Translational Medical Research Commons^™

Cocaine Sensitizes The Cd4+ T Cells For Hiv Infection By Co-Stimulating Nfat And Ap-1, Adhikarimayum Lakhikumar Sharma, Dylan Shafer, Daniel Netting, Mudit Tyagi

Center for Translational Medicine Faculty Papers

The productive infection of HIV, which generates new viral progeny, depends on the activation status of the cell. In this study, we found cocaine exposure sensitizes partially active CD4+ T cells and makes them poised for productive HIV infection. We discovered that cocaine treatment enhances the metabolic state of the cells by co-stimulating several transcription factors, mainly NFAT and AP-1, the two transcription factors, which specifically play a crucial role in enhancing both HIV and the overall cellular gene expression in T cells. We found that cocaine-induced AP-1 works in tandem with NFAT to boost HIV transcription. The enhanced HIV …

Expansion Of The Detrusor Muscular Ring Surrounding The Bladder Neck On Mri: Moving Beyond The Prostate As An Etiology Of Lower Urinary Tract Symptoms Due To Benign Prostatic Hyperplasia, Kiran Nandalur, David Walker, Hong Ye, Sayf A. Al-Katib, Brian Seifman, David Gangwish, Abhay Dhaliwal, Connor Ervin, Kayla Dobies, Channing Sesoko, Sirisha Nandalur, Bernadette Zwaans, Jennifer Nguyen, Jason Hafron

Conference Presentation Abstracts

Purpose: The etiology of lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH) remains uncertain. The purpose of our study was to quantitatively analyze pelvic anatomic characteristics on magnetic resonance imaging (MRI) to assess for independent factors for symptoms.
*Methods and Materials: This retrospective single-institution study evaluated treatment-naïve men who underwent prostate MRI within 3 months of International Prostate Symptom Score (IPSS) from June 2021 to February 2022. Factors measured on MRI included: detrusor muscular ring surrounding the bladder neck measured as area and alternatively diameter, central gland (CG) mean apparent diffusion coefficient (ADC), levator hiatus (LH) volume, intrapelvic …

Piperine Attenuates Cigarette Smoke-Induced Oxidative Stress, Lung Inflammation, And Epithelial-Mesenchymal Transition By Modulating The Sirt1/Nrf2 Axis, Pritam Saha, Sneha Durugkar, Siddhi Jain, P A Shantanu, Samir R Panda, Aishwarya Jala, Sharad Gokhale, Pawan Sharma, V G M Naidu

Center for Translational Medicine Faculty Papers

Piperine (PIP) is a major phytoconstituent in black pepper which is responsible for various pharmacological actions such as anti-inflammatory, antioxidant, and antitumor activity. To investigate the effects and mechanisms of PIP on cigarette smoke (CS)-induced lung pathology using both in-vitro and in-vivo models. BEAS-2B and A549 cells were exposed to CS extract (CSE) for 48 h; BALB/c mice were exposed to CS (9 cigarettes/day, 4 days) to induce features of airway disease. PIP at doses of (0.25, 1.25, and 6.25 µM, in vitro; 1 and 10 mg/kg, in vivo, i.n) and DEX (1 µM, in vitro; 1 mg/kg, in vivo, …

Regulation Of Airway Smooth Muscle Cell Proliferation By Diacylglycerol Kinase: Relevance To Airway Remodeling In Asthma, Miguel Angel Hernandez-Lara, Santosh K Yadav, Sushrut D. Shah, Mariko Okumura, Yuichi Yokoyama, Raymond B. Penn,, Taku Kambayashi, Deepak A. Deshpande

Center for Translational Medicine Faculty Papers

Airway remodeling in asthma involves the hyperproliferation of airway smooth muscle (ASM) cells. However, the molecular signals that regulate ASM growth are not completely understood. Gq-coupled G protein-coupled receptor and receptor tyrosine kinase signaling regulate ASM cell proliferation via activation of phospholipase C, generation of inositol triphosphate (IP3) and diacylglycerol (DAG). Diacylglycerol kinase (DGK) converts DAG into phosphatidic acid (PA) and terminates DAG signaling while promoting PA-mediated signaling and function. Herein, we hypothesized that PA is a pro-mitogenic second messenger in ASM, and DGK inhibition reduces the conversion of DAG into PA resulting in inhibition of ASM cell proliferation. We …

Addressing The Underdiagnosis Of Familial Hypercholesterolemia: A Mixed Methods Study Exploring The Knowledge And Practice Behaviors Of Cardiology Healthcare Providers, Isha Kalia Ms, Mph, Cgc

Doctor of Philosophy in Translational Health Sciences Dissertations

Background: Familial Hypercholesterolemia (FH) is a common genetic disorder that is vastly underdiagnosed and undertreated. FH causes lifelong elevated low-density lipoprotein cholesterol, resulting in an increased risk for coronary heart disease, myocardial infarctions, and sudden cardiac death. Cardiology healthcare providers (CHCPs) are in an ideal position to not only screen cardiology patients for FH but also to diagnose and manage FH patients.

Objectives: Describe the practice behaviors of CHCPs in the screening, diagnosis, and management of FH, as well as gain a deeper understanding of the perspectives of CHCPs regarding FH screening and diagnostic interventions that can be implemented in …

Anxiolytics For Bronchodilation: Refinements To Gaba, Ajay P Nayak, Steven S An

Department of Medicine Faculty Papers

No abstract provided.

Grk2 Regulates Adp Signaling In Platelets Via P2y1 And P2y12., Xuefei Zhao, Matthew Cooper, James V Michael, Yanki Yarman, Aiden Baltz, J Kurt Chuprun, Walter J Koch, Steven E. Mckenzie, Maurizio Tomaiuolo, Timothy J Stalker, Li Zhu, Peisong Ma

Department of Medicine Faculty Papers

The critical role of G protein-coupled receptor kinase 2 (GRK2) in regulating cardiac function has been well documented for >3 decades. Targeting GRK2 has therefore been extensively studied as a novel approach to treating cardiovascular disease. However, little is known about its role in hemostasis and thrombosis. We provide here the first evidence that GRK2 limits platelet activation and regulates the hemostatic response to injury. Deletion of GRK2 in mouse platelets causes increased platelet accumulation after laser-induced injury in the cremaster muscle arterioles, shortens tail bleeding time, and enhances thrombosis in adenosine 5'-diphosphate (ADP)-induced pulmonary thromboembolism and in FeCl3-induced carotid …

Development Of A Decellularized Hydrogel Composite And Its Application In A Novel Model Of Disc-Associated Low Back Pain In Female Sprague Dawley Rats, David Lillyman

Department of Agricultural and Biological Systems Engineering: Dissertations, Theses, and Student Research

Chronic low back pain is a global socioeconomic crisis compounded by an absence of reliable, curative treatments. The predominant pathology associated with chronic low back pain is degeneration of intervertebral discs in the lumbar spine. During degeneration, nerves can sprout into the intervertebral disc tissue and be chronically subjected to inflammatory and mechanical stimuli, resulting in pain. Pain arising from the intervertebral disc, or disc-associated pain, is a complex, multi-faceted disorder which necessitates valid animal models to screen therapeutics and study pathomechanisms of pain.

While many research teams have created animal models of disc degeneration, the translation of these platforms …

Lost In Translation? Communicating Nutrition Science, Lindsay Yarabek Datlow

Doctor of Philosophy in Translational Health Sciences Dissertations

Diet is directly correlated with overall health; therefore, nutrition is a critical piece of the obesity-epidemic puzzle. The news media has become a primary source for nutrition information yet results from International Food Information Council surveys indicate that the majority of Americans view the nutrition news they read as inconsistent and confusing. Very recent inquiry provides empirical evidence that nutrition confusion could be fueled by media. Nutrition confusion has been causally linked to “nutrition backlash,” which is complete disregard for even the most strongly supported nutrition advice. Understanding how nutrition research is translated in the news media and the mechanisms …

Characterization And Assessment Of Barriers And Facilitators To The Decision-Making Process For Blood And Blood Donor Safety In The United States: A Collective Case Study, Lauren A. Crowder

Doctor of Philosophy in Translational Health Sciences Dissertations

Background: Over 16 million blood components are transfused to patients in need every year in the United States (Jones et al., 2021). Because of the reliance on human blood donors, the donation and transfusion of blood will always be associated with some level of risk for both donors and recipients; the tolerability of these risks may vary from stakeholder to stakeholder. While the U.S. Food and Drug Administration (FDA) concedes that attaining a blood supply with zero risk for transmission of infectious diseases may be unattainable (U.S. Food and Drug Administration, 2019), they continue to strive for the lowest …

Regulation Of Oxidative Phosphorylation Of Liver Mitochondria In Sepsis, Pierre Eyenga, Benjamin Rey, Lilia Eyenga, Shey-Shing Sheu

Center for Translational Medicine Faculty Papers

The link between liver dysfunction and decreased mitochondrial oxidative phosphorylation in sepsis has been clearly established in experimental models. Energy transduction is plastic: the efficiency of mitochondrial coupling collapses in the early stage of sepsis but is expected to increase during the recovery phases of sepsis. Among the mechanisms regulating the coupling efficiency of hepatic mitochondria, the slipping reactions at the cytochrome oxidase and ATP synthase seem to be a determining element, whereas other regulatory mechanisms such as those involving proton leakage across the mitochondrial membrane have not yet been formally proven in the context of sepsis. If the dysfunction …

Akt Inhibition In The Central Nervous System Induces Signaling Defects Resulting In Psychiatric Symptomatology, Apostolia-Maria Tsimberidou, Antonis Skliris, Alan Valentine, Jamie Shaw, Ursula Hering, Henry Hiep Vo, Tung On Chan, Roger S Armen, Jeffrey R Cottrell, Jen Q Pan, Philip N Tsichlis

Center for Translational Medicine Faculty Papers

Background: Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms.

Methods: (1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain. (2) We analyzed the results of earlier genome-wide association studies to determine the distribution of schizophrenia-associated single-nucleotide polymorphisms …

Potential Benefits Of Combined Statin And Metformin Therapy On Resistance Training Response In Older Individuals, Douglas E. Long, Kate Kosmac, Cory M. Dungan, Marcas M. Bamman, Charlotte A. Peterson, Phillip A. Kern

Clinical and Translational Science Faculty Publications

Metformin and statins are currently the focus of large clinical trials testing their ability to counter age-associated declines in health, but recent reports suggest that both may negatively affect skeletal muscle response to exercise. However, it has also been suggested that metformin may act as a possible protectant of statin-related muscle symptoms. The potential impact of combined drug use on the hypertrophic response to resistance exercise in healthy older adults has not been described. We present secondary statin analyses of data from the MASTERS trial where metformin blunted the hypertrophy response in healthy participants (>65 years) following 14 weeks …

Augmented Immunomodulation Of Endogenous Marrow-Derived Stem Cells In The Setting Of Acl Rupture, Mackenzie Fleischer, Michael Newton, Samantha Hartner, John A. Driscoll, Anthony Arveschoug, Chritopher C. Vasileff, Kevin Baker

Conference Presentation Abstracts

PURPOSE: Augmentation of MSC immunomodulation is an unexplored, potentially useful therapeutic to combat PTOA following ACLR. Lower kynurenine-to-tryptophan ratios observed in synovial fluid of ACL rupture (ACLR) rats suggests decreased activity of tryptophan metabolizing enzyme, Ido, known to be secreted by MSCs to promote T-reg expansion and Th17 suppression. This study aims to characterize the immunomodulatory capacity of pharmacologically mobilized MSCs in conjunction with exogenously delivered Ido. METHODS: Rats (N = 48) underwent ACLR to evaluate the effects of mobilized MCSs on Ido1 and inflammatory cytokine expression profiles in the synovial fluid. Additionally, rats (N = 160) underwent ACLR to …

Evaluating Simulation-Based Tobacco Treatment Scenarios For Providers Delivering Treatment For People Living With Mental Illnesses, Chizimuzo T. C. Okoli, Janet Otachi, Sarret Seng, Bassema Abufarsakh, Lovoria B. Williams

Clinical and Translational Science Faculty Publications

Background: People living with mental illnesses (PMI) experience elevated tobacco use and related morbidity and mortality. Despite the availability of effective and safe tobacco treatments along with evidence that PMI are motivated and able to quit successfully, few Mental and behavioral healthcare providers (MHPs) engage PMI in such treatment. MHPs may lack the confidence or skills to engage their clients in tobacco treatment. Currently, there are limited training modalities to prepare MHPs in delivering tobacco treatment for PMI. However, animated scenario-based simulated encounters can bridge this gap to effectively provide tailored MHP training to enhance treatment delivery. Hence, the purpose …

Tumor Suppressor Par-4 Regulates Complement Factor C3 And Obesity, Nathália Araujo, James Sledziona, Sunil K. Noothi, Ravshan Burikhanov, Nikhil Hebbar, Saptadwipa Ganguly, Tripti Shrestha-Bhattarai, Beibei Zhu, Wendy S. Katz, Yi Zhang, Barry S. Taylor, Jinze Liu, Li Chen, Heidi L. Weiss, Daheng He, Chi Wang, Andrew J. Morris, Lisa A. Cassis, Mariana N. Nikolova‑Karakashian, Prabhakara R. Nagareddy, Olle Melander, B. Mark Evers, Phillip A. Kern, Vivek M. Rangnekar

Clinical and Translational Science Faculty Publications

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4^-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4^-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed …

Aorta In Pathologies May Function As An Immune Organ By Upregulating Secretomes For Immune And Vascular Cell Activation, Differentiation And Trans-Differentiation-Early Secretomes May Serve As Drivers For Trained Immunity, Yifan Lu, Yu Sun, Keman Xu, Fatma Saaoud, Ying Shao, Charles Drummer, Sheng Wu, Wenhui Hu, Jun Yu, Satya P Kunapuli, John R Bethea, Roberto I Vazquez-Padron, Jianxin Sun, Xiaohua Jiang, Hong Wang, Xiaofeng Yang

Center for Translational Medicine Faculty Papers

To determine whether aorta becomes immune organ in pathologies, we performed transcriptomic analyses of six types of secretomic genes (SGs) in aorta and vascular cells and made the following findings: 1) 53.7% out of 21,306 human protein genes are classified into six secretomes, namely, canonical, caspase 1, caspase 4, exosome, Weibel-Palade body, and autophagy; 2) Atherosclerosis (AS), chronic kidney disease (CKD) and abdominal aortic aneurysm (AAA) modulate six secretomes in aortas; and Middle East Respiratory Syndrome Coronavirus (MERS-CoV, COVID-19 homologous) infected endothelial cells (ECs) and angiotensin-II (Ang-II) treated vascular smooth muscle cells (VSMCs) modulate six secretomes; 3) AS aortas upregulate …

Pkcε Activation Restores Loss Of Pkcε, Manganese Superoxide Dismutase, Vascular Endothelial Growth Factor, And Microvessels In Aged And Alzheimer's Disease Hippocampus, Guetchyn Millien, Huaixing Wang, Zongxiu Zhang, Dan L Alkon, Jarin Hongpaisan

Center for Translational Medicine Faculty Papers

Vascular endothelial dysfunction and capillary loss are currently considered to be a primary phenotype of normal human aging and Alzheimer's disease (AD). Activation of protein kinase C (PKCε) improves several molecular, cellular, physiological, and behavioral endpoints, yet it is not known whether a loss of PKCε activity occurs in the microvascular endothelium in aged and AD hippocampi, whether this loss contributes to microvascular change, or whether activation of PKCε protects against microvascular damage, an early change that induces age-associated memory defect and AD. We investigated the effect of the PKCε activation on microvascular loss in the hippocampus, important for memory …

Abi1 Mediates Airway Smooth Muscle Cell Proliferation And Airway Remodeling Via Jak2/Stat3 Signaling, Ruping Wang, Yinna Wang, Guoning Liao, Bohao Chen, Reynold A. Panettieri, Jr., Raymond B. Penn, Albany Medical College

Center for Translational Medicine Faculty Papers

Asthma is a complex pulmonary disorder with multiple pathological mechanisms. A key pathological feature of chronic asthma is airway remodeling, which is largely attributed to airway smooth muscle (ASM) hyperplasia that contributes to thickening of the airway wall and further drives asthma pathology. The cellular processes that mediate ASM cell proliferation are not completely elucidated. Using multiple approaches, we demonstrate that the adapter protein Abi1 (Abelson interactor 1) is upregulated in ∼50% of ASM cell cultures derived from patients with asthma. Loss-of-function studies demonstrate that Abi1 regulates the activation of Jak2 (Janus kinase 2) and STAT3 (signal transducers and activators …

29 M 6 A-Rna Methylation (Epitranscriptomic) Regulators Are Regulated In 41 Diseases Including Atherosclerosis And Tumors Potentially Via Ros Regulation - 102 Transcriptomic Dataset Analyses, Ming Liu, Keman Xu, Fatma Saaoud, Ying Shao, Ruijing Zhang, Yifan Lu, Yu Sun, Charles Drummer Iv, Li Li, Sheng Wu, Satya P Kunapuli, Gerard J Criner, Jianxin Sun, Huimin Shan, Xiaohua Jiang, Hong Wang, Xiaofeng Yang

Center for Translational Medicine Faculty Papers

We performed a database mining on 102 transcriptomic datasets for the expressions of 29 m6A-RNA methylation (epitranscriptomic) regulators (m6A-RMRs) in 41 diseases and cancers and made significant findings: (1) a few m6A-RMRs were upregulated; and most m6A-RMRs were downregulated in sepsis, acute respiratory distress syndrome, shock, and trauma; (2) half of 29 m6A-RMRs were downregulated in atherosclerosis; (3) inflammatory bowel disease and rheumatoid arthritis modulated m6A-RMRs more than lupus and psoriasis; (4) some organ failures shared eight upregulated m6A-RMRs; end-stage renal failure (ESRF) downregulated 85% of m6A-RMRs; (5) Middle-East respiratory syndrome coronavirus infections modulated m6A-RMRs the most among viral infections; …

Ovarian Cancer G Protein-Coupled Receptor 1 Inhibits A549 Cells Migration Through Casein Kinase 2Α Intronless Gene And Neutral Endopeptidase, Adhikarimayum Lakhikumar Sharma, Puyam Milan Meitei, Takhellambam Chanu Machathoibi, Naorem Tarundas Singh, Thiyam Ramsing Singh, Lisam Shanjukumar Singh

Center for Translational Medicine Faculty Papers

Background: We have previously reported that a new intronless gene for casein kinase 2α (CK2α), CSNK2A3, is expressed in human cells. The promoter of the well-known CK2α, CSNK2A1, displays characteristics of a housekeeping gene, whereas CSNK2A3 has a characteristic of a regulated promoter with two TATA boxes and a CAAT box. GPR68, a family of the G protein-coupled receptors, is also known as ovarian cancer G protein-coupled receptor 1 (OGR1). In the current study, we analyzed the roles of CK2α genes and neutral endopeptidase (NEP), a key enzyme that influences a variety of malignancies, in the OGR1-induced inhibition of A549 …

Retraction Note: Obesity-Induced Adipokine Imbalance Impairs Mouse Pulmonary Vascular Endothelial Function And Primes The Lung For Injury, Dilip Shah, Freddy Romero, Michelle Duong, Nadan Wang, Bishnuhari Paudyal, Benjamin T Suratt, Caleb B Kallen, Jianxin Sun, Ying Zhu, Kenneth Walsh, Ross Summer

Center for Translational Medicine Faculty Papers

The Authors have retracted this Article. Afer publication of this Article, concerns have been raised about irregularities in the western blot data. In particular, the following bands appear to be duplicated: – Fig. 1e HFD/p-Src lane 1 and 3; – Fig. 4c NCD/Ve-cadherin lane 1 and 3 – Fig. 5e HFD+APN/ICAM-1 lane 1 and 2 – Fig. 5f HFD/beta-catenin lane 2 and HFD+APN/beta-catenin lane 1 – Fig. S1d HFD/beta-catenin all lanes – Fig. S4c NCD/beta-catenin lane 1 and 3. Additionally, the beta-catenin subpanel in Fig. 5f was subsequently reused in another study [1] and described as showing GRP87. Te Authors …

Regulatory T Cells Control Effector T Cell Inflammation In Human Prediabetes, Rui Liu, Gabriella H. Pugh, Erin Tevonian, Katherine Thompson, Douglas A. Lauffenburger, Philip A. Kern, Barbara S. Nikolajczyk

Clinical and Translational Science Faculty Publications

A disparate array of plasma/serum markers provides evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and metaflammation. These remain largely nonactionable and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state. Regulatory T cells (Treg) control mitochondrial function and cytokine production by CD4+ effector T cells (Teff) in prediabetes and type 2 diabetes by supporting T helper (Th)17 or Th1 cytokine production, respectively. These data suggest …

Path To Publication: A Peer Mentorship Model For Student-Lead Surgical Research, Usama Waqar, Hareem Rauf, Muskaan Abdul Qadir, Hina Inam

Medical College Documents

Early and sustained involvement in research is imperative for medical students to ensure better career prospects in addition to provision of high-quality, evidence-based care to patients. However, involvement of students in surgical research still remains limited, owing to inadequate research training. The current paper was planned to describe the structure of the "Path to Publication" series, incorporating peer mentorship with capacity-building research workshops for medical students. A total of 25 students were grouped into 8 surgical subspecialty groups to conduct research, supervised by experienced student research and faculty mentors. In addition, a series of research workshops were organized in synchronization …

Crossroads Of Drug Abuse And Hiv Infection: Neurotoxicity And Cns Reservoir, Shilpa Sonti, Kratika Tyagi, Amit Pande, René Daniel, Adhikarimayum Lakhikumar Sharma, Mudit Tyagi

Center for Translational Medicine Faculty Papers

Drug abuse is a common comorbidity in people infected with HIV. HIV-infected individuals who abuse drugs are a key population who frequently experience suboptimal outcomes along the HIV continuum of care. A modest proportion of HIV-infected individuals develop HIV-associated neurocognitive issues, the severity of which further increases with drug abuse. Moreover, the tendency of the virus to go into latency in certain cellular reservoirs again complicates the elimination of HIV and HIV-associated illnesses. Antiretroviral therapy (ART) successfully decreased the overall viral load in infected people, yet it does not effectively eliminate the virus from all latent reservoirs. Although ART increased …

Optimizing Biomedical Discoveries As An Engine Of Culture Change In An Academic Medical Center, Anne K. Dechant, Stephen Fening, Michael Haag, William Harte, Mark R. Chance

Faculty Scholarship

Academic discovery in biomedicine is a growing enterprise with tens of billions of dollars in research funding available to universities and hospitals. Protecting and optimizing the resultant intellectual property is required in order for the discoveries to have an impact on society. To achieve that, institutions must create a multidisciplinary, collaborative system of review and support, and utilize connections to industry partners. In this study, we outline the efforts of Case Western Reserve University, coordinated through its Clinical and Translational Science Collaborative (CTSC), to promote entrepreneurial culture, and achieve goals of product development and startup formation for biomedical and population …