Medicine and Health Sciences Commons^™

Usp37 Counteracts Hltf To Protect Damaged Replication Forks And Promote Survival Of Brca1-Deficient Cells And Parp Inhibitor Resistance, Mengfan Tang, Siting Li, Ziqiang Zhu, Chao Wang, Shuai Ding, Huimin Zhang, Min Huang, Sarah Keast, Zhen Chen, Ling Yin, Litong Nie, Dan Su, Xu Feng, Junjie Chen

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase inhibitors (PARPi) have greatly improved survival of cancer patients harboring BRCA1 mutations. However, therapy resistance develops via either restoration of homologous recombination or replication fork stabilization. Therapeutic targets to overcome PARPi resistance are critically needed. We identified the deubiquitinase USP37 as a key determinant of PARPi toxicity in BRCA1-deficient cells via whole-genome CRISPR screens. USP37 ablation enhanced PARPi sensitivity in BRCA1-deficient cells and also overcame PARPi resistance due to 53BP1 loss. USP37 interacts with and deubiquitinates replication protein A (RPA) at stalled replication forks to limit excessive RPA accumulation, progressive RPA exhaustion, and the conversion of RPA-coated single-stranded …

Protocol To Analyze Trna And Rrna Processing Using Biotin-Labeled Probes, Sseu-Pei Hwang, Katherine Barondeau, Catherine Denicourt

Faculty, Staff and Student Publications

Mature tRNAs and rRNAs are derived from larger precursor transcripts through intricate endo- and exonuclease processing steps. Here, we present a protocol to analyze rRNA and tRNA processing using total RNA extracted from human cells. We describe steps for separating RNA by denaturing electrophoresis, followed by northern blotting. We detail procedures for detecting pre-rRNA intermediates or specific tRNA species using biotin-labeled probes imaged via fluorescence or chemiluminescence. This non-radioactive, high-sensitivity assay enables the investigation of rRNA and tRNA expression dynamics. For complete details on the use and execution of this protocol, please refer to Hwang et al.

Monoclonal Antibodies Targeting The Fimh Adhesin Protect Against Uropathogenic E. Coli Uti, Edward D B Lopatto, Jesús M Santiago-Borges, Denise A Sanick, Sameer Kumar Malladi, Philippe N Azimzadeh, Morgan W Timm, Isabella F Fox, Aaron J Schmitz, Jackson S Turner, Shaza M Sayed Ahmed, Lillian Ortinau, Nathaniel C Gualberto, Jerome S Pinkner, Karen W Dodson, Ali H Ellebedy, Andrew L Kau, Scott J Hultgren

2020-Current year OA Pubs

As antimicrobial resistance increases, urinary tract infections (UTIs) are expected to pose an increased burden in morbidity and expense on the health care system, increasing the need for alternative antibiotic-sparing treatments. Most UTIs are caused by uropathogenic

Multi-Ancestry Genome-Wide Association Analyses Incorporating Snp-By-Psychosocial Interactions Identify Novel Loci For Serum Lipids, Amy R Bentley, Michael R Brown, Solomon K Musani, Karen L Schwander, Thomas W Winkler, Mario Sims, Tuomas O Kilpeläinen, Hugues Aschard, Traci M Bartz, Lawrence F Bielak, Jin-Fang Chai, Kumaraswamy Naidu Chitrala, Nora Franceschini, Mariaelisa Graff, Xiuqing Guo, Fernando P Hartwig, Andrea R V R Horimoto, Elise Lim, Yongmei Liu, Alisa K Manning, Ilja M Nolte, Raymond Noordam, Melissa A Richard, Albert V Smith, Yun Ju Sung, Dina Vojinovic, Rujia Wang, Yujie Wang, Mary F Feitosa, Sarah E Harris, Leo-Pekka Lyytikäinen, Giorgio Pistis, Rainer Rauramaa, Peter J Van Der Most, Erin Ware, Stefan Weiss, Wanqing Wen, Lisa R Yanek, Dan E Arking, Donna K Arnett, Christie Ballantyne, Eric Boerwinkle, Yii-Der Ida Chen, Martha L Daviglus, Lisa De Las Fuentes, Paul S De Vries, Joseph A C Delaney, Amanda M Fretts, Lynette Ekunwe, Jessica D Faul, Linda C Gallo, Sami Heikkinen, Georg Homuth, M Arfan Ikram, Carmen R Isasi, Jost Bruno Jonas, Liisa Keltikangas-Järvinen, Pirjo Komulainen, Aldi T Kraja, Jose E Krieger, Lenore Launer, Lifelines Cohort Study, Jianjun Liu, Kurt Lohman, Annemarie I Luik, Ani W Manichaikul, Pedro Marques-Vidal, Yuri Milaneschi, Stanford E Mwasongwe, Jeffrey R O'Connell, Kenneth Rice, Stephen S Rich, Pamela J Schreiner, Lars Schwettmann, James M Shikany, Xiao-Ou Shu, Jennifer A Smith, Harold Snieder, Nona Sotoodehnia, E Shyong Tai, Kent D Taylor, Lesley Tinker, Michael Y Tsai, André G Uitterlinden, Cornelia M Van Duijn, Diana Van Heemst, Melanie Waldenberger, Robert B Wallace, Hwee-Lin Wee, David R Weir, Wen-Bin Wei, Ko Willems Van Dijk, Gregory Wilson, Jie Yao, Kristin L Young, Xiaoyu Zhang, Wei Zhao, Xiaofeng Zhu, Alan B Zonderman, Ian J Deary, Christian Gieger, Hans Jörgen Grabe, Timo A Lakka, Terho Lehtimäki, Albertine J Oldehinkel, Martin Preisig, Ya-Xing Wang, Wei Zheng, Michele K Evans, Michael Province, James Gauderman, Vilmundur Gudnason, Catharina A Hartman, Bernardo L Horta, Sharon L R Kardia, Charles Kooperberg, Ching-Ti Liu, Dennis O Mook-Kanamori, Brenda Wjh Penninx, Alexandre C Pereira, Patricia A Peyser, Bruce M Psaty, Jerome I Rotter, Xueling Sim, Kari E North, Dabeeru C Rao, Laura Bierut, Clint L Miller, Alanna C Morrison, Charles N Rotimi, Myriam Fornage, Ervin R Fox

Faculty, Staff and Student Publications

Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis …

Elucidating Brain Transport Pathways And Cell Type-Dependent Gene Silencing Of A Durable Lipid-Sirna Conjugate Administered Into Cerebrospinal Fluid, Alexander G Sorets, Kathleen M Schoch, Timothy M Miller, Et Al.

2020-Current year OA Pubs

The clinical neurosciences are in the midst of a renaissance spurred by the development of new therapeutic modalities. Short interfering RNAs (siRNAs), in particular, are gaining interest for treating neurological diseases owing to their capacity to sustain inhibition of nearly any gene target. However, to be effective, siRNA therapies must achieve delivery and on-target gene silencing activity in specific sites and cells in the brain. To this end, we developed a lipid-siRNA conjugate (L2-siRNA) that transports effectively throughout the brain when injected into cerebrospinal fluid (CSF). We provide a detailed examination of regional bulk tissue gene silencing in mice, highlighting …

Rcpneoperu Trial: A Cluster Randomized Pilot Trial To Assess Traditional Neonatal Resuscitation Compared To Partially Virtual Training In Remote Areas., Carlos A Delgado, Enrique Gómez Pomar, Pablo Velásquez, Víctor Sánchez, Roberto Shimabuku, Luis Huicho

Pediatrics Faculty Publications

OBJECTIVE: To assess the effects of a neonatal resuscitation training program using traditional training and partial distance learning.

METHOD: Through an open cluster-randomized trial, the authors compared a traditional approach involving face-to-face theory and practice sessions using information and communication technology to offer theory and distance examination, followed by face-to-face practice. Twelve health facilities were allocated by blocked randomization. Comparisons were made adjusting for clustering in qualitative and quantitative data. The primary outcome was the percentage of infants with heart rates ≥100 per minute at the second minute after birth. The authors performed a cluster-level analysis for cluster randomized trials, …

Effect Of Perioperative Haemodynamic Management Based On Cerebral Autoregulation Monitored By Cerebral Oximetry Index During Carotid Endarterectomy: Protocol Of A Randomised Trial, Muhan Li, Xueke Yin, Chuanyu Liang, Chenyang Tao, Qixiao Yan, Min Zeng, Shu Li, Daniel I Sessler, Rong Wang, Lei Zhao, Yuming Peng

Faculty, Staff and Student Publications

Introduction: Impaired cerebral autoregulation is associated with postoperative ischaemic brain injury and often occurs in patients with carotid artery stenosis. Adequate cerebral perfusion should therefore be maintained during carotid endarterectomies. Whether guiding intraoperative blood pressure to the Cerebral Oximetry Index (a measure of cerebral perfusion adequacy) reduces postoperative cerebral ischaemia remains unclear.

Methods and analysis: We plan a dual-centre randomised blinded trial. A total of 560 patients having elective carotid endarterectomy will be randomly assigned to guided versus routine haemodynamic management. In patients randomised to guided management, mean arterial pressure will be titrated to maintain a normal cerebral oximetry index. …

Blood-Based Proteomic Profiling Identifies Osmr As A Novel Biomarker Of Aml Outcomes, Patrick K Reville, Bofei Wang, Jennifer Marvin-Peek, Bin Yuan, Yu-An Kuo, Araceli Garza, Jessica Root, Wei Qiao, Andrea Arruda, Ivo Veletic, Yiwei Liu, Nicholas J Short, Courtney D Dinardo, Tapan M Kadia, Naval G Daver, Philip L Lorenzi, Koji Sasaki, Steven Kornblau, Mark D Minden, Farhad Ravandi, Hagop M Kantarjian, Hussein A Abbas

Faculty, Staff and Student Publications

Inflammation is increasingly recognized as a critical factor in acute myeloid leukemia (AML) pathogenesis. We performed blood-based proteomic profiling of 251 inflammatory proteins in 543 patients with newly diagnosed AML. Using a machine learning model, we derived an 8-protein prognostic score termed the leukemia inflammatory risk score (LIRS). Individual proteins were evaluated in multivariable Cox models, and model performance was assessed by cumulative concordance index. Findings were validated in internal and external cohorts across 2 institutions. Blood-based LIRS significantly outperformed the European LeukemiaNet 2022 risk model and was independently prognostic of overall survival after accounting for known clinical and molecular …

Risk Factors For Serious Bacterial Infections Among Young Infants With Hypothermia: Protocol For A Multicenter, Retrospective Case-Control Study, Sriram Ramgopal, Paul Aronson, Douglas Lorenz, Alexander Joseph Rogers, Andrea Tania Cruz

Faculty, Staff and Students Publications

Background: Hypothermia in young infants presenting to the emergency department (ED) may indicate a serious bacterial infection (SBI) such as a urinary tract infection, bacteremia, or bacterial meningitis. Improved understanding of the epidemiology of SBI in infants with hypothermia and the development of prediction models can help avoid unnecessary invasive procedures and antimicrobial exposure.

Objective: The aim of the study is to (1) describe the epidemiology of SBI and herpes simplex virus (HSV) among infants with hypothermia, (2) assess the role of biomarkers in predicting SBI, and (3) derive and internally validate a multivariable predictive model for SBI among infants …

The Effect Of Sars-Cov-2 Reinfection On Long-Term Symptoms In The Innovative Support For Patients With Sars-Cov-2 Infections Registry (Inspire), John J. Openshaw, Ji Chen, Robert Rodriguez, Michael Gottlieb, Kalyani Mccullough, Michelle Santangelo, Mandy J. Hill, Kristyn Gatling, Ahamed H. Idris, Samuel Mcdonald, Lauren E. Wisk, Jonathan Dyal, Ralph C. Wang, Kristin L. Rising, Efrat Kean, Kelli N. O'Laughlin, Kari A. Stephens, Caitlin Malicki, Zhenqiu Lin, Erica S. Spatz, Huihui Yu, Robert A. Weinstein, Joann Elmore

Department of Emergency Medicine Faculty Papers

BACKGROUND: The clinical consequences of repeated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not clear, especially as they relate to long-term symptoms after infection. We analyzed data collected for the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) to determine whether reinfection changes the likelihood of symptoms 3-6 months after reinfection compared with the likelihood in individuals experiencing a single infection.

METHODS: Individuals reporting a single SARS-CoV-2 infection or a single reinfection were included in this analysis. A positive SARS-CoV-2 test occurring ≥90 days after a first infection was considered a reinfection. Outcomes included severe fatigue (fatigue …

When Access Is Not Enough: The Role Of Utilization Barriers In Nutrition Security And Cardiometabolic Risk, Maha Almohamad, Ruosha Li, Natalia I Heredia, Jayna M Dave, Eric E Calloway, Anjail Z Sharrief, Shreela V Sharma

Faculty, Staff and Student Publications

Background: Food and nutrition security are key social determinants of cardiometabolic health. While food security reflects access to sufficient food, nutrition security incorporates the quality, consistency, and usability of food that supports long-term health. However, few studies have examined how household-level barriers to food utilization shape these relationships. Objective: This study assessed whether tangible (e.g., equipment, storage) and intangible (e.g., time, knowledge) food utilization barriers modify the associations between food and nutrition security and cardiometabolic outcomes in low-income adults.

Methods: A cross-sectional survey was conducted among 486 low-income adults across five U.S. states. Participants reported household food security (USDA …

Exploring Facilitators And Barriers Of Medically Tailored Meal Interventions For Patients Hospitalized With Acute Heart Failure: A Qualitative Study, Ihab Hassanieh, Sang Gune K Yoo, Jing Li, Virginia Mckay, Mark D Huffman

2020-Current year OA Pubs

BACKGROUND: Acute heart failure (AHF) is associated with high rehospitalization, morbidity, and mortality rates. Implementing medically tailored meal (MTM) interventions may help to optimize nutrition and improve outcomes for patients with AHF. This study aimed to explore facilitators and barriers to implementing an MTM intervention in a tertiary hospital.

METHODS: From August 2023 to October 2023, we conducted semistructured interviews with health care workers and patients with AHF at Barnes Jewish Hospital in Saint Louis, Missouri. The study used the updated Consolidated Framework for Implementation Research 2.0 to assess 5 domains: MTM characteristics, inner and outer settings, individual characteristics, and …

Cardiovascular Health In Cardiac Rehabilitation: Applying The American Heart Association Life's Simple 7 Framework In A Center-Based Cohort, Audry Chacin-Suarez, Tomoaki Hama, Matthew P. Johnson, Helayna Abraham, Thomas P. Olson, Laprincess C. Brewer

Einstein Health Papers

BACKGROUND: Cardiac rehabilitation (CR) is a comprehensive secondary cardiovascular disease program with structured lifestyle interventions to reduce morbidity and mortality. The American Heart Association cardiovascular health (CVH) framework measures health-promoting behaviors and clinical factors, but it has not been rigorously evaluated in the CR setting.

METHODS: This retrospective cohort study analyzed patients attending CR from January 2018 to September 2020. Patients were evaluated at baseline (pre-CR) and completion (post-CR) using 3 clinical factors (blood pressure, cholesterol, and hemoglobin A1c) and 4 health behaviors (smoking, body mass index, physical activity, and diet). CVH score was computed as a composite of each …

X-Linked Hypophosphatemia Management In Children: An International Working Group Clinical Practice Guideline., Dalal S. Ali, Thomas O. Carpenter, Erik A. Imel, Leanne M. Ward, Natasha M. Appelman-Dijkstra, Catherine Chaussain, Suzanne M. Jan De Beur, Pablo Florenzano, Hajar Abu Alrob, Rana Aldabagh, R Todd Alexander, Farah Alsarraf, Signe Sparre Beck-Nielsen, Martin Biosse-Duplan, Rachel K. Crowley, Karel Dandurand, Guido Filler, Lisa Friedlander, Seiji Fukumoto, Claudia Gagnon, Paul Goodyer, Corinna Grasemann, Chelsey Grimbly, Salma Hussein, Muhammad K. Javaid, Sarah Khan, Aneal Khan, Anna Lehman, Willem F. Lems, E Michael Lewiecki, Ciara Mcdonnell, Reza D. Mirza, Emmett Morgante, Archibald Morrison, Anthony A. Portale, Christina Rao, Yumie Rhee, Eric T. Rush, Heide Siggelkow, Sotirios Tetradis, Laura Tosi, Gordon Guyatt, Maria Luisa Brandi, Aliya A. Khan

Manuscripts, Articles, Book Chapters and Other Papers

CONTEXT: An International Working Group (IWG) developed new guidelines on the diagnosis, evaluation, management, and monitoring of X-linked hypophosphatemia (XLH) in children. Over the past 5 years, important advances have occurred in our understanding of the presentation, complications, and treatment of XLH.

METHODS: A group of 50 international experts in XLH from Canada, the United States, Europe, Asia, and South America, along with methodology experts and a patient partner, held 18 teleconference meetings in 2023-2024. These meetings addressed key issues regarding diagnosing, evaluating, managing, and monitoring XLH in children. Two systematic reviews were conducted to examine the impact of burosumab …

Clinical And Radiological Features Of Atypical Adrenal Masses-A Multicenter Retrospective Study, Vania Balderrama-Brondani, Ruaa Al-Ward, Katja Kiseljak-Vassiliades, Lauren Fishbein, Danielle Dawes, Oksana Hamidi, Reza Pishdad, Juan Pablo Perdomo Rodriguez, Mohamad Anas Sukkari, Joseph R Grajo, Hans Kumar Ghayee, Sara Bedrose, Roland L Bassett, Amir H Hamrahian, Mouhammed Amir Habra

Faculty, Staff and Students Publications

Context: The natural history and malignant potential of cases classified as atypical adrenal masses (AAMs) are unknown.

Objective: To describe the radiological characteristics and clinical outcomes of AAMs.

Design and participants: A multicenter retrospective study. Patients ≥18 years old with AAMs [diameter of 10-39 mm on first imaging study and pre-contrast attenuation of >10 Hounsfield units (HU) on computed tomography] were studied. We excluded adrenal metastasis, pheochromocytoma, sarcoma, lymphoma, infiltrative lesions, and adrenal hemorrhage, as well as patients with genetic predisposition to adrenal neoplasms. Data are presented as percentages and median values with interquartile ranges (IQRs).

Results: We included 217 …

The Maturity-Onset Diabetes Of The Young (Mody) Calculator Overestimates Mody Probability In Hispanic Youth, Guido Alarcon, Anh Nguyen, Angus Jones, Beverley Shields, Maria J Redondo, Mustafa Tosur

Children’s Nutrition Research Center Staff Publications

Context: The applicability of the maturity-onset diabetes of the young (MODY) risk calculator to non-White European populations remains unknown.

Objective: We aimed to test its real-world application in Hispanic youth.

Methods: We conducted a retrospective chart review of Hispanic youth (< 23 years) with diabetes (n = 2033) in a large pediatric tertiary care center in the United States. We calculated MODY probability for all subjects, splitting them into 2 cohorts based on the original model: individuals who were started on insulin within 6 months of diabetes diagnosis (Cohort 1) and those who were not (Cohort 2).

Results: Cohort 1 consisted of 1566 individuals (median age [25p, 75p]: 16 [13, 19] years, 49% female), while Cohort 2 comprised 467 youth (median age [25p, 75p]: 17 [15, 20] years, 62% female). The mean MODY probability was 5.9% and 61.9% in Cohort 1 and Cohort 2, respectively. The mean probability for both cohorts combined was 18.8%, suggesting an …

Btp2 Restricts Tulane Virus And Human Norovirus Replication Independent Of Store-Operated Calcium Entry, Francesca J Scribano, J Thomas Gebert, Kristen A Engevik, Nicole M Hayes, Jorge Villanueva, Son Pham, Soni Kaundal, Janam J Dave, B V Venkataram Prasad, Mary K Estes, Sasirekha Ramani, Joseph M Hyser

Faculty, Staff and Students Publications

Human norovirus is the leading cause of viral gastroenteritis across all age groups. While there is a need for human norovirus antivirals, therapeutic development has been hindered by a lack of cell culture systems and animal models of infection. Surrogate viruses, such as Tulane virus (TV), have provided tractable systems to screen potential antiviral compounds. Our previous work demonstrated that TV encodes a viral ion channel, which dysregulates cytosolic calcium signaling. We set out to investigate whether host pathways triggered by viral ion channel activity, including store-operated calcium entry (SOCE), play a role in virus replication. Using pharmacologic inhibitors and …

Proteogenomic Analysis Of The Calgb 40601 (Alliance) Her2+ Breast Cancer Neoadjuvant Trial Reveals Resistance Biomarkers, Eric J Jaehnig, Aranzazu Fernandez-Martinez, Tanmayi D Vashist, Matthew V Holt, Laterrica Williams, Jonathan T Lei, Chang In Moon, Beom-Jun Kim, Yongchao Dou, Haoquan Zhao, Viktoriya Korchina, Richard A Gibbs, Donna Marie Muzny, Harshavardhan Doddapaneni, Charles M Perou, Lisa A Carey, Ana I Robles, Terry Hyslop, Yujia Wen, Linda Mccart, Azra Krek, Francesca Petralia, George Miles, Shyam M Kavuri, Michael A Gillette, D R Mani, Steven A Carr, Bing Zhang, Matthew J Ellis, Shankha Satpathy, Meenakshi Anurag

Faculty, Staff and Students Publications

Proteogenomic analysis is applied to samples from the CALGB 40601 (Alliance) randomized neoadjuvant trial of trastuzumab, lapatinib, or the combination to identify biomarkers associated with pathological response status. Absence of ERBB2 gene amplification and human epidermal growth factor receptor 2 (HER2) protein overexpression by proteogenomics is associated with non-pathological compete response (pCR) (p < 0.05), highlighting potential false positives from standard diagnostics. Pathway analysis in proteogenomics-confirmed HER2+ samples identifies elevated epithelial-mesenchymal transition (EMT) and WNT-β-catenin signaling in non-pCR cases before treatment. Twenty-four pCR-associated proteins reproduce in a second proteomic dataset, and four (GPRC5A, TPBG, SP140L, and NEU1) are significant in a third. A meta-analysis of ten diverse neoadjuvant anti-HER2 treatment regimens from four independent studies confirms that non-pCR cases express higher levels of mRNA for G protein-coupled receptor class C group 5 member A (GPRC5A, p = 0.0002) and trophoblast glycoprotein (TPBG, p = 0.00008). Thus, proteogenomic analysis identifies negative biomarkers for pCR and alternative plasma membrane targets for treatment-resistant HER2+ breast cancer.

Effectiveness Of Digital Behavioral Activation Interventions For Depression And Anxiety: Systematic Review And Meta-Analysis, Eric Jia, Jushawn Macon, Michelle Doering, Joanna Abraham

2020-Current year OA Pubs

BACKGROUND: As digital interventions gain prominence in mental health care, they present opportunities to improve access and scalability. Despite their potential, the overall impact of digital behavioral activation (BA) interventions across different formats and populations is not yet fully understood.

OBJECTIVE: This systematic review examines the characteristics and functions of digital BA interventions and evaluates their effectiveness for mental health and other patient-related outcomes.

METHODS: A comprehensive search of databases (PubMed, Embase, Web of Science, APA PsycInfo, and ClinicalTrials.gov) was performed in November 2023 to identify randomized controlled trials (RCTs) assessing the effectiveness of digital BA interventions for depression and …

Ldl Receptor-Mediated Endocytosis Of Escherichia Coli Α-Hemolysin Mediates Renal Epithelial Toxicity, Hunter W Kuhn, Madeleine R Smither, Rachel J Jin, Christina A Collins, Hongming Ma, Jason Sina, Joseph P Gaut, Michael S Diamond, David A Hunstad

2020-Current year OA Pubs

The α-hemolysin (HlyA) of uropathogenic

Sars-Cov-2 Nsp15 Enhances Viral Virulence By Subverting Host Antiviral Defenses, Allen Caobi, Tamarand L Darling, Adrianus C M Boon, Et Al.

2020-Current year OA Pubs

SARS-CoV-2 encodes numerous virulence factors, yet their precise mechanisms of action remain unknown. We provide evidence that the SARS-CoV-2 nonstructural protein 15 (nsp15) enhances viral virulence by suppressing the production of viral double-stranded (dsRNA), a potent inducer of antiviral signaling. The viral variants lacking nsp15 endoribonuclease activity elicited higher innate immune responses and exhibited reduced replication in human stem cell-derived lung alveolar type II epithelial cells, as well as in the lungs of infected hamsters. Consistently, these variants caused significantly less weight loss and mortality compared to wild-type (WT) virus in K18-hACE2 mice. Mechanistically, the cells infected with nsp15 mutants …

Applying The Nonadoption, Abandonment, Scale-Up, Spread, And Sustainability (Nasss) Framework To Adapt The Champ App For Pediatric Feeding Tube Weaning: Application And Case Report., Dana Bakula, Alexandra Zax, Sarah T. Edwards, Kristina Nash, April Escobar, Rachel Graham, Amy Ricketts, Ryan Thompson, Sarah Bullard, Julianne Brogren, Leah Shimmens, Lori A. Erickson

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Evidence-based tube feeding (TF) weaning involves reducing the volume of tube feeds to induce hunger, with interdisciplinary monitoring to allow for proactive medical, nutritional, and behavioral intervention as needed. This can be done outpatient; however, the current standard of care requires a high degree of medical monitoring and care coordination, which can be challenging to implement. The CHAMP App is a mobile app designed for remote patient monitoring of children born with congenital heart conditions who are at high risk for medical morbidity and mortality. The CHAMP App remote patient monitoring program would be ideally suited to improve medical …

The Tumor Suppressor Hnrnpk Induces P53-Dependent Nucleolar Stress To Drive Ribosomopathies, Pedro Aguilar-Garrido, María Velasco-Estévez, Miguel Ángel Navarro-Aguadero, Álvaro Otero-Sobrino, Marta Ibáñez-Navarro, Miguel Ángel Marugal, María Hernández-Sánchez, Prerna Malaney, Ashley Rodriguez, Oscar Benitez, Xiaroui Zhang, Marisa Jl Aitken, Alejandra Ortiz-Ruiz, Diego Megías, Manuel Pérez, Gadea Mata, Jesús Gomez, Miguel Lafarga, Orlando Domínguez, Osvaldo Graña-Castro, Eduardo Caleiras, Pilar Ximénez-Embun, Marta Isasa, Paloma Jimena De Andres, Sandra Rodríguez-Perales, Raúl Torres-Ruiz, Enrique Revilla, Rosa María García-Martín, Daniel Azorín, Josune Zubicaray, Julián Sevilla, Oleksandra Sirozh, Vanesa Lafarga, Joaquín Martínez-López, Sean M Post, Miguel Gallardo

Faculty, Staff and Student Publications

The nucleolus is a membraneless organelle and an excellent stress sensor. Any changes in its architecture or composition lead to nucleolar stress, resulting in cell cycle arrest and interruption of ribosomal activity, critical factors in aging and cancer. In this study, we identified and described the pivotal role of the RNA-binding protein HNRNPK in ribosome and nucleolar dynamics. We developed an in vitro model of endogenous HNRNPK overexpression and an in vivo mouse model of ubiquitous HNRNPK overexpression. These models showed disruptions in translation as the HNRNPK overexpression caused alterations in the nucleolar structure, resulting in p53-dependent nucleolar stress, cell …

Single-Cell Expression Analysis Of Ductal Carcinoma In Situ Identifies Complex Genotypic-Phenotypic Relationships Altering Epithelial Composition, Xiaodi Qin, Xiaoke Luo, Graham A Colditz, Shu Jiang, Et Al.

2020-Current year OA Pubs

UNLABELLED: Ductal carcinoma in situ (DCIS) is a risk factor for subsequent invasive breast cancer (IBC). To identify events in DCIS that lead to invasive cancer, we performed single-cell RNA sequencing on DCIS lesions and matched normal breast tissue. Inferred copy-number variation was used to identify neoplastic epithelial cells from clinical specimens, which contained a mixture of DCIS and normal ducts. Phylogenetic analysis demonstrated intratumoral clonal heterogeneity that was associated with significant gene expression differences. Classification of epithelial cells into mammary cell states revealed that subclones contained a mixture of cell states, suggesting an ongoing pattern of differentiation after neoplastic …

Adenovirus Species In U.S. Children With Acute Respiratory Illness, 2016-2019, Varvara Probst, Tess Stopczynski, Justin Z Amarin, Adam Gailani, Herdi K Rahman, Laura S Stewart, Rangaraj Selvarangan, Jennifer E Schuster, Marian G Michaels, John V Williams, Julie A Boom, Leila C Sahni, Vasanthi Avadhanula, Mary Allen Staat, Elizabeth P Schlaudecker, Christina Quigley, Christopher J Harrison, Mary E Moffatt, Geoffrey A Weinberg, Peter G Szilagyi, Janet A Englund, Eileen J Klein, Aaron T Curns, Heidi L Moline, Ariana P Toepfer, Susan I Gerber, James D Chappell, Andrew J Spieker, Natasha B Halasa

Faculty, Staff and Students Publications

Background: Human adenovirus (HAdV) is a common cause of pediatric acute respiratory illness (ARI). HAdV-B, -C, and -E species have been associated with ARI, though relative detection frequencies in United States (U.S.) and respective roles in symptomatic respiratory infections remain unclear.

Methods: We conducted a multicenter, prospective viral surveillance study at 7 U.S. children's hospitals comprising the New Vaccine Surveillance Network from January 12, 2016 to November 30, 2019. Children < 18 years old in the emergency department or hospitalized with fever and/or respiratory symptoms were enrolled, and respiratory specimens were tested for HAdV and other viral pathogens. HAdV-positive specimens were subsequently typed using single-plex real-time PCR assays targeting sequences in the hexon gene. Demographics, clinical characteristics, and outcomes (hospitalization and supplemental oxygen use as severity indicators) were compared between HAdV-B and HAdV-C species.

Results: Of the 29 381 children with ARI, 1843 (6.3%) had HAdV detected, with 1402 specimens (76.0%) successfully typed. HAdV-C was the most frequently detected species (73.0%), followed by HAdV-B …

Performance Of A Novel Stool Quantitative Polymerase Chain Reaction Assay For Pediatric Tuberculosis Detection In Sub-Saharan Africa, Anca Vasiliu, Lucia Carratala-Castro, Abigail Seeger, Joanna Ehrlich, Babongile Nkala, Tara Ness, Miguel Mario Cumbe, Durbbin Mulengwa, Shilzia Munguambe, Bariki Mtafya, Edson Mambuque, Nosisa Shiba, Sozinho Acacio, Lilian Komba, Clement Gascua Adu-Gyamfi, H Lester Kirchner, Christoph Lange, Andrew R Dinardo, Alberto L Garcia-Basteiro, Anna Maria Mandalakas, Alexander Kay

Faculty, Staff and Students Publications

Background: Children have paucibacillary tuberculosis and cannot provide expectorated sputum. Invasive specimen collection, by gastric aspiration or sputum induction, has a low diagnostic yield. In this study, we aimed to evaluate the diagnostic performance and additive yield of a novel stool-based assay in children diagnosed with tuberculosis in sub-Saharan Africa.

Methods: We conducted a prospective case-control study from October 2020 to June 2023 in Eswatini, Mozambique, and Tanzania. Children under 15 years newly diagnosed with tuberculosis completed clinical examination, chest radiography, culture, sputum Xpert Ultra, stool Xpert Ultra, and stool-based quantitative polymerase chain reaction (stool qPCR) assessment. Stool qPCR sensitivity …

Type I Interferon Protects Against Bone Loss In Periodontitis By Mitigating An Interleukin (Il)-17-Neutrophil Axis, Jinmei Zhang, Qiong Ding, Angela X Wang, Maoxuan Lin, Ning Yu, Kevin Moss, Megumi A Williamson, Di Miao, Julie T Marchesan, Erliang Zeng, Wei Shi, Hongli Sun, Yu Leo Lei, Shaoping Zhang

Faculty, Staff and Student Publications

Type I interferons (IFNs-I), a group of pleiotropic cytokines, critically modulate host response in various inflammatory diseases. However, the role of the IFN-I pathway in periodontitis remains largely unknown. In this report, we describe that the IFN-β levels in the gingival crevicular fluid of human subjects were negatively associated with periodontitis and clinical gingival inflammation. Disruption of IFN-I signaling worsened alveolar bone resorption in a ligature-induced periodontitis murine model. Deficiency of the IFN-I pathway resulted in an exaggerated inflammatory response in myeloid cells and drastically increased the interleukin-17 (IL-17)-mediated neutrophil recruitment in the gingiva. We further identified that the myeloid …

Management And Optimization Of Chronic Renal Insufficiency In The Setting Of Kidney Cancer A Systematic Review, Jessica K. Cobb, Hiroko Miyagi, Jad Chahoud, Claude Bassil, Philippe E. Spiess

Division of Internal Medicine Faculty Papers & Presentations

PURPOSE: There is a bidirectional relationship between chronic kidney disease and the incidence of renal cell carcinoma. Despite the frequency of patients with both chronic kidney disease and renal cell carcinoma, there are limited systematic reviews detailing the nuanced treatment. This review provides comprehensive insights for clinicians for managing chronic kidney disease, and renal cell carcinoma. Methods and Methods: We reviewed published literature that examined either chronic kidney disease and renal cell carcinoma or an indirect contributor of both.

RESULTS: We compare and contrast renal cell carcinoma treatment with partial and radical nephrectomies, ablative techniques, and radiation and their impact …

Asymmetric Cingulum Bundle Connectivity Is Modulated By Paracingulate Sulcus Morphology, Isabel A Danstrom, Joshua A Adkinson, Meghan E Robinson, Lu Lin, Atul Maheshwari, Ben Shofty, Garrett Banks, Mohammed Hasen, Sameer A Sheth, Alica M Goldman, Eleonora Bartoli, Sarah R Heilbronner, Kelly R Bijanki

Faculty, Staff and Students Publications

The cingulum bundle (CB) is a group of axons supporting connectivity among several functional brain networks relevant in healthy and diseased states. The paracingulate sulcus (PCS) is present in at least one cerebral hemisphere across 70% of the population. PCS presence versus absence is linked to differences in structure and function of the anterior cingulate cortex, though the influence of PCS on the white matter of the CB remains unknown. The objective of this work was to define the CB electrographic connectivity profile and determine the impact of PCS morphology on CB engagement. Single-pulse electrical stimulation in combination with stereo-electroencephalography …

Virus Against Cancer: Paradigm-Shifting Biological Concepts, Dong Ho Shin, Marta M Alonso, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

Purpose of review: Virotherapy has emerged as a promising approach to cancer treatment. Over the past two decades, early-phase clinical trials have demonstrated the safety and promising efficacy of virotherapy in subsets of cancer patients. However, a significant knowledge gap needs to be filled to propel the field further and achieve substantial anti-cancer benefits for more than the current 10-20% of treated patients. This article reviews the most relevant current challenges in cancer virotherapy.

Recent findings: Recent clinical observations suggest that patients who respond to virotherapy experience a shift in their immune response from an initial or concomitant response against …