Medicine and Health Sciences Commons^™

Achondroplasia Natural History Study (Clarity): 60-Year Experience In Orthopedic Surgery From Four Skeletal Dysplasia Centers, Nickolas J Nahm, W G Stuart Mackenzie, William G Mackenzie, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Janet M Legare, Mary Ellen Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria Elena Serna, Cory J Smid, Julie Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. …

Targeting Cxcr4 Abrogates Resistance To Trastuzumab By Blocking Cell Cycle Progression And Synergizes With Docetaxel In Breast Cancer Treatment, Shuying Liu, Shelly M Xie, Wenbin Liu, Mihai Gagea, Ariella B Hanker, Nguyen Nguyen, Akshara Singareeka Raghavendra, Gloria Yang-Kolodji, Fuliang Chu, Sattva S Neelapu, Adriano Marchese, Samir Hanash, Johann Zimmermann, Carlos L Arteaga, Debasish Tripathy

Faculty, Staff and Student Publications

Background: Although trastuzumab and other HER2-targeted therapies have significantly improved survival in patients with HER2 overexpressed or amplified (HER2+) breast cancer, a significant proportion of patients do not respond or eventually develop clinical resistance. Strategies to reverse trastuzumab resistance remain a high clinical priority. We were the first to report the role of CXCR4 in trastuzumab resistance. The present study aims to explore the therapeutic potential of targeting CXCR4 and better understand the associated mechanisms.

Methods: Immunofluorescent staining, confocal microscopy analysis, and immunoblotting were used to analyze CXCR4 expression. BrdU incorporation assays and flow cytometry were used to analyze dynamic …

17Β-Estradiol Promotes Extracellular Vesicle Release And Selective Mirna Loading In Erα-Positive Breast Cancer, Rares Drula, Barbara Pardini, Xiao Fu, Mireia Cruz De Los Santos, Ancuta Jurj, Lan Pang, Sherien M El-Daly, Linda Fabris, Erik Knutsen, Mihnea P Dragomir, Recep Bayraktar, Yongfeng Li, Meng Chen, Filippo Del Vecchio, Léa Berland, Jessica Dae, Daniel Fan, Masayoshi Shimizu, Anh M Tran, Mercedes Barzi, Carlotta Pioppini, Angelica M Gutierrez, Cristina Ivan, Salyna Meas, Carolyn S Hall, Suresh K Alahari, Ioana Berindan-Neagoe, Muller Fabbri, Anthony Lucci, Banu Arun, Simone Anfossi, George A Calin

Faculty, Staff and Student Publications

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor-positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7's miRNAs into EVs. In multiple patient cohorts, …

Non-Homologous End-Joining Pathway Genotypes Significantly Associated With Nasopharyngeal Carcinoma Susceptibility, Chia-Wen Tsai, Liang-Chun Shih, Wen-Shin Chang, Che-Lun Hsu, Jie-Long He, Te-Chun Hsia, Yun-Chi Wang, Jian Gu, Da-Tian Bau

Faculty, Staff and Student Publications

Defects in the non-homologous end-joining (NHEJ) DNA repair pathway lead to genomic instability and carcinogenesis. However, the roles of individual NHEJ genes in nasopharyngeal carcinoma (NPC) etiology are not well-understood. The aim of this study was to assess the contribution of NHEJ genotypes, including XRCC4 (rs6869366, rs3734091, rs28360071, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and Ligase4 rs1805388, to NPC risk, with 208 NPC patients and 416 controls. Genotype-phenotype correlations were also investigated by measuring mRNA and protein expression in adjacent normal tissues and assessing the NHEJ repair capacity in blood lymphocytes from 43 …

Variant Spectrum Of Von Hippel-Lindau Disease And Its Genomic Heterogeneity In Japan, Kenji Tamura, Yuki Kanazashi, Chiaki Kawada, Yuya Sekine, Kazuhiro Maejima, Shingo Ashida, Takashi Karashima, Shohei Kojima, Nickolas F Parrish, Shunichi Kosugi, Chikashi Terao, Shota Sasagawa, Masashi Fujita, Todd A Johnson, Yukihide Momozawa, Keiji Inoue, Taro Shuin, Hidewaki Nakagawa

Faculty, Staff and Student Publications

Von Hippel-Lindau (VHL) disease is an autosomal dominant, inherited syndrome with variants in the VHL gene, causing predisposition to multi-organ neoplasms with vessel abnormality. Germline variants in VHL can be detected in 80-90% of patients clinically diagnosed with VHL disease. Here, we summarize the results of genetic tests for 206 Japanese VHL families, and elucidate the molecular mechanisms of VHL disease, especially in variant-negative unsolved cases. Of the 206 families, genetic diagnosis was positive in 175 families (85%), including 134 families (65%) diagnosed by exon sequencing (15 novel variants) and 41 (20%) diagnosed by multiplex ligation-dependent probe amplification (MLPA) (one …

Bk Channel Modulation By Positively Charged Peptides And Auxiliary Γ Subunits Mediated By The Ca2+-Bowl Site, Guanxing Chen, Qin Li, Timothy I Webb, Mark A Hollywood, Jiusheng Yan

Faculty, Staff and Student Publications

The large-conductance, Ca2+-, and voltage-activated K+ (BK) channel consists of the pore-forming α (BKα) subunit and regulatory β and γ subunits. The γ1-3 subunits facilitate BK channel activation by shifting the voltage-dependence of channel activation toward the hyperpolarization direction by about 50-150 mV in the absence of Ca2+. We previously found that the intracellular C-terminal positively charged regions of the γ subunits play important roles in BK channel modulation. In this study, we found that the intracellular C-terminal region of BKα is indispensable in BK channel modulation by the γ1 subunit. Notably, synthetic peptide mimics of the γ1-3 subunits' C-terminal …

Irinotecan- Vs Oxaliplatin-Based Doublets In Krasg12c-Mutated Metastatic Colorectal Cancer—A Multicentre Propensity-Score-Matched Retrospective Analysis, Vincenzo Formica, Cristina Morelli, Veronica Conca, Maria Alessandra Calegari, Jessica Lucchetti, Emanuela Dell'aquila, Marta Schirripa, Marco Messina, Lisa Salvatore, Federica Lo Prinzi, Giovanni Dima, Giovanni Trovato, Silvia Riondino, Mario Roselli, Ferdinandos Skoulidis, Hendrik-Tobias Arkenau, Chiara Cremolini

Faculty, Staff and Student Publications

Background: KRASG12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown.

Methods: A multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/- bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis …

Tubectomy With Delayed Oophorectomy As An Alternative To Risk-Reducing Salpingo-Oophorectomy In High-Risk Women To Assess The Safety Of Prevention: The Tuba-Wisp Ii Study Protocol, Miranda P Steenbeek, Majke H D Van Bommel, Joanna Inthout, Christine B Peterson, Michiel Simons, Kit C B Roes, Marleen Kets, Barbara M Norquist, Elizabeth M Swisher, Rosella P M G Hermens, Tuba-Wisp Ii Consortium, Karen H Lu, Joanne A De Hullu

Faculty, Staff and Student Publications

Background: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy.

Primary objective: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk.

Study hypothesis: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 (BRCA1) …

Studies On Diketopiperazine And Dipeptide Analogs As Opioid Receptor Ligands, Siavash Shahbazi Nia, Mohammad Anwar Hossain, Guangchen Ji, Sravan K Jonnalagadda, Samuel Obeng, Md Ashrafur Rahman, Ali Ehsan Sifat, Saeideh Nozohouri, Collin Blackwell, Dhavalkumar Patel, Jon Thompson, Scott Runyon, Takato Hiranita, Christopher R Mccurdy, Lance Mcmahon, Thomas J Abbruscato, Paul C Trippier, Volker Neugebauer, Nadezhda A German

Faculty, Staff and Student Publications

Using the structure of gliotoxin as a starting point, we have prepared two different chemotypes with selective affinity to the kappa opioid receptor (KOR). Using medicinal chemistry approaches and structure-activity relationship (SAR) studies, structural features required for the observed affinity were identified, and advanced molecules with favorable Multiparameter Optimization (MPO) and Ligand Lipophilicity (LLE) profiles were prepared. Using the Thermal Place Preference Test (TPPT), we have shown that compound2 blocks the antinociceptive effect of U50488, a known KOR agonist. Multiple reports suggest that modulation of KOR signaling is a promising therapeutic strategy in treating neuropathic pain (NP). As a …

The Role Of Native Cysteine Residues In The Oligomerization Of Kcnq1 Channels, Alison Bates, Rebecca B Stowe, Elizabeth M Travis, Lauryn E Cook, Carole Dabney-Smith, Gary A Lorigan

Faculty, Staff and Student Publications

KCNQ1, the major component of the slow-delayed rectifier potassium channel, is responsible for repolarization of cardiac action potential. Mutations in this channel can lead to a variety of diseases, most notably long QT syndrome. It is currently unknown how many of these mutations change channel function and structure on a molecular level. Since tetramerization is key to proper function and structure of the channel, it is likely that mutations modify the stability of KCNQ1 oligomers. Presently, the C-terminal domain of KCNQ1 has been noted as the driving force for oligomer formation. However, truncated versions of this protein lacking the C-terminal …

Utility Of Patient-Reported Symptom And Functional Outcomes To Indicate Recovery After First 90 Days Of Radical Cystectomy: A Longitudinal Study, Xin Shelley Wang, Kelly K Bree, Neema Navai, Mona Kamal, Shu-En Shen, Elizabeth Letona, Charles S Cleeland, Qiuling Shi, Vijaya Gottumukkala

Faculty, Staff and Student Publications

This is a longitudinal prospective study that tracked multiple symptom burden and functioning status for bladder cancer (BLC) patients for 3 months post-radical cystectomy at The University of Texas MD Anderson Cancer Center, using a validated disease-specific patient-reported outcome measure (PROM) tool, the MD Anderson Symptom Inventory (the MDASI-PeriOp-BLC). The feasibility of collecting an objective measure for physical functioning, using "Timed Up & Go test" (TUGT) and PRO scores at baseline, discharge and end of study, was tested. Patients (

Mitotrace: A Computational Framework For Analyzing Mitochondrial Variation In Single-Cell Rna Sequencing Data, Mingqiang Wang, Wankun Deng, David C Samuels, Zhongming Zhao, Lukas M Simon

Faculty, Staff and Student Publications

Genetic variation in the mitochondrial genome is linked to important biological functions and various human diseases. Recent progress in single-cell genomics has established single-cell RNA sequencing (scRNAseq) as a popular and powerful technique to profile transcriptomics at the cellular level. While most studies focus on deciphering gene expression, polymorphisms including mitochondrial variants can also be readily inferred from scRNAseq. However, limited attention has been paid to investigate the single-cell landscape of mitochondrial variants, despite the rapid accumulation of scRNAseq data in the community. In addition, a diploid context is assumed for most variant calling tools, which is not appropriate for …

Improving Microbiome Research Through Enhanced Reporting And Modeling The Effects Of Antibiotic Usage, Chloe A. Mirzayi

Dissertations and Theses

I consider two key areas in the growing field of human microbiome research: improving the quality of study reporting and the impact of antibiotics on participants in human gut microbiome research studies. In the first chapter, a team of evaluators used the Strengthening the Organization and Reporting of Microbiome Studies (STORMS) checklist to assess recently published microbiome literature. I found moderate agreement and reliability between evaluators, identified several items in STORMS that could be improved, and confirmed that the STORMS checklist can serve as a tool for assessing the reporting quality of published microbiome study. The next chapter considers pre-exposure …

Digital Health Technologies For Peripartum Depression Management Among Low-Socioeconomic Populations: Perspectives From Patients, Providers, And Social Media Channels, Alexandra Zingg, Tavleen Singh, Amy Franklin, Angela Ross, Sudhakar Selvaraj, Jerrie Refuerzo, Sahiti Myneni

Faculty, Staff and Student Publications

BACKGROUND: Peripartum Depression (PPD) affects approximately 10-15% of perinatal women in the U.S., with those of low socioeconomic status (low-SES) more likely to develop symptoms. Multilevel treatment barriers including social stigma and not having appropriate access to mental health resources have played a major role in PPD-related disparities. Emerging advances in digital technologies and analytics provide opportunities to identify and address access barriers, knowledge gaps, and engagement issues. However, most market solutions for PPD prevention and management are produced generically without considering the specialized needs of low-SES populations. In this study, we examine and portray the information and technology needs …

Cxcr2 Expression During Melanoma Tumorigenesis Controls Transcriptional Programs That Facilitate Tumor Growth, J Yang, K Bergdorf, C Yan, W Luo, S C Chen, G D Ayers, Q Liu, X Liu, M Boothby, V L Weiss, S M Groves, A N Oleskie, X Zhang, D Y Maeda, J A Zebala, V Quaranta, A Richmond

Faculty, Staff and Student Publications

Background: Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established.

Methods: To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven BrafV600E/Pten-/-/Cxcr2-/- and NRasQ61R/INK4a-/-/Cxcr2-/- melanoma models. In addition, the effects of a CXCR1/CXCR2 antagonist, SX-682, on melanoma tumorigenesis were evaluated in BrafV600E/Pten-/- and NRasQ61R/INK4a-/- mice and in melanoma cell lines. Potential mechanisms by which Cxcr2 affects melanoma tumorigenesis in these murine models were explored using RNAseq, mMCP-counter, …

Evaluating The Use Of Blood Pressure Polygenic Risk Scores Across Race/Ethnic Background Groups, Nuzulul Kurniansyah, Matthew O Goodman, Alyna T Khan, Jiongming Wang, Elena Feofanova, Joshua C Bis, Kerri L Wiggins, Jennifer E Huffman, Tanika Kelly, Tali Elfassy, Xiuqing Guo, Walter Palmas, Henry J Lin, Shih-Jen Hwang, Yan Gao, Kendra Young, Gregory L Kinney, Jennifer A Smith, Bing Yu, Simin Liu, Sylvia Wassertheil-Smoller, Joann E Manson, Xiaofeng Zhu, Yii-Der Ida Chen, I-Te Lee, C Charles Gu, Donald M Lloyd-Jones, Sebastian Zöllner, Myriam Fornage, Charles Kooperberg, Adolfo Correa, Bruce M Psaty, Donna K Arnett, Carmen R Isasi, Stephen S Rich, Robert C Kaplan, Susan Redline, Braxton D Mitchell, Nora Franceschini, Daniel Levy, Jerome I Rotter, Alanna C Morrison, Tamar Sofer

Faculty, Staff and Student Publications

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs …

Association Of Circulating Markers With Cognitive Decline After Radiation Therapy For Brain Metastasis, Kristin Huntoon, S Keith Anderson, Karla V Ballman, Erin Twohy, Katharine Dooley, Wen Jiang, Yi An, Jing Li, Christina Von Roemeling, Yaqing Qie, Owen A Ross, Jane H Cerhan, Anthony C Whitton, Jeffrey N Greenspoon, Ian F Parney, Jonathan B Ashman, Jean-Paul Bahary, Constantinos Hadjipanayis, James J Urbanic, Elana Farace, Deepak Khuntia, Nadia N Laack, Paul D Brown, David Roberge, Betty Y S Kim

Faculty, Staff and Student Publications

BACKGROUND: A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline.

METHODS: In this retrospective analysis of prospectively collected …

A Guide To The Brain Initiative Cell Census Network Data Ecosystem, Michael Hawrylycz, Maryann E Martone, Giorgio A Ascoli, Jan G Bjaalie, Hong-Wei Dong, Satrajit S Ghosh, Jesse Gillis, Ronna Hertzano, David R Haynor, Patrick R Hof, Yongsoo Kim, Ed Lein, Yufeng Liu, Jeremy A Miller, Partha P Mitra, Eran Mukamel, Lydia Ng, David Osumi-Sutherland, Hanchuan Peng, Patrick L Ray, Raymond Sanchez, Aviv Regev, Alex Ropelewski, Richard H Scheuermann, Shawn Zheng Kai Tan, Carol L Thompson, Timothy Tickle, Hagen Tilgner, Merina Varghese, Brock Wester, Owen White, Hongkui Zeng, Brian Aevermann, David Allemang, Seth Ament, Thomas L Athey, Cody Baker, Katherine S Baker, Pamela M Baker, Anita Bandrowski, Samik Banerjee, Prajal Bishwakarma, Ambrose Carr, Min Chen, Roni Choudhury, Jonah Cool, Heather Creasy, Florence D'Orazi, Kylee Degatano, Benjamin Dichter, Song-Lin Ding, Tim Dolbeare, Joseph R Ecker, Rongxin Fang, Jean-Christophe Fillion-Robin, Timothy P Fliss, James Gee, Tom Gillespie, Nathan Gouwens, Guo-Qiang Zhang, Yaroslav O Halchenko, Nomi L Harris, Brian R Herb, Houri Hintiryan, Gregory Hood, Sam Horvath, Bingxing Huo, Dorota Jarecka, Shengdian Jiang, Farzaneh Khajouei, Elizabeth A Kiernan, Huseyin Kir, Lauren Kruse, Changkyu Lee, Boudewijn Lelieveldt, Yang Li, Hanqing Liu, Lijuan Liu, Anup Markuhar, James Mathews, Kaylee L Mathews, Chris Mezias, Michael I Miller, Tyler Mollenkopf, Shoaib Mufti, Christopher J Mungall, Joshua Orvis, Maja A Puchades, Lei Qu, Joseph P Receveur, Bing Ren, Nathan Sjoquist, Brian Staats, Daniel Tward, Cindy T J Van Velthoven, Quanxin Wang, Fangming Xie, Hua Xu, Zizhen Yao, Zhixi Yun, Yun Renee Zhang, W Jim Zheng, Brian Zingg

Faculty, Staff and Student Publications

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman …

Rapid-Query For Fast Identity By Descent Search And Genealogical Analysis, Yuan Wei, Ardalan Naseri, Degui Zhi, Shaojie Zhang

Faculty, Staff and Student Publications

MOTIVATION: Due to the rapid growth of the genetic database size, genealogical search, a process of inferring familial relatedness by identifying DNA matches, has become a viable approach to help individuals finding missing family members or law enforcement agencies locating suspects. A fast and accurate method is needed to search an out-of-database individual against millions of individuals. Most existing approaches only offer all-versus-all within panel match. Some prototype algorithms offer one-versus-all query from out-of-panel individual, but they do not tolerate errors.

RESULTS: A new method, random projection-based identity-by-descent (IBD) detection (RaPID) query, is introduced to make fast genealogical search possible. …

5s Rrna Pseudogene Transcripts Are Associated With Interferon Production And Inflammatory Responses In Alcohol-Associated Hepatitis, Jianguo Wu, Adam Kim, Xiaoqin Wu, Semanti Ray, Daniela S Allende, Nicole Welch, Annette Bellar, Jaividhya Dasarathy, Srinivasan Dasarathy, Laura E Nagy

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Interferon (IFN) signaling is critical to the pathogenesis of alcohol-associated hepatitis (AH), yet the mechanisms for activation of this system are elusive. We hypothesize that host-derived 5S rRNA pseudogene (RNA5SP) transcripts regulate IFN production and modify immunity in AH.

APPROACH AND RESULTS: Mining of transcriptomic datasets revealed that in patients with severe alcohol-associated hepatitis (sAH), hepatic expression of genes regulated by IFNs was perturbed and gene sets involved in IFN production were enriched. RNA5SP transcripts were also increased and correlated with expression of type I IFNs. Interestingly, inflammatory mediators upregulated in sAH, but not in other liver …

Camonsertib In Dna Damage Response-Deficient Advanced Solid Tumors: Phase 1 Trial Results, Timothy A Yap, Elisa Fontana, Elizabeth K Lee, David R Spigel, Martin Højgaard, Stephanie Lheureux, Niharika B Mettu, Benedito A Carneiro, Louise Carter, Ruth Plummer, Gregory M Cote, Funda Meric-Bernstam, Joseph O'Connell, Joseph D Schonhoft, Marisa Wainszelbaum, Adrian J Fretland, Peter Manley, Yi Xu, Danielle Ulanet, Victoria Rimkunas, Mike Zinda, Maria Koehler, Ian M Silverman, Jorge S Reis-Filho, Ezra Rosen

Faculty, Staff and Student Publications

Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose …

Phase Ii Trial Of Nelipepimut-S Peptide Vaccine In Women With Ductal Carcinoma In Situ, Anne E O'Shea, Guy T Clifton, Na Qiao, Brandy M Heckman-Stoddard, Malgorzata Wojtowicz, Eileen Dimond, Isabelle Bedrosian, Diane Weber, Judy E Garber, Alexander Husband, Ricardo Pastorello, J Jack Lee, Mike Hernandez, Diane D Liu, Lana A Vornik, Powel H Brown, Gheath Alatrash, George E Peoples, Elizabeth A Mittendorf

Faculty, Staff and Student Publications

UNLABELLED: NeuVax is a vaccine comprised of the HER2-derived MHC class I peptide E75 (nelipepimut-S, NPS) combined with GM-CSF. We completed a randomized trial of preoperative vaccination with NeuVax versus GM-CSF alone in patients with ductal carcinoma in situ (DCIS). The primary objective was to evaluate for NPS-specific cytotoxic T lymphocyte (CTL) responses. Patients with human leukocyte antigen (HLA)-A2-positive DCIS were enrolled and randomized 2:1 to NeuVax versus GM-CSF alone and received two inoculations prior to surgery. The number of NPS-specific CTL was measured pre-vaccination, at surgery, and 1 and 3 to 6 months post-operation by dextramer assay. Differences in …

Representing And Utilizing Clinical Textual Data For Real World Studies: An Ohdsi Approach, Vipina K Keloth, Juan M Banda, Michael Gurley, Paul M Heider, Georgina Kennedy, Hongfang Liu, Feifan Liu, Timothy Miller, Karthik Natarajan, Olga V Patterson, Yifan Peng, Kalpana Raja, Ruth M Reeves, Masoud Rouhizadeh, Jianlin Shi, Xiaoyan Wang, Yanshan Wang, Wei-Qi Wei, Andrew E Williams, Rui Zhang, Rimma Belenkaya, Christian Reich, Clair Blacketer, Patrick Ryan, George Hripcsak, Noémie Elhadad, Hua Xu

Faculty, Staff and Student Publications

Clinical documentation in electronic health records contains crucial narratives and details about patients and their care. Natural language processing (NLP) can unlock the information conveyed in clinical notes and reports, and thus plays a critical role in real-world studies. The NLP Working Group at the Observational Health Data Sciences and Informatics (OHDSI) consortium was established to develop methods and tools to promote the use of textual data and NLP in real-world observational studies. In this paper, we describe a framework for representing and utilizing textual data in real-world evidence generation, including representations of information from clinical text in the Observational …

Learning Through Doing: Comprehensive Programming For A Training Program In Cancer Disparities, Kayce D Solari Williams, Kamisha Hamilton Escoto, Crystal Roberson, Kathy Le, Lorraine R Reitzel, Lorna H Mcneill, Shine Chang

Faculty, Staff and Student Publications

In the United States, preparing researchers and practitioners for careers in cancer requires multiple components for success. In this reflection article, we discuss our approach to designing a comprehensive research training program in cancer disparities. We focused on elements that provide students and early career scientists a deep understanding of disparities through first-hand experiences and skills training necessary to build a research career in the area. Our Educational Program sits within the framework of an NCI P20 program, "UHAND (University of Houston/MD Anderson Cancer Center)", jointly established by an NCI-designated comprehensive cancer center and a minority-serving university as a collaborative …

Piloting The Sexual And Gender Minority Cancer Curricular Advances For Research And Education (Sgm Cancer Care) Workshop: Research Training In The Service Of Sgm Cancer Health Equity, Miria Kano, Irene Tamí-Maury, Mandi L Pratt-Chapman, Shine Chang, Mikaela Kosich, Gwendolyn P Quinn, Tonia Poteat, Peter A Kanetsky, Ronit Elk, Ulrike Boehmer, Julian Sanchez, Charles Kamen, Nelson F Sanchez

Faculty, Staff and Student Publications

The purpose of this study is to describe the context, curriculum design, and pilot evaluation of the educational program "Sexual and Gender Minority Cancer Curricular Advances for Research and Education" (SGM Cancer CARE), a workshop for early-career researchers and healthcare providers interested in gaining knowledge and skills in sexual and gender minority (SGM) cancer research and healthcare advocacy. A needs assessment of a sample of clinicians and researchers (n = 104) and feedback from an Advisory Board informed the curriculum design of the SGM Cancer CARE workshop. Four SGM-tailored modules, focusing on epidemiology, clinical research, behavioral science and interventions, and …

Deep Single-Cell Rna-Seq Data Clustering With Graph Prototypical Contrastive Learning, Junseok Lee, Sungwon Kim, Dongmin Hyun, Namkyeong Lee, Yejin Kim, Chanyoung Park

Faculty, Staff and Student Publications

MOTIVATION: Single-cell RNA sequencing enables researchers to study cellular heterogeneity at single-cell level. To this end, identifying cell types of cells with clustering techniques becomes an important task for downstream analysis. However, challenges of scRNA-seq data such as pervasive dropout phenomena hinder obtaining robust clustering outputs. Although existing studies try to alleviate these problems, they fall short of fully leveraging the relationship information and mainly rely on reconstruction-based losses that highly depend on the data quality, which is sometimes noisy.

RESULTS: This work proposes a graph-based prototypical contrastive learning method, named scGPCL. Specifically, scGPCL encodes the cell representations using Graph …

A Highly Selective Humanized Ddr1 Mab Reverses Immune Exclusion By Disrupting Collagen Fiber Alignment In Breast Cancer, Junquan Liu, Huai-Chin Chiang, Wei Xiong, Victor Laurent, Samuel C Griffiths, Jasmin Dülfer, Hui Deng, Xiujie Sun, Y Whitney Yin, Wenliang Li, Laurent P Audoly, Zhiqiang An, Thomas Schürpf, Rong Li, Ningyan Zhang

Faculty, Staff and Student Publications

BACKGROUND: Immune exclusion (IE) where tumors deter the infiltration of immune cells into the tumor microenvironment has emerged as a key mechanism underlying immunotherapy resistance. We recently reported a novel role of discoidin domain-containing receptor 1 (DDR1) in promoting IE in breast cancer and validated its critical role in IE using neutralizing rabbit monoclonal antibodies (mAbs) in multiple mouse tumor models.

METHODS: To develop a DDR1-targeting mAb as a potential cancer therapeutic, we humanized mAb9 with a complementarity-determining region grafting strategy. The humanized antibody named PRTH-101 is currently being tested in a Phase 1 clinical trial. We determined the binding …

Community Perspectives On Ai/Ml And Health Equity: Aim-Ahead Nationwide Stakeholder Listening Sessions, Jamboor K Vishwanatha, Allison Christian, Usha Sambamoorthi, Erika L Thompson, Katie Stinson, Toufeeq Ahmed Syed

Faculty, Staff and Student Publications

Artificial intelligence and machine learning (AI/ML) tools have the potential to improve health equity. However, many historically underrepresented communities have not been engaged in AI/ML training, research, and infrastructure development. Therefore, AIM-AHEAD (Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity) seeks to increase participation and engagement of researchers and communities through mutually beneficial partnerships. The purpose of this paper is to summarize feedback from listening sessions conducted by the AIM-AHEAD Coordinating Center in February 2022, titled the "AIM-AHEAD Community Building Convention (ACBC)." A total of six listening sessions were held over three days. A total of 977 …

Maternal Embryonic Leucine Zipper Kinase Is Associated With Metastasis In Triple-Negative Breast Cancer, Xuemei Xie, Gaurav B Chauhan, Ramakrishna Edupuganti, Takahiro Kogawa, Jihyun Park, Moises Tacam, Alex W Tan, Mohd Mughees, Fnu Vidhu, Diane D Liu, Juliana M Taliaferro, Mary Kathryn Pitner, Luke S Browning, Ju-Hyeon Lee, Yu Shen, Jian Wang, Naoto T Ueno, Savitri Krishnamurthy, Gabriel N Hortobagyi, Debu Tripathy, Steven J Van Laere, Geoffrey Bartholomeusz, Kevin N Dalby, Chandra Bartholomeusz

Faculty, Staff and Student Publications

UNLABELLED: Triple-negative breast cancer (TNBC) has high relapse and metastasis rates and a high proportion of cancer stem-like cells (CSC), which possess self-renewal and tumor initiation capacity. MELK (maternal embryonic leucine zipper kinase), a protein kinase of the Snf1/AMPK kinase family, is known to promote CSC maintenance and malignant transformation. However, the role of MELK in TNBC metastasis is unknown; we sought to address this in the current study. We found that

SIGNIFICANCE: These findings indicate that MELK is a driver of aggressiveness and metastasis in TNBC.

A Novel Integrated Approach To Predicting Cancer Immunotherapy Efficacy, Ruihan Luo, Jacqueline Chyr, Jianguo Wen, Yanfei Wang, Weiling Zhao, Xiaobo Zhou

Faculty, Staff and Student Publications

Immunotherapies have revolutionized cancer treatment modalities; however, predicting clinical response accurately and reliably remains challenging. Neoantigen load is considered as a fundamental genetic determinant of therapeutic response. However, only a few predicted neoantigens are highly immunogenic, with little focus on intratumor heterogeneity (ITH) in the neoantigen landscape and its link with different features in the tumor microenvironment. To address this issue, we comprehensively characterized neoantigens arising from nonsynonymous mutations and gene fusions in lung cancer and melanoma. We developed a composite NEO2IS to characterize interplays between cancer and CD8+ T-cell populations. NEO2IS improved prediction accuracy of patient responses to immune-checkpoint …