Digital Commons Network^™

Unexpected Diagnosis Of Arrhythmogenic Right Ventricular Cardiomyopathy After Routine Preoperative Evaluation Leads To Life-Saving Intervention, Parth Desai, Alexandra Maloof, Linda Vong, Savitri Fedson, Dhaval Parekh, Wilson W Lam

Faculty, Staff and Students Publications

Background: A healthy 44-year-old woman presented for preoperative evaluation of planned bunionectomy. Electrocardiogram showed T-wave inversions in leads V1 to V5 and epsilon waves in precordium prompting further evaluation.

Case summary: Imaging studies and genetic testing revealed diagnosis of arrhythmogenic right ventricular cardiomyopathy. Patient met Class IIb indication for primary prevention with implantable cardioverter-defibrillator (ICD). Despite weak guideline indication, shared decision-making with the patient led to ICD implantation. Six months later, she had a ventricular tachycardia arrest resulting in ICD shock and return to sinus rhythm.

Discussion: Routine preoperative evaluation led to the diagnosis of a rare pathology. Prompt evaluation …

Kidney Function Trajectories With Mechanical Circulatory Support, Carl P Walther, Harveen K Lamba, Ajith P Nair, Andrew B Civitello, Nandan K Mondal, Kenneth K Liao, Sankar D Navaneethan

Faculty, Staff and Students Publications

Introduction: Adverse long-term kidney outcomes with left ventricular assist devices (LVADs) are common but little understood. Creatinine-based estimated glomerular filtration rate (eGFR) is used clinically in this setting; however, it is of uncertain validity and tends to change nonlinearly after LVAD implantation with an early peak followed by decline. We investigated nonlinear eGFR trajectories over 90 days following LVAD implantation and the relationships with patient factors and outcomes.

Methods: We used 2 complementary cohorts of LVAD recipients, a single-center cohort (n = 190) and a US national cohort (n = 10794). Segmented linear regression with 2 segments was …

Unravelling The Distinct Effects Of Vhl Mutations And Chromosome 3p Loss In Clear Cell Renal Cell Carcinoma: Implications For Prognosis And Treatment, Xiang Wang, Jian-Rong Li, Naail Raed Chowdhury, Lang Wu, Cheng Chao

Faculty, Staff and Students Publications

No abstract provided.

Nonprofit Hospital Ceo Compensation: Does Quality Matter?, Derek Jenkins, Marah Short, Vivian Ho

Faculty, Staff and Students Publications

Background: Past research has documented that increases in profits and health system size, as well as increases in the reward generosity for improving these metrics play an important role in explaining increases in nonprofit hospital CEO pay between 2012 and 2019.

Objectives: To test whether hospital quality measures play a supplemental role in determining CEO pay.

Research design: We estimated linear regressions for 2012 and 2019 of the log of CEO wages on system or independent hospital characteristics, including quality. The regressions were used to construct a Oaxaca decomposition of factors associated with CEO compensation.

Subjects: One thousand forty-seven nonprofit …

Single Cell Sequencing Analysis Of Respiratory Syncytial Virus-Infected Pediatric And Adult Human Nose Organoids Reveals Age Differences, Proliferative Diversity And Identifies Novel Cellular Tropism, Anubama Rajan, Divya Nagaraj, Carolyn Bomidi, Gina M Aloisio, Ashley M Murray, Emily M Schultz, Amal Kambal, Mary K Estes, Erin Nicholson, Vasanthi Avadhanula, Sarah E Blutt, Pedro A Piedra

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) is a leading cause of infant death across the globe. Age is a significant factor that contributes to the severity of infection in young children. RSV primarily infects the ciliated cells of the airway epithelium, induces mucus hypersecretion, and impaired mucociliary clearance. Better understanding of RSV infection at the cellular level is needed for the development of effective therapeutic interventions. To investigate the age difference and comprehensively understand gene signatures associated with RSV infection, we performed single-cell transcriptomic analysis of adult and pediatric human nose organoids (HNOs) infected with RSV. Our analysis revealed a significant difference …

Exploring The Transformative Effects Of Calorie Restriction On The Lacrimal Gland In Adult Mice, Olivier Mauduit, Prashant Kumar, Kaitlin K Scholand, Emre Aksan, Laura Schaefer, Anmar Abu-Romman, Vanessa Delcroix, Zhiyuan Yu, Aude I Sindikubwabo, Ron Korstanje, Helen P Makarenkova, Cintia S De Paiva

Faculty, Staff and Students Publications

Advanced age is one of the most recognizable risk factors for dry eye. Dry eye disease affects millions worldwide and can result from age-related lacrimal gland dysfunction, which correlates with a decline in lacrimal gland secretory cell function and chronic inflammation. This study investigated the potential of calorie restriction to maintain lacrimal gland and ocular surface health. Adult female C57BL/6 J mice were subjected to a 40% calorie restriction for 4 months, starting at 6-7 months and continuing until 10-11 months. These mice were compared to controls fed ad libitum. Bulk RNA sequencing of lacrimal glands, conjunctiva, and cornea subjected …

Author Correction: Clonal Dynamics And Somatic Evolution Of Haematopoiesis In Mouse, Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia

Faculty, Staff and Students Publications

No abstract provided.

Plasma Proteome Correlations With Liver Stiffness In Pediatric Cholestasis Implicate Epithelial To Mesenchymal Transition, Benjamin L Shneider, Rupa S Kanchi, Sandra L Grimm, Sridevi Devaraj, Juliet Emamaullee, Jeremy Schraw, Philip J Lupo, Jorge A Bezerra, Kathleen M Loomes, John C Magee, Ronald J Sokol, Kasper S Wang, Alyssa Kriegmeier, Evelyn Hsu, Jean P Molleston, Philip Rosenthal, Rohit Kohli, Saul J Karpen, Simon P Horslen, M Kyle Jensen, Arianna Barbetta, Cristian Coarfa

Faculty, Staff and Students Publications

Background: Pediatric cholestatic liver diseases can be characterized by rapidly progressive fibrosis. A multicenter cross-sectional analysis of vibration-controlled elastography in biliary atresia (BA), alpha-1 antitrypsin deficiency (A1AT), and Alagille syndrome (ALGS) was leveraged to interrogate the plasma proteome relative to liver stiffness measurements (LSM).

Methods: Slow off-rate modified aptamer scanning profiling of >7000 proteins in plasma from 187 children with BA (n=93), A1AT (n=31), ALGS (n=46), and healthy pediatric controls (n=17) was performed, and correlations with LSM were undertaken.

Results: There was an abundance of LSM correlated proteins (BA n=2720, A1AT n=694, ALGS n=5968). Interestingly, a distinct plasma proteome was …

Examining The Relationship Between Dysphagia, Eating-Related Symptoms, And Diet Quality Among Oropharyngeal Cancer Patients During Critical Stages Of Cancer Survivorship: The U-Dine Study, Beatrice Manduchi, Vlad C Sandulache, Ji Yun Tark, Shreela Sharma, Ruosha Li, Emily Roller, Andrew Bevelhimer, Katherine A Hutcheson, Marcia C De Oliveira Otto

Faculty, Staff and Students Publications

Background: Diet quality is a modifiable factor impacting treatment outcomes in oropharyngeal cancer (OPC), yet the effect of dysphagia and self-reported eating-related symptoms remains unclear. This study examined their associations with diet quality in OPC patients.

Methods: A cross-sectional analysis was conducted with two parallel cohorts from MD Anderson Cancer Center and Michael E. DeBakey Veterans Affairs Medical Center as part of the Uncovering the Long-Term Impact of OPC and Dysphagia on Dietary Quality and Nutrition Among Cancer Survivors (U-DINE) Study. Participants at varying survivorship stages (prediagnosis, 3-6 and 18+ months posttreatment) were assessed for dysphagia (DIGEST scale) and six …

Nrf2 Hyperactivation As A Driver Of Radiotherapy Resistance And Suppressed Antitumor Immunity In Head And Neck Squamous Cell Carcinoma, Rutulkumar Patel, Kalil Saab, Lixia Luo, Yan Ma, Rashid Abdullah Osman, Nerissa T Williams, Jeffrey Everitt, Maciej J Zelazowski, Patricia Castro, William K Decker, William H Hudson, Jeffrey N Myers, Vlad C Sandulache, Mitchell J Frederick, Yvonne M Mowery, David G Kirsch

Faculty, Staff and Students Publications

Purpose: Alterations in the KEAP1/NFE2L2 (NRF2)/CUL3 pathway occur in ∼20% of human head and neck squamous cell carcinomas (HNSCC) and are associated with resistance to standard-of-care therapy. However, this pathway's role in radiotherapy resistance in HNSCC has not been well studied.

Experimental design: We generated genetically engineered mouse models and developed primary murine cancer cell lines harboring mutations commonly observed in human HNSCC, including inducible activation of PIK3CA and deletion of Trp53, with or without Keap1 loss. Primary tumors were initiated via 4-hydroxytamoxifen injection ± the tobacco carcinogen benzo[a]pyrene (BAP) into the oral buccal mucosa. Tumors were analyzed by Western …

Dominant Negative Atp5f1a Variants Disrupt Oxidative Phosphorylation Causing Neurological Disorders, Sara M Fielder, Marisa W Friederich, Daniella H Hock, Jessie R Zhang, Liana M Valin, Jill A Rosenfeld, Kevin T A Booth, Natasha J Brown, Rocio Rius, Tanavi Sharma, Liana N Semcesen, Kim C Worley, Lindsay C Burrage, Kayla Treat, Tara Samson, Sarah Govert, Sara Dacunha, Weimin Yuan, Jian Chen, Jacob Lesinski, Hieu Hoang, Stephanie A Morrison, Farah A Ladha, Roxanne A Van Hove, Cole R Michel, Richard Reisdorph, Eric Tycksen, Dustin Baldridge, Gary A Silverman, Claudia Soler-Alfonso, Erin Conboy, Francesco Vetrini, Lisa Emrick, William J Craigen, Undiagnosed Diseases Network, Stephen M Sykes, David A Stroud, Johan L K Van Hove, Tim Schedl, Stephen C Pak

Faculty, Staff and Students Publications

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP …

Inhibition Of Ros1 Activity With Lorlatinib Reversibly Suppresses Fertility In Male Mice, Yuki Oyama, Kentaro Shimada, Haruhiko Miyata, Rie Iida-Norita, Chihiro Emori, Maki Kamoshita, Seiya Oura, Ryohei Katayama, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Background: Inhibition of sperm maturation in the epididymis is a promising post-testicular strategy for short-acting male contraceptives. It has been shown that ROS1, a receptor tyrosine kinase expressed in the epididymis, is essential for epididymal differentiation, sperm maturation, and male fertility in mice. However, it is unknown if inhibition of ROS1 suppresses male fertility reversibly.

Objectives: Our study aimed to investigate the effects of ROS1 inhibitor administration in male mice on sperm function and fertility.

Materials and methods: We used lorlatinib, an anti-cancer drug that inhibits ROS1. We treated 10-week-old sexually mature male mice with lorlatinib for 3 weeks and …

Germline Cancer Predisposition Results From The National Cancer Institute-Children's Oncology Group Pediatric Match Trial, Sarah Scollon, Sharon E Plon, Steven Joffe, Jaclyn A Biegel, Shashikant Kulkarni, George Miles, David R Patton, Brent Coffey, Cynthia L Winter, Gregory J Tsongalis, Mark J Routbort, Nilsa C Ramirez, Lauren Saguilig, Jin Piao, Todd A Alonzo, Stacey L Berg, Elizabeth Fox, Brenda Weigel, Douglas S Hawkins, Jeffrey S Abrams, Margaret Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D Williams Parsons

Faculty, Staff and Students Publications

Purpose: Precision oncology trials have generally focused on tumor testing to identify actionable alterations. The National Cancer Institute-Children's Oncology Group Pediatric MATCH trial incorporated return of germline results to assess feasibility of reporting in a cooperative group setting and characterize germline cancer predisposition in patients with refractory cancers.

Patients and methods: Tumor and blood DNA from patients 1-21 years of age with treatment-refractory solid tumors, non-Hodgkin lymphomas, or histiocytic disorders underwent cancer gene panel sequencing. Clinical germline reports returned to 151 study sites included pathogenic/likely pathogenic (P/LP) germline variants found in 38 cancer predisposition genes (CPGs). European Society of Medical …

Bi-Allelic Loss-Of-Function Variants In Poc5 Cause A Syndromic Retinal, Endocrine, And Neuromuscular Ciliopathy, Anneke T Vulto-Van Silfhout, Ingrid M Jazet, Suzanne Yzer, Jeroen Pas, Serwet Demirdas, Elisabeth F C Van Rossum, Alberta A H J Thiadens, Ronald Van Beek, Lonneke Haer-Wigman, Daniela Q C M Barge-Schaapveld, Charlotte Brasch-Andersen, Simon Frost, Miriam Bauwens, Elfride De Baere, Irina Balikova, Filip Van Den Broeck, Monika Weisz-Hubshman, Pascal Joset, Peter Miny, Isabel Filges, Susanne Kohl, Pietro De Angeli, Laura Kühlewein, Jan-Philipp Bodenbender, Tobias Haack, Karin Poths, Lidia Fernandez-Caballero, Marta Corton, Fiona Blanco Kelly, Carmen Ayuso, Peggy Martínez-Esteban, John Vissing, Jordi Díaz-Manera, Volker Straub, Ana Töpf, Siying Lin, Gavin Arno, William L Macken, Jennifer Spillane, Radha Ramachandran, Erik De Vrieze, Tjakko Van Ham, Susanne Roosing, Machteld M Oud

Faculty, Staff and Students Publications

Purpose: A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants.

Methods: We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines.

Results: Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with …

Phosphorylation At Serine 214 Correlates With Tau Seeding Activity In An Age-Dependent Manner In Two Mouse Models For Tauopathies And Is Required For Tau Transsynaptic Propagation, Pablo Martinez, Nur Jury-Garfe, Henika Patel, Yanwen You, Abigail Perkins, Yingjian You, Audrey Lee-Gosselin, Ruben Vidal, Cristian A Lasagna-Reeves

Faculty, Staff and Students Publications

Background

Tau aggregation and propagation are hallmark features of Alzheimer's disease and related tauopathies. The molecular identity and post-translational modifications that contribute to tau seeding activity remain incompletely understood.

Objective

To characterize the temporal dynamics of tau seeding activity and identify specific phosphorylated tau species associated with tau propagation in vivo.

Methods

We profiled tau seeding activity using a FRET-based biosensor cell line and correlated it with the abundance of phospho- and conformational tau species in two transgenic mouse models of tauopathy (P301S-1N4R and P301S-0N4R). Immunohistochemistry and subcellular fractionation were used to examine the spatial distribution of tau species. Functional …

Systematic Targeting Of Gd2-Positive Neuroblastoma Tumors With A Photooncolytic Phage Nanovector Platform, Suleman Khan Zadran, Nicola Facchinello, Piergiuseppe De Rosa, Roberto Saporetti, Paolo Emidio Costantini, Luca Ulfo, Michela Nigro, Annapaola Petrosino, Lucia Pappagallo, Sara Aloisi, Giorgio Milazzo, Zainul Abe Din, Alberto Rigamonti, Leonardo Flora, Martina Santulli, Leonardo Cimadom, Giampaolo Zuccheri, Mattia Zangoli, Manuele Di Sante, Matteo Di Giosia, Francesca Di Maria, Roberto Bernardoni, Eveline Barbieri, Matteo Calvaresi, Alberto Danielli, Giovanni Perini

Faculty, Staff and Students Publications

Disialoganglioside-GD2 is a key molecular target for Neuroblastoma (NB) immunotherapy based on the employment of GD2-targeting antibodies. However, about 50% of treated patients can experience tumor relapse due to limited immune-mediated cytotoxicity and poor antibody penetration into tumors. To address this problem, a tumor-penetrating photo-oncolytic phage nanovector platform is genetically and chemically developed that selectively targets GD2-expressing NB cells. The phage bioconjugates, functionalized with different photosensitizers, result in specific and selective oncolysis of GD2-positive NB cells upon light irradiation, without affecting GD2-negative ones. The photo-oncolytic phage vectors are shown to deeply penetrate into GD2-positive tumor spheroids in vitro, and to …

Tigit Affects Car Nk-Cell Effector Function In The Solid Tumor Microenvironment By Modulating Immune Synapse Strength, Ishwar Navin, Matthew Dysthe, Prashant S Menon, Corrine Baumgartner, Tim Sauer, Navin Varadarajan, Robin Parihar

Faculty, Staff and Students Publications

Therapies using NK cells that express chimeric antigen receptors (CAR-NK) have been successfully employed against hematologic malignancies. However, solid tumors resist CAR-NKs partly by enriching tumor microenvironments with ligands for NK cell inhibitory receptors. Although the NK inhibitory receptor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) has been implicated in impaired antitumor activity of endogenous NK cells, the consequences of TIGIT expression on engineered CAR-NKs have not been explored. To address this gap, we compared TIGIT-expressing and TIGIT-deleted human CAR-NKs targeting the GD2 solid tumor antigen in tumor immune microenvironment co-cultures and in vivo tumor immune …

Cutaneous Tuberculosis With Multisystem Involvement In An Immunocompetent Refugee, Nabor S Mireles, Natalie Garcia, Omid Jalali

Faculty, Staff and Students Publications

Cutaneous tuberculosis (CTB) is an uncommon skin infection that can mimic other dermatologic conditions and delay recognition. Herein, we present a case of TB chancre, a form of CTB caused by exogenous inoculation. A 19-year-old immunocompetent male refugee from Sudan presented with a five-month history of non-healing wounds on his right shoulder and three weeks of bilateral lower extremity weakness. Diagnostic examination revealed the presence of a spinal epidural abscess and lung consolidation, with culture of the spinal abscess positive for Mycobacterium tuberculosis (MTB). Skin biopsy of the shoulder lesion revealed granulomatous dermatitis, with subsequent culture confirming MTB from the …

Exploring Patients' Perceptions Of An Advance Care Planning Intervention In The Emergency Department: A Qualitative Study, Youkie Shiozawa, Saaya Morton, Nanako Shirai, Hannah Oelschlager, Lucy Kiernat, Anita N Chary, Anna C Revette, Adrian Haimovich, Smit Desai, Kai-Wei Chang, Shan W Liu, Maura Kennedy, Mara A Schonberg, Kei Ouchi

Faculty, Staff and Students Publications

Objectives: Emergency department (ED) visits offer opportunities for seriously ill patients to formulate future medical care goals, yet ED clinicians lack practical strategies for these conversations. ED GOAL, a behavioral intervention, engages seriously ill yet clinically stable older adults in the ED to address advance care planning (ACP) with their outpatient clinicians. In a randomized trial, goals-of-care documentation was significantly higher in the intervention group compared to controls after three (24.3% vs. 9.9%, p = 0.03) and 6 months (31.4% vs. 12.7%, p < 0.01). This study is a sub-analysis to learn about intervention arm participants' perceived benefits and obstacles of the intervention.

Methods: We conducted semi-structured interviews between October 2022 and August 2024 (N = 52) with intervention-arm patients …

Lp(A) Testing For The Primary Prevention Of Cardiovascular Disease In High-Income Countries: A Cost-Effectiveness Analysis, Jedidiah I Morton, Florian Kronenberg, Magdalena Daccord, Nicola Bedlington, Marius Geanta, Tobias Silberzahn, Zhenyue Chen, Jean-Luc Eisele, Bogi Eliasen, Mariko Harada-Shiba, Marc Rijken, Albert Wiegman, George Thanassoulis, Pia R Kamstrup, Iñaki Gutierrez-Ibarluzea, Pablo Coral, Raul D Santos, Erik Stroes, Michal Vrablik, Gerald F Watts, Christie M Ballantyne, Samia Mora, Børge G Nordestgaard, Kausik K Ray, Stephen J Nicholls, Zanfina Ademi, Lp(A) International Taskforce (Itf) Initiative

Faculty, Staff and Students Publications

Background and aims: Cost-effectiveness of Lipoprotein(a) [Lp(a)] testing is not established. We aimed to evaluate the cost-effectiveness of Lp(a) testing in the cardiovascular disease (CVD) primary prevention population from healthcare and societal perspectives.

Methods: We constructed and validated a multi-state microsimulation Markov model for a population of 10,000 individuals aged between 40 and 69 years without CVD, selected randomly from the UK Biobank. The model evaluated Lp(a) testing in individuals not initially classified as high-risk based on age, diabetes status, or the SCORE-2 algorithm. Those with an Lp(a) level ≥105 nmol/L (50 mg/dL) were treated as high risk (initiation of …

Pan-Uk Biobank Genome-Wide Association Analyses Enhance Discovery And Resolution Of Ancestry-Enriched Effects, Konrad J Karczewski, Rahul Gupta, Masahiro Kanai, Wenhan Lu, Kristin Tsuo, Ying Wang, Raymond K Walters, Patrick Turley, Shawneequa Callier, Nirav N Shah, Nikolas Baya, Duncan S Palmer, Jacqueline I Goldstein, Gopal Sarma, Matthew Solomonson, Nathan Cheng, Sam Bryant, Claire Churchhouse, Caroline M Cusick, Timothy Poterba, John Compitello, Daniel King, Wei Zhou, Cotton Seed, Hilary K Finucane, Mark J Daly, Benjamin M Neale, Elizabeth G Atkinson, Alicia R Martin

Faculty, Staff and Students Publications

Large biobanks, such as the UK Biobank (UKB), enable massive phenome by genome-wide association studies that elucidate genetic etiology of complex traits. However, individuals from diverse genetic ancestry groups are often excluded from association analyses due to concerns about population structure introducing false positive associations. Here, we generate mixed model associations and meta-analyses across genetic ancestry groups, inclusive of a larger fraction of the UKB than previous efforts, to produce freely-available summary statistics for 7,266 traits. We build a quality control and analysis framework informed by genetic architecture. Overall, we identify 14,676 significant loci (p < 5 × 10−8) in the meta-analysis that were not found in the EUR genetic ancestry group alone, including novel associations for example between CAMK2D and triglycerides. We also …

Adeno-Associated Virus-Mediated Silencing Of Sox4 Leads To Long-Term Amelioration Of Liver Phenotypes In Mouse Models Of Alagille Syndrome, Duncan Fox, Jun Xie, Jennifer L Burwinkel, Josh M Adams, Kashish Chetal, Marzieh Keivandarian, Yaniv Faingelernt, Sanjay Subramanian, Mario F Lopez, Anna L Peters, Nathan Salomonis, Neda Zarrin-Khameh, Guangping Gao, Stacey S Huppert, Hamed Jafar-Nejad

Faculty, Staff and Students Publications

Background & aims: In patients with Alagille syndrome (ALGS), bile duct paucity often leads to severe cholestatic phenotypes for which liver transplantation remains the only definitive treatment. No Food and Drug Administration-approved mechanism-based strategies exist to enhance biliary development in ALGS or other diseases with bile duct paucity. We aimed to identify a therapeutic target to address this unmet need.

Methods: Preclinical ALGS mouse models lacking 1 copy of Jag1 with or without conditional deletion of 1 or both copies of Sox9 were used. Sox4 levels were reduced genetically or with adeno-associated virus 8 (AAV8) vectors driving a Sox4-silencing sequence. …

Normal Urinary Oxalate Excretion In 4-Hydroxy-2-Oxo-Glutarate Aldolase 1 (Hoga1) Deficient Mice With Agt Expression In Peroxisomes And Not In Mitochondria, Iolanda Boffa, Rosa Ferriero, Mariarosaria Cancelliere, Edoardo Nusco, Leonardo Gatticchi, Donna Palmer, Philip Ng, Pasquale Piccolo, Barbara Cellini, Kyle Wood, John Knight, Nicola Brunetti-Pierri

Faculty, Staff and Students Publications

Primary hyperoxaluria type 3 (PH3) is caused by mutations in Hoga1 gene. PH3 individuals develop nephrolithiasis, but the mechanism underlying hyperoxaluria is unclear and a mouse model recapitulating the human disease can provide insights into the pathogenesis of PH3. Hoga1−/− mice do not have increased urinary oxalate excretion, probably due to the murine mitochondrial alanine-glioxylate-aminotransferase (AGT) activity, which in humans is only expressed in peroxisomes. However, Hoga1−/−/Agxt−/− mice with AGT installed on peroxisome and not on mitochondria did not show increased urinary oxalate, suggesting that AGT expression in both cellular compartments is not an explanation for …

Molecular And Genetic Landscapes Of Retina And Brain Microglia In Neurodegenerative Diseases, Khang Ma, Rinki Ratnapriya

Faculty, Staff and Students Publications

Microglia-driven dysregulation has emerged as a significant underlying mechanism in many neurodegenerative diseases, such as age-related macular degeneration (AMD) and Alzheimer's disease (AD). Although both brain and retinal microglia originate from the yolk sac, it is uncertain whether they share molecular similarities or genetic and molecular foundations related to neurodegenerative diseases. In this study, we examine the transcriptomic and epigenetic profiles of retina and brain microglia through integrative analyses of single-nucleus RNA sequencing (snRNA-seq) and single-nucleus ATAC sequencing (snATAC-seq) from 97 independent human samples across 11 different studies. Our findings reveal that retina and brain microglia share similar expression and …

0896: John F. Smith Collection, 1978-2017, Marshall University Special Collections

Guides to Manuscript Collections

John F. Smith was a retired lieutenant colonel in the United States Army and former director of the Big Green Scholarship Foundation at Marshall University in Huntington, West Virginia.

The collection includes records of the Big Green Scholarship Foundation, research and papers of John F. Smith, and framed Marshall University basketball and football memorabilia.

Peritoneal Immunosurgery: Immunotherapy Augmented Surgery For The Treatment Of Peritoneal Cancers, Ada I Ozcan, Arianexys Aquino López, Mary K Mckenna, Malcolm K Brenner, Alastair M Thompson

Faculty, Staff and Students Publications

Peritoneal malignancy often indicates disruptions in multiple physiological systems resulting from widespread cancer. The heterogenous origin and dynamic nature of peritoneal cancer make it difficult to treat with standard approaches that fit into guidelines. We describe how successful treatment should address the underlying pathology, the systemic response to surgical treatments and target the immune perturbations that facilitate the establishment and propagation of this multifaceted disease.

Cul3 Postnatal Homozygous Deletion In Forebrain Results In Behavioral Differences, Prathibha Sekar, Qiang‐Qiang Xia, Alex C. Stokes, Feiyu Quan, Jeffrey Singer, Craig M. Powell

Biology Faculty Publications and Presentations

Large-scale human genetic studies implicate multiple genes that regulate protein ubiquitination in autism spectrum disorder (ASD). De novo loss-of-function mutations in the gene CULLIN3 (CUL3) are implicated in autism and intellectual disability (ID). CUL3 is an essential component of an E3 ubiquitin ligase complex required for ubiquitination of substrates, often a signal for proteasomal degradation. Homozygous deletion of Cul3 is embryonically lethal. Recent studies show heterozygous deletion of Cul3 results in phenotypes with some face validity for autism in constitutive and conditional Cul3 heterozygotes. To understand the function of Cul3 in late postnatal development and function in the brain, we …

Sustained Response To Pan-Braf Inhibitor Plixorafenib (Fore8394, Plx8394) In A Young Adult With Neurodegenerative Langerhans Cell Histiocytosis, Joanna S Yi, Kathleen S Mccarthy, Kate Mazur, Rebecca Kudlaty, Terry Armstrong, Nilesh Desai, Stacie Peacock Shepherd, Daniel Zinn, Jessica Velazquez, Brooks Scull, Carl Allen, Kenneth Mcclain

Faculty, Staff and Students Publications

No abstract provided.

Exploring Student Thriving: A Comparative Analysis Of First-Generation And Continuing-Generation Undergraduate College Students At A Private, Faith-Based University, Melissa A. Maisenbacher

Doctor of Education (Ed.D)

This quantitative study explored the thriving of first-generation undergraduate students enrolled full-time at a mid-sized, private, faith-based, open-enrollment university in the southeastern United States. Using the validated Thriving Quotient™ instrument, this research measured thriving across five domains: engaged learning, academic determination, positive perspective, social connectedness, and diverse citizenship, along with three subscales: spirituality, sense of community, and institutional integrity. The study compared thriving perceptions of first-generation college students (FGCSs) and continuing-generation college students (CGCSs) to determine if generational status influenced students’ experiences of thriving. Despite documented challenges faced by FGCSs—including financial stress, limited familial guidance, and lower academic preparedness—this study …

Teachers As First Responders: Transferring Trauma-Informed Strategies Into The Classroom, Lauren A. Daley-Norris

Doctor of Education (Ed.D)

Research suggests that nearly two-thirds of students experience a traumatic event by the age of 16 (Elmore et al, 2023; Wall, 2021). Despite this prevalence, a standardized training module for trauma-informed care (TIC) in K-12 education remains absent. Existing studies primarily focus on school or district-wide implementations (Avery et al, 2020; Champine et al., 2022; Plumb et al., 2016). The quantitative, quasi-experimental within-subjects repeated measures research design was used to address the study’s topic. Two research questions were formally stated to address the study’s purpose. Descriptive and inferential statistical techniques were used to analyze study data. Teachers (N = 12) …