Digital Commons Network^™

A Novel Vision Transformer Model Produces Clock Drawing Test Scores As Accurate As Expert Human Coders, Mengyao Hu, Tian Qin, Richard Gonzalez, Vicki A Freedman, Laura B Zahodne, Edmundo R Melipillán, Yi Lu Murphey

Faculty, Staff and Student Publications

Alzheimer's disease and related dementias is a growing public health concern. The clock-drawing test, where subjects draw a clock, typically with hands showing 11:10, has been widely used for dementia screening. A limitation of including the clock-drawing test in large-scale studies is that it requires manual coding, which could result in biases if coders interpret and implement coding rules differently. This study created and evaluated an intelligent Clock Scoring system built with deep learning neural networks to automatically code clock-drawing images. We used a large, publicly available repository of clock-drawing images from the 2011-2019 National Health and Aging Trends Study …

Genome-Wide Gene By Sleepiness Interaction Analysis For Sleep Apnea, Pavithra Nagarajan, Nuzulul Kurniansyah, Jiwon Lee, Sina A Gharib, Yushan Xu, Yiyan Zhang, Brian Spitzer, Tariq Faquih, Hufeng Zhou, Eric Boerwinkle, Han Chen, Daniel J Gottlieb, Xiuqing Guo, Nancy L Heard-Costa, Bertha A Hidalgo, Daniel Levy, Peter Y Liu, Hao Mei, Rebecca Montalvan, Sutapa Mukherjee, Kari E North, George T O'Connor, Lyle J Palmer, Sanjay R Patel, Bruce M Psaty, Shaun M Purcell, Laura M Raffield, Stephen S Rich, Jerome I Rotter, Richa Saxena, Albert V Smith, Katie L Stone, Xiaofeng Zhu, Topmed Sleep Trait Working Group, Brian E Cade, Tamar Sofer, Susan Redline, Heming Wang

Faculty, Staff and Student Publications

Study objectives: Excessive daytime sleepiness (EDS), influenced by environmental and social-behavioral factors, is reported by a subset of patients with sleep apnea-a group that may be at elevated cardiovascular risk. However, it is unclear whether sleep apnea with and without EDS have distinct genetic underpinnings. In this study, we perform gene-by-EDS interaction analyses for apnea hypopnea index, a diagnostic marker of sleep apnea severity, to understand EDS's influence on its underlying genetic risk.

Methods: Discovery interaction analyses for common variants and gene-based rare variants were conducted respectively using multi-ethnic Trans-Omics for Precision Medicine (N = 11 619) data, followed by …

Mini-Hyper-Cvd Plus Venetoclax And Navitoclax For Relapsed/Refractory Acute Lymphoblastic Leukemia, Nicholas J Short, Hagop Kantarjian, Nitin Jain, Tapan M Kadia, Jayastu Senapati, Fadi G Haddad, Manuel M Maroun, Koji Sasaki, Lianchun Xiao, Xuelin Huang, Omer Karrar, Regina Abramova, Min Zhao, Rebecca Garris, Marina Konopleva, Farhad Ravandi, Elias Jabbour

Faculty, Staff and Student Publications

No abstract provided.

Therapeutic Responses In Patients With Advanced Nsclc Enrolled In Early-Phase Clinical Trials At Md Anderson, Jeong Uk Lim, Heather Y Lin, Lei Kang, Hung Le, Tin-Yun Tang, Stephane Champiat, Ecaterina Elena Dumbrava, Xiuning Le, Aung Naing, Sarina A Piha-Paul, Jordi Rodon Ahnert, Apostolia Maria Tsimberidou, Timothy A Yap, Siqing Fu, Funda Meric-Bernstam, David S Hong

Faculty, Staff and Student Publications

We evaluated clinical outcomes and safety profiles in patients with non-small cell lung cancer (NSCLC) treated in early-phase trials. A retrospective review of 546 NSCLC cases treated from January 2016 to December 2024 at The University of Texas MD Anderson Cancer Center was performed using the MD Anderson CHIMERA database. Patients were categorized into seven groups based on treatment regimen. The overall objective response rate (ORR) was 19.9%, and the highest ORRs were in the targeted combination (30.8%) and targeted monotherapy (29.7%) groups. Gene alteration–matched therapy, serum albumin level, metastatic burden, treatment group, and liver metastasis were independently associated with …

Efficacy And Safety Of Oral Pcsk9 Inhibitor Enlicitide In Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial, Christie M Ballantyne, Laura Gellis, Jean-Claude Tardif, Puja Banka, Ann Marie Navar, Emil Andreas Asprusten, Russell Scott, Erik S G Stroes, Samar Froman, Geraldine Mendizabal, Fan Wang, Alberico L Catapano

Faculty, Staff and Students Publications

Importance: Persons with heterozygous familial hypercholesterolemia (HeFH) are at increased risk of atherosclerotic cardiovascular disease due to lifelong elevated levels of low-density lipoprotein cholesterol (LDL-C). Many patients with HeFH do not achieve guideline-recommended LDL-C goals with the currently available lipid-lowering therapies.

Objective: To evaluate the efficacy of enlicitide decanoate (an oral proprotein convertase subtilisin/kexin type 9 inhibitor) vs placebo in adults with HeFH requiring further lowering of LDL-C levels despite use of statin therapy.

Design, setting, and participants: This phase 3, randomized clinical trial included persons aged 18 years or older with HeFH currently using lipid-lowering therapy (taking at least …

Tumor-Specific Immune Responses And Biomarkers In Pediatric Patients With High-Risk Hodgkin Lymphoma, Keri Toner, Lindsay A Renfro, Hema Dave, Gloria Pezzella, Qinglin Pei, Lisa Giulino-Roth, Terzah Horton, Frank G Keller, Kara M Kelly, Sharon M Castellino, Catherine M Bollard

Faculty, Staff and Students Publications

There is an unmet need to examine antitumor immune responses and predictive biomarkers in the peripheral blood to guide effective combination immunotherapies in classical Hodgkin lymphoma (cHL). We sought to evaluate T-cell specific immune responses as well as cytokine and chemokine profiles including levels of soluble CD30 (sCD30), sCD163, and thymus and activation-regulated chemokine (TARC) in relation to event-free survival in patients with cHL. The Children’s Oncology Group (COG) clinical trial AHOD1331 was a randomized phase 3 trial for patients with newly diagnosed high-risk cHL, aged 2 to 21 years, which compared standard chemotherapy and doxorubicin, bleomycin, vincristine, etoposide, prednisone, …

Identifying Priority Research Questions For Decentralized Wastewater, Bryan W Brooks, Timothy Callahan, Jacob K Stanley, Jamie Holodak, Kevin M Stroski, Alissa H Cox, Thomas W Groves, Anish Jantrania, Jeff C Moeller, Kris Neset, Christopher Walker, Harry Zhang, Amal Bakchan, Kelly D Alley, Jim Bell, Allison Blodig, Eric Casey, Donna Cosper, Victor D'Amato, Mark A Elliott, Greg Graves, Roxanne Groover, Robert Himschoot, Mary G Lusk, Jillian Maxcy-Brown, David Meints, Rojelio Mejia, Matt Pace, Benjamin J Ryan, Brian Scheffe, Tom Schimelfenig, June E Wolfe, Sara F Heger

Faculty, Staff and Students Publications

Decentralized wastewater treatment and reuse represent critical infrastructure across the rural-periurban-urban continuum around the world. Effective, efficient, resilient, and equitable implementation of on-premise technologies and management systems is part of a One Water approach and necessary to protect public health and the environment, yet inconsistent delivery of essential public health services persists in many regions, including across states, tribes, and territories of the United States. We initiated a groundbreaking effort to understand challenges and to identify research opportunities related to the science and practice of decentralized wastewater. A horizon scanning exercise using a bottom up and transparent key questions approach …

The Biomedical Landscape Of Genomic Structural Variation In The Qatari Population, Elbay Aliyev, Najeeb Syed, Alessia Visconti, Taghi Aliyev, Aziz Belkadi, Mohammadmersad Ghorbani, Niccolò Rossi, Haroon Naeem, Geethanjali Devadoss Gandhi, Gaurav Thareja, Aljazi Al-Maraghi, Waleed Aamer, Amal Abdulsalam Ibrahim, Rulan Shaath, Farooq Omar Al-Ajli, Rozaimi Mohamad Razali, Fritz J Sedlazeck, Sonia Davila, Ammira Akil, Karsten Suhre, Younes Mokrab, Mario Falchi, Khalid A Fakhro

Faculty, Staff and Students Publications

We present a large-scale study of structural variation (SV) in the Qatari population, based on short-read whole-genome sequencing (WGS) of 6,141 individuals, identifying 153,946 variants across 5 classes reflecting the region's diversity and evolutionary history. Leveraging consanguinity and biobank phenotypes, we identify >180 putative gene knockouts, and use proteomics to show functional consequences in homozygotes. Conversely, 52 genes show significant depletion of homozygous deletions, eight of which cause severe pediatric disease or murine embryonic lethality. Examining phenotypic extremes uncovers several non-exonic homozygous deletions with large effect, including in SPIRE2 (creatinine), MAGI2 (leanness) and a chr19 microRNA cluster (extreme obesity). Further, …

Self-Efficacy Change Among Diverse Family Caregivers In Dementia Care, Deborah M Oyeyemi, Erich J Greene, Yunshan Xu, David R Lee, Rafael Samper-Ternent, Maya L Lichtenstein, Alan Stevens, Jeff D Williamson, Arun S Karlamangla, Debra Saliba, David B Reuben

Faculty, Staff and Student Publications

Objectives: To determine whether changes in caregiver self-efficacy (beliefs about one's ability to manage dementia-related problems and access help) differed by caregiver race and ethnicity across all participants enrolled in a large pragmatic trial of comprehensive dementia care.

Methods: In the Dementia Care Study (D-CARE), community-dwelling older adults with dementia and their unpaid family caregivers were randomized to receive usual care, community-based, or health system-based comprehensive dementia care. Caregiver self-efficacy was assessed at baseline, 6 months, and 18 months using a 4-item scale (range 4-20, higher scores indicate greater self-efficacy). Among all caregivers, we compared least squares means for overall …

Tumor-Infiltrating Bacteria Disrupt Cancer Epithelial Cell Interactions And Induce Cell-Cycle Arrest, Jorge Luis Galeano Niño, Falk Ponath, Victor A Ajisafe, Clara R Becker, Andrew G Kempchinsky, Martha A Zepeda-Rivera, Javier A Gomez, Hanrui Wu, Jessica G Terrazas, Heather Bouzek, Elizabeth Cromwell, Pritha Chanana, Matthew Wong, Ashish Damania, Michael G White, Y Nancy You, Scott Kopetz, Nadim J Ajami, Jennifer A Wargo, Christopher D Johnston, Susan Bullman

Faculty, Staff and Student Publications

Tumor-infiltrating bacteria are increasingly recognized as modulators of cancer progression and therapy resistance. We describe a mechanism by which extracellular intratumoral bacteria, including Fusobacterium, modulate cancer epithelial cell behavior. Spatial imaging and single-cell spatial transcriptomics show that these bacteria predominantly localize extracellularly within tumor microniches of colorectal and oral cancers, characterized by reduced cell density, transcriptional activity, and proliferation. In vitro, Fusobacterium nucleatum disrupts epithelial contacts, inducing G0-G1 arrest and transcriptional quiescence. This state confers 5-fluorouracil resistance and remodels the tumor microenvironment. Findings were validated by live-cell imaging, spatial profiling, mouse models, and a 52-patient colorectal cancer cohort. Transcriptomics reveals …

Spatial Omics At The Forefront: Emerging Technologies, Analytical Innovations, And Clinical Applications, Yunhe Liu, Yibo Dai, Linghua Wang

Faculty, Staff and Student Publications

Spatial omics transforms our understanding of cancer by revealing how tumor cells and the microenvironment are organized, interact, and evolve within tissues. Here, we synthesize advances in spatial technologies that map tumor ecosystems with unprecedented fidelity. We highlighted analytical breakthroughs-including multimodal integration and emerging spatial foundation models-that resolve functional niches and spatial communities, converting spatial patterns into mechanistic insights. We summarize how spatially organized features, from immune hubs to microbiota and neural interfaces, shape tumor evolution and clinical outcomes. We then outline how spatial approaches illuminate precancer biology, metastatic adaptation, and therapy response. Bridging discovery and translation, we provide a …

Tet2-Mutant Clonal Hematopoiesis Enhances Macrophage Antigen Presentation And Improves Immune Checkpoint Therapy In Solid Tumors, Shelley Herbrich, Mehdi Chaib, Swetha Anandhan, Samuel W Andrewes, Ashwat Nagarajan, Baoxiang Guan, Nishant Gandhi, Jared Gilliam, Milan Radovich, Padmanee Sharma

Faculty, Staff and Student Publications

Clonal hematopoiesis (CH) is detectable in upwards of 20% of patients with solid tumors and is associated with worsened prognosis; however, its role in tumor immunology and immune checkpoint therapy (ICT) is unknown. Using a bone marrow chimera model of Tet2+/mut CH in mice with solid tumors, we found the Tet2-mutant myeloid cells are abundant in the tumor microenvironment and contributed to an improved response to ICT. Mechanistically, Tet2+/mut macrophages inside the tumor act as immunogenic antigen-presenting cells that more effectively cross-prime naive CD8+ T cells in response to IFNγ. In human cohorts of 35,971 non-small cell lung cancer patients …

Adipose Stromal Cell-Derived Cancer-Associated Fibroblasts Promote Pancreatic Adenocarcinoma Progression Through Sfrp4 Signaling, Joseph Rupert, Lingyi Cai, Alexes C Daquinag, Dimitris Anastassiou, Mikhail G Kolonin

Faculty, Staff and Student Publications

Background/objectives: Progression of pancreatic ductal adenocarcinoma (PDAC) and other carcinomas relies on cancer-associated fibroblasts (CAFs). A subset of CAFs is derived from adipose stromal cells (ASCs) recruited by tumors and the ASC-CAF conversion has been associated with invasiveness and poor prognosis.

Methods: To explore the underlying molecular mechanisms, we used a model based on primary ASCs derived from human visceral adipose tissue co-cultured with human PDAC cell line Capan-1. To investigate cancer progression in vivo, we also used mice orthotopically grafted with mouse KPC cells.

Results: Genomic analysis revealed that Capan-1 co-culture induces Wnt and TGFβ signaling and extracellular matrix …

Chek2 Loss Endows Chemotherapy Resistance To Hematopoietic Stem Cells, Jing Zhou, Tianyuan Hu, Dian Li, Sanming Li, Minhua Li, Xiangguo Shi, Daisuke Nakada

Faculty, Staff and Students Publications

Individuals with history of chemo- or radiotherapy frequently exhibit somatic mosaicism in the blood, often involving mutations in genes responsible for DNA damage responses (DDR), such as CHEK2. However, the mechanisms by which CHEK2 mutations promote the expansion of mutant cells following chemo- or radiotherapy remain poorly understood. Here, we demonstrate that loss of CHEK2 confers resistance to chemotherapy in hematopoietic stem and progenitor cells (HSPCs). Through a CRISPR-based screen, we identified CHEK2 as a gene whose loss enhances resistance to cytotoxic chemotherapies. A complementary drug screen revealed that CHEK2-mutant cells are also resistant to DNA hypomethylating agents. Chek2-deficient HSPCs …

Germline Hla Heterozygosity Is Associated With Decreased Lung Cancer Risk, Taotao Tan, Vikram R Shaw, Jinyoung Byun, Hyun-Sung Lee, Younghun Han, Yafang Li, Rayjean J Hung, David C Christiani, Xin-An Wang, Mattias Johansson, Xiangjun Xiao, David Zaridze, Stig Egil Bojesen, Sanjay Shete, Demetrios Albanes, Melinda C Aldrich, Adonina Tardon, Guillermo Fernandez-Tardon, Loïc Le Marchand, Gad Rennert, Heike Bickeböller, H-Erich Wichmann, Angela Risch, John K Field, Michael Davies, Penella Woll, Lambertus A Kiemeney, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Mikael Johansson, Kjell Grankvist, Matthew B Schabath, Angeline Andrew, Philip Lazarus, Susanne M Arnold, Dakai Zhu, Maria Teresa Landi, James Mckay, Christopher Amos, Chao Cheng

Faculty, Staff and Students Publications

Heterozygosity at human leukocyte antigen (HLA) loci may improve lung cancer immunosurveillance by increasing recognition of the tumor by the immune system. Previous studies utilizing data from population-level biobanks, such as the United Kingdom Biobank and FinnGen, have identified an association between germline HLA class-II heterozygosity and reduced lung cancer risk in smokers. In the present study, we evaluate the association between HLA heterozygosity and lung cancer in a large case-control study (15,302 cases; 14,580 controls) with imputed HLA allele-type information, comparing differences in HLA heterozygosity between smokers and non-smokers, amongst lung cancer subtypes, and at 2- and 4-digit HLA …

Dynamic Fib-4 Score Changes And Hcc Risk In Patients With Masld And Elevated Liver Enzymes: A Nationwide Cohort Study, Yee Hui Yeo, Hsiu J Ho, Tsai-Wei Huang, Teng-Yu Lee, Ju Dong Yang, George Cholankeril, Chien-Jen Chen, Hawi-I Yang, Chuen-Fei Chen, Hung-Chuen Chang, Chun-Ying Wu

Faculty, Staff and Students Publications

Introduction: Hepatocellular carcinoma (HCC) can develop in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) without cirrhosis, especially in those with elevated liver enzymes. However, there is currently no low-cost, scalable screening tool for this population. To address this need, we investigated the association between serial changes in FIB-4 (fibrosis-4) scores over a 3-year period and the risk of developing HCC in a large, diverse cohort of patients with MASLD without cirrhosis.

Methods: This study utilized a nationwide cohort from the National Health Insurance Research Database (NHIRD), including 810,698 patients with MASLD who had demographic and laboratory data at baseline …

Large-Scale Blood Pressure Gwas Accounting For Gene-Depression Interactions In 564,680 Individuals From Diverse Populations, Songmi Lee, Clint L Miller, Amy R Bentley, Michael R Brown, Pavithra Nagarajan, Raymond Noordam, John L Morrison, Karen Schwander, Kenneth Westerman, Minjung Kho, Aldi T Kraja, Paul S De Vries, Farah Ammous, Hughes Aschard, Traci M Bartz, Anh Do, Charles T Dupont, Mary F Feitosa, Valborg Gudmundsdottir, Xiuqing Guo, Sarah E Harris, Keiko Hikino, Zhijie Huang, Christophe Lefevre, Leo-Pekka Lyytikäinen, Yuri Milaneschi, Giuseppe Giovanni Nardone, Aurora Santin, Helena Schmidt, Botong Shen, Tamar Sofer, Quan Sun, Ye An Tan, Jingxian Tang, Sébastien Thériault, Peter J Van Der Most, Erin B Ware, Stefan Weiss, Wang Ya Xing, Chenglong Yu, Wei Zhao, Md Abu Yusuf Ansari, Pramod Anugu, John R Attia, Lydia A Bazzano, Joshua C Bis, Max Breyer, Brian Cade, Guanjie Chen, Stacey Collins, Janie Corley, Gail Davies, Marcus Dörr, Jiawen Du, Todd L Edwards, Tariq Faquih, Jessica D Faul, Alison E Fohner, Amanda M Fretts, Srushti Gangireddy, Adam Gepner, Mariaelisa Graff, Edith Hofer, Georg Homuth, Michelle M Hood, Xu Jie, Mika Kähönen, Sharon L R Kardia, Carrie A Karvonen-Gutierrez, Lenore J Launer, Daniel Levy, Maitreiyi Maheshwari, Lisa W Martin, Koichi Matsuda, John J Mcneil, Ilja M Nolte, Tomo Okochi, Laura M Raffield, Olli T Raitakari, Lorenz Risch, Martin Risch, Ana Diez Roux, Edward A Ruiz-Narvaez, Tom C Russ, Takeo Saito, Pamela J Schreiner, Rodney J Scott, James Shikany, Jennifer A Smith, Harold Snieder, Beatrice Spedicati, E Shyong Tai, Adele M Taylor, Kent D Taylor, Paola Tesolin, Rob M Van Dam, Rujia Wang, Wei Wenbin, Tian Xie, Jie Yao, Kristin L Young, Ruiyuan Zhang, Alan B Zonderman, Biobank Japan Project, Lifelines Cohort Study, Maria Pina Concas, David Conen, Simon R Cox, Michele K Evans, Ervin R Fox, Lisa De Las Fuentes, Ayush Giri, Giorgia Girotto, Hans J Grabe, Charles Gu, Vilmundur Gudnason, Sioban D Harlow, Elizabeth Holliday, Jonas B Jost, Paul Lacaze, Seunggeun Lee, Terho Lehtimäki, Changwei Li, Ching-Ti Liu, Alanna C Morrison, Kari E North, Brenda W J H Penninx, Patricia A Peyser, Michael M Province, Bruce M Psaty, Susan Redline, Frits R Rosendaal, Charles N Rotimi, Jerome I Rotter, Reinhold Schmidt, Xueling Sim, Chikashi Terao, David R Weir, Xiaofeng Zhu, Nora Franceschini, Jeffrey R O'Connell, Cashell E Jaquish, Heming Wang, Alisa Manning, Patricia B Munroe, Dabeeru C Rao, Han Chen, W James Gauderman, Laura J Bierut, Thomas W Winkler, Myriam Fornage

Faculty, Staff and Student Publications

Gene-environment interactions may enhance our understanding of blood pressure (BP) biology. We conducted a meta-analysis of multi-population genome-wide association studies (GWASs) of BP traits accounting for gene-depressive symptomatology (DEPR) interactions. Our study included 564,680 adults from 67 cohorts and four population backgrounds: African (5%), Asian (7%), European (85%), and Hispanic (3%). We discovered seven previously unreported BP loci showing gene-DEPR interaction. These loci mapped to genes implicated in neurogenesis (TGFA and CASP3), lipid metabolism (ACSL1), neuronal apoptosis (CASP3), and synaptic activity (CNTN6 and DBI). We also showed evidence for gene-DEPR interaction at nine known BP loci, further suggesting links between …

Proton Versus Photon Radiotherapy For Patients With Oropharyngeal Cancer In The Usa: A Multicentre, Randomised, Open-Label, Non-Inferiority Phase 3 Trial, Steven J Frank, Paul M Busse, J Jack Lee, David I Rosenthal, Mike Hernandez, David M Swanson, Adam S Garden, G Brandon Gunn, Samir H Patel, James W Snider, Daniel J Ma, Jason K Molitoris, Nancy Y Lee, Upendra Parvathaneni, Mark W Mcdonald, Noah S Kalman, Alexander Lin, Nasiruddin Mohammed, Christina Henson, Christian Hyde, Gopal K Bajaj, Sanford R Katz, Roi Dagan, William H Morrison, Jay P Reddy, C David Fuller, Shalin J Shah, Jack Phan, Gregory M Chronowski, Lauren Mayo, Erich M Sturgis, Renata Ferrarotto, Xiaorong R Zhu, Xiaodong Zhang, Li Wang, Katherine A Hutcheson, Adel K El-Naggar, Amy C Moreno, Anna Lee, Michael T Spiotto, Neil D Gross, Stephen Y Lai, Jay J Liao, Jonathan Paly, Zhongxing Liao, Robert L Foote

Faculty, Staff and Student Publications

Background: Radiotherapy is an integral component of treatment for oropharyngeal cancer. Toxicity from the current state-of-the-art photon radiotherapy, intensity-modulated radiation therapy (IMRT), has prompted the search for alternative, less toxic therapies. One such alternative that might de-intensify treatment is proton therapy. In this trial, we aimed to directly compare IMRT with intensity-modulated proton therapy (IMPT), both concurrent with systemic therapy, hypothesising comparable disease control and survival and lower toxicity.

Methods: This randomised, multicentre, open-label, non-inferiority, phase 3 trial was conducted in 21 sites (cancer centres or universities) in the USA. Patients (aged ≥18 years) with stage III or stage IV …

Secure Distributed Multiple Imputation Enables Missing Data Inference For Private Data Proprietors, Haris Smajlović, Yi Lian, Qi Long, Ibrahim Numanagić, Xiaoqian Jiang

Faculty, Staff and Student Publications

Scattered between many healthcare providers across the US, Electronic Health Records (EHR) are extensively used for research purposes. Collaboration and sharing of EHRs between multiple institutions often provide access to more diverse datasets and a chance to conduct comprehensive studies. However, these collaboration efforts are usually hindered by privacy issues that render the pooling of such data at a centralized database impossible. Furthermore, EHRs are often incomplete and require statistical imputation prior to the study. To enable collaborative studies on top of incomplete, private EHRs, here we provide a provably secure solution built with secure multiparty computation (SMC) that provides …

Association Of Neighborhood Economic Trajectories And Risk Of Mortality Among Older Adults, Erika Figueroa-Solis, Qian Xiao

Faculty, Staff and Student Publications

Background

Lower neighborhood socioeconomic status (SES) and decline in neighborhood SES have been linked to detrimental health outcomes, such as cardiovascular disease (CVD), cancer, and mortality. However, few studies have investigated distinct types of neighborhood economic trajectories in relation to mortality. We examined the association between the recently developed multidimensional measure of neighborhood trajectories and mortality in older adults enrolled in the National Institutes of Health-AARP Diet and Health Study (NIH-AARP).

Methods

Neighborhoods were classified into five groups based on economic change patterns from 2000 to 2016 using American Community Survey data: Stability, Growth, Displacement, Abandonment, and Poverty Concentration. Mortality …

Characteristics And Effectiveness Of Maternal Health Interventions To Prevent Mother-To-Child Transmission (Pmtct) Of Syphilis In A Global Setting: A Scoping Review Using Intervention Mapping As A Framework, Jinni Tang, Anusha Sajja, Christine Markham, Emily T Hebert, Irene Stafford, Sheryl Dacso, Melissa F Peskin

Faculty, Staff and Student Publications

Background: Despite the availability of cost-effective treatments, maternal syphilis continues to contribute significantly to preventable stillbirths and congenital syphilis cases worldwide. This scoping review aimed to identify and characterize maternal health interventions designed to prevent mother-to-child transmission (PMTCT) of syphilis globally, using a modified Intervention Mapping (IM) framework.

Methods: We conducted a scoping review of maternal health interventions targeting PMTCT of syphilis published between January 2010 and August 2023. Searches were performed in PubMed, Medline Ovid, and Embase, supplemented by manual reference screening. Eligible studies described at least one maternal health intervention addressing syphilis PMTCT and were analyzed using a …

Identification Of Cadm1 As An Immunotherapeutic Target And Evaluation Of A Novel Cadm1-Targeting Antibody-Drug Conjugate In Preclinical Osteosarcoma Models, Yifei Wang, Zhongting Zhang, Caterina Longo, Wendong Zhang, Qi Wang, Amer Najjar, Xiangjun Tian, Rossana N Lazcano Segura, Michael E Roth, Jonathan Gill, Douglas J Harrison, Zhaohui Xu, Yanhua Yi, Xin Zhou, Sylvester Jusu, Timothy M Stearns, Steven B Neuhauser, Carol J Bult, Jing Wang, Alexander J Lazar, Richard Gorlick

Faculty, Staff and Student Publications

Due to the paucity of validated cell surface osteosarcoma-specific targets, patients with this condition have long been excluded from the benefits of antibody-drug conjugate (ADC) therapy observed in patients with several solid and hematologic malignancies. Our comprehensive surfaceome profiling approach previously identified osteosarcoma-specific cell-surface antigens that are highly expressed in osteosarcomas but minimally expressed in normal tissues. As a result, one such antigen, CADM1, was selected for the generation of an ADC. We tested a CADM1-targeting ADC with a tesirine payload (SG3249) in vitro in osteosarcoma, rhabdomyosarcoma, and neuroblastoma patient-derived xenograft cell lines. In vivo, we tested six CADM1-expressing osteosarcoma …

Il-18 Metabolically Reprograms Car-Expressing Natural Killer T Cells And Enhances Their Antitumor Activity, Gabriel A Barragán Bravo, David A De La Cerda, Elisa Landoni, Kshiti Dholakia, Piotr Humeniuk, Leidy D Caraballo Galva, Ying Wang, Gengwen Tian, Boning Yang, Linjie Guo, Michael S Wood, Xavier Rios, Xin Xu, Amy N Courtney, Erica J Di Pierro, Joan Jacob, Yi-Han Li, Akshaya Adaikkalavan, Norihiro Watanabe, Sufeng Mao, George Miles, Gianpietro Dotti, Leonid S Metelitsa

Faculty, Staff and Students Publications

Invariant natural killer T cells (NKTs) have intrinsic anti-tumor properties that make them promising candidates for chimeric antigen receptor (CAR) immunotherapies. Transgenic cytokine expression can enhance cellular therapy potency, and we hypothesized that co-expressing IL-18 alone or with IL-15 would boost CAR-NKT therapeutic potential. To test this, we generated retroviral constructs expressing IL-15 and/or IL-18 with an inducible caspase 9 safety switch and co-transduced them with a GD2-specific CAR into human NKTs. Co-expression of IL-18 or IL-15/IL-18 increased CAR-NKT cytotoxicity, proliferation, and cytokine secretion in vitro compared to IL-15 alone. IL-18 also enhanced GPC3.CAR and CD19.CAR NKT activity against hepatocellular …

Transcriptomic Signature-Guided Depletion Of Intermediate Alveolar Epithelial Cells Ameliorates Pulmonary Fibrosis In Mice, Fei Peng, Chun-Sun Jiang, Zhen Zheng, Shahram Aliyari, Dan Shan, Aaryan Sabharwal, Qinyan Yin, Shigeki Saito, Chao He, Ivan O Rosas, Joseph A Lasky, Victor J Thannickal, Yong Zhou

Faculty, Staff and Students Publications

Single-cell RNA sequencing (scRNA-seq) has identified intermediate epithelial states in pulmonary fibrosis, including KRT5-/KRT17+ aberrant basaloid cells in humans and Krt8+ alveolar differentiation intermediates (ADIs) in mice. Their functional contributions to fibrogenesis, however, remain unclear. Here, we introduce an RNA-sensing-dependent protein translation technology that enables selective targeting of Krt8+ ADI cells in vitro and in vivo. Transcriptomic analysis revealed Small Proline-Rich Protein 1 A (SPRR1A) mRNA as a shared marker of murine Krt8+ ADIs and human KRT5-/KRT17+ basaloid cells, distinguishing them from other lung cell populations. Using programmable RNA sensors, we demonstrated selective EGFP-labeling of Krt8+ ADI cells in vivo, …

Plasma Proteomics And Incident Coronary Heart Disease, Matthew P Huber, Jennifer A Brody, Colleen M Sitlani, Thomas R Austin, Usman A Tahir, Shuliang Deng, Devendra Meena, Jingsha Chen, Kunihiro Matsushita, Christie M Ballantyne, Josef Coresh, Robert E Gerszten, Russell P Tracy, Ting Ye, Bruce M Psaty, Joshua C Bis, James S Floyd

Faculty, Staff and Students Publications

Background: Systematic profiling of plasma proteins in population studies offers a complementary approach to discovery of novel risk factors and may provide new insights into the causes of coronary heart disease.

Methods: To explore relationships between the circulating proteome and coronary heart disease (CHD), we evaluated associations of 4780 plasma proteins with incident CHD in the Cardiovascular Health Study (CHS, N=2856, 575 CHD events) and replicated significant associations in the Atherosclerosis Risk in Communities Study (ARIC, N = 10456; 1375 events).

Results: We find that 11 proteins significantly associate with incident CHD after adjusting for risk factors; and eight significantly …

Clinical And Dosimetric Dataset Of Time-To-Event Normal Tissue Complication Probability For Osteoradionecrosis, Natalie A West, Serageldin Kamel, Andrew Wentzel, Zaphanlene Kaffey, Moamen Abdelaal, G Elisabeta Marai, Guadalupe Canahuate, Xinhua Zhang, Melissa M Chen, Kareem A Wahid, Jillian Rigert, Kristy K Brock, Mark Chambers, Adegbenga O Otun, Ruth Aponte-Wesson, Renjie He, Mohamed A Naser, Katherine A Hutcheson, Abdallah S R Mohamed, Lisanne V Van Dijk, Amy C Moreno, Stephen Y Lai, Clifton D Fuller, Laia Humbert-Vidan

Faculty, Staff and Student Publications

Osteoradionecrosis of the jaw (ORNJ) is a radiation-induced late toxicity that can dramatically decrease patients' quality of life. Recent increases in survival rates of head and neck cancers associated with human papillomavirus (HPV) infection have resulted in a higher frequency of radiation-induced toxicities, particularly ORNJ. Recent work with Normal Tissue Complication Probability (NTCP) models and a Weibull Accelerated Failure Time (WAFT) model have further developed our understanding of ORNJ clinical/dosimetric risk factors and longitudinal features, respectively. In this data descriptor, 1129 head and neck cancer (HNC) patients received curative intent radiotherapy (RT) at MD Anderson Cancer Center and were followed …

An Integrated Single-Cell And Spatial Transcriptomic Atlas Of Thyroid Cancer Progression Identifies Prognostic Fibroblast Subpopulations, Matthew A Loberg, George J Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C Wahoski, Kailey P Caroland, Megan L Tigue, Heather A Hartmann, Jean-Nicolas Gallant, Courtney J Phifer, Andres A Ocampo, Dayle K Wang, Reilly G Fankhauser, Kirti A Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M Shaddy, James L Netterville, Sarah L Rohde, Carmen C Solórzano, Lindsay A Bischoff, Naira Baregamian, Barbara A Murphy, Jennifer H Choe, Jennifer R Wang, Eric C Huang, Quanhu Sheng, Luciane T Kagohara, Elizabeth M Jaffee, Ryan H Belcher, Ken S Lau, Fei Ye, Ethan Lee, Vivian L Weiss

Faculty, Staff and Student Publications

Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts …

Primary Cortical Neurons Precipitate And Extrude Large Mitochondria-Associated Calcium-Phosphate Sheets With A Bone-Precursor-Like Ultrastructure, Erik D Anderson, Christopher A Cronkite, Philip R Baldwin, Carlota P Abella, Joseph G Duman, Ashleigh N Simmonds, M Neal Waxham, Kimberley F Tolias, Steven J Ludtke

Faculty, Staff and Students Publications

Calcium-phosphate (CaP) is a ubiquitous inorganic compound that plays an important structural role in healthy bone and teeth formation, but its pathologic buildup can occur in dyshomeostatic calcium disorders like Alzheimer's disease and Leigh syndrome. The nexus of pathologic extracellular CaP in the nervous system is not well understood, but prior evidence suggests mitochondria could be a source. We have observed mitochondria-sized sheet-like CaP aggregates within functional wild type cortical neuron cultures at 1 and 20 days in vitro. Neurons were extracted from embryonic day 18 (E18) rat embryos following standard protocols to study neuronal structure and function. We have …

Maternal Immunization With Vp8* Mrna Vaccine Yields Superior Passive Transfer Of Rotavirus-Neutralizing Antibodies To Foals, Karin E R Borba, Rebecca M Legere, Nathan M Canaday, Jill W Skrobarczyk, Zachary W T Arnold, Elena Cotton-Betteridge, Cristina Poveda, Michael F Criscitiello, Angela I Bordin, Luc R Berghman, Jeroen B K Pollet, Noah D Cohen

Faculty, Staff and Students Publications

Background: Despite the availability of a killed whole-virus (KV) vaccine, diarrhea caused by equine rotavirus group A (ERVA) remains a significant health concern for foals in the United States. The vaccine is administered to pregnant mares, with foals protected by passive transfer of colostral antibodies. However, KV-induced immunity is only partially protective and maternal antibody levels in foals are often low and wane rapidly. To address these limitations, we developed a mRNA-based ERVA vaccine encoding the highly conserved VP8* protein to evaluate whether it can provide improved immune protection.

Methods: Pregnant mares (n = 12 per group) were …

Fibrinogen-Associated Plasma Metabolites And Implications For Coagulation, Inflammation, And Vascular Diseases, Jayna C Nicholas, Taryn Alkis, Joshua C Bis, Eric Boerwinkle, Jennifer A Brody, Clary B Clish, Paul S De Vries, Yan Gao, Robert E Gerzsten, Xiuqing Guo, Andrew D Johnson, Martin G Larson, Rozenn N Lemaitre, Bruce M Psaty, Vasan Ramachandran, Alexander P Reiner, Stephen S Rich, Benjamin Rodriguez, Jian Rong, Jerome I Rotter, Jeanette Simino, Nicholas L Smith, James Wilson, Jie Yao, Alanna C Morrison, Bing Yu, Laura M Raffield

Faculty, Staff and Student Publications

Background: Fibrinogen is a critical coagulation factor that plays an essential role in thrombosis and is elevated in individuals with chronic inflammation. Here, we used fibrinogen as a representative quantitative measure of pro-coagulant risk and evaluated metabolites associated with fibrinogen levels through non-targeted plasma metabolomic profiling (Broad and Metabolon platforms).

Methods: Our analysis included 10,533 individuals across six U.S. based cohorts representing diverse population groups. The cross-sectional relationship between each of 789 tested metabolites and plasma fibrinogen concentration was assessed with adjustment for relevant covariates such as age, sex, body mass index, and circulating lipoprotein levels.

Results: Meta-analysis of per-cohort …