Biomedical Informatics Commons^™

Comprehensive Immunogenomic Profiling Of Idh1-/2-Altered Cholangiocarcinoma, Shalini Makawita, Sunyoung Lee, Elisabeth Kong, Lawrence N Kwong, Zeyad Abouelfetouh, Anaemy Danner De Armas, Lianchun Xiao, Karthikeyan Murugesan, Natalie Danziger, Dean Pavlick, Anil Korkut, Jeffrey S Ross, Milind Javle

Faculty, Staff and Student Publications

Purpose: Isocitrate dehydrogenase (IDH)1/2 genomic alterations (GA) occur in 20% of intrahepatic cholangiocarcinoma (iCCA); however, the immunogenomic landscape of IDH1-/2-mutated iCCA is largely unknown.

Methods: Comprehensive genomic profiling (CGP) was performed on 3,067 cases of advanced iCCA. Tumor mutational burden (TMB), PD-L1 expression (Dako 22C3), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) as a surrogate marker for homologous recombination deficiency were examined. RNA sequencing of 73 patient samples was analyzed for differences in stromal/immune cell infiltration, immune marker expression, and T-cell inflammation. Tissue microarray arrays were subjected to multiplex immunohistochemistry and colocalization …

Omics-Based Profiles And Biomarkers Of Respiratory Infections: Are We There Yet?, Jezreel Pantaleon Garcia, Scott E Evans

Faculty, Staff and Student Publications

Descriptive omics-based clinical research provides valuable early steps in understanding host immune responses to respiratory pathogens in our global efforts to mitigate the impacts of severe respiratory infections with rapidly evolving technologies https://bit.ly/4bjJsvL

Glycoprotein Nonmetastatic Melanoma Protein B (Gpnmb) Immunohistochemistry Can Be A Useful Ancillary Tool To Identify Perivascular Epithelioid Cell Tumor, Sintawat Wangsiricharoen, Davis R Ingram, Rohini R Morey, Khalida Wani, Alexander J Lazar, Wei-Lien Wang

Faculty, Staff and Student Publications

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors that express smooth muscle and melanocytic makers. Diagnosis of PEComas can be challenging due to focal or lost expression of traditional immunohistochemical markers, limited availability of molecular testing, and morphological overlap with much more common smooth muscle tumors. This study evaluates the use of glycoprotein nonmetastatic melanoma protein B (GPNMB) immunohistochemical staining as a surrogate marker for TSC1/2/MTOR alteration or TFE3 rearrangement to differentiate PEComas from other mesenchymal tumors. Cathepsin K was also assessed for comparison. A total of 399 tumors, including PEComas, alveolar soft part sarcomas, and other histologic PEComa …

Surrogate Endpoints In Clinical Trials Of P16-Positive Squamous Cell Carcinoma Of The Oropharynx: An Individual Patient Data Meta-Analysis, Laila A Gharzai, Emily Morris, Krithika Suresh, Phuc Felix Nguyen-Tân, David I Rosenthal, Maura L Gillison, Paul M Harari, Adam S Garden, Shlomo Koyfman, Jimmy J Caudell, Christopher U Jones, Darrion L Mitchell, Greg Krempl, John A Ridge, Michael F Gensheimer, James A Bonner, Edith Filion, Neal E Dunlap, William A Stokes, Quynh-Thu Le, Pedro Torres-Saavedra, Michelle Mierzwa, Matthew J Schipper

Faculty, Staff and Student Publications

Background: The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy.

Methods: We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as …

Image-Based Multiplex Immune Profiling Of Cancer Tissues: Translational Implications A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, Chowdhury Arif Jahangir, David B Page, Glenn Broeckx, Claudia A Gonzalez, Caoimbhe Burke, Clodagh Murphy, Jorge S Reis-Filho, Amy Ly, Paul W Harms, Rajarsi R Gupta, Michael Vieth, Akira I Hida, Mohamed Kahila, Zuzana Kos, Paul J Van Diest, Sara Verbandt, Jeppe Thagaard, Reena Khiroya, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Sylvia Adams, Jonas S Almeida, Isabel Alvarado-Cabrero, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Octavio Burgues, Alexandros Chardas, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Sarah N Dudgeon, Mahmoud Elghazawy, Claudio Fernandez-Martín, Susan Fineberg, Stephen B Fox, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Steven N Hart, Johan Hartman, Stephen Hewitt, Hugo M Horlings, Zaheed Husain, Sheeba Irshad, Emiel Am Janssen, Tatsuki R Kataoka, Kosuke Kawaguchi, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Guray Akturk, Ely Scott, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Durga Kharidehal, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Joana M Ribeiro, David Rimm, Anne Vincent-Salomon, Joel Saltz, Shahin Sayed, Evangelos Hytopoulos, Sarah Mahon, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Gregory E Verghese, Giuseppe Viale, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, John Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Elisabeth Specht Stovgaard, Roberto Salgado, William M Gallagher, Arman Rahman

Faculty, Staff and Student Publications

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour …

Biomarker-Directed Targeted Therapy Plus Durvalumab In Advanced Non-Small-Cell Lung Cancer: A Phase 2 Umbrella Trial, Benjamin Besse, Elvire Pons-Tostivint, Keunchil Park, Sylvia Hartl, Patrick M Forde, Maximilian J Hochmair, Mark M Awad, Michael Thomas, Glenwood Goss, Paul Wheatley-Price, Frances A Shepherd, Marie Florescu, Parneet Cheema, Quincy S C Chu, Sang-We Kim, Daniel Morgensztern, Melissa L Johnson, Sophie Cousin, Dong-Wan Kim, Mor T Moskovitz, David Vicente, Boaz Aronson, Rosalind Hobson, Helen J Ambrose, Sajan Khosla, Avinash Reddy, Deanna L Russell, Mohamed Reda Keddar, James P Conway, J Carl Barrett, Emma Dean, Rakesh Kumar, Marlene Dressman, Philip J Jewsbury, Sonia Iyer, Simon T Barry, Jan Cosaert, John V Heymach

Faculty, Staff and Student Publications

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance—which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment—and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure …

Novel Avenues Of Tau Research, Claire E Sexton, Gal Bitan, Kathryn R Bowles, Miroslaw Brys, Luc Buée, Mahmoud Bukar Maina, Claire D Clelland, Ann D Cohen, John F Crary, Jeffrey L Dage, Kristophe Diaz, Bess Frost, Li Gan, Alison M Goate, Lawrence I Golbe, Oskar Hansson, Celeste M Karch, Hartmuth C Kolb, Renaud La Joie, Suzee E Lee, Diana Matallana, Bruce L Miller, Chiadi U Onyike, Yakeel T Quiroz, Jessica E Rexach, Jonathan D Rohrer, Amy Rommel, Ghazaleh Sadri-Vakili, Suzanne E Schindler, Julie A Schneider, Reisa A Sperling, Charlotte E Teunissen, Stacie C Weninger, Susan L Worley, Hui Zheng, Maria C Carrillo

Faculty, Staff and Students Publications

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years.

METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation.

RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research.

DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration …

An Extended Bayesian Semi-Mechanistic Dose-Finding Design For Phase I Oncology Trials Using Pharmacokinetic And Pharmacodynamic Information, Chao Yang, Yisheng Li

Faculty, Staff and Student Publications

We propose a model-based, semi-mechanistic dose-finding (SDF) design for phase I oncology trials that incorporates pharmacokinetic/pharmacodynamic (PK/PD) information when modeling the dose-toxicity relationship. This design is motivated by a phase Ib/II clinical trial of anti-CD20/CD3 T cell therapy in non-Hodgkin lymphoma patients; it extends a recently proposed SDF model framework by incorporating measurements of a PD biomarker relevant to the primary dose-limiting toxicity (DLT). We propose joint Bayesian modeling of the PK, PD, and DLT outcomes. Our extensive simulation studies show that on average the proposed design outperforms some common phase I trial designs, including modified toxicity probability interval (mTPI) …

Circulating Microrna Biomarkers Of Thiazide Response In Hypertension, Lakshmi Manasa S Chekka, Marwa Tantawy, Taimour Langaee, Danxin Wang, Rolf Renne, Arlene B Chapman, John G Gums, Eric Boerwinkle, Rhonda M Cooper-Dehoff, Julie A Johnson

Faculty, Staff and Student Publications

Background: Thiazide diuretics are the second most frequently prescribed class of antihypertensives, but up to 50% of patients with hypertension have minimal antihypertensive response to thiazides. We explored circulating microRNAs (miRNAs) in search of predictive biomarkers of thiazide response.

Methods and results: We profiled 754 miRNAs in baseline plasma samples of 36 hypertensive European American adults treated with hydrochlorothiazide, categorized into responders (n=18) and nonresponders (n=18) on the basis of diastolic blood pressure response to hydrochlorothiazide. miRNAs with ≥2.5-fold differential expression between responders and nonresponders were considered for validation in 3 cohorts (n=50 each): hydrochlorothiazide-treated European Americans, chlorthalidone-treated European Americans, …

Circulating Microrna Panel For Prediction Of Recurrence And Survival In Early-Stage Lung Adenocarcinoma, Mei-Chee Tai, Leonidas E Bantis, Gargy Parhy, Taketo Kato, Ichidai Tanaka, Chi-Wan Chow, Junya Fujimoto, Carmen Behrens, Tetsunari Hase, Koji Kawaguchi, Johannes F Fahrmann, Edwin J Ostrin, Kohei Yokoi, Toyofumi F Chen-Yoshikawa, Yoshinori Hasegawa, Samir M Hanash, Ignacio I Wistuba, Ayumu Taguchi

Faculty, Staff and Student Publications

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and …

Tumor- And Circulating-Free Dna Methylation Identifies Clinically Relevant Small Cell Lung Cancer Subtypes, Simon Heeke, Carl M Gay, Marcos R Estecio, Hai Tran, Benjamin B Morris, Bingnan Zhang, Ximing Tang, Maria Gabriela Raso, Pedro Rocha, Siqi Lai, Edurne Arriola, Paul Hofman, Veronique Hofman, Prasad Kopparapu, Christine M Lovly, Kyle Concannon, Luana Guimaraes De Sousa, Whitney Elisabeth Lewis, Kimie Kondo, Xin Hu, Azusa Tanimoto, Natalie I Vokes, Monique B Nilsson, Allison Stewart, Maarten Jansen, Ildikó Horváth, Mina Gaga, Vasileios Panagoulias, Yael Raviv, Danny Frumkin, Adam Wasserstrom, Aharona Shuali, Catherine A Schnabel, Yuanxin Xi, Lixia Diao, Qi Wang, Jianjun Zhang, Peter Van Loo, Jing Wang, Ignacio I Wistuba, Lauren A Byers, John V Heymach

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype …

Serum Tumor Markers And Outcomes In Patients With Appendiceal Adenocarcinoma, Abdelrahman Yousef, Mahmoud Yousef, Mohammad A Zeineddine, Aditya More, Mohammad Fanaeian, Saikat Chowdhury, Mark Knafl, Paul Edelkamp, Ichiaki Ito, Yue Gu, Vinay Pattalachinti, Zahra Alavi Naini, Fadl A Zeineddine, Jennifer Peterson, Kristin Alfaro, Wai Chin Foo, Jeff Jin, Neal Bhutiani, Victoria Higbie, Christopher P Scally, Bryan Kee, Scott Kopetz, Drew Goldstein, Madeleine Strach, Andrew Williamson, Omer Aziz, Jorge Barriuso, Abhineet Uppal, Michael G White, Beth Helmink, Keith F Fournier, Kanwal P Raghav, Melissa W Taggart, Michael J Overman, John Paul Shen

Faculty, Staff and Student Publications

IMPORTANCE: Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma.

OBJECTIVE: To assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma.

DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD …

Trps1 And Gata3 Expression In Invasive Breast Carcinoma With Apocrine Differentiation, Jing Wang, Yan Peng, Hongxia Sun, Phyu P Aung, Erika Resetkova, Clinton Yam, Aysegul A Sahin, Lei Huo, Qingqing Ding

Faculty, Staff and Student Publications

Context.—: The recently identified immunohistochemical marker TRPS1 is highly sensitive and specific for invasive breast carcinoma, especially triple-negative breast carcinoma. However, TRPS1 expression in special morphologic subtypes of breast cancer is unclear.

Objective.—: To investigate the expression of TRPS1 in invasive breast cancer with apocrine differentiation, in comparison to the expression of GATA3.

Design.—: A total of 52 invasive breast carcinomas with apocrine differentiation, comprising 41 triple-negative breast carcinomas and 11 estrogen receptor (ER) and progesterone receptor (PR)-negative, human epidermal growth factor receptor 2 (HER2)-positive cases, along with 11 triple-negative breast carcinomas without apocrine differentiation, were evaluated for TRPS1 and …

Circulating Tumor Dna And Radiological Tumor Volume Identify Patients At Risk For Relapse With Resected, Early-Stage Non-Small-Cell Lung Cancer, H T Tran, S Heeke, S Sujit, N Vokes, J Zhang, M Aminu, V K Lam, A Vaporciyan, S G Swisher, M C B Godoy, T Cascone, B Sepesi, D L Gibbons, J Wu, J V Heymach

Faculty, Staff and Student Publications

Background: Predicting relapse and overall survival (OS) in early-stage non-small-cell lung cancer (NSCLC) patients remains challenging. Therefore, we hypothesized that detection of circulating tumor DNA (ctDNA) can identify patients with increased risk of relapse and that integrating radiological tumor volume measurement along with ctDNA detectability improves prediction of outcome.

Patients and methods: We analyzed 366 serial plasma samples from 85 patients who underwent surgical resections and assessed ctDNA using a next-generation sequencing liquid biopsy assay, and measured tumor volume using a computed tomography-based three-dimensional annotation.

Results: Our results showed that patients with detectable ctDNA at baseline or after treatment and …

Gli1-Altered Mesenchymal Tumors With Actb Or Ptch1 Fusion: A Molecular And Clinicopathologic Analysis, Darcy A Kerr, Jeffrey M Cloutier, Matthew Margolis, Douglas A Mata, Nathalie J Rodrigues Simoes, William C Faquin, Dora Dias-Santagata, Shefali Chopra, Gregory W Charville, Sintawat Wangsiricharoen, Alexander J Lazar, Wei-Lien Wang, Andrew E Rosenberg, Julie Y Tse

Faculty, Staff and Student Publications

Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, …

Minimal Information For Studies Of Extracellular Vesicles (Misev2023): From Basic To Advanced Approaches, Joshua A Welsh, Deborah C I Goberdhan, Lorraine O'Driscoll, Edit I Buzas, Cherie Blenkiron, Benedetta Bussolati, Houjian Cai, Dolores Di Vizio, Tom A P Driedonks, Uta Erdbrügger, Juan M Falcon-Perez, Qing-Ling Fu, Andrew F Hill, Metka Lenassi, Sai Kiang Lim, Mỹ G Mahoney, Sujata Mohanty, Andreas Möller, Rienk Nieuwland, Takahiro Ochiya, Susmita Sahoo, Ana C Torrecilhas, Lei Zheng, Andries Zijlstra, Sarah Abuelreich, Reem Bagabas, Paolo Bergese, Esther M Bridges, Marco Brucale, Dylan Burger, Randy P Carney, Emanuele Cocucci, Rossella Crescitelli, Edveena Hanser, Adrian L Harris, Norman J Haughey, An Hendrix, Alexander R Ivanov, Tijana Jovanovic-Talisman, Nicole A Kruh-Garcia, Vroniqa Ku'ulei-Lyn Faustino, Diego Kyburz, Cecilia Lässer, Kathleen M Lennon, Jan Lötvall, Adam L Maddox, Elena S Martens-Uzunova, Rachel R Mizenko, Lauren A Newman, Andrea Ridolfi, Eva Rohde, Tatu Rojalin, Andrew Rowland, Andras Saftics, Ursula S Sandau, Julie A Saugstad, Faezeh Shekari, Simon Swift, Dmitry Ter-Ovanesyan, Juan P Tosar, Zivile Useckaite, Francesco Valle, Zoltan Varga, Edwin Van Der Pol, Martijn J C Van Herwijnen, Marca H M Wauben, Ann M Wehman, Sarah Williams, Andrea Zendrini, Alan J Zimmerman, Clotilde Théry, Kenneth W Witwer

Faculty, Staff and Student Publications

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional …

Glucose Metabolism In Posterior Cingulate Cortex Has Supplementary Value To Predict The Progression Of Cognitively Unimpaired To Dementia Due To Alzheimer’S Disease: An Exploratory Study Of 18f-Fdg-Pet, Qi Zhang, Chunqiu Fan, Luyao Wang, Taoran Li, Min Wang, Ying Han, Jiehui Jiang, Alzheimer’S Disease Neuroimaging Initiative

Faculty, Staff and Student Publications

Amyloid-β (Aβ) and tau are important biomarkers to predict the progression of cognitively unimpaired (CU) to dementia due to Alzheimer's disease (AD), according to the diagnosis framework from the US National Institute on Aging and the Alzheimer's Association (NIA-AA). However, it is clinically difficult to predict those subjects who were already with Aβ positive (A +) or tau positive (T +). As a typical characteristic of neurodegeneration in the diagnosis framework, the hypometabolism of the posterior cingulate cortex (PCC) has significant clinical value in the early prediction and prevention of AD. In this paper, we proposed the glucose metabolism in …

The Biology Of Hope: Inflammatory And Neuroendocrine Profiles In Ovarian Cancer Patients, Susan K Lutgendorf, Rachel M Telles, Brendan Whitney, Premal H Thaker, George M Slavich, Michael J Goodheart, Frank J Penedo, Alyssa E Noble, Steven W Cole, Anil K Sood, Benjamin W Corn

Faculty, Staff and Student Publications

INTRODUCTION: Although the concept of hope is highly relevant for cancer patients, little is known about its association with cancer-relevant biomarkers. Here we examined how hope was related to diurnal cortisol and interleukin-6 (IL-6), a pro-inflammatory cytokine previously associated with tumor biology and survival in ovarian cancer. Secondly, we examined whether hope and hopelessness are distinctly associated with these biomarkers.

METHOD: Participants were 292 high-grade ovarian cancer patients who completed surveys and provided saliva samples 4x/daily for 3 days pre-surgery to assess diurnal cortisol. Blood (pre-surgery) and ascites were assessed for IL-6. Hope and hopelessness were assessed using standardized survey …

Harnessing Physical Activity Monitoring And Digital Biomarkers Of Frailty From Pendant Based Wearables To Predict Chemotherapy Resilience In Veterans With Cancer, Gozde Cay, Yvonne H Sada, Mohammad Dehghan Rouzi, Md Moin Uddin Atique, Naima Rodriguez, Mehrnaz Azarian, M G Finco, Sarvari Yellapragada, Bijan Najafi

Center on Aging Staff Publications

This study evaluated the use of pendant-based wearables for monitoring digital biomarkers of frailty in predicting chemotherapy resilience among 27 veteran cancer patients (average age: 64.6 ± 13.4 years), undergoing bi-weekly chemotherapy. Immediately following their first day of chemotherapy cycle, participants wore a water-resistant pendant sensor for 14 days. This device tracked frailty markers like cadence (slowness), daily steps (inactivity), postural transitions (weakness), and metrics such as longest walk duration and energy expenditure (exhaustion). Participants were divided into resilient and non-resilient groups based on adverse events within 6 months post-chemotherapy, including dose reduction, treatment discontinuation, unplanned hospitalization, or death. A …

Evaluation Of Potential Biomarkers For Lenvatinib Plus Pembrolizumab Among Patients With Advanced Endometrial Cancer: Results From Study 111/Keynote-146, Vicky Makker, Matthew H Taylor, Carol Aghajanian, Allen L Cohn, Marcia S Brose, Christopher Di Simone, Zhu Alexander Cao, Leah Suttner, Andrey Loboda, Razvan Cristescu, Petar Jelinic, Robert Orlowski, Lea Dutta, Junji Matsui, Corina E Dutcus, Yukinori Minoshima, Mark J Messing

Faculty, Staff and Student Publications

BACKGROUND: Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest.

METHODS: Patients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell-inflamed gene expression profile (Tcell …

Pressing Need Of Precision Care In Her2-Positive Colorectal Cancer: The Elephant In The Room, Kanwal P S Raghav, Jonathan M Loree, Scott Kopetz

Faculty, Staff and Student Publications

Although dual HER2 inhibition has shown promising clinical activity in patients with RAS wild-type HER2-positive metastatic colorectal cancer, predictive biomarkers of response/resistance are less well characterized. Activating HER2/RTK/MAPK genomic alterations appears to blunt the clinical benefit of dual anti-HER2 therapy and may hold a potential albeit partial role in patient selection. See related article by Randon et al., p. 436.

Associations Between Genetically Predicted Plasma Protein Levels And Alzheimer’S Disease Risk: A Study Using Genetic Prediction Models, Jingjing Zhu, Shuai Liu, Keenan A Walker, Hua Zhong, Dalia H Ghoneim, Zichen Zhang, Praveen Surendran, Sarah Fahle, Adam Butterworth, Md Ashad Alam, Hong-Wen Deng, Chong Wu, Lang Wu

Faculty, Staff and Student Publications

BACKGROUND: Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer's disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets.

METHODS: We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 …

Delineating The Mechanism Of Fragility At Bcl6 Breakpoint Region Associated With Translocations In Diffuse Large B Cell Lymphoma, Vidya Gopalakrishnan, Urbi Roy, Shikha Srivastava, Khyati M Kariya, Shivangi Sharma, Saniya M Javedakar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into …

Ageannomo: A Knowledgebase Of Multi-Omics Annotation For Animal Aging, Kexin Huang, Xi Liu, Zhaocan Zhang, Tiangang Wang, Haixia Xu, Qingxuan Li, Yuhao Jia, Liyu Huang, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

Aging entails gradual functional decline influenced by interconnected factors. Multiple hallmarks proposed as common and conserved underlying denominators of aging on the molecular, cellular and systemic levels across multiple species. Thus, understanding the function of aging hallmarks and their relationships across species can facilitate the translation of anti-aging drug development from model organisms to humans. Here, we built AgeAnnoMO (https://relab.xidian.edu.cn/AgeAnnoMO/#/), a knowledgebase of multi-omics annotation for animal aging. AgeAnnoMO encompasses an extensive collection of 136 datasets from eight modalities, encompassing 8596 samples from 50 representative species, making it a comprehensive resource for aging and longevity research. AgeAnnoMO characterizes …

Proteogenomic Characterization Of Small Cell Lung Cancer Identifies Biological Insights And Subtype-Specific Therapeutic Strategies, Qian Liu, Jing Zhang, Chenchen Guo, Mengcheng Wang, Chenfei Wang, Yilv Yan, Liangdong Sun, Di Wang, Lele Zhang, Huansha Yu, Likun Hou, Chunyan Wu, Yuming Zhu, Gening Jiang, Hongwen Zhu, Yanting Zhou, Shanhua Fang, Tengfei Zhang, Liang Hu, Junqiang Li, Yansheng Liu, Hui Zhang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Daming Gao, Hongbin Ji, Hu Zhou, Peng Zhang

Faculty, Staff and Students Publications

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the …

Class Ii Hla-Drb4 Is A Predictive Biomarker For Survival Following Immunotherapy In Metastatic Non-Small Cell Lung Cancer, Cindy Y Jiang, Lili Zhao, Michael D Green, Shashidhar Ravishankar, Andrea M H Towlerton, Anthony J Scott, Malini Raghavan, Matthew F Cusick, Edus H Warren, Nithya Ramnath

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker. We performed HLA typing on 85 patients with mNSCLC, on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 genotype was seen in 34/85 (40%) and its presence correlated …

Proteome-Wide Association Study And Functional Validation Identify Novel Protein Markers For Pancreatic Ductal Adenocarcinoma, Jingjing Zhu, Ke Wu, Shuai Liu, Alexandra Masca, Hua Zhong, Tai Yang, Dalia H Ghoneim, Praveen Surendran, Tanxin Liu, Qizhi Yao, Tao Liu, Sarah Fahle, Adam Butterworth, Md Ashad Alam, Jaydutt V Vadgama, Youping Deng, Hong-Wen Deng, Chong Wu, Yong Wu, Lang Wu

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified …

A Phase 2, Multicenter, Open-Label Study Of Anti-Lag-3 Ieramilimab In Combination With Anti-Pd-1 Spartalizumab In Patients With Advanced Solid Malignancies, Chia-Chi Lin, Elena Garralda, Patrick Schöffski, David S Hong, Lillian L Siu, Miguel Martin, Michela Maur, Rina Hui, Ross A Soo, Joanne Chiu, Tian Zhang, Brigette Ma, Chrisann Kyi, Daniel Sw Tan, Philippe A Cassier, John Sarantopoulos, Andrew Weickhardt, Richard D Carvajal, Jennifer Spratlin, Taito Esaki, Fréderic Rolland, Wallace Akerley, Barbara Deschler-Baier, Lawrence Rispoli, Tanay S Samant, Niladri Roy Chowdhury, Daniel Gusenleitner, Eunice L Kwak, Vasileios Askoxylakis, Filippo De Braud

Faculty, Staff and Student Publications

Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along …

Candidate Circulating Microrna Biomarkers In Dogs With Chronic Pancreatitis, Susan K Armstrong, Robert W Hunter, Wilna Oosthyuzen, Maciej Parys, Adam G Gow, Silke Salavati Schmitz, James W Dear, Richard J Mellanby

Faculty, Staff and Student Publications

BACKGROUND: Pancreatitis is an important cause of disease and death in dogs. Available circulating biomarkers are not sufficiently sensitive and specific for a definitive diagnosis.

HYPOTHESIS: Circulating microRNAs would be differentially expressed in dogs with chronic pancreatitis and could have potential as diagnostic biomarkers.

ANIMALS: Healthy controls (n = 19) and dogs with naturally occurring pancreatitis (n = 17).

METHODS: A retrospective case-control study. Dogs with pancreatitis were included if they satisfied diagnostic criteria for pancreatitis as adjudicated by 3 experts. MicroRNA was extracted from stored serum samples and sequenced. Reads were mapped to mature microRNA sequences in the canine, …

Harnessing Microrna-Enriched Extracellular Vesicles For Liquid Biopsy, Song Yi Ko, Wonjae Lee, Honami Naora

Faculty, Staff and Student Publications

Extracellular microRNAs (miRNAs) can be detected in body fluids and hold great potential as cancer biomarkers. Extracellular miRNAs are protected from degradation by binding various proteins and through their packaging into extracellular vesicles (EVs). There is evidence that the diagnostic performance of cancer-associated extracellular miRNAs can be improved by assaying EV-miRNA instead of total cell-free miRNA, but several challenges have hampered the advancement of EV-miRNA in liquid biopsy. Because almost all types of cells release EVs, cancer cell-derived EVs might constitute only a minor fraction of EVs in body fluids of cancer patients with low volume disease. Furthermore, a given …