Translational Medical Research Commons^™

Hdac6 Inhibition Reverses Long-Term Doxorubicin-Induced Cognitive Dysfunction By Restoring Microglia Homeostasis, Blake Mcalpin

Dissertations and Theses (Open Access)

One in 8 women in the US will be diagnosed with breast cancer. Currently, doxorubicin is one of the most effective chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed, and executive functioning. Currently, no interventions for CICD have been approved by the US Food and Drug Administration. I show here that a 14-day treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor successfully reverses long-term CICD following a therapeutic doxorubicin dosing schedule in female mice, as assessed by the puzzle box test …

Development And Application Of 3d Kinematic Methodologies For Biomechanical Modelling In Adaptive Sports And Rehabilitation, Anne Marie Severyn

All Dissertations

Biomechanical analysis is widely used to assess human movement sciences, specifically using three-dimensional motion capture modelling. There are unprecedented opportunities to increase quantitative knowledge of rehabilitation and recreation for disadvantaged population groups. Specifically, 3D models and movement profiles for human gait analysis were generated with emphasis on post-stroke patients, with direct model translation to analyze equivalent measurements while horseback riding in use of the alternative form of rehabilitation, equine assisted activities and therapies (EAAT) or hippotherapy (HPOT). Significant improvements in gait symmetry and velocity were found within an inpatient rehabilitation setting for patients following a stroke, and the developed movement …

Insulin Therapy Versus Oral Sitagliptin For Treatment Of Latent Autoimmune Diabetes In Adults, Sarah Nasser

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Hals IK, Fiskvik Fleiner H, Reimers N, et al. Investigating optimal β-cell-preserving treatment in latent autoimmune diabetes in adults: Results from a 21-month randomized trial. Diabetes Obes Metab. 2019;21(10):2219-2227. https://doi.org/10.1111/dom.13797

for a patient with an aversion to needles.

Indications For Esophagogastroduodenoscopy In Anemic Patients Without Overt Signs Of Upper Gastrointestinal Bleeding, Geoffrey M. Ginter

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Majid S, Salih M, Wasaya R, Jafri W. Predictors of gastrointestinal lesions on endoscopy in iron deficiency anemia without gastrointestinal symptoms. BMC Gastroenterol. 2008;8:52. https://doi.org/10.1186/1471-230X-8-52

for a patient with a complicated presentation of severe anemia

Exercise Therapy Improves Quality Of Life In Patients With Postural Orthostatic Tachycardia Syndrome (Pots), Heya Batah, Scott L. Baughan

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using

George SA, Bivens TB, Howden EJ, et al. The international POTS registry: Evaluating the efficacy of an exercise training intervention in a community setting. Heart Rhythm. 2016;13(4):943-950. https://doi.org/10.1016/j.hrthm.2015.12.012

for exercise efficacy in patients with POTS.

Sotrovimab: Neutralizing Antibody To Combat Covid-19, Aya Allam, Steven Lippmann

The University of Louisville Journal of Respiratory Infections

No abstract provided.

Are Antipyretic Medications Compatible With Sars-Cov-2 Vaccines?, Sharanya S E Santhi, Niguma Rayamajhi, Steven B Lippmann

The University of Louisville Journal of Respiratory Infections

No abstract provided.

Leptospirosis Presenting As Diffuse Alveolar Hemorrhage, Alejandra González, Paola Alvarez, Mariano Fielli, Analia Santos, Neil Gomez Querales, Elkin Rodriguez Arzuaga

The University of Louisville Journal of Respiratory Infections

Diffuse alveolar hemorrhage (DAH) syndrome has a mortality rate of 30 to 60%. A 15-year-old male patient presented with a seven-day abdominal pain, vomiting, non-dysenteric diarrhea, conjunctival injection, and fever. Chest radiography revealed bilateral interstitial infiltrates predominating in the lower left lobe. The patient’s condition worsened within hours, with the development of massive hemoptysis, acute respiratory distress syndrome (ARDS), arterial hypotension, and hematocrit decline requiring mechanical ventilation. A chest computed tomography (CT) showed ground-glass opacities with consolidation areas in lower lobes, diffuse tree-in-bud opacities, and centrilobular nodules. A bronchoscopy was conducted without endoluminal lesions and bronchoalveolar lavage (BAL) consistent with …

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 …

Mucormycosis: Covid-19 And Corticosteroids, Mittal Savaliya, Nivedita Jha, Steven B Lippmann

The University of Louisville Journal of Respiratory Infections

No abstract provided.

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 …

Pulmonary Post-Acute Sequelae Of Covid-19, Usman Akbar, Shivam Gulati, Johnny Zakhour Md, Alex Glynn, Jose Bordon

The University of Louisville Journal of Respiratory Infections

Introduction: Persistent symptoms have been observed in a substantial proportion of survivors of COVID-19 since relatively early in the pandemic. Among these post-acute sequelae of COVID-19 (PASC), respiratory symptoms appear to be the most prevalent.

Methods: We conducted a literature review of peer-reviewed publications in English on the clinical and epidemiological features of respiratory PASC in cohorts of 100 or more patients with a follow-up of four weeks or more after acute infection. Included studies reported the prevalence of persistent respiratory symptoms and/or the results of follow-up pulmonary function tests.

Results: On our review included 14 studies across eight countries …

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 …

Compliance With Guidelines For Treatment Of Staphylococcus Aureus Bacteremia Is Associated With Decreased Mortality In Patients Hospitalized For Community-Acquired Pneumonia With Staphylococcus Aureus Bacteremia, Leslie Beavin, Vidyulata Salunkhe, Shashvin Singh, Ahmed Gana, Balaji Sekaran, Mahder A. Tella, Stephen P. Furmanek, Forest W. Arnold

The University of Louisville Journal of Respiratory Infections

Introduction: Staphylococcus aureus bacteremia has a minimum treatment duration of two weeks, while S. aureus community-acquired pneumonia (CAP) treatment is at least five days. Treatment failure, persistent bacteremia, and recurrence are common among patients with community-acquired S. aureus bacteremia. There is conflicting information in the current Infectious Diseases Society of America (IDSA) guidelines for the treatment of S.aureus bacteremia patients with CAP. Therefore, the appropriate treatment duration and modality for S. aureus CAP with bacteremia is unclear. The objective of this study was to compare outcomes among patients with S. aureus CAP and bacteremia treated in compliance versus non-compliance with …

Spatial Transcriptomics Of Dorsal Root Ganglia Identifies Molecular Signatures Of Human Nociceptors, Diana Tavares-Ferreira, Stephanie Shiers, Pradipta R Ray, Andi Wangzhou, Vivekanand Jeevakumar, Ishwarya Sankaranarayanan, Anna M Cervantes, Jeffrey C Reese, Alexander Chamessian, Bryan A Copits, Patrick M Dougherty, Robert W Gereau, Michael D Burton, Gregory Dussor, Theodore J Price

Faculty, Staff and Student Publications

Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG …

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; …