Medicine and Health Sciences Commons^™

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 …

Prolonged Cytopenia Following Cd19 Car T Cell Therapy Is Linked With Bone Marrow Infiltration Of Clonally Expanded Ifnγ-Expressing Cd8 T Cells, Paolo Strati, Xubin Li, Qing Deng, Mario L Marques-Piubelli, Jared Henderson, Grace Watson, Laurel Deaton, Taylor Cain, Haopeng Yang, Vida Ravanmehr, Luis E Fayad, Swaminathan P Iyer, Loretta J Nastoupil, Frederick B Hagemeister, Edwin R Parra, Neeraj Saini, Koichi Takahashi, Nathan H Fowler, Jason R Westin, Raphael E Steiner, Ranjit Nair, Christopher R Flowers, Linghua Wang, Sairah Ahmed, Gheath Al-Atrash, Francisco Vega, Sattva S Neelapu, Michael R Green

Faculty, Staff and Student Publications

Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade ≥3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1hi cytotoxic T cells, expressing high interferon (IFN)-γ and cytokine …

Indoor Airborne Microbiome And Endotoxin: Meteorological Events And Occupant Characteristics Are Important Determinants, Hesham Amin, Tina Šantl-Temkiv, Christine Cramer, Kai Finster, Francisco Gomez Real, Thorarinn Gislason, Mathias Holm, Christer Janson, Nils Oskar Jögi, Rain Jogi, Andrei Malinovschi, Ian P G Marshall, Lars Modig, Dan Norbäck, Rajesh Shigdel, Torben Sigsgaard, Cecilie Svanes, Hulda Thorarinsdottir, Inge M Wouters, Vivi Schlünssen, Randi J Bertelsen

Faculty, Staff and Student Publications

Airborne bacteria and endotoxin may affect asthma and allergies. However, there is limited understanding of the environmental determinants that influence them. This study investigated the airborne microbiomes in the homes of 1038 participants from five cities in Northern Europe: Aarhus, Bergen, Reykjavik, Tartu, and Uppsala. Airborne dust particles were sampled with electrostatic dust fall collectors (EDCs) from the participants’ bedrooms. The dust washed from the EDCs’ clothes was used to extract DNA and endotoxin. The DNA extracts were used for quantitative polymerase chain (qPCR) measurement and 16S rRNA gene sequencing, while endotoxin was measured using the kinetic chromogenic limulus amoebocyte …

Estrogen-Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis And Muscle Recovery In Preclinical Model Of Pad, Danesh H Sopariwala, Andrea S Rios, Addison Saley, Ashok Kumar, Vihang A Narkar

Faculty, Staff and Student Publications

Background Peripheral arterial disease and critical limb ischemia are cardiovascular complications associated with vascular insufficiency, oxidative metabolic dysfunction, and myopathy in the limbs. Estrogen-related receptor gamma (ERRγ) has emerged as a dual regulator of paracrine angiogenesis and oxidative metabolism through transgenic mouse studies. Here our objective was to investigate whether postischemic intramuscular targeting of ERRγ via gene therapy promotes ischemic recovery in a preclinical model of peripheral arterial disease/critical limb ischemia. Methods and Results Adeno-associated virus 9 (AAV9)

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 …

A Multidimensional Connectomics- And Radiomics-Based Advanced Machine-Learning Framework To Distinguish Radiation Necrosis From True Progression In Brain Metastases, Yilin Cao, Vishwa S Parekh, Emerson Lee, Xuguang Chen, Kristin J Redmond, Jay J Pillai, Luke Peng, Michael A Jacobs, Lawrence R Kleinberg

Faculty, Staff and Student Publications

We introduce tumor connectomics, a novel MRI-based complex graph theory framework that describes the intricate network of relationships within the tumor and surrounding tissue, and combine this with multiparametric radiomics (mpRad) in a machine-learning approach to distinguish radiation necrosis (RN) from true progression (TP). Pathologically confirmed cases of RN vs. TP in brain metastases treated with SRS were included from a single institution. The region of interest was manually segmented as the single largest diameter of the T1 post-contrast (T1C) lesion plus the corresponding area of T2 FLAIR hyperintensity. There were 40 mpRad features and 6 connectomics features extracted, as …

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 …

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 …

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, …

Bacteroides Uniformis-Induced Perturbations In Colonic Microbiota And Bile Acid Levels Inhibit Th17 Differentiation And Ameliorate Colitis Developments, Yiting Yan, Yu Lei, Ying Qu, Zhen Fan, Ting Zhang, Yangbin Xu, Qian Du, Daniel Brugger, Yulin Chen, Ke Zhang, Enping Zhang

Faculty, Staff and Student Publications

Inflammatory bowel disease (IBD) is associated with gut dysbiosis and can lead to colitis-associated malignancies. Bacteroides uniformis (Bu) regulates animal intestinal homeostasis; however, the mechanism by which it alleviates colitis in mice remains unknown. We investigated the effects of B. uniformis JCM5828 and its metabolites on female C57BL/6J mice with dextran sulfate sodium salt (DSS) induced colitis. Treatment with Bu considerably alleviated colitis progression and restored the mechanical and immune barrier protein expression. Additionally, Bu increased the abundance of the symbiotic bacteria Bifidobacterium and Lactobacillus vaginalis while decreasing that of pathogenic Escherichia-Shigella, and modulated intestinal bile acid metabolism. Bu largely …

Hepatitis A Virus And Hepatitis E Virus As Food- And Waterborne Pathogens—Transmission Routes And Methods For Detection In Food, Katalin Nemes, Sofia Persson, Magnus Simonsson

Faculty, Staff and Student Publications

Foodborne viruses are an important threat to food safety and public health. Globally, there are approximately 5 million cases of acute viral hepatitis due to hepatitis A virus (HAV) and hepatitis E virus (HEV) every year. HAV is responsible for numerous food-related viral outbreaks worldwide, while HEV is an emerging pathogen with a global health burden. The reported HEV cases in Europe have increased tenfold in the last 20 years due to its zoonotic transmission through the consumption of infected meat or meat products. HEV is considered the most common cause of acute viral hepatitis worldwide currently. This review focuses …

Lvpt: Lazy Velocity Pseudotime Inference Method, Shuainan Mao, Jiajia Liu, Weiling Zhao, Xiaobo Zhou

Faculty, Staff and Student Publications

The emergence of RNA velocity has enriched our understanding of the dynamic transcriptional landscape within individual cells. In light of this breakthrough, we embarked on integrating RNA velocity with cellular pseudotime inference, aiming to improve the prediction of cell orders along biological trajectories beyond existing methods. Here, we developed LVPT, a novel method for pseudotime and trajectory inference. LVPT introduces a lazy probability to indicate the probability that the cell stays in the original state and calculates the transition matrix based on RNA velocity to provide the probability and direction of cell differentiation. LVPT shows better and comparable performance of …

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) …

Prevalence Of Symptoms ≤12 Months After Acute Illness, By Covid-19 Testing Status Among Adults — United States, December 2020–March 2023, Juan Carlos C Montoy, James Ford, Huihui Yu, Michael Gottlieb, Dana Morse, Michelle Santangelo, Kelli N O'Laughlin, Kevin Schaeffer, Pamela Logan, Kristin Rising, Mandy J Hill, Lauren E Wisk, Wafah Salah, Ahamed H Idris, Ryan M Huebinger, Erica S Spatz, Robert M Rodriguez, Robin E Klabbers, Kristyn Gatling, Ralph C Wang, Joann G Elmore, Samuel A Mcdonald, Kari A Stephens, Robert A Weinstein, Arjun K Venkatesh, Sharon Saydah, Innovative Support For Patients With Sars-Cov-2 Infections Registry (Inspire) Group

Faculty, Staff and Student Publications

To further the understanding of post-COVID conditions, and provide a more nuanced description of symptom progression, resolution, emergence, and reemergence after SARS-CoV-2 infection or COVID-like illness, analysts examined data from the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE), a prospective multicenter cohort study. This report includes analysis of data on self-reported symptoms collected from 1,296 adults with COVID-like illness who were tested for SARS-CoV-2 using a Food and Drug Administration-approved polymerase chain reaction or antigen test at the time of enrollment and reported symptoms at 3-month intervals for 12 months. Prevalence of any symptom decreased substantially between baseline …

Add-On Soft Electronic Interfaces For Continuous Cuffless Blood Pressure Monitoring, Myeong Namkoong, Balaji Baskar, Lakhvir Singh, Heng Guo, Justin Mcmurray, Kimberly Branan, Md Saifur Rahman, Chin-To Hsiao, Josh Kuriakose, Joanna Hernandez, Arda A Arikan, Luis E Garza-Rivera, Gerard L Coté, Limei Tian

Faculty, Staff and Student Publications

Continuous monitoring of arterial blood pressure is clinically important for the diagnosis and management of cardiovascular diseases. Soft electronic devices with skin-like properties show promise in a wide range of applications, including the human-machine interface, the Internet of things, and health monitoring. Here, we report the use of add-on soft electronic interfaces to address the connection challenges between soft electrodes and rigid data acquisition circuitry for bioimpedance monitoring of cardiac signals, including heart rate and cuffless blood pressure. Nanocomposite films in add-on electrodes provide robust electrical and mechanical contact with the skin and the rigid circuitry. We demonstrate bioimpedance sensors …

In Situ Characterization Of 17-4ph Stainless Steel By Small-Angle Neutron Scattering, Shibo Yan, Zijun Wang, Tianfu Li, Zhong Chen, Xiaoming Du, Yuntao Liu, Dongfeng Chen, Kai Sun, Rongdeng Liu, Bing Bai, Xinfu He, Kaitai Liu, Shuanzhu Wang

Faculty, Staff and Student Publications

17-4PH martensitic steel is usually used as valve stems in nuclear power plants and it suffers from thermal aging embrittlement due to long-time service in a high-temperature and high-pressure environment. Here, we characterized the evolution of microstructures at the nano-scale in 17-4PH steel by in situ small-angle neutron scattering (SANS) with a thermo-mechanically coupled loading device. The device could set different temperatures and tensile so that an in situ SANS experiment could dynamically characterize the process of nanoscale structural changes. The results showed that with increasing thermal aging time, the ε-Cu phase precipitates and grows as the temperature is 475 …

Swarmdeepsurv: Swarm Intelligence Advances Deep Survival Network For Prognostic Radiomics Signatures In Four Solid Cancers, Qasem Al-Tashi, Maliazurina B Saad, Ajay Sheshadri, Carol C Wu, Joe Y Chang, Bissan Al-Lazikani, Christopher Gibbons, Natalie I Vokes, Jianjun Zhang, J Jack Lee, John V Heymach, David Jaffray, Seyedali Mirjalili, Jia Wu

Faculty, Staff and Student Publications

Survival models exist to study relationships between biomarkers and treatment effects. Deep learning-powered survival models supersede the classical Cox proportional hazards (CoxPH) model, but substantial performance drops were observed on high-dimensional features because of irrelevant/redundant information. To fill this gap, we proposed SwarmDeepSurv by integrating swarm intelligence algorithms with the deep survival model. Furthermore, four objective functions were designed to optimize prognostic prediction while regularizing selected feature numbers. When testing on multicenter sets (n = 1,058) of four different cancer types, SwarmDeepSurv was less prone to overfitting and achieved optimal patient risk stratification compared with popular survival modeling algorithms. Strikingly, …

Perioperative Pembrolizumab For Early-Stage Non-Small-Cell Lung Cancer, Heather Wakelee, Moishe Liberman, Terufumi Kato, Masahiro Tsuboi, Se-Hoon Lee, Shugeng Gao, Ke-Neng Chen, Christophe Dooms, Margarita Majem, Ekkehard Eigendorff, Gastón L Martinengo, Olivier Bylicki, Delvys Rodríguez-Abreu, Jamie E Chaft, Silvia Novello, Jing Yang, Steven M Keller, Ayman Samkari, Jonathan D Spicer, Keynote-671 Investigators

Faculty, Staff and Student Publications

BACKGROUND: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.

METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 …

Multifocal And Multicentric Glioblastoma: Imaging Signature, Molecular Characterization, Patterns Of Spread, And Treatment, Maguy Farhat, Gregory N Fuller, Max Wintermark, Caroline Chung, Vinodh A Kumar, Melissa Chen

Faculty, Staff and Student Publications

Multifocal and multicentric glioblastoma (GBM) or collectively, m-GBM, is an imaging diagnosis present in up to 34% of patients with GBM. Compared to unifocal disease, patients with m-GBM have worse outcomes owing to the enhanced aggressive nature of the disease and its resistance to currently available treatments. To improve the understanding of its complex behavior, many associations have been established between the radiologic findings of m-GBM and its gross histology, genetic composition, and patterns of spread. Additionally, the holistic knowledge of the exact mechanisms of m-GBM genesis and progression is crucial for identifying potential targets permitting enhanced diagnosis and treatment. …

Estimation Of Health Risks Caused By Metals Contained In E-Cigarette Aerosol Through Passive Vaping, Wei-Chung Su, Jinho Lee, Kai Zhang, Su-Wei Wong, Anne Buu

Faculty, Staff and Student Publications

It is expected that secondary exposure to e-cigarette aerosol (passive vaping) will soon become an issue of public health. Passive vaping inhales e-cigarette aerosol containing similar harmful substances as active vaping. However, parallel studies on passive vaping are minimal. Therefore, there is a need for passive vaping-related health risk studies to assess the impact of vaping on public health. This research conducted a series of experiments in a room using a puffing machine and the Mobile Aerosol Lung Deposition Apparatus (MALDA) to study e-cigarette aerosol respiratory deposition through passive vaping. The experimental data acquired were applied to estimate the deposited …

Real-World Experience Of Patients With Multiple Myeloma Receiving Ide-Cel After A Prior Bcma-Targeted Therapy, Christopher J Ferreri, Michelle A T Hildebrandt, Hamza Hashmi, Leyla O Shune, Joseph P Mcguirk, Douglas W Sborov, Charlotte B Wagner, M Hakan Kocoglu, Aaron Rapoport, Shebli Atrash, Peter M Voorhees, Jack Khouri, Danai Dima, Aimaz Afrough, Gurbakhash Kaur, Larry D Anderson, Gary Simmons, James A Davis, Nilesh Kalariya, Lauren C Peres, Yi Lin, Murali Janakiram, Omar Nadeem, Melissa Alsina, Frederick L Locke, Surbhi Sidana, Doris K Hansen, Krina K Patel, Omar Alexis Castaneda Puglianini

Faculty, Staff and Student Publications

Most patients with multiple myeloma experience disease relapse after treatment with a B-cell maturation antigen-targeted therapy (BCMA-TT), and data describing outcomes for patients treated with sequential BCMA-TT are limited. We analyzed clinical outcomes for patients infused with standard-of-care idecabtagene vicleucel, an anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, at 11 US medical centers. A total of 50 patients with prior BCMA-TT exposure (38 antibody-drug conjugate, 7 bispecific, 5 CAR T) and 153 patients with no prior BCMA-TT were infused with ide-cel, with a median follow-up duration of 4.5 and 6.0 months, respectively. Safety outcomes between cohorts were comparable. The prior …

Genetic Control Of Mrna Splicing As A Potential Mechanism For Incomplete Penetrance Of Rare Coding Variants, Jonah Einson, Dafni Glinos, Eric Boerwinkle, Peter Castaldi, Dawood Darbar, Mariza De Andrade, Patrick Ellinor, Myriam Fornage, Stacey Gabriel, Soren Germer, Richard Gibbs, Craig P Hersh, Jill Johnsen, Robert Kaplan, Barbara A Konkle, Charles Kooperberg, Rami Nassir, Ruth J F Loos, Deborah A Meyers, Braxton D Mitchell, Bruce Psaty, Ramachandran S Vasan, Stephen S Rich, Michael Rienstra, Jerome I Rotter, Aabida Saferali, Moore Benjamin Shoemaker, Edwin Silverman, Albert Vernon Smith, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium; Pejman Mohammadi, Pejman Mohammadi, Stephane E Castel, Ivan Iossifov, Tuuli Lappalainen

Faculty, Staff and Student Publications

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce …

Feasibility And Value Of Genomic Profiling In Cancer Of Unknown Primary: Real-World Evidence From Prospective Profiling Study, Ryan W Huey, Aakash Tushar Shah, Honey V Reddi, Priyadarsini Dasari, James T Topham, Hyunsoo Hwang, Nishat Dhillon, Anneleis Willett, Brandon G Smaglo, Jeannelyn S Estrella, Asif Rashid, Aurelio Matamoros, Michael J Overman, Linda Choquette, Greg Omerza, Kevin Kelly, Xuemei Wang, Jonathan M Loree, Jens Rueter, Gauri R Varadhachary, Kanwal Raghav

Faculty, Staff and Student Publications

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (October 2016-September 2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients of which GAs with US Food and Drug Administration-approved genomically matched therapy were seen in 25 (40.9%) patients. A change in therapy was recommended and implemented (primary endpoint of the study) in 16 (10.1%) and …

Successful Treatment Of Non-Langerhans Cell Histiocytosis With The Mek Inhibitor Trametinib: A Multicenter Analysis, Ashley Aaroe, Razelle Kurzrock, Gaurav Goyal, Aaron M Goodman, Harsh Patel, Gordon Ruan, Gary Ulaner, Jason Young, Ziyi Li, Derek Dustin, Ronald S Go, Eli L Diamond, Filip Janku

Faculty, Staff and Student Publications

Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs), for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with a favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed the outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at 4 major US …

Phylogenetic Inference From Single-Cell Rna-Seq Data, Xuan Liu, Jason I Griffiths, Isaac Bishara, Jiayi Liu, Andrea H Bild, Jeffrey T Chang

Faculty, Staff and Student Publications

Tumors are comprised of subpopulations of cancer cells that harbor distinct genetic profiles and phenotypes that evolve over time and during treatment. By reconstructing the course of cancer evolution, we can understand the acquisition of the malignant properties that drive tumor progression. Unfortunately, recovering the evolutionary relationships of individual cancer cells linked to their phenotypes remains a difficult challenge. To address this need, we have developed PhylinSic, a method that reconstructs the phylogenetic relationships among cells linked to their gene expression profiles from single cell RNA-sequencing (scRNA-Seq) data. This method calls nucleotide bases using a probabilistic smoothing approach and then …

Molecular Mechanisms Of Snorna-Ll-15 Crosstalk In Adipocyte Lipolysis And Nk Cell Rejuvenation, Yaohua Zhang, Zilong Zhao, Lisa A Huang, Yuan Liu, Jun Yao, Chengcao Sun, Yajuan Li, Zhao Zhang, Youqiong Ye, Fei Yuan, Tina K Nguyen, Nikhil Reddy Garlapati, Andrew Wu, Sergey D Egranov, Abigail S Caudle, Aysegul A Sahin, Bora Lim, Laura Beretta, George A Calin, Dihua Yu, Mien-Chie Hung, Michael A Curran, Katayoun Rezvani, Boyi Gan, Zhi Tan, Leng Han, Chunru Lin, Liuqing Yang

Faculty, Staff and Student Publications

Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced …

Traf3-Ewsr1 Signaling Axis Acts As A Checkpoint On Germinal Center Responses, Yanchuan Li, Lele Zhu, Chun-Jung Ko, Jin-Young Yang, Hongjiao Wang, Ganiraju Manyam, Jing Wang, Xuhong Cheng, Shuli Zhao, Zuliang Jie

Faculty, Staff and Student Publications

The formation of germinal centers (GCs) is crucial for humoral immunity and vaccine efficacy. Constant stimulation through microbiota drives the formation of constitutive GCs in Peyer's patches (PPs), which generate B cells that produce antibodies against gut antigens derived from commensal bacteria and infectious pathogens. However, the molecular mechanism that regulates this persistent process is poorly understood. We report that Ewing Sarcoma Breakpoint Region 1 (EWSR1) is a brake to constitutive GC generation and immunoglobulin G (IgG) production in PPs, vaccination-induced GC formation, and IgG responses. Mechanistically, EWSR1 suppresses Bcl6 upregulation after antigen encounter, thereby negatively regulating induced GC B …