Diseases Commons^™

Atrial Septal Defect Closure Is Associated With Improved Clinical Status In Patients ≤ 10 Kg With Bronchopulmonary Dysplasia, Melissa K Webb, Milenka Cuevas Guaman, S Kristen Sexson Tejtel, Neil Cambronero, Ryan D Coleman, Corey A Chartan, Betul Yilmaz Furtun, Shaine A Morris, Nidhy P Varghese, Natalie M Villafranco

Faculty, Staff and Students Publications

Patients with bronchopulmonary dysplasia (BPD) have shown clinical improvement after secundum atrial septal defect (ASD) closure. We sought to determine if this post‐ASD closure improvement is secondary to the expected course in BPD patients or related to the closure itself. A novel BPD‐ASD score was created to assess patients' clinical status (higher score = worse disease) and applied to 10 BPD‐ASD inpatients weighing ≤ 10 kg who underwent ASD closure. The score and its subcomponents were retrospectively calculated serially ranging from 8 weeks pre‐ to 8 weeks post‐intervention, and pre‐ and post‐intervention score slopes were created. These slopes were compared …

Plasma Amino Acid Signatures Define Types Of Pediatric Diabetes, Mustafa Tosur, Jean W Hsu, Saima Deen, Xiaofan Huang, Danielle Guffey, Serife Uysal, Marcela Astudillo, Maria J Redondo, Farook Jahoor, Ashok Balasubramanyam

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Metabolic biomarkers with pathophysiological relevance is lacking in pediatric diabetes. We aimed to identify novel metabolic biomarkers in pediatric type 1 (T1D) and type 2 diabetes (T2D). We hypothesized that (1) targeted plasma metabolomics, focused on plasma amino acid concentrations, could identify distinctively altered patterns in children with T1D or T2D, and (2) there are specific changes in concentrations of metabolites related to branch chain amino acids (BCAA) and arginine metabolism in children with T2D.

METHODS: In a pilot study, we enrolled children with T1D (n = 15) and T2D (n = 13), and healthy controls (n …

Current Perspectives On Mass Spectrometry-Based Immunopeptidomics: The Computational Angle To Tumor Antigen Discovery, Bing Zhang, Michal Bassani-Sternberg

Faculty, Staff and Students Publications

Identification of tumor antigens presented by the human leucocyte antigen (HLA) molecules is essential for the design of effective and safe cancer immunotherapies that rely on T cell recognition and killing of tumor cells. Mass spectrometry (MS)-based immunopeptidomics enables high-throughput, direct identification of HLA-bound peptides from a variety of cell lines, tumor tissues, and healthy tissues. It involves immunoaffinity purification of HLA complexes followed by MS profiling of the extracted peptides using data-dependent acquisition, data-independent acquisition, or targeted approaches. By incorporating DNA, RNA, and ribosome sequencing data into immunopeptidomics data analysis, the proteogenomic approach provides a powerful means for identifying …

Quality Improvement Initiative To Improve Time And Adherence To Revaccination After Hematopoietic Cell Transplantation: Implementation Of A Revaccination Clinic Within The Transplantation Program, Caitlin Elgarten, Anne Wohlschlaeger, Ellen Levy, Katharine Tadley, Lei Wang, Megan Atkinson, Houston Roberson, Timothy Olson, Nancy Bunin, Jennifer Heimall, Brian Fisher, Stephan Grupp, Jason Freedman

Faculty, Staff and Students Publications

Background:

Revaccination after hematopoietic cell transplantation (HCT) is critical to prevent morbidity and mortality from vaccine preventable illnesses. While earlier re-vaccination after HCT is desirable, they may be ineffective if deployed before partial reconstitution of adaptive immunity. Increasingly, personalized approaches to re-vaccination after HCT have replaced time-based protocols in order to minimize unvaccinated time and enhance vaccine effectiveness. Furthermore, for revaccination to be maximally beneficial, compliance with, and timely delivery of the complete revaccination schedule is imperative, but rare, and there is little data on strategies to optimize vaccine delivery.

Objectives:

The global aim of our quality improvement initiative was …

Bioresorbable Mesenchymal Stem Cell-Loaded Electrospun Polymeric Scaffold Inhibits Neointimal Hyperplasia Following Arteriovenous Fistula Formation In A Rat Model Of Chronic Kidney Disease, Allan John R Barcena, Joy Vanessa D Perez, Marvin R Bernardino, Jossana A Damasco, Andrea Cortes, Huckie C Del Mundo, Erin Marie D San Valentin, Carleigh Klusman, Gino Martin Canlas, Francisco M Heralde, Rony Avritscher, Natalie Fowlkes, Richard R Bouchard, Jizhong Cheng, Steven Y Huang, Marites P Melancon

Faculty, Staff and Students Publications

Bioresorbable perivascular scaffolds loaded with antiproliferative agents have been shown to enhance arteriovenous fistula (AVF) maturation by inhibiting neointimal hyperplasia (NIH). These scaffolds, which can mimic the three-dimensional architecture of the vascular extracellular matrix, also have an untapped potential for the local delivery of cell therapies against NIH. Hence, an electrospun perivascular scaffold from polycaprolactone (PCL) to support mesenchymal stem cell (MSC) attachment and gradual elution at the AVF's outflow vein is fabricated. Chronic kidney disease (CKD) in Sprague-Dawley rats is induced by performing 5/6th nephrectomy, then AVFs for scaffold application are created. The following groups of CKD rats are …

Single Cell Analysis Of Short-Term Dry Eye Induced Changes In Cornea Immune Cell Populations, Brandon D Ayres, Eric Donnenfeld, Marjan Farid, Ian Benjamin Gaddie, Preeya K Gupta, Edward Holland, Paul M Karpecki, Richard Lindstrom, Kelly K Nichols, Stephen C Pflugfelder, Christopher E Starr, Elizabeth Yeu

Faculty, Staff and Students Publications

BACKGROUND: Twelve ocular surface disease experts convened to achieve consensus about Demodex blepharitis (DB) using a modified Delphi panel process.

METHODS: Online surveys were administered using scaled, open-ended, true/false, and multiple-choice questions. Consensus for questions using a 1 to 9 Likert scale was predefined as median scores of 7-9 and 1-3. For other question types, consensus was achieved when 8 of 12 panellists agreed. Questions were randomized, and results of each survey informed the following survey.

RESULTS: Twelve practitioners comprised the Demodex Expert Panel on Treatment and Eyelid Health (DEPTH). Following 3 surveys, experts agreed that DB is chronic (n …

Tnf Is A Critical Cytokine In Age-Related Dry Eye Disease, Yashaswini Kelagere, Kaitlin K Scholand, Erica N Dejong, Andrea I Boyd, Zhiyuan Yu, Roger A Astley, Michelle C Callegan, Dawn Me Bowdish, Helen P Makarenkova, Cintia S De Paiva

Faculty, Staff and Students Publications

Aging is a complex biological process that is characterized by low-grade inflammation, called inflammaging. Aging affects multiple organs including eye and lacrimal gland. Tumor necrosis factor (TNF) is a pleiotropic cytokine that participates in inflammation, activation of proteases such as cathepsin S, and formation of ectopic lymphoid organs. Using genetic and pharmacological approaches, we investigated the role of TNF in age-related dry eye disease, emphasizing the ocular surface and lacrimal gland inflammation. Our results show the increased protein and mRNA levels of TNF in aged lacrimal glands, accompanied by increased TNF, IL1β, IL-18, CCL5, CXCL1, IL-2, IL-2 receptor alpha (CD25), …

Validation Of A Pre-Endoscopy Risk Score For Predicting The Presence Of Gastric Intestinal Metaplasia In A Us Population, Mimi C Tan, Ahana Sen, Eugene Kligman, Mohamed O Othman, Yan Liu, Hashem B El-Serag, Aaron P Thrift

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Surveillance of gastric intestinal metaplasia (GIM) may lead to early gastric cancer detection. Our purpose was to externally validate a predictive model for endoscopic GIM previously developed in a veteran population in a second U.S.

METHODS: We previously developed a pre-endoscopy risk model for detection of GIM using 423 GIM cases and 1796 control subjects from the Houston Veterans Affairs Hospital. The model included sex, age, race/ethnicity, smoking, and Helicobacter pylori infection with an area under the receiver-operating characteristic curve (AUROC) of .73 for GIM and .82 for extensive GIM. We validated this model in a second …

Age-Related Differences In The Contribution Of Systolic Blood Pressure And Biomarkers To Cardiovascular Disease Risk Prediction: The Atherosclerosis Risk In Communities (Aric) Study, Mahmoud Al Rifai, George E Taffet, Kunihiro Matsushita, Salim S Virani, James De Lemos, Amit Khera, Jarrett Berry, Chiadi Ndumele, David Aguilar, Caroline Sun, Ron C Hoogeveen, Elizabeth Selvin, Christie M Ballantyne, Vijay Nambi

Faculty, Staff and Students Publications

We sought to determine how biomarkers known to be associated with hypertension-induced end-organ injury complement the use of systolic blood pressure (SBP) for cardiovascular disease (CVD) risk prediction at different ages. Using data from visits 2 (1990 to 1992) and 5 (2011 to 2013) of the Atherosclerosis Risk in Communities (ARIC) study, 3 models were used to predict CVD (composite of coronary heart disease, stroke, and heart failure). Model A included traditional risk factors (TRFs) except SBP, model B-TRF plus SBP, and model C-TRF plus biomarkers (high-sensitivity troponin T [hsTnT] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]). Harrel's C-statistics were used …

A Novel Prediction Model Of The Risk Of Pancreatic Cancer Among Diabetes Patients Using Multiple Clinical Data And Machine Learning, Shih-Min Chen, Phan Thanh Phuc, Phung-Anh Nguyen, Whitney Burton, Shwu-Jiuan Lin, Weei-Chin Lin, Christine Y Lu, Min-Huei Hsu, Chi-Tsun Cheng, Jason C Hsu

Faculty, Staff and Students Publications

INTRODUCTION: Pancreatic cancer is associated with poor prognosis. Considering the increased global incidence of diabetes cases and that individuals with diabetes are considered a high-risk subpopulation for pancreatic cancer, it is critical to detect the risk of pancreatic cancer within populations of person living = with diabetes. This study aimed to develop a novel prediction model for pancreatic cancer risk among patients with diabetes, using = a real-world database containing clinical features and employing numerous artificial intelligent approach algorithms.

METHODS: This retrospective observational study analyzed data on patients with Type 2 diabetes from a multisite Taiwanese EMR database between 2009 …

Understanding The Gap Between Nursing Workforce In The United States And Population Needs-A Policy Brief, Mayar Al Mohajer

Faculty, Staff and Students Publications

Purpose  This report is intended to analyze the root causes for the current gap between the nursing workforce and population needs in the United States. It aims to consolidate what is known about these contributing reasons and provide evidence-based recommendations for action.

Methods  The report utilized the Sample, Phenomenon of Interest, Design, Evaluation, Research type framework to develop the research question and the 5 Whys methodology for the root cause analysis.

Results  This report highlighted six major causative problems, including workforce market mismatch, poor financing design, inadequate governance, flawed technologies, insufficient research, and suboptimal service delivery. A detailed evaluation of …

Variant Of Fii Gene Plays A Critical Role In Coagulation Potential In Mexican-Americans, Hoang Anh T. Nguyen, Shuchita Vijay Jhaveri, Marcio A. Almeida, Vincent P. Diego, Satish Kumar, Juan M. Peralta, Joanne E. Curran, Bernadette W. Luu, Donna M. Lehman, Ralph A. Defronzo, Laura Almasy, Sarah Williams-Blangero, Ravi Duggirala, John Blangero, Tom Howard

Research Symposium

Background: Disruption in the balance between coagulation and bleeding can result in varying phenotypes such as hypercoagulability and can lead to the development of cardiovascular disease. In our study utilizing extended families of Mexican-Americans from South Texas, we performed a search for protein-altering variants influencing coagulation potential.

Methods: Mexican-Americans in the study were genotyped using Illumina-(human)-exome-24 chip to screen for protein-altering variants. Variants were analyzed for their association with FII activity, aPTT, and PT. Linear-mixed-model analysis was performed to estimate trait heritabilities and to interrogate single nucleotide variations (SNV) for evidence of genetic association. To control for multiple testing, associations …

Heterogenous Lung Inflammation Ct Patterns Distinguish Pneumonia And Immune Checkpoint Inhibitor Pneumonitis And Complement Blood Biomarkers In Acute Myeloid Leukemia: Proof Of Concept, Muhammad Aminu, Naval Daver, Myrna C B Godoy, Girish Shroff, Carol Wu, Luis F Torre-Sada, Alberto Goizueta, Vickie R Shannon, Saadia A Faiz, Mehmet Altan, Guillermo Garcia-Manero, Hagop Kantarjian, Farhad Ravandi-Kashani, Tapan Kadia, Marina Konopleva, Courtney Dinardo, Sherry Pierce, Aung Naing, Sang T Kim, Dimitrios P Kontoyiannis, Fareed Khawaja, Caroline Chung, Jia Wu, Ajay Sheshadri

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint inhibitors (ICI) may cause pneumonitis, resulting in potentially fatal lung inflammation. However, distinguishing pneumonitis from pneumonia is time-consuming and challenging. To fill this gap, we build an image-based tool, and further evaluate it clinically alongside relevant blood biomarkers.

MATERIALS AND METHODS: We studied CT images from 97 patients with pneumonia and 29 patients with pneumonitis from acute myeloid leukemia treated with ICIs. We developed a CT-derived signature using a habitat imaging algorithm, whereby infected lungs are segregated into clusters ("habitats"). We validated the model and compared it with a clinical-blood model to determine whether imaging can add …

Vadadustat For Treatment Of Anemia In Patients With Dialysis-Dependent Chronic Kidney Disease Receiving Peritoneal Dialysis, Mark J Sarnak, Rajiv Agarwal, Neil Boudville, Pradip C P Chowdhury, Kai-Uwe Eckardt, Carlos R Gonzalez, Laura A Kooienga, Mark J Koury, Kwabena A Ntoso, Wenli Luo, Patrick S Parfrey, Dennis L Vargo, Wolfgang C Winkelmayer, Zhiqun Zhang, Glenn M Chertow

Faculty, Staff and Students Publications

BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear.

METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular …

Alzheimer’S Disease Studies In The Tex-Mex Border: Dissecting A Complex Multifactorial Problem, Ney Alliey-Rodriguez, Rosa V. Pirela, Alvaro Diaz-Badillo, Karla Lopez Lorenzo, Noe Garza, Frank Gilliam, Eron G. Manusov, Gladys E. Maestre

Research Symposium

Purpose: Alzheimer’s Disease (ALZ) is the leading cause of dementia in the aging population, and Latinos have >3 times higher risk to develop dementia than the overall US population. Although several studies have examined for possible causes of this increased risk, lack of comprehensive information plus a reduced number of Latino samples available in each study have hindered the answers.

Description: The University of Texas Rio Grande Valley has joined two large studies looking for multiple biomarkers associated with ALZ: The South Texas Alzheimer’s Center Clinical Data Repository and Biobank (STAC) and the Texas Alzheimer’s Research and Care Consortium (TARCC). …

Understanding The Resources, Barriers, Facilitators And Interests About Aging And Dementia Research Of Community Members From The Rio Grande Valley, Karla Daniela Lopez Lorenzo, Rosa V. Pirela Mavarez, Gabriela Osuna, Kendra Stine, Nathalie Chacon, Noe Garza, Gladys E. Maestre

Research Symposium

Background: One of ten people aged 65 develops Alzheimer’s Disease and it is one of the sixth-leading cause of death in the United States. The Rio Grande Valley (RGV) is mostly constituted by Hispanic/Latinos (93%), a population that has a 1.5X increased risk of AD onset. Nevertheless, there are not enough resources to support people living with dementia and their care partners. This study will leverage research efforts deployed by the RGV Alzheimer’s Disease Resource Center for Minority Aging Research to understand the social representations about the resources, barriers, facilitators, and interests of the RGV community about dementia and Alzheimer’s …

Insulin Resistance And Insulin Handling In Chronic Kidney Disease, Vishnu P Parvathareddy, Jiao Wu, Sandhya S Thomas

Faculty, Staff and Students Publications

Insulin regulates energy metabolism involving multiple organ systems. Insulin resistance (IR) occurs when organs exhibit reduced insulin sensitivity, leading to difficulties in maintaining glucose homeostasis. IR ensures decades prior to development of overt diabetes and can cause silent metabolic derangements. IR is typically seen very early in the course of chronic kidney disease (CKD) and is evident even when the estimated glomerular filtration rate (eGFR) is within the normal range and IR persists at various stages of kidney disease. In this article, we will discuss insulin handling by the kidneys, mechanisms responsible for IR in CKD, measurements and management of …

Current Approaches To Spinal Cord Protection During Open Thoracoabdominal Aortic Aneurysm Repair, Joseph S Coselli, Scott A Lemaire, Vicente Orozco-Sevilla, Ourania Preventza, Marc R Moon, Lauren M Barron, Subhasis Chatterjee

Faculty, Staff and Students Publications

Spinal cord deficit (SCD) is a feared complication after thoracoabdominal aortic aneurysm repair. Vigilant management throughout the perioperative period is necessary to reduce the risk of SCD. Measures for preventing SCD during the intraoperative period include preoperative optimization and recognizing patients at a higher risk of SCD. In this manuscript, we discuss intraoperative adjuncts including utilization of cerebrospinal fluid drainage, left heart bypass, mild hypothermia, selective reimplantation of intercostal and lumbar arteries, and renal and visceral vessel perfusion. From the operative to the postoperative period, careful attention to avoiding hypotension and anemia is important. If SCD is recognized early, therapeutic …

Pca-Clf: A Classifier Of Prostate Cancer Patients Into Patients With Indolent And Aggressive Tumors Using Machine Learning, Yashwanth Karthik Kumar Mamidi, Tarun Karthik Kumar Mamidi, Md Wasi Ul Kabir, Jiande Wu, Md Tamjidul Hoque, Chindo Hicks

School of Medicine Faculty Publications

A critical unmet medical need in prostate cancer (PCa) clinical management centers around distinguishing indolent from aggressive tumors. Traditionally, Gleason grading has been utilized for this purpose. However, tumor classification using Gleason Grade 7 is often ambiguous, as the clinical behavior of these tumors follows a variable clinical course. This study aimed to investigate the application of machine learning techniques (ML) to classify patients into indolent and aggressive PCas. We used gene expression data from The Cancer Genome Atlas and compared gene expression levels between indolent and aggressive tumors to identify features for developing and validating a range of ML …

Adjunctive Diagnostic Studies Completed Following Detection Of Candidemia In Children: Secondary Analysis Of Observed Practice From A Multicenter Cohort Study Conducted By The Pediatric Fungal Network, Rachel L Wattier, Robert F T Bucayu, Craig L K Boge, Rachael K Ross, Inci Yildirim, Theoklis E Zaoutis, Debra L Palazzi, Surabhi B Vora, Elio Castagnola, Martha Avilés-Robles, Lara Danziger-Isakov, Alison C Tribble, Tanvi S Sharma, Antonio C Arrieta, Gabriela Maron, David M Berman, Dwight E Yin, Lillian Sung, Michael Green, Emmanuel Roilides, Kiran Belani, José Romero, Pere Soler-Palacin, Eduardo López-Medina, Dawn Nolt, Ibrahim Zaid Bin Hussain, William J Muller, Sarmistha B Hauger, Natasha Halasa, Daniel Dulek, Alice Pong, Blanca E Gonzalez, Mark J Abzug, Fabianne Carlesse, Anna R Huppler, Sujatha Rajan, Catherine Aftandilian, Monica I Ardura, Arunaloke Chakrabarti, Benjamin Hanisch, Christine M Salvatore, Lena Klingspor, Elizabeth D Knackstedt, Irja Lutsar, Maria E Santolaya, Sydney Shuster, Sarah K Johnson, William J Steinbach, Brian T Fisher

Faculty, Staff and Students Publications

BACKGROUND: Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown.

METHODS: Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days to 17 years with invasive candidiasis (predominantly candidemia) from 2014 to 2017. Ophthalmologic examination (OE), abdominal imaging (AbdImg), echocardiogram, neuroimaging, and lumbar puncture (LP) were performed per clinician discretion. Adjunctive diagnostic studies performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics …

Differential Effects Of Pancreatic Cancer-Derived Extracellular Vesicles Driving A Suppressive Environment, Anurag Purushothaman, Jacqueline Oliva-Ramírez, Warapen Treekitkarnmongkol, Deivendran Sankaran, Mark W Hurd, Nagireddy Putluri, Anirban Maitra, Cara Haymaker, Subrata Sen

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) cells display extensive crosstalk with their surrounding environment to regulate tumor growth, immune evasion, and metastasis. Recent advances have attributed many of these interactions to intercellular communication mediated by small extracellular vesicles (sEVs), involving cancer-associated fibroblasts (CAF). To explore the impact of sEVs on monocyte lineage transition as well as the expression of checkpoint receptors and activation markers, peripheral blood monocytes from healthy subjects were exposed to PDAC-derived sEVs. Additionally, to analyze the role of sEV-associated HA in immune regulation and tissue-resident fibroblasts, monocytes and pancreatic stellate cells were cultured in the presence of PDAC sEVs …

Pet Imaging Of Microglia Using Pbr28suv Determines Therapeutic Efficacy Of Autologous Bone Marrow Mononuclear Cells Therapy In Traumatic Brain Injury, Supinder S Bedi, Michael C Scott, Max A Skibber, Akshita Kumar, Henry W Caplan, Hasen Xue, David Sequeira, Alison L Speer, Fanni Cardenas, Franciska Gudenkauf, Karen Uray, Amit K Srivastava, Alan R Prossin, Charles S Cox

Faculty, Staff and Student Publications

Traumatic brain injury (TBI) results in activated microglia. Activated microglia can be measured in vivo by using positron emission topography (PET) ligand peripheral benzodiazepine receptor standardized uptake values (PBR28suv). Cell based therapies have utilized autologous bone marrow mononuclear cells (BMMNCs) to attenuate activated microglia after TBI. This study aims to utilize in vivo PBR28suv to assess the efficacy of BMMNCs therapy after TBI. Seventy-two hours after CCI injury, BMMNCs were harvested from the tibia and injected via tail-vein at 74 h after injury at a concentration of 2 million cells per kilogram of body weight. There were three groups of …

Inhibition Of Trap1 Accelerates The Dna Damage Response, Activation Of The Heat Shock Response And Metabolic Reprogramming In Colon Cancer Cells, Nobel Bhasin, Prerna Dabral, Lakmini Senavirathna, Sheng Pan, Ru Chen

Faculty, Staff and Students Publications

BACKGROUND: Colorectal cancer (CRC) is one of the major causes of cancer-related mortality worldwide. The tumor microenvironment plays a significant role in CRC development, progression and metastasis. Oxidative stress in the colon is a major etiological factor impacting tumor progression. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial member of the heat shock protein 90 (HSP90) family that is involved in modulating apoptosis in colon cancer cells under oxidative stress. We undertook this study to provide mechanistic insight into the role of TRAP1 under oxidative stress in colon cells.

METHODS: We first assessed the The Cancer Genome Atlas …

Setd2 Safeguards The Genome Against Isochromosome Formation, Frank M Mason, Emily S Kounlavong, Anteneh T Tebeje, Rashmi Dahiya, Tiffany Guess, Abid Khan, Logan Vlach, Stephen R Norris, Courtney A Lovejoy, Ruhee Dere, Brian D Strahl, Ryoma Ohi, Peter Ly, Cheryl Lyn Walker, W Kimryn Rathmell

Faculty, Staff and Students Publications

Isochromosomes are mirror-imaged chromosomes with simultaneous duplication and deletion of genetic material which may contain two centromeres to create isodicentric chromosomes. Although isochromosomes commonly occur in cancer and developmental disorders and promote genome instability, mechanisms that prevent isochromosomes are not well understood. We show here that the tumor suppressor and methyltransferase SETD2 is essential to prevent these errors. Using cellular and cytogenetic approaches, we demonstrate that loss of SETD2 or its epigenetic mark, histone H3 lysine 36 trimethylation (H3K36me3), results in the formation of isochromosomes as well as isodicentric and acentric chromosomes. These defects arise during DNA replication and are …

Novel Genetic And Phenotypic Expansion In Gosr2-Related Progressive Myoclonus Epilepsy, Lea Hentrich, Mered Parnes, Timothy Edward Lotze, Rohini Coorg, Tom J De Koning, Kha M Nguyen, Calvin K Yip, Heinz Jungbluth, Anne Koy, Hormos Salimi Dafsari

Faculty, Staff and Students Publications

Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age …

Blockade Of Interferon Signaling Decreases Gut Barrier Integrity And Promotes Severe West Nile Virus Disease, Shih-Ching Lin, Fang R Zhao, Hana Janova, Adrian Gervais, Summer Rucknagel, Kristy O Murray, Jean-Laurent Casanova, Michael S Diamond

Faculty, Staff and Students Publications

The determinants of severe disease caused by West Nile virus (WNV) and why only ~1% of individuals progress to encephalitis remain poorly understood. Here, we use human and mouse enteroids, and a mouse model of pathogenesis, to explore the capacity of WNV to directly infect gastrointestinal (GI) tract cells and contribute to disease severity. At baseline, WNV poorly infects human and mouse enteroid cultures and enterocytes in mice. However, when STAT1 or type I interferon (IFN) responses are absent, GI tract cells become infected, and this is associated with augmented GI tract and blood-brain barrier (BBB) permeability, accumulation of gut-derived …

Prevalence Of Fibromyalgia And Chronic Fatigue Syndrome Among Individuals With Irritable Bowel Syndrome: An Analysis Of United States National Inpatient Sample Database, Zahid Ijaz Tarar, Umer Farooq, Ahmad Nawaz, Mustafa Gandhi, Yezaz A Ghouri, Asmeen Bhatt, Brooks D Cash

Faculty, Staff and Student Publications

Background and Aim: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with other somatic disorders. We studied the prevalence and predictors of fibromyalgia and chronic fatigue syndrome (CFS) in IBS patients. Methods: We used the National Inpatient Sample and included hospitalization of individuals with IBS, using ICD-10 codes, from 2016–2019. The prevalence and predictors of fibromyalgia and CFS in IBS patients were studied. Univariate and multivariate patient- and hospital-level regression models were used to calculate the adjusted odds of fibromyalgia and CFS in the IBS patient population. Results: Of 1,256,325 patients with an ICD-10 code of IBS included …

Integrated Inflammatory Signaling Landscape Response After Delivering Elovanoid Free-Fatty-Acid Precursors Leading To Experimental Stroke Neuroprotection, Madigan M. Reid, Ludmila Belayev, Larissa Khoutorova, Pranab K. Mukherjee, Andre Obenaus, Kierany Shelvin, Stacey Knowles, Sung Ha Hong, Nicolas G. Bazan

School of Graduate Studies Faculty Publications

Despite efforts to identify modulatory neuroprotective mechanisms of damaging ischemic stroke cascade signaling, a void remains on an effective potential therapeutic. The present study defines neuroprotection by very long-chain polyunsaturated fatty acid (VLC-PUFA) Elovanoid (ELV) precursors C-32:6 and C-34:6 delivered intranasally following experimental ischemic stroke. We demonstrate that these precursors improved neurological deficit, decreased T2WI lesion volume, and increased SMI-71 positive blood vessels and NeuN positive neurons, indicating blood–brain barrier (BBB) protection and neurogenesis modulated by the free fatty acids (FFAs) C-32:6 and C-34:6. Gene expression revealed increased anti-inflammatory and pro-homeostatic genes and decreases in expression of pro-inflammatory genes in …

Comparative Genomics Analysis Of Three Conserved Plasmid Families In The Western Hemisphere Soft Tick-Borne Relapsing Fever Borreliae Provides Insight Into Variation In Genome Structure And Antigenic Variation Systems, Alexander R Kneubehl, Job E Lopez

Faculty, Staff and Students Publications

Borrelia spirochetes, causative agents of Lyme disease and relapsing fever (RF), have uniquely complex genomes, consisting of a linear chromosome and both circular and linear plasmids. The plasmids harbor genes important for the vector-host life cycle of these tick-borne bacteria. The role of plasmids from Lyme disease causing spirochetes is more refined compared to RF Borrelia because of limited plasmid-resolved genome assemblies for the latter. We recently addressed this limitation and found that three linear plasmid families (F6, F27, and F28) were syntenic across all the RF Borrelia species that we examined. Given this conservation, we further investigated the three …

Epichaperome Inhibition Targets Tp53-Mutant Aml And Aml Stem/Progenitor Cells, Bing Z Carter, Po Yee Mak, Muharrem Muftuoglu, Wenjing Tao, Baozhen Ke, Jingqi Pei, Andrea D Bedoy, Lauren B Ostermann, Yuki Nishida, Sevinj Isgandarova, Mary Sobieski, Nghi Nguyen, Reid T Powell, Margarita Martinez-Moczygemba, Clifford Stephan, Mahesh Basyal, Naveen Pemmaraju, Steffen Boettcher, Benjamin L Ebert, Elizabeth J Shpall, Barbara Wallner, Robert A Morgan, Georgios I Karras, Ute M Moll, Michael Andreeff

Faculty, Staff and Student Publications

TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53-wild-type (WT) and -mutant AML cells. We detected epichaperomes in AML cells and stem/progenitor cells with TP53 mutations but not in healthy bone marrow (BM) cells. Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to …