Medical Specialties Commons^™

Pirtobrutinib In Covalent Bruton Tyrosine Kinase Inhibitor Pretreated Mantle-Cell Lymphoma, Michael L Wang, Wojciech Jurczak, Pier Luigi Zinzani, Toby A Eyre, Chan Y Cheah, Chaitra S Ujjani, Youngil Koh, Koji Izutsu, James N Gerson, Ian Flinn, Benoit Tessoulin, Alvaro J Alencar, Shuo Ma, David Lewis, Ewa Lech-Maranda, Joanna Rhodes, Krish Patel, Kami Maddocks, Nicole Lamanna, Yucai Wang, Constantine S Tam, Talha Munir, Hirokazu Nagai, Francisco Hernandez-Ilizaliturri, Anita Kumar, Timothy S Fenske, John F Seymour, Andrew D Zelenetz, Binoj Nair, Donald E Tsai, Minna Balbas, Richard A Walgren, Paolo Abada, Chunxiao Wang, Junjie Zhao, Anthony R Mato, Nirav N Shah

Faculty, Staff and Student Publications

Purpose: Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis.

Methods: Patients with cBTKi pretreated relapsed/refractory (R/R) MCL received pirtobrutinib monotherapy in a multicenter phase I/II trial (BRUIN; ClinicalTrials.gov identifier: NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary end point was overall response rate (ORR). Secondary end points included duration of response (DOR) and safety. …

Systematic Design And Data-Driven Evaluation Of Social Determinants Of Health Ontology (Sdoho), Yifang Dang, Fang Li, Xinyue Hu, Vipina K Keloth, Meng Zhang, Sunyang Fu, Muhammad F Amith, J Wilfred Fan, Jingcheng Du, Evan Yu, Hongfang Liu, Xiaoqian Jiang, Hua Xu, Cui Tao

Faculty, Staff and Student Publications

Objective: Social determinants of health (SDoH) play critical roles in health outcomes and well-being. Understanding the interplay of SDoH and health outcomes is critical to reducing healthcare inequalities and transforming a "sick care" system into a "health-promoting" system. To address the SDOH terminology gap and better embed relevant elements in advanced biomedical informatics, we propose an SDoH ontology (SDoHO), which represents fundamental SDoH factors and their relationships in a standardized and measurable way.

Material and methods: Drawing on the content of existing ontologies relevant to certain aspects of SDoH, we used a top-down approach to formally model classes, relationships, and …

Early-Adulthood Spike In Protein Translation Drives Aging Via Juvenile Hormone/Germline Signaling, Harper S Kim, Danitra J Parker, Madison M Hardiman, Erin Munkácsy, Nisi Jiang, Aric N Rogers, Yidong Bai, Colin Brent, James A Mobley, Steven N Austad, Andrew M Pickering

Faculty, Staff and Student Publications

Protein translation (PT) declines with age in invertebrates, rodents, and humans. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing an early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age-related …

The Interplay Between H3k36 Methylation And Dna Methylation In Cancer, Jiameng Dan, Zeling Du, Jinghong Zhang, Taiping Chen

Faculty, Staff and Student Publications

No abstract provided.

Developing Electronic Clinical Quality Measures To Assess The Cancer Diagnostic Process, Daniel R Murphy, Andrew J Zimolzak, Divvy K Upadhyay, Li Wei, Preeti Jolly, Alexis Offner, Dean F Sittig, Saritha Korukonda, Riyaa Murugaesh Rekha, Hardeep Singh

Faculty, Staff and Student Publications

OBJECTIVE: Measures of diagnostic performance in cancer are underdeveloped. Electronic clinical quality measures (eCQMs) to assess quality of cancer diagnosis could help quantify and improve diagnostic performance.

MATERIALS AND METHODS: We developed 2 eCQMs to assess diagnostic evaluation of red-flag clinical findings for colorectal (CRC; based on abnormal stool-based cancer screening tests or labs suggestive of iron deficiency anemia) and lung (abnormal chest imaging) cancer. The 2 eCQMs quantified rates of red-flag follow-up in CRC and lung cancer using electronic health record data repositories at 2 large healthcare systems. Each measure used clinical data to identify abnormal results, evidence of …

Cultivated Autologous Limbal Epithelial Cell (Calec) Transplantation: Development Of Manufacturing Process And Clinical Evaluation Of Feasibility And Safety, Ula V Jurkunas, Jia Yin, Lynette K Johns, Sanming Li, Helene Negre, Kit L Shaw, Lassana Samarakoon, Allison R Ayala, Ahmad Kheirkhah, Kishore Katikireddy, Alex Gauthier, Stephan Ong Tone, Aaron R Kaufman, Stacey Ellender, Diego E Hernandez Rodriguez, Heather Daley, Reza Dana, Myriam Armant, Jerome Ritz

Faculty, Staff and Student Publications

To treat unilateral limbal stem cell (LSC) deficiency, we developed cultivated autologous limbal epithelial cells (CALEC) using an innovative xenobiotic-free, serum-free, antibiotic-free, two-step manufacturing process for LSC isolation and expansion onto human amniotic membrane with rigorous quality control in a good manufacturing practices facility. Limbal biopsies were used to generate CALEC constructs, and final grafts were evaluated by noninvasive scanning microscopy and tested for viability and sterility. Cultivated cells maintained epithelial cell phenotype with colony-forming and proliferative capacities. Analysis of LSC biomarkers showed preservation of "stemness." After preclinical development, a phase 1 clinical trial enrolled five patients with unilateral LSC …

Defining The Roles Of Pyruvate Oxidation, Tca Cycle, And Mannitol Metabolism In Methicillin-Resistant Staphylococcus Aureus Catheter-Associated Urinary Tract Infection, Santosh Paudel, Sarah Guedry, Chloe L P Obernuefemann, Scott J Hultgren, Jennifer N Walker, Ritwij Kulkarni

Faculty, Staff and Student Publications

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of complicated urinary tract infection (UTI) associated with the use of indwelling urinary catheters. Previous reports have revealed host and pathogen effectors critical for MRSA uropathogenesis. Here, we sought to determine the significance of specific metabolic pathways during MRSA UTI. First, we identified four mutants from the Nebraska transposon mutant library in the MRSA JE2 background that grew normally in rich medium but displayed significantly reduced growth in pooled human urine (HU). This prompted us to transduce the uropathogenic MRSA 1369 strain with the transposon mutants in sucD and fumC (tricarboxylic acid …

Sickle Cell Disease Treatment With Arginine Therapy (Start): Study Protocol For A Phase 3 Randomized Controlled Trial., Chris A Rees, David C. Brousseau, Daniel M Cohen, Anthony Villella, Carlton Dampier, Kathleen Brown, Andrew Campbell, Corrie E Chumpitazi, Gladstone Airewele, Todd Chang, Christopher Denton, Angela Ellison, Alexis Thompson, Fahd Ahmad, Nitya Bakshi, Keli D Coleman, Sara Leibovich, Deborah Leake, Dunia Hatabah, Hagar Wilkinson, Michelle Robinson, T Charles Casper, Elliott Vichinsky, Claudia R Morris

Department of Pediatrics Faculty Papers

BACKGROUND: Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults.

METHODS: STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 …

Pyruvate Anaplerosis Is A Targetable Vulnerability In Persistent Leukaemic Stem Cells, Kevin M Rattigan, Zuzana Brabcova, Daniele Sarnello, Martha M Zarou, Kiron Roy, Ryan Kwan, Lucie De Beauchamp, Amy Dawson, Angela Ianniciello, Ahmed Khalaf, Eric R Kalkman, Mary T Scott, Karen Dunn, David Sumpton, Alison M Michie, Mhairi Copland, Saverio Tardito, Eyal Gottlieb, G Vignir Helgason

Faculty, Staff and Student Publications

Deregulated oxidative metabolism is a hallmark of leukaemia. While tyrosine kinase inhibitors (TKIs) such as imatinib have increased survival of chronic myeloid leukaemia (CML) patients, they fail to eradicate disease-initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays, we generate multi-omics datasets that offer unique insight into metabolic adaptation and nutrient fate in patient-derived CML LSCs. We demonstrate that LSCs have increased pyruvate anaplerosis, mediated by increased mitochondrial pyruvate carrier 1/2 (MPC1/2) levels and pyruvate carboxylase (PC) activity, in comparison to normal counterparts. While imatinib reverses BCR::ABL1-mediated LSC metabolic …

Detection Method Has Independent Prognostic Significance In The Plco Lung Screening Trial, James P Long, Yu Shen

Faculty, Staff and Student Publications

Prognostic models in cancer use patient demographic and tumor characteristics to predict survival and dynamic disease prognosis. Past work in breast cancer has shown that cancer detection method, screen-detected or symptom-detected, has prognostic significance. We investigate this phenomenon in the lung component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial. Patients were randomized to intervention, receiving four annual chest x-rays (CXRs), or to control, receiving usual care. Patients were followed for a total of approximately 13 years. In PLCO, lung cancer detection method has independent prognostic value exceeding that of variables commonly used in lung cancer prognostic models, …

Computational Modeling And Minimization Of Unintended Neuronal Excitation In A Lifu Stimulation, Boqiang Fan, Wayne Goodman, Raymond Y Cho, Sameer A Sheth, Richard R Bouchard, Behnaam Aazhang

Faculty, Staff and Student Publications

The neuromodulation effect of low-intensity focused ultrasound (LIFU) is highly target-specific. Unintended off-target neuronal excitation can be elicited when the beam focusing accuracy and resolution are limited, whereas the resulted side effect has not been evaluated quantitatively. There is also a lack of methods addressing the minimization of such side effects. Therefore, this work introduces a computational model of unintended neuronal excitation during LIFU neuromodulation, which evaluates the off-target activation area (OTAA) by integrating an ultrasound field model with the neuronal spiking model. In addition, a phased array beam focusing scheme called constrained optimal resolution beamforming (CORB) is proposed to …

The Rise Of Degrader Drugs, Mingxing Teng, Nathanael S Gray

Faculty, Staff and Students Publications

The cancer genomics revolution has served up a plethora of promising and challenging targets for the drug discovery community. The field of targeted protein degradation (TPD) uses small molecules to reprogram the protein homeostasis system to destroy desired target proteins. In the last decade, remarkable progress has enabled the rational development of degraders for a large number of target proteins, with over 20 molecules targeting more than 12 proteins entering clinical development. While TPD has been fully credentialed by the prior development of immunomodulatory drug (IMiD) class for the treatment of multiple myeloma, the field is poised for a "Gleevec …

Genome-Wide Association Studies And Fine-Mapping Identify Genomic Loci For N-3 And N-6 Polyunsaturated Fatty Acids In Hispanic American And African American Cohorts, Chaojie Yang, Jenna Veenstra, Traci M Bartz, Matthew C Pahl, Brian Hallmark, Yii-Der Ida Chen, Jason Westra, Lyn M Steffen, Christopher D Brown, David Siscovick, Michael Y Tsai, Alexis C Wood, Stephen S Rich, Caren E Smith, Timothy D O'Connor, Dariush Mozaffarian, Struan F A Grant, Floyd H Chilton, Nathan L Tintle, Rozenn N Lemaitre, Ani Manichaikul

Faculty, Staff and Students Publications

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 × 10

Class-Driven Synergy And Antagonism Between A Pseudomonas Phage And Antibiotics, Paul Nicholls, Justin R Clark, Carmen Gu Liu, Austen Terwilliger, Anthony W Maresso

Faculty, Staff and Students Publications

The ubiquitous bacterial pathogen Pseudomonas aeruginosa is responsible for severe infections in patients with burns, cystic fibrosis, and neutropenia. Biofilm formation gives physical refuge and a protected microenvironment for sessile cells, rendering cure by antibiotics a challenge. Bacteriophages have evolved to prey on these biofilms over millions of years, using hydrolases and depolymerases to penetrate biofilms and reach cellular targets. Here, we assessed how a newly discovered KMV-like phage (ΦJB10) interacts with antibiotics to treat P. aeruginosa more effectively in both planktonic and biofilm forms. By testing representatives of four classes of antibiotics (cephalosporins, aminoglycosides, fluoroquinolones, and carbapenems), we demonstrated …

Dynamics Of Anti-Influenza Mucosal Iga Over A Season In A Cohort Of Individuals Living Or Working In A Long-Term Care Facility, Matt D T Hitchings, Brooke A Borgert, Adam Shir, Bingyi Yang, Kyra H Grantz, Jacob Ball, Carlos A Moreno, Kenneth Rand, Parker A Small, Keith R Fowke, Derek A T Cummings

Faculty, Staff and Student Publications

BACKGROUND: Serological surveys are used to ascertain influenza infection and immunity, but evidence for the utility of mucosal immunoglobulin A (IgA) as a correlate of infection or protection is limited.

METHODS: We performed influenza-like illness (ILI) surveillance on 220 individuals living or working in a retirement community in Gainesville, Florida from January to May 2018, and took pre- and postseason nasal samples of 11 individuals with polymerase chain reaction (PCR)-confirmed influenza infection and 60 randomly selected controls. Mucosal IgA against 10 strains of influenza was measured from nasal samples.

RESULTS: Overall, 28.2% and 11.3% of individuals experienced a 2-fold and …

Anterior Shoulder Instability And Open Procedures: History, Indications, And Clinical Outcomes, Mohamad Y. Fares, Peter Boufadel, Mohammad Daher, Jonathan Koa, Akshay Khanna, Joseph A. Abboud

Rothman Institute Papers

The shoulder, being the most mobile joint in the human body, is often susceptible to dislocations and subluxations more so than other joints. As such, shoulder instability constitutes a common complaint among patients worldwide, especially those who are young, participate in contact sports, and have increased innate flexibility in their joints. Management options in the setting of instability vary between conservative and surgical options that aim to mitigate symptoms and allow return of function. Surgical options can be arthroscopic and open, with a general shift among surgeons towards utilizing arthroscopic surgery in the past several decades. Nevertheless, open procedures still …

Targeting Bcl2 Overcomes Resistance And Augments Response To Aurora Kinase B Inhibition By Azd2811 In Small Cell Lung Cancer, Kavya Ramkumar, Azusa Tanimoto, Carminia M Della Corte, C Allison Stewart, Qi Wang, Li Shen, Robert J Cardnell, Jing Wang, Urszula M Polanska, Courtney Andersen, Jamal Saeh, J Elizabeth Pease, Jon Travers, Giulia Fabbri, Carl M Gay, Jelena Urosevic, Lauren A Byers

Faculty, Staff and Student Publications

PURPOSE: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy.

EXPERIMENTAL DESIGN: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. …

Enigma Chek2gether Project: A Comprehensive Study Identifies Functionally Impaired Chek2 Germline Missense Variants Associated With Increased Breast Cancer Risk, Lenka Stolarova, Petra Kleiblova, Petra Zemankova, Barbora Stastna, Marketa Janatova, Jana Soukupova, Maria Isabel Achatz, Christine Ambrosone, Paraskevi Apostolou, Banu K Arun, Paul Auer, Mollie Barnard, Birgitte Bertelsen, Biobank Japan, Marinus J Blok, Nicholas Boddicker, Joan Brunet, Elizabeth S Burnside, Mariarosaria Calvello, Ian Campbell, Sock Hoai Chan, Fei Chen, Jian Bang Chiang, Anna Coppa, Laura Cortesi, Ana Crujeiras-González, Consortium Czecanca, Kim De Leeneer, Robin De Putter, Allison Depersia, Lisa Devereux, Susan Domchek, Anna Efremidis, Christoph Engel, Corinna Ernst, D Gareth R Evans, Lidia Feliubadaló, Florentia Fostira, Olivia Fuentes-Ríos, Encarna B Gómez-García, Sara González, Christopher Haiman, Thomas Van Overeem Hansen, Jan Hauke, James Hodge, Chunling Hu, Hongyan Huang, Nur Diana Binte Ishak, Yusuke Iwasaki, Irene Konstantopoulou, Peter Kraft, James Lacey, Conxi Lázaro, Na Li, Weng Khong Lim, Sara Lindstrom, Adriana Lori, Elana Martinez, Alexandra Martins, Koichi Matsuda, Giuseppe Matullo, Simone Mcinerny, Kyriaki Michailidou, Marco Montagna, Alvaro N A Monteiro, Luigi Mori, Katherine Nathanson, Susan L Neuhausen, Heli Nevanlinna, Janet E Olson, Julie Palmer, Barbara Pasini, Alpa Patel, Maria Piane, Bruce Poppe, Paolo Radice, Alessandra Renieri, Nicoletta Resta, Marcy E Richardson, Toon Rosseel, Kathryn J Ruddy, Marta Santamariña, Elizabeth Santana Dos Santos, Lauren Teras, Amanda E Toland, Amy Trentham-Dietz, Celine M Vachon, Alexander E Volk, Nana Weber-Lassalle, Jeffrey N Weitzel, Lisa Wiesmuller, Stacey Winham, Siddhartha Yadav, Drakoulis Yannoukakos, Song Yao, Valentina Zampiga, Magnus Zethoven, Ze Wen Zhang, Tomas Zima, Amanda B Spurdle, Ana Vega, Maria Rossing, Jesús Del Valle, Arcangela De Nicolo, Eric Hahnen, Kathleen B M Claes, Joanne Ngeow, Yukihide Momozawa, Paul A James, Fergus J Couch, Libor Macurek, Zdenek Kleibl

Faculty, Staff and Student Publications

PURPOSE: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT).

EXPERIMENTAL DESIGN: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including …

Home-Based Self-Sampling Vs Clinician Sampling For Anal Precancer Screening: The Prevent Anal Cancer Self-Swab Study, Alan G Nyitray, Jenna Nitkowski, Timothy L Mcauliffe, Bridgett Brzezinski, Michael D Swartz, María E Fernandez, Ashish A Deshmukh, Timothy J Ridolfi, Sarah J Lundeen, Leslie Cockerham, Dave Wenten, Andrew Petroll, Brian Hilgeman, Jennifer S Smith, Elizabeth Y Chiao, Anna R Giuliano, Vanessa Schick, Prevent Anal Cancer Self-Swab Study Team

Faculty, Staff and Student Publications

Sexual minority men are at increased risk for anal squamous cell carcinoma. Our objective was to compare screening engagement among individuals randomized to self-collect an anal canal specimen at home or to attend a clinic appointment. Specimen adequacy was then assessed for human papillomavirus (HPV) DNA genotyping. A randomized trial recruited cisgendered sexual minority men and transgender people in the community and assigned them to use a home-based self-collection swabbing kit or attend a clinic-based swabbing. Swabs were sent for HPV genotyping. The proportions of participants completing screening in each study arm and the adequacy of their specimens for HPV …

Spatial Immunoprofiling Of Adenoid Cystic Carcinoma Reveals B7-H4 Is A Therapeutic Target For Aggressive Tumors, Luana Guimaraes Sousa, Daniel J Mcgrail, Felippe Lazar Neto, Kaiyi Li, Mario L Marques-Piubelli, Sammy Ferri-Borgogno, Hui Dai, Yoshitsugu Mitani, Nicole Spardy Burr, Zachary A Cooper, Krista Kinneer, Maria Angelica Cortez, Shiaw-Yih Lin, Diana Bell, Adel El Naggar, Jared Burks, Renata Ferrarotto

Faculty, Staff and Student Publications

PURPOSE: Adenoid cystic carcinoma (ACC) is a heterogeneous malignancy, and no effective systemic therapy exists for metastatic disease. We previously described two prognostic ACC molecular subtypes with distinct therapeutic vulnerabilities, ACC-I and ACC-II. In this study, we explored the ACC tumor microenvironment (TME) using RNA-sequencing and spatial biology to identify potential therapeutic targets.

EXPERIMENTAL DESIGN: Tumor samples from 62 ACC patients with available RNA-sequencing data that had been collected as part of previous studies were stained with a panel of 28 validated metal-tagged antibodies. Imaging mass cytometry (IMC) was performed using the Fluidigm Helios CyTOF instrument and analyzed with Visiopharm …

Compass: Joint Copy Number And Mutation Phylogeny Reconstruction From Amplicon Single-Cell Sequencing Data, Etienne Sollier, Jack Kuipers, Koichi Takahashi, Niko Beerenwinkel, Katharina Jahn

Faculty, Staff and Student Publications

Reconstructing the history of somatic DNA alterations can help understand the evolution of a tumor and predict its resistance to treatment. Single-cell DNA sequencing (scDNAseq) can be used to investigate clonal heterogeneity and to inform phylogeny reconstruction. However, most existing phylogenetic methods for scDNAseq data are designed either for single nucleotide variants (SNVs) or for large copy number alterations (CNAs), or are not applicable to targeted sequencing. Here, we develop COMPASS, a computational method for inferring the joint phylogeny of SNVs and CNAs from targeted scDNAseq data. We evaluate COMPASS on simulated data and apply it to several datasets including …

Impact Of Geroscience On Therapeutic Strategies For Older Adults With Cardiovascular Disease: Jacc Scientific Statement, Daniel E Forman, George A Kuchel, John C Newman, James L Kirkland, Elena Volpi, George E Taffet, Nir Barzilai, Ambarish Pandey, Dalane W Kitzman, Peter Libby, Luigi Ferrucci

Faculty, Staff and Students Publications

Geroscience posits that cardiovascular disease (CVD) and other chronic diseases result from progressive erosion of the effectiveness of homeostatic mechanisms that oppose age-related accumulation of molecular damage. This hypothetical common root to chronic diseases explains why patients with CVD are often affected by multimorbidity and frailty and why older age negatively affects CVD prognosis and treatment response. Gerotherapeutics enhance resilience mechanisms that counter age-related molecular damage to prevent chronic diseases, frailty, and disability, thereby extending healthspan. Here, we describe the main resilience mechanisms of mammalian aging, with a focus on how they can affect CVD pathophysiology. We next present novel …

A Multiparameter Molecular Classifier To Predict Response To Neoadjuvant Lapatinib Plus Trastuzumab Without Chemotherapy In Her2+ Breast Cancer, Jamunarani Veeraraghavan, Carolina Gutierrez, Carmine De Angelis, Robert Davis, Tao Wang, Tomas Pascual, Pier Selenica, Katherine Sanchez, Hiroaki Nitta, Monesh Kapadia, Anne C Pavlick, Patricia Galvan, Brent Rexer, Andres Forero-Torres, Rita Nanda, Anna M Storniolo, Ian E Krop, Matthew P Goetz, Julie R Nangia, Antonio C Wolff, Britta Weigelt, Jorge S Reis-Filho, Susan G Hilsenbeck, Aleix Prat, C Kent Osborne, Rachel Schiff, Mothaffar F Rimawi

Faculty, Staff and Student Publications

PURPOSE: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-"addicted" tumors who may benefit from a chemotherapy-sparing strategy.

EXPERIMENTAL DESIGN: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor-positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based …

Electric Field Navigated 1-Hz Rtms For Poststroke Motor Recovery: The E-Fit Randomized Controlled Trial, Dylan J. Edwards, Charle Y. Liu, Kari Dunning, Felipe Fregni, Jarmo Laine, Benjamin E. Leiby, Lynn M. Rogers, Richard L. Harvey

Moss-Magee Rehabilitation Papers

BACKGROUND: To determine if low-frequency repetitive transcranial magnetic stimulation targeting the primary motor cortex contralateral (M1_CL) to the affected corticospinal tract in patients with hemiparetic stroke augments intensive training–related clinical improvement; an extension of the NICHE trial (Navigated Inhibitory rTMS to Contralesional Hemisphere Trial) using an alternative sham coil.

METHODS: The present E-FIT trial (Electric Field Navigated 1Hz rTMS for Post-stroke Motor Recovery Trial) included 5 of 12 NICHE trial outpatient US rehabilitation centers. The stimulation protocol remained identical (1 Hz repetitive transcranial magnetic stimulation, M1_CL, preceding 60-minute therapy, 18 sessions/6 wks; parallel arm randomized clinical …

Immunological Monitoring In Hepatitis C Virus Controlled Human Infection Model, Naglaa H Shoukry, Andrea L Cox, Christopher M Walker

Faculty, Staff and Student Publications

Controlled human infection model trials for hepatitis C virus represent an important opportunity to identify correlates of protective immunity against a well-characterized inoculum of hepatitis C virus and how such responses are modified by vaccination. In this article, we discuss the approach to immunological monitoring during such trials, including a set of recommendations for optimal sampling schedule and preferred immunological assays to examine the different arms of the immune response. We recommend that this approach be adapted to different trial designs. Finally, we discuss how these studies can provide surrogate predictors of the success of candidate vaccines.

Evolution Of Immune And Stromal Cell States And Ecotypes During Gastric Adenocarcinoma Progression, Ruiping Wang, Shumei Song, Jiangjiang Qin, Katsuhiro Yoshimura, Fuduan Peng, Yanshuo Chu, Yuan Li, Yibo Fan, Jiankang Jin, Minghao Dang, Enyu Dai, Guangsheng Pei, Guangchun Han, Dapeng Hao, Yating Li, Deyali Chatterjee, Kazuto Harada, Melissa Pool Pizzi, Ailing W Scott, Ghia Tatlonghari, Xinmiao Yan, Zhiyuan Xu, Can Hu, Shaowei Mo, Namita Shanbhag, Yang Lu, Matheus Sewastjanow-Silva, Ahmed Adel Fouad Abdelhakeem, Guang Peng, Samir M Hanash, George A Calin, Cassian Yee, Pawel Mazur, Autumn N Marsden, Andrew Futreal, Zhenning Wang, Xiangdong Cheng, Jaffer A Ajani, Linghua Wang

Faculty, Staff and Student Publications

Understanding tumor microenvironment (TME) reprogramming in gastric adenocarcinoma (GAC) progression may uncover novel therapeutic targets. Here, we performed single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and compositions as GAC progresses. Abundant IgA+ plasma cells exist in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominate late-stage GACs. We identified six TME ecotypes (EC1–6). EC1 is exclusive to blood, while EC4, EC5, and EC2 are highly enriched in uninvolved tissues, premalignant lesions, and metastases, respectively. EC3 and EC6, two distinct ecotypes in primary GACs, associate with histopathological and genomic characteristics, and prognosis. …

Loss Of Syncrip Unleashes Apobec-Driven Mutagenesis, Tumor Heterogeneity, And Ar-Targeted Therapy Resistance In Prostate Cancer, Xiaoling Li, Yunguan Wang, Su Deng, Guanghui Zhu, Choushi Wang, Nickolas A Johnson, Zeda Zhang, Carla Rodriguez Tirado, Yaru Xu, Lauren A Metang, Julisa Gonzalez, Atreyi Mukherji, Jianfeng Ye, Yuqiu Yang, Wei Peng, Yitao Tang, Mia Hofstad, Zhiqun Xie, Heewon Yoon, Liping Chen, Xihui Liu, Sujun Chen, Hong Zhu, Douglas Strand, Han Liang, Ganesh Raj, Housheng Hansen He, Joshua T Mendell, Bo Li, Tao Wang, Ping Mu

Faculty, Staff and Student Publications

Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, …

Proteogenomic Data And Resources For Pan-Cancer Analysis, Yize Li, Yongchao Dou, Felipe Da Veiga Leprevost, Yifat Geffen, Anna P Calinawan, François Aguet, Yo Akiyama, Shankara Anand, Chet Birger, Song Cao, Rekha Chaudhary, Padmini Chilappagari, Marcin Cieslik, Antonio Colaprico, Daniel Cui Zhou, Corbin Day, Marcin J Domagalski, Myvizhi Esai Selvan, David Fenyö, Steven M Foltz, Alicia Francis, Tania Gonzalez-Robles, Zeynep H Gümüş, David Heiman, Michael Holck, Runyu Hong, Yingwei Hu, Eric J Jaehnig, Jiayi Ji, Wen Jiang, Lizabeth Katsnelson, Karen A Ketchum, Robert J Klein, Jonathan T Lei, Wen-Wei Liang, Yuxing Liao, Caleb M Lindgren, Weiping Ma, Lei Ma, Michael J Maccoss, Fernanda Martins Rodrigues, Wilson Mckerrow, Ngoc Nguyen, Robert Oldroyd, Alexander Pilozzi, Pietro Pugliese, Boris Reva, Paul Rudnick, Kelly V Ruggles, Dmitry Rykunov, Sara R Savage, Michael Schnaubelt, Tobias Schraink, Zhiao Shi, Deepak Singhal, Xiaoyu Song, Erik Storrs, Nadezhda V Terekhanova, Ratna R Thangudu, Mathangi Thiagarajan, Liang-Bo Wang, Joshua M Wang, Ying Wang, Bo Wen, Yige Wu, Matthew A Wyczalkowski, Yi Xin, Lijun Yao, Xinpei Yi, Hui Zhang, Qing Zhang, Maya Zuhl, Gad Getz, Li Ding, Alexey I Nesvizhskii, Pei Wang, Ana I Robles, Bing Zhang, Samuel H Payne

Faculty, Staff and Students Publications

The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics datasets connecting genomic aberrations to cancer phenotypes. To facilitate pan-cancer investigations, we have generated harmonized genomic, transcriptomic, proteomic, and clinical data for >1000 tumors in 10 cohorts to create a cohesive and powerful dataset for scientific discovery. We outline efforts by the CPTAC pan-cancer working group in data harmonization, data dissemination, and computational resources for aiding biological discoveries. We also discuss challenges for multi-omics data integration and analysis, specifically the unique challenges of working with both nucleotide sequencing and mass spectrometry …

Predicting Pediatric Tuberculosis: The Need For Age-Specific Host Biosignatures, Sara Suliman, Devan Jaganath, Andrew Dinardo

Faculty, Staff and Students Publications

No abstract provided.

Characterizing Cancer Metabolism From Bulk And Single-Cell Rna-Seq Data Using Metaflux, Yuefan Huang, Vakul Mohanty, Merve Dede, Kyle Tsai, May Daher, Li Li, Katayoun Rezvani, Ken Chen

Faculty, Staff and Student Publications

Cells often alter metabolic strategies under nutrient-deprived conditions to support their survival and growth. Characterizing metabolic reprogramming in the tumor microenvironment (TME) is of emerging importance in cancer research and patient care. However, recent technologies only measure a subset of metabolites and cannot provide in situ measurements. Computational methods such as flux balance analysis (FBA) have been developed to estimate metabolic flux from bulk RNA-seq data and can potentially be extended to single-cell RNA-seq (scRNA-seq) data. However, it is unclear how reliable current methods are, particularly in TME characterization. Here, we present a computational framework METAFlux (METAbolic Flux balance analysis) …