Digital Commons Network^™

Hand Hygiene Roles, Challenges, And Intervention Feedback From School Staff: A Qualitative Analysis, Belize, 2022-2023, Anh N Ly, Christina Craig, Dian Maheia, Yolanda Gongora, Vickie Romero, Rosalva Blanco, Allison Lino, Kelsey Mcdavid, Allison Stewart, Victoria Trinies, Alexandra Medley, Francis Morey, Russell Manzanero, Matthew Lozier, Kristy O Murray

Faculty, Staff and Students Publications

Hand hygiene (HH) in school settings can reduce the spread of infectious diseases and student absenteeism due to illness. During the COVID-19 pandemic, the World Health Organization recommended HH as a public health measure to prevent disease transmission. Understanding school staff's experiences with school-based programs is important for future program development and improvement. As part of a mixed-methods study, we conducted in-depth interviews in March 2022 with school administrators and teachers at 12 primary schools in Belize, selected based on high gaps in HH resources, to understand HH responsibilities, supplies, and challenges. An intervention was implemented to increase HH knowledge …

Extracorporeal Membrane Oxygenation For Systemic Lupus Erythematosus: An Elso Registry Analysis, Maria Pereira, Danielle Guffey, Katherine Doane, Eyal Muscal, Carla Levin, Peter Rycus, Marc Anders, Andrea Ontaneda

Faculty, Staff and Students Publications

The success of extracorporeal membrane oxygenation (ECMO) in treating Systemic Lupus Erythematosus (SLE) and the risk factors associated with mortality remain uncertain. Methods: We describe the survival outcomes at discharge of the largest SLE cohort on ECMO support. We performed a retrospective cohort study of the Extracorporeal Life Support Organization registry database from 2012 to 2022. Pediatric and adult survivor groups were analyzed using descriptive statistics for the primary study outcome of survival to hospital discharge. Risk predictors for survival were determined by logistic regression.Results: We included 48 children and 368 adults with SLE. Overall, 198 patients (54%) survived …

Comprehensive Evaluation Of Phosphoproteomic-Based Kinase Activity Inference, Sophia Müller-Dott, Eric J Jaehnig, Khoi Pham Munchic, Wen Jiang, Tomer M Yaron-Barir, Sara R Savage, Martin Garrido-Rodriguez, Jared L Johnson, Alessandro Lussana, Evangelia Petsalaki, Jonathan T Lei, Aurelien Dugourd, Karsten Krug, Lewis C Cantley, D R Mani, Bing Zhang, Julio Saez-Rodriguez

Faculty, Staff and Students Publications

Kinases regulate cellular processes and are essential for understanding cellular function and disease. To investigate the regulatory state of a kinase, numerous methods have been developed to infer kinase activities from phosphoproteomics data using kinase-substrate libraries. However, few phosphorylation sites can be attributed to an upstream kinase in these libraries, limiting the scope of kinase activity inference. Moreover, inferred activities vary across methods, necessitating evaluation for accurate interpretation. Here, we present benchmarKIN, an R package enabling comprehensive evaluation of kinase activity inference methods. Alongside classical perturbation experiments, benchmarKIN introduces a tumor-based benchmarking approach utilizing multi-omics data to identify highly active …

Untargeted Proteomics Enables Ultra-Rapid Variant Prioritisation In Mitochondrial And Other Rare Diseases, Daniella H Hock, Nikeisha J Caruana, Liana N Semcesen, Nicole J Lake, Luke E Formosa, Sumudu S C Amarasekera, Tegan Stait, Simone Tregoning, Leah E Frajman, Adam M Bournazos, David R L Robinson, Megan Ball, Boris Reljic, Bryony Ryder, Mathew J Wallis, Anand Vasudevan, Cara Beck, Heidi Peters, Joy Lee, Natalie B Tan, Mary-Louise Freckmann, Mitomdt Diagnostic Network For Genomics And Omics, Vasiliki Karlaftis, Chantal Attard, Paul Monagle, Amanda Samarasinghe, Rosie Brown, Weimin Bi, Monkol Lek, Robert Mcfarland, Robert W Taylor, Michael T Ryan, Sandra T Cooper, Zornitza Stark, John Christodoulou, Alison G Compton, David R Thorburn, David A Stroud

Faculty, Staff and Students Publications

Background: Only half of individuals with suspected rare diseases receive a genetic diagnosis following genomic testing. A genetic diagnosis allows access to appropriate care, restores reproductive confidence and reduces the number of potentially unnecessary interventions. A major barrier is the lack of disease agnostic functional tests suitable for implementation in routine diagnostics that can provide evidence supporting pathogenicity of novel variants, especially those refractory to RNA sequencing.

Methods: Focusing on mitochondrial disease, we describe an untargeted mass-spectrometry based proteomics pipeline that can quantify proteins encoded by > 50% of Mendelian disease genes and > 80% of known mitochondrial disease genes in clinically …

The Perk/Atf4 Pathway Is Required For Metabolic Reprogramming And Progressive Lung Fibrosis, Jyotsana Pandey, Jennifer L Larson-Casey, Mallikarjun H Patil, Chao He, Nisarat Pinthong, A Brent Carter

Faculty, Staff and Students Publications

Asbestosis is a prototypical type of fibrosis that is progressive and does not resolve. ER stress is increased in multiple cell types that contribute to fibrosis; however, the mechanism(s) by which ER stress in lung macrophages contributes to fibrosis is poorly understood. Here, we show that ER stress resulted in protein kinase RNA-like ER kinase (PERK; Eif2ak3) activation in humans with asbestosis. Similar results were seen in asbestos-injured mice. Mice harboring a conditional deletion of Eif2ak3 were protected from fibrosis. Lung macrophages from asbestosis individuals had evidence of metabolic reprogramming to fatty acid oxidation (FAO). Eif2ak3fl/fl mice had increased oxygen …

Approach To The Patient: From Endocrinopathy To The Diagnosis Of A Histiocytic Disorder, Polyzois Makras, Dana Erickson, Caroline J Davidge-Pitts, Eli L Diamond, Carl E Allen, Kenneth L Mcclain, Jithma P Abeykoon, Ronald S Go, Krishmita Siwakoti, Houman Sotoudeh, Aishwarya Ravindran, Lucinda M Gruber, Gaurav Goyal

Faculty, Staff and Students Publications

Endocrinopathies are frequently the initial presentation of histiocytic neoplasms, which are rare hematologic disorders affecting multiple organ systems. Langerhans cell histiocytosis and Erdheim-Chester disease are 2 such disorders known to infiltrate the hypothalamus and/or pituitary gland, leading to arginine vasopressin deficiency (AVP-D) and anterior pituitary dysfunction (APD) in 20% to 30% of cases, often as the first manifestation. Conversely, histiocytic disorders account for a notable proportion (10-15%) of all pituitary stalk lesions. The diagnosis of histiocytoses is often delayed in such cases due to the nonspecific presentation of endocrinopathies and pituitary involvement. Consequently, endocrinologists are at the frontline and uniquely …

Ccaat/Enhancer-Binding Proteins Α And Β Regulate Ovulation And Gene Expression Via Dose- And Stage-Dependent Mechanisms, Hanxue Zhang, Rainer B Lanz, Jimmy Dhillon, Paul D Soloway, Bo Shui, Yi Athena Ren

Faculty, Staff and Students Publications

The preovulatory luteinizing hormone (LH) surge orchestrates complex cellular and molecular events leading to ovulation. CCAAT/enhancer-binding proteins α and β (C/EBPα/β) are transcription factors acutely induced by the LH surge and crucial for ovulation and granulosa cell luteinization. However, biological processes (BPs) and their regulatory mechanisms downstream of C/EBPα/β in the preovulatory ovary are not completely understood. To address this knowledge gap, we generated Cebpa/bfl/fl;Pgr-Cre mutants and compared them with Cebpa/bfl/fl;Cyp19a1-Cre mutant female mice: Cebpa/bfl/fl;Cyp19a1-Cre mutants have undetectable levels of C/EBPα/β throughout the preovulatory stages and do not ovulate, aligning with previous reports; and Cebpa/bfl/fl;Pgr-Cre mutants present gradual depletion of …

Functional Analysis Of Pathogenic Variants In Lamb1-Related Leukoencephalopathy Reveals Genotype-Phenotype Correlations And Suggests Its Role In Glial Cells, Rei Yasuda, Hirokazu Hashimoto, Mikiko Oka, Jung-Wan Mok, Marium Waqar, Brigitte Dauwalder, Oguz Kanca, Toshiki Mizuno, Shinya Yamamoto

Faculty, Staff and Students Publications

Laminin B1 (LAMB1) is one of the extracellular matrix (ECM) proteins that make up the basement membrane. Early frameshift, late frameshift, and missense variants in LAMB1 have been reported to cause rare monogenic neurological disorders that are collectively known as LAMB1-related leukoencephalopathy. Although there is some genotype-phenotype correlation, functional consequences of pathogenic LAMB1 variants are largely unknown. In this study, we aimed to elucidate function of the fly ortholog of this gene (LanB1) in the nervous system and to further study the functional consequences of the LAMB1 variants using Drosophila melanogaster. We found that the LanB1 gene is expressed on …

Roles Of Class Iii Phosphatidylinositol 3-Kinase, Vps34, In Phagocytosis, Autophagy, And Endocytosis In Retinal Pigmented Epithelium, Feng He, Ralph M Nichols, Melina A Agosto, Theodore G Wensel

Faculty, Staff and Students Publications

Phosphatidylinositol-3-phosphate (PI(3)P) is important for multiple functions of retinal pigmented epithelial (RPE) cells, but its functions in RPE have not been studied. In RPE from mouse eyes and in cultured human RPE cells, PI(3)P-enriched membranes include endosomes, the trans-Golgi network, phagosomes, and autophagophores. Mouse RPE cells lacking activity of the PI-3 kinase, Vps34, lack detectable PI(3)P and die prematurely. Phagosomes containing rod discs accumulate, as do membrane aggregates positive for autophagosome markers. These autophagy-related membranes recruit LC3/Atg8 without Vps34, but phagosomes do not. Vps34 loss leads to accumulation of lysosomes which do not fuse with phagosomes or membranes with …

The Identification Of Xpr1 As A Voltage- And Phosphate-Activated Phosphate-Permeable Ion Channel, Hongjiang Wu, Liang Sun, Tong Huo, Theodore G Wensel, Frank T Horrigan, Zhao Wang

Faculty, Staff and Students Publications

Maintaining a balance of inorganic phosphate (Pi) is vital for cellular functionality. Proper phosphate levels are managed through Pi import and export; and the processes governing Pi export remain the least understood. Xenotropic and Polytropic retrovirus Receptor 1 (XPR1) has been identified as the only known Pi export protein in mammals. In this study, we introduce the cryogenic electron microscopy structure of human XPR1 (hXPR1), unveiling a structural arrangement distinct from that of any known ion transporter. Our structural results suggest that hXPR1 may operate as an ion channel, a hypothesis supported by patch clamp recordings revealing hXPR1's voltage- and …

Theta Oscillons In Behaving Rats, M S Zobaer, Nastaran Lotfi, Carli M Domenico, Clarissa Hoffman, Luca Perotti, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Students Publications

Recently discovered constituents of the brain waves—the oscillons—provide a high-resolution representation of the extracellular field dynamics. Here, we study the most robust, highest-amplitude oscillons recorded in actively behaving male rats, which underlie the traditional θ-waves. The resemblances between θ-oscillons and the conventional θ-waves are manifested primarily at the ballpark level—mean frequencies, mean amplitudes, and bandwidths. In addition, both hippocampal and cortical oscillons exhibit a number of intricate, behavior-attuned, transient properties that suggest a new vantage point for understanding the θ-rhythms’ structure, origins and functions. In particular, we demonstrate that oscillons are frequency-modulated waves, with speed-controlled …

Genome-Wide Allele-Specific Expression In Multi-Tissue Samples From Healthy Male Baboons Reveals The Transcriptional Complexity Of Mammals, Ramesh Ramasamy, Muthuswamy Raveendran, R Alan Harris, Hiep D Le, Ludovic S Mure, Giorgia Benegiamo, Ouria Dkhissi-Benyahya, Howard Cooper, Jeffrey Rogers, Satchidananda Panda

Faculty, Staff and Students Publications

Allele-specific expression (ASE) is pivotal in understanding the genetic underpinnings of phenotypic variation within species, differences in disease susceptibility, and responses to environmental factors. We processed 11 different tissue types collected from 12 age-matched healthy olive baboons (Papio anubis) for genome-wide ASE analysis. By sequencing their genomes at a minimum depth of 30×, we identified over 16 million single-nucleotide variants (SNVs). We also generated long-read sequencing data, enabling the phasing of all variants present within the coding regions of 96.5% of assayable protein-coding genes as a single haplotype block. Given the extensive heterozygosity of baboons relative to humans, we could …

The Genestar Manual For Biospecimen Collection Biobanking And Omics Data Generation From Commercial Space Missions, Aparna Krishnavajhala, Marie-Claude Gingras, Emmanuel Urquieta, Hsu Chao, Dilrukshi Bandaranaike, Yi Chen, Sravya Bhamidipati, Viktoriya Korchina, S Michelle Griffin, Michal M Masternak, Hannah Moreno, Javid Mohammed, Mullai Murugan, Jennifer E Posey, Jimmy H Wu, Donna Muzny, Richard A Gibbs, Harsha Doddapaneni

Faculty, Staff and Students Publications

The surge in commercial and civilian spaceflight enables the systematic and longitudinal, large-scale biospecimen collection to understand the prospective effects of space travel on human health. The Genomics and Space Medicine (Space Omics) project at BCM-HGSC involves a comprehensive biospecimen collection plan from commercial/private space flight participants. The manuscript addresses the critical gaps in the biospecimen collection process including details of the informed consent process, a provision for subjects to obtain custom CLIA-WGS reports, a data dictionary and a LIMS enabled biobank. The manuscript also discusses the biospecimens collection, processing methodologies and nucleic acid suitability for Omics data generation. Results …

Role Of Systemic Therapy In Localized Renal Cell Carcinoma: Where Do We Stand And Where Are We Heading?, Deepa Raghavan, Viktoriya Gibatova, Nikhil Vojjala, Nagaishwarya Moka, Aihua Edward Yen

Faculty, Staff and Students Publications

The effectiveness of immunotherapy and targeted therapy has been well established in metastatic renal cell cancer (mRCC). These therapies demonstrated higher overall response rates and led to prolonged survival. In contrast, in localized RCC, conventional treatment is either partial or complete nephrectomy. While surgery is a curative option in early stages, high recurrence rates remain a concern, with survival rates ranging from 53% to 85%, depending on the initial stage at the time of diagnosis. Given favorable outcomes with systemic therapies in the metastatic setting, there has also been an increased interest in utilizing these therapies for the localized stage …

Loss Of Progesterone Receptor In Smooth Muscle Cells Has No Impact On Oviductal Contractions And Preimplantation Embryo Development†, Emily A Mcglade, Jiude Mao, Kalli K Stephens, Cayce N Rose, John P Lydon, Wipawee Winuthayanon

Faculty, Staff and Students Publications

No abstract provided.

Effect Of Race On Procedural And Clinical Outcomes In Middle Meningeal Artery Embolization For Primary And Adjunctive Treatment Of Chronic Subdural Hematoma, Santiago Gomez-Paz, Mohamed M Salem, Cordell Baker, Okkes Kuybu, Georgios S Sioutas, Kate T Carroll, Mira Salih, Adam A Dmytriw, Jane Khalife, William Smith, Diego Alejandro Ortega Moreno, Robert W Regenhardt, Nicole M Cancelliere, Alejandro M Spiotta, Omar Tanweer, Christopher J Stapleton, Michael Lang, Vitor M Pereira, Aman B Patel, Adnan H Siddiqui, Elad I Levy, Christopher S Ogilvy, Daniel Tonetti, Ajith J Thomas, Visish M Srinivasan, Brian T Jankowitz, Michael R Levitt, Bradley A Gross, Jan-Karl Burkhardt, Ramesh Grandhi

Faculty, Staff and Students Publications

Background

We investigated racial disparities in radiologic and clinical outcomes of patients after middle meningeal artery embolization (MMAE) for chronic subdural hematoma (CSDH) with or without evacuation surgery.

Methods

This multicenter retrospective study includes consecutive patients who underwent MMAE across 11 institutions in North America (10 in the United States and 1 in Canada). Patients were stratified using self-reported racial data. Outcomes of interest were complications, treatment failure/reoperations, resolution of hematoma, and functional independence at last follow-up. Multivariable regression models were used to assess and adjust for relevant confounders.

Results

A total of 557 patients underwent 663 MMAEs, including 323 …

Long-Term Outcomes Of Resolute Onyx Zotarolimus-Eluting Stents For Symptomatic Intracranial Stenosis: A Multicenter Propensity Score-Matched Comparison With Stenting Versus Aggressive Medical Management For Preventing Recurrent Stroke In Intracranial Stenosis Trial, Omid Shoraka, Ramesh Grandhi, Samantha Miller, Joanna Roy, Vinay Jaikumar, Basel Musmar, Omar Tanweer, Jan-Karl Burkhardt, Pascal M Jabbour, Adnan H Siddiqui, Farhan Siddiq, Ameer E Hassan

Faculty, Staff and Students Publications

Background

Intracranial atherosclerotic disease (ICAD) is a leading cause of ischemic stroke. The Medtronic Resolute Onyx Zotarolimus-eluting stents (RO-ZES) are promising in preventing stroke recurrence compared with medical management (MM) and percutaneous angioplasty and stenting (PTAS) at both 30-day and one-year follow-ups. We evaluated long-term outcomes for patients treated with RO-ZES, PTAS, or MM.

Methods

A retrospective multicenter study was conducted including patients who underwent RO-ZES stenting for symptomatic ICAD between March 2018 and May 2023, with follow-up through October 2024. Propensity score-matched control groups, representing MM and PTAS, were derived from the SAMMPRIS trial. Primary outcomes included recurrence rates …

Disruption Of Oocyte Sumoylation Impacts Critical Regulatory Processes During Folliculogenesis In Mice, Zian Liao, Tessa E Steenwinkel, Bruno Moscoso, Ernesto Salas, Bethany K Patton, Amanda Rodriguez, Anna Malovannaya, Stephanie A Pangas

Faculty, Staff and Students Publications

The conjugation of small ubiquitin-like modifiers (SUMO) to target proteins, known as SUMOylation, plays a crucial role in regulating protein homeostasis, activity, interaction with other proteins, and subcellular localization. Loss of SUMOylation in nongrowing oocytes by conditional deletion of the E2 SUMO conjugating enzyme, Ube2i, at the primordial follicle stage leads to female sterility due to complex changes in oocyte development, including altered folliculogenesis, defective meiotic progression, and premature loss of the ovarian reserve. In this study, proteomics was used to compare control and Ube2i conditional knockout ovaries during the first wave of folliculogenesis to identify key differences that may …

Temporal Regulation Of Early-Stage Cytokine Expression In Diabetic Wound Healing Under Negative Pressure Wound Therapy, Hua-Sheng Chiu, Ting-Shuo Huang, Chien-Tzung Chen, Xin-Yu Lin, Po-Cheng Liao, Cai-Cin Liou, Chih-Chin Hsu, Sonal Somvanshi, Pavel Sumazin, Pang-Hung Hsu, Chi-Chin Sun, Yu-Chiau Shyu

Faculty, Staff and Students Publications

Negative pressure wound therapy (NPWT) is widely recognized for its efficacy in treating diabetic wounds, but the mechanisms involved in the wound healing process remain unclear. By examining changes in blood cytokine levels as molecular signaling precursors, we aim to provide a comprehensive cytokine profile to support adjunctive therapy research and clinical applications. A diabetic mouse wound model was established to compare cytokine profiles between NPWT-treated and standard dressing groups, identifying key signaling candidates that may facilitate wound healing. By integrating normal mouse data with large-scale cytokine analysis, we developed a time-stratified NPWT approach to track acute-phase cytokine fluctuations in …

Defining Three Principles For Credible Evidence Synthesis And Reviews In Health Professions Education, Michelle Daniel, Morris Gordon, Hussein Uraiby, Peter Boedeker, Janice Hanson, Diana Dolmans, Satid Thammasitboon

Faculty, Staff and Students Publications

As reviews become increasingly central to informing educational practice and guiding research in health professions education, the need for methodological clarity and quality has grown. This Commentary highlights three foundational principles - alignment, rigor, and transparency - that underpin high-quality reviews, regardless of type. We illustrate how these principles apply across commonly used review types, including systematic, scoping, realist, and narrative reviews. By aligning the research question with the appropriate review methodology, employing rigorous processes for evidence collection and synthesis, and maintaining transparency in methodological reporting, review teams can produce credible, transferable, and dependable findings. Embracing these principles not only …

Structural Proteomics Defines A Sequential Priming Mechanism For The Progesterone Receptor, Matthew D Mann, Min Wang, Josephine C Ferreon, Phoebe S Tsoi, Michael P Suess, Antrix Jain, Anna Malovannaya, Roberto Vera Alvarez, Bruce D Pascal, Raj Kumar, Dean P Edwards, Patrick R Griffin

Faculty, Staff and Students Publications

The progesterone receptor (PR) is a steroid-responsive nuclear receptor with two isoforms: PR-A and PR-B. Disruption of PR-A:PR-B signaling is associated with breast cancer through interactions with oncogenic co-regulatory proteins (CoRs). However, molecular details of isoform-specific PR-CoR interactions remain poorly understood. Using structural mass spectrometry, we investigate the sequential binding mechanism of purified full-length PR and intact CoRs, steroid receptor coactivator 3 (SRC3) and p300, as complexes on target DNA. Our findings reveal selective CoR NR-box binding by PR and unique interaction surfaces between PR and CoRs during complex assembly, providing a structural basis for CoR sequential binding on PR. …

Let-7 Restrains An Epigenetic Circuit In At2 Cells To Prevent Fibrogenic Intermediates In Pulmonary Fibrosis, Matthew J Seasock, Md Shafiquzzaman, Maria E Ruiz-Echartea, Rupa S Kanchi, Brandon T Tran, Lukas M Simon, Matthew D Meyer, Phillip A Erice, Shivani L Lotlikar, Stephanie C Wenlock, Scott A Ochsner, Anton Enright, Alex F Carisey, Freddy Romero, Ivan O Rosas, Katherine Y King, Neil J Mckenna, Cristian Coarfa, Antony Rodriguez

Faculty, Staff and Students Publications

MicroRNA-mediated post-transcriptional regulation of lung alveolar type 2 (AT2) and AT1 cell differentiation remains understudied. Here, we demonstrate that the let-7 miRNA family plays a homeostatic role in AT2 quiescence by preventing the uncontrolled accumulation of AT2 transitional cells and promoting AT1 differentiation. Using mouse and organoid models, we show that genetic ablation of let-7a1/let-7f1/let-7d cluster (let-7afd) in AT2 cells prevents AT1 differentiation and leads to KRT8 transitional cell accumulation in progressive pulmonary fibrosis. Integration of AGO2-eCLIP with RNA-sequencing identified direct let-7 targets within an oncogene feed-forward regulatory network, including BACH1/EZH2/MYC, which drives an aberrant fibrotic cascade. Additional CUT&RUN-sequencing analyses …

Sustained Growth-Promoting Effects Of Vosoritide In Children With Achondroplasia From An Ongoing Phase 3 Extension Study, Ravi Savarirayan, Melita Irving, William R Wilcox, Carlos A Bacino, Julie E Hoover-Fong, Paul Harmatz, Lynda E Polgreen, Katja Palm, Carlos E Prada, Takuo Kubota, Paul Arundel, Yumiko Kotani, Antonio Leiva-Gea, Michael B Bober, Jacqueline T Hecht, Janet M Legare, Sue Lawrinson, Andrea Low, Ian Sabir, Alice Huntsman-Labed, Jonathan R S Day

Faculty, Staff and Students Publications

Background: Vosoritide is a C-type natriuretic peptide analog that addresses an underlying pathway causing reduced bone growth in achondroplasia. Understanding the vosoritide treatment effect requires evaluation over an extended duration and comparison with outcomes in untreated children.

Methods: After completing ≥6 months of a baseline observational growth study and 52 weeks in a double-blind, placebo-controlled study (ClinicalTrials.gov: NCT03197766), participants were eligible to continue treatment in an open-label extension (ClinicalTrials.gov: NCT03424018) wherein all received 15 μg/kg vosoritide daily. Data from the CLARITY achondroplasia study provided an external untreated control population and reference data.

Findings: The population comprised 119 participants. …

Reply To: Is Gauchian Genotyping Of Gba1 Variants Reliable?, Marco Toffoli, Anthony H V Schapira, Fritz J Sedlazeck, Christos Proukakis

Faculty, Staff and Students Publications

No abstract provided.

Improved Outcomes Of Acute Lymphoblastic Leukemia After Allogeneic Blood Or Marrow Transplantation With High-Dose Post-Transplantation Cyclophosphamide In The Era Of More Effective Pre-Transplant Therapy, Jonathan A Webster, Madison Reed, Hua-Ling Tsai, Philip H Imus, Douglas B Smith, Alexander J Ambinder, Mark J Levis, Amy E Dezern, Gabrielle T Prince, Tania Jain, Javier Bolaños-Meade, Lukasz P Gondek, Gabriel Ghiaur, William Brian Dalton, Theodoros Karantanos, Suman Paul, Ephraim J Fuchs, Cole Sterling, Lode J Swinnen, Nina Wagner-Johnston, Richard F Ambinder, Christian B Gocke, Syed Abbas Ali, Carol Ann Huff, Leo Luznik, Ravi Varadhan, Richard J Jones, Ivana Gojo

Faculty, Staff and Students Publications

The therapeutic landscape in ALL has changed dramatically over the last decade. Allogeneic blood or marrow transplantation (AlloBMT) has also evolved and remains an important option for consolidation. We assessed the interplay between these factors by analyzing the outcomes of 251 adult ALL (214 B and 37 T ALL) patients undergoing alloBMT with post-transplantation cyclophosphamide (PTCy) across two eras: 2008-2014 (ERA1) and 2015-2022 (ERA2). ERA1 patients were younger (median age 45.5 vs. 50, p=0.03), less likely to have an HCT-CI ≥4 (9% vs. 21%, p=0.01), more likely to have MRD by flow cytometry (20% vs. 9%, p=0.01) and receive myeloablative …

Human Genetic Variation Determines 24-Hour Rhythmic Gene Expression And Disease Risk, Ying Chen, Panpan Liu, Aniko Sabo, Dongyin Guan

Faculty, Staff and Students Publications

24-hour biological rhythms are essential to maintain physiological homeostasis. Disruption of these rhythms increases the risks of multiple diseases. Biological rhythms are known to have a genetic basis formed by core clock genes, but how individual genetic variation shapes the oscillating transcriptome and contributes to human chronophysiology and disease risk is largely unknown. Here, we mapped interactions between temporal gene expression and genotype to identify quantitative trait loci (QTLs) contributing to rhythmic gene expression. These newly identified QTLs were termed as rhythmic QTLs (rhyQTLs), which determine previously unappreciated rhythmic genes in human subpopulations with specific genotypes. Functionally, rhyQTLs and their …

Protocol For A Randomized Controlled Trial To Determine If Biomarkers Predict Response To A Pediatric Chronic Pain Symptom Management Program, Rona L Levy, Tasha B Murphy, Margaret M Heitkemper, Miranda A L Van Tilburg, Ann R Mcmeans, Jocelyn Chang, Cynthia Boutte, Katherine Lamparyk, Bruno P Chumpitazi, Robert J Shulman

Faculty, Staff and Students Publications

Background/Objectives: Disorders of gut-brain interaction (DGBI), characterized by chronic abdominal pain and significant disability, affect 15-20% of children and adults and continue into adulthood in ~60% of cases. Costs for adults reach USD 30 billion per year, yet effective management strategies are elusive. Studies support using cognitive behavioral therapy (CBT), but abdominal pain only improves in ~40% of patients. Dietary management (low FODMAP diet; LFD) has also shown promise but it is effective in only a similar percentage of patients. Studies suggest that biologic factors (biomarkers) contribute to CBT response. Similarly, gut microbiome composition appears to influence abdominal pain …

Gut Dysbiosis Patterns In Cvid Patients With Noninfectious Complications Observed In A Germ-Free Mouse Model Through Fecal Microbiota Transplantation, Joud Hajjar, Anita Y Voigt, Margaret E Conner, Alton G Swennes, Stephanie Fowler, Chadi Calarge, Danielle D Mendonca, Dominique Armstrong, Chen-Yen Chang, Jolan E Walter, Manish J Butte, Tor Savidge, Julia Oh, Farrah Kheradmand, Joseph F Petrosino

Faculty, Staff and Students Publications

Patients with common variable immunodeficiency (CVID) who develop noninfectious complications (NIC) have worse clinical outcomes than those with infections only (INF). While gut microbiome aberrations have been linked to NIC, reductionist animal models that accurately recapitulate CVID are lacking. Our aim in this study was to uncover potential microbiome roles in the development of NIC in CVID. We performed whole-genome shotgun sequencing on fecal samples from CVID patients with NIC, INF, and their household controls. We also performed fecal microbiota transplants from CVID patients to germ-free mice. We found potentially pathogenic microbes

Catecholaminergic Polymorphic Ventricular Tachycardia-Linked Ryanodine Receptor Variants Exhibit Domain-Specific Calcium Leak And Calmodulin Affinity Properties, Hitoshi Uchinoumi, Xiaoqiong Dong, Ivanita Stefanon, Yi Yang, Eduardo Hertel Ribeiro, Bengt Svensson, Xander H T Wehrens, Takeshi Yamamoto, Razvan L Cornea, Robyn T Rebbeck, Masafumi Yano, Donald M Bers

Faculty, Staff and Students Publications

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited stress-induced arrhythmogenic disease often caused by point variants in the cardiac ryanodine receptor (RyR2) that enhance diastolic sarcoplasmic reticulum (SR) Ca2+ leak. These RyR2 variants cluster in three hot-spots (N-terminal, central and C-terminal domains). We previously demonstrated a pathologic diastolic RyR2 conformation in heart failure, oxidative stress and CaMKII phosphorylation exhibiting a trilogy of effects: (1) reduced calmodulin (CaM)-RyR2 affinity, (2) enhanced unzipping peptide (DPc10) binding and (3) elevated diastolic SR Ca2+ leak that are dantrolene-sensitive. Here we test whether this pathological trilogy occurs in CPVT knock-in (KI) mice bearing N-terminal (R176Q/+), …

Artificial Intelligence-Based Virtual Staining Platform For Identifying Tumor-Associated Macrophages From Hematoxylin And Eosin-Stained Images, Arpit Aggarwal, Mayukhmala Jana, Amritpal Singh, Tanmoy Dam, Himanshu Maurya, Tilak Pathak, Sandra Orsulic, Kailin Yang, Deborah Chute, Justin A Bishop, Farhoud Faraji, Wade M Thorstad, Shlomo Koyfman, Scott Steward, Qiuying Shi, Vlad Sandulache, Nabil F Saba, James S Lewis, Germán Corredor, Anant Madabhushi

Faculty, Staff and Students Publications

Background: Virtual staining is an artificial intelligence-based approach that transforms pathology images between stain types, such as hematoxylin and eosin (H&E) to immunohistochemistry (IHC), providing a tissue-preserving and efficient alternative to traditional IHC staining. However, existing methods for translating H&E to virtual IHC often fail to generate images of sufficient quality for accurately delineating cell nuclei and IHC+ regions. To address these limitations, we introduce VISTA, an artificial intelligence-based virtual staining platform designed to translate H&E into virtual IHC.

Methods: We applied VISTA to identify M2-subtype tumor-associated macrophages (M2-TAMs) in H&E images from 968 patients with HPV+ oropharyngeal squamous cell …