Medical Specialties Commons^™

Fruquintinib In Less Pretreated Patients: Multivariate Profile-Matching Analysis Of Fresco-2 To Fresco, Arvind Dasari, Cathy Eng, Sara Lonardi, Rocio Garcia-Carbonero, Toshiki Masuishi, Chiara Cremolini, François Ghiringhelli, Joleen Hubbard, Tanios Bekaii-Saab, Jeremy Jones, Rui-Hua Xu, Lin Shen, Jianming Xu, Yuxian Bai, Yanhong Deng, Ying Yuan, Wei Wei, Jianchang Lin, Lucy Chen, Zhao Yang, William R Schelman, Shukui Qin, Jin Li

Faculty, Staff and Student Publications

Background: In the phase 3 FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) studies, fruquintinib vs placebo, plus best supportive care, significantly improved overall survival (OS) in patients with metastatic colorectal cancer (mCRC). These studies were conducted in temporally and geographically diverse populations that received distinct prior therapies; FRESCO patients were less pretreated than FRESCO-2 patients. This analysis assessed the efficacy and safety of fruquintinib in a less pretreated global population than the FRESCO-2 intention-to-treat (ITT) population.

Methods: In FRESCO and FRESCO-2, patients were randomized 2:1 to receive oral fruquintinib 5 mg or matched placebo. Profile matching was undertaken …

Fetal Body Composition And Organ Growth In Pregnancies Complicated By First-Trimester Vaginal Bleeding Status: Nichd Fetal 3d Study, Alexandra Jean-Louis, Jessica L Gleason, Zhen Chen, Kathryn A Wagner, Dian He, Roger Newman, William A Grobman, Robert Gore-Langton, Seth Sherman, Magdalena Sanz Cortes, Edward K Chien, Luis F Goncalves, Jagteshwar Grewal, Katherine L Grantz

Faculty, Staff and Students Publications

Objective

This study aimed to explore associations between self-reported first-trimester vaginal bleeding status and fetal body composition and organ volumes measured by three-dimensional (3D) ultrasound across pregnancy.

Study Design

The NICHD Fetal 3D Study (2015–2019) included individuals with singleton pregnancies at low risk for fetal growth abnormalities (n = 2,634). Fetal body composition measures of arm, abdomen, and thigh, and organ volumes including cerebellum, lung, kidney, and liver, were measured up to five times between 15 and 40 weeks using 3D ultrasound. Women were grouped by cumulative days of self-reported first-trimester vaginal bleeding: 0 (no bleeding, reference), 1, or …

Dissecting The Effect Of Mitochondrial Bcat Inhibition In Methylmalonic Acidemia, Madeline G Hemmingsen, Guo-Fang Zhang, Yunhan Ma, Hannah Marchuk, Kalyani R Patel, Tong Chen, Xinning Li, Mark Chapman, Sabrina Collias, Dolores H Lopez-Terrada, James Beasley, Ashlee R Stiles, Randy J Chandler, Charles P Venditti, Sarah P Young, Mercedes Barzi, Beatrice Bissig-Choisat, Doug Krafte, Christopher B Newgard, Karl-Dimiter Bissig

Faculty, Staff and Students Publications

Methylmalonic acidemia (MMA) is a severe metabolic disorder affecting multiple organs because of a distal block in branched-chain amino acid (BCAA) catabolism. Standard of care is limited to protein restriction and supportive care during metabolic decompensation. Severe cases require liver/kidney transplantation, and there is a clear need for better therapy. Here, we investigated the effects of a small molecule branched-chain amino acid transaminase (BCAT) inhibitor in human MMA hepatocytes and an MMA mouse model. Mitochondrial BCAT is the first step in BCAA catabolism, and reduction of flux through an early enzymatic step is successfully used in other amino acid metabolic …

Predicting Weaning Failure From Invasive Mechanical Ventilation: The Promise And Pitfalls Of Clinical Prediction Scores, Maneesh Gaddam, Dedeepya Gullapalli, Zayaan A Adrish, Arnav Y Reddy, Muhammad Adrish

Faculty, Staff and Students Publications

Prediction of weaning success from invasive mechanical ventilation remains a challenge in everyday clinical practice. Several prediction scores have been developed to guide success during spontaneous breathing trials to help with weaning decisions. These scores aim to provide a structured framework to support clinical judgment. However, their effectiveness varies across patient populations, and their predictive accuracy remains inconsistent. In this review, we aim to identify the strengths and limitations of commonly used clinical prediction tools in assessing readiness for ventilator liberation. While scores such as the Rapid Shallow Breathing Index and the Integrative Weaning Index are widely adopted, their sensitivity …

Testis Expressed 50 Is Essential For Maintaining Sperm Acrosome Integrity During Epididymal Transit, Saori Haga, Kaori Nozawa, Ferheen Abbasi, Katarzyna Kent, Naoko Nagasawa, Tsutomu Endo, Haruhiko Miyata, Masahito Ikawa, Martin M Matzuk, Yoshitaka Fujihara

Faculty, Staff and Students Publications

In mammals, sperm formation is completed in the seminiferous tubules within the testis, and sperm maturation occurs during the epididymal transit of the spermatozoa. Sperm morphology drastically changes when abnormal spermatozoa migrate from the testis to the epididymis. Detailed molecular mechanisms for sperm survival in the epididymis have not been determined yet. Globozoospermia is a cause of male infertility and is characterized by round-headed spermatozoa without acrosomes, an abnormal sperm nuclear membrane, and sperm midpiece defects. Testis expressed 50 (Tex50) is a testis-enriched gene that is expressed in mice and humans. Using CRISPR-Cas9, we generated Tex50 knockout (KO) …

Minimum Standards For Training In Colorectal Endoscopic Mucosal Resection Among Advanced Endoscopy Trainees, Dennis Yang, Ernesto Robalino Gonzaga, Muhammad Khalid Hasan, Arvind Julius Trindade, Mark Radlinski, Rebecca A Burbridge, Jeffrey Mosko, Pushpak Taunk, Salmaan Jawaid, Mohamed O Othman, David L Diehl, Harshit S Khara, Quin Liu, Srinivas Gaddam, Harry Aslanian, Shailendra S Chauhan, Amrita Sethi, John Poneros, Jason Samarasena, Ali M Ahmed, Uzma D Siddiqui, Dennis Chen, Moamen Gabr, Andrew Y Wang

Faculty, Staff and Students Publications

Background and study aims: Data on colorectal endoscopic mucosal resection (C-EMR) training during advanced endoscopy fellowship remain limited. We aimed to determine the number of procedures required by an "average" advanced endoscopy trainee (AET) to achieve competence in cognitive and technical C-EMR skills.

Methods: AETs from advanced endoscopy training programs (AETPs) were graded on every C-EMR using a standardized assessment tool. Cumulative sum (CUSUM) analysis was used to generate individual and aggregate learning curves to estimate the minimum number of cases required to achieve competence for overall, technical, and cognitive components of C-EMR. AETs completed a self-assessment questionnaire on C-EMR …

Detection Of Heterogeneous Resistance Mechanisms To Tyrosine Kinase Inhibitors From Cell-Free Dna, Heather A Parsons, Conor Messer, Katheryn Santos, Jakob Weiss, David Merrell, Brian P Danysh, Melissa E Hughes, Gregory J Kirkner, Ashka Patel, Julian Hess, Kerry Sendrick, Chip Stewart, Elizabeth Grant, Kristy Schlueter-Kuck, Albert Grinshpun, Nikhil Wagle, Jamunarani Veeraraghavan, Jose Pablo Leone, Rachel A Freedman, Otto Metzger, Rachel Schiff, Eric P Winer, Sara M Tolaney, Mothaffar Rimawi, Ian E Krop, Gad Getz, Nancy U Lin

Faculty, Staff and Students Publications

Though there has been substantial progress in the development of anti-human epidermal growth factor receptor 2 (HER2) therapies to treat HER2-positive metastatic breast cancer (MBC) within the past two decades, most patients still experience disease progression and cancer-related death. HER2-directed tyrosine kinase inhibitors can be highly effective therapies for patients with HER2-positive MBC; however, an understanding of resistance mechanisms is needed to better inform treatment approaches. We performed whole-exome sequencing on 111 patients with 73 tumor biopsies and 120 cell-free DNA samples to assess mechanisms of resistance. In 11 of 26 patients with acquired resistance, we identified alterations in previously …

Defining Breast Epithelial Cell Types In The Single-Cell Era, G Kenneth Gray, Eric G Carlson, Tatyana Lev, Bailey Marshall, Austin D Reed, Alex P Sánchez-Covarrubias, Alecia-Jane Twigger, Aleix Puig-Barbe, Aatish Thennavan, Ayodele Omotoso, Lyndsay M Murrow, Deeptiman Chatterjee, Siyuan He, Sara Pensa, Brian Aevermann, Norbert K Tavares, Natalie Chen, Jason A Hilton, Kerrigan Blake, Yunlong Liu, Kiet Phong, Zev J Gartner, Devon A Lawson, Alexander Swarbrick, Camila O Dos Santos, Sophia H L George, Joan S Brugge, Mark A Labarge, Harikrishna Nakshatri, Nicholas Navin, Kai Kessenbrock, Walid T Khaled

Faculty, Staff and Student Publications

Single-cell studies on breast tissue have contributed to a change in our understanding of breast epithelial diversity that has, in turn, precipitated a lack of consensus on breast cell types. The confusion surrounding this issue highlights a possible challenge for advancing breast atlas efforts. In this perspective, we present our consensus on the identities, properties, and naming conventions for breast epithelial cell types and propose goals for future atlas endeavors. Our proposals and their underlying thought processes aim to catalyze the adoption of a shared model for this tissue and to serve as guidance for other investigators facing similar challenges.

Author Correction: Functional Mechanisms Underlying Pleiotropic Risk Alleles At The 19p131 Breast-Ovarian Cancer Susceptibility Locus, Kate Lawrenson, Siddhartha Kar, Karen Mccue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan Tyrer, Jonathan Beesley, Susan J Ramus, Qiyuan Li, Melissa K Delgado, Janet M Lee, Kristiina Aittomäki, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K Arun, Brita Arver, Elisa V Bandera, Monica Barile, Rosa B Barkardottir, Daniel Barrowdale, Matthias W Beckmann, Javier Benitez, Andrew Berchuck, Maria Bisogna, Line Bjorge, Carl Blomqvist, William Blot, Natalia Bogdanova, Anders Bojesen, Stig E Bojesen, Manjeet K Bolla, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Fiona Bruinsma, Joan Brunet, Shaik Ahmad Buhari, Barbara Burwinkel, Ralf Butzow, Saundra S Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Rikki Cannioto, Jenny Chang-Claude, Jocelyne Chiquette, Ji-Yeob Choi, Kathleen B M Claes, Linda S Cook, Angela Cox, Daniel W Cramer, Simon S Cross, Cezary Cybulski, Kamila Czene, Mary B Daly, Francesca Damiola, Agnieszka Dansonka-Mieszkowska, Hatef Darabi, Joe Dennis, Peter Devilee, Orland Diez, Jennifer A Doherty, Susan M Domchek, Cecilia M Dorfling, Thilo Dörk, Martine Dumont, Hans Ehrencrona, Bent Ejlertsen, Steve Ellis, Christoph Engel, Eunjung Lee, D Gareth Evans, Peter A Fasching, Lidia Feliubadalo, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lenka Foretova, Florentia Fostira, William D Foulkes, Brooke L Fridley, Eitan Friedman, Debra Frost, Gaetana Gambino, Patricia A Ganz, Judy Garber, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Maya Ghoussaini, Graham G Giles, Rosalind Glasspool, Andrew K Godwin, Mark S Goldberg, David E Goldgar, Anna González-Neira, Ellen L Goode, Marc T Goodman, Mark H Greene, Jacek Gronwald, Pascal Guénel, Christopher A Haiman, Per Hall, Emily Hallberg, Ute Hamann, Thomas V O Hansen, Patricia A Harrington, Mikael Hartman, Norhashimah Hassan, Sue Healey, Florian Heitz, Josef Herzog, Estrid Høgdall, Claus K Høgdall, Frans B L Hogervorst, Antoinette Hollestelle, John L Hopper, Peter J Hulick, Tomasz Huzarski, Evgeny N Imyanitov, Kconfab Investigators, Australian Ovarian Cancer Study Group, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Allan Jensen, Esther M John, Nichola Johnson, Maria Kabisch, Daehee Kang, Miroslav Kapuscinski, Beth Y Karlan, Sofia Khan, Lambertus A Kiemeney, Susanne Kruger Kjaer, Julia A Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Jolanta Kupryjanczyk, Ava Kwong, Miguel De La Hoya, Yael Laitman, Diether Lambrechts, Nhu Le, Kim De Leeneer, Jenny Lester, Douglas A Levine, Jingmei Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jennifer T Loud, Karen Lu, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Loic Le Marchand, Sara Margolin, Frederik Marme, Leon F A G Massuger, Keitaro Matsuo, Sylvie Mazoyer, Lesley Mcguffog, Catriona Mclean, Iain Mcneish, Alfons Meindl, Usha Menon, Arjen R Mensenkamp, Roger L Milne, Marco Montagna, Kirsten B Moysich, Kenneth Muir, Anna Marie Mulligan, Katherine L Nathanson, Roberta B Ness, Susan L Neuhausen, Heli Nevanlinna, Silje Nord, Robert L Nussbaum, Kunle Odunsi, Kenneth Offit, Edith Olah, Olufunmilayo I Olopade, Janet E Olson, Curtis Olswold, David O'Malley, Irene Orlow, Nick Orr, Ana Osorio, Sue Kyung Park, Celeste L Pearce, Tanja Pejovic, Paolo Peterlongo, Georg Pfeiler, Catherine M Phelan, Elizabeth M Poole, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Valerie Rhenius, Kerstin Rhiem, Harvey A Risch, Gus Rodriguez, Mary Anne Rossing, Anja Rudolph, Helga B Salvesen, Suleeporn Sangrajrang, Elinor J Sawyer, Joellen M Schildkraut, Marjanka K Schmidt, Rita K Schmutzler, Thomas A Sellers, Caroline Seynaeve, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Weiva Sieh, Christian F Singer, Olga M Sinilnikova, Susan Slager, Honglin Song, Penny Soucy, Melissa C Southey, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony Swerdlow, Sandrine Tchatchou, Manuel R Teixeira, Soo H Teo, Kathryn L Terry, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Amanda Ewart Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Chiu-Chen Tseng, Nadine Tung, Shelley S Tworoger, Celine Vachon, Ans M W Van Den Ouweland, Helena C Van Doorn, Elizabeth J Van Rensburg, Laura J Van't Veer, Adriaan Vanderstichele, Ignace Vergote, Joseph Vijai, Qin Wang, Shan Wang-Gohrke, Jeffrey N Weitzel, Nicolas Wentzensen, Alice S Whittemore, Hans Wildiers, Robert Winqvist, Anna H Wu, Drakoulis Yannoukakos, Sook-Yee Yoon, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Kum Kum Khanna, Jacques Simard, Alvaro N Monteiro, Juliet D French, Fergus J Couch, Matthew L Freedman, Douglas F Easton, Alison M Dunning, Paul D Pharoah, Stacey L Edwards, Georgia Chenevix-Trench, Antonis C Antoniou, Simon A Gayther

Faculty, Staff and Student Publications

No abstract provided.

Gene Context Drift Identifies Drug Targets To Mitigate Cancer Treatment Resistance, Amir Jassim, Birgit V Nimmervoll, Sabrina Terranova, Erica Nathan, Linda Hu, Jessica T Taylor, Katherine E Masih, Lisa Ruff, Matilde Duarte, Elizabeth Cooper, Gunjan Katyal, Melika Akhbari, Reuben J Gilbertson, Jennifer C Coleman, Joseph S Toker, Colton Terhune, Gabriel Balmus, Stephen P Jackson, Hailong Liu, Tao Jiang, Michael D Taylor, Kui Hua, Jean E Abraham, Mariella G Filbin, Anthony Hill, Anarita Patrizi, Neil Dani, Aviv Regev, Maria K Lehtinen, Richard J Gilbertson

Faculty, Staff and Students Publications

Cancer treatment often fails because combinations of different therapies evoke complex resistance mechanisms that are hard to predict. We introduce REsistance through COntext DRift (RECODR): a computational pipeline that combines co-expression graph networks of single-cell RNA sequencing profiles with a graph-embedding approach to measure changes in gene co-expression context during cancer treatment. RECODR is based on the idea that gene co-expression context, rather than expression level alone, reveals important information about treatment resistance. Analysis of tumors treated in preclinical and clinical trials using RECODR unmasked resistance mechanisms -invisible to existing computational approaches- enabling the design of highly effective combination treatments …

Reasons For Maintaining The Classification Of Esmethadone As An Investigational Uncompetitive Nmdar Antagonist Rapid Antidepressant: Reply To Ferré And Michaelides, Sara De Martin, Stefano Comai, Andrea Mattarei, Thomas R Kosten, Frank J Vocci, Charles W Gorodetzky, Marco Pappagallo, Paolo L Manfredi

Faculty, Staff and Students Publications

No abstract provided.

Results Of Tor001: An Open-Label Single Patient Study Using Targeted Bacteriophage Therapy For The Treatment Of A Chronic Urinary Tract Infection, Jonathan D Cook, Payton B Hooey, Keiko C Salazar, Justin R Clark, Umesh Jain, Carlos Fernando, Hanjeong Harvey, Alexander Cervantes, Stephanie Omagari, Udi Blankstein, Andrew M Kropinski, Alan R Davidson, Karen L Maxwell, Lori L Burrows, Austen L Terwilliger, Anthony W Maresso, Greg J German

Faculty, Staff and Students Publications

Chronic urinary tract infections are persistent bacterial infections with the potential to drive antibiotic resistance. Like other persistent bacterial infections, intracellular bacterial reservoirs and biofilm formation hinder the clearance of pathogens despite long courses of antibiotic therapy. New strategies for treatment of these persistent infections are needed. Here we describe the results of an open-label individual patient study using bacteriophage therapy to treat a chronic urinary tract infection in an immunocompetent 72-year-old woman without underlying urolithiasis or indwelling devices. We co-administered HP3.1, HP3, and ES19 bacteriophages with demonstrated in vitro activity via bladder instillation, orally, and as a topical formulation. …

Regulation Of Food Intake By Connexin43 Via Adipocyte-Sensory Neuron Electrical Synapses, Xi Chen, Xing Fang, Hong Zhou, Jieyi Meng, Yang He, Leon G Straub, Andrew Lemoff, Clair Crewe, Shangang Zhao, Yong Xu, Yi Zhu

Duncan NRI Faculty and Staff Publications

Background and objective: Connexin43 (Cx43), encoded by Gja1, forms gap junctions between adjacent cells. In adipose tissue, it is upregulated during adipose beiging while downregulated by high-fat-diet (HFD) feeding. Adipocyte-specific Gja1 overexpression enhances adipose tissue beiging in response to mild cold stress of room temperature. Moreover, those mice display a surprising decrease in food intake, but the mechanism remains unclear. This study investigates how adipocyte Cx43 influences feeding behavior.

Methods: Mice with adipose tissue-specific Gja1 overexpression (Adipoq-Cx43) were fed with HFD. Food intake, weight gain, substrate utilization, and serum lipolysis were assessed. RNA-seq, proteomics, and cytokine measurements were employed to …

Association Between Body Mass Index And Uterotonic Use In Postpartum Hemorrhage: A Retrospective Cohort Study, Cece Cheng, Bryce T Munter, Michaela Y Lee, Claire D Sundjaja, Natasha D Paul, Margaret M Klausmeyer, Nastassia A Yammine, Patrick S Ramsey, John J Byrne

Faculty, Staff and Student Publications

Background/Objectives: Our primary objective was to determine whether patients with a higher body mass index (BMI) who experienced postpartum hemorrhage (PPH) required ≥2 uterotonics more often than those with lower BMI.

Methods: We conducted a retrospective cohort study that included all patients who experienced a PPH between 1 August 2020 and 31 July 2022. Extracted data included patient demographics, PPH risk factors, details regarding the labor course and hemorrhage management, and maternal and neonatal outcomes, such as mode of delivery, etiology of hemorrhage, need for nonpharmacological management, neonatal Apgar scores, requirement for phototherapy, neonatal intensive care unit (NICU) admission, and …

Identifying Bio-Behavioural Signatures Of Persistent Opioid Use Risk In Trauma Injury Patients: A Protocol For A Prospective Cohort Study, Joy M Schmitz, Jin Ho Yoon, Bruno Kluwe-Schiavon, John A Harvin, Preethi H Gunaratne, Darrion Mouton, Kandice Motley, Erin E Fox, Jessica Vincent, Megan Tarbet, Consuelo Walss-Bass

Faculty, Staff and Student Publications

Introduction: Exposure to prescription opioids following traumatic injury can increase the risk of developing tolerance, persistent opioid use and opioid use disorder. The mechanisms underlying opioid tolerance or dependence are not well understood, and no biomarkers predict risk. Opioid exposure causes epigenetic modifications, including alterations in microRNA (miRNA) expression. Several miRNAs, which regulate synaptic plasticity, are hypothesised to underlie substance use disorders and influence µ-opioid receptor levels, modulating opioid tolerance. This project aims to develop a bio-behavioural signature to predict persistent opioid use and chronic pain up to 6 months post-discharge.

Methods and analysis: The study will use a prospective …

Establishing Best Practices Guidelines For Collaborative Research In Global Surgery: Developing A Delphi Survey, Ramitha Eshan Ruwanpathirana, Swati Deshpande, Sophia Abdulhai, Mathilde Djeneba Billau, Sumeja Catic, Theresa L Chin, Julia N Harrison, Pratyush Kumar, Maria Cecilia T Leyson, Helen W Li, Katayoun S Madani, Arthur Serumaga, Margaret Tarpley, Grayson Wright, Nia N Zalamea, Joshua S Ng-Kamstra

Faculty, Staff and Students Publications

Background: Collaborative research in global surgery has resulted in the rapid development of the field via knowledge creation and dissemination, research capacity building, and direct improvements in the delivery of clinical care. Yet the establishment and maintenance of trans-boundary collaborations carries significant risk to health systems, clinicians, patients, and researchers, particularly if such collaborations are not developed thoughtfully and with appropriate guardrails. In recent years, there has been significant growth in the literature on the pervasiveness and impact of neocolonialism on global health research.

Methods: To harness the benefits of global surgery research collaboration while mitigating these risks, we reviewed …

Upper Gastrointestinal Symptoms And Gulf War Illness In A Clinical Cohort Of Us Veterans: A Retrospective, Cross-Sectional Study, Abdelrahman Yousef, Sarah T Ahmed, Theresa H Nguyen Wenker, Alice B S Nono-Djotsa, Stephen H Boyle, Elizabeth J Gifford, Deeksha Malhotra, Helena Chandler, Sandhya Bandi, Drew A Helmer

Faculty, Staff and Students Publications

Objective: Approximately 30% of the 700 000 US Gulf War Veterans (GWVs) report symptoms collectively termed Gulf War Illness (GWI), a multisymptom illness of uncertain pathophysiology. Prior studies in GWI focus on overlap with irritable bowel syndrome. This study examines the associations between upper gastrointestinal (UGI) symptoms, GWI and specialty GI care.

Methods: This cross-sectional study analysed GWVs referred to a Veterans Health Administration clinical War-Related Illness and Injury Study Center (2008-2020). Symptoms, demographics, military service and clinical history were obtained from self-reported intake packets. GWI was defined by the Centers for Disease Control and Prevention criteria requiring moderate-to-severe symptoms …

Implementing A Training Resource For Large-Scale Genomic Data Analysis In The All Of Us Researcher Workbench, Jasmine Baker, Erik Stricker, Julie Coleman, Shamika Ketkar, Taotao Tan, Ashley M Butler, Laterrica Williams, Latanya Hammonds-Odie, Debra Murray, Brendan Lee, Kim C Worley, Elizabeth G Atkinson

Duncan NRI Faculty and Staff Publications

A lack of representation in genomic research and limited access to computational training create barriers for many researchers seeking to analyze large-scale genetic datasets. The All of Us Research Program provides an unprecedented opportunity to address these gaps by offering genomic data from a broad range of participants, but its impact depends on equipping researchers with the necessary skills to use it effectively. The All of Us Biomedical Researcher (BR) Scholars Program at Baylor College of Medicine aims to break down these barriers by providing early-career researchers with hands-on training in computational genomics through the All of Us Evenings with …

Lewy Body Dementia Promotion By Air Pollutants, Xiaodi Zhang, Haiqing Liu, Xiao Wu, Longgang Jia, Kundlik Gadhave, Lena Wang, Kevin Zhang, Hanyu Li, Rong Chen, Ramhari Kumbhar, Ning Wang, Chantelle E Terrillion, Bong Gu Kang, Bin Bai, Minhan Park, Ma Cristine Faye Denna, Shu Zhang, Wenqiang Zheng, Denghui Ye, Xiaoli Rong, Liu Yang, Lili Niu, Han Seok Ko, Weiyi Peng, Lingtao Jin, Mingyao Ying, Liana S Rosenthal, David W Nauen, Alex Pantelyat, Mahima Kaur, Kezia Irene, Liuhua Shi, Rahel Feleke, Sonia García-Ruiz, Mina Ryten, Valina L Dawson, Francesca Dominici, Rodney J Weber, Xuan Zhang, Pengfei Liu, Ted M Dawson, Shizhong Han, Xiaobo Mao

Faculty, Staff and Student Publications

Evidence links air pollution to dementia, yet its role in Lewy body dementia (LBD) remains unclear. Here we showed in a cohort of 56.5 million individuals across the U.S. that PM2.5 exposure raises LBD risk. Mechanistically, we found PM2.5 exposure led to brain atrophy in wild-type mice, an effect not seen in α-synuclein (αSyn)-deficient mice. PM2.5 exposure generated a highly pathogenic αSyn strain, PM-PFF, with enhanced proteinase K-resistance and neurotoxicity, resembling αSyn LBD strains. PM2.5 samples from China, the U.S., and Europe consistently induced proteinase-resistant αSyn strains and in vivo pathology. Transcriptomic analyses revealed shared responses between PM2.5-exposed mice and …

Dissecting Microbial Communities With Single-Cell Transcriptome Analysis, Andrew W Pountain, Itai Yanai

Faculty, Staff and Student Publications

Revealing insights into the function of microbial communities requires moving beyond measuring bulk taxonomic composition to detecting interactions between subpopulations. Following the transformative impact of single-cell gene expression profiling techniques on numerous fields of human biology, recent years have seen increased application to microbes. We review progress in the development of these techniques and discuss challenges in applying them to microbial communities. We highlight applications for dissecting the microbiome in human health and disease that reveal functional heterogeneity within gut communities, antibiotic responses, and the dynamics of mobile genetic elements. As single-cell gene expression technologies continue to develop, they are …

Human Papillomavirus Integration Induces Oncogenic Host Gene Fusions In Oropharyngeal Cancers, Nusrat Khan, Keiko Akagi, Shiming Jiang, Joe Dan Dunn, Bo Jiang, Weihong Xiao, Madison P O'Hara, Li Shen, Qi Wang, Vakul Mohanty, Jing Wang, Sara Goodwin, Jamie L Hutchins, Kevin R Coombes, Jagannadha K Sastry, David E Symer, Maura L Gillison

Faculty, Staff and Student Publications

HPV integration disrupts host genomic structure and expression, but whether these alterations promote cancer development remains unclear. Multiple genomic analyses of oropharyngeal cancers identified several host fusion genes, including recurrent FGFR3-TACC3 fusions, expressed from rearranged genomic loci adjacent to HPV integration sites. Evolutionary modeling implicated integration of virus concatemers into the host genome as a common initiating event in fusion formation. Co-expression of HPV16 E6/E7 and FGFR3-TACC3, but neither alone, was sufficient for tumor development in both xenograft and syngeneic mouse models and led to unique transcriptional programs implicated in carcinogenesis. FGFR3-TACC3 expression decreased the ubiquitination and degradation of …

Detection Of Cancers Three Years Prior To Diagnosis Using Plasma Cell-Free Dna, Yuxuan Wang, Corinne E Joshu, Samuel D Curtis, Christopher Douville, Vernon A Burk, Meng Ru, Maria Popoli, Janine Ptak, Lisa Dobbyn, Natalie Silliman, Josef Coresh, Eric Boerwinkle, Anna Prizment, Chetan Bettegowda, Kenneth W Kinzler, Nickolas Papadopoulos, Elizabeth A Platz, Bert Vogelstein

Faculty, Staff and Student Publications

To explore how early can cancers be detected prior to clinical signs or symptoms, we assessed prospectively collected serial plasma samples from the Atherosclerosis Risk in Communities (ARIC) study, including 26 participants diagnosed with cancer and 26 matched controls. At the index time point, eight of these 52 participants scored positively with a multicancer early detection (MCED) test. All eight participants were diagnosed with cancer within 4 months after blood collection. In six of these 8 participants, we were able to assess an earlier plasma sample collected 3.1 to 3.5 years prior to clinical diagnosis. In four of these six …

The Causal Pivot: A Structural Approach To Genetic Heterogeneity And Variant Discovery In Complex Diseases, Chad A Shaw, C J Williams, Taotao Tan, Daniel Illera, Nicholas Di, Joshua M Shulman, John W Belmont

Center on Aging Staff Publications

We present the Causal Pivot (CP) as a structural causal model (SCM) for analyzing genetic heterogeneity in complex diseases. The CP leverages an established causal factor or factors to detect the contribution of additional suspected causes. Specifically, polygenic risk scores (PRSs) serve as known causes, while rare variants (RVs) or RV ensembles are evaluated as candidate causes. The CP incorporates outcome-induced association by conditioning on disease status. We derive a conditional maximum-likelihood procedure for binary and quantitative traits and develop the Causal Pivot likelihood ratio test (CP-LRT) to detect causal signals. Through simulations, we demonstrate the CP-LRT’s robust power and …

Investigating Bacterial Vaginosis Pathogenesis Using Peptide Nucleic Acid-Fluorescence In Situ Hybridization With A Focus On The Roles Of Gardnerella Species, Prevotella Bivia, And Fannyhessea Vaginae, Sheridan D. George, Megan H. Amerson-Brown, Lúcia G.V. Sousa, Tyler M. Carter, Alexa H. Rinehart, Ashleigh N. Riegler, Sixto M. Leal, Kristal J. Aaron, Jiaying Hao, Ashutosh Tamhane, Chaoling Dong, John W. Lammons, Jacob H. Elnaggar, Keonte J. Graves, Paweł Łaniewski, Melissa M. Herbst-Kralovetz, Christopher M. Taylor, Nuno Cerca, Christina A. Muzny

School of Graduate Studies Faculty Publications

Background. Bacterial vaginosis (BV) is a vaginal dysbiosis characterized by polymicrobial communities of BV-associated bacteria (BVAB) adhered to the vaginal epithelium. Despite decades of research, its etiology remains unknown. We aimed to investigate BV biofilm formation over time among women who developed incident BV (iBV) using peptide nucleic acid-fluorescence in situ hybridization (PNA-FISH), focusing on 3 key BVAB (Gardnerella species, Prevotella bivia, and Fannyhessea vaginae). Methods. Heterosexual, nonpregnant women ages 18–45 with optimal vaginal microbiota were enrolled to self-collect twice-daily vaginal specimens for 60 days. iBV was defined as a Nugent score of 7–10 on ≥ 4 consecutive specimens. For …

An Allele-Agnostic Mutant-Kras Inhibitor Suppresses Tumor Maintenance Signals And Reprograms Tumor Immunity In Pancreatic Cancer, Kathleen M Mcandrews, Francesca Paradiso, Clint A Stalnecker, Benson S Chellakkan, Fredrik I Thege, David H Peng, Barbara A Moreno Diaz, Hikaru Sugimoto, Sarah I Patel, Krishnan K Mahadevan, Michelle L Kirtley, Danielle Wills, Amari M Sockwell, Andre Luis F Fonseca, Yunhe Liu, Kimal I Rajapakshe, Nathaniel G Yee, Phuong Thao Tran, Huda Alchikh Omar, Antonio Tedeschi, Fiorella Schischlik-Siegl, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Dorothea Rudolph, Martin Aichinger, Florian Ebner, Artem V Artemov, Jesse Lipp, Laura Pisarsky, Valerie Laura Herrmann, John Park, Jörg F Rippmann, Otmar Schaaf, Vanessa Chandler, Mariah Williams, Charles E Deckard, Linghua Wang, Channing J Der, Christopher Vellano, Paola A Guerrero, Timothy P Heffernan, Raghu Kalluri, Anirban Maitra

Faculty, Staff and Student Publications

KRAS is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluate the pre-clinical efficacy of BI-2493 a panKRASi, a first-in-class allele agnostic mutant KRAS inhibitor, in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), syngeneic orthotopic models, and prolonged survival in genetically engineered mouse …

An Isoform-Specific Runx1c-Btg2 Axis Governs Aml Quiescence And Chemoresistance, Cuijuan Han, Zhiping Zhang, Edie I Crosse, Sogand Sajedi, Bin Lu, Xiyue Wang, Sadik Karma, Mitch Kostich, Sakthi Harini Rajendran, Dylan B Udy, Steven Chen, Alexander Arnuk, Abimbola Eunice Lawal, Kayla R Koenig, Meryl Mckenna, Patrick K Reville, Hussein A Abbas, Omar Abdel-Wahab, Pedro Miura, Robert K Bradley, Eric Wang

Faculty, Staff and Student Publications

Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet their role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in patients with AML before therapy and at relapse after chemotherapy and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long-isoform RUNX1C through its alternative distal promoter. The unique N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. …

Amoxicillin Vs Ceftriaxone To Treat Pneumonia Caused By Amoxicillin-Non-Susceptible Streptococcus Pneumoniae, Daniel M Musher

Faculty, Staff and Students Publications

Although the article by J Càmara, I Grau, A González-Díaz, N Santos, et al. (Antimicrob Agents Chemother 69:e00237-25, 2025, https://doi.org/10.1128/aac.00237-25) suggests that ceftriaxone is greatly superior to amoxicillin in treating pneumonia due to pneumococci with an MIC > 2 mg/L, much of the difference in efficacy of the two drugs may have been due to dosage, route, and times of administration of the amoxicillin.

Nebulization Of An Mrna-Encoded Monoclonal Antibody For Passive Immunization Of Foals Against Rhodococcus Equi, Rebecca M Legere, Jeannine A Ott, Cristina Poveda, Daryll Vanover, Karin E R Borba, Jae Yeon Joo, Cameron L Martin, Bibiana P Da Silveira, Jocelyne M Bray, Kerstin Landrock, Gus A Wright, J Chistensen Blazier, Andrew E Hillhouse, Ashley L Benham-Duret, Brandon Mistretta, Rafaela L Klein, Sarah M Thompson, Amelia R Woolums, Michael F Criscitiello, Luc R Berghman, Angela I Bordin, Philip J Santangelo, Jeroen Pollet, Noah D Cohen

Faculty, Staff and Students Publications

Inhalation of Rhodococcus equi causes severe pneumonia in humans and animals worldwide, most commonly affecting horse foals. The standard for preventing R. equi pneumonia in foals is transfusion of hyperimmune plasma, which is expensive and carries the risk of adverse effects. Our goal was to passively immunize foals against R. equi by nebulizing mRNA encoding an equine monoclonal antibody (mAb) against the virulence-associated protein A (VapA) directly into the lungs. VapA-specific memory B cells from an immunized horse were used to identify and select the sequence for an equine immunoglobulin (Ig)G1 mAb. In vitro-transcribed mRNA encoding this sequence expressed …

Subtype-Specific Her3 Enrichment In Basal-Like Breast Cancer Is Regulated Via The Gata2/Gata3–Foxa1 Axis, Congcong Tan, Hui Lyu, Sanbao Ruan, Yakun Wu, Margaret E. Larsen, Shou Ching Tang, Bolin Liu

School of Medicine Faculty Publications

Basal-like breast cancer (BLBC) is a major subtype of triple-negative breast cancer (TNBC), characterized by aggressive behavior, limited treatment options, and poor prognosis. While HER3 overexpression is frequently observed in TNBC and associated with poor outcomes, its subtype-specific expression and therapeutic potential remain unclear. Here, we demonstrated that HER3 signaling is selectively hyperactivated in BLBC compared to claudin-low breast cancer (CLBC) using transcriptomic profiling. Histone deacetylase inhibitors (HDACi), Romidepsin and Panobinostat, exerted potent antitumor effects on BLBC by selectively downregulating HER3 expression. HER3 levels were positively correlated with FOXA1, a key transcriptional activator. Mechanistically, we identified GATA2 and GATA3 as …

Targeting Aldh16a1 Mediated Thioredoxin Lysosomal Degradation To Enhance Ferroptosis Susceptibility In Smarca4-Deficient Nsclc, Guoshu Bi, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Shencheng Ren, Haochun Shi, Xiaolong Huang, Junkan Zhu, Qun Wang, Wei Jiang, Boyi Gan, Cheng Zhan

Faculty, Staff and Student Publications

Ferroptosis, an iron-dependent form of cell death, holds promise for cancer therapy. However, the intricate link between ferroptosis and oncogenic mutations remains unclear. Here we show that SMARCA4, a well-established tumour suppressor whose deficiency is associated with poor prognosis and resistance to treatments, sensitizes non-small cell lung cancer (NSCLC) cells to ferroptosis. Mechanistically, SMARCA4 promotes chromatin accessibility and expression of ALDH16A1. Surprisingly, ALDH16A1 lacks ALDH enzymatic activity, but binds to the anti-ferroptotic oxidoreductase thioredoxin (TXN), facilitating its translocation to the lysosome and subsequent degradation. Meanwhile, ALDH16A1 directly inhibits TXN's oxidoreductase function by occluding its active site. We also show that …