Medicine and Health Sciences Commons^™

Role Of Sam68 In Sunitinib Induced Renal Cell Carcinoma Apoptosis, Zeshen Wu, Yulu Peng, Longbin Xiong, Jun Wang, Zhen Li, Kang Ning, Minhua Deng, Ning Wang, Wensu Wei, Zhiyong Li, Pei Dong, Chunping Yu, Fangjian Zhou, Zhiling Zhang

Faculty, Staff and Student Publications

Sunitinib is one of the first-line targeted drugs for metastatic renal cell carcinoma (RCC) with dual effects of antiangiogensis and proapoptosis. Sam68 (Src-associated in mitosis, 68 KDa), is found being involved in cell apoptosis. This article reveals that Sam68 impacts the sensitivity to sunitinib by mediating the apoptosis of RCC cells. Immunohistochemical staining indicated that the Sam68 expression levels in sunitinib sensitive tumor tissues were markedly higher than those in sunitinib resistant tumor tissues. Sunitinib induced RCC cell apoptosis in a concentration-dependent manner and inhibited the expression of total and phosphorylated Sam68 (p-Sam68). Downregulation of Sam68 expression inhibited RCC cell …

The Impact Of Covid-19 Pandemic Upon Non-Elective Admissions And Surgery At A Safety-Net Hospital: A Retrospective Cohort Study, Artem Boyev, Srinivas Sanjeevi, Martha M Estrada, Tien C Ko, Curtis J Wray

Faculty, Staff and Student Publications

Introduction: In response to the COVID-19 pandemic, hospitals reported decreased admissions for acute surgical diagnoses, but scant data was available to quantify the decrease and its consequences. The objective of this study was to examine the incidence of acute care surgery encounters before and during the COVID-19 pandemic.

Materials and methods: A retrospective cohort study was performed at a single, urban, United States safety-net hospital. Emergency room encounters, admissions, non-elective surgical procedures, patient acuity, and surgical complications were compared before and after the start of the COVID-19 pandemic. The primary outcome of the study was the incidence rate (IR) and …

A Population-Based Meta-Analysis Of Circulating Gfap For Cognition And Dementia Risk, Mitzi M Gonzales, Crystal Wiedner, Chen-Pin Wang, Qianqian Liu, Joshua C Bis, Zhiguang Li, Jayandra J Himali, Saptaparni Ghosh, Emy A Thomas, Danielle M Parent, Tiffany F Kautz, Matthew P Pase, Hugo J Aparicio, Luc Djoussé, Kenneth J Mukamal, Bruce M Psaty, William T Longstreth, Thomas H Mosley, Vilmundur Gudnason, Djass Mbangdadji, Oscar L Lopez, Kristine Yaffe, Stephen Sidney, R Nick Bryan, Ilya M Nasrallah, Charles S Decarli, Alexa S Beiser, Lenore J Launer, Myriam Fornage, Russell P Tracy, Sudha Seshadri, Claudia L Satizabal

Faculty, Staff and Student Publications

Objective: Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population-based level are necessary to broaden generalizability to community settings.

Methods: Circulating GFAP levels were assayed using a Simoa HD-1 analyzer in 4338 adults without prevalent dementia from four longitudinal community-based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, …

Thromboembolism In Children With Multisystem Inflammatory Syndrome: A Literature Review, Neethu M Menon, Lakshmi V Srivaths

Faculty, Staff and Student Publications

Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory response observed in children several weeks to months after acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). On review of all published cases of thromboembolism (TE) as a complication of MIS-C, 33 cases of TE were found with incidence ranging from 1.4 to 6.5%. TE occurred mostly in children aged 12 years and above. One-third of the cases were cerebral infarcts and the remaining cases included intracardiac and radial arterial thromboses, upper and lower extremity deep vein thrombosis, pulmonary embolism, and splenic infarcts. Five were asymptomatic cases and 3/33 (9%) …

Heterozygous Variants In Myh10 Associated With Neurodevelopmental Disorders And Congenital Anomalies With Evidence For Primary Cilia-Dependent Defects In Hedgehog Signaling, Alexander M Holtz, Rachel Vancoillie, Elizabeth A Vansickle, Deanna Alexis Carere, Kara Withrow, Erin Torti, Jane Juusola, Francisca Millan, Richard Person, Maria J Guillen Sacoto, Yue Si, Ingrid M Wentzensen, Jada Pugh, Georgia Vasileiou, Melissa Rieger, André Reis, Emanuela Argilli, Elliott H Sherr, Kimberly A Aldinger, William B Dobyns, Theresa Brunet, Julia Hoefele, Matias Wagner, Benjamin Haber, Urania Kotzaeridou, Boris Keren, Delphine Heron, Cyril Mignot, Solveig Heide, Thomas Courtin, Julien Buratti, Serini Murugasen, Kirsten A Donald, Emily O'Heir, Shade Moody, Katherine H Kim, Barbara K Burton, Grace Yoon, Miguel Del Campo, Diane Masser-Frye, Mariya Kozenko, Christina Parkinson, Susan L Sell, Patricia L Gordon, Jeremy W Prokop, Amel Karaa, Caleb Bupp, Benjamin A Raby

Faculty, Staff and Student Publications

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10.

METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis.

RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a …

Aging After Stroke: How To Define Post-Stroke Sarcopenia And What Are Its Risk Factors?, Sheng Li, Javier Gonzalez-Buonomo, Jaskiran Ghuman, Xinran Huang, Aila Malik, Nuray Yozbatiran, Elaine Magat, Gerard E Francisco, Hulin Wu, Walter R Frontera

Faculty, Staff and Student Publications

BACKGROUND: Sarcopenia, generally described as "aging-related loss of skeletal muscle mass and function", can occur secondary to a systemic disease.

AIM: This project aimed to study the prevalence of sarcopenia in chronic ambulatory stroke survivors and its associated risk factors using the two most recent diagnostic criteria.

DESIGN: A cross-sectional observational study.

SETTING: A scientific laboratory.

POPULATION: Chronic stroke.

METHODS: Twenty-eight ambulatory chronic stroke survivors (12 females; mean age=57.8±11.8 years; time after stroke=76±45 months), hand-grip strength, gait speed, and appendicular skeletal muscle mass (ASM) were measured to define sarcopenia. Risk factors, including motor impairment and spasticity, were identified using regression …

Aging After Stroke: How To Define Post-Stroke Sarcopenia And What Are Its Risk Factors?, Sheng Li, Javier Gonzalez-Buonomo, Jaskiran Ghuman, Xinran Huang, Aila Malik, Nuray Yozbatiran, Elaine Magat, Gerard E Francisco, Hulin Wu, Walter R Frontera

Faculty, Staff and Student Publications

BACKGROUND: Sarcopenia, generally described as "aging-related loss of skeletal muscle mass and function", can occur secondary to a systemic disease.

AIM: This project aimed to study the prevalence of sarcopenia in chronic ambulatory stroke survivors and its associated risk factors using the two most recent diagnostic criteria.

DESIGN: A cross-sectional observational study.

SETTING: A scientific laboratory.

POPULATION: Chronic stroke.

METHODS: Twenty-eight ambulatory chronic stroke survivors (12 females; mean age=57.8±11.8 years; time after stroke=76±45 months), hand-grip strength, gait speed, and appendicular skeletal muscle mass (ASM) were measured to define sarcopenia. Risk factors, including motor impairment and spasticity, were identified using regression …

Comparative Safety And Effectiveness Of Roux-En-Y Gastric Bypass And Sleeve Gastrectomy For Weight Loss And Type 2 Diabetes Across Race And Ethnicity In The Pcornet Bariatric Study Cohort, Karen J Coleman, Robert Wellman, Stephanie L Fitzpatrick, Molly B Conroy, Callie Hlavin, Kristina H Lewis, R Yates Coley, Kathleen M Mctigue, Jonathan N Tobin, Corrigan L Mcbride, Jay R Desai, Jeanne M Clark, Sengwee Toh, Jessica L Sturtevant, Casie E Horgan, Meredith C Duke, Neely Williams, Jane Anau, Michael A Horberg, Marc P Michalsky, Andrea J Cook, David E Arterburn, Caroline M Apovian, Pcornet Bariatric Study Collaborative

Faculty, Staff and Student Publications

IMPORTANCE: Bariatric surgery is the most effective treatment for severe obesity; yet it is unclear whether the long-term safety and comparative effectiveness of these operations differ across racial and ethnic groups.

OBJECTIVE: To compare outcomes of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) across racial and ethnic groups in the National Patient-Centered Clinical Research Network (PCORnet) Bariatric Study.

DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective, observational, comparative effectiveness cohort study that comprised 25 health care systems in the PCORnet Bariatric Study. Patients were adults and adolescents aged 12 to 79 years who underwent a primary (first nonrevisional) RYGB …

American Association Of Endocrine Surgeons Guidelines For Adrenalectomy: Executive Summary, Linwah Yip, Quan-Yang Duh, Heather Wachtel, Camilo Jimenez, Cord Sturgeon, Cortney Lee, David Velázquez-Fernández, Eren Berber, Gary D Hammer, Irina Bancos, James A Lee, Jamie Marko, Lilah F Morris-Wiseman, Marybeth S Hughes, Masha J Livhits, Mi-Ah Han, Philip W Smith, Scott Wilhelm, Sylvia L Asa, Thomas J Fahey, Travis J Mckenzie, Vivian E Strong, Nancy D Perrier

Faculty, Staff and Student Publications

IMPORTANCE: Adrenalectomy is the definitive treatment for multiple adrenal abnormalities. Advances in technology and genomics and an improved understanding of adrenal pathophysiology have altered operative techniques and indications.

OBJECTIVE: To develop evidence-based recommendations to enhance the appropriate, safe, and effective approaches to adrenalectomy.

EVIDENCE REVIEW: A multidisciplinary panel identified and investigated 7 categories of relevant clinical concern to practicing surgeons. Questions were structured in the framework Population, Intervention/Exposure, Comparison, and Outcome, and a guided review of medical literature from PubMed and/or Embase from 1980 to 2021 was performed. Recommendations were developed using Grading of Recommendations, Assessment, Development and Evaluation methodology …

Wide-Necked Middle Cerebral Artery Aneurysm Clipping Following Failed Occlusion After Woven Endobridge Placement: 2-Dimensional Operative Video, Stephen Capone, Anil Roy, Matthew Kole, Spiros L Blackburn

Faculty, Staff and Student Publications

No abstract provided.

Aging After Stroke: How To Define Post-Stroke Sarcopenia And What Are Its Risk Factors?, Sheng Li, Javier Gonzalez-Buonomo, Jaskiran Ghuman, Xinran Huang, Aila Malik, Nuray Yozbatiran, Elaine Magat, Gerard E Francisco, Hulin Wu, Walter R Frontera

Faculty, Staff and Student Publications

Background: Sarcopenia, generally described as "aging-related loss of skeletal muscle mass and function", can occur secondary to a systemic disease.

Aim: This project aimed to study the prevalence of sarcopenia in chronic ambulatory stroke survivors and its associated risk factors using the two most recent diagnostic criteria.

Design: A cross-sectional observational study.

Setting: A scientific laboratory.

Population: Chronic stroke.

Methods: Twenty-eight ambulatory chronic stroke survivors (12 females; mean age=57.8±11.8 years; time after stroke=76±45 months), hand-grip strength, gait speed, and appendicular skeletal muscle mass (ASM) were measured to define sarcopenia. Risk factors, including motor impairment and spasticity, were identified using regression …

A Hydrogen-Sulfide Derivative Of Mesalamine Reduces The Severity Of Intestinal And Lung Injury In Necrotizing Enterocolitis Through Endothelial Nitric Oxide Synthase, Brian D Hosfield, Chelsea E Hunter, Hongge Li, Natalie A Drucker, Anthony R Pecoraro, Krishna Manohar, W Christopher Shelley, Troy A Markel

Faculty, Staff and Student Publications

Necrotizing enterocolitis (NEC) remains a devastating disease that affects preterm infants. Hydrogen sulfide (H2S) donors have been shown to reduce the severity of NEC, but the optimal compound has yet to be identified. We hypothesized that oral H2S-Mesalamine (ATB-429) would improve outcomes in experimental NEC, and its benefits would be dependent on endothelial nitric oxide synthase (eNOS) pathways. NEC was induced in 5-day-old wild-type (WT) and eNOS knockout (eNOSKO) pups by formula feeding and stress. Four groups were studied in both WT and eNOSKO mice: 1) breastfed controls, 2) NEC, 3) NEC + 50 mg/kg mesalamine, and …

Comparison Of Brain Nicotine Uptake From Electronic Cigarettes And Combustible Cigarettes, Yantao Zuo, Alexey G Mukhin, Hannah Berg, Janiece D Morgan, Akiva Mintz, Jed E Rose, Kiran Kumar Solingapuram Sai

Faculty, Staff and Student Publications

Brain accumulation rate and magnitude are critical for the acute reinforcing effects of nicotine. Despite electronic cigarettes’ (E-cigs) appeal as substitutes for traditional combustible cigarettes (C-cigs), brain nicotine accumulation (BNA) from E-cigs has not been compared with that from C-cigs using a within-subjects design. BNA was directly assessed with 16 adult dual users (10 females) of E-cigs (e-liquid pH 9.4) and C-cigs, using 11C-nicotine and positron emission tomography (PET). Participants went through two 15-min head scanning sessions during which they inhaled a single puff of E-cig vapor or C-cig smoke containing 11C-nicotine in a randomized order. A full-body scan was …

Ags And Nia Bench-To Bedside Conference Summary: Cancer And Cardiovascular Disease, Supriya Mohile, Caroline S Blaum, Peter M Abadir, William Dale, Daniel E Forman, Chunkit Fung, Holly M Holmes, Javid Moslehi, Karen M Mustian, Michael W Rich, Heather E Whitson

Faculty, Staff and Student Publications

This report summarizes the presentations, discussions, and recommendations of the most recent American Geriatrics Society and National Institute on Aging research conference, "Cancer and Cardiovascular Disease," on October 18-19, 2021. The purpose of this virtual meeting was to address the interface between cancer and heart disease, which are the two leading causes of death among older Americans. Age-related physiologic changes are implicated in the pathogenesis of both conditions. Emerging data suggest that cancer-related cardiovascular disease (CVD) involves disrupted cell signaling and cellular senescence. The risk factors for CVD are also risk factors for cancer and an increased likelihood of cancer …

Ocrelizumab Reduces Thalamic Volume Loss In Patients With Rms And Ppms, Douglas L Arnold, Till Sprenger, Amit Bar-Or, Jerry S Wolinsky, Ludwig Kappos, Shannon Kolind, Ulrike Bonati, Stefano Magon, Johan Van Beek, Harold Koendgen, Oscar Bortolami, Corrado Bernasconi, Laura Gaetano, Anthony Traboulsee

Faculty, Staff and Student Publications

Background: In multiple sclerosis (MS), thalamic integrity is affected directly by demyelination and neuronal loss, and indirectly by gray/white matter lesions outside the thalamus, altering thalamic neuronal projections.

Objective: To assess the efficacy of ocrelizumab compared with interferon beta-1a (IFNβ1a)/placebo on thalamic volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II; NCT01247324/NCT01412333) and in primary progressive MS (PPMS, ORATORIO; NCT01194570).

Methods: Thalamic volume change was computed using paired Jacobian integration and analyzed using an adjusted mixed-effects repeated measurement model.

Results: Over the double-blind period, …

Early Versus Delayed Treatment With Glatiramer Acetate: Analysis Of Up To 27 Years Of Continuous Follow-Up In A Us Open-Label Extension Study, Corey C Ford, Jeffrey A Cohen, Andrew D Goodman, John W Lindsey, Robert P Lisak, Christopher Luzzio, Amy Pruitt, John Rose, Horea Rus, Jerry S Wolinsky, Shaul E Kadosh, Emily Bernstein-Hanlon, Yafit Stark, Jessica K Alexander

Faculty, Staff and Student Publications

BACKGROUND: Glatiramer acetate (GA) is US-approved for relapsing multiple sclerosis.

OBJECTIVES: To describe GA long-term clinical profile. To compare effectiveness of early start (ES) versus delayed start (DS; up to 3 years) with GA.

METHODS: Phase 3 trial participants entered a randomized placebo-controlled period then an open-label extension (OLE) with GA.

RESULTS: Overall, 208 out of 251 (82.9%) randomized participants entered the OLE; 24 out of 101 (23.8%, ES) and 28 out of 107 (26.2%, DS) participants completed the OLE. Median GA treatment was 9.8 (0.1-26.3) years. Annualized change in Expanded Disability Status Scale (EDSS) score was lower with ES …

The Ubiquitin-Proteasome System Is Necessary For Long-Term Synaptic Depression In Aplysia, Jennifer S Love, Dana L Karshenas, Meghan B Spyres, Lynn A Farrugia, A Min Kang, Hoanvu Nguyen, Sharan L Campleman, Shao Li, Paul M Wax, Jeffery Brent, Kim Aldy, Toxicology Investigators Consortium Study Group

Faculty, Staff and Student Publications

The Toxicology Investigators Consortium (ToxIC) Core Registry was established by the American College of Medical Toxicology in 2010. The Core Registry collects data from participating sites with the agreement that all bedside and telehealth medical toxicology consultations will be entered. This twelfth annual report summarizes the registry's 2021 data and activity with its additional 8552 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from January 1 to December 31, 2021. Detailed data was collected from these cases and aggregated to provide information, which included demographics, reason for medical …

Racial/Ethnic And Gender Disparities Of The Impact Of The Covid-19 Pandemic In Out-Of-Hospital Cardiac Arrest (Ohca) In Texas, Summer Chavez, Ryan Huebinger, Hei Kit Chan, Kevin Schulz, Micah Panczyk, Normandy Villa, Renee Johnson, Robert Greenberg, Veer Vithalani, Rabab Al-Araji, Bentley Bobrow

Faculty, Staff and Student Publications

INTRODUCTION: Prior research shows a greater disease burden, lower BCPR rates, and worse outcomes in Black and Hispanic patients after OHCA. Female OHCA patients have lower rates of BCPR compared to men and other survival outcomes vary. The influence of the COVID-19 pandemic on OHCA incidence and outcomes in different health disparity populations is unknown.

METHODS: We used data from the Texas Cardiac Arrest Registry to Enhance Survival (CARES). We determined the association of both prehospital characteristics and survival outcomes with the pandemic period in each study group through Pearson's χ

RESULTS: Black OHCA patients (aOR = 0.73; 95% CI: …

Oxidation Of Two Cysteines Within Yeast Hsp70 Impairs Proteostasis While Directly Triggering An Hsf1-Dependent Cytoprotective Response, Alec Santiago, Kevin A Morano

Faculty, Staff and Student Publications

Neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases affect millions of Americans every year. One factor linked to the formation of aggregates associated with these diseases is damage sustained to proteins by oxidative stress. Management of protein misfolding by the ubiquitous Hsp70 chaperone family can be modulated by modification of two key cysteines in the ATPase domain by oxidizing or thiol-modifying compounds. To investigate the biological consequences of cysteine modification on the Hsp70 Ssa1 in budding yeast, we generated cysteine null (cysteine to serine) and oxidomimetic (cysteine to aspartic acid) mutant variants of both C264 and C303 and demonstrate …

Targeting Hemoglobin To Reduce Delayed Cerebral Ischemia After Subarachnoid Hemorrhage, Hussein A Zeineddine, Pedram Honarpisheh, Devin Mcbride, Peeyush Kumar Thankamani Pandit, Ari Dienel, Sung-Ha Hong, James Grotta, Spiros Blackburn

Faculty, Staff and Student Publications

Delayed cerebral ischemia (DCI) continues to be a sequela of aneurysmal subarachnoid hemorrhage (aSAH) that carries significant morbidity and mortality. Aside from nimodipine, no therapeutic agents are available to reduce the incidence of DCI. Pathophysiologic mechanisms contributing to DCI are poorly understood, but accumulating evidence over the years implicates several factors. Those have included microvessel vasoconstriction, microthrombosis, oxidative tissue damage, and cortical spreading depolarization as well as large vessel vasospasm. Common to these processes is red blood cell leakage into the cerebrospinal fluids (CSF) and subsequent lysis which releases hemoglobin, a central instigator in these events. This has led to …

A Retrospective Analysis Of Ebv-Dna Status With The Prognosis Of Lymphoma, Lihua Qiu, Junqi Si, Junnan Kang, Zehui Chen, Rexidan Nuermaimaiti, Zhengzi Qian, Lanfang Li, Shiyong Zhou, Mingjian James You, Huilai Zhang, Chen Tian

Faculty, Staff and Student Publications

Epstein-Barr virus (EBV) infection is proved to be associated with clinicopathology of lymphoma. However, little is known about the relationship between EBV-DNA status after treatment and prognosis. In this study, real-time polymerase chain reaction (PCR) was used for quantitative detection of EBV-DNA load in peripheral blood of all 26,527 patients with lymphoma, and the clinical characteristics and prognosis of 202 patients were retrospectively analysed, including 100 patients with positive EBV-DNA and 102 randomly selected patients with negative EBV-DNA. We found that the average rate of EBV-DNA positivity in lymphomas was 0.376%, and EBV-DNA-positive patients presented higher risk with elevated lactate …

Handling Informative Premature Treatment Or Study Discontinuation For Assessing Between-Group Differences In A Comparative Oncology Trial, Bo Huang, Ryan Sun, Brian Claggett, Lu Tian, Ethan B Ludmir, Lee-Jen Wei

Faculty, Staff and Student Publications

This decision analytical model study examines premature treatment discontinuation in clinical trials for patients with advanced renal cell carcinoma.

Lurbinectedin, A Selective Inhibitor Of Oncogenic Transcription, In Patients With Pretreated Germline Brca1/2 Metastatic Breast Cancer: Results From A Phase Ii Basket Study, V Boni, B Pistilli, I Braña, G I Shapiro, J Trigo, V Moreno, D Castellano, C Fernández, C Kahatt, V Alfaro, M Siguero, A Zeaiter, F Longo, K Zaman, A Antón, A Paredes, G Huidobro, V Subbiah

Faculty, Staff and Student Publications

Background: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer.

Patients and methods: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival …

Targeting The Alk-Cdk9-Tyr19 Kinase Cascade Sensitizes Ovarian And Breast Tumors To Parp Inhibition Via Destabilization Of The P-Tefb Complex, Yu-Yi Chu, Mei-Kuang Chen, Yongkun Wei, Heng-Huan Lee, Weiya Xia, Ying-Nai Wang, Clinton Yam, Jennifer L Hsu, Hung-Ling Wang, Wei-Chao Chang, Hirohito Yamaguchi, Zhou Jiang, Chunxiao Liu, Ching-Fei Li, Lei Nie, Li-Chuan Chan, Yuan Gao, Shao-Chun Wang, Jinsong Liu, Shannon N Westin, Sanghoon Lee, Anil K Sood, Liuqing Yang, Gabriel N Hortobagyi, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor …

Neuroinflammation And Covid-19, Abigail Vanderheiden, Robyn S. Klein

2020-Current year OA Pubs

Coronavirus disease 2019 (COVID-19) has caused a historic pandemic of respiratory disease. COVID-19 also causes acute and post-acute neurological symptoms, which range from mild, such as headaches, to severe, including hemorrhages. Current evidence suggests that there is no widespread infection of the central nervous system (CNS) by SARS-CoV-2, thus what is causing COVID-19 neurological disease? Here, we review potential immunological mechanisms driving neurological disease in COVID-19 patients. We begin by discussing the implications of imbalanced peripheral immunity on CNS function. Next, we examine the evidence for dysregulation of the blood-brain barrier during SARS-CoV-2 infection. Last, we discuss the role myeloid …

Margetuximab With Retifanlimab As First-Line Therapy In Her2+/Pd-L1+ Unresectable Or Metastatic Gastroesophageal Adenocarcinoma: Mahogany Cohort A, D. V. T. Catenacci, H. Park, Et Al.

2020-Current year OA Pubs

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA.

PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort …

Antimicrobial Stewardship For Sepsis In The Intensive Care Unit: Survey Of Critical Care And Infectious Diseases Physicians, M Cristina Vazquez Guillamet, Jason P Burnham, Maria Pérez, Marin H Kollef, Constantine A Manthous, Donna B Jeffe

2020-Current year OA Pubs

OBJECTIVE: To evaluate the attitudes of infectious diseases (ID) and critical care physicians toward antimicrobial stewardship in the intensive care unit (ICU).

DESIGN: Anonymous, cross-sectional, web-based surveys.

SETTING: Surveys were completed in March-November 2017, and data were analyzed from December 2017 to December 2019.

PARTICIPANTS: ID and critical care fellows and attending physicians.

METHODS: We included 10 demographic and 17 newly developed, 5-point, Likert-scaled items measuring attitudes toward ICU antimicrobial stewardship and transdisciplinary collaboration. Exploratory principal components analysis (PCA) was used for data reduction. Multivariable linear regression models explored demographic and attitudinal variables.

RESULTS: Of 372 respondents, 315 physicians had …

Functional Characterization Of Enhancer Activity During A Long Terminal Repeat's Evolution, Alan Y Du, Xiaoyu Zhuo, Vasavi Sundaram, Nicholas O Jensen, Hemangi G Chaudhari, Nancy L Saccone, Barak A Cohen, Ting Wang

2020-Current year OA Pubs

Many transposable elements (TEs) contain transcription factor binding sites and are implicated as potential regulatory elements. However, TEs are rarely functionally tested for regulatory activity, which in turn limits our understanding of how TE regulatory activity has evolved. We systematically tested the human LTR18A subfamily for regulatory activity using massively parallel reporter assay (MPRA) and found AP-1- and CEBP-related binding motifs as drivers of enhancer activity. Functional analysis of evolutionarily reconstructed ancestral sequences revealed that LTR18A elements have generally lost regulatory activity over time through sequence changes, with the largest effects occurring owing to mutations in the AP-1 and CEBP …

Influence Of Pregabalin Maintenance On Cannabis Effects And Related Behaviors In Daily Cannabis Users, Joshua A Lile, Joseph L Alcorn, Lon R Hays, Thomas H Kelly, William W Stoops, Michael J Wesley, Philip M Westgate

Faculty, Staff and Student Publications

No medications are approved for cannabis use disorder (CUD), though a small clinical trial demonstrated that the voltage-dependent calcium channel (VDCC) ligand gabapentin reduced cannabis use in treatment seekers. VDCCs are modulated by cannabinoid (CB) ligands, and there are shared effects between CB agonists and VDCC ligands. This overlapping neuropharmacology and the initial clinical results supported the evaluation of pregabalin, a "next-generation" VDCC ligand, as a CUD medication. Two separate placebo-controlled, double-blind, counterbalanced, within-subjects human laboratory studies tested placebo and 300 (N = 2 females, 11 males; Experiment [EXP] 1) or 450 (N = 3 females, 11 males; …

Monkeypox: What Do Dental Professionals Need To Know?, Charifa Zemouri, Edgar O Beltrán, Richard Holliday, Nicholas S Jakubovics, James R Allison

Faculty, Staff and Student Publications

Infection control is critical for the safe delivery of dental care. Infection control practices must be responsive to emerging and re-emerging infectious diseases and outbreaks, as was clearly seen during the peak of the COVID-19 pandemic. An emerging global outbreak of the monkeypox virus has again raised potential challenges for infection control in dentistry. Monkeypox is an infectious disease, characterised by a rash affecting the skin and soft tissues, including the oral cavity. Previously, cases were mostly seen following contact with infected animals in Central and West Africa, with limited human-to-human transmission within and outside of these areas. However, since …