Biomedical Informatics Commons^™

Advances In The Radiological Evaluation Of And Theranostics For Glioblastoma, Grayson W Hooper, Shehbaz Ansari, Jason M Johnson, Daniel T Ginat

Faculty, Staff and Student Publications

Imaging is essential for evaluating patients with glioblastoma. Traditionally a multimodality undertaking, CT, including CT cerebral blood profusion, PET/CT with traditional fluorine-18 fluorodeoxyglucose (18F-FDG), and MRI have been the mainstays for diagnosis and post-therapeutic assessment. However, recent advances in these modalities, in league with the emerging fields of radiomics and theranostics, may prove helpful in improving diagnostic accuracy and treating the disease.

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 …

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 …

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 …

The Pyrimidinosome: Orchestrating Pyrimidine Biosynthesis And Ferroptosis Defense, Boyi Gan

Faculty, Staff and Student Publications

A recent study by Yang et al.1 uncovers the pyrimidinosome, a multienzyme complex where enzymes from different subcellular compartments collaborate to enable efficient pyrimidine biosynthesis and ferroptosis defense, highlighting the remarkable adaptability of cellular metabolism and new therapeutic opportunities.

Genetic Dissection Of Crossover Mutants Defines Discrete Intermediates In Mouse Meiosis, Tolkappiyan Premkumar, Lakshmi Paniker, Rhea Kang, Mathilde Biot, Ericka Humphrey, Honorine Destain, Isabella Ferranti, Iyinyeoluwa Okulate, Holly Nguyen, Vindhya Kilaru, Melissa Frasca, Parijat Chakraborty, Francesca Cole

Faculty, Staff and Student Publications

Crossovers (COs), the exchange of homolog arms, are required for accurate chromosome segregation during meiosis. Studies in yeast have described the single-end invasion (SEI) intermediate: a stabilized 3' end annealed with the homolog as the first detectible CO precursor. SEIs are thought to differentiate into double Holliday junctions (dHJs) that are resolved by MutLgamma (MLH1/MLH3) into COs. Currently, we lack knowledge of early steps of mammalian CO recombination or how intermediates are differentiated in any organism. Using comprehensive analysis of recombination in thirteen different genetic conditions with varying levels of compromised CO resolution, we infer CO precursors include asymmetric SEI-like …

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, …

Enhanced Cerebroprotection Of Xenon-Loaded Liposomes In Combination With Rtpa Thrombolysis For Embolic Ischemic Stroke, Tao Peng, Keith Booher, Melanie R Moody, Xing Yin, Jaroslaw Aronowski, David D Mcpherson, Sean I Savitz, Hyunggun Kim, Shao-Ling Huang

Faculty, Staff and Student Publications

Xenon (Xe) has shown great potential as a stroke treatment due to its exceptional ability to protect brain tissue without inducing side effects. We have previously developed Xe-loaded liposomes for the ultrasound-activated delivery of Xe into the cerebral region and demonstrated their therapeutic efficacy. At present, the sole FDA-approved thrombolytic agent for stroke treatment is recombinant tissue plasminogen activator (rtPA). In this study, we aimed to investigate the potential of combining Xe-liposomes with an intravenous rtPA treatment in a clinically relevant embolic rat stroke model. We evaluated the combinational effect using an in vitro clot lysis model and an in …

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 …

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)

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 …

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 …

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 …

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) …

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. …

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 …

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 …

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 …

Psilocybin-Assisted Psychotherapy For Cancer-Related Anxiety And Depression, Dan Yaniv, Lois Michelle Ramondetta, Lorenzo Cohen, Moran Amit

Faculty, Staff and Student Publications

No abstract provided.

Metabolic Liver Cancer: Associations Of Rare And Common Germline Variants In One-Carbon Metabolism And Dna Methylation Genes, Samuel O Antwi, Michael Heckman, Launia White, Irene Yan, Vivekananda Sarangi, Kimberly P Lauer, Joseph Reddy, Fowsiyo Ahmed, Swathi Veliginti, Ellis D Mejías Febres, Rikita I Hatia, Ping Chang, Laura Izquierdo-Sanchez, Loreto Boix, Angela Rojas, Jesus M Banales, Maria Reig, Per Stål, Manuel Romero Gómez, Amit G Singal, Donghui Li, Manal M Hassan, Lewis R Roberts, Tushar Patel

Faculty, Staff and Student Publications

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in …