Biomedical Informatics Commons^™

Prostein Expression On Circulating Tumor Cells As A Prognostic Marker In Metastatic Castration-Resistant Prostate Cancer, Zhenchao Zhang, Rui Luo, William K Kelly, Joshua Chen, Shane Donahue, Kevan Ip, Nathan R Handley, William J Tester, Miranda L Tsang, Felix J Kim, Ronald Myers, Grace Lu-Yao, Jian Gu, Jianqing Lin, Bingshan Li, Chun Wang, Hushan Yang

Faculty, Staff and Student Publications

Background: Identification of emerging molecular biomarkers on circulating tumor cells (CTCs) represents an attractive feature of liquid biopsy that facilitates precision and tailored medicine in the management of metastatic castration-resistant prostate cancer (mCRPC). Prostein is an androgen-regulated transmembrane protein with high prostate specificity. Prostein-positive circulating tumor cell (CTC) was recently suggested to have diagnostic potential; however, no study has been conducted to evaluate its prognostic value in mCRPC.

Methods: CTCs from mCRPC patients were enumerated using the CellSearch System. Prostein-positive CTCs were identified by immunostaining results. The relationships between prostein expression on CTCs and PSA response rate, PSA progression-free survival …

Diagnostic And Prognostic Biomarkers Of Chronic Pancreatitis: A Conceptual Framework Based On The Probe Design, Dhiraj Yadav, Darwin L Conwell, Stephen J Pandol, Hanno Steen, Ziding Feng, Liang Li

Faculty, Staff and Student Publications

No abstract provided.

Molecular Classification And Biomarkers Of Outcome With Immunotherapy In Extensive-Stage Small-Cell Lung Cancer: Analyses Of The Caspian Phase 3 Study, Mingchao Xie, Miljenka Vuko, Jaime Rodriguez-Canales, Johannes Zimmermann, Markus Schick, Cathy O'Brien, Luis Paz-Ares, Jonathan W Goldman, Marina Chiara Garassino, Carl M Gay, John V Heymach, Haiyi Jiang, J Carl Barrett, Ross A Stewart, Zhongwu Lai, Lauren A Byers, Charles M Rudin, Yashaswi Shrestha

Faculty, Staff and Student Publications

BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial.

METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue …

Validation Of A Blood-Based Protein Biomarker Panel For A Risk Assessment Of Lethal Lung Cancer In The Physicians' Health Study, Lulu Song, Ehsan Irajizad, Andrew Rundle, Howard D Sesso, John Michael Gaziano, Jody V Vykoukal, Kim-Anh Do, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Frederica Perera, Samir Hanash

Faculty, Staff and Student Publications

This study aimed to assess a four-marker protein panel (4MP)'s performance, including the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19, for predicting lung cancer in a cohort enriched with never- and ever-smokers. Blinded pre-diagnostic plasma samples collected within 2 years prior to a lung cancer diagnosis from 25 cases and 100 sex-, age-, and smoking-matched controls were obtained from the Physicians' Health Study (PHS). The 4MP yielded AUC performance estimates of 0.76 (95% CI: 0.61-0.92) and 0.69 (95% CI: 0.56-0.82) for predicting lung cancer within one year and within two years of diagnosis, respectively. …

The Long-Term Effects Of Blood Urea Nitrogen Levels On Cardiovascular Disease And All-Cause Mortality In Diabetes: A Prospective Cohort Study, Hongfang Liu, Xiaoqin Xin, Jinghui Gan, Jungao Huang

Faculty, Staff and Student Publications

BACKGROUND: The long-term effects of blood urea nitrogen(BUN) in patients with diabetes remain unknown. Current studies reporting the target BUN level in patients with diabetes are also limited. Hence, this prospective study aimed to explore the relationship of BUN with all-cause and cardiovascular mortalities in patients with diabetes.

METHODS: In total, 10,507 participants with diabetes from the National Health and Nutrition Examination Survey (1999-2018) were enrolled. The causes and numbers of deaths were determined based on the National Death Index mortality data from the date of NHANES interview until follow-up (December 31, 2019). Multivariate Cox proportional hazard regression models were …

Ataxia-Telangiectasia Mutated Loss-Of-Function Displays Variant And Tissue-Specific Differences Across Tumor Types, Patrick G Pilié, Virginia Giuliani, Wei-Lien Wang, Daniel J Mcgrail, Christopher A Bristow, Natalie Y L Ngoi, Keith Kyewalabye, Khalida M Wani, Hung Le, Erick Campbell, Nora S Sanchez, Dong Yang, Jinesh S Gheeya, Rohit Vivek Goswamy, Vijaykumar Holla, Kenna Rael Shaw, Funda Meric-Bernstam, Chiu-Yi Liu, Xiaoyan Ma, Ningping Feng, Annette A Machado, Jennifer P Bardenhagen, Christopher P Vellano, Joseph R Marszalek, Eeson Rajendra, Desiree Piscitello, Timothy I Johnson, Maria Likhatcheva, Elias Elinati, Jayesh Majithiya, Joana Neves, Vera Grinkevich, Marco Ranzani, Marina Roy Luzarraga, Marie Boursier, Lucy Armstrong, Lerin Geo, Giorgia Lillo, Wai Yiu Tse, Alexander J Lazar, Scott E Kopetz, Mary K Geck Do, Sarah Lively, Michael G Johnson, Helen M R Robinson, Graeme C M Smith, Christopher L Carroll, M Emilia Di Francesco, Philip Jones, Timothy P Heffernan, Timothy A Yap

Faculty, Staff and Student Publications

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed.

EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF …

Integrative Molecular Analyses Of The Md Anderson Prostate Cancer Patient-Derived Xenograft (Mda Pca Pdx) Series, Nicolas Anselmino, Estefania Labanca, Peter D A Shepherd, Jiabin Dong, Jun Yang, Xiaofei Song, Subhiksha Nandakumar, Ritika Kundra, Cindy Lee, Nikolaus Schultz, Jianhua Zhang, John C Araujo, Ana M Aparicio, Sumit K Subudhi, Paul G Corn, Louis L Pisters, John F Ward, John W Davis, Elba S Vazquez, Geraldine Gueron, Christopher J Logothetis, Andrew Futreal, Patricia Troncoso, Yu Chen, Nora M Navone

Faculty, Staff and Student Publications

PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer.

EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived …

Transcriptomic Profiling Of Plasma Extracellular Vesicles Enables Reliable Annotation Of The Cancer-Specific Transcriptome And Molecular Subtype, Vahid Bahrambeigi, Jaewon J Lee, Vittorio Branchi, Kimal I Rajapakshe, Zhichao Xu, Naishu Kui, Jason T Henry, Wang Kun, Bret M Stephens, Sarah Dhebat, Mark W Hurd, Ryan Sun, Peng Yang, Eytan Ruppin, Wenyi Wang, Scott Kopetz, Anirban Maitra, Paola A Guerrero

Faculty, Staff and Student Publications

Longitudinal monitoring of patients with advanced cancers is crucial to evaluate both disease burden and treatment response. Current liquid biopsy approaches mostly rely on the detection of DNA-based biomarkers. However, plasma RNA analysis can unleash tremendous opportunities for tumor state interrogation and molecular subtyping. Through the application of deep learning algorithms to the deconvolved transcriptomes of RNA within plasma extracellular vesicles (evRNA), we successfully predicted consensus molecular subtypes in patients with metastatic colorectal cancer. Analysis of plasma evRNA also enabled monitoring of changes in transcriptomic subtype under treatment selection pressure and identification of molecular pathways associated with recurrence. This approach …

Stellae-123 Gene Expression Signature Improved Risk Stratification In Taiwanese Acute Myeloid Leukemia Patients, Yu-Hung Wang, Adrián Mosquera Orgueira, Chien-Chin Lin, Chi-Yuan Yao, Min-Yen Lo, Cheng-Hong Tsai, Adolfo De La Fuente Burguera, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien

Faculty, Staff and Student Publications

The European Leukemia Net recommendations provide valuable guidance in treatment decisions of patients with acute myeloid leukemia (AML). However, the genetic complexity and heterogeneity of AML are not fully covered, notwithstanding that gene expression analysis is crucial in the risk stratification of AML. The Stellae-123 score, an AI-based model that captures gene expression patterns, has demonstrated robust survival predictions in AML patients across four western-population cohorts. This study aims to evaluate the applicability of Stellae-123 in a Taiwanese cohort. The Stellae-123 model was applied to 304 de novo AML patients diagnosed and treated at the National Taiwan University Hospital. We …

Endotrophin, A Key Marker And Driver For Fibroinflammatory Disease, Kim Henriksen, Federica Genovese, Alexander Reese-Petersen, Laurent P Audoly, Kai Sun, Morten A Karsdal, Philipp E Scherer

Faculty, Staff and Student Publications

Our overview covers several key areas related to recent results obtained for collagen type VI and endotrophin (ETP). (1) An introduction to the history of ETP, including how it was identified, how it is released, and its function and potential receptors. (2) An introduction to the collagen family, with a focus on what differentiates collagen type VI from an evolutionary standpoint. (3) An overview of collagen type VI, the 6 individual chains (COL6A1, A2, A3, A4, A5, and A6), their differences and similarities, as well as their expression profiles and function. (4) A detailed analysis of COL6A3, including the cleaved …

Programming A Ferroptosis-To-Apoptosis Transition Landscape Revealed Ferroptosis Biomarkers And Repressors For Cancer Therapy, Yaron Vinik, Avi Maimon, Vinay Dubey, Harsha Raj, Ifat Abramovitch, Sergey Malitsky, Maxim Itkin, Avi Ma'ayan, Frank Westermann, Eyal Gottlieb, Eytan Ruppin, Sima Lev

Faculty, Staff and Student Publications

Ferroptosis and apoptosis are key cell-death pathways implicated in several human diseases including cancer. Ferroptosis is driven by iron-dependent lipid peroxidation and currently has no characteristic biomarkers or gene signatures. Here a continuous phenotypic gradient between ferroptosis and apoptosis coupled to transcriptomic and metabolomic landscapes is established. The gradual ferroptosis-to-apoptosis transcriptomic landscape is used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization using multiple ferroptotic and apoptotic datasets revealed highly specific ferroptosis biomarkers, which are robustly validated in vitro and in vivo. A subset of …

Updates On Who Classification For Small Round Cell Tumors: Ewing Sarcoma Vs Everything Else, Carina A Dehner, Alexander J Lazar, John S A Chrisinger

Faculty, Staff and Student Publications

The WHO Classification of Soft Tissue and Bone Tumours currently recognizes four categories of undifferentiated small round cell sarcoma: Ewing sarcoma, round cell sarcoma with EWSR1-non-ETS fusions including NFATc2 and PATZ1, CIC-rearranged sarcoma, and sarcoma with BCOR genetic alterations. These neoplasms frequently pose significant diagnostic challenges due to rarity and overlapping morphologic and immunohistochemical findings. Further, molecular testing, with accompanying pitfalls, may be needed to establish a definitive diagnosis. This review summarizes the clinical, histologic, immunohistochemical, and molecular features of these neoplasms. In addition, differential diagnosis and areas of uncertainty and ongoing investigation are discussed.

Discovering Genetic Biomarkers For Targeted Cancer Therapeutics With Explainable Artificial Intelligence, Debaditya Chakraborty, Elizabeth Gutierrez-Chakraborty, Cristian Rodriguez-Aguayo, Hakan Başağaoğlu, Gabriel Lopez-Berestein, Paola Amero

Faculty, Staff and Student Publications

No abstract provided.

Recent Advances In Nanomaterial-Based Biosensor For Periodontitis Detection, Mohammad Hosseini Hooshiar, Masoud Amiri Moghaddam, Mohammad Kiarashi, Athraa Y Al-Hijazi, Abbas Fadel Hussein, Hareth A Alrikabi, Sara Salari, Samar Esmaelian, Hassan Mesgari, Saman Yasamineh

Faculty, Staff and Student Publications

Periodontitis, a chronic inflammatory condition caused by bacteria, often causes gradual destruction of the components that support teeth, such as the alveolar bone, cementum, periodontal ligament, and gingiva. This ultimately results in teeth becoming loose and eventually falling out. Timely identification has a crucial role in preventing and controlling its progression. Clinical measures are used to diagnose periodontitis. However, now, there is a hunt for alternative diagnostic and monitoring methods due to the progress of technology. Various biomarkers have been assessed using multiple bodily fluids as sample sources. Furthermore, conventional periodontal categorization factors do not provide significant insights into the …

Comprehensive Analysis Of Transcription Factor-Based Molecular Subtypes And Their Correlation To Clinical Outcomes In Small-Cell Lung Cancer, Sehhoon Park, Tae Hee Hong, Soohyun Hwang, Simon Heeke, Carl M Gay, Jiyeon Kim, Hyun-Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Jong Ho Cho, Yong Soo Choi, Jhingook Kim, Young Mog Shim, Hong Kwan Kim, Lauren Averett Byers, John V Heymach, Yoon-La Choi, Se-Hoon Lee, Keunchil Park

Faculty, Staff and Student Publications

BACKGROUND: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes.

METHODS: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype.

FINDINGS: IHC-based …

Systemic Neutrophil Gelatinase-Associated Lipocalin Alterations In Chronic Pancreatitis: A Multicenter, Cross-Sectional Study, Kristyn Gumpper-Fedus, Kaylin Chasser, Valentina Pita-Grisanti, Molly Torok, Timothy Pfau, Thomas A Mace, Rachel M Cole, Martha A Belury, Stacey Culp, Phil A Hart, Somashekar G Krishna, Luis F Lara, Mitchell L Ramsey, William Fisher, Evan L Fogel, Chris E Forsmark, Liang Li, Stephen Pandol, Walter G Park, Jose Serrano, Stephen K Van Den Eeden, Santhi Swaroop Vege, Dhiraj Yadav, Darwin L Conwell, Zobeida Cruz-Monserrate, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Introduction: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations.

Methods: NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear …

Identifying Cancer Subtypes Based On Embryonic And Hematopoietic Stem Cell Signatures In Pan-Cancer, Jiali Lei, Jiangti Luo, Qian Liu, Xiaosheng Wang

Faculty, Staff and Student Publications

Purpose: Cancer cells with stem cell-like properties may contribute to cancer development and therapy resistance. The advancement of multi-omics technology has sparked interest in exploring cancer stemness from a multi-omics perspective. However, there is a limited number of studies that have attempted to subtype cancer by combining different types of stem cell signatures.

Methods: In this study, 10,323 cancer specimens from 33 TCGA cancer types were clustered based on the enrichment scores of six stemness gene sets, representing two types of stem cell backgrounds: embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs).

Results: We identified four subtypes of pan-cancer, …

Tp53 Mutation Is Frequent In Mantle Cell Lymphoma With Ezh2 Expression And Have Dismal Outcome When Both Are Present, Do Hwan Kim, Saima Siddiqui, Preetesh Jain, Michael Wang, Beenu Thakral, Shaoying Li, Roberto Miranda, Francisco Vega, L Jeffrey Medeiros, Chi Young Ok

Faculty, Staff and Student Publications

Enhancer of zeste homolog 2 (EZH2) expression is found in about 40% of mantle cell lymphoma (MCL) patients, which is associated with aggressive histology, high Ki-67 proliferation rate, p53 mutant pattern and inferior overall survival (OS). We conducted 11-gene (ATM, BIRC3, CCND1, KMT2C, KMT2D, NOTCH1, NOTCH2, RB1, TP53, TRAF2 and UBR5) next generation sequencing panel to shed more light on MCL with EZH2 expression (EZH2+ MCL). EZH2+ MCL more frequently harbor TP53 mutation compared to EZH2(-) MCL (41.2% vs. 19.1%, respectively, p = 0.045). TP53 mutation and EZH2 expression demonstrated overlapping features including aggressive histology, high Ki-67 proliferation rate and …

Tp53 Mutation Is Frequent In Mantle Cell Lymphoma With Ezh2 Expression And Have Dismal Outcome When Both Are Present, Do Hwan Kim, Saima Siddiqui, Preetesh Jain, Michael Wang, Beenu Thakral, Shaoying Li, Roberto Miranda, Francisco Vega, L Jeffrey Medeiros, Chi Young Ok

Faculty, Staff and Student Publications

Enhancer of zeste homolog 2 (EZH2) expression is found in about 40% of mantle cell lymphoma (MCL) patients, which is associated with aggressive histology, high Ki-67 proliferation rate, p53 mutant pattern and inferior overall survival (OS). We conducted 11-gene (ATM, BIRC3, CCND1, KMT2C, KMT2D, NOTCH1, NOTCH2, RB1, TP53, TRAF2 and UBR5) next generation sequencing panel to shed more light on MCL with EZH2 expression (EZH2+ MCL). EZH2+ MCL more frequently harbor TP53 mutation compared to EZH2(-) MCL (41.2% vs. 19.1%, respectively, p = 0.045). TP53 mutation and EZH2 expression demonstrated overlapping features including aggressive histology, high Ki-67 proliferation rate and …

Cancer Biomarkers: Emerging Trends And Clinical Implications For Personalized Treatment, Antonio Passaro, Maise Al Bakir, Emily G Hamilton, Maximilian Diehn, Fabrice André, Sinchita Roy-Chowdhuri, Giannis Mountzios, Ignacio I Wistuba, Charles Swanton, Solange Peters

Faculty, Staff and Student Publications

The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of cancer patients. The development of personalized medicine represents a turning point and a new paradigm in cancer management, as biomarkers enable oncologists to tailor treatments based on the unique molecular profile of each patient's tumor. In this review, we discuss the scientific milestones of cancer biomarkers and explore future possibilities to improve the management of patients with solid tumors. This progress is primarily attributed to the biological characterization of cancers, advancements in testing methodologies, elucidation of the immune microenvironment, …

A Novel Machine Learning Algorithm Selects Proteome Signature To Specifically Identify Cancer Exosomes, Bingrui Li, Fernanda G Kugeratski, Raghu Kalluri

Faculty, Staff and Student Publications

Non-invasive early cancer diagnosis remains challenging due to the low sensitivity and specificity of current diagnostic approaches. Exosomes are membrane-bound nanovesicles secreted by all cells that contain DNA, RNA, and proteins that are representative of the parent cells. This property, along with the abundance of exosomes in biological fluids makes them compelling candidates as biomarkers. However, a rapid and flexible exosome-based diagnostic method to distinguish human cancers across cancer types in diverse biological fluids is yet to be defined. Here, we describe a novel machine learning-based computational method to distinguish cancers using a panel of proteins associated with exosomes. Employing …

Validation Of A Multiomic Model Of Plasma Extracellular Vesicle Pd-L1 And Radiomics For Prediction Of Response To Immunotherapy In Nsclc, Diego De Miguel-Perez, Murat Ak, Priyadarshini Mamindla, Alessandro Russo, Serafettin Zenkin, Nursima Ak, Vishal Peddagangireddy, Luis Lara-Mejia, Muthukumar Gunasekaran, Andres F Cardona, Aung Naing, Fred R Hirsch, Oscar Arrieta, Rivka R Colen, Christian Rolfo

Faculty, Staff and Student Publications

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have showed unprecedent efficacy in the treatment of patients with advanced non-small cell lung cancer (NSCLC). However, not all patients manifest clinical benefit due to the lack of reliable predictive biomarkers. We showed preliminary data on the predictive role of the combination of radiomics and plasma extracellular vesicle (EV) PD-L1 to predict durable response to ICIs.

MAIN BODY: Here, we validated this model in a prospective cohort of patients receiving ICIs plus chemotherapy and compared it with patients undergoing chemotherapy alone. This multiparametric model showed high sensitivity and specificity at identifying non-responders to ICIs and outperformed …

Effect Of Neutralizing Monoclonal Antibody Treatment On Early Trajectories Of Virologic And Immunologic Biomarkers In Patients Hospitalized With Covid-19, Tomas O Jensen, Greg A Grandits, Mamta K Jain, Thomas A Murray, Birgit Grund, Kathryn Shaw-Saliba, Michael A Matthay, Mahsa Abassi, Magdalena Ardelt, Jason V Baker, Peter Chen, Robin L Dewar, Anna L Goodman, Timothy J Hatlen, Helene C Highbarger, Mark Holodniy, Perrine Lallemand, Sylvain Laverdure, Bradley G Leshnower, David Looney, Charalampos D Moschopoulos, Henry Mugerwa, Daniel D Murray, Eleftherios Mylonakis, Stephanie Nagy-Agren, M Tauseef Rehman, Adam Rupert, Randy A Stevens, Stuart Turville, Amy Weintrob, Katherine Wick, Jens Lundgren, Emily R Ko, Activ-3/Tico Study Group

Faculty, Staff and Student Publications

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood.

METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models.

RESULTS: Analysis included 2149 participants enrolled between …

Evaluation Of Treatment Parameters For Focused-Extracorporeal Shock Wave Therapy In Knee Osteoarthritis Patients With Bone Marrow Lesions: A Pilot Study, Hani Al-Abbad, Jacqueline E Reznik, Erik Biros, Bruce Paulik, Rob Will, Samuel Gane, Penny Moss, Anthony Wright

Faculty, Staff and Student Publications

OBJECTIVES: To evaluate the effect of different dosage parameters of focused-extracorporeal shock wave therapy on pain and physical function in knee osteoarthritis patients with bone marrow lesions. In addition, to investigate pathophysiological changes based on imaging and biomarker measures.

METHODS: Using a single-case experimental design, a total of 12 participants were randomly allocated in 4 equal groups of 3 to receive different dosages of focused-extracorporeal shock wave therapy. Each group received either 4 or 6 sessions of 1500 or 3000 shocks over 4 or 6 weekly sessions. Participants underwent repeated measurements during the baseline, intervention, and post-intervention phases for Western …

Protein Biomarkers And Alternatively Methylated Cell-Free Dna Detect Early Stage Pancreatic Cancer, Roni Ben-Ami, Qiao-Li Wang, Jinming Zhang, Julianna G Supplee, Johannes F Fahrmann, Roni Lehmann-Werman, Lauren K Brais, Jonathan Nowak, Chen Yuan, Maureen Loftus, Ana Babic, Ehsan Irajizad, Tal Davidi, Aviad Zick, Ayala Hubert, Daniel Neiman, Sheina Piyanzin, Ofer Gal-Rosenberg, Amit Horn, Ruth Shemer, Benjamin Glaser, Natalia Boos, Kunal Jajoo, Linda Lee, Thomas E Clancy, Douglas A Rubinson, Kimmie Ng, John A Chabot, Fay Kastrinos, Michael Kluger, Andrew J Aguirre, Pasi A Jänne, Nabeel Bardeesy, Ben Stanger, Mark H O'Hara, Jacob Till, Anirban Maitra, Erica L Carpenter, Andrea J Bullock, Jeanine Genkinger, Samir M Hanash, Cloud P Paweletz, Yuval Dor, Brian M Wolpin

Faculty, Staff and Student Publications

Objective: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.

Design: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.

Results: Comparative methylome analysis identified nine loci that were differentially …

Chimeric Oncolytic Adenovirus Evades Neutralizing Antibodies From Human Patients And Exhibits Enhanced Anti-Glioma Efficacy In Immunized Mice, Dong Ho Shin, Hong Jiang, Andrew G Gillard, Debora Kim, Xuejun Fan, Sanjay K Singh, Teresa T Nguyen, Sagar S Sohoni, Andres R Lopez-Rivas, Akhila Parthasarathy, Chibawanye I Ene, Joy Gumin, Frederick F Lang, Marta M Alonso, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent …

Potential Protein Signatures For Recurrence Prediction Of Ischemic Stroke, Chengyi Zhang, Yang Liu, Huimin Zhu, Xinying Huang, Cang Guo, Si Cheng, Meng Yuan, Yong Jiang, Xia Meng, S Claiborne Johnston, Yongjun Wang, Wei-Na Jin, Fu-Dong Shi

Faculty, Staff and Student Publications

Background: Acute ischemic stroke is a major cause of mortality and disability worldwide, with approximately 7.4% to 7.7% recurrence within the first 3 months. This study aimed to identify potential biomarkers for predicting stroke recurrence.

Methods and results: We conducted a nested case-control study using a hospital-based cohort from the Third China National Stroke Registry selecting 214 age- and sex-matched patients with ischemic stroke with hypertension and no history of diabetes or heart disease. Using data-independent acquisition for discovery and multiple reaction monitoring for quantitative validation, we identified 26 differentially expressed proteins in large-artery atherosclerosis (Causative Classification of Ischemic Stroke …

Unraveling The Intraday Variations In The Tear Fluid Proteome, Garrett Jones, Jeremy Altman, Saleh Ahmed, Tae Jin Lee, Wenbo Zhi, Shruti Sharma, Ashok Sharma

Faculty, Staff and Student Publications

PURPOSE: Tear fluid is a complex and dynamic biological fluid that plays essential roles in maintaining ocular homeostasis and protecting against the external environment. Owing to the small sample volume, studying the tear proteome is challenging. However, advances in high-resolution mass spectrometry have expanded tear proteome profiling, revealing >500 unique proteins. Tears are emerging as a noninvasive source of biomarkers for both ocular and systemic diseases; nevertheless, intraday variability of proteins in tear fluid remains questionable. This study investigates intraday variations in the tear fluid proteome to identify stable proteins that could act as candidate biomarkers.

METHODS: Tear samples from …

Outcomes In Biomarker-Selected Subgroups From The Kestrel Study Of Durvalumab And Tremelimumab In Recurrent Or Metastatic Head And Neck Squamous Cell Carcinoma, Tanguy Y Seiwert, Sophie Wildsmith, Jérôme Fayette, Kevin Harrington, Maura Gillison, Myung-Ju Ahn, Shunji Takahashi, Jared Weiss, Jean-Pascal Machiels, Shrujal Baxi, Valerie Baker, Brent Evans, Nassim Morsli, Jill Walker, Katia Real, Anne L'Hernault, Amanda Psyrri

Faculty, Staff and Student Publications

BACKGROUND: Selective biomarkers may improve outcomes in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitor therapy. We investigated three independent biomarkers for association with efficacy in the randomized, phase III KESTREL study (NCT02551159) of first-line durvalumab monotherapy or durvalumab plus tremelimumab versus the EXTREME regimen: programmed cell death ligand-1 (PD-L1) immunohistochemistry, blood tumor mutational burden (bTMB) via circulating tumor DNA, and neutrophil-to-lymphocyte ratio (NLR).

METHODS: Tumor or blood samples from patients enrolled in the KESTREL study were analyzed for PD-L1, bTMB, and NLR. Associations with overall survival (OS) or objective …

Autoantibodies, Antigen-Autoantibody Complexes And Antigens Complement Ca125 For Early Detection Of Ovarian Cancer, Chae Young Han, Jacob S Bedia, Wei-Lei Yang, Sarah J Hawley, Lindsay Bergan, Marika Hopper, Joseph Celestino, Jing Guo, Terrie G Gornet, Antoninus Soosaipillai, Hailing Yang, Samantha D Doskocil, Anna E Lokshin, Beverly C Handy, Eleftherios P Diamandis, Richard G Moore, Karen H Lu, Zhen Lu, Karen S Anderson, Charles W Drescher, Steven J Skates, Robert C Bast

Faculty, Staff and Student Publications

BACKGROUND: Multiple antigens, autoantibodies (AAb), and antigen-autoantibody (Ag-AAb) complexes were compared for their ability to complement CA125 for early detection of ovarian cancer.

METHODS: Twenty six biomarkers were measured in a single panel of sera from women with early stage (I-II) ovarian cancers (n = 64), late stage (III-IV) ovarian cancers (186), benign pelvic masses (200) and from healthy controls (502), and then split randomly (50:50) into a training set to identify the most promising classifier and a validation set to compare its performance to CA125 alone.

RESULTS: Eight biomarkers detected ≥ 8% of early stage cases at 98% specificity. …