Digital Commons Network^™

Cgas-Agonistic Spherical Nucleic Acids Reprogram The Glioblastoma Immune Microenvironment And Promote Antitumor Immunity, Akanksha S Mahajan, Corey Dussold, Seunghyun Kim, Rachel Jarvis, Lisa A Hurley, Serena Tommasini-Ghelfi, Jungsoo Park, Connor M Forsyth, Bin Zhang, Jason Miska, Amy B Heimberger, Chad A Mirkin, Alexander H Stegh

2020-Current year OA Pubs

The cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) pathway is an important DNA-sensing mechanism that increases T cell trafficking and activation in tumors and reverses the immunosuppressive phenotype of myeloid cells. Therefore, direct STING targeting using synthetic cyclic dinucleotides (CDNs) is an attractive strategy for treating lymphocyte-depleted and myeloid cell-enriched tumors, such as glioblastoma (GBM). However, inadequate bioavailability and poor cellular accumulation limit the clinical development of CDNs, particularly for noninvasive administration strategies. Spherical nucleic acids (SNAs) have emerged as promising modular constructs for creating therapeutic lead compounds for many diseases, including different forms of cancer. Here, we report the …

A Prodrug Strategy For Sustained Release Of Lactic Acid From Silicone Elastomer Vaginal Rings., Yahya H. Dallal Bashi, Xinyu Zhao, Clare F. Mccoy, Narender Kumar, Natalia Teleshova, Dolores J. Lamb, José A. Fernández Romero, Abigail Meyer, Patrick Barnable, Meropi Aravantinou, Osaretin E. Asowata, Melissa A. White, Alexander J. Travis, Lisa B. Haddad, Xin Shen, Vicky-Leigh Young, Peter Boyd, R Karl Malcolm

Manuscripts, Articles, Book Chapters and Other Papers

Lactic acid is the most abundant organic weak acid in the healthy human vagina and plays a pivotal role in maintaining an acidic vaginal environment protective against exogenous bacteria and viruses. However, in dysbiotic or non-optimal vaginal environments, significantly decreased concentrations of lactobacilli result in reduced lactic acid production, increased vaginal pH, and enhanced risk of sexually transmitted infections (including human immunodeficiency virus), and bacterial vaginosis. Various gel-based products are marketed to administer lactic acid vaginally for the treatment of bacterial vaginosis and non-hormonal contraception, and there is interest in developing vaginal ring products for sustained/controlled release of lactic acid. …

Genome-Wide Crispr Screens Identify Critical Targets To Enhance Car-Nk Cell Antitumor Potency, Alexander Biederstädt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstädt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Elizabeth J Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced …

Peripheral Microvascular And Cerebral White Matter Dysfunction In Schizophrenia: Implications Of A Body-Brain Endothelial Pathophysiology, Eric L Goldwaser, Alexa Yuen, Wyatt Marshall, Bhim M Adhikari, Joshua Chiappelli, Andrew Van Der Vaart, Mark Kvarta, Yizhou Ma, Xiaoming Du, Si Gao, Heather Bruce, Patrick Donnelly, Braxton Mitchell, Charles Hong, Danny J J Wang, Peter Kochunov, L Elliot Hong

Faculty, Staff and Student Publications

Background and hypothesis: Schizophrenia spectrum disorder (SSD) is a chronic neuropsychiatric illness accompanied by significant brain structural and functional abnormalities and higher rate of cardio- and cerebrovascular comorbidities. We hypothesized that genetic and environmental risk factors that led to SSD act throughout the body and demonstrated the association between lower integrity of peripheral vascular endothelium and white matter (WM) microstructure.

Study design: Microvascular endothelial function was evaluated using brachial artery post-occlusive reactive hyperemia (PORH), in which endothelial responses are measured under reduced blood flow and after blood flow is restored. White matter microstructure was assessed by multi-shell diffusion tensor imaging …

Serum Response Factor Is Essential For Endometrial Function And Prevention Of Inflammatory Fibrosis, Ryan M Marquardt, Sara A Grimm, San-Pin Wu, Peter F Lais, Shu-Yun Li, Xin Xu, Erin Smithberger, David Cunefare, Charan Ganta, David Olson, Eunhee M Jeong, Jae-Wook Jeong, Bruce A Lessey, John P Lydon, Francesco J Demayo

Faculty, Staff and Students Publications

Pregnancy requires a supportive uterine environment facilitated by steroid hormone–regulated differentiation of endometrial stromal fibroblasts into decidual cells and tight control of inflammation. Serum response factor (SRF) is a widely expressed transcription factor essential for mesenchymal cell growth and differentiation with noted roles in hormonal regulation of muscle tissues but little characterization in reproductive organs. Here, we reveal that endometrial SRF is dysregulated in human endometriosis and is critical for female reproductive success in mice through regulation of endometrial stromal and epithelial cells. Immunohistochemical analysis identified decreased endometrial SRF expression in infertile endometriosis patient tissues. RNAi-based SRF knockdown in human …

Optimising Drowning Prevention Counselling Through A Physician Maintenance Of Certification (Moc) Quality Improvement (Qi) Initiative, Tracy E Mccallin, Anthony R Arredondo, Elizabeth A Camp, Shabana Yusuf

Faculty, Staff and Students Publications

Drowning is the leading cause of death in children 1–4 years old in the USA. Paediatricians play an important role in giving anticipatory guidance on drowning prevention. This quality improvement initiative aimed to increase the rate of drowning prevention counselling with provision of educational materials to caregivers of children aged 0–10 years during clinical encounters in an outpatient setting.

We refined a previously published Texas state educational programme that included evidence-based counselling strategies across three Plan Do Study Act (PDSA) cycles, with the addition of preintervention baseline counselling phase during expansion of the programme nationally to 17 and 21 states …

Global Trends And Forecast Of Cardiovascular Diseases, Cancer, And Shared Risk Factors: Insights From The Gbd 2021, Chieh Y Koo, Bryan Chong, Jayanth Jayabaskaran, Srinithy Nagarajan, Silingga M Jauhari, Yiming Chen, Li L Tan, Anurag Mehta, Muhammad S Khan, Mark Muthiah, Derek Hausenloy, A M Richards, Dennis T Ko, Christian D Mallen, Eric A Secemsky, Mark Y Chan, Paaladinesh Thavendiranathan, Nicholas W S Chew, Mamas A Mamas

Faculty, Staff and Students Publications

Background: Cardiovascular disease (CVD) and cancer share multiple risk factors and are the leading causes of morbidity and death worldwide. This study aims to examine historical and projected trends of the combined CVD-cancer global estimates and their shared risk factors.

Methods: Death and disability-adjusted life years (DALYs) associated with CVDs, cancers, and their risk factors were obtained from the GBD (Global Burden of Disease) 2021 study. Historical estimates from 1990 to 2021 and forecast data from 2025 to 2050 were examined across age groups, regions, sociodemographic index, and sex.

Results: In 2021, CVD-cancer resulted in age-standardized DALY rates of 8009 …

Lrp8 Is An Entry Receptor For Tick-Borne Encephalitis Viruses, Pengfei Li, Sean Hui, Zhenlu Chong, Michael N Nguyen, Stefanie P Muraro, Hana Janova, Hongming Ma, Shiqi Cao, Tomasz Kaszuba, Brian Imbiakha, Sathvik Palakurty, David A Price, Gaya K Amarasinghe, Daisy W Leung, Daved H Fremont, Michael S Diamond, Et Al.

2020-Current year OA Pubs

Orthoflaviviruses are a genus of arthropod-transmitted RNA viruses that infect humans and other vertebrate animals on a global scale, resulting in extensive morbidity and mortality. Among the orthoflaviviruses, tick-borne encephalitis viruses (TBEV) are an antigenic group that causes severe neurological disease in humans. However, the entry receptors for TBEV, which contribute to cell and tissue tropism, remain largely unknown. Because recent studies identified members of the low-density lipoprotein receptor (LDLR) family as possible receptors for some orthoflaviviruses and distantly related alphaviruses, we performed a targeted screen in transgenic cells expressing different LDLR members and identified LRP8 (also called ApoER2) as …

Human Kallikrein 2: A Novel Lineage-Specific Surface Target In Prostate Cancer, Fei Shen, Ryan Smith, Theresa Mcdevitt, Krista Menard, Shaozhou Tian, Gerald Chu, Ruchi Chaudhary, Jennifer Mccann, Halley Oyer, Sherry C. Wang, Steven Max, Peter Francis, William K. Kelly, Charles G. Drake

Kimmel Cancer Center Faculty Papers

PURPOSE: Targeted therapies for metastatic prostate cancer are limited, highlighting the need for novel drug targets and mechanisms of action (MoA). Human kallikrein 2 (KLK2) is a prostate-specific antigen expressed across the prostate cancer disease continuum. However, it was not recognized as a therapeutic target for prostate cancer in the past due to limited evidence of its cell surface expression. In this study, we systematically characterized KLK2 expression in prostate cancer, confirmed its cell surface expression, and demonstrated the preclinical efficacy of three KLK2-targeting therapeutics with distinct MoA.

EXPERIMENTAL DESIGN: The KLK2 expression profile in different stages of prostate cancer …

Integrative Proteogenomics And Forward Genetics Reveal A Novel Mitotic Vulnerability In Triple-Negative Breast Cancer, Nicholas J Neill, Shankha Satpathy, Karsten Krug, Jitendra K Meena, Nivetha Ramesh Babu, Cheyenne Calderon, Desmon Reed, Marcus J Weber, Lacey E Dobrolecki, Alaina Lewis, Christina Sallas, Meenakshi Anurag, Kimberly R Holloway, Chen Huang, Suhas Vasaikar, Maria F Cardenas, Beom-Jun Kim, Doug W Chan, Shayan C Avanessian, Siddhartha Tyagi, Mayra Orellana, Sufeng Mao, Heyuan Li, Fade Gong, Sarah J Kurley, Kristen L Meerbrey, Calla M Olson, Amritha Nair, Tingting Sun, Hsiang-Ching Chung, Elizabeth A Bowling, Jarey H Wang, Pengju Zhang, Peng Xiao, Duxiao Yang, Fabio Stossi, Mei-Yin C Polley, Alexander B Saltzman, Filip Mundt, D R Mani, Michael A Gillette, Susan G Hilsenbeck, George Miles, Carolina Gutierrez, C Kent Osborne, Charles Y Lin, Nathanael S Gray, Jinpeng Sun, David A Wheeler, Charles M Perou, Anna Malovannaya, Michael T Lewis, Bing Zhang, Matthew J Ellis, Steven A Carr, Thomas F Westbrook

Faculty, Staff and Students Publications

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTAs) are frontline chemotherapies for TNBC; however, the molecular pathways that cause TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening. We discovered that PTPN12 inactivation drives mitotic defects through aberrant hyperactivation of the ubiquitin ligase complex APCFZR1, a critical regulator of the cell cycle. Consistent …

Therapeutic Radiation Drives Leptomeningeal Dissemination Of Medulloblastoma Through An Innate Immune Process, Carolina Nör, Kaitlin Kharas, Alex Rasnitsyn, Maria C Vladoiu, Nam Woo Cho, Jacob S Young, Felipe Nör, Ncedile Mankahla, Joonas Haapasalo, Kristiina Nordfors, Sara Rapic, Patryk Skowron, Raúl A Suárez, Alexander T Bahcheli, Oliver Ocsenas, Xin Chen, Shahrzad Bahrampour, Ali Momin, Lakshmikirupa Sundaresan, Winnie Ong, Liam D Hendrikse, Namal Abeysundara, Kyle Juraschka, Michelle Ly, Jonelle G Pallota, Tajana Douglas, Ning Huang, Hao Wang, Esta Mak, Lei Qin, Jessica Liu, Lily Shen, Betty Luu, Alex Manno, Sachin A Kumar, Laura K Donovan, Vernon Fong, Cory Richman, Craig Daniels, Livia Garzia, Jeremy N Rich, Cynthia Hawkins, Xiaochong Wu, Ralph Dacosta, Jüri Reimand, Xi Huang, Vijay Ramaswamy, David R Raleigh, Michael D Taylor

Faculty, Staff and Students Publications

Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally. In murine medulloblastoma model systems, provision of a single dose of radiation to the tumor drives leptomeningeal dissemination. An inflammatory response after radiation-induced tumor cell death recruits a variety of immune cells. Inflammation opens the local blood-brain barrier, allowing intravasation of medulloblastoma cells. Experimental induction of inflammation with lipopolysaccharide drives …

An Annotated Biobank Of Triple-Negative Breast Cancer Patient-Derived Xenografts Features Treatment-Naïve And Longitudinal Samples During Neoadjuvant Chemotherapy, Amanda L Rinkenbaugh, Yuan Qi, Shirong Cai, Jiansu Shao, Faiza Baameur Hancock, Sabrina L Jeter-Jones, Xiaomei Zhang, Emily Powell, Lei Huo, Rosanna Lau, Chunxiao Fu, Rebekah Gould, Petra Den Hollander, Elizabeth E Ravenberg, Jason B White, Gaiane M Rauch, Banu Arun, Clinton Yam, Alastair M Thompson, Gloria V Echeverria, Stacy L Moulder, W Fraser Symmans, Jeffrey T Chang, Helen Piwnica-Worms

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443), including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT treatment and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of the PDX models were capable of metastasizing …

Overexpression Of The Signaling Coordinator Gab2 Can Play An Important Role In Acute Myeloid Leukemia Progression, Michael H. Kramer, Stephanie N. Richardson, Yang Li, Tiankai Yin, Nichole M. Helton, Daniel R. George, Michelle Cai, Sai Mukund Ramakrishnan, Casey Ds Katerndahl, Christopher A. Miller, Timothy J. Ley

2020-Current year OA Pubs

Mutations that initiate acute myeloid leukemia (AML) can cause clonal expansion without transformation (clonal hematopoiesis). Cooperating mutations, usually in signaling genes, are needed to cause overt disease, but these may require a specific fitness state to be tolerated. Here, we show that nearly all AMLs arising in a mouse model expressing 2 common AML-initiating mutations (Dnmt3aR878H and Npm1cA) acquired a single copy amplification of chromosome 7 (chr7), followed by activating mutations in signaling genes. We show that overexpression of a single gene on chr7 (Gab2, which coordinates signaling pathways) was tolerated in the presence of the Npm1cA mutation, could accelerate …

Exploring The Future Of Occupational Safety Research: A Strategic Foresight Approach, Jessica M K Streit, Sarah A Felknor, Nicole T Edwards, John J Howard

Faculty, Staff and Student Publications

A team from the U.S. National Institute for Occupational Safety and Health conducted a strategic foresight project to explore the future of occupational safety research (OSR). Data collected via systematic horizon scanning and key informant interviews were synthesized into six drivers of OSR change: (1) technological advancement, (2) partnerships and public trust, (3) prioritizing research investments, (4) safety and health integration, (5) data and science quality, and (6) worker protections. These drivers served as the basis for envisioning four potential OSR futures. Analysis of the resulting scenarios identified opportunities to enhance and advance OSR methods and approaches, innovation, systems thinking, …

Exploring Multimodal Large Language Models On Transthoracic Echocardiogram (Tte) Tasks For Cardiovascular Decision Support, Jianfu Li, Yiming Li, Zenan Sun, Evan Yu, Ahmed M Abdelhameed, Weiguo Cao, Haifang Li, Jianping He, Pengze Li, Jingna Feng, Yue Yu, Xinyue Hu, Manqi Li, Rakesh Kumar, Yifang Dang, Fang Li, Shahyar M Gharacholou, Cui Tao

Faculty, Staff and Student Publications

Objective: Multimodal large language models (LLMs) offer new potential for enhancing cardiovascular decision support, particularly in interpreting echocardiographic data. This study systematically evaluates and benchmarks foundation models from diverse domains on echocardiogram-based tasks to assess their effectiveness, limitations and potential in clinical cardiovascular applications.

Methods: We curated three cardiovascular imaging datasets-EchoNet-Dynamic, TMED2, and an expert-annotated echocardiogram (TTE) dataset-to evaluate performance on four critical tasks: (1) cardiac function evaluation through ejection fraction (EF) prediction, (2) cardiac view classification, (3) aortic stenosis (AS) severity assessment, and (4) cardiovascular disease classification. We evaluated six multimodal LLMs: EchoClip (cardiovascular-specific), BiomedGPT and LLaVA-Med (medical-domain), and …

In Silico Assessment Of Cellular Damage From Lu-177, Ac-225, And Pb-212 Therapeutic Radionuclides, Konstantinos P Chatzipapas, Konstantinos Papachristou, Dimitris Visvikis, Sebastien Incerti, John D Hazle, George C Kagadis

Faculty, Staff and Student Publications

Background: Targeted radionuclide therapy (TRT) has emerged as a unique and effective treatment modality for cancer. Monte Carlo simulations have greatly advanced investigations into radiation-caused DNA damage, including the complexity of this damage.

Purpose: This study aimed to evaluate DNA damage induced by high-linear energy transfer therapeutic radionuclides used in TRT, specifically 225Ac, 177Lu, and 212Pb, using Geant4-DNA Monte Carlo simulations.

Methods: The Geant4-DNA toolkit, incorporating the "molecularDNA" example, was employed to simulate radiation interactions within a human fibroblast cell model featuring a fractal chromatin fiber geometry within an ellipsoidal nucleus. Three source geometries (membrane, cytoplasm, nucleus) were modeled to …

Analysis Of Content Related To Retrograde Cricopharyngeal Dysfunction On Tiktok: Opportunities For Patient Education And Advocacy, Aidan Wright, Nathaniel Hunter, Vivian Jin, Andrew Tritter

Faculty, Staff and Student Publications

Objective: TikTok has experienced exponential growth as a social media platform, with over 1 billion active users. Concurrently, retrograde cricopharyngeal dysfunction (RCPD) has seen a surge in awareness among patients and on social media. Our objective was to characterize the most popular RCPD-related content on TikTok.

Methods: The top 50 videos associated with the following hashtags were analyzed: "RCPD," "noburp," "retrograde cricopharyngeal dysfunction," and "noburpsyndrome." Recorded metrics included views, likes, and comments, along with information regarding the creator's identity, gender, geographical location, and the video's purpose.

Results: One hundred and three videos were included in the final analysis, with a …

Depression Polygenicity And Disease Activity And Disability Worsening In Multiple Sclerosis, Ali Manouchehrinia, Kathryn C Fitzgerald, Amber Salter, Ruth Ann Marrie, Lars Alfredsson, Charles N Bernstein, James M Bolton, Gary Cutter, John D Fisk, Lesley A Graff, Carol A Hitchon, Jan Hillert, Ingrid Kockum, Yi Lu, Fred D Lublin, Kyla Mckay, Tomas Olsson, Scott Patten, Amit Patki, Hayley Riel, Klementy Shchetynsky, Pernilla Stridh, Hemant K Tiwari, Jerry S Wolinsky, Kaarina Kowalec

Faculty, Staff and Student Publications

Objective: A better understanding of factors associated with multiple sclerosis (MS) disease activity and disability is needed. Given the strong link between comorbid depression and MS disease activity and disability, we aimed to determine whether the depression genetic burden, as modelled using its polygenic score, is associated with MS disease activity and disability worsening.

Methods: In this cohort study, we used samples from neurologist-defined adult people with MS (PwMS) followed in clinical care or during a clinical trial from existing cohorts: Canada, the United States (US), and Sweden with extensive longitudinal phenotypes. We computed the depression polygenic score (PGS) and …

Use Of Osteopathic Manipulation Techniques For Management Of Acute Otitis Media In Pediatric Patients: A Scoping Review., Cory Hyun-Su Kim, Lauren R Mccray, Shaun A Nguyen, Carl Shermetaro, Wayne K Robbins

Ambulatory and Primary Care Articles

OBJECTIVE: To map and summarize the existing literature on the use of osteopathic manipulative techniques (OMT) in the management of acute otitis media (AOM) in pediatric patients, with an emphasis on reported outcomes and identifying gaps in the current evidence.

DATA SOURCES: CINAHL, PubMed, and SCOPUS.

REVIEW METHODS: A comprehensive literature search was conducted across multiple databases following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. Studies were charted and summarized based on key characteristics, including study design, population, types of OMT applied, and reported outcomes on management of AOM and recurrent AOM …

Apol2 Stabilizes Ku80 To Confer Nhej-Mediated Radioresistance In Gastric Cancer, Dan Zu, Qimei Bao, Hanyi He, Yuke Zhong, Mingcong Deng, Yangchan Hu, Chunkai Zhang, Chen Liang, Yixing Huang, Haidong Liu, Xiao Li, Yanhua He, Guoyan Luo, Weixin Wu, Fenghui Guan, Shengfeng Xu, Min Liu, Albino Bacolla, Ji Jing, Yian Du, John A Tainer, Yin Shi, Zu Ye, Xiangdong Cheng

Faculty, Staff and Student Publications

Radiotherapy is one of the most important adjuvant treatment methods for gastric cancer (GC). However, radioresistance remains a major clinical obstacle. In this study, APOL2 is identified as a key player in promoting non-homologous end joining (NHEJ)-mediated double-strand break (DSB) repair and enhancing radioresistance in GC. Bioinformatics and clinical data revealed that high APOL2 expression is correlated with poor prognosis in GC patients. Functional experiments showed that APOL2 overexpression enhances genomic stability by accelerating DSB repair via the NHEJ pathway, while APOL2 knockout impairs repair capacity. Mechanistically, APOL2 binds to and stabilizes Ku80 by enhancing USP7-mediated deubiquitylation, thereby increasing Ku80 …

Restricting Metabolic Plasticity Enhances Stress Adaptation Through The Modulation Of Pdh And Hif1a In Trap1-Depleted Colon Cancer, Hong-Yuan Tsai, Miao-Hsueh Chen, Jihye Yun, Lisa A Lai, John F Valentine, Mary P Bronner, Teresa A Brentnall, Sheng Pan, Ru Chen

Faculty, Staff and Student Publications

Metabolic plasticity allows cancer cells to survive under adverse conditions. To investigate the role of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) in this process, we used CRISPR/Cas9 mediated genetic deletion to knock out (KO) TRAP1 in colon cancer cells. Depletion of TRAP1 triggered a series of events: induced metabolic reprogramming, increased glycolytic flux, downregulation of mitochondrial complex I, and elevated ROS generation. TRAP1-deficient cells showed tolerance to Oxidative Phosphorylation (OXPHOS) inhibitors and exhibited a higher extracellular acidification rate (ECAR). Additionally, TRAP1 depletion activated hypoxia response elements (HREs) and upregulated HIF1A target genes such as GLUT1 and MCT1. …

Using Video Ethnography And Stimulated Recall Interviews To Describe The Diagnostic Process In The Emergency Department, Milisa Manojlovich, Caitlin Cassady, Sarah J Parker, Ellie Davis, Charlotte Ahr, David Ryamukuru, Anna Wang, Kalyan Pasupathy, Hardeep Singh, Prashant Mahajan

Faculty, Staff and Students Publications

Objectives: Understanding how physicians make diagnoses is challenging because cognitive processes are unobservable and partly unconscious, making it difficult for physicians to describe how they arrived at a diagnosis. Physicians who work in emergency departments (EDs) are especially vulnerable to making diagnostic errors because the ED is a fast-paced, dynamic setting where complex decision-making occurs under severe time, information, and resource constraints. The purpose of our study was to describe how the diagnostic process evolves for ED clinicians in both pediatric and adult ED settings.

Methods: We used a qualitative, video ethnography study design to capture in situ, real-time ED …

Call To Action-Pediatric Masld Requires Immediate Attention To Curb Health Crisis, Phillipp Hartmann, Marialena Mouzaki, Sara Hassan, Mohit Kehar, Krupa R Mysore, Erin Mauney, Dieudonne Nonga, Sara Karjoo, Shilpa Sood, Andrea Tou, Christine Brichta, Rachel E Herdes, Nikhil Pai, Donna K Garner, Mary E Rinella, Mazen Noureddin, Zobair Younossi, Alina M Allen, Arun Sanyal, Taisa Kohut, Rohit Kohli, Charina M Ramirez, Stavra Xanthakos, Miriam B Vos, Jeffrey B Schwimmer, Samar H Ibrahim, Jennifer Panganiban

Faculty, Staff and Students Publications

Pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) has become more prevalent on a global scale over the last decades and is associated with significant comorbidities in childhood and a 40-fold higher risk of early mortality in young adulthood. MASLD has now become the leading indication for liver transplantation in young adults in the United States. However, pediatric MASLD is still perceived as an indolent condition by many patients, families, and clinicians. In this Call to Action, we aim to raise awareness of pediatric MASLD as a public health crisis. Herein, we describe insufficient screening and disease staging practices, and a …

Inhibition Of Bmper Mitigates Pulmonary Hypertension By Modulating Lrp1-Yap Interaction In Smooth Muscle Cells, Hua Mao, Claire M Li, Bing Sun, Christopher S Ward, Alan R Waich-Cohen, Ivan O Rosas, Howard J Huang, Harry Karmouty-Quintana, Liang Xie, Lavannya M Pandit, Xinchun Pi

Faculty, Staff and Students Publications

Background: BMPER (bone morphogenetic protein-binding endothelial regulator) is a secreted protein that is highly expressed in endothelial cells. It regulates the BMP (bone morphogenetic protein) pathway during vascular development and adulthood. Mutations in the BMP pathway are recognized as risk factors for pulmonary arterial hypertension group 1 pulmonary hypertension (PH). However, the roles of BMPER in pulmonary arterial hypertension remain unknown.

Methods: We assessed BMPER expression in Group 1 pulmonary arterial hypertension patient samples and examined its role in vascular remodeling using in vivo and in vitro approaches.

Results: BMPER level was elevated in pulmonary arterial hypertension lungs and significantly …

Six Drivers Of Aging Identified Among Genes Differentially Expressed With Age, Ariella Coler-Reilly, Zachary Pincus, Erica L Scheller, Roberto Civitelli

2020-Current year OA Pubs

Many studies have compared gene expression in young and old samples to gain insights on aging, the primary risk factor for most chronic diseases. However, these studies only identify associations without distinguishing drivers of aging from compensatory geroprotective responses or incidental downstream effects. Here, we introduce a workflow to characterize causal effects of differentially expressed genes on lifespan. First, we performed a meta-analysis of 25 gene expression datasets comprising samples of various tissues from healthy, untreated adult mammals (humans, dogs, and rodents) at two distinct ages. Genes were ranked by the number of datasets in which they exhibited consistent differential …

Nasal Microbionts Differentially Colonize And Elicit Cytokines In Human Nasal Epithelial Organoids, Andrea I Boyd, Leah A Kafer, Isabel F Escapa, Amal Kambal, Hira Tariq, Susan G Hilsenbeck, Hoa Nguyen-Phuc, Anubama Rajan, Joshua M Lensmire, Kathryn A Patras, Pedro A Piedra, Sarah E Blutt, Katherine P Lemon

Faculty, Staff and Students Publications

Nasal colonization by Staphylococcus aureus or Streptococcus pneumoniae is associated with an increased risk of infection by these pathobionts, whereas nasal colonization by Dolosigranulum species is associated with health. Human nasal epithelial organoids (HNOs) differentiated at air-liquid interface (ALI) physiologically recapitulate human nasal respiratory epithelium with a robust mucociliary blanket. Due to their natural stem-like properties, HNO lines are a long-term experimental resource that offers genetic diversity based on the different donors. To develop HNOs as a new model system for bacterial nasal colonization, we reproducibly monocolonized HNOs differentiated at ALI with S. aureus, S. pneumoniae, or Dolosigranulum …

Correcting For The Inflated Adult Population Denominator In An English Nationwide Health Care Cohort: Database Analysis Study, Sudhir Venkatesan, Mark Joy, Gavin Jamie, Debasish Kar, Robert Williams, Xuejuan Fan, Wilhelmine Meeraus, Ruby S.M. Tsang, Kathryn S. Taylor, Sylvia Taylor, F. D. Richard Hobbs, Sneha N. Anand, Chris Robertson, Simon De Lusignan

Peninsula Medical School

Background:Electronic health care databases are widely used for epidemiological studies. However, they may contain inactive records of individuals no longer participating in the health care system. These inactive records create a methodological challenge as they systematically appear as unexposed with no recorded outcomes. Given the widespread health care system engagement during the COVID-19 pandemic, the English National Health Service (NHS), which hosts a national pandemic planning and research dataset with linkage to COVID-19 vaccination and emergency care data, makes it an ideal setting to identify the extent of overrepresentation due to inactive health care records and assess ways to mitigate …

In Utero Rescue Of Neurological Dysfunction In A Mouse Model Of Wiedemann-Steiner Syndrome., Tinna Reynisdottir, Kimberley J Anderson, Katrin Möller, Stefán Pétursson, Andrew Brinn, Katheryn P Franklin, Juan Ouyang, Asbjorg O Snorradottir, Cathleen Lutz, Aamir Zuberi, Valerie B Deleon, Hans T Bjornsson

Faculty Research 2025

Wiedemann-Steiner syndrome (WDSTS) is a rare genetic cause of intellectual disability that is primarily caused by heterozygous loss-of-function variants in the gene encoding the histone lysine methyltransferase 2A (KMT2A). Prior studies have shown successful postnatal amelioration of disease phenotypes for Rett, Rubinstein-Taybi, and Kabuki syndromes, which are related Mendelian disorders of the epigenetic machinery. To explore whether the neurological phenotype in WDSTS is treatable in utero, we created a mouse model carrying a loss-of-function variant placed between 2 loxP sites. Kmt2a+/LSL mice demonstrated core features of WDSTS including growth retardation, craniofacial abnormalities, and hypertrichosis as well as hippocampal memory defects. …

Acute Mastoiditis In Children During The Covid Era: A Systematic Review And Meta-Analysis, Erin Briggs, Isabelle J. Chau, Shaun A. Nguyen, Justin C. Pelic, Erin A. Harvey, Ted A. Meyer

SKMC Student Presentations and Publications

OBJECTIVE: Explore the impact of the COVID-19 pandemic on pediatric acute mastoiditis (AM).

DATA SOURCES: CINAHL, Cochrane Library, PubMed, Scopus.

METHODS: Literature was searched from 2014 to 2025 for articles reporting AM in children. Specific outcomes included clinical presentation, bacterial epidemiology, complications, and management. Primary outcome measures included continuous measures (mean), proportions (%), mean difference (Δ), and relative risk (RR) with 95 % confidence intervals (CI).

RESULTS: There were seven included studies (N = 1001 children) with 632 patients in the pre-COVID cohort and 369 in the COVID-era cohort. There was a significant difference in the proportion of intracranial complications …

Mir147 Promotes Mucosal Integrity And Healing In Intestinal Inflammation, Agnieszka K Czopik, Arash Dabiri, Chia-Hao Tung, Victoria Vaughn, Xiangsheng Huang, Jinlian Wang, Hui Li, Nicolas F Moreno, Natalia V Piwko, Katherine Figarella, Hongfang Liu, Zhongming Zhao, Xiaoyi Yuan, Holger K Eltzschig

Faculty, Staff and Student Publications

The intestinal mucosal epithelium forms a barrier between luminal contents and the body. MicroRNAs (miRNAs) regulate mucosal homeostasis by controlling inflammatory responses and structural integrity. Here, we discovered a protective role for miR147 in intestinal inflammation using a miR147tdTomato reporter mouse. miR147 was enriched in the intestines, with the highest expression in the colonic epithelial cells at the luminal surface, with prominent expression in differentiated enterocytes. Mice with general or intestinal epithelial deletion of miR147 showed increased intestinal inflammation and diminished mucosal healing during colitis. RNA sequencing of miR147-deficient cells showed dysregulated immune signaling, with upregulated proinflammatory cytokine pathways and …