Digital Commons Network^™

Multiplexed Transgenic Selection And Counterselection Strategies To Expedite Genetic Manipulation Workflows Using Drosophila Melanogaster, Koen J T Venken, Nick Matinyan, Yezabel Gonzalez, Herman A Dierick

Faculty, Staff and Students Publications

We recently described a set of four selectable and two counterselectable markers that provide resistance and sensitivity, respectively, against their corresponding drugs using the model organism Drosophila melanogaster. The four selectable markers provide animal resistance against G418 sulfate, Puromycin HCl, Blasticidin S, or Hygromycin B, while the two counterselection markers make animals sensitive to Ganciclovir/Acyclovir, or 5-Fluorocytosine. Unlike classical phenotypic markers, visual or fluorescent, which require extensive screening progeny of a genetic cross for desired genotypes, resistance and sensitivity markers eliminate this laborious procedure by directly selecting for, or counterselecting against, the desired genotypes. We demonstrated the usefulness of …

Pediatric Rhabdomyosarcoma Incidence And Survival In The United States: An Assessment Of 5656 Cases, 2001–2017, Matthew T Mcevoy, David A Siegel, Shifan Dai, Mehmet Fatih Okcu, Mark Zobeck, Rajkumar Venkatramani, Philip J Lupo

Faculty, Staff and Students Publications

BACKGROUND: While rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents, past epidemiology studies of this malignancy used data that covered

METHODS: Incidence and survival were assessed for pediatric patients diagnosed with RMS during 2003-2017 and 2001-2016, respectively. Both demographic and clinical variables were evaluated. Age-adjusted incidence rates, average annual percent change (AAPC), and 5-year relative survival (RS) were calculated, all with corresponding 95% confidence intervals (CIs). Cox regression models were used to evaluate the impact of demographic and clinical variables on survival.

RESULTS: We identified 5656 primary RMS cases in USCS during 2003-2017. The age-adjusted …

Associations Of Serum And Dialysate Potassium Concentrations With Incident Atrial Fibrillation In A Cohort Study Of Older Us Persons Initiating Hemodialysis For Kidney Failure, Austin Hu, Sai Liu, Maria E Montez-Rath, Pascale Khairallah, Jingbo Niu, Mintu P Turakhia, Tara I Chang, Wolfgang C Winkelmayer

Faculty, Staff and Students Publications

INTRODUCTION: Atrial fibrillation (AF) disproportionally affects persons on maintenance hemodialysis (HD). Associations of serum and dialysate potassium concentrations [K+] with AF incidence are poorly understood.

METHODS: We conducted a cohort study using Medicare claims merged with clinical data from a dialysis provider to determine whether serum-[K+] and/or dialysate-[K+] independently associated with AF incidence. Persons insured by fee-for-service Medicare aged ≥67 years at dialysis initiation and free from diagnosed AF prior to day 120 of dialysis were eligible. Serum-[K+] and dialysate-[K+] were assessed in 30-day intervals and patients were followed-up with for AF incidence in subsequent 30-day intervals.

RESULTS: During 2006 …

Characterizing Mechanism-Based Pain Phenotypes In Patients With Chronic Pancreatitis: A Cross-Sectional Analysis Of The Prospective Evaluation Of Chronic Pancreatitis For Epidemiologic And Translational Studies, Jami L Saloman, Darwin L Conwell, Evan Fogel, Santhi Swaroop Vege, Liang Li, Shuang Li, Dana K Andersen, William E Fisher, Christopher E Forsmark, Phil A Hart, Stephen J Pandol, Walter G Park, Anna Evans Phillips, Mark Topazian, Stephen K Van Den Eeden, Jose Serrano, Dhiraj Yadav

Faculty, Staff and Students Publications

Pain is common in chronic pancreatitis (CP) and profoundly reduces quality of life (QoL). Multiple underlying mechanisms contribute to a heterogenous pain experience and reduce efficacy of pain management. This study was designed to characterize the distribution of mechanism-based pain phenotypes in painful CP. The data analyzed were collected as part of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, an NCI/NIDDK-funded longitudinal study of the natural history of CP. The PROspective Evaluation of Chronic pancreatitis for EpidEmiologic and translational stuDies includes patient-reported outcome (PRO) measures of pain, medication use, global health, and QoL. Of subjects (N …

Ancillary Documents For Nih Grant Applications: The Pages Beyond The Scienceancillary Documents For Nih Grant Applications: The Pages Beyond The Science, Monica Fahrenholz, Lily S Cheng, Oluyinka Olutoye, Anjali A Degala, Sonya S Keswani, Taylor Lee, Allan M Goldstein, Sundeep G Keswani

Faculty, Staff and Students Publications

Preparing a grant proposal is no small feat, especially for research (R-series) grants from the National Institutes of Health. The National Institutes of Health is the largest public funder of biomedical research in the world, and as such, procuring a research grant from the National Institutes of Health is one of the ultimate benchmarks of success for a surgeon-scientist. Most investigators are familiar with the page limits for most R-series grants (12 pages for an R01 and 6 pages for an R21), with the addition of a single page allotted for the specific aims. Interestingly, despite the usual focus on …

A Synthesis Of Evidence For Cancer-Specific Screening Interventions: A Preventive Medicine Golden Jubilee Review, Suvi Rintala, Kristina R Dahlstrom, Eduardo L Franco, Karolina Louvanto

Faculty, Staff and Students Publications

The goal of cancer screening guidelines is to inform health practitioners to practice evidence-based cancer prevention. Cancer screening aims to detect treatable precancerous lesions or early-stage disease to enable actions aimed at decreasing morbidity and mortality. Continuous assessment of the available evidence for or against screening interventions by various organizations often results in conflicting recommendations and create challenges for providers and policymakers. Here we have summarized the current cancer screening recommendations by five leading organizations in North America and Europe: the National Cancer Institute's Physician Data Query (PDQ), the U.S. Preventive Services Task Force (USPSTF), the Canadian Task Force on …

Biallelic Variants In Hect E3 Paralogs, Hectd4 And Ube3c, Encoding Ubiquitin Ligases Cause Neurodevelopmental Disorders That Overlap With Angelman Syndrome, Eissa A Faqeih, Malak Ali Alghamdi, Marwa A Almahroos, Essa Alharby, Makki Almuntashri, Amnah M Alshangiti, Prouteau Clément, Daniel G Calame, Leila Qebibo, Lydie Burglen, Martine Doco-Fenzy, Mario Mastrangelo, Annalaura Torella, Filippo Manti, Vincenzo Nigro, Ziegler Alban, Ghadeer Saleh Alharbi, Jamil Amjad Hashmi, Rawya Alraddadi, Razan Alamri, Tadahiro Mitani, Barth Magalie, Zeynep Coban-Akdemir, Bilgen Bilge Geckinli, Davut Pehlivan, Antonio Romito, Vasiliki Karageorgou, Javier Martini, Estelle Colin, Dominique Bonneau, Aida Bertoli-Avella, James R Lupski, Annalisa Pastore, Roy W A Peake, Ashraf Dallol, Majid Alfadhel, Naif A M Almontashiri

Faculty, Staff and Students Publications

Purpose: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified.

Methods: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes.

Results: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, …

Embracing Monogenic Parkinson's Disease: The Mjff Global Genetic Pd Cohort, Eva-Juliane Vollstedt, Susen Schaake, Katja Lohmann, Shalini Padmanabhan, Alexis Brice, Suzanne Lesage, Christelle Tesson, Marie Vidailhet, Isabel Wurster, Faycel Hentati, Anat Mirelman, Nir Giladi, Karen Marder, Cheryl Waters, Stanley Fahn, Meike Kasten, Norbert Brüggemann, Max Borsche, Tatiana Foroud, Eduardo Tolosa, Alicia Garrido, Grazia Annesi, Monica Gagliardi, Maria Bozi, Leonidas Stefanis, Joaquim J Ferreira, Leonor Correia Guedes, Micol Avenali, Simona Petrucci, Lorraine Clark, Ekaterina Y Fedotova, Natalya Y Abramycheva, Victoria Alvarez, Manuel Menéndez-González, Silvia Jesús Maestre, Pilar Gómez-Garre, Pablo Mir, Andrea Carmine Belin, Caroline Ran, Chin-Hsien Lin, Ming-Che Kuo, David Crosiers, Zbigniew K Wszolek, Owen A Ross, Joseph Jankovic, Kenya Nishioka, Manabu Funayama, Jordi Clarimon, Caroline H Williams-Gray, Marta Camacho, Mario Cornejo-Olivas, Luis Torres-Ramirez, Yih-Ru Wu, Guey-Jen Lee-Chen, Ana Morgadinho, Teeratorn Pulkes, Pichet Termsarasab, Daniela Berg, Gregor Kuhlenbäumer, Andrea A Kühn, Friederike Borngräber, Giuseppe De Michele, Anna De Rosa, Alexander Zimprich, Andreas Puschmann, George D Mellick, Jolanta Dorszewska, Jonathan Carr, Rosangela Ferese, Stefano Gambardella, Bruce Chase, Katerina Markopoulou, Wataru Satake, Tatsushi Toda, Malco Rossi, Marcelo Merello, Timothy Lynch, Diana A Olszewska, Shen-Yang Lim, Azlina Ahmad-Annuar, Ai Huey Tan, Bashayer Al-Mubarak, Hasmet Hanagasi, Dariusz Koziorowski, Sibel Ertan, Gençer Genç, Patricia De Carvalho Aguiar, Melinda Barkhuizen, Marcia M G Pimentel, Rachel Saunders-Pullman, Bart Van De Warrenburg, Susan Bressman, Mathias Toft, Silke Appel-Cresswell, Anthony E Lang, Matej Skorvanek, Agnita J W Boon, Rejko Krüger, Esther M Sammler, Vitor Tumas, Bao-Rong Zhang, Gaetan Garraux, Sun Ju Chung, Yun Joong Kim, Juliane Winkelmann, Carolyn M Sue, Eng-King Tan, Joana Damásio, Péter Klivényi, Vladimir S Kostic, David Arkadir, Mika Martikainen, Vanderci Borges, Jens Michael Hertz, Laura Brighina, Mariana Spitz, Oksana Suchowersky, Olaf Riess, Parimal Das, Brit Mollenhauer, Emilia M Gatto, Maria Skaalum Petersen, Nobutaka Hattori, Ruey-Meei Wu, Sergey N Illarioshkin, Enza Maria Valente, Jan O Aasly, Anna Aasly, Roy N Alcalay, Avner Thaler, Matthew J Farrer, Kathrin Brockmann, Jean-Christophe Corvol, Christine Klein, Mjff Global Genetic Parkinson's Disease Study Group

Faculty, Staff and Students Publications

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited.

Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.

Methods: We conducted …

Pediatric Eosinophilia: A Review And Multiyear Investigation Into Etiologies, Tara E Ness, Timothy A Erickson, Veronica Diaz, Amanda B Grimes, Ryan Rochat, Sara Anvari, Joud Hajjar, Jill Weatherhead

Faculty, Staff and Students Publications

Objectives: To identify the etiology of peripheral eosinophilia in a large pediatric population and to develop a diagnostic algorithm to help guide diagnosis and management of peripheral eosinophilia in the outpatient pediatric population.

Study design: We performed a retrospective chart review of children presenting to Texas Children's Hospital in Houston with peripheral eosinophilia between January 1, 2011 and December 31, 2019. Eosinophilia was classified as mild (absolute eosinophil count [AEC] >500 and < 1500 cells/μL), moderate (AEC >1500 and < 4500 cells/μL), or severe (AEC >4500 cells/μL). Demographic information and diagnostic workup data were collected.

Results: A total of 771 patients aged < 18 years were evaluated. The most common cause of eosinophilia was allergy (n = 357; 46%), with atopy (n = 296) and drug reaction (n = 54) the most common subcauses. This was followed by unknown etiology (n = 274; 36%), infectious causes (n = 72; 9%), and eosinophilic disorders (n = 47; 6%). Many patients with an unknown cause (n = 202; 74%) had limited or no follow-up testing.

Conclusions: More information on the etiology of pediatric eosinophilia …

Dynamic Errors In Pulse Oximetry Preclude Use Of Correction Factor, Ashraf Fawzy, Valeria S M Valbuena, Christopher F Chesley, Tianshi David Wu, Theodore J Iwashyna

Faculty, Staff and Students Publications

No abstract provided.

The Nlrp3 Inflammasome Fires Up Heme-Induced Inflammation In Hemolytic Conditions, Suruchi Salgar, Beatriz E Bolívar, Jonathan M Flanagan, Shaniqua J Anum, Lisa Bouchier-Hayes

Faculty, Staff and Students Publications

Overactive inflammatory responses are central to the pathophysiology of many hemolytic conditions including sickle cell disease. Excessive hemolysis leads to elevated serum levels of heme due to saturation of heme scavenging mechanisms. Extracellular heme has been shown to activate the NLRP3 inflammasome, leading to activation of caspase-1 and release of pro-inflammatory cytokines IL-1β and IL-18. Heme also activates the non-canonical inflammasome pathway, which may contribute to NLRP3 inflammasome formation and leads to pyroptosis, a type of inflammatory cell death. Some clinical studies indicate there is a benefit to blocking the NLRP3 inflammasome pathway in patients with sickle cell disease and …

Genetic Variants In Arhgef6 Cause Congenital Anomalies Of The Kidneys And Urinary Tract In Humans, Mice, And Frogs, Verena Klämbt, Florian Buerger, Chunyan Wang, Thomas Naert, Karin Richter, Theresa Nauth, Anna-Carina Weiss, Tobias Sieckmann, Ethan Lai, Dervla M Connaughton, Steve Seltzsam, Nina Mann, Amar J Majmundar, Chen-Han W Wu, Ana C Onuchic-Whitford, Shirlee Shril, Sophia Schneider, Luca Schierbaum, Rufeng Dai, Mir Reza Bekheirnia, Marieke Joosten, Omer Shlomovitz, Asaf Vivante, Ehud Banne, Shrikant Mane, Richard P Lifton, Karin M Kirschner, Andreas Kispert, Georg Rosenberger, Klaus-Dieter Fischer, Soeren S Lienkamp, Mirjam M P Zegers, Friedhelm Hildebrandt

Faculty, Staff and Students Publications

Background: About 40 disease genes have been described to date for isolated CAKUT, the most common cause of childhood CKD. However, these genes account for only 20% of cases. ARHGEF6, a guanine nucleotide exchange factor that is implicated in biologic processes such as cell migration and focal adhesion, acts downstream of integrin-linked kinase (ILK) and parvin proteins. A genetic variant of ILK that causes murine renal agenesis abrogates the interaction of ILK with a murine focal adhesion protein encoded by Parva , leading to CAKUT in mice with this variant.

Methods: To identify novel genes that, when mutated, result in …

Characterizing Mechanism-Based Pain Phenotypes In Patients With Chronic Pancreatitis: A Cross-Sectional Analysis Of The Prospective Evaluation Of Chronic Pancreatitis For Epidemiologic And Translational Studies, Jami L Saloman, Darwin L Conwell, Evan Fogel, Santhi Swaroop Vege, Liang Li, Shuang Li, Dana K Andersen, William E Fisher, Christopher E Forsmark, Phil A Hart, Stephen J Pandol, Walter G Park, Anna Evans Phillips, Mark Topazian, Stephen K Van Den Eeden, Jose Serrano, Dhiraj Yadav, Consortium For The Study Of Chronic Pancreatitis, Diabetes And Pancreatic Cancer

Faculty, Staff and Students Publications

Pain is common in chronic pancreatitis (CP) and profoundly reduces quality of life (QoL). Multiple underlying mechanisms contribute to a heterogenous pain experience and reduce efficacy of pain management. This study was designed to characterize the distribution of mechanism-based pain phenotypes in painful CP. The data analyzed were collected as part of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, an NCI/NIDDK-funded longitudinal study of the natural history of CP. The PROspective Evaluation of Chronic pancreatitis for EpidEmiologic and translational stuDies includes patient-reported outcome (PRO) measures of pain, medication use, global health, and QoL. Of subjects (N …

Do We Need Patient-Specific Qa For Adaptively Generated Plans? Retrospective Evaluation Of Delivered Online Adaptive Treatment Plans On Varian Ethos, Xiaodong Zhao, Dennis N Stanley, Carlos E Cardenas, Joseph Harms, Richard A Popple

2020-Current year OA Pubs

BACKGROUND: The clinical introduction of dedicated treatment units for online adaptive radiation therapy (OART) has led to widespread adoption of daily adaptive radiotherapy. OART allows for rapid generation of treatment plans using daily patient anatomy, potentially leading to reduction of treatment margins and increased normal tissue sparing. However, the OART workflow does not allow for measurement of patient-specific quality assurance (PSQA) during treatment delivery sessions and instead relies on secondary dose calculations for verification of adapted plans. It remains unknown if independent dose verification is a sufficient surrogate for PSQA measurements.

PURPOSE: To evaluate the plan quality of previously treated …

Anxiety Sensitivity And Cigarette Use On Cannabis Use Problems, Perceived Barriers For Cannabis Cessation, And Self-Efficacy For Quitting Among Adults With Cannabis Use Disorder, Michael F Orr, Luke F Heggeness, Nirvi Mehta, Jacob Moya, Kara Manning, Lorra Garey, Julianna Hogan, Marcel De Dios, Michael J Zvolensky

Faculty, Staff and Students Publications

Many individuals diagnosed with cannabis use disorder (CUD) report a desire to quit using cannabis due to problems associated with use. Yet, successful abstinence is difficult for a large subset of this population. Thus, the present study sought to elucidate potential risk factors for cannabis use problems, perceived barriers for quitting, and diminished self-efficacy for remaining abstinent. Specifically, this investigation examined cigarette user status, anxiety sensitivity, and the interplay between these individual difference factors in terms of cannabis-related problems, perceived barriers for cannabis cessation, and self-efficacy for quitting cannabis use. The sample consisted of 132 adult cannabis users who met …

Maternal Western Diet Is Associated With Distinct Preclinical Pediatric Nafld Phenotypes In Juvenile Nonhuman Primate Offspring, Michael J Nash, Evgenia Dobrinskikh, Rachel C Janssen, Mark A Lovell, Deborah A Schady, Claire Levek, Kenneth L Jones, Angelo D'Alessandro, Paul Kievit, Kjersti M Aagaard, Carrie E Mccurdy, Maureen Gannon, Jacob E Friedman, Stephanie R Wesolowski

Faculty, Staff and Students Publications

Pediatric NAFLD has distinct and variable pathology, yet causation remains unclear. We have shown that maternal Western-style diet (mWSD) compared with maternal chow diet (CD) consumption in nonhuman primates produces hepatic injury and steatosis in fetal offspring. Here, we define the role of mWSD and postweaning Western-style diet (pwWSD) exposures on molecular mechanisms linked to NAFLD development in a cohort of 3-year-old juvenile nonhuman primates offspring exposed to maternal CD or mWSD followed by CD or Western-style diet after weaning. We used histologic, transcriptomic, and metabolomic analyses to identify hepatic pathways regulating NAFLD. Offspring exposed to mWSD showed increased hepatic …

Reduction In Junctophilin 2 Expression In Cardiac Nodal Tissue Results In Intracellular Calcium-Driven Increase In Nodal Cell Automaticity, Andrew P Landstrom, Qixin Yang, Bo Sun, Robin M Perelli, Minu-Tshyeto Bidzimou, Zhushan Zhang, Yuriana Aguilar-Sanchez, Katherina M Alsina, Shuyi Cao, Julia O Reynolds, Tarah A Word, Niels M R Van Der Sangen, Quinn Wells, Prince J Kannankeril, Andreas Ludwig, Jeffrey J Kim, Xander H T Wehrens

Faculty, Staff and Students Publications

Background: Spontaneously depolarizing nodal cells comprise the pacemaker of the heart. Intracellular calcium (Ca2+) plays a critical role in mediating nodal cell automaticity and understanding this so-called Ca2+ clock is critical to understanding nodal arrhythmias. We previously demonstrated a role for Jph2 (junctophilin 2) in regulating Ca2+-signaling through inhibition of RyR2 (ryanodine receptor 2) Ca2+ leak in cardiac myocytes; however, its role in pacemaker function and nodal arrhythmias remains unknown. We sought to determine whether nodal Jph2 expression silencing causes increased sinoatrial and atrioventricular nodal cell automaticity due to aberrant RyR2 Ca2+ leak.

Methods: A tamoxifen-inducible, nodal tissue-specific, knockdown mouse …

In Vivo Editing Of The Pan-Endothelium By Immunity Evading Simian Adenoviral Vector, Reka Lorincz, Aluet Borrego Alvarez, Christopher J Walkey, Samir A Mendonça, Zhi Hong Lu, Alexa E Martinez, Cecilia Ljungberg, Jason D Heaney, William R Lagor, David T Curiel

Faculty, Staff and Students Publications

Biological applications deriving from the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 site-specific nuclease system continue to impact and accelerate gene therapy strategies. Safe and effective in vivo co-delivery of the CRISPR/Cas9 system to target somatic cells is essential in the clinical therapeutic context. Both non-viral and viral vector systems have been applied for this delivery matter. Despite elegant proof-of-principle studies, available vector technologies still face challenges that restrict the application of CRISPR/Cas9-facilitated gene therapy. Of note, the mandated co-delivery of the gene-editing components must be accomplished in the potential presence of pre-formed anti-vector immunity. Additionally, methods must be sought …

Magel2 Truncation Alters Select Behavioral And Physiological Outcomes In A Rat Model Of Schaaf-Yang Syndrome, Derek L Reznik, Mingxiao V Yang, Pedro Albelda De La Haza, Antrix Jain, Melanie Spanjaard, Susanne Theiss, Christian P Schaaf, Anna Malovannaya, Theresa V Strong, Surabi Veeraragavan, Rodney C Samaco

Faculty, Staff and Students Publications

Previous studies in mice have utilized Magel2 gene deletion models to examine the consequences of its absence. We report the generation, molecular validation and phenotypic characterization of a novel rat model with a truncating Magel2 mutation modeling variants associated with Schaaf-Yang syndrome-causing mutations. Within the hypothalamus, a brain region in which human MAGEL2 is paternally expressed, we demonstrated, at the level of transcript and peptide detection, that rat Magel2 exhibits a paternal, parent-of-origin effect. In evaluations of behavioral features across several domains, juvenile Magel2 mutant rats displayed alterations in anxiety-like behavior and sociability measures. Moreover, the analysis of peripheral organ …

Why Does The X Chromosome Lag Behind Autosomes In Gwas Findings?, Ivan P Gorlov, Christopher I Amos

Faculty, Staff and Students Publications

The X-chromosome is among the largest human chromosomes. It differs from autosomes by a number of important features including hemizygosity in males, an almost complete inactivation of one copy in females, and unique patterns of recombination. We used data from the Catalog of Published Genome Wide Association Studies to compare densities of the GWAS-detected SNPs on the X-chromosome and autosomes. The density of GWAS-detected SNPs on the X-chromosome is 6-fold lower compared to the density of the GWAS-detected SNPs on autosomes. Differences between the X-chromosome and autosomes cannot be explained by differences in the overall SNP density, lower X-chromosome coverage …

Pd-L1 Translocation To The Plasma Membrane Enables Tumor Immune Evasion Through Mib2 Ubiquitination, Xinfang Yu, Wei Li, Haidan Liu, Xu Wang, Cristian Coarfa, Chao Cheng, Xinlian Yu, Zhaoyang Zeng, Ya Cao, Ken H Young, Yong Li

Faculty, Staff and Students Publications

Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is a transmembrane protein synthesized in the endoplasmic reticulum of tumor cells and transported to the plasma membrane to interact with programmed death 1 (PD-1) expressed on T cell surface. This interaction delivers coinhibitory signals to T cells, thereby suppressing their function and allowing evasion of antitumor immunity. Most companion or complementary diagnostic devices for assessing PD-L1 expression levels in tumor cells used in the clinic or in clinical trials require membranous staining. However, the mechanism driving PD-L1 translocation to the plasma membrane after de novo synthesis is poorly understood. Herein, …

Serum Biomarkers Correlated With Liver Stiffness Assessed In A Multicenter Study Of Pediatric Cholestatic Liver Disease, Daniel H Leung, Sridevi Devaraj, Nathan P Goodrich, Xinpu Chen, Deepthi Rajapakshe, Wen Ye, Victor Andreev, Charles G Minard, Danielle Guffey, Jean P Molleston, Lee M Bass, Saul J Karpen, Binita M Kamath, Kasper S Wang, Shikha S Sundaram, Philip Rosenthal, Patrick Mckiernan, Kathleen M Loomes, M Kyle Jensen, Simon P Horslen, Jorge A Bezerra, John C Magee, Robert M Merion, Ronald J Sokol, Benjamin L Shneider, Estella Alonso, Lee Bass, Susan Kelly, Mary Riordan, Hector Melin-Aldana, Jorge Bezerra, Kevin Bove, James Heubi, Alexander Miethke, Greg Tiao, Julie Denlinger, Erin Chapman, Ronald Sokol, Amy Feldman, Cara Mack, Michael Narkewicz, Frederick Suchy, Shikha S Sundaram, Johan Van Hove, Benigno Garcia, Mikaela Kauma, Kendra Kocher, Matthew Steinbeiss, Mark Lovell, Kathleen M Loomes, David Piccoli, Elizabeth Rand, Pierre Russo, Nancy Spinner, Jessi Erlichman, Samantha Stalford, Dina Pakstis, Sakya King, Robert Squires, Rakesh Sindhi, Veena Venkat, Kathy Bukauskas, Patrick Mckiernan, Lori Haberstroh, James Squires, Philip Rosenthal, Laura Bull, Joanna Curry, Camille Langlois, Grace Kim, Jeffery Teckman, Vikki Kociela, Rosemary Nagy, Shraddha Patel, Jacqueline Cerkoski, Jean P Molleston, Molly Bozic, Girish Subbarao, Ann Klipsch, Cindy Sawyers, Oscar Cummings, Simon P Horslen, Karen Murray, Evelyn Hsu, Kara Cooper, Melissa Young, Laura Finn, Binita M Kamath, Vicky Ng, Claudia Quammie, Juan Putra, Deepika Sharma, Aishwarya Parmar, Stephen Guthery, Kyle Jensen, Ann Rutherford, Amy Lowichik, Linda Book, Rebecka Meyers, Tyler Hall, Kasper S Wang, Sonia Michail, Danny Thomas, Catherine Goodhue, Rohit Kohli, Larry Wang, Nisreen Soufi, Daniel Thomas, Saul Karpen, Nitika Gupta, Rene Romero, Miriam B Vos, Rita Tory, John-Paul Berauer, Carlos Abramowsky, Jeanette Mcfall, Benjamin L Shneider, Sanjiv Harpavat, Paula Hertel, Daniel Leung, Mary Tessier, Deborah Schady, Laurel Cavallo, Diego Olvera, Christina Banks, Cynthia Tsai, Richard Thompson, Edward Doo, Jay Hoofnagle, Averell Sherker, Rebecca Torrance, Sherry Hall, John Magee, Robert Merion, Cathie Spino, Wen Ye

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.

APPROACH AND RESULTS: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM …

Relief Of Malignant Gastric Outlet Obstruction With Lumen-Apposing Metallic Stent-Assisted Percutaneous Endoscopic Gastrostomy Tube After Roux-En-Y Gastric Bypass, Scott N Berger, Juan D Gomez Cifuentes, Tara Keihanian, Wasif M Abidi, Kalpesh K Patel

Faculty, Staff and Students Publications

No abstract provided.

Automated In Vivo High-Resolution Imaging To Detect Human Papillomavirus-Associated Anal Precancer In Persons Living With Hiv, David Brenes, Alex Kortum, Jennifer Carns, Tinaye Mutetwa, Richard Schwarz, Yuxin Liu, Keith Sigel, Rebecca Richards-Kortum, Sharmila Anandasabapathy, Michael Gaisa, Elizabeth Chiao

Faculty, Staff and Students Publications

INTRODUCTION: In the United States, the effectiveness of anal cancer screening programs has been limited by a lack of trained professionals proficient in high-resolution anoscopy (HRA) and a high patient lost-to-follow-up rate between diagnosis and treatment. Simplifying anal intraepithelial neoplasia grade 2 or more severe (AIN 2+) detection could radically improve the access and efficiency of anal cancer prevention. Novel optical imaging providing point-of-care diagnoses could substantially improve existing HRA and histology-based diagnosis. This work aims to demonstrate the potential of high-resolution microendoscopy (HRME) coupled with a novel machine learning algorithm for the automated, in vivo diagnosis of anal precancer. …

Dynamics Of Gametes And Embryos In The Oviduct: What Can In Vivo Imaging Reveal?, Shang Wang, Irina V Larina

Faculty, Staff and Students Publications

IN BRIEF: In vivo imaging of gametes and embryos in the oviduct enables new studies of the native processes that lead to fertilization and pregnancy. This review article discusses recent advancements in the in vivo imaging methods and insights which contribute to understanding the oviductal function.

ABSTRACT: Understanding the physiological dynamics of gametes and embryos in the fallopian tube (oviduct) has significant implications for managing reproductive disorders and improving assisted reproductive technologies. Recent advancements in imaging of the mouse oviduct in vivo uncovered fascinating dynamics of gametes and embryos in their native states. These new imaging approaches and observations are …

Synthetic Assembly Dna Cloning To Build Plasmids For Multiplexed Transgenic Selection, Counterselection Or Any Other Genetic Strategies Using Drosophila Melanogaster, Koen J T Venken, Nick Matinyan, Yezabel Gonzalez, Alejandro Sarrion-Perdigones, Herman A Dierick

Faculty, Staff and Students Publications

We recently described a drug-based selectable and counterselectable genetic platform for the animal model system Drosophila melanogaster, consisting of four resistance and two sensitivity markers that allow direct selection for, or counterselection against, a desired genotype. This platform eliminates the need to identify modified progeny by traditional laborious screening using dominant eye and body color markers, white⁺ and yellow⁺, respectively. The four resistance markers permit selection of animals using G418 sulfate, Puromycin HCl, Blasticidin S, or Hygromycin B, while the two sensitivity markers allow counterselection of animals against Ganciclovir or Acyclovir, and 5-Fluorocytosine. The six markers …

The Roles Of Cyp1a2 And Cyp2d In Pharmacokinetic Profiles Of Serotonin And Norepinephrine Reuptake Inhibitor Duloxetine And Its Metabolites In Mice, Xuan Qin, Cen Xie, John M Hakenjos, Kevin R Mackenzie, Shelton R Boyd, Mercedes Barzi, Karl-Dimiter Bissig, Damian W Young, Feng Li

Faculty, Staff and Students Publications

Duloxetine (DLX) is widely used to treat major depressive disorder. Little is known about the mechanistic basis for DLX-related adverse effects (e.g., liver injury). Human CYP1A2 and CYP2D6 mainly contributes to DLX metabolism, which was proposed to be involved in its adverse effects. Here, we investigated the roles of Cyp1a2 and Cyp2d on DLX pharmacokinetic profile and tissue distribution using a Cyp1a2 knockout (Cyp1a2-KO) mouse model together with a Cyp2d inhibitor (propranolol). Cyp1a2-KO has the few effects on the systematic exposure (area under the plasma concentration-time curve, AUC) and tissue disposition of DLX and its primary metabolites. Propranolol dramatically increased …

Final Results From A Phase 2b Randomized, Placebo-Controlled Clinical Trial Of Rbx2660: A Microbiota-Based Drug For The Prevention Of Recurrent Clostridioides Difficile Infection, Erik R Dubberke, Robert Orenstein, Sahil Khanna, Beth Guthmueller, Christine Lee

2020-Current year OA Pubs

INTRODUCTION: Effective treatments for recurrent Clostridioides difficile infection (rCDI) are urgently needed. RBX2660 is an investigational microbiota-based live biotherapeutic to reduce CDI recurrence following standard-of-care antibiotic treatment in individuals with rCDI. Here we report the final safety data through 24 months of follow-up as well as final efficacy data, reflecting alignment of the pre-specified statistical analysis plan definitions with the data presented.

METHODS: The PUNCH CD2 clinical trial was a prospective, multicenter, randomized, double-blinded, placebo-controlled, three-arm phase 2b study conducted to evaluate the efficacy and safety of RBX2660 for the reduction of rCDI compared to placebo. Eligible patients were at …

Missed Opportunities In The Diagnosis Of Tuberculosis Meningitis, Niamh Simmons, Margaret A Olsen, Joanna Buss, Thomas C Bailey, Carlos Mejia-Chew

2020-Current year OA Pubs

BACKGROUND: Tuberculosis meningitis (TBM) has high mortality and morbidity. Diagnostic delays can impact TBM outcomes. We aimed to estimate the number of potentially missed opportunities (MOs) to diagnose TBM and determine its impact on 90-day mortality.

METHODS: This is a retrospective cohort of adult patients with a central nervous system (CNS) TB

RESULTS: Of 893 patients with TBM, median age at diagnosis was 50 years (interquartile range, 37-64), 61.3% were male, and 35.2% had Medicaid as primary payer. Overall, 407 (45.6%) had a prior hospital or ED visit with an MO code. In-hospital 90-day mortality was not different between those …

Biallelic Variants In Ogdh Encoding Oxoglutarate Dehydrogenase Lead To A Neurodevelopmental Disorder Characterized By Global Developmental Delay, Movement Disorder, And Metabolic Abnormalities, Ella F Whittle, Madison Chilian, Ehsan Ghayoor Karimiani, Helga Progri, Daniela Buhas, Melis Kose, Rebecca D Ganetzky, Mehran Beiraghi Toosi, Paria Najarzadeh Torbati, Reza Shervin Badv, Ivan Shelihan, Hui Yang, Houda Zghal Elloumi, Sukyeong Lee, Yalda Jamshidi, Alan M Pittman, Henry Houlden, Erika Ignatius, Shamima Rahman, Reza Maroofian, Wan Hee Yoon, Christopher J Carroll

Faculty, Staff and Students Publications

PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.

METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells.

RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme …