Medicine and Health Sciences Commons^™

Sox2 Regulates Foregut Squamous Epithelial Homeostasis And Is Lost During Barrett’S Esophagus Development, Ramon U Jin, Yuanwei Xu, T Mamie Lih, Yang-Zhe Huang, Toni M Nittolo, Blake E Sells, Olivia M Dres, Jean S Wang, Qing K Li, Hui Zhang, Jason C Mills

Faculty, Staff and Students Publications

Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-KO (Krt5CreER/+ Sox2Δ/Δ ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at …

Integration Of Spatial Protein Imaging And Transcriptomics In The Human Kidney Tracks The Regenerative Potential Of Proximal Tubules, Mahla Asghari, Sanjay Jain, Et Al.

2020-Current year OA Pubs

The organizational principles of nephronal segments are based on anatomical and physiological attributes that are linked to the homeostatic functions of the kidney. Recent molecular approaches have uncovered layers of deeper signatures and states in tubular cells that arise at various time points on the disease trajectory. Here, we introduce an analytical pipeline of multiplexed spatial protein imaging integrated with RNA expression to characterize proximal tubular subpopulations and neighborhoods in human kidney tissue. We demonstrate that, in reference tissue, a large proportion of S1 proximal tubular epithelial cells expresses thymus antigen 1 (THY1), a mesenchymal stromal and stem cell marker …

Sox2 Regulates Foregut Squamous Epithelial Homeostasis And Is Lost During Barrett's Esophagus Development, Ramon U. Jin, Yuanwei Xu, T. Mamie Lih, Yang-Zhe Huang, Toni M. Nittolo, Blake E. Sells, Olivia M. Dres, Jean S. Wang, Qing K. Li, Hui Zhang, Jason C. Mills

2020-Current year OA Pubs

Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-KO (Krt5CreER/+ Sox2Δ/Δ ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at …

Informatics At The Frontier Of Cancer Research, Kathleen Noller, Malachi Griffith, Daniel Marcus, Et Al.

2020-Current year OA Pubs

Digitized healthcare data, high-throughput profiling technologies, and data repositories have facilitated the emergence of a new era of cancer research. Each data stream requires specialized analysis methods for interpretation. The data-driven era of cancer research requires the development, enhancement, and sustainment of informatics technology software infrastructure, including fundamental methodology development in artificial intelligence and data science. We review current and emerging informatics technology developments for cancer research and discovery, spanning molecular and cellular characterizations, image analysis, informatics, and therapeutics. Summarizing the diverse methods and applications of informatics throughout cancer research identifies themes and emerging areas for the next generation of …

Implementation Of Clinical Practice Guidelines To Prevent Cervical Cancer: Mixed Methods Study, Oliver C Ezechi, Folahanmi T Akinsolu, Olunike R Abodunrin, Oluwabukola M Ola, Chisom Obi-Jeff, Ishak K Lawal, George U Eleje, Joseph D Tucker, Juliet I Iwelunmor

2020-Current year OA Pubs

BACKGROUND: Cervical cancer is a common cause of death among women globally, particularly in Africa. Each year, an average of 7093 women in Nigeria die from cervical cancer. Clinical practice guidelines developed by the Society of Obstetrics and Gynecology of Nigeria (SOGON) aim to prevent cervical cancer. However, the extent of their adoption among gynecologists remains unclear.

OBJECTIVE: This study aimed to assess Nigerian gynecologists' awareness, understanding, and incorporation of the SOGON clinical practice guidelines for cervical cancer prevention in their clinical practices.

METHODS: A convergent parallel mixed methods design was used. Quantitative data were collected via a web-based and …

Multidimensional Analysis Of B7 Homolog 3 Rna Expression In Small Cell Lung Cancer Molecular Subtypes, Carl M Gay, Taofeek K Owonikoko, Lauren A Byers, Noura J Choudhury, Sajid Ahmed, Zachary Cain, Xiaozhong Qian, Matthew Brentnall, Simon Heeke, Ming Poi, Sharon Wu, Charles M Rudin

Faculty, Staff and Student Publications

Purpose: B7 homolog 3 (B7-H3) is a promising target for antibody-drug conjugates, with ifinatamab deruxtecan demonstrating an objective response rate of 54.8% in previously treated extensive-stage small cell lung cancer (SCLC). This analysis aimed to characterize B7-H3 RNA expression with reference to SCLC molecular subtypes (SCLC-A, SCLC-N, SCLC-P, and SCLC-I) and immune-related parameters.

Experimental design: Tumor RNA expression and mutational burden for 1,721 patients with SCLC were derived from a real-world database (Caris Life Sciences). A predominant molecular subtype was assigned based on RNA expression using a gene-ratio classifier. PD-L1 expression was assessed by IHC (antibody 22C3; positive cutoff: tumor …

Large-Scale Crispr Screening In Primary Human 3d Gastric Organoids Enables Comprehensive Dissection Of Gene-Drug Interactions, Yuan-Hung Lo, Hudson T Horn, Mo-Fan Huang, Wei-Chieh Yu, Chia-Mei Young, Qing Liu, Madeline Tomaske, Martina Towers, Antonia Dominguez, Michael C Bassik, Dung-Fang Lee, Lei S Qi, Jonathan S Weissman, Jin Chen, Calvin J Kuo

Faculty, Staff and Student Publications

Understanding how genes influence drug responses is critical for advancing personalized cancer treatments. However, identifying these gene-drug interactions in a physiologically relevant human system remains a challenge, as it requires a model that reflects the complexity and heterogeneity among individuals. Here we show that large-scale CRISPR-based genetic screens, including knockout, interference (CRISPRi), activation (CRISPRa), and single-cell approaches, can be applied in primary human 3D gastric organoids to systematically identify genes that affect sensitivity to cisplatin. Our screens uncover genes that modulate cisplatin response. By combining CRISPR perturbations with single-cell transcriptomics, we resolve how genetic alterations interact with cisplatin at the …

Transcriptional Remodeling Shapes Therapeutic Vulnerability To Necroptosis In Acute Lymphoblastic Leukemia, Anna Saorin, Anna Dehler, Bartimée Galvan, Fabio Steffen, Marine Ray, Dong Lu, Xin Yu, James Kim, Aneta Drakul, Samanta Kisele, Jin Wang, Jean-Pierre Bourquin, Beat C Bornhauser

Faculty, Staff and Students Publications

Insufficient eradication of cancer cells and survival of drug tolerant clones are major relapse driving forces. Underlying molecular mechanisms comprise activated prosurvival and antiapoptotic signaling, leading to insufficient apoptosis and drug resistance. The identification of programmed cell death pathways alternative to apoptosis opens up possibilities to antagonize apoptosis escape routes. We have earlier shown that acute lymphoblastic leukemia (ALL) harbors a distinct propensity to undergo cell death by receptor-interacting protein kinase 1 (RIPK1)-dependent necroptosis, activated by small-molecule second mitochondria-derived activators of caspase (SMAC) mimetics. Despite demonstrated safety and tolerability of SMAC mimetics in clinical trials, their efficacy as single agent …

Inter- And Intra-Observer Agreement In Ultrasound Diagnosis Of Steatotic Liver Disease: Implications For Screening In Resource-Limited Settings, Maria Spencer-Sandino, Maya Balakrishnan, David Wynne, Ilona Argirion, Paz Cook, Vanessa Van De Wyngard, Noldy Mardones, Ruth Pfeiffer, Allan Hildesheim, Catterina Ferreccio, Jill Koshiol

Faculty, Staff and Students Publications

Steatotic liver disease (SLD), which is associated with increased risk of cancer-related mortality, needs timely and cost-effective detection. Although liver biopsy remains the diagnostic gold standard, its invasiveness and high-cost limit widespread use. Ultrasound is a practical and affordable alternative. We evaluated inter- and intra-observer agreement for ultrasound-based diagnosis of SLD using images from the Chile Biliary Longitudinal Study (Chile BiLS), a cohort of women with gallstones. These women have a high burden of obesity and related metabolic disorders, putting them at higher risk for SLD. A radiologist (observer 1) reviewed a randomly selected subset of 425 baseline images and …

Baby Open Brains: An Open-Source Dataset Of Infant Brain Segmentations, Eric Feczko, Dimitrios Alexopoulos, Christopher D Smyser, Et Al.

2020-Current year OA Pubs

Reproducibility of neuroimaging research on infant brain development remains limited due to highly variable processing approaches. Progress towards reproducible pipelines is limited by a lack of benchmarks such as gold-standard brain segmentations. These segmentations are limited by the difficulty of infant brain segmentations, which require extensive neuroanatomical knowledge and are time-consuming in nature. Addressing this, we constructed the Baby Open Brains (BOBs) Dataset, an open source resource of manually curated and expert reviewed infant brain segmentations. Anatomical MRI data was segmented from 71 infant imaging visits across 51 participants, using both T1w and T2w images per visit. Images showed dramatic …

Multimodal Spatial Transcriptomic Characterization Of Mouse Kidney Injury And Repair, Qiao Xuanyuan, Haojia Wu, Hemalatha Sundaramoorthi, Pierre Isnard, Changfeng Chen, Waleed Rahmani, Benjamin D Humphreys

2020-Current year OA Pubs

The transition from acute kidney injury to chronic kidney disease is characterized by significant changes in the cellular composition and molecular interactions within the kidney. Utilizing high-resolution Xenium and whole transcriptome Visium spatial transcriptomics platforms, we analyze over a million cells on 12 male mouse kidneys across six stages of renal injury and repair. We define and validate 20 major kidney cell populations and delineate distinct cellular neighborhoods through this multimodal spatial analysis. We further reveal a specific fibro-inflammatory niche enriched in failed-repair proximal tubule cells, fibroblasts, and immune cells, with conserved neighborhood gene signatures across mouse and human. Within …

Cortical Spectral Dynamics Of Vibrotactile Frequency Processing, Nabi Rustamov, Phillip Demarest, Zhuangyu Han, Safia Mohamud, Simon Haroutounian, Eric C Leuthardt

2020-Current year OA Pubs

While scientific research has extensively explored how the brain integrates touch and pain signals, the cerebral processing of specific vibrotactile frequencies remains poorly understood. This gap is particularly significant given clinical evidence that vibrotactile stimulation can reduce pain in both chronic pain patients and experimental settings. Our study investigated the cortical electrophysiological correlates of peripheral vibrotactile stimulation across different frequencies in healthy volunteers, with a focus on frequency-dependent patterns of neuronal activation. While electroencephalogram (EEG) was recorded, healthy participants received vibrotactile stimulation (high-frequency burst stimulation with different inter-burst intervals) to the left index fingertip at frequencies corresponding to established neural …

Artificial Intelligence Algorithm Predicts Response To Immune Checkpoint Inhibitors, Faisal Fa'ak, Nicolas Coudray, George Jour, Milad Ibrahim, Irineu Illa-Bochaca, Shi Qiu, Adalberto Claudio Quiros, Ke Yuan, Douglas B Johnson, David L Rimm, Jeffrey S Weber, Aristotelis Tsirigos, Iman Osman

2020-Current year OA Pubs

PURPOSE: Cancer treatment has been revolutionized by immune checkpoint inhibitors (ICI). However, a subset of patients do not respond and/or they experience significant adverse events. Attempts to integrate reliable biomarkers of ICI response as part of standard care have been hampered by limited generalizability. We previously reported our supervised machine learning (ML) model in a retrospective cohort of metastatic melanoma.

EXPERIMENTAL DESIGN: In this study, we expanded our testing to include larger cohorts of patients with melanoma accrued at several sites, including patients enrolled in clinical trials in both adjuvant and metastatic settings. We examined pretreatment hematoxylin and eosin slides …

Gastrointestinal Fistulas-What Gastroenterologists Need To Know In 2025, Monjur Ahmed

Division of Gastroenterology and Hepatology Faculty Papers

Gastrointestinal fistulas are increasingly being encountered in our clinical practice because of the increased burden of Crohn's disease, bariatric surgeries, interventional endoscopic procedures, nonsurgical trauma, and war and disaster zones worldwide. Presentation depends on the location and specific type of the fistula. Symptomatic ones can have a tremendous impact on social life and can cause dehydration, electrolyte imbalance, malnutrition, increased morbidity, and mortality. Different imaging studies and endoscopic procedures are done to establish the diagnosis. Treatment modalities to close the fistula depend on the underlying disease and the type of fistula. They include conservative treatment, medical therapy, endoscopic interventions, and …

Advanced Specificity And Sensitivity Studies Relative To A Research Use Only Transcription-Mediated Amplification-Based Assay For Treponema Pallidum Rna Detection, Trinity Krueger, Grace Kadonsky, Elizabeth Thelen, Amanda Zapp, Josephine Moore, Ahmet Muslu, Allan Pillay, Irene A Stafford, Erik Munson

Faculty, Staff and Student Publications

Preliminary experimentation has suggested that a research-use-only real-time transcription-mediated amplification assay for Treponema pallidum (RUO T. pallidum TMA) yields instances of T. pallidum nucleic acid detection that coincide with non-treponemal serology in men who have sex with men (MSM) at increased risk for sexually transmitted infection. To further characterize the specificity of RUO T. pallidum TMA testing, 3,586 rectal swab specimens reported as “not detected” by the assay generated a mean endpoint FAM fluorescence of 637.5 units. Introduction of Treponema denticola, Treponema phagedenis, and Treponema refringens nucleic acid into matrices generated mean endpoint FAM fluorescence ranging from 620.7 …

Csf-Exosomal Mirnas And Delayed Cerebral Ischemia: Insights Into Pathophysiology But No Definitive Biomarkers, Chathathayil M Shafeeque, Devin W Mcbride, Yuanqing Yan, Hussein A Zeineddine, John P Hagen, H Alex Choi, Jude P Savarraj, Ari Dienel, Spiros L Blackburn, Peeyush Kumar Thankamani

Faculty, Staff and Student Publications

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is notoriously known for its high mortality and morbidity. Approximately one-third of the patients who survive aneurysm rupture are reported to develop delayed cerebral ischemia (DCI), which contributes to a poor clinical outcome. Currently, there are no biomarkers for identifying which aSAH patients are at risk of developing DCI. We aimed to determine the feasibility of cerebrospinal fluid (CSF) exosomal microRNAs (miRNAs) for predicting DCI post-aSAH.

Methods: aSAH patients were prospectively enrolled, and CSF samples were collected at two time points (< 24 h and 72 h post-aSAH) from individuals undergoing external ventricular drainage. Exosomal miRNAs were isolated from the CSF for analysis. In the initial group of patients (discovery cohort), an exploratory analysis was conducted using a CSF panel containing 84 miRNAs, assessed by quantitative real-time PCR (RT-qPCR). Based on this analysis, 27 miRNAs were selected for further evaluation in a second group of patients (validation cohort). Among these, 10 miRNAs had previously been reported in SAH-related CSF studies, supporting their relevance for continued investigation.

Results: In this study, RT-qPCR analysis of 84 miRNAs in CSF samples from …

Dalbavancin For Treatment Of Staphylococcus Aureus Bacteremia: The Dots Randomized Clinical Trial, Nicholas A Turner, Toshimitsu Hamasaki, Sarah B Doernberg, Thomas P Lodise, Heather A King, Varduhi Ghazaryan, Sara E Cosgrove, Timothy C Jenkins, Catherine Liu, Shrabani Sharma, Smitha Zaharoff, Lana Wahid, Valerie J Renard, Paul Cook, Issam Raad, Ray Hachem, Anne-Marie Chaftari, Matthew Sims, Carmen Demarco, Loren G Miller, Matthew W Mccarthy, Caryn G Morse, Chris Lucasti, Graeme N Forrest, Kartikeya Cherabuddi, Christopher Polk, Tasaduq Fazili, Mark E Rupp, George R Thompson, Kami Kim, Luke Strnad, Amanda E Schnee, James A Mckinnell, Mayur Ramesh, Fernanda P Silveira, Todd P Mccarty, Todd C Lee, Emily G Mcdonald, Kristopher Paolino, Katie Wiegand, Alison Wall, Todd Riccobene, Rinal Patel, Urania Rappo, Scott Evans, Henry F Chambers, Vance G Fowler, Thomas L Holland

Faculty, Staff and Student Publications

Importance: Dalbavancin is a long-acting intravenous lipoglycopeptide that may be effective for treatment of complicated Staphylococcus aureus bacteremia without requiring long-term intravenous access.

Objective: To evaluate the efficacy and safety of dalbavancin vs standard therapy for completion of treatment of complicated S aureus bacteremia.

Design, setting, and participants: Open-label, assessor-masked, randomized clinical trial conducted from April 2021 to December 2023 at 23 medical centers in the US (n = 22) and Canada (n = 1). Participant follow-up lasted 70 days (180 days for participants with osteomyelitis); date of final follow-up was December 1, 2023. Hospitalized adults with complicated S aureus …

Macrophage Phagocytosis Of Human Norovirus-Infected Cells In An Ex Vivo Human Enteroid-Macrophage Coculture Model, Ngan Fung Li, Sue E Crawford, Sydney R Mittiga, Cristian Coarfa, Hoa Nguyen-Phuc, Budi Utama, Sarah E Blutt, Sasirekha Ramani, Mary K Estes

Faculty, Staff and Students Publications

Human norovirus (HuNoV) causes acute gastroenteritis in immunocompetent hosts and chronic infection in immunocompromised individuals. Many recent studies of replication and innate immune responses following HuNoV infection have utilized epithelium-only human intestinal enteroids (HIEs), which lack immune cells. Here, we utilized an ex vivo enteroid-macrophage coculture model consisting of HIEs and different subtypes of human peripheral blood mononuclear cell-derived macrophages to better recapitulate in vivo gut biology and explore the role of macrophages in HuNoV replication and pathogenesis. We show that HuNoV infection in HIEs polarized on Transwells leads to bilateral release of the viral genome, with predominant apical virus …

Cardiovascular Autonomic Neuropathy Defined By Indices Of Heart Rate Variability Is Associated With Cardiovascular Disease: A Longitudinal Cohort Study Of Participants With Type 1 Diabetes, Barbara H Braffett, Laure El Ghormli, Catherine Martin, Neil H White, Irl B Hirsch, Anne Bantle, Anders Carlson, Ellen Leschek, Rose Gubitosi-Klug, Elsayed Z Soliman, Adrian Vella, Bruce A Perkins, Ionut Bebu, Rodica Pop-Busui, Dcct/Edic Research Group

2020-Current year OA Pubs

BACKGROUND: To describe longitudinal prevalence and risk factors associated with cardiovascular autonomic neuropathy (CAN), defined by heart rate variability (HRV) indices, and evaluate the impact of CAN on cardiovascular disease (CVD), in adults with type 1 diabetes (T1D) from the Epidemiology of Diabetes Interventions and Complications (EDIC) study.

METHODS: Standard resting electrocardiogram (ECG) recordings were obtained annually in 997 participants (mean ± SD age 56.2 ± 6.8 years; T1D duration 34.7 ± 7.9 years; 48% female) between 2015 and 2022. The standard deviation of normally conducted R-R intervals (SDNN) and root mean square of successive differences between normal-to-normal R-R intervals …

Development Of Emerin Mrna Lipid Nanoparticles To Rescue Myogenic Differentiation., Nicholas Marano, Liza Elif Guner, Rachel S Riley, James M Holaska

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Emery-Dreifuss muscular dystrophy 1 (EDMD1) arises from mutations in EMD. Most EDMD1 patients lack detectable emerin expression. They experience symptoms such as skeletal muscle wasting, joint contractures, and cardiac conduction defects. Currently, physicians rely on treating patient symptoms without addressing the underlying cause-lack of functional emerin protein. Thus, there is a need for therapeutic approaches that restore emerin protein expression to improve patient outcomes. One way would be to deliver emerin mRNA or protein directly to affected tissues to restore tissue homeostasis. Here, we evaluated the utility of lipid nanoparticles (LNPs) to deliver emerin mRNA to diseased cells. LNPs …

Variability In Long Covid Definitions And Validation Of Published Prevalence Rates, Lauren E. Wisk, Michelle L'Hommedieu, Kate Diaz Roldan, Imtiaz Ebna Mannan, Erica S. Spatz, Robert A. Weinstein, Arjun K. Venkatesh, Michael Gottlieb, Ryan Huebinger, Kristin L. Rising, Juan Carlos C. Montoy, Kari A. Stephens, Robert M. Rodriguez, Mandy J. Hill, Kelli N. O'Laughlin, Nicole L. Gentile, Ahamed H. Idris, Shu-Xia Li, Michelle Santangelo, Efrat R. Kean, Samuel A. Mcdonald, Kristyn Gatling, Joann G Elmore

Jefferson Center for Connected Care Faculty Papers

IMPORTANCE: Long COVID definitions vary widely, and no consensus exists on how to accurately measure its prevalence, complicating both clinical care and research.

OBJECTIVE: To assess long COVID prevalence using various definitions from published literature.

DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter cohort study used data from the longitudinal Innovative Support for Patients With SARS-CoV-2 Infections Registry (INSPIRE). Participants aged 18 years or older with symptoms suggestive of COVID-19 illness at the time of their index SARS-CoV-2 test enrolled at 8 sites across the US from December 11, 2020, through August 29, 2022, with follow-up surveys collected through February 28, …

Tracing Sars-Cov-2 Clusters Across Local Scales Using Genomic Data, Leke Lyu, Mandev Gill, Guppy Stott, Sachin Subedi, Cody Dailey, Gabriella Veytsel, Magdy Alabady, Kayo Fujimoto, Ryker Penn, Pamela Brown, Roger Sealy, Justin Bahl

Faculty, Staff and Student Publications

A quantitative understanding of local transmission dynamics is essential for designing effective prevention strategies. In this study, we developed a computational workflow to identify viral introductions and trace locally circulating clusters. We analyzed over 26,000 SARS-CoV-2 genomes and their associated metadata, collected between January and October 2021, to explore introduction and local dispersal patterns in Greater Houston, a major metropolitan area known for its demographic diversity. Our analysis identified more than 1,000 independent introduction events, resulting in clusters of varying sizes. The majority of introductions originated from domestic sources, while international introductions occurred earlier and were associated with larger cluster …

Molecular Inflammatory Expression Profiles Associated With The Frequency Of Pain In Individuals With Sickle Cell Disease, Lana Mucalo Katunaric, Shuang Jia, Ashima Singh, Mark F. Roethle, Julie A. Panepinto, David C. Brousseau, Martin J. Hessner, Amanda M. Brandow

Department of Pediatrics Faculty Papers

Pain is the most common complication of sickle cell disease (SCD). The underlying biology of SCD pain is not well understood, which is a barrier to novel, effective analgesic and preventive therapies. A wide variability in the phenotypic expression of pain exists among individuals with SCD, despite the inheritance of a similar defective hemoglobin gene. This interindividual pain variability further complicates the ability to understand the biology and effectively treat pain. We sought to discover a biological signature comprising differentially expressed genes unique to SCD that could differentiate between individuals with varied pain frequency. We conducted plasma-induced transcription analysis from …

Assessing The Muc5b Promoter Variant In A Large Cohort Of Systemic Sclerosis-Associated Interstitial Lung Disease, Carlos Rosa-Baez, Carlos Rangel-Pelaez, Inmaculada Rodriguez-Martin, Martin Kerick, Alfredo Guillen-Del-Castillo, Carmen P Simeon-Aznar, José Luis Callejas, Alexandre E Voskuyl, Alexander Kreuter, Oliver Distler, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Jeska K De Vries-Bouwstra, Ariane L Herrick, Yannick Allanore, Lorenzo Beretta, Maureen D Mayes, Christopher P Denton, Shervin Assassi, Javier Martin, Marialbert Acosta-Herrera

Faculty, Staff and Student Publications

Objective: The common gain-of-function variant rs35705950, located in the promoter of MUC5B gene, has been strongly associated with interstitial lung diseases (ILDs) of different aetiology, such as idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated ILD (RA-ILD). In this study, we aimed to investigate the association of this variant and its nearby single nucleotide polymorphisms (SNPs) in the largest cohort of systemic sclerosis-associated ILD (SSc-ILD) to date.

Methods: Samples were collected from blood/saliva, followed by DNA extraction and genotyping using SNP arrays. Data for rs35705950 and additional 903 variants within 100 Kb were obtained using genomic imputation. Subsequently, we tested their …

Video-Based Intervention To Reduce Treatment And Outcome Disparities In Adults Living With Stroke Or Transient Ischemic Attack (Virtual): Protocol For A Randomized Controlled Trial, Munachi Okpala, Chigozirim Izeogu, Mengxi Wang, Charles Green, Gabretta Cooksey, Thuy Nguyen, Sarah Cohen, Latonya Bryant, Daphne C Hernandez, Elmer V Bernstam, Michael Gonzales, Rhonda Conyers, Olasimbo Chiadika, Kristin Varacalli, Sean I Savitz, Jose-Miguel Yamal, Anjail Z Sharrief

Faculty, Staff and Student Publications

Background: Racial and ethnic disparities in post-stroke blood pressure (BP) control persist, and effective interventions to address post-stroke care inequities are needed. We designed a randomized comparative effectiveness trial to evaluate the Video-based Intervention to Reduce Treatment and Outcome Disparities in Adults Living with Stroke or Transient Ischemic Attack (VIRTUAL) model of care for post-stroke BP reduction.

Methods: The study will enroll 534 stroke survivors in a randomized trial to receive either the VIRTUAL intervention or enhanced standard care. Individuals with ischemic stroke, hemorrhagic stroke, or transient ischemic attack (TIA) are enrolled before hospital discharge and randomized (1:1) to VIRTUAL …

Extracellular Vesicles For Clinical Diagnostics: From Bulk Measurements To Single-Vesicle Analysis, Hai Linh Tran, Wenshu Zheng, David A Issadore, Hyungsoon Im, Yoon-Kyoung Cho, Yuanqing Zhang, Dingbin Liu, Yang Liu, Bo Li, Fei Liu, David Tai Wai Wong, Jiashu Sun, Kun Qian, Mei He, Meihua Wan, Yong Zeng, Ke Cheng, Tony Jun Huang, Daniel T Chiu, Luke P Lee, Lei Zheng, Andrew K Godwin, Raghu Kalluri, Steven A Soper, Tony Y Hu

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) play a crucial role in intercellular communication, signaling pathways, and disease pathogenesis by transporting biomolecules such as DNA, RNA, proteins, and lipids derived from their cells of origin, and they have demonstrated substantial potential in clinical applications. Their clinical significance underscores the need for sensitive methods to fully harness their diagnostic potential. In this comprehensive review, we explore EV heterogeneity related to biogenesis, structure, content, origin, sample type, and function roles; the use of EVs as disease biomarkers; and the evolving landscape of EV measurement for clinical diagnostics, highlighting the progression from bulk measurement to single vesicle …

Non-Isolated Tetralogy Of Fallot (Tof+): Exome Sequencing Efficacy And Phenotypic Expansions, Julia Volpi, Xiaonan Zhao, Nichole Owen, Tia Evans, Muriel Holder-Espinasse, Nayana Lahiri, Eleanor Sherlock, Gemma Poke, Jeroen Breckpot, Koen Devriendt, Bjorn Cools, Alfredo Brusco, Giovanni Battista Ferrero, Enrico Grosso, Pradeep Vasudevan, Sara Loddo, Antonio Novelli, Maria Cristina Digilio, Aafke Engwerda, Marrit Hitzert, Alison Male, Lucy Bownass, Ruth Newbury-Ecob, Zosia Miedzybrodzka, Ruth Armstrong, Sally Ann Lynch, Gunnar Houge, Shiyi Xiong, Seema R Lalani, Jill A Rosenfeld, Pamela N Luna, Chad A Shaw, Daryl A Scott

Faculty, Staff and Students Publications

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD). TOF may present in isolation or in conjunction with one or more non-cardiac congenital anomalies or neurodevelopmental disorders (TOF+). Uncertainty regarding the efficacy of various genetic testing strategies, and an incomplete understanding of the genetic causes of TOF+, may lead to hesitancy in recommending genetic testing, particularly, clinical exome sequencing (cES). Here, we analyzed cES data from 131 individuals with TOF+. A definitive or probable diagnosis was made for 31 individuals, yielding a diagnostic rate of 23.6% (31/131). One individual received three diagnoses. Commercially available CHD panels …

Pd-1 Inhibition For Relapse After Allogeneic Transplantation In Acute Myeloid Leukemia And Myelodysplastic Syndrome, John M Magenau, David G Frame, Mary Riwes, John Maciejewski, Sarah Anand, Attaphol Pawarode, Anamarija M Perry, Marcus Geer, Thomas Braun, Monalisa Ghosh, Pavan Reddy

Faculty, Staff and Students Publications

Relapse of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains the primary source of mortality after allogeneic hematopoietic stem cell transplantation (HCT). Targeting programmed death-1 (PD-1) for reversing T-cell exhaustion and restoring the graft-versus-leukemia (GVL) effect may have logistical advantages over donor lymphocyte infusion. In a prospective phase 1B clinical trial, pembrolizumab was administered every 3 weeks to 16 patients with AML (n = 12) and MDS (n = 4) in relapse after HCT to assess graft-versus-host disease (GVHD), clinical response, and survival. The median time to relapse after HCT was 5.5 months and the median pretreatment bone marrow …

Shared And Distinct Alterations In Brain Structure Of Youth With Internalizing Or Externalizing Disorders: Findings From The Enigma Antisocial Behavior, Adhd, Mdd, And Anxiety Working Groups, Sophie Townend, Marlene Staginnus, Yidian Gao, Nina Alexander, Volker Arolt, Tobias Banaschewski, Mark A Bellgrove, Vivek Benegal, Robert J Blair, Laura Blanco-Hinojo, Ole Jonas Boeken, Joscha Böhnlein, Sven Bölte, Linda M Bonnekoh, Daniel Brandeis, Rodrigo A Bressan, Fabian Breuer, Willem B Bruin, Jan K Buitelaar, Katie L Burkhouse, Monica E Calkins, Marta Cano, Narcis Cardoner, Hui Chen, Xianliang Chen, David R Coghill, Olivier F Colins, Colm G Connolly, Michael C Craig, Kathryn R Cullen, Udo Dannlowski, Christopher G Davey, Andrea Dietrich, Daifeng Dong, Christine M Freitag, Thomas Frodl, Liesbet Goossens, Dominik Grotegerd, Raquel E Gur, Ruben C Gur, Jan Haavik, Cindy C Hagan, Tim Hahn, Alfons O Hamm, Ben J Harrison, Catharina A Hartman, Martin J Herrmann, Tiffany C Ho, Pieter J Hoekstra, Bharath Holla, Karim Ibrahim, Andrea Jackowski, Hamidreza Jamalabadi, Yali Jiang, Tilo Kircher, Kerstin Konrad, Anna Kraus, Jonna Kuntsi, Till Langhammer, Luisa Lazaro, Elisabeth J Leehr, Ulrike Lueken, Ren Ma, Frank P Macmaster, Gisele G Manfro, Anne Martinelli, Hannah Meinert, Susanne Meinert, Jarosław M Michałowski, Qingsen Ming, Robert Moeck, Lilianne R Mujica-Parodi, Benson Mwangi, Janina Neufeld, Joel T Nigg, Ruth L O'Gorman Tuura, Hyuntaek Oh, Jaap Oosterlaan, Yannis Paloyelis, Pedro M Pan, Luca Passamonti, Wenceslao Peñate, K Luan Phan, Kerstin J Plessen, Jesus Pujol, Karl Lundin Remnélius, Francisco Rivero, Katya Rubia, Ramiro Salas, Giovanni A Salum, Theodore D Satterthwaite, Anne Schienle, Elisabeth Schrammen, Koen R J Schruers, Gunter Schumann, Arjun Sethi, Tim Silk, Norbert Skokauskas, Jordan Smoller, Jair C Soares, Lin Sørensen, Christina Stadler, Michael C Stevens, Benjamin Straube, Thomas Straube, Andreas Ströhle, Gustavo Sudre, Denis G Sukhodolsky, Kate Sully, Xiaoqiang Sun, Chad M Sylvester, Nicola Toschi, Steven J A Van Der Werff, Alasdair Vance, Robert Vermeiren, Albert Wabnegger, Xiaoping Wang, Julia Wendt, Sarah Whittle, Julian Wiemer, Anderson M Winkler, Hans U Wittchen, Mon-Ju Wu, Qiong Wu, Tony T Yang, Yunbo Yang, Shuqiao Yao, Jibiao Zhang, Jiansong Zhou, Andre Zugman, Giovana B Zunta-Soares, Peter M Zwanzger, Sophia I Thomopoulos, Neda Jahanshad, Paul M Thompson, Kevin Hilbert, Arielle Baskin-Sommers, Charlotte A M Cecil, Moji Aghajani, Daniel S Pine, Nic J A Van Der Wee, Dan J Stein, Nynke A Groenewold, Janna Marie Bas-Hoogendam, Laura K M Han, Elena Pozzi, Lianne Schmaal, Barbara Franke, Martine Hoogman, Esther Walton, Stephane A De Brito, Graeme Fairchild, Enigma Antisocial Behavior, Anxiety, Adhd, And Mdd Working Groups

Staff and Researcher Publications

BACKGROUND: Externalizing and internalizing disorders are common in youth but are often studied separately, preventing researchers from identifying shared (i.e., transdiagnostic) alterations in brain structure. Using data from the ENIGMA Consortium, we conducted a mega-analysis to identify shared and distinct cortical and subcortical brain alterations across internalizing (anxiety disorders and depression) and externalizing disorders (attention-deficit/hyperactivity disorder [ADHD] and conduct disorder [CD]) in youth.

METHODS: 3D T1-weighted MRI data from youth (aged 4-21 years) with anxiety disorders (n=1,044), depression (n=504), ADHD (n=1,317), and CD (n=1,172), along with healthy controls (n=4,743) were analyzed. We assessed group differences in regional cortical thickness, surface …

Structural Basis For Membrane Microdomain Formation By A Human Stomatin Complex, Jack Stoner, Shufang Li, Ziao Fu

2020-Current year OA Pubs

Biological membranes are not just passive barriers-they actively sense and respond to mechanical forces, in part through specialized proteins embedded within them. Among these are Stomatin-family proteins, which are known to influence membrane stiffness and regulate ion channels, yet how they achieve these functions at the molecular level has remained elusive. Here, we report the 2.2 Å cryo-electron microscopy structure of the human Stomatin complex in a native membrane environment. We find that Stomatin assembles into a 16-subunit ring-shaped homo-oligomer, forming a ~12 nm-wide cage that defines a mechanically distinct, curvature-resistant membrane microdomain. While the majority of the complex exhibits …