Digital Commons Network^™

A Phase 2 Study Of Obinutuzumab Combined With Lenalidomide In Previously Untreated High Tumor Burden Follicular Lymphoma, Neha Akkad, Lei Feng, Jason R Westin, Fredrick B Hagemeister, Hun Ju Lee, Luis Fayad, Sairah Ahmed, Ranjit Nair, Maria Alma Rodriguez, Paolo Strati, Dai Chihara, Christopher R Flowers, Linda Claret, Karina Ibanez, Michael Wang, Nathan H Fowler, Jared Henderson, R Eric Davis, Sattva S Neelapu, Michael Green, Loretta J Nastoupil

Faculty, Staff and Student Publications

Follicular lymphoma (FL) has a clinical course that is often characterized by high response rates to first-line therapy, followed by multiple relapses over a prolonged natural history. Currently, there are multiple possible approaches to frontline therapy for untreated advanced-stage FL, but there is an ongoing debate around what is the preferred approach. Based on the benefits seen with combining lenalidomide, an immunomodulatory agent, with rituximab, an anti-CD20 antibody, we aimed to evaluate the safety and efficacy of lenalidomide in combination with obinuzutumab, an anti-CD20 antibody with enhanced antibody-dependent cellular cytotoxicity. The eligibility criteria included a diagnosis of FL, grade 1 …

Whole Genome Sequence Analysis Of Low-Density Lipoprotein Cholesterol Across 246 K Individuals, Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Eric Van Buren, Sara Haidermota, Darina Postupaka, Whitney Hornsby, Joshua C Bis, Jennifer A Brody, Brian E Cade, Ren-Hua Chung, Joanne E Curran, Scott M Damrauer, Lisa De Las Fuentes, Paul S De Vries, Ravindranath Duggirala, Barry I Freedman, Mariaelisa Graff, Xiuqing Guo, Bertha A Hidalgo, Lifang Hou, Ryan Irvin, Renae Judy, Rita R Kalyani, Tanika N Kelly, Iain R Konigsberg, Brian G Kral, Lydia Coulter Kwee, Daniel Levy, Changwei Li, Ani W Manichaikul, Lisa Warsinger Martin, May E Montasser, Alanna C Morrison, Take Naseri, Kari E North, Jeffrey R O'Connell, Nicholette D Palmer, Patricia A Peyser, Alex P Reiner, Svati H Shah, Roelof A J Smit, Jennifer A Smith, Kent D Taylor, Hemant Tiwari, Michael Y Tsai, Satupa'itea Viali, Zhe Wang, Yuxuan Wang, Wei Zhao, Donna K Arnett, John Blangero, Eric Boerwinkle, Donald W Bowden, Jenna C Carlson, Yii-Der Ida Chen, Patrick T Ellinor, Myriam Fornage, Jiang He, Nancy Heard-Costa, Robert C Kaplan, Sharon L R Kardia, Charles Kooperberg, William E Kraus, Leslie A Lange, Ruth J F Loos, Braxton D Mitchell, Bruce M Psaty, Daniel J Rader, Susan Redline, Stephen S Rich, Lisa R Yanek, Richard Gibbs, Stacey Gabriel, Karine A Viaud-Martinez, Susan K Dutcher, Soren Germer, Ryan Kim, Jerome I Rotter, Xihong Lin, Gina M Peloso, Pradeep Natarajan

The Brown Foundation: Institute of Molecular Medicine

Background: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability.

Results: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics …

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) …

Computationally Resolved Neuroprogenitor Cell Biomarkers Associate With Human Disorders, Gerarda Cappuccio, William T Choi, Fatih Semerci, Jill A Rosenfeld, Toni Claire Tacorda, Guantong Qi, Anthony W Zoghbi, Yi Zhong, Hu Chen, Pengfei Liu, Zhandong Liu, Mirjana Maletić-Savatić

Duncan NRI Faculty and Staff Publications

Adult hippocampal neurogenesis, the process of generating new neurons, relies on a rare population of neural stem and progenitor cells (NPCs) within the dentate gyrus complex microenvironment. Discovering the specific genes that define these cells is vital yet challenging due to overlapping expression patterns, limiting detection of rare cell populations using traditional approaches. By employing the computational digital sorting algorithm (DSA) that deconvolves complex gene expression data based on pattern recognition, we identified 129 genes enriched in murine NPCs. We validated these genes against published single-cell RNA sequencing (scRNA-seq) data and discovered that 25 human orthologs were known to cause …

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 …

Direct Oral Anticoagulant Transition Strategies Using Anti-Xa Concentrations Upon Intensive Care Unit Admission, Mariah I Sigala, Corey V Dinunno, Chelsea N Lopez, Luma Succar, Jenny H Petkova, Edward A Graviss, Duc T Nguyen, Kevin R Donahue

Faculty, Staff and Students Publications

Background: The increased utilization of oral factor Xa inhibitors (FXaI) has led to a growing interest in the clinical utility of FXaI-specific anti-Xa concentrations. Critically ill populations are at risk of bleeding secondary to FXaI accumulation in the setting of end-organ dysfunction. To mitigate this risk, an FXaI anti-Xa concentration-guided approach to transitioning between oral and parenteral anticoagulation has been explored.

Objective: To compare the incidence of bleeding upon intensive care unit (ICU) admission between 2 different FXaI transition strategies: concentration versus non-concentration-guided.

Methods: We performed a retrospective chart review of patients admitted between January 2019 and May 2022 with …

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 …

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 …

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 …

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 …

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.

Drills Or Distress? Understanding The Psychological Effects Of Active Shooter Drills On Adolescents, Jeff R Temple, Elizabeth Baumler, Christian Paige Owen, Leila Wood

Faculty, Staff and Student Publications

Background: We sought to better understand the impact of exposure to active shooter drills (ASDs) on students' perceived stress, including those with disabilities and prior experiences with trauma.

Methods: We used data from a longitudinal study of ethnically diverse students (n = 2,033; 53.5% female) originally recruited in 2018 and followed annually thereafter. In addition to self-reporting on their perceived stress with ASDs, participants responded to questions about adverse childhood experiences, anxiety, suicidal ideation, and disability.

Results: Female students and those with a disability, probable anxiety, and suicidal ideation were more likely to be anxious after an ASD.

Conclusion: While …

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.

Integrative Analysis Of Lung Adenocarcinoma Across Diverse Ethnicities And Exposures, Shankha Satpathy, Natalie M Clark, Yi-Ju Chen, Noshad Hosseini, Ya-Hsuan Chang, Yi Hsiao, Jonathan T Lei, Francesca Petralia, Jin-Shing Chen, Yifat Geffen, David I Heiman, Indranil Paul, Hanbyul Cho, Michelle Hollenberg, Giacomo B Marino, Kuen-Tyng Lin, Rahul Mannan, C Jackson White, Joe Allen, Shayan C Avanessian, M Harry Kane, Ashley Wolfe, Miloni Kinarivala, Wenke Liu, Shankara Anand, Mong-Wei Lin, Moe Haines, Erik J Bergstrom, Grant Hussey, Ginny Xiaohe Li, Deepak C Mani, Hao Fang, Eric J Jaehnig, Hasmik Keshishian, Brecca Miller, Kang-Yi Su, Yi-Jing Hsiao, Hsao-Hsun Hsu, Min-Shu Hsieh, Kuo-Hsuan Hsu, Alexi Monovoukas, Simone Gohsman, John R Thorup, Yamei Deng, Yo Akiyama, Eden Deng, Eric Sheng-Wen Chen, Azra Krek, Rodrigo Espinoza, Weiping Ma, Daniel Charytonowicz, Robert Sebra, Jyun-Hong Lin, Yan-Si Chen, Yin-Chen Hsu, Ze-Shiang Lin, Kun-Chieh Chen, Chang-Wei Yeh, Yu-Tai Wang, Alexander J Lazar, Mehdi Mesri, Eunkyung An, Xu Zhang, Karl R Clauser, David Fenyö, Arul M Chinnaiyan, Bing Zhang, Li Ding, Kelly Ruggles, Chelsea Newton, Hui Zhang, Pei Wang, Galen Hostetter, Gilbert S Omenn, Chandan Kumar-Sinha, Mathangi Thiagarajan, Ramaswamy Govindan, Paul Paik, Abhijit Parolia, Qing K Li, Avi Ma'ayan, Gad A Getz, Saravana M Dhanasekaran, Ana I Robles, Gee-Chen Chang, Pan-Chyr Yang, Sung-Liang Yu, Hsuan-Yu Chen, Alexey I Nesvizhskii, Steven A Carr, D R Mani, Marcin P Cieslik, Yu-Ju Chen, Michael A Gillette, Taiwan Cancer Moonshot Program, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Lung adenocarcinomas (LUAD) are a pressing global health problem with enduring lethality and rapidly shifting epidemiology. Proteogenomic studies integrating proteomics and post-translational modifications with genomics can identify clinical strata and oncogenic mechanisms, but have been underpowered to examine effects of ethnicity, smoking and environmental exposures, or sex on this heterogeneous disease. This comprehensive proteogenomic analysis of LUAD tumors and matched normal adjacent tissues from 406 patients across diverse geographic and demographic backgrounds explores the impact of understudied driver mutations, prognostic role of chromosomal instability, patterns of immune signaling, differential and sex-specific effects of endogenous mutagens and environmental carcinogens, and pathobiology …

Identification Of Cobra And Viper Bites In Southern India Using Enzyme-Linked Immunosorbent Assay, Tejeswara Rao Asuru, Raskin Erusan Rajagopal, Albert Rajendran, Gulistan Parveen, Anushka Das, Pabitha Devi, Swapan K Dasgupta, Shantaraman Kalyanaraman, Prasenjit Guchhait, Perumal Thiagarajan

Faculty, Staff and Students Publications

Introduction: Snakebite-related deaths are major concerns in populations worldwide that lack access to medical care. Current treatment of snakebites includes administration of polyspecific and polyvalent heterologous equine antiserum. Swift diagnosis of the species of snake responsible is essential to initiate a specific treatment.

Methods: We generated murine monoclonal and rabbit polyclonal antibodies against the venom of the 3 most common venomous snakes in southern India: the Russell viper, the saw-scaled viper, and the Indian cobra. We developed an enzyme-linked immunosorbent assay to distinguish the snake by analyzing the exudates from the snakebite wound.

Results: Monoclonal antibody EC3 reacts specifically with …

Co-Occurrence Of Congenital Anomalies And Childhood Brain Tumors In 22 Million Live Births, Thanh T Hoang, Jeremy M Schraw, Charles Shumate, Tania A Desrosiers, Wendy N Nembhard, Mahsa Yazdy, Eirini Nestoridi, Amanda E Janitz, Russell S Kirby, Jason L Salemi, Jean Paul Tanner, Tiffany M Chambers, Michael D Taylor, Chad D Huff, Sharon E Plon, Philip J Lupo, Michael E Scheurer

Faculty, Staff and Students Publications

Background: Children born with a congenital anomaly have a higher risk of developing a brain tumor during childhood or adolescence, but the co-occurrence between specific types of congenital anomalies and specific types of childhood brain tumors (CBTs) is not well described. This study characterized the associations between specific congenital anomalies and CBTs.

Methods: We leveraged a population-based registry linkage study of births (1990-2018), congenital anomalies, and cancer from 9 states (n = 22,599,099 births). Congenital anomalies were classified as major structural without a known chromosomal or genetic syndrome, chromosomal, neurofibromatosis, and/or tuberous sclerosis complex. CBT classification was based on the …

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 …

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. …

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.

Cosine-100 Full Dataset Challenges The Annual Modulation Signal Of Dama/Libra, Nelson Carlin, Jae Young Cho, Jae Jin Choi, Seonho Choi, Anthony C Ezeribe, Luis Eduardo França, Chang Hyon Ha, In Sik Hahn, Sophia J Hollick, Eunju Jeon, Han Wool Joo, Woon Gu Kang, Matthew Kauer, Bongho Kim, Hongjoo Kim, Jinyoung Kim, Kyungwon Kim, Sunghyun Kim, Sun Kee Kim, Won Kyung Kim, Yeongduk Kim, Yong-Hamb Kim, Young Ju Ko, Doohyeok Lee, Eun Kyung Lee, Hyunseok Lee, Hyun Su Lee, Hye Young Lee, In Soo Lee, Jaison Lee, Jooyoung Lee, Moo Hyun Lee, Seo Hyun Lee, Seung Mok Lee, Yujin Lee, Douglas S Leonard, Nguyen Thanh Luan, Vitor Hugo De Almeida Machado, Bruno B Manzato, Reina H Maruyama, Robert J Neal, Stephen L Olsen, Byung Ju Park, Hyang Kyu Park, Hyeonseo Park, Jong-Chul Park, Kangsoon Park, Se Dong Park, Ricardo L C Pitta, Hafizh Prihtiadi, Sejin Ra, Carsten Rott, Keon Ah Shin, David F F S Cavalcante, Min Ki Son, Neil J C Spooner, Lam Tan Truc, Liang Yang, Gyun Ho Yu

Faculty and Staff Publications

For over 25 years, the DAMA/LIBRA collaboration has claimed to observe an annual modulation signal, suggesting the existence of dark matter interactions. However, no experiment using different target materials has observed a dark matter signal consistent with their result. To address this puzzle, the COSINE-100 collaboration conducted a model-independent test using sodium iodide crystal detectors, the same target material as DAMA/LIBRA. Analyzing data collected over 6.4 years by the effective mass of 61.3 kilograms, with improved energy calibration and time-dependent background modeling, we found no evidence of an annual modulation signal, challenging the DAMA/LIBRA result with a confidence level greater …

Modeling The Impact Of Mmr Vaccination Strategies On Measles Outbreaks In Texas, Kaiming Bi, Thuy Nguyen, Boya Peng, Trudy Krause, Cecilia Ganduglia Cazaban, Janelle Rios, Cici Bauer, Catherine Troisi, Eric Boerwinkle, Aanand D Naik

Faculty, Staff and Student Publications

No abstract provided.

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 …

An Evolutionary Preamble Towards A Multilevel Framework To Understand Adolescent Mental Health: An International Delphi Study, Federica Sancassiani, Vanessa Barrui, Fabrizio Bert, Sara Carucci, Fatma Charfi, Giulia Cossu, Arne Holte, Jutta Lindert, Simone Marchini, Alessandra Perra, Samantha Pinna, Antonio Egidio Nardi, Alessandra Scano, Cesar A Soutullo, Massimo Tusconi, Diego Primavera

Faculty, Staff and Student Publications

Background/objectives: Adolescence is a sensitive developmental window shaped by both vulnerabilities and adaptive potential. From an evolutionary standpoint, mental health difficulties in this period may represent functional responses to environmental stressors rather than mere dysfunctions. Despite increasing interest, integrative models capturing the dynamic interplay of risk and protective factors in adolescent mental health remain limited. This study presents a holistic, multi-level framework grounded in ecological and evolutionary theories to improve understanding and intervention strategies.

Methods: A two-round Delphi method was used to develop and validate the framework. Twelve experts in adolescent mental health evaluated a preliminary draft derived from the …

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 …

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 …

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 …