Digital Commons Network^™

Multi-Ancestry Genome-Wide Study Identifies Effector Genes And Druggable Pathways For Coronary Artery Calcification, Maryam Kavousi, Maxime M Bos, Hanna J Barnes, Christian L Lino Cardenas, Doris Wong, Haojie Lu, Chani J Hodonsky, Lennart P L Landsmeer, Adam W Turner, Minjung Kho, Natalie R Hasbani, Paul S De Vries, Donald W Bowden, Sandesh Chopade, Joris Deelen, Ernest Diez Benavente, Xiuqing Guo, Edith Hofer, Shih-Jen Hwang, Sharon M Lutz, Leo-Pekka Lyytikäinen, Lotte Slenders, Albert V Smith, Maggie A Stanislawski, Jessica Van Setten, Quenna Wong, Lisa R Yanek, Diane M Becker, Marian Beekman, Matthew J Budoff, Mary F Feitosa, Chris Finan, Austin T Hilliard, Sharon L R Kardia, Jason C Kovacic, Brian G Kral, Carl D Langefeld, Lenore J Launer, Shaista Malik, Firdaus A A Mohamed Hoesein, Michal Mokry, Reinhold Schmidt, Jennifer A Smith, Kent D Taylor, James G Terry, Jeroen Van Der Grond, Joyce Van Meurs, Rozemarijn Vliegenthart, Jianzhao Xu, Kendra A Young, Nuno R Zilhão, Robert Zweiker, Themistocles L Assimes, Lewis C Becker, Daniel Bos, J Jeffrey Carr, L Adrienne Cupples, Dominique P V De Kleijn, Menno De Winther, Hester M Den Ruijter, Myriam Fornage, Barry I Freedman, Vilmundur Gudnason, Aroon D Hingorani, John E Hokanson, M Arfan Ikram, Ivana Išgum, David R Jacobs, Mika Kähönen, Leslie A Lange, Terho Lehtimäki, Gerard Pasterkamp, Olli T Raitakari, Helena Schmidt, P Eline Slagboom, André G Uitterlinden, Meike W Vernooij, Joshua C Bis, Nora Franceschini, Bruce M Psaty, Wendy S Post, Jerome I Rotter, Johan L M Björkegren, Christopher J O'Donnell, Lawrence F Bielak, Patricia A Peyser, Rajeev Malhotra, Sander W Van Der Laan, Clint L Miller

Faculty, Staff and Student Publications

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci …

Nuclear Receptors As Potential Therapeutic Targets In Peripheral Arterial Disease And Related Myopathy, Ashok Kumar, Vihang A Narkar

Faculty, Staff and Student Publications

Peripheral arterial disease (PAD) is a prevalent cardiovascular complication of limb vascular insufficiency, causing ischemic injury, mitochondrial metabolic damage and functional impairment in the skeletal muscle, and ultimately leading to immobility and mortality. While potential therapies have been mostly focussed on revascularization, none of the currently available pharmacological treatments are fully effective in PAD, often leading to amputations, particularly in chronic metabolic diseases. One major limitation of focussed angiogenesis and revascularization as a therapeutic strategy is a limited effect on metabolic restoration and muscle regeneration in the affected limb. Therefore, additional preclinical investigations are needed to discover novel treatment options …

Kunitz-Type Protease Inhibitor Tfpi2 Remodels Stemness And Immunosuppressive Tumor Microenvironment In Glioblastoma, Lizhi Pang, Madeline Dunterman, Songlin Guo, Fatima Khan, Yang Liu, Erfan Taefi, Atousa Bahrami, Changiz Geula, Wen-Hao Hsu, Craig Horbinski, Charles David James, Peiwen Chen

Faculty, Staff and Student Publications

Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy …

Advances In Vaccine Development For Cancer Prevention And Treatment In Lynch Syndrome, Ana M Bolivar, Fahriye Duzagac, Krishna M Sinha, Eduardo Vilar

Faculty, Staff and Student Publications

Lynch Syndrome (LS) is one of the most common hereditary cancer syndromes, and is caused by mutations in one of the four DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6 and PMS2. Tumors developed by LS carriers display high levels of microsatellite instability, which leads to the accumulation of large numbers of mutations, among which frameshift insertion/deletions (indels) within microsatellite (MS) loci are the most common. As a result, MMR-deficient (MMRd) cells generate increased rates of tumor-specific neoantigens (neoAgs) that can be recognized by the immune system to activate cancer cell killing. In this context, LS is an ideal …

Emerging Therapeutics And Evolving Assessment Criteria For Intracranial Metastases In Patients With Oncogene-Driven Non-Small-Cell Lung Cancer, Kelsey Pan, Kyle Concannon, Jing Li, Jianjun Zhang, John V Heymach, Xiuning Le

Faculty, Staff and Student Publications

The improved survival outcomes of patients with non-small-cell lung cancer (NSCLC), largely owing to the improved control of systemic disease provided by immune-checkpoint inhibitors and novel targeted therapies, have highlighted the challenges posed by central nervous system (CNS) metastases as a devastating yet common complication, with up to 50% of patients developing such lesions during the course of the disease. Early-generation tyrosine-kinase inhibitors (TKIs) often provide robust systemic disease control in patients with oncogene-driven NSCLCs, although these agents are usually unable to accumulate to therapeutically relevant concentrations in the CNS owing to an inability to cross the blood-brain barrier. However, …

Renal Cell Carcinoma Of Variant Histology: Biology And Therapies, Pavlos Msaouel, Giannicola Genovese, Nizar M Tannir

Faculty, Staff and Student Publications

The term variant histology renal cell carcinomas (vhRCCs), also known as non-clear cell RCCs, refers to a diverse group of malignancies with distinct biologic and therapeutic considerations. The management of vhRCC subtypes is often based on extrapolating results from the more common clear cell RCC studies or basket trials that are not specific to each histology. The unique management of each vhRCC subtype necessitates accurate pathologic diagnosis and dedicated research efforts. Herein, we discuss tailored recommendations for each vhRCC histology informed by ongoing research and clinical experience.

Cytosolic Dna Accumulation Promotes Breast Cancer Immunogenicity Via A Sting-Independent Pathway, Jing Zhang, Hui Dai, Lei Huo, Jared K Burks, Daniel J Mcgrail, Shiaw-Yih Lin

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, ICB alone has demonstrated only benefit in a small subset of patients with breast cancer. Recent studies have shown that agents targeting DNA damage response improve the efficacy of ICB and promote cytosolic DNA accumulation. However, recent clinical trials have shown that these agents are associated with hematological toxicities. More effective therapeutic strategies are urgently needed.

METHODS: Primary triple negative breast cancer tumors were stained for cytosolic single-stranded DNA (ssDNA) using multiplex immunohistochemical staining. To increase cytosolic ssDNA, we genetically silenced TREX1. The role of tumor cytosolic ssDNA in promoting …

A Translational Blueprint For Developing Intraoperative Imaging Agents Via Radiopharmaceutical-Guided Drug Design, Teresa E Sullivan, Servando Hernandez Vargas, Sukhen C Ghosh, Solmaz Aghaamiri, Naruhiko Ikoma, Ali Azhdarinia

Faculty, Staff and Student Publications

Cancer imaging is a rapidly evolving field due to the discovery of novel molecular targets and the availability of corresponding techniques to detect them with high precision, accuracy, and sensitivity. Nuclear medicine is the most widely used molecular imaging modality and has a growing toolkit of clinically used radiopharmaceuticals that enable whole-body tumor visualization, staging, and treatment monitoring for a variety of tumors in a non-invasive manner. The need for similar imaging capabilities in the operating room has led to the emergence of fluorescence-guided surgery (FGS) as a powerful technique that gives surgeons unprecedented ability to distinguish tumors from healthy …

Pd-1 Blockade In Combination With Dasatinib Potentiates Induction Of Anti-Acute Lymphocytic Leukemia Immunity, Paul Koller, Natalia Baran, Karine Harutyunyan, Antonio Cavazos, Saradhi Mallampati, Renee L Chin, Zhou Jiang, Xian Sun, Heng-Huan Lee, Jennifer L Hsu, Patrick Williams, Xuelin Huang, Michael A Curran, Mien-Chie Hung, Marina Konopleva

Faculty, Staff and Student Publications

Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism …

Electrophysiological Responses To Emotional And Cocaine Cues Reveal Individual Neuroaffective Profiles In Cocaine Users, Heather E Webber, Constanza De Dios, Margaret C Wardle, Robert Suchting, Charles E Green, Joy M Schmitz, Scott D Lane, Francesco Versace

Faculty, Staff and Student Publications

Smokers with stronger neuroaffective responses to drug-related cues compared to non-drug-related pleasant images (C>P) are more vulnerable to compulsive smoking than individuals with the opposite brain reactivity profile (P>C). However, it is unknown if these neurobehavioral profiles exist in individuals abusing other drugs. We tested whether individuals with cocaine use disorder (CUD) show similar neuroaffective profiles to smokers. We also monitored eye movements to assess attentional bias toward cues and we further performed exploratory analyses on demographics, personality, and drug use between profiles. Participants with CUD (n=43) viewed pleasant, unpleasant, cocaine, and neutral images while we recorded electroencephalogram. …

Erythrocyte Ent1-Ampd3 Axis Is An Essential Purinergic Hypoxia Sensor And Energy Regulator Combating Ckd In A Mouse Model, Changhan Chen, Tingting Xie, Yujin Zhang, Yiyan Wang, Fang Yu, Lizhen Lin, Weiru Zhang, Benjamin C Brown, Xin Zhang, Rodney E Kellems, Angelo D'Alessandro, Yang Xia

Faculty, Staff and Student Publications

Significance statement: Hypoxia drives kidney damage and progression of CKD. Although erythrocytes respond rapidly to hypoxia, their role and the specific molecules sensing and responding to hypoxia in CKD remain unclear. In this study, we demonstrated in a mouse model that erythrocyte ENT1-AMPD3 is a master energy regulator of the intracellular purinergic hypoxic compensatory response that promotes rapid energy supply from extracellular adenosine, eAMPK-dependent metabolic reprogramming, and O 2 delivery, which combat renal hypoxia and progression of CKD. ENT1-AMPD3-AMPK-BPGM comprise a group of circulating erythroid-specific biomarkers, providing early diagnostic and novel therapeutic targets for CKD.

Background: Hypoxia drives kidney damage …

Clinical And Biological Significance Of Circulating Mirnas In Chronic Pancreatitis Patients Undergoing Total Pancreatectomy With Islet Autotransplantation, Srividya Vasu, Giovanna Saracino, Carly M Darden, Kenjiro Kumano, Yang Liu, Michael C Lawrence, Bashoo Naziruddin

Faculty, Staff and Student Publications

Background: Specific microRNAs (miRNAs) were elevated in chronic pancreatitis (CP) patients during islet infusion after total pancreatectomy (TPIAT). We aimed to identify circulating miRNA signatures of pancreatic damage, predict miRNA-mRNA networks to identify potential links to CP pathogenesis and identify islet isolation and transplantation functional outcomes.

Methods: Small RNA sequencing was performed to identify distinct circulating miRNA signatures in CP. Plasma miRNAs were measured using miRCURY LNA SYBR green quantitative real-time polymerase chain reaction assays. Correlation analyses were performed using R software. The miRNA target and disease interactions were determined using miRNet and the miRNA enrichment and annotation tool.

Results: …

Diagnosis Of Chronic Pancreatitis Using Semi-Quantitative Mri Features Of The Pancreatic Parenchyma: Results From The Multi-Institutional Minimap Study, Temel Tirkes, Dhiraj Yadav, Darwin L Conwell, Paul R Territo, Xuandong Zhao, Scott A Persohn, Anil K Dasyam, Zarine K Shah, Sudhakar K Venkatesh, Naoki Takahashi, Ashley Wachsman, Liang Li, Yan Li, Stephen J Pandol, Walter G Park, Santhi Swaroop Vege, Phil A Hart, Mark Topazian, Dana K Andersen, Evan L Fogel, Consortium For The Study Of Chronic Pancreatitis, Diabetes, Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Purpose: To determine the diagnostic performance of parenchymal MRI features differentiating CP from controls.

Methods: This prospective study performed abdominal MRI scans at seven institutions, using 1.5 T Siemens and GE scanners, in 50 control and 51 definite CP participants, from February 2019 to May 2021. MRI parameters included the T1-weighted signal intensity ratio of the pancreas (T1 score), arterial-to-venous enhancement ratio (AVR) during venous and delayed phases, pancreas volume, and diameter. We evaluated the diagnostic performance of these parameters individually and two semi-quantitative MRI scores derived using logistic regression: SQ-MRI Model A (T1 score, AVR venous, and tail diameter) …

Preclinical Development Of 1b7/Cd3, A Novel Anti-Tslpr Bispecific Antibody That Targets Crlf2-Rearranged Ph-Like B-All, Ze Tian, Chunhua Shi, Guojun Yang, Jason K Allen, Qing Shi, Amin Al-Shami, Jill Wardell Olson, Melinda G Smith, Qing Chang, Jasbir Kaur, Junping You, Timothy E Lofton, Michelle A Gonzalez, Qi Zhang, Dongxing Zha, Sarah K Tasian, Nitin Jain, Marina Y Konopleva, Timothy Heffernan, Jeffrey J Molldrem

Faculty, Staff and Student Publications

Patients harboring CRLF2-rearranged B-lineage acute lymphocytic leukemia (B-ALL) face a 5-year survival rate as low as 20%. While significant gains have been made to position targeted therapies for B-ALL treatment, continued efforts are needed to develop therapeutic options with improved duration of response. Here, first we have demonstrated that patients with CRLF2-rearranged Ph-like ALL harbor elevated thymic stromal lymphopoietin receptor (TSLPR) expression, which is comparable with CD19. Then we present and evaluate the anti-tumor characteristics of 1B7/CD3, a novel CD3-redirecting bispecific antibody (BsAb) that co-targets TSLPR. In vitro, 1B7/CD3 exhibits optimal binding to both human and cynomolgus CD3 and TSLPR. …

Circulating Short Chain Fatty Acids And Fatigue In Patients With Head And Neck Cancer: A Longitudinal Prospective Study, Canhua Xiao, Veronika Fedirko, Henry Claussen, H Richard Johnston, Gang Peng, Sudeshna Paul, Kristal M Maner-Smith, Kristin A Higgins, Dong M Shin, Nabil F Saba, Evanthia C Wommack, Deborah W Bruner, Andrew H Miller

Faculty, Staff and Student Publications

Fatigue among patients with head and neck cancer (HNC) has been associated with higher inflammation. Short-chain fatty acids (SCFAs) have been shown to have anti-inflammatory and immunoregulatory effects. Therefore, this study aimed to examine the association between SCFAs and fatigue among patients with HNC undergoing treatment with radiotherapy with or without concurrent chemotherapy. Plasma SCFAs and the Multidimensional Fatigue Inventory-20 were collected prior to and one month after the completion of treatment in 59 HNC patients. The genome-wide gene expression profile was obtained from blood leukocytes prior to treatment. Lower butyrate concentrations were significantly associated with higher fatigue (p = …

Partnering With Patients And Families To Improve Diagnostic Safety Through The Ourdx Tool: Effects Of Race, Ethnicity, And Language Preference, Fabienne C Bourgeois, Nicholas J Hart, Zhiyong Dong, Long H Ngo, Catherine M Desroches, Eric J Thomas, Sigall K Bell

Faculty, Staff and Student Publications

BACKGROUND: Patients and families at risk for health disparities may also be at higher risk for diagnostic errors but less likely to report them.

OBJECTIVES: This study aimed to explore differences in race, ethnicity, and language preference associated with patient and family contributions and concerns using an electronic previsit tool designed to engage patients and families in the diagnostic process (DxP).

METHODS: Cross-sectional study of 5,731 patients and families presenting to three subspecialty clinics at an urban pediatric hospital May to December 2021 who completed a previsit tool, codeveloped and tested with patients and families. Prior to each visit, patients/families …

Hmg-Coa Reductase Inhibitors For Traumatic Brain Injury, Kalman Katlowitz, Shankar Gopinath, Jovany Cruz Navarro, Claudia Robertson

Faculty, Staff and Students Publications

Traumatic brain injuries (TBIs) are associated with high morbidity and mortality due to both the original insult as well as the destructive biological response that follows. Medical management aims to slow or even halt secondary neurological injury while simultaneously laying the groundwork for recovery. Statins are one class of medications that is showing increased promise in the management of TBI. Used extensively in cardiovascular disease, these drugs were originally developed as competitive inhibitors within the cholesterol production pipeline. They are now used in diverse disease states due to their pleiotropic effects on other biological processes such as inflammation and angiogenesis. …

Molecular Insights Using Spatial Transcriptomics Of The Distal Lung In Congenital Diaphragmatic Hernia, Krithika Lingappan, Oluyinka O Olutoye, Abiud Cantu, Manuel Eliezer Cantu Gutierrez, Nahir Cortes-Santiago, J D Hammond, Jamie Gilley, Joselyn Rojas Quintero, Hui Li, Francesca Polverino, Jason P Gleghorn, Sundeep G Keswani

Faculty, Staff and Students Publications

Abnormal pulmonary vascular development and function in congenital diaphragmatic hernia (CDH) is a significant factor leading to pulmonary hypertension. The lung is a very heterogenous organ and has marked cellular diversity that is differentially responsive to injury and therapeutic agents. Spatial transcriptomics provides the unmatched capability of discerning the differences in the transcriptional signature of these distinct cell subpopulations in the lung with regional specificity. We hypothesized that the distal lung parenchyma (selected as a region of interest) would show a distinct transcriptomic profile in the CDH lung compared with control (normal lung). We subjected lung sections obtained from male …

Neurodevelopmental Deficits And Cell-Type-Specific Transcriptomic Perturbations In A Mouse Model Of Hnrnpu Haploinsufficiency, Sarah A Dugger, Ryan S Dhindsa, Gabriela De Almeida Sampaio, Andrew K Ressler, Elizabeth E Rafikian, Sabrina Petri, Verity A Letts, Jiajie Teoh, Junqiang Ye, Sophie Colombo, Yueqing Peng, Mu Yang, Michael J Boland, Wayne N Frankel, David B Goldstein

Faculty, Staff and Students Publications

Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated global developmental delay, impaired ultrasonic vocalizations, cognitive dysfunction and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory …

Human Intestinal Organoids As Models To Study Enteric Bacteria And Viruses, Grace Adeniyi-Ipadeola, Hephzibah Nwanosike, Sasirekha Ramani

Faculty, Staff and Students Publications

Laboratory studies of host-microbe interactions have historically been carried out using transformed cell lines and animal models. Although much has been learned from these models, recent advances in the development of multicellular, physiologically active, human intestinal organoid (HIO) cultures are allowing unprecedented discoveries of host-microbe interactions. Here, we review recent literature using HIOs as models to investigate the pathogenesis of clinically important enteric bacteria and viruses and study commensal intestinal microbes. We also discuss limitations of current HIO culture systems and how technical advances and innovative engineering approaches are providing new directions to improve the model. The studies discussed here …

Blocking The Functional Domain Of Tip1 By Antibodies Sensitizes Cancer To Radiation Therapy, Abhay K Singh, David Ya Dadey, Michael J Rau, James Fitzpatrick, Harendra K Shah, Minakshi Saikia, Reid Townsend, Dinesh Thotala, Dennis E Hallahan, Vaishali Kapoor

2020-Current year OA Pubs

Non-small-cell lung cancer (NSCLC) and glioblastoma (GB) have poor prognoses. Discovery of new molecular targets is needed to improve therapy. Tax interacting protein 1 (TIP1), which plays a role in cancer progression, is overexpressed and radiation-inducible in NSCLC and GB. We evaluated the effect of an anti-TIP1 antibody alone and in combination with ionizing radiation (XRT) on NSCLC and GB in vitro and in vivo. NSCLC and GB cells were treated with anti-TIP1 antibodies and evaluated for proliferation, colony formation, endocytosis, and cell death. The efficacy of anti-TIP1 antibodies in combination with XRT on tumor growth was measured in mouse …

A Cross-Species Proteomic Map Reveals Neoteny Of Human Synapse Development, Li Wang, Kaifang Pang, Li Zhou, Arantxa Cebrián-Silla, Susana González-Granero, Shaohui Wang, Qiuli Bi, Matthew L White, Brandon Ho, Jiani Li, Tao Li, Yonatan Perez, Eric J Huang, Ethan A Winkler, Mercedes F Paredes, Rothem Kovner, Nenad Sestan, Alex A Pollen, Pengyuan Liu, Jingjing Li, Xianhua Piao, José Manuel García-Verdugo, Arturo Alvarez-Buylla, Zhandong Liu, Arnold R Kriegstein

Faculty, Staff and Students Publications

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the …

Predictors And Moderators Of Treatment Outcomes For Anxious Children Randomized To Computer-Assisted Cognitive Behavioral Therapy Or Standard Community Care, Orri Smárason, Andrew G Guzick, Wayne K Goodman, Alison Salloum, Eric A Storch

Faculty, Staff and Students Publications

Introduction:

Computer-assisted cognitive behavioral therapy (CCBT) for childhood anxiety disorders may aid the dissemination of CBT, while maintaining treatment fidelity. Although CCBT is an effective intervention, not everyone benefits equally from treatment. Identifying patient characteristics that predict who will benefit from treatment and to what extent can help with matching patients to suitable interventions, and allow researchers and clinicians to modify, and individualize, their treatment formats more effectively. Such predictors and moderators have not yet been examined for CCBT outcomes in anxious children and studies of more traditional treatment formats have yielded inconsistent results.

Methods:

Using data from a randomized …

A Pilot Genome-Wide Association Study Meta-Analysis Of Gastroparesis, Leticia Camargo Tavares, Tenghao Zheng, Madeline Kwicklis, Emily Mitchell, Anita Pandit, Suraj Pullapantula, Cheryl Bernard, Maris Teder-Laving, Francine Z Marques, Tonu Esko, Braden Kuo, Robert J Shulman, Bruno P Chumpitazi, Kenneth L Koch, Irene Sarosiek, Thomas L Abell, Richard W Mccallum, Henry P Parkman, Pankaj J Pasricha, Frank A Hamilton, James Tonascia, Matthew Zawistowski, Gianrico Farrugia, Madhusudan Grover, Mauro D'Amato

Faculty, Staff and Students Publications

BACKGROUND: Gastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction.

OBJECTIVE: Genetic predisposition may play a role; however, investigation at the genome-wide level has not been performed.

METHODS: We carried out a genome-wide association study (GWAS) meta-analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population-based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non-gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high-quality SNPs were tested on …

Review Of Toxocariasis At A Children's Hospital Prompting Need For Public Health Interventions, Mary B Fortini, Timothy A Erickson, Lauren M Leining, Karina M Robinson, Megan N Carey, Sarah J Smith, Brendan Sullivan, Alisa R Nelson, Sarah M Gunter, Jill E Weatherhead

Faculty, Staff and Students Publications

BACKGROUND: Toxocariasis, caused the by dog and cat roundworm, is one of the most common zoonotic helminth infections in the United States and can lead to severe lifelong morbidity in children. Although historical seroprevalence studies have identified a high frequency of toxocariasis regionally in the United States, there are few studies linking epidemiology and clinical disease in children. The study objective was to examine the contemporary epidemiology of pediatric toxocariasis within an endemic US region.

METHODS: We conducted an epidemiologic study analyzing children diagnosed with toxocariasis presenting to a tertiary pediatric hospital in Texas from 2010 to 2021. We examined …

Bronchopulmonary Dysplasia – Associated Pulmonary Hypertension: An Updated Review, Ahmed El-Saie, Nidhy P Varghese, Melissa K Webb, Natalie Villafranco, Bheru Gandhi, Milenka Cuevas Guaman, Binoy Shivanna

Faculty, Staff and Students Publications

Bronchopulmonary dysplasia (BPD) is the leading cause of chronic lung disease in infants and the commonest complication of prematurity. Advances in respiratory and overall neonatal care have increased the survival of extremely low gestational age newborns, leading to the continued high incidence of BPD. Pulmonary hypertension (PH) represents the severe form of the pulmonary vascular disease associated with BPD, and affects almost one-third of infants with moderate to severe BPD. PH responds suboptimally to pulmonary vasodilators and increases morbidity and mortality in BPD infants. An up-to-date knowledge of the pathogenesis, pathophysiology, diagnosis, treatment, and outcomes of BPD-PH can be helpful …

Seminar: Extracellular Vesicles As Mediators Of Environmental Stress In Human Disease, Vrinda Kalia, Andrea A Baccarelli, Christine Happel, Jonathan A Hollander, Anne Marie Jukic, Kimberly A Mcallister, Ramkumar Menon, Bruce A Merrick, Aleksander Milosavljevic, Lingamanaidu V Ravichandran, Matthew E Roth, Anita Subramanian, Frederick L Tyson, Leroy Worth, Daniel T Shaughnessy

Faculty, Staff and Students Publications

Background: Extracellular vesicles (EVs), membrane-bound particles containing a variety of RNA types, DNA, proteins, and other macromolecules, are now appreciated as an important means of communication between cells and tissues, both in normal cellular physiology and as a potential indicator of cellular stress, environmental exposures, and early disease pathogenesis. Extracellular signaling through EVs is a growing field of research for understanding fundamental mechanisms of health and disease and for the potential for biomarker discovery and therapy development. EVs are also known to play important roles in mediating the effects of exposure to environmental stress.

Objectives: This seminar addresses the application …

Identifying And Addressing Barriers To Implementing Core Electronic Health Record Use Metrics For Ambulatory Care: Virtual Consensus Conference Proceedings, Deborah R. Levy, Amanda J. Moy, Nate Apathy, Julia Adler-Milstein, Lisa Rotenstein, Bidisha Nath, S. Trent Rosenbloom, Thomas Kannampallil, Rebecca G. Mishuris, Aram Alexanian, Amber Sieja, Michelle R. Hribar, Jigar S. Patel, Christine A. Sinsky, Edward R. Melnick

2020-Current year OA Pubs

Precise, reliable, valid metrics that are cost-effective and require reasonable implementation time and effort are needed to drive electronic health record (EHR) improvements and decrease EHR burden. Differences exist between research and vendor definitions of metrics. PROCESS:  We convened three stakeholder groups (health system informatics leaders, EHR vendor representatives, and researchers) in a virtual workshop series to achieve consensus on barriers, solutions, and next steps to implementing the core EHR use metrics in ambulatory care. CONCLUSION:  Actionable solutions identified to address core categories of EHR metric implementation challenges include: (1) maintaining broad stakeholder engagement, (2) reaching agreement on standardized measure …

Short Tandem Repeat Profiling Via Next-Generation Sequencing For Cell Line Authentication, Yi-Hsien Chen, Jon P Connelly, Colin Florian, Xiaoxia Cui, Shondra M Pruett-Miller

2020-Current year OA Pubs

Cell lines are indispensable models for modern biomedical research. A large part of their usefulness derives from the ability of a cell line to proliferate over multiple passages (often indefinitely), allowing multiple experiments to be performed. However, over time, cell line identity and purity can be compromised by human errors. Cross-contamination from other cell lines and complete misidentification are both possible. Routine cell line authentication is a necessary preventive measure and has become a requirement for many funding applications and publications. Short tandem repeat (STR) profiling is the most common method for cell line authentication and is usually carried out …

A Novel Pathogenic Mutation Of Mecp2 Impairs Chromatin Association Independent Of Protein Levels, Jian Zhou, Claudia Cattoglio, Yingyao Shao, Harini P Tirumala, Carlo Vetralla, Sameer S Bajikar, Yan Li, Hu Chen, Qi Wang, Zhenyu Wu, Bing Tang, Mahla Zahabiyon, Aleksandar Bajic, Xiangling Meng, Jack J Ferrie, Anel Lagrone, Ping Zhang, Jean J Kim, Jianrong Tang, Zhandong Liu, Xavier Darzacq, Nathaniel Heintz, Robert Tjian, Huda Y Zoghbi

Faculty, Staff and Students Publications

Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before in MECP2, in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived iPSCs and a knock-in mouse line. G118E mutation partially reduces MeCP2 abundance …