophoresis (ITP) coupled with an ionic spacer to both react and separate SOMAmer-protein complex from free SOMAmer reagent. ITP accelerates the reaction kinetics as the ionic spacer concurrently separates the reaction products. We developed a numerical and analytical model to describe ITP spacer assays, which involve low-mobility, nonfocusing targets that are recruited into the ITP zone by higher-mobility, ITP-focused probes. We demonstrated a proof-of-concept of this assay using C-reactive protein (CRP) in buffer, and achieved a 2 nM limit of detection (LOD) with a combined 20 min assay time (10 min off-chip preparation of reagents and 10 min on-chip run). Our findings suggest that this approach has potential as a simple and rapid alternative to other homogeneous immunoassays. We also explore the extension of this assay to a diluted serum sample spiked with CRP, where we observe decreased sensitivity (an LOD of 25 nM in 20-fold diluted serum). We describe the challenges in extending this assay to complex samples and achieving higher sensitivity and specificity for clinical applications. Eid, Charbel Palko, James W Katilius, Evaldas Santiago, Juan G eng Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Anal Chem. Jul 7;87(13):-43. doi: 10./acs.analchem.5b. Epub Jun 16.I SomaScan 05/30/ Voyle N, et al. Blood Protein Markers of Neocortical Amyloid-beta Burden: A Candidate Study Using SOMAscan Technology J Alzheimers Dis 46 4 947-61 https://www.doi.org/10./JAD- 25,881,911 Aged Aged, 80 and over Aging/blood/pathology Alzheimer Disease/*blood/*pathology Amyloid beta-Peptides/*metabolism Aniline Compounds/metabolism Apolipoproteins E/genetics Australia Blood Proteins/*metabolism Cohort Studies Female Humans Male Middle Aged Neocortex/*metabolism Positron-Emission Tomography Proteins Proteomics Thiazoles/metabolism Alzheimer's disease amyloid plaques blood positron emission tomography scan BACKGROUND: Four previously reported studies have tested for association of blood proteins with neocortical amyloid-beta burden (NAB). If shown to be robust, these proteins could have utility as a blood test for enrichment in clinical trials of Alzheimer's disease (AD) therapeutics. OBJECTIVE: This study aimed to investigate whether previously identified blood proteins also show evidence for association with NAB in serum samples from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL). The study considers candidate proteins seen in cohorts other than AIBL and candidates previously discovered in the AIBL cohort. METHODS: Our study used the SOMAscan platform for protein quantification in blood serum. Linear and logistic regressions were used to model continuous NAB and dichotomized NAB respectively using single proteins as a predictor. Multiple protein models were built using stepwise regression techniques and support vectors machines. Age and APOEvarepsilon4 carriage were used as covariates for all analysis. RESULTS: Of the 41 proteins previously reported, 15 AIBL candidates and 20 non-AIBL candidates were available for testing. Of these candidates, pancreatic polypeptide (PPY) and IgM showed a significant association with NAB. Notably, IgM was found to associate with continuous NAB across cognitively normal control subjects. CONCLUSIONS: We have further demonstrated the association of PPY and IgM with NAB, despite technical differences between studies. There are several reasons for a lack of significance for the other candidates including platform differences and the use of serum rather than plasma samples. To investigate the possibility of technical differences causing lack of replication, further studies are required. Voyle, Nicola Baker, David Burnham, Samantha C Covin, Antonia Zhang, Zhanpan Sangurdekar, Dipen P Tan Hehir, Cristina A Bazenet, Chantal Lovestone, Simon Kiddle, Steven Dobson, Richard J B eng 122/ALZS_/Alzheimer's Society/United Kingdom 171/ALZS_/Alzheimer's Society/United Kingdom MR/L/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Netherlands J Alzheimers Dis. ;46(4):947-61. doi: 10./JAD-.I SomaScan 04/18/ Rohloff JC, et al. Practical synthesis of cytidine-5-carboxamide-modified nucleotide reagents Nucleosides Nucleotides Nucleic Acids 34 3 180-98 https://www.doi.org/10./.. 25,710,355 Cytidine/analogs & derivatives/*chemical synthesis/chemistry Oligonucleotides/*chemical synthesis/chemistry Solid-Phase Synthesis Techniques Aptamer Selex cytidine-5-carboxamide modified nucleotide Chemically-modified derivatives of cytidine, bearing a 5-(N-substituted-carboxamide) functional group, are new reagents for use in aptamer discovery via the SELEX process (Systematic Evolution of Ligands by EXponential enrichment). Herein, we disclose a practical synthesis of 5-(N-benzylcarboxamide)-2'-deoxycytidine, and the corresponding 5-(N-1-naphthylmethylcarboxamide)- and 5-(N-3-phenylpropylcarboxamide)-2'-deoxycytidine analogs, as both the suitably-protected 3'-O-cyanoethylphosphoramidite reagents (CEP; gram scale) and the 5'-O-triphosphate reagents (TPP; milligram-scale). The key step in the syntheses is a mild, palladium(0)-catalyzed carboxyamidation of an unprotected 5-iodo-cytidine. Use of the CEP reagents for solid-phase oligonucleotide synthesis was demonstrated and incorporation of the TPP reagents by KOD polymerase in a primer extension assay confirmed the utility of these reagents for SELEX. Finally, the carboxyamidation reaction was also used to prepare the nuclease-resistant sugar-variants: 5-(N-benzylcarboxamide)-2'-O-methyl-cytidine and 5-(N-3-phenylpropylcarboxamide)-2'-deoxy-2'-fluoro-cytidine. Rohloff, John C Fowler, Catherine Ream, Brian Carter, Jeffrey D Wardle, Greg Fitzwater, Tim eng Nucleosides Nucleotides Nucleic Acids. ;34(3):180-98. doi: 10./...I SomaScan 02/25/ Menni C, et al. Circulating Proteomic Signatures of Chronological Age J Gerontol A Biol Sci Med Sci 70 7 809-16 https://www.doi.org/10./gerona/glu121 25,123,647 Adult Aged Aged, 80 and over Aging/*blood Biomarkers/blood Carrier Proteins/blood Cohort Studies Cytokines/blood Eye Proteins/blood Female Humans Insulin-Like Growth Factor Binding Protein 6/blood Male Matrix Metalloproteinase 12/blood Middle Aged Nerve Tissue Proteins/blood Phenotype *Proteomics *Registries Twins United Kingdom Aging Aptamers. Blood biomarkers Early development Nucleotide Proteomics To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis beta [SE] = 0.013 [0.001], p = 3.66 x 10(-46)) and pleiotrophin (0.012 [0.005], p = 3.88 x 10(-41)). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 x 10(-5)). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging. Menni, Cristina Kiddle, Steven J Mangino, Massimo Vinuela, Ana Psatha, Maria Steves, Claire Sattlecker, Martina Buil, Alfonso Newhouse, Stephen Nelson, Sally Williams, Stephen Voyle, Nicola Soininen, Hilkka Kloszewska, Iwona Mecocci, Patrizia Tsolaki, Magda Vellas, Bruno Lovestone, Simon Spector, Tim D Dobson, Richard Valdes, Ana M eng 171/ALZS_/Alzheimer's Society/United Kingdom G/MRC_/Medical Research Council/United Kingdom MR/L/1/MRC_/Medical Research Council/United Kingdom MR/M/1/MRC_/Medical Research Council/United Kingdom Twin Study J Gerontol A Biol Sci Med Sci. Jul;70(7):809-16. doi: 10./gerona/glu121. Epub Aug 14.I SomaScan 08/16/ Zhao X, et al. A candidate plasma protein classifier to identify Alzheimer's disease J Alzheimers Dis 43 2 549-63 https://www.doi.org/10./JAD- 25,114,072 Aged Aged, 80 and over Alzheimer Disease/*blood/cerebrospinal fluid/*diagnosis Amyloid beta-Peptides/cerebrospinal fluid Area Under Curve Blood Proteins/*classification/*metabolism Female Humans Male Middle Aged Peptide Fragments/cerebrospinal fluid Predictive Value of Tests Principal Component Analysis Proteomics Reproducibility of Results tau Proteins/cerebrospinal fluid Alzheimer's disease aptamers biomarkers blood proteome Biomarkers currently used in the aid for the diagnosis of Alzheimer's disease (AD) are cerebrospinal fluid (CSF) protein markers and brain neuroimaging markers. These biomarkers, however, either involve semi-invasive procedures or are costly to measure. Thus, AD biomarkers from more easily accessible body fluids, such as plasma, are very enticing. Using an aptamer-based proteomic technology, we profiled 1,129 plasma proteins of AD patients and non-demented control individuals. A 5-protein classifier for AD identification was constructed in the discovery study with excellent 10-fold cross-validation performance (90.1% sensitivity, 84.2% specificity, 87.9% accuracy, and AUC as 0.94). In an independent validation study, the classifier was applied and correctly predicted AD with 100.0% sensitivity, 80.0% specificity, and 90.0% accuracy, matching or outperforming the CSF Abeta42 and tau biomarkers whose performance were assessed in individual-matched CSF samples obtained at the same visit as plasma sample collection. Moreover, the classifier also correctly predicted mild cognitive impairment, an early pre-dementia state of the disease, with 96.7% sensitivity, 80.0% specificity, and 92.5% accuracy. These studies demonstrate that plasma proteins could be used effectively and accurately to contribute to the clinical diagnosis of AD. Although additional and more diverse cohorts are needed for further validation of the robustness, including the support of postmortem diagnosis, the 5-protein classifier appears to be a promising blood test to contribute diagnosis of AD. Zhao, Xuemei Lejnine, Serguei Spond, Jeffrey Zhang, Chunsheng Ramaraj, T C Holder, Daniel J Dai, Hongyue Weiner, Russell Laterza, Omar F eng Research Support, Non-U.S. Gov't Netherlands J Alzheimers Dis. ;43(2):549-63. doi: 10./JAD-.I SomaScan 08/13/ Carlson M, et al. Improved preparation of 2_M triethylammonium bicarbonate Green Chem Lett Rev 8 4 37-39 https://www.doi.org/10./.. The widely used chromatographic eluent, aqueous triethylammonium bicarbonate, can be efficiently prepared as 2 M stock solution by carbonation of a mixture of triethylamine and water in a commercially available pressure reactor (20–25 psi). This improved process reduces carbon dioxide waste emissions by ca. 90% compared to traditional gas bubbling at atmospheric pressure. Carlson, M. Carter, J. D. Rohloff, J. SomaScan Steele FR, et al. DTC-and-Me: Patient, Provider, Proteins and Regulators J Pers Med 4 1 79-87 https://www.doi.org/10./jpm 25,562,144 The yet-unrealized potential for more personalized" Direct-to-Consumer (DTC) tests to fundamentally alter the practice and economics of healthcare is undeniable. However, there are also many challenges to be met, including the herculean task of ensuring that the information provided by such tests is scientifically sound and, ideally, medically actionable. We consider recent events in DTC testing and suggest a "thought experiment" of an approach that could ultimately meet the needs of patients, providers and regulatory authorities." Steele, Fintan R Gold, Larry eng Switzerland J Pers Med. Mar 18;4(1):79-87. doi: 10./jpm.I SomaScan 01/07/ Rohloff JC, et al. Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents Mol Ther Nucleic Acids 3 10 e201 https://www.doi.org/10./mtna..49 25,291,143 Limited chemical diversity of nucleic acid libraries has long been suspected to be a major constraining factor in the overall success of SELEX (Systematic Evolution of Ligands by EXponential enrichment). Despite this constraint, SELEX has enjoyed considerable success over the past quarter of a century as a result of the enormous size of starting libraries and conformational richness of nucleic acids. With judicious introduction of functional groups absent in natural nucleic acids, the diversity gap" between nucleic acid-based ligands and protein-based ligands can be substantially bridged, to generate a new class of ligands that represent the best of both worlds. We have explored the effect of various functional groups at the 5-position of uracil and found that hydrophobic aromatic side chains have the most profound influence on the success rate of SELEX and allow the identification of ligands with very low dissociation rate constants (named Slow Off-rate Modified Aptamers or SOMAmers). Such modified nucleotides create unique intramolecular motifs and make direct contacts with proteins. Importantly, SOMAmers engage their protein targets with surfaces that have significantly more hydrophobic character compared with conventional aptamers, thereby increasing the range of epitopes that are available for binding. These improvements have enabled us to build a collection of SOMAmers to over 3,000 human proteins encompassing major families such as growth factors, cytokines, enzymes, hormones, and receptors, with additional SOMAmers aimed at pathogen and rodent proteins. Such a large and growing collection of exquisite affinity reagents expands the scope of possible applications in diagnostics and therapeutics." Rohloff, John C Gelinas, Amy D Jarvis, Thale C Ochsner, Urs A Schneider, Daniel J Gold, Larry Janjic, Nebojsa eng Review Mol Ther Nucleic Acids. Oct 7;3(10):e201. doi: 10./mtna..49.I SomaScan 10/08/ Mehan MR, et al. Validation of a blood protein signature for non-small cell lung cancer Clin Proteomics 11 1 32 https://www.doi.org/10./--11-32 25,114,662 Biomarker Diagnosis Lung cancer Preanalytic variability Proteomic SOMAmer Sample bias Squamous cell carcinoma BACKGROUND: CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations. RESULTS: Blood-based proteomic profiles were generated with SOMAscan technology, which measured proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation. CONCLUSIONS: Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules. Mehan, Michael R Williams, Stephen A Siegfried, Jill M Bigbee, William L Weissfeld, Joel L Wilson, David O Pass, Harvey I Rom, William N Muley, Thomas Meister, Michael Franklin, Wilbur Miller, York E Brody, Edward N Ostroff, Rachel M eng P50 CA/CA/NCI NIH HHS/ P50 CA/CA/NCI NIH HHS/ England Clin Proteomics. Aug 1;11(1):32. doi: 10./--11-32. eCollection .I SomaScan 08/13/ Motzer RJ, et al. Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma Cancer Chemother Pharmacol 74 4 739-50 https://www.doi.org/10./s-014--0 25,100,134 Adult Angiogenesis Inhibitors/administration & dosage/adverse effects/pharmacokinetics Angiopoietin-2/*blood Antigens, Neoplasm/blood/genetics Biomarkers, Tumor/blood/genetics Carbonic Anhydrase IX Carbonic Anhydrases/blood/genetics *Carcinoma, Renal Cell/drug therapy/genetics/metabolism/pathology Disease-Free Survival Drug Administration Schedule Drug Monitoring/methods Drug Screening Assays, Antitumor Female Humans Hypoxia-Inducible Factor 1, alpha Subunit/blood/genetics *Indoles/administration & dosage/adverse effects/pharmacokinetics *Kidney Neoplasms/drug therapy/genetics/metabolism/pathology Male Matrix Metalloproteinase 2/*blood Polymorphism, Single Nucleotide Prognosis *Pyrroles/administration & dosage/adverse effects/pharmacokinetics Sunitinib Treatment Outcome Vascular Endothelial Growth Factor A/*genetics Vascular Endothelial Growth Factor Receptor-3/*genetics *Von Hippel-Lindau Tumor Suppressor Protein/blood/genetics PURPOSE: Sunitinib is a first-line advanced renal cell carcinoma (RCC) standard of care. In a randomized phase II trial comparing sunitinib treatment schedules, separate exploratory biomarker analyses investigated the correlations of efficacy with selected serum, germ line single-nucleotide polymorphism (SNP), or tumor markers. METHODS: Advanced RCC patients received first-line sunitinib 50 mg/day on the approved 4-week-on-2-week-off schedule (n = 146) or 37.5 mg/day continuous dosing (n = 146). The following correlation analyses were performed: (1) response evaluation criteria in solid tumors-defined tumor response with serum soluble protein levels via two distinct multiplex (n < 1,000) platforms; (2) response and time-to-event outcomes with germ line SNPs in vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)3 genes; and (3) response and time-to-event outcomes with tumor immunohistochemistry status for hypoxia-inducible factor 1-alpha (HIF-1alpha) and carbonic anhydrase-IX or tumor Von Hippel-Lindau (VHL) gene inactivation status. RESULTS: Lower baseline angiopoietin-2 (Ang-2) and higher baseline matrix metalloproteinase-2 (MMP-2) levels were identified by both platforms as statistically significantly associated with tumor response. There were no significant correlations between VEGF-A or VEGFR3 SNPs and outcomes. Progression-free survival was longer for HIF-1alpha percent of tumor expression groups 0-2 (HIF-1alpha low) versus 3-4 (HIF-1alpha high; p = 0.034). There were no significant correlations between outcomes and each VHL inactivation mechanism [mutation (86% of VHL-inactive patients), methylation (14%), and large deletion (7%)] or mechanisms combined. CONCLUSIONS: Serum Ang-2 and MMP-2 and tumor HIF-1alpha were identified as relevant baseline biomarkers of sunitinib activity in advanced RCC, warranting further research into their prognostic versus predictive value. Motzer, Robert J Hutson, Thomas E Hudes, Gary R Figlin, Robert A Martini, Jean-Francois English, Patricia A Huang, Xin Valota, Olga Williams, J Andrew eng Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't Germany Cancer Chemother Pharmacol. Oct;74(4):739-50. doi: 10./s-014--0. Epub Aug 7.I SomaScan 08/08/ Baumstummler A, et al. Specific capture and detection of Staphylococcus aureus with high-affinity modified aptamers to cell surface components Lett Appl Microbiol 59 4 422-31 https://www.doi.org/10./lam. 24,935,714 Antibody Affinity Aptamers, Peptide/chemistry/*metabolism Bacterial Proteins/chemistry/*metabolism Cell Membrane/chemistry/*metabolism Gene Expression Regulation, Bacterial Protein Binding Sensitivity and Specificity Staphylococcus aureus/genetics/*metabolism Staphylococcus aureus aptamer cell capture cell surface protein A staining Slow off-rate modified aptamer (SOMAmer) reagents were generated to several Staphylococcus aureus cell surface-associated proteins via SELEX with multiple modified DNA libraries using purified recombinant or native proteins. High-affinity binding agents with sub-nanomolar Kd 's were obtained for staphylococcal protein A (SpA), clumping factors (ClfA, ClfB), fibronectin-binding proteins (FnbA, FnbB) and iron-regulated surface determinants (Isd). Further screening revealed several SOMAmers that specifically bound to Staph. aureus cells from all strains that were tested, but not to other staphylococci or other bacteria. SpA and ClfA SOMAmers proved useful for the selective capture and enrichment of Staph. aureus cells, as shown by culture and PCR, leading to improved limits of detection and efficient removal of PCR inhibitors. Detection of Staph. aureus cells was enhanced by several orders of magnitude when the bacterial cell surface was coated with SOMAmers followed by qPCR of the SOMAmers. Furthermore, fluorescence-labelled SpA SOMAmers demonstrated their utility as direct detection agents in flow cytometry. Significance and impact of the study: Monitoring for microbial contamination of food, water, nonsterile products or the environment is typically based on culture, PCR or antibodies. Aptamers that bind with high specificity and affinity to well-conserved cell surface epitopes represent a promising novel type of reagents to detect bacterial cells without the need for culture or cell lysis, including for the capture and enrichment of bacteria present at low cell densities and for the direct detection via qPCR or fluorescent staining. Baumstummler, A Lehmann, D Janjic, N Ochsner, U A eng Research Support, Non-U.S. Gov't England Lett Appl Microbiol. Oct;59(4):422-31. doi: 10./lam.. Epub Jul 2.I SomaScan 06/18/ Morine MJ, et al. Genetic associations with micronutrient levels identified in immune and gastrointestinal networks Genes Nutr 9 4 408 https://www.doi.org/10./s-014--4 24,879,315 The discovery of vitamins and clarification of their role in preventing frank essential nutrient deficiencies occurred in the early s. Much vitamin research has understandably focused on public health and the effects of single nutrients to alleviate acute conditions. The physiological processes for maintaining health, however, are complex systems that depend upon interactions between multiple nutrients, environmental factors, and genetic makeup. To analyze the relationship between these factors and nutritional health, data were obtained from an observational, community-based participatory research program of children and teens (age 6-14) enrolled in a summer day camp in the Delta region of Arkansas. Assessments of erythrocyte S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), plasma homocysteine (Hcy) and 6 organic micronutrients (retinol, 25-hydroxy vitamin D3, pyridoxal, thiamin, riboflavin, and vitamin E), and 1,129 plasma proteins were performed at 3 time points in each of 2 years. Genetic makeup was analyzed with 1 M SNP genotyping arrays, and nutrient status was assessed with 24-h dietary intake questionnaires. A pattern of metabolites (met_PC1) that included the ratio of erythrocyte SAM/SAH, Hcy, and 5 vitamins were identified by principal component analysis. Met_PC1 levels were significantly associated with (1) single-nucleotide polymorphisms, (2) levels of plasma proteins, and (3) multilocus genotypes coding for gastrointestinal and immune functions, as identified in a global network of metabolic/protein-protein interactions. Subsequent mining of data from curated pathway, network, and genome-wide association studies identified genetic and functional relationships that may be explained by gene-nutrient interactions. The systems nutrition strategy described here has thus associated a multivariate metabolite pattern in blood with genes involved in immune and gastrointestinal functions. Morine, Melissa J Monteiro, Jacqueline Pontes Wise, Carolyn Teitel, Candee Pence, Lisa Williams, Anna Ning, Baitang McCabe-Sellers, Beverly Champagne, Catherine Turner, Jerome Shelby, Beatrice Bogle, Margaret Beger, Richard D Priami, Corrado Kaput, Jim eng Germany Genes Nutr. Jul;9(4):408. doi: 10./s-014--4. Epub May 31.I SomaScan 06/01/ Sattlecker M, et al. Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology Alzheimers Dement 10 6 724-34 https://www.doi.org/10./j.jalz..09.016 24,768,341 Aged Aged, 80 and over Alzheimer Disease/*blood Atrophy/etiology Biomarkers/*blood Blood Proteins/*metabolism Brain/pathology Cognitive Dysfunction/blood Cohort Studies Female Humans Logistic Models *Magnetic Resonance Imaging Male *Proteomics ROC Curve Alzheimer's disease Blood biomarkers Proteins Rate of progression SOMAscan sMRI Blood proteins and their complexes have become the focus of a great deal of interest in the context of their potential as biomarkers of Alzheimer's disease (AD). We used a SOMAscan assay for quantifying proteins in blood samples from 331 AD, 211 controls, and 149 mild cognitive impaired (MCI) subjects. The strongest associations of protein levels with AD outcomes were prostate-specific antigen complexed to alpha1-antichymotrypsin (AD diagnosis), pancreatic prohormone (AD diagnosis, left entorhinal cortex atrophy, and left hippocampus atrophy), clusterin (rate of cognitive decline), and fetuin B (left entorhinal atrophy). Multivariate analysis found that a subset of 13 proteins predicted AD with an accuracy of area under the curve of 0.70. Our replication of previous findings provides further evidence that levels of these proteins in plasma are truly associated with AD. The newly identified proteins could be potential biomarkers and are worthy of further investigation. Sattlecker, Martina Kiddle, Steven J Newhouse, Stephen Proitsi, Petroula Nelson, Sally Williams, Stephen Johnston, Caroline Killick, Richard Simmons, Andrew Westman, Eric Hodges, Angela Soininen, Hilkka Kloszewska, Iwona Mecocci, Patrizia Tsolaki, Magda Vellas, Bruno Lovestone, Simon Dobson, Richard J B eng 167/ALZS_/Alzheimer's Society/United Kingdom 171/ALZS_/Alzheimer's Society/United Kingdom G/MRC_/Medical Research Council/United Kingdom MR/L/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Alzheimers Dement. Nov;10(6):724-34. doi: 10./j.jalz..09.016. Epub Apr 25.I SomaScan 04/29/ Monteiro JP, et al. Methylation potential associated with diet, genotype, protein, and metabolite levels in the Delta Obesity Vitamin Study Genes Nutr 9 3 403 https://www.doi.org/10./s-014--9 24,760,553 Micronutrient research typically focuses on analyzing the effects of single or a few nutrients on health by analyzing a limited number of biomarkers. The observational study described here analyzed micronutrients, plasma proteins, dietary intakes, and genotype using a systems approach. Participants attended a community-based summer day program for 6-14 year old in 2 years. Genetic makeup, blood metabolite and protein levels, and dietary differences were measured in each individual. Twenty-four-hour dietary intakes, eight micronutrients (vitamins A, D, E, thiamin, folic acid, riboflavin, pyridoxal, and pyridoxine) and 3 one-carbon metabolites [homocysteine (Hcy), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH)], and 1,129 plasma proteins were analyzed as a function of diet at metabolite level, plasma protein level, age, and sex. Cluster analysis identified two groups differing in SAM/SAH and differing in dietary intake patterns indicating that SAM/SAH was a potential marker of nutritional status. The approach used to analyze genetic association with the SAM/SAH metabolites is called middle-out: SNPs in 275 genes involved in the one-carbon pathway (folate, pyridoxal/pyridoxine, thiamin) or were correlated with SAM/SAH (vitamin A, E, Hcy) were analyzed instead of the entire 1M SNP data set. This procedure identified 46 SNPs in 25 genes associated with SAM/SAH demonstrating a genetic contribution to the methylation potential. Individual plasma metabolites correlated with 99 plasma proteins. Fourteen proteins correlated with body mass index, 49 with group age, and 30 with sex. The analytical strategy described here identified subgroups for targeted nutritional interventions. Monteiro, Jacqueline Pontes Wise, Carolyn Morine, Melissa J Teitel, Candee Pence, Lisa Williams, Anna McCabe-Sellers, Beverly Champagne, Catherine Turner, Jerome Shelby, Beatrice Ning, Baitang Oguntimein, Joan Taylor, Lauren Toennessen, Terri Priami, Corrado Beger, Richard D Bogle, Margaret Kaput, Jim eng Germany Genes Nutr. May;9(3):403. doi: 10./s-014--9. Epub Apr 24.I SomaScan 04/25/ Ochsner UA, et al. Systematic selection of modified aptamer pairs for diagnostic sandwich assays Biotechniques 56 3 125-8, 130, 132-3 https://www.doi.org/10./ 24,641,476 Affinity Labels/chemistry *Aptamers, Nucleotide/chemistry Humans Molecular Diagnostic Techniques Protein Binding Proteins/chemistry/*isolation & purification Recombinant Proteins/chemistry/isolation & purification SELEX Aptamer Technique/*methods Selex aptamer diagnostics epitope selection modified nucleotides sandwich assay Protein diagnostic applications typically require pairs of analyte-specific reagents for capture and detection. We developed methods for the systematic isolation of slow off-rate modified aptamer (SOMAmer) reagents that bind to different epitopes and allow efficient pair-wise screening of multiple ligands. SOMAmers were generated via a second systematic evolution of ligands by exponential enrichment (SELEX), using complexes of target proteins with a primary, non-amplifiable SOMAmer and employing different modified nucleotides (e.g., naphthylmethyl- or tryptaminocarbonyl-dU) to favor alternate binding epitopes. Non-competing binding of primary and secondary SOMAmers was tested in radiolabel competition and sandwich binding assays. Multiplexed high-throughput screening for sandwich pairs utilized the Luminex platform, with primary SOMAmers as capture agents attached to different types of LumAvidin beads, which were then pooled for testing the secondary SOMAmers individually as detection agents. Functional SOMAmer pairs were obtained for Clostridium difficile binary toxin (CdtA) and for a panel of human proteins (ANGPT2, TSP2, CRDL1, MATN2, GPVI, C7, PLG) that had been previously identified as promising markers for cardiovascular risk. The equilibrium dissociation constants (Kd values) ranged from 0.02-2.7 nM, and the detection limits were in the low picomolar range for these proteins in SOMAmer sandwich assays. These results indicate that SOMAmer pairs hold promise for the development of rapid tests or specific diagnostic panels. Ochsner, Urs A Green, Louis S Gold, Larry Janjic, Nebojsa eng England Biotechniques. Mar 1;56(3):125-8, 130, 132-3. doi: 10./. eCollection .I SomaScan 03/20/ Nahid P, et al. Aptamer-based proteomic signature of intensive phase treatment response in pulmonary tuberculosis Tuberculosis (Edinb) 94 3 187-96 https://www.doi.org/10./j.tube..01.006 24,629,635 Adult Antitubercular Agents/*therapeutic use Bacterial Proteins/*metabolism Biomarkers/metabolism Drug Therapy, Combination Female Humans Male Middle Aged Pilot Projects Prospective Studies Proteomics/methods SELEX Aptamer Technique/methods Treatment Outcome Tuberculosis, Pulmonary/blood/*drug therapy Young Adult Biomarkers Logistic regression model Multiplex analysis Proteomics SOMAscan Treatment response Tuberculosis of SomaLogic. MAD is a paid SomaLogic consultant. BACKGROUND: New drug regimens of greater efficacy and shorter duration are needed for tuberculosis (TB) treatment. The identification of accurate, quantitative, non-culture based markers of treatment response would improve the efficiency of Phase 2 TB drug testing. METHODS: In an unbiased biomarker discovery approach, we applied a highly multiplexed, aptamer-based, proteomic technology to analyze serum samples collected at baseline and after 8 weeks of treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in a Centers for Disease Control and Prevention (CDC) TB Trials Consortium Phase 2B treatment trial. RESULTS: We identified protein expression differences associated with 8-week culture status, including Coagulation Factor V, SAA, XPNPEP1, PSME1, IL-11 Ralpha, HSP70, Galectin-8, alpha2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. Markers noted to have differential changes between responders and slow-responders included nectin-like protein 2, EphA1 (Ephrin type-A receptor 1), gp130, CNDP1, TGF-b RIII, MRC2, ADAM9, and CDON. A logistic regression model combining markers associated with 8-week culture status revealed an ROC curve with AUC = 0.96, sensitivity = 0.95 and specificity = 0.90. Additional markers showed differential changes between responders and slow-responders (nectin-like protein), or correlated with time-to-culture-conversion (KLRK1). CONCLUSIONS: Serum proteins involved in the coagulation cascade, neutrophil activity, immunity, inflammation, and tissue remodeling were found to be associated with TB treatment response. A quantitative, non-culture based, five-marker signature predictive of 8-week culture status was identified in this pilot study. Nahid, Payam Bliven-Sizemore, Erin Jarlsberg, Leah G De Groote, Mary A Johnson, John L Muzanyi, Grace Engle, Melissa Weiner, Marc Janjic, Nebojsa Sterling, David G Ochsner, Urs A eng R01 AI/AI/NIAID NIH HHS/ 1R01AI/AI/NIAID NIH HHS/ Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Scotland Tuberculosis (Edinb). May;94(3):187-96. doi: 10./j.tube..01.006. Epub Feb 7.I SomaScan 03/19/ Webber J, et al. Proteomics analysis of cancer exosomes using a novel modified aptamer-based array (SOMAscan) platform Mol Cell Proteomics 13 4 -64 https://www.doi.org/10./mcp.M113. 24,505,114 Biomarkers, Tumor/metabolism Cell Line, Tumor Exosomes/genetics/*metabolism Genes, Essential Humans Male Microarray Analysis/*methods Nanotechnology Prostatic Neoplasms/*metabolism Proteomics/*methods We have used a novel affinity-based proteomics technology to examine the protein signature of small secreted extracellular vesicles called exosomes. The technology uses a new class of protein binding reagents called SOMAmers(R) (slow off-rate modified aptamers) and allows the simultaneous precise measurement of over proteins. Exosomes were highly purified from the Du145 prostate cancer cell line, by pooling selected fractions from a continuous sucrose gradient (within the density range of 1.1 to 1.2 g/ml), and examined under standard conditions or with additional detergent treatment by the SOMAscan array (version 3.0). Lysates of Du145 cells were also prepared, and the profiles were compared. Housekeeping proteins such as cyclophilin-A, LDH, and Hsp70 were present in exosomes, and we identified almost 100 proteins that were enriched in exosomes relative to cells. These included proteins of known association with cancer exosomes such as MFG-E8, integrins, and MET, and also those less widely reported as exosomally associated, such as ROR1 and ITIH4. Several proteins with no previously known exosomal association were confirmed as exosomally expressed in experiments using individual SOMAmer(R) reagents or antibodies in micro-plate assays. Western blotting confirmed the SOMAscan-identified enrichment of exosomal NOTCH-3, L1CAM, RAC1, and ADAM9. In conclusion, we describe here over 300 proteins of hitherto unknown association with prostate cancer exosomes and suggest that the SOMAmer(R)-based assay technology is an effective proteomics platform for exosome-associated biomarker discovery in diverse clinical settings. Webber, Jason Stone, Timothy C Katilius, Evaldas Smith, Breanna C Gordon, Bridget Mason, Malcolm D Tabi, Zsuzsanna Brewis, Ian A Clayton, Aled eng G-03/PCUK_/Prostate Cancer UK/United Kingdom CRUK_/Cancer Research UK/United Kingdom Research Support, Non-U.S. Gov't Mol Cell Proteomics. Apr;13(4):-64. doi: 10./mcp.M113.. Epub Feb 6.I SomaScan 02/08/ Gelinas AD, et al. Crystal structure of interleukin-6 in complex with a modified nucleic acid ligand J Biol Chem 289 12 -34 https://www.doi.org/10./jbc.M113. 24,415,767 Aptamers, Nucleotide/*chemistry/*pharmacology Crystallography, X-Ray Drug Discovery Humans Interleukin-6/*chemistry/*metabolism Ligands Models, Molecular Protein Conformation Recombinant Proteins/chemistry/metabolism SELEX Aptamer Technique Aptamers DNA Structure G-quartet Interleukin Molecular Evolution Nucleic Acid Chemistry Protein-Nucleic Acid Interaction Selex IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Ralpha and gp130. Because of its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOMAmers (S low Off-rate Modified Aptamers) that bind IL-6 and inhibit its biologic activity. SOMAmers exploit the chemical diversity of protein-like side chains assembled on flexible nucleic acid scaffolds, resulting in an expanded repertoire of intra- and intermolecular interactions not achievable with conventional aptamers. Here, we report the co-crystal structure of a high affinity SOMAmer (Kd = 0.20 nm) modified at the 5-position of deoxyuridine in a complex with IL-6. The SOMAmer, comprised of a G-quartet domain and a stem-loop domain, engages IL-6 in a clamp-like manner over an extended surface exhibiting close shape complementarity with the protein. The interface is characterized by substantial hydrophobic interactions overlapping the binding surfaces of the IL-6Ralpha and gp130 receptors. The G-quartet domain retains considerable binding activity as a disconnected autonomous fragment (Kd = 270 nm). A single substitution from our diversely modified nucleotide library leads to a 37-fold enhancement in binding affinity of the G-quartet fragment (Kd = 7.4 nm). The ability to probe ligand surfaces in this manner is a powerful tool in the development of new therapeutic reagents with improved pharmacologic properties. The SOMAmer.IL-6 structure also expands our understanding of the diverse structural motifs achievable with modified nucleic acid libraries and elucidates the nature with which these unique ligands interact with their protein targets. Gelinas, Amy D Davies, Douglas R Edwards, Thomas E Rohloff, John C Carter, Jeffrey D Zhang, Chi Gupta, Shashi Ishikawa, Yuichi Hirota, Masao Nakaishi, Yuichiro Jarvis, Thale C Janjic, Nebojsa eng J Biol Chem. Mar 21;289(12):-34. doi: 10./jbc.M113.. Epub Jan 12.I SomaScan 01/15/ Gupta S, et al. Chemically modified DNA aptamers bind interleukin-6 with high affinity and inhibit signaling by blocking its interaction with interleukin-6 receptor J Biol Chem 289 12 -19 https://www.doi.org/10./jbc.M113. 24,415,766 Amino Acid Sequence Animals Anti-Inflammatory Agents/chemistry/metabolism/*pharmacology Aptamers, Nucleotide/chemistry/metabolism/*pharmacology Base Sequence CHO Cells Cricetulus Drug Discovery Humans Interleukin-6/*antagonists & inhibitors/chemistry/*immunology/metabolism Macaca fascicularis Mice Molecular Sequence Data Rats Receptors, Interleukin-6/*immunology SELEX Aptamer Technique/methods Serum/metabolism Aptamers Cell Signaling Interleukin Molecular Evolution Nuclease Stability Nucleic Acid Chemistry Protein-DNA Interaction Selex SOMAmer Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immune and inflammatory responses, and its overproduction is a hallmark of inflammatory diseases. Inhibition of IL-6 signaling with the anti-IL-6 receptor antibody tocilizumab has provided some clinical benefit to patients; however, direct cytokine inhibition may be a more effective option. We used the systematic evolution of ligands by exponential enrichment (SELEX) process to discover slow off-rate modified aptamers (SOMAmers) with hydrophobic base modifications that inhibit IL-6 signaling in vitro. Two classes of IL-6 SOMAmers were isolated from modified DNA libraries containing 40 random positions and either 5-(N-benzylcarboxamide)-2'-deoxyuridine (Bn-dU) or 5-[N-(1-naphthylmethyl)carboxamide]-2'-deoxyuridine (Nap-dU) replacing dT. These modifications facilitate the high affinity binding interaction with IL-6 and provide resistance against degradation by serum endonucleases. Post-SELEX optimization of one Bn-dU and one Nap-dU SOMAmer led to improvements in IL-6 binding (10-fold) and inhibition activity (greater than 20-fold), resulting in lead SOMAmers with sub-nanomolar affinity (Kd = 0.2 nm) and potency (IC50 = 0.2 nm). Although similar in inhibition properties, the two SOMAmers have unique sequences and different ortholog specificities. Furthermore, these SOMAmers were stable in human serum in vitro for more than 48 h. Both SOMAmers prevented IL-6 signaling by blocking the interaction of IL-6 with its receptor and inhibited the proliferation of tumor cells in vitro as effectively as tocilizumab. This new class of IL-6 inhibitor may be an effective therapeutic alternative for patients suffering from inflammatory diseases. Gupta, Shashi Hirota, Masao Waugh, Sheela M Murakami, Ikuo Suzuki, Tomoki Muraguchi, Masahiro Shibamori, Masafumi Ishikawa, Yuichi Jarvis, Thale C Carter, Jeffrey D Zhang, Chi Gawande, Bharat Vrkljan, Michael Janjic, Nebojsa Schneider, Daniel J eng J Biol Chem. Mar 21;289(12):-19. doi: 10./jbc.M113.. Epub Jan 12.I SomaScan 01/15/ Lollo B, et al. Beyond antibodies: new affinity reagents to unlock the proteome Proteomics 14 6 638-44 https://www.doi.org/10./pmic. 24,395,722 Animals Antibodies/analysis Aptamers, Nucleotide/*chemistry Humans Protein Array Analysis/methods Proteome/*analysis Proteomics/*methods Aptamer Biomarker Protein arrays SOMAmer SOMAscan Antibodies have been the workhorse reagents of protein capture and quantification since their debut in the RIAs developed by Yalow and Berson. However, there are technical challenges to the use of antibodies in highly multiplexed arrays aimed at measuring hundreds or even thousands of proteins at one time. We describe here a recently developed class of synthetic protein-binding reagents (slow off-rate modified aptamer). We discuss the chemical makeup and protein binding specifications of slow off-rate modified aptamer reagents, compare them to traditional aptamers and antibodies, briefly describe the novel proteomic assay that takes advantage of their unique properties, and provide several examples of their multiple applications to biomarker discovery and validation across a range of biomedical science questions. Lollo, Bridget Steele, Fintan Gold, Larry eng Germany Proteomics. Mar;14(6):638-44. doi: 10./pmic.. Epub Feb 20.I SomaScan 01/08/ Kiddle SJ, et al. Candidate blood proteome markers of Alzheimer's disease onset and progression: a systematic review and replication study J Alzheimers Dis 38 3 515-31 https://www.doi.org/10./JAD- 24,121,966 Alzheimer Disease/*blood/*diagnosis Biomarkers/*blood Blood Proteins/*metabolism Disease Progression Humans Proteome Alzheimer's disease biomarkers blood magnetic resonance imaging nucleotide aptamers A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of Alzheimer's disease (AD) would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (> 100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes in five independent research cohorts in these 21 studies: alpha-1-antitrypsin, alpha-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic's SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer's Research UK/Maudsley BRC Dementia Case Registry at King's Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value < 0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency. Kiddle, Steven J Sattlecker, Martina Proitsi, Petroula Simmons, Andrew Westman, Eric Bazenet, Chantal Nelson, Sally K Williams, Stephen Hodges, Angela Johnston, Caroline Soininen, Hilkka Kloszewska, Iwona Mecocci, Patrizia Tsolaki, Magda Vellas, Bruno Newhouse, Stephen Lovestone, Simon Dobson, Richard J B eng 171/ALZS_/Alzheimer's Society/United Kingdom MR/L/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Review Systematic Review Netherlands J Alzheimers Dis. ;38(3):515-31. doi: 10./JAD-.I SomaScan 10/15/ Xie Y, et al. Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin EMBO Rep 14 12 -6 https://www.doi.org/10./embor..167 24,165,923 Amino Acid Motifs Binding Sites HEK293 Cells Humans Protein Binding Receptors, G-Protein-Coupled/*metabolism Thrombospondins/chemistry/*metabolism Ubiquitin-Protein Ligases/*metabolism *Wnt Signaling Pathway R-spondin proteins sensitize cells to Wnt signalling and act as potent stem cell growth factors. Various membrane proteins have been proposed as potential receptors of R-spondin, including LGR4/5, membrane E3 ubiquitin ligases ZNRF3/RNF43 and several others proteins. Here, we show that R-spondin interacts with ZNRF3/RNF43 and LGR4 through distinct motifs. Both LGR4 and ZNRF3 binding motifs are required for R-spondin-induced LGR4/ZNRF3 interaction, membrane clearance of ZNRF3 and activation of Wnt signalling. Importantly, Wnt-inhibitory activity of ZNRF3, but not of a ZNRF3 mutant with reduced affinity to R-spondin, can be strongly suppressed by R-spondin, suggesting that R-spondin primarily functions by binding and inhibiting ZNRF3. Together, our results support a dual receptor model of R-spondin action, where LGR4/5 serve as the engagement receptor whereas ZNRF3/RNF43 function as the effector receptor. Xie, Yang Zamponi, Raffaella Charlat, Olga Ramones, Melissa Swalley, Susanne Jiang, Xiaomo Rivera, Daniel Tschantz, William Lu, Bo Quinn, Lisa Dimitri, Chris Parker, Jefferson Jeffery, Doug Wilcox, Sheri K Watrobka, Mike LeMotte, Peter Granda, Brian Porter, Jeffrey A Myer, Vic E Loew, Andreas Cong, Feng eng England EMBO Rep. Dec;14(12):-6. doi: 10./embor..167. Epub Oct 29.I SomaScan 10/30/ Park NJ, et al. Measurement of cetuximab and panitumumab-unbound serum EGFR extracellular domain using an assay based on slow off-rate modified aptamer (SOMAmer) reagents PLoS One 8 8 e https://www.doi.org/10./journal.pone. 23,990,977 Antibodies, Monoclonal/administration & dosage/*metabolism Antibodies, Monoclonal, Humanized/administration & dosage/*metabolism Antineoplastic Agents/administration & dosage/metabolism Aptamers, Nucleotide/genetics/metabolism Binding Sites Binding, Competitive Biomarkers/blood Cetuximab Clinical Laboratory Techniques/*methods Enzyme-Linked Immunosorbent Assay ErbB Receptors/antagonists & inhibitors/*blood/metabolism Humans Panitumumab Polymerase Chain Reaction Receptor, ErbB-2/antagonists & inhibitors/blood/metabolism Receptor, ErbB-3/antagonists & inhibitors/blood/metabolism Receptor, ErbB-4 Reproducibility of Results BACKGROUND: Response to cetuximab (Erbitux(R)) and panitumumab (Vectibix(R)) varies among individuals, and even those who show response ultimately gain drug resistance. One possible etiologic factor is differential interaction between the drug and target. We describe the development of an assay based on Slow Off-rate Modified Aptamer (SOMAmer()) reagents that can distinguish drug-bound from unbound epidermal growth factor receptor (EGFR). METHODS: This quantitative assay uses a SOMAmer reagent specific for EGFR extracellular domain (ECD) as a capturing reagent. Captured SOMAmer is quantitated using PCR. Linearity and accuracy (recovery) of the assay were assessed using normal sera and purified EGFR ECD. RESULTS: This EGFR ECD assay showed linearity between 2.5 and 600 ng/mL. Average recovery was 101%. The assay detected EGFR but showed little cross-reactivity to other ErbB proteins: 0.4% for ErbB2, 6.9% for ErbB3, and 1.3% for ErbB4. Preincubation of normal serum with either cetuximab or panitumumab resulted in a dose-dependent decrease in EGFR ECD levels measured using the SOMAmer assay; preincubation did not affect measurement with an ELISA. CONCLUSIONS: This SOMAmer-based serum EGFR ECD assay accurately and specifically measures EGFR in serum. Detection of significant amounts of drug-unbound EGFR in patients undergoing cetuximab or panitumumab treatment could be an indicator of poor drug response. Further studies are needed to evaluate the utility of the assay as an indicator of drug efficacy or as a guide to dosing. Park, Noh Jin Wang, Xiuqiang Diaz, Angelica Goos-Root, Dana M Bock, Christopher Vaught, Jonathan D Sun, Weimin Strom, Charles M eng PLoS One. Aug 21;8(8):e. doi: 10./journal.pone.. eCollection .I SomaScan 08/31/ Ochsner UA, et al. Detection of Clostridium difficile toxins A, B and binary toxin with slow off-rate modified aptamers Diagn Microbiol Infect Dis 76 3 278-85 https://www.doi.org/10./j.diagmicrobio..03.029 23,680,240 Aptamers, Nucleotide Bacterial Proteins/analysis/*chemistry/metabolism Clostridioides difficile/*metabolism Culture Media, Conditioned/analysis Enterocolitis, Pseudomembranous/diagnosis/microbiology Enterotoxins/analysis/*chemistry/metabolism Enzyme-Linked Immunosorbent Assay Humans Limit of Detection Peptide Fragments/chemistry Protein Binding SELEX Aptamer Technique Rapid and accurate diagnostic tests for Clostridium difficile infections (CDI) are crucial for management of patients with suspected CDI and for infection control. Enzyme immunoassays for detection of the toxins are routinely used but lack adequate sensitivity. We generated slow off-rate modified aptamers (SOMAmer reagents) via in vitro selection (SELEX) that bind toxins A, B and binary toxin with high affinity and specificity. Using SOMAmers alone or in conjunction with antibodies, we have developed toxin assays with a 1 pmol/L (300 pg/mL) limit of detection and a 3 log dynamic range. SOMAmers proved useful as capture or detection agents in equilibrium solution binding radioassays, pull-down capture assays, dot blots, and plate- or membrane-based sandwich assays, thus represent a promising alternative to antibodies in diagnostic applications. SOMAmers detected toxins A, B and binary toxin in culture supernatants from toxigenic C. difficile, including a BI/NAP1 strain and historic strains. Ochsner, Urs A Katilius, Evaldas Janjic, Nebojsa eng Research Support, Non-U.S. Gov't Diagn Microbiol Infect Dis. Jul;76(3):278-85. doi: 10./j.diagmicrobio..03.029. Epub May 13.I SomaScan 05/18/ Loffredo FS, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy Cell 153 4 828-39 https://www.doi.org/10./j.cell..04.015 23,663,781 *Aging Animals Blood Pressure Bone Morphogenetic Proteins/*metabolism Cardiomegaly/*metabolism Female Forkhead Transcription Factors/metabolism Growth Differentiation Factors/*metabolism Humans Hypertrophy, Left Ventricular/metabolism Induced Pluripotent Stem Cells/cytology/metabolism Male Mice Mice, Inbred C57BL Myocytes, Cardiac/cytology/*metabolism *Parabiosis The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-beta superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging. Loffredo, Francesco S Steinhauser, Matthew L Jay, Steven M Gannon, Joseph Pancoast, James R Yalamanchi, Pratyusha Sinha, Manisha Dall'Osso, Claudia Khong, Danika Shadrach, Jennifer L Miller, Christine M Singer, Britta S Stewart, Alex Psychogios, Nikolaos Gerszten, Robert E Hartigan, Adam J Kim, Mi-Jeong Serwold, Thomas Wagers, Amy J Lee, Richard T eng 5U01 HL/HL/NHLBI NIH HHS/ 1R01 AG/AG/NIA NIH HHS/ K99 HL/HL/NHLBI NIH HHS/ 1R01 AG/AG/NIA NIH HHS/ DP2 OD/OD/NIH HHS/ R00 HL/HL/NHLBI NIH HHS/ 1DP2 OD/OD/NIH HHS/ K08 DK/DK/NIDDK NIH HHS/ P30DK/DK/NIDDK NIH HHS/ R01 AG/AG/NIA NIH HHS/ R01 AG/AG/NIA NIH HHS/ HHMI/Howard Hughes Medical Institute/ R01 AG/AG/NIA NIH HHS/ U01 HL/HL/NHLBI NIH HHS/ P30 DK/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell. May 9;153(4):828-39. doi: 10./j.cell..04.015.I SomaScan 05/15/ De Groote MA, et al. Elucidating novel serum biomarkers associated with pulmonary tuberculosis treatment PLoS One 8 4 e https://www.doi.org/10./journal.pone. 23,637,781 Adult Biomarkers/*blood C-Reactive Protein/metabolism Female Humans Male Middle Aged Phospholipases A2/blood Proteomics Serum Amyloid A Protein/metabolism Tuberculosis, Pulmonary/*therapy In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO) to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in the Center for Disease Control and Prevention's Tuberculosis Trials Consortium (TBTC) Study 29. This work represents the first large-scale proteomic analysis employing modified DNA aptamers in a study of active tuberculosis (TB). We identified multiple proteins that exhibit significant expression differences during the intensive phase of TB therapy. There was enrichment for proteins in conserved networks of biological processes and function including antimicrobial defense, tissue healing and remodeling, acute phase response, pattern recognition, protease/anti-proteases, complement and coagulation cascade, apoptosis, immunity and inflammation pathways. Members of cytokine pathways such as interferon-gamma, while present, were not as highly represented as might have been predicted. The top proteins that changed between baseline and 8 weeks of therapy were TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, and LBP. The novel proteins elucidated in this work may provide new insights for understanding TB disease, its treatment and subsequent healing processes that occur in response to effective therapy. De Groote, Mary A Nahid, Payam Jarlsberg, Leah Johnson, John L Weiner, Marc Muzanyi, Grace Janjic, Nebojsa Sterling, David G Ochsner, Urs A eng Research Support, Non-U.S. Gov't PLoS One. Apr 18;8(4):e. doi: 10./journal.pone.. Print .I SomaScan 05/03/ Mehan MR, et al. Highly multiplexed proteomic platform for biomarker discovery, diagnostics, and therapeutics Adv Exp Med Biol 735 283-300 https://www.doi.org/10./978-1---2_20 23,402,035 Animals Biomarkers/*analysis Blood Proteins/chemistry Complement Inactivating Agents/pharmacology Complement System Proteins/physiology *Diagnosis Drug Therapy/*methods Humans Proteins/chemistry Proteomics/*methods Progression from health to disease is accompanied by complex changes in protein expression in both the circulation and affected tissues. Large-scale comparative interrogation of the human proteome can offer insights into disease biology as well as lead to the discovery of new biomarkers for diagnostics, new targets for therapeutics, and can identify patients most likely to benefit from treatment. Although genomic studies provide an increasingly sharper understanding of basic biological and pathobiological processes, they ultimately only offer a prediction of relative disease risk, whereas proteins offer an immediate assessment of real-time" health and disease status. We have recently developed a new proteomic technology, based on modified aptamers, for biomarker discovery that is capable of simultaneously measuring more than a thousand proteins from small volumes of biological samples such as plasma, tissues, or cells. Our technology is enabled by SOMAmers (Slow Off-rate Modified Aptamers), a new class of protein binding reagents that contain chemically modified nucleotides that greatly expand the physicochemical diversity of nucleic acid-based ligands. Such modifications introduce functional groups that are absent in natural nucleic acids but are often found in protein-protein, small molecule-protein, and antibody-antigen interactions. The use of these modifications expands the range of possible targets for SELEX (Systematic Evolution of Ligands by EXponential Enrichment), results in improved binding properties, and facilitates selection of SOMAmers with slow dissociation rates. Our assay works by transforming protein concentrations in a mixture into a corresponding DNA signature, which is then quantified on current commercial DNA microarray platforms. In essence, we take advantage of the dual nature of SOMAmers as both folded binding entities with defined shapes and unique nucleic acid sequences recognizable by specific hybridization probes. Currently, our assay is capable of simultaneously measuring 1,030 proteins, extending to sub-pM detection limits, an average dynamic range of each analyte in the assay of > 3 logs, an overall dynamic range of at least 7 logs, and a throughput of one million analytes per week. Our collection includes SOMAmers that specifically recognize most of the complement cascade proteins. We have used this assay to identify potential biomarkers in a range of diseases such as malignancies, cardiovascular disorders, and inflammatory conditions. In this chapter, we describe the application of our technology to discovering large-scale protein expression changes associated with chronic kidney disease and non-small cell lung cancer. With this new proteomics technology-which is fast, economical, highly scalable, and flexible--we now have a powerful tool that enables whole-proteome proteomics, biomarker discovery, and advancing the next generation of evidence-based, "personalized" diagnostics and therapeutics." Mehan, Michael R Ostroff, Rachel Wilcox, Sheri K Steele, Fintan Schneider, Daniel Jarvis, Thale C Baird, Geoffrey S Gold, Larry Janjic, Nebojsa eng Review Adv Exp Med Biol. ;735:283-300. doi: 10./978-1---2_20.I SomaScan 02/14/ Davies DR, et al. Unique motifs and hydrophobic interactions shape the binding of modified DNA ligands to protein targets Proc Natl Acad Sci U S A 109 49 -6 https://www.doi.org/10./pnas. 23,139,410 Amino Acid Motifs/genetics Aptamers, Nucleotide/*chemistry/*metabolism Becaplermin Crystallography, X-Ray DNA Primers/genetics *Hydrophobic and Hydrophilic Interactions *Models, Molecular Molecular Sequence Data Molecular Structure Phosphorylation Protein Binding Proto-Oncogene Proteins c-sis/chemistry/*metabolism SELEX Aptamer Technique/*methods Sequence Analysis, DNA Transition Temperature Selection of aptamers from nucleic acid libraries by in vitro evolution represents a powerful method of identifying high-affinity ligands for a broad range of molecular targets. Nevertheless, a sizeable fraction of proteins remain difficult targets due to inherently limited chemical diversity of nucleic acids. We have exploited synthetic nucleotide modifications that confer protein-like diversity on a nucleic acid scaffold, resulting in a new generation of binding reagents called SOMAmers (Slow Off-rate Modified Aptamers). Here we report a unique crystal structure of a SOMAmer bound to its target, platelet-derived growth factor B (PDGF-BB). The SOMAmer folds into a compact structure and exhibits a hydrophobic binding surface that mimics the interface between PDGF-BB and its receptor, contrasting sharply with mainly polar interactions seen in traditional protein-binding aptamers. The modified nucleotides circumvent the intrinsic diversity constraints of natural nucleic acids, thereby greatly expanding the structural vocabulary of nucleic acid ligands and considerably broadening the range of accessible protein targets. Davies, Douglas R Gelinas, Amy D Zhang, Chi Rohloff, John C Carter, Jeffrey D O'Connell, Daniel Waugh, Sheela M Wolk, Steven K Mayfield, Wesley S Burgin, Alex B Edwards, Thomas E Stewart, Lance J Gold, Larry Janjic, Nebojsa Jarvis, Thale C eng Proc Natl Acad Sci U S A. Dec 4;109(49):-6. doi: 10./pnas.. Epub Nov 8.I SomaScan 11/10/ Ostroff RM, et al. Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool PLoS One 7 10 e https://www.doi.org/10./journal.pone. 23,056,237 Adult Aged Aged, 80 and over Asbestos Biomarkers, Tumor/blood Carcinogens Case-Control Studies Cohort Studies Enzyme-Linked Immunosorbent Assay Female Humans Lectins/blood Male Mesothelioma/chemically induced/*diagnosis/metabolism Middle Aged Pleural Neoplasms/chemically induced/*diagnosis/metabolism Principal Component Analysis Proteomics/*methods Public Health Surveillance/*methods Reproducibility of Results Sensitivity and Specificity Young Adult BACKGROUND: Malignant pleural mesothelioma (MM) is an aggressive, asbestos-related pulmonary cancer that is increasing in incidence. Because diagnosis is difficult and the disease is relatively rare, most patients present at a clinically advanced stage where possibility of cure is minimal. To improve surveillance and detection of MM in the high-risk population, we completed a series of clinical studies to develop a noninvasive test for early detection. METHODOLOGY/PRINCIPAL FINDINGS: We conducted multi-center case-control studies in serum from 117 MM cases and 142 asbestos-exposed control individuals. Biomarker discovery, verification, and validation were performed using SOMAmer proteomic technology, which simultaneously measures over proteins in unfractionated biologic samples. Using univariate and multivariate approaches we discovered 64 candidate protein biomarkers and derived a 13-marker random forest classifier with an AUC of 0.99+/-0.01 in training, 0.98+/-0.04 in independent blinded verification and 0.95+/-0.04 in blinded validation studies. Sensitivity and specificity at our pre-specified decision threshold were 97%/92% in training and 90%/95% in blinded verification. This classifier accuracy was maintained in a second blinded validation set with a sensitivity/specificity of 90%/89% and combined accuracy of 92%. Sensitivity correlated with pathologic stage; 77% of Stage I, 93% of Stage II, 96% of Stage III and 96% of Stage IV cases were detected. An alternative decision threshold in the validation study yielding 98% specificity would still detect 60% of MM cases. In a paired sample set the classifier AUC of 0.99 and 91%/94% sensitivity/specificity was superior to that of mesothelin with an AUC of 0.82 and 66%/88% sensitivity/specificity. The candidate biomarker panel consists of both inflammatory and proliferative proteins, processes strongly associated with asbestos-induced malignancy. SIGNIFICANCE: The SOMAmer biomarker panel discovered and validated in these studies provides a solid foundation for surveillance and diagnosis of MM in those at highest risk for this disease. Ostroff, Rachel M Mehan, Michael R Stewart, Alex Ayers, Deborah Brody, Edward N Williams, Stephen A Levin, Stephen Black, Brad Harbut, Michael Carbone, Michele Goparaju, Chandra Pass, Harvey I eng U01 CA/CA/NCI NIH HHS/ 2U01CA-04/CA/NCI NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. ;7(10):e. doi: 10./journal.pone.. Epub Oct 3.I SomaScan 10/12/ Brody E, et al. Life's simple measures: unlocking the proteome J Mol Biol 422 5 595-606 https://www.doi.org/10./j.jmb..06.021 22,721,953 Aptamers, Nucleotide/*analysis/*metabolism Body Fluids/*chemistry Protein Binding Proteome/*analysis SELEX Aptamer Technique/*methods Using modified nucleotides and selecting for slow off-rates in the SELEX procedure, we have evolved a special class of aptamers, called SOMAmers (slow off-rate modified aptamers), which bind tightly and specifically to proteins in body fluids. We use these in a novel assay that yields 1:1 complexes of the SOMAmers with their cognate proteins in body fluids. Measuring the SOMAmer concentrations of the resultant complexes reflects the concentration of the proteins in the fluids. This is simply done by hybridization to complementary sequences on solid supports, but it can also be done by any other DNA quantification technology (including NexGen sequencing). We use measurements of over proteins in under 100 muL of serum or plasma to answer important medical questions, two of which are reviewed here. A number of bioinformatics methods have guided our discoveries, including principal component analysis. We use various methods to evaluate sample handling procedures in our clinical samples and can identify many parameters that corrupt proteomics analysis. Brody, Edward Gold, Larry Mehan, Mike Ostroff, Rachel Rohloff, John Walker, Jeff Zichi, Dom eng Netherlands J Mol Biol. Oct 5;422(5):595-606. doi: 10./j.jmb..06.021. Epub Jun 19.I SomaScan 06/23/ Lourdusamy A, et al. Identification of cis-regulatory variation influencing protein abundance levels in human plasma Hum Mol Genet 21 16 -26 https://www.doi.org/10./hmg/dds186 22,595,970 Aged Aged, 80 and over Aptamers, Nucleotide Blood Proteins/*genetics Female Genetic Predisposition to Disease Genome-Wide Association Study Humans Male Middle Aged *Polymorphism, Single Nucleotide Proteomics/methods Quantitative Trait Loci *Regulatory Sequences, Nucleic Acid Proteins are central to almost all cellular processes, and dysregulation of expression and function is associated with a range of disorders. A number of studies in human have recently shown that genetic factors significantly contribute gene expression variation. In contrast, very little is known about the genetic basis of variation in protein abundance in man. Here, we assayed the abundance levels of proteins in plasma from 96 elderly Europeans using a new aptamer-based proteomic technology and performed genome-wide local (cis-) regulatory association analysis to identify protein quantitative trait loci (pQTL). We detected robust cis-associations for 60 proteins at a false discovery rate of 5%. The most highly significant single nucleotide polymorphism detected was rs (false discovery rate, 2.5 x 10(-12)), mapped within the gene coding sequence of Tenascin C (TNC). Importantly, we identified evidence of cis-regulatory variation for 20 previously disease-associated genes encoding protein, including variants with strong evidence of disease association show significant association with protein abundance levels. These results demonstrate that common genetic variants contribute to the differences in protein abundance levels in human plasma. Identification of pQTLs will significantly enhance our ability to discover and comprehend the biological and functional consequences of loci identified from genome-wide association study of complex traits. This is the first large-scale genetic association study of proteins in plasma measured using a novel, highly multiplexed slow off-rate modified aptamer (SOMAmer) proteomic platform. Lourdusamy, Anbarasu Newhouse, Stephan Lunnon, Katie Proitsi, Petra Powell, John Hodges, Angela Nelson, Sally K Stewart, Alex Williams, Stephen Kloszewska, Iwona Mecocci, Patrizia Soininen, Hilkka Tsolaki, Magda Vellas, Bruno Lovestone, Simon Dobson, Richard eng K01 AG/AG/NIA NIH HHS/ P30 AG/AG/NIA NIH HHS/ U01 AG/AG/NIA NIH HHS/ U19 AG/AG/NIA NIH HHS/ Research Support, Non-U.S. Gov't England Hum Mol Genet. Aug 15;21(16):-26. doi: 10./hmg/dds186. Epub May 16.I SomaScan 05/19/ Mehan MR, et al. Protein signature of lung cancer tissues PLoS One 7 4 e https://www.doi.org/10./journal.pone. 22,509,397 Aged Apoptosis/genetics Biomarkers, Tumor/blood/genetics/metabolism Carcinoma, Non-Small-Cell Lung/blood/genetics/*metabolism Female *Gene Expression Regulation, Neoplastic Humans Inflammation/genetics Lung Neoplasms/blood/genetics/*metabolism Male Middle Aged Neoplasm Invasiveness/genetics Neoplasm Metastasis Neovascularization, Pathologic/genetics Proteome/*analysis Lung cancer remains the most common cause of cancer-related mortality. We applied a highly multiplexed proteomic technology (SOMAscan) to compare protein expression signatures of non small-cell lung cancer (NSCLC) tissues with healthy adjacent and distant tissues from surgical resections. In this first report of SOMAscan applied to tissues, we highlight 36 proteins that exhibit the largest expression differences between matched tumor and non-tumor tissues. The concentrations of twenty proteins increased and sixteen decreased in tumor tissue, thirteen of which are novel for NSCLC. NSCLC tissue biomarkers identified here overlap with a core set identified in a large serum-based NSCLC study with SOMAscan. We show that large-scale comparative analysis of protein expression can be used to develop novel histochemical probes. As expected, relative differences in protein expression are greater in tissues than in serum. The combined results from tissue and serum present the most extensive view to date of the complex changes in NSCLC protein expression and provide important implications for diagnosis and treatment. Mehan, Michael R Ayers, Deborah Thirstrup, Derek Xiong, Wei Ostroff, Rachel M Brody, Edward N Walker, Jeffrey J Gold, Larry Jarvis, Thale C Janjic, Nebojsa Baird, Geoffrey S Wilcox, Sheri K eng PLoS One. ;7(4):e. doi: 10./journal.pone.. Epub Apr 11.I SomaScan 04/18/ Gold L, et al. Advances in human proteomics at high scale with the SOMAscan proteomics platform N Biotechnol 29 5 543-9 https://www.doi.org/10./j.nbt..11.016 22,155,539 Biomarkers/metabolism DNA/*metabolism Humans Proteins/metabolism Proteomics/*instrumentation/methods/*trends In , while still working at NeXstar Pharmaceuticals, several of us made a proteomic bet. We thought then, and continue to think, that proteomics offers a chance to identify disease-specific biomarkers and improve healthcare. However, interrogating proteins turned out to be a much harder problem than interrogating nucleic acids. Consequently, the 'omics' revolution has been fueled largely by genomics. High-scale proteomics promises to transform medicine with personalized diagnostics, prevention, and treatment. We have now reached into the human proteome to quantify more than proteins in any human matrix - serum, plasma, CSF, BAL, and also tissue extracts - with our new SOMAmer-based proteomics platform. The surprising and pleasant news is that we have made unbiased protein biomarker discovery a routine and fast exercise. The downstream implications of the platform are substantial. Gold, Larry Walker, Jeffrey J Wilcox, Sheri K Williams, Stephen eng Review Netherlands N Biotechnol. Jun 15;29(5):543-9. doi: 10./j.nbt..11.016. Epub Dec 7.I SomaScan 12/14/ Baird GS, et al. Age-dependent changes in the cerebrospinal fluid proteome by slow off-rate modified aptamer array Am J Pathol 180 2 446-56 https://www.doi.org/10./j.ajpath..10.024 22,122,984 Adult Aged Aged, 80 and over Aging/genetics/*metabolism Aptamers, Nucleotide/*metabolism Biomarkers/cerebrospinal fluid Cerebrospinal Fluid Proteins/*analysis Female Humans Male Middle Aged Protein Array Analysis/*methods Proteome/genetics/*metabolism Young Adult An important precondition for the successful development of diagnostic assays of cerebrospinal fluid (CSF) biomarkers of age-related neurodegenerative diseases is an understanding of the dynamic nature of the CSF proteome during the normal aging process. In this study, a novel proteomic technology was used to quantify hundreds of proteins simultaneously in the CSF from 90 cognitively normal adults 21 to 85 years of age. SomaLogic's highly multiplexed proteomic platform can measure more than 800 proteins simultaneously from small volumes of biological fluids using novel slow off-rate modified aptamer (SOMAmer) protein affinity reagents with sensitivity, specificity, and dynamic ranges that meet or exceed those of enzyme-linked immunosorbent assays. In the first application of this technology to CSF, we detected 248 proteins that possessed signals greater than twofold over background. Several novel correlations between detected protein concentrations and age were discovered that indicate that both inflammation and response to injury in the central nervous system may increase with age. Applying this powerful proteomic approach to CSF provides potential new insight into the aging of the human central nervous system that may have utility in discovering new disease-related changes in the CSF proteome. Baird, Geoffrey S Nelson, Sally K Keeney, Tracy R Stewart, Alex Williams, Stephen Kraemer, Stephan Peskind, Elaine R Montine, Thomas J eng P50 AG/AG/NIA NIH HHS/ AG/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Am J Pathol. Feb;180(2):446-56. doi: 10./j.ajpath..10.024. Epub Nov 26.I SomaScan 11/30/ Gold L, et al. Aptamers and the RNA world, past and present Cold Spring Harb Perspect Biol 4 3 https://www.doi.org/10./cshperspect.a 21,441,582 Aptamers, Nucleotide/*chemistry Biomarkers/blood/chemistry History, 20th Century Humans Proteomics/methods RNA/*chemistry/physiology SELEX Aptamer Technique/*history Aptamers and the SELEX process were discovered over two decades ago. These discoveries have spawned a productive academic and commercial industry. The collective results provide insights into biology, past and present, through an in vitro evolutionary exploration of the nature of nucleic acids and their potential roles in ancient life. Aptamers have helped usher in an RNA renaissance. Here we explore some of the evolution of the aptamer field and the insights it has provided for conceptualizing an RNA world, from its nascence to our current endeavor employing aptamers in human proteomics to discover biomarkers of health and disease. Gold, Larry Janjic, Nebojsa Jarvis, Thale Schneider, Dan Walker, Jeffrey J Wilcox, Sheri K Zichi, Dom eng Historical Article Review Cold Spring Harb Perspect Biol. Mar 1;4(3):a. doi: 10./cshperspect.a.I SomaScan 03/29/ Kraemer S, et al. From SOMAmer-based biomarker discovery to diagnostic and clinical applications: a SOMAmer-based, streamlined multiplex proteomic assay PLoS One 6 10 e https://www.doi.org/10./journal.pone. 22,022,604 Automation Biological Assay/*methods Biomarkers/*analysis Case-Control Studies *Diagnostic Techniques and Procedures Humans Limit of Detection Nucleic Acids/metabolism Oligonucleotides/chemistry/*metabolism Proteomics/*methods Reproducibility of Results Titrimetry Recently, we reported a SOMAmer-based, highly multiplexed assay for the purpose of biomarker identification. To enable seamless transition from highly multiplexed biomarker discovery assays to a format suitable and convenient for diagnostic and life-science applications, we developed a streamlined, plate-based version of the assay. The plate-based version of the assay is robust, sensitive (sub-picomolar), rapid, can be highly multiplexed (upwards of 60 analytes), and fully automated. We demonstrate that quantification by microarray-based hybridization, Luminex bead-based methods, and qPCR are each compatible with our platform, further expanding the breadth of proteomic applications for a wide user community. Kraemer, Stephan Vaught, Jonathan D Bock, Christopher Gold, Larry Katilius, Evaldas Keeney, Tracy R Kim, Nancy Saccomano, Nicholas A Wilcox, Sheri K Zichi, Dom Sanders, Glenn M eng Research Support, Non-U.S. Gov't PLoS One. ;6(10):e. doi: 10./journal.pone.. Epub Oct 17.I SomaScan 10/25/ Gupta S, et al. Rapid histochemistry using slow off-rate modified aptamers with anionic competition Appl Immunohistochem Mol Morphol 19 3 273-8 https://www.doi.org/10./PAI.0b013ec29 21,217,521 Aptamers, Peptide/chemistry/*metabolism Breast Neoplasms/*diagnosis/metabolism/pathology Carcinoma/*diagnosis/metabolism/pathology Epidermal Growth Factor/metabolism Female Fluorescent Dyes/chemistry/*metabolism Humans *Molecular Diagnostic Techniques Protein Binding Sensitivity and Specificity Immunohistochemistry is used in both research and clinical settings to identify proteins in tissue samples. Despite the power and versatility of immunohistochemistry, limitations are imposed by the slow diffusion of antibodies through tissue and the need for secondary staining or signal amplification. Aptamers can circumvent these limitations, but their application has been hindered by nonspecific binding to cellular components, particularly in the nucleus. Here we describe unique slow off-rate modified aptamers that facilitate rapid and selective binding to target proteins in tissue. Specifically, we have developed a fluorescent aptamer that binds to the human epidermal growth factor receptor 2 (HER2) in breast carcinomas quickly and specifically, and we have shown that the slow off-rate of the aptamer from the HER2 protein contributes to its selectivity. These findings open the door to aptamer histochemistry applications in both research and clinical settings, including intraoperative diagnostics in which speed and accuracy are paramount. Gupta, Shashi Thirstrup, Derek Jarvis, Thale C Schneider, Daniel J Wilcox, Sheri K Carter, Jeff Zhang, Chi Gelinas, Amy Weiss, Allison Janjic, Nebojsa Baird, Geoffrey S eng Research Support, Non-U.S. Gov't Appl Immunohistochem Mol Morphol. May;19(3):273-8. doi: 10./PAI.0b013ec29.I SomaScan 01/11/ Ostroff RM, et al. Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer PLoS One 5 12 e https://www.doi.org/10./journal.pone. 21,170,350 Algorithms Autoantibodies/chemistry Biomarkers/*metabolism Biomarkers, Tumor/*metabolism Carcinoma, Non-Small-Cell Lung/*metabolism Case-Control Studies Cohort Studies Early Detection of Cancer/*methods Humans Lung Neoplasms/*metabolism Mass Spectrometry/methods Models, Statistical Proteomics/*methods Sensitivity and Specificity Smoking/adverse effects BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with >/= 10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90alpha, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES) that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC. CONCLUSIONS/SIGNIFICANCE: This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification of classifier performance provides evidence against over-fitting and is encouraging for the next development phase, independent validation. This careful study provides a solid foundation to develop tests sorely needed to identify early stage lung cancer. Ostroff, Rachel M Bigbee, William L Franklin, Wilbur Gold, Larry Mehan, Mike Miller, York E Pass, Harvey I Rom, William N Siegfried, Jill M Stewart, Alex Walker, Jeffrey J Weissfeld, Joel L Williams, Stephen Zichi, Dom Brody, Edward N eng U01 CA/CA/NCI NIH HHS/ P50 CA/CA/NCI NIH HHS/ P50-CA/CA/NCI NIH HHS/ P50 CA/CA/NCI NIH HHS/ 5P30CA/CA/NCI NIH HHS/ U01 CA-10/CA/NCI NIH HHS/ U01-CA/CA/NCI NIH HHS/ U01 CA/CA/NCI NIH HHS/ 5U01CA/CA/NCI NIH HHS/ P30 CA/CA/NCI NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. Dec 7;5(12):e. doi: 10./journal.pone..I SomaScan 12/21/ Gold L, et al. Aptamer-based multiplexed proteomic technology for biomarker discovery PLoS One 5 12 e https://www.doi.org/10./journal.pone. 21,165,148 Aged *Aptamers, Nucleotide Biomarkers/*metabolism Evidence-Based Medicine Female Gene Library Genetic Techniques Glomerular Filtration Rate Humans Kidney Failure, Chronic/metabolism Kinetics Male Mass Spectrometry/methods Middle Aged Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis Proteome Proteomics/*methods Reproducibility of Results BACKGROUND: The interrogation of proteomes (proteomics") in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine. METHODOLOGY/PRINCIPAL FINDINGS: We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 microL of serum or plasma). Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (~100 fM-1 microM), and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states. CONCLUSIONS/SIGNIFICANCE: We describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine." Gold, Larry Ayers, Deborah Bertino, Jennifer Bock, Christopher Bock, Ashley Brody, Edward N Carter, Jeff Dalby, Andrew B Eaton, Bruce E Fitzwater, Tim Flather, Dylan Forbes, Ashley Foreman, Trudi Fowler, Cate Gawande, Bharat Goss, Meredith Gunn, Magda Gupta, Shashi Halladay, Dennis Heil, Jim Heilig, Joe Hicke, Brian Husar, Gregory Janjic, Nebojsa Jarvis, Thale Jennings, Susan Katilius, Evaldas Keeney, Tracy R Kim, Nancy Koch, Tad H Kraemer, Stephan Kroiss, Luke Le, Ngan Levine, Daniel Lindsey, Wes Lollo, Bridget Mayfield, Wes Mehan, Mike Mehler, Robert Nelson, Sally K Nelson, Michele Nieuwlandt, Dan Nikrad, Malti Ochsner, Urs Ostroff, Rachel M Otis, Matt Parker, Thomas Pietrasiewicz, Steve Resnicow, Daniel I Rohloff, John Sanders, Glenn Sattin, Sarah Schneider, Daniel Singer, Britta Stanton, Martin Sterkel, Alana Stewart, Alex Stratford, Suzanne Vaught, Jonathan D Vrkljan, Mike Walker, Jeffrey J Watrobka, Mike Waugh, Sheela Weiss, Allison Wilcox, Sheri K Wolfson, Alexey Wolk, Steven K Zhang, Chi Zichi, Dom eng Research Support, Non-U.S. Gov't PLoS One. Dec 7;5(12):e. doi: 10./journal.pone..I SomaScan 12/18/ Brody EN, et al. High-content affinity-based proteomics: unlocking protein biomarker discovery Expert Rev Mol Diagn 10 8 -22 https://www.doi.org/10./erm.10.89 21,080,818 *Aptamers, Nucleotide Biomarkers/*analysis/*chemistry Enzyme-Linked Immunosorbent Assay/methods Genetic Variation Humans Mass Spectrometry Molecular Diagnostic Techniques Proteins/*analysis/chemistry *Proteomics SELEX Aptamer Technique Single protein biomarkers measured with antibody-based affinity assays are the basis of molecular diagnostics in clinical practice today. There is great hope in discovering new protein biomarkers and combinations of protein biomarkers for advancing medicine through monitoring health, diagnosing disease, guiding treatment, and developing new therapeutics. The goal of high-content proteomics is to unlock protein biomarker discovery by measuring many (thousands) or all ( approximately 23,000) proteins in the human proteome in an unbiased, data-driven approach. High-content proteomics has proven technically difficult due to the diversity of proteins, the complexity of relevant biological samples, such as blood and tissue, and large concentration ranges (in the order of 10(12) in blood). Mass spectrometry and affinity methods based on antibodies have dominated approaches to high-content proteomics. For technical reasons, neither has achieved adequate simultaneous performance and high-content. Here we review antibody-based protein measurement, multiplexed antibody-based protein measurement, and limitations of antibodies for high-content proteomics due to their inherent cross-reactivity. Finally, we review a new affinity-based proteomic technology developed from the ground up to solve the problem of high content with high sensitivity and specificity. Based on a new generation of slow off-rate modified aptamers (SOMAmers), this technology is unlocking biomarker discovery. Brody, Edward N Gold, Larry Lawn, Richard M Walker, Jeffrey J Zichi, Dom eng Research Support, Non-U.S. Gov't Review England Expert Rev Mol Diagn. Nov;10(8):-22. doi: 10./erm.10.89.I SomaScan 11/18/ Vaught JD, et al. Expanding the chemistry of DNA for in vitro selection J Am Chem Soc 132 12 -51 https://www.doi.org/10./jag 20,201,573 Aptamers, Nucleotide/*chemistry/genetics/metabolism Base Sequence Gene Library Humans Molecular Sequence Data Molecular Structure Polymerase Chain Reaction Tumor Necrosis Factor Receptor Superfamily, Member 9/*chemistry/genetics/metabolism Six new 5-position modified dUTP derivatives connected by a unique amide linkage were synthesized and tested for compatibility with the enzymatic steps of in vitro selection. Six commercially available DNA polymerases were tested for their ability to efficiently incorporate each of these dUTP derivatives during PCR. It was not possible to perform PCR under standard conditions using any of the modified dUTP derivatives studied. In contrast, primer extension reactions of random templates, as well as defined sequence templates, were successful. KOD XL and D. Vent DNA polymerases were found to be the most efficient at synthesizing full-length primer extension product, with all of the dUTP derivatives tested giving yields similar to those obtained with TTP. Several of these modified dUTPs were then used in an in vitro selection experiment comparing the use of modified dUTP derivatives with TTP for selecting aptamers to a protein target (necrosis factor receptor superfamily member 9, TNFRSF9) that had previously been found to be refractory to in vitro selection using DNA. Remarkably, selections employing modified DNA libraries resulted in the first successful isolation of DNA aptamers able to bind TNFRSF9 with high affinity. Vaught, Jonathan D Bock, Chris Carter, Jeff Fitzwater, Tim Otis, Matt Schneider, Dan Rolando, Justin Waugh, Sheela Wilcox, Sheri K Eaton, Bruce E eng Research Support, U.S. Gov't, Non-P.H.S. J Am Chem Soc. Mar 31;132(12):-51. doi: 10./jag.I SomaScan 03/06/ Ostroff R, et al. The stability of the circulating human proteome to variations in sample collection and handling procedures measured with an aptamer-based proteomics array J Proteomics 73 3 649-66 https://www.doi.org/10./j.jprot..09.004 19,755,178 Algorithms Aptamers, Peptide/chemistry Blood Coagulation/physiology Blood Preservation/adverse effects/methods Blood Proteins/analysis/*metabolism Blood Specimen Collection/adverse effects/*methods/standards Cluster Analysis Freezing/adverse effects Humans Models, Biological Observer Variation Protein Array Analysis/instrumentation/methods *Protein Stability Proteome/*analysis/*metabolism Proteomics/instrumentation/methods SELEX Aptamer Technique/instrumentation/*methods Time Factors Blood-based protein biomarkers hold great promise to advance medicine with applications that detect and diagnose diseases and aid in their treatment. We are developing such applications with our proteomics technology that combines high-content with low limits of detection. Biomarker discovery relies heavily on archived blood sample collections. Blood is dynamic and changes with different sampling procedures potentially confounding biomarker studies. In order to better understand the effects of sampling procedures on the circulating proteome, we studied three sample collection variables commonly encountered in archived sample sets. These variables included (1) three different sample tube types, PPT plasma, SST serum, and Red Top serum, (2) the time from venipuncture to centrifugation, and (3) the time from centrifugation to freezing. We profiled 498 proteins for each of 240 samples and compared the results by ANOVA. The results found no significant variation in the measurements for most proteins (approximately 99%) when the two sample processing times tested were 2h or less, regardless of sample tube type. Even at the longest timepoints, 20 h, approximately 82% of the proteins, on average for the three collection tube types, showed no significant change. These results are encouraging for proteomic biomarker discovery. Ostroff, Rachel Foreman, Trudi Keeney, Tracy R Stratford, Suzanne Walker, Jeffrey J Zichi, Dom eng Evaluation Study Research Support, Non-U.S. Gov't Netherlands J Proteomics. Jan 3;73(3):649-66. doi: 10./j.jprot..09.004. Epub Sep 13.I SomaScan 09/17/ Zichi D, et al. Proteomics and diagnostics: Let's Get Specific, again Curr Opin Chem Biol 12 1 78-85 https://www.doi.org/10./j.cbpa..01.016 18,275,862 Animals Antibodies/immunology Aptamers, Peptide/metabolism *Diagnosis Humans Protein Array Analysis Proteomics/*methods Sensitivity and Specificity DNA array technology has changed all discussions about proteomics. Whole genome arrays allow unbiased experimentation, and the surprises that flow from those approaches. 'Whole proteome' proteomics is not possible today, and might never be possible unless experiments are guided by careful evaluation of reagent specificity. In this paper we explore some possible ways to increase the content of proteomic analysis. Zichi, Dom Eaton, Bruce Singer, Britta Gold, Larry eng Review England Curr Opin Chem Biol. Feb;12(1):78-85. doi: 10./j.cbpa..01.016. Epub Mar 7.I SomaScan 02/16/ Petach H, et al. Processing of photoaptamer microarrays Methods Mol Biol 264 101-10 https://www.doi.org/10./1--759-9:101 15,020,783 Cross-Linking Reagents/metabolism Endostatins/metabolism Fluorescent Dyes/metabolism *Light Nucleic Acids/*metabolism Protein Array Analysis/instrumentation/*methods Protein Binding Photoaptamers are single-stranded nucleic acids selected for their high affinity to specific proteins of interest. Photoaptamer microarrays capture and quantify proteins from complex samples using a unique protocol that leverages both high-affinity capture with covalent retention of analytes. The initial capture of proteins from solution is similar to the well-known antibody capture, but the secondary binding event" affected by photoaptamers is a covalent crosslink between the photoaptamer capture agent and the protein analyte. The nature of this specific covalent reaction allows a unique microarray processing that is described in detail in this chapter." Petach, Helen Ostroff, Rachel Greef, Chad Husar, Gregory M eng Methods Mol Biol. ;264:101-10. doi: 10./1--759-9:101.I SomaScan 03/17/ Smith D, et al. Sensitivity and specificity of photoaptamer probes Mol Cell Proteomics 2 1 8-Nov https://www.doi.org/10./mcp.m-mcp200 12,601,078 Bromodeoxyuridine/*pharmacology Cross-Linking Reagents/*pharmacology Escherichia coli/metabolism HIV Envelope Protein gp120/chemistry Kinetics Oligonucleotide Array Sequence Analysis Peptides/*chemistry Protein Array Analysis Protein Binding Proteomics/methods Sensitivity and Specificity The potential of photoaptamers as proteomic probes was investigated. Photoaptamers are defined as aptamers that bear photocross-linking functionality, in this report, 5-bromo-2'-deoxyuridine. A key question regarding the use of photoaptamer probes is the specificity of the cross-linking reaction. The specificity of three photoaptamers was explored by comparing their reactions with target proteins and non-target proteins. The range of target/non-target specificity varies from 100- to >10(6)-fold with most values >10(4)-fold. The contributions of the initial binding step and the photocross-linking step were evaluated for each reaction. Photocross-linking never degraded specificity and significantly increased aptamer specificity in some cases. The application of photoaptamer technology to proteomics was investigated in microarray format. Immobilized anti-human immunodeficiency virus-gp120 aptamer was able to detect subnanomolar concentrations of target protein in 5% human serum. The levels of sensitivity and specificity displayed by photoaptamers, combined with other advantageous properties of aptamers, should facilitate development of protein chip technology. Smith, Drew Collins, Brian D Heil, James Koch, Tad H eng Research Support, Non-U.S. Gov't Mol Cell Proteomics. Jan;2(1):11-8. doi: 10./mcp.m-mcp200.I SomaScan 02/26/ Gold L, et al. One, two, infinity: genomes filled with aptamers Chem Biol 9 12 -64 https://www.doi.org/10./s-(02)-7 12,498,875 Evolution, Molecular Gene Expression Regulation/genetics Genome Oligonucleotides/*genetics/therapeutic use RNA/chemistry/genetics Gold, Larry Brody, Ed Heilig, Joe Singer, Britta eng Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Chem Biol. Dec;9(12):-64. doi: 10./s-(02)-7.I SomaScan 12/25/ Petach H, et al. Dimensionality is the issue: use of photoaptamers in protein microarrays Curr Opin Biotechnol 13 4 309-14 https://www.doi.org/10./s-(02)-4 12,323,351 Electrophoresis, Gel, Two-Dimensional/*methods Enzyme-Linked Immunosorbent Assay/*methods Indicators and Reagents/chemistry Ligands Molecular Probes Photochemistry/*methods Protein Array Analysis/*methods/trends Proteins/*analysis/*chemistry Proteomics/methods Sensitivity and Specificity The development of high-density arrays for proteomics has become a goal of SomaLogic, many other companies, and a wide variety of academic entities. Unfortunately, the word proteomics has come to mean virtually everything. We define proteomics as being derived from arrays of analyte-specific reagents (ASRs) used to measure (something about) proteins. As the density of the ASRs on a chip increases toward the number of proteins in an organism, the concept of proteomics moves toward comprehensive proteomics. At issue then, is what constitutes an ASR, and what differences between them lead toward more or less biological information from a high-density panel of ASRs. Petach, Helen Gold, Larry eng Review England Curr Opin Biotechnol. Aug;13(4):309-14. doi: 10./s-(02)-4.I SomaScan 09/27/ Zimmermann GR, et al. Interlocking structural motifs mediate molecular discrimination by a theophylline-binding RNA Nat Struct Biol 4 8 644-9 https://www.doi.org/10./nsb-644 9,253,414 Bronchodilator Agents/*chemistry Caffeine/chemistry Cytosine/chemistry Magnetic Resonance Spectroscopy Models, Molecular Molecular Sequence Data *Nucleic Acid Conformation RNA/*chemistry Sensitivity and Specificity Theophylline/*chemistry To visualize the interplay of RNA structural interactions in a ligand binding site, we have determined the solution structure of a high affinity RNA-theophylline complex using NMR spectroscopy. The structure provides insight into the ability of this in vitro selected RNA to discriminate theophylline from the structurally similar molecule caffeine. Numerous RNA structural motifs combine to form a well-ordered binding pocket where an intricate network of hydrogen bonds and stacking interactions lock the theophylline into the complex. Two internal loops interact to form the binding site which consists of a sandwich of three base triples. The complex also contains novel base-zipper and 1-3-2 stacking motifs, in addition to an adenosine platform and a reversed sugar. An important feature of the RNA is that many of the conserved core residues participate in multiple overlapping tertiary interactions. This complex illustrates how interlocking structural motifs can be assembled into a highly specific ligand-binding site that possesses high levels of affinity and molecular discrimination. Zimmermann, G R Jenison, R D Wick, C L Simorre, J P Pardi, A eng Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Nat Struct Biol. Aug;4(8):644-9. doi: 10./nsb-644.I SomaScan 08/01/ Eaton BE, et al. Let's get specific: the relationship between specificity and affinity Chem Biol 2 10 633-8 https://www.doi.org/10./-(95)-3 9,383,468 Animals Drug Design Humans Protein Binding Receptors, Drug/*chemistry Surface Properties The factors that lead to high-affinity binding are a good fit between the surfaces of the two molecules in their ground state and charge complementarity. Exactly the same factors give high specificity for a target. We argue that selection for high-affinity binding automatically leads to highly specific binding. This principle can be used to simplify screening approaches aimed at generating useful drugs. Eaton, B E Gold, L Zichi, D A eng Review Chem Biol. Oct;2(10):633-8. doi: 10./-(95)-3.I SomaScan 10/01/