Translational Medical Research Commons^™

Twenty Novel Disease Group-Specific And 12 New Shared Macrophage Pathways In Eight Groups Of 34 Diseases Including 24 Inflammatory Organ Diseases And 10 Types Of Tumors., Bin Lai, Jiwei Wang, Alexander Fagenson, Yu Sun, Jason Saredy, Yifan Lu, Gayani Nanayakkara, William Y Yang, Daohai Yu, Ying Shao, Charles Drummer, Candice Johnson, Fatma Saaoud, Ruijing Zhang, Qian Yang, Keman Xu, Kevin Mastascusa, Ramon Cueto, Hangfei Fu, Susu Wu, Lizhe Sun, Peiqian Zhu, Xuebin Qin, Jun Yu, Daping Fan, Ying H Shen, Jianxin Sun, Thomas Rogers, Eric T Choi, Hong Wang, Xiaofeng Yang

Center for Translational Medicine Faculty Papers

The mechanisms underlying pathophysiological regulation of tissue macrophage (Mφ) subsets remain poorly understood. From the expression of 207 Mφ genes comprising 31 markers for 10 subsets, 45 transcription factors (TFs), 56 immunometabolism enzymes, 23 trained immunity (innate immune memory) enzymes, and 52 other genes in microarray data, we made the following findings. (1) When 34 inflammation diseases and tumor types were grouped into eight categories, there was differential expression of the 31 Mφ markers and 45 Mφ TFs, highlighted by 12 shared and 20 group-specific disease pathways. (2) Mφ in lung, liver, spleen, and intestine (LLSI-Mφ) express higher M1 Mφ …

Association Of Urine Levels Of C-Reactive Protein With Clinical Outcomes In Patients With Pneumonia: A Pilot Study, Subathra Marimuthu, Vidyulata Salunkhe, Stephen P. Furmanek, Leslie A Wolf

The University of Louisville Journal of Respiratory Infections

Finding relevant biomarkers as a potential predictor of severity for patients hospitalized with community acquired pneumonia (CAP), in addition to the clinical scoring system, could advance progress towards more effective patient management. The inflammatory marker, C-reactive protein (CRP), which is elevated in the pathogenesis of many infectious diseases, may be a key biomarker target for CAP. Previous studies have shown that serum CRP may be a useful diagnostic marker for pneumonia in hospitalized patients with acute respiratory symptoms. The main aims of this study were to determine the correlation between serum and urine CRP levels in hospitalized patients with CAP, …

Managing A Conflict-Related, Open Fracture With Drug-Resistant Infections: The Case Of A Wounded Syrian Refugee In The Hashemite Kingdom Of Jordan, Alex Green

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Uruc V, Ozden R, Duman IG, Dogramaci Y, Yengil E, Karapinar S, Karakus A, Kalaci A. Major musculoskeletal injuries and applied treatments in the current conflicts in Syria. Acta Medica Mediterranea. 2014;30(3):637-644.

Fondaparinux Is An Effective Alternative To Other Non-Heparin Anticoagulants In The Treatment Of Heparin-Induced Thrombocytopenia, Allan J. Brazier Jr.

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2014;125(6):924-929. doi: 10.1182/blood-2014-09-599498.

The Value Of Innovation To Implementation Program (Vi2p): A Strategic Approach To Aligning And Leveraging Academic Research And Clinical Care Missions, Jing Li, Mark V. Williams, Cecilia Page, Lisa A. Cassis, Philip A. Kern, Robert S. Dipaola

Clinical and Translational Science Faculty Publications

Problem: Inefficient implementation of evidence-based care garners increasing attention as a source of suboptimal value of clinical care, and integration of quality improvement methodology into clinical practice represents a potential solution. Academic medical centers (AMCs) often have expertise in implementation science, yet it is not leveraged effectively to solve operational inefficiencies or to rapidly implement evidence-based practices (EBPs).

Approach: To leverage in-house research expertise, the University of Kentucky (UK) College of Medicine and Center for Health Services Research (CHSR) launched a pilot awards program—Value of Innovation to Implementation Program (VI2P)—across its health system and six health professional colleges. Criteria for …

Amantadine Minimally Improves Arousal In Patients With Severe Traumatic Brain Injury, Michelle Eventov

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Giacino JT, Whyte J, Bagiella E, et al. Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain Injury. New England Journal of Medicine. 2012;366(9):819-826. doi: 10.1056/nejmoa1102609.

Gsk3Β-Dependent Phosphorylation Of Cypd And Regulation Of Mptp Opening During Myocardial Infarction, Stephen Hurst, Ludovic Gomez, Shey-Shing Sheu

Center for Translational Medicine Posters

Background

Mitochondrial calcium overload and oxidative stress during ischemia reperfusion (I/R) injury remains a major obstacle during percutaneous coronary intervention after acute myocardial infarction. It often leads to an increased susceptibility for mitochondria permeability transition pore (mPTP) opening leading to cell death. Mitochondrial calcium overload and ROS have been identified as key triggers to open the mPTP for over 30 years, yet the exact mechanism has remained elusive. Additionally, glycogen synthase kinase 3β; (GSK-3β;) is proposed as one of the key molecules that regulate mitochondrial dysfunction and injury during I/R. Indeed inhibition of GSK-3β has been shown to be required …

Pyk2 Expression And Localization In Cardiac Mitochondria And Its Role In Mitochondrial Calcium Regulation, Ariele Baggett, Celia Fernandez-Sanz, Sergio De La Fuente, Johannes Hoek, Shey-Shing Sheu

Center for Translational Medicine Posters

TRPM2 is a non-selective cation channel located in the plasma membrane of the cell. Upon activation, the channel opens, allowing calcium to enter into the cytosol of the cell, leading ultimately to the phosphorylation and activation of the enzyme Pyk2 (proline-rich tyrosine kinase 2). Once phosphorylated, Pyk2 translocates from the cytosol to the mitochondria, where it regulates the formation of the pore component of the mitochondrial calcium uniporter (MCU) complex. Consequently, this interaction is a key factor in mitochondrial calcium uptake and therefore mitochondrial bioenergetics.

Metformin Blunts Muscle Hypertrophy In Response To Progressive Resistance Exercise Training In Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial: The Masters Trial, R. Grace Walton, Cory M. Dungan, Douglas E. Long, S. Craig Tuggle, Kate Kosmac, Bailey D. Peck, Heather M. Bush, Alejandro G. Villasante Tezanos, Gerald Mcgwin, Samuel T. Windham, Fernando Ovalle, Marcas M. Bamman, Philip A. Kern, Charlotte A. Peterson

Clinical and Translational Science Faculty Publications

Progressive resistance exercise training (PRT) is the most effective known intervention for combating aging skeletal muscle atrophy. However, the hypertrophic response to PRT is variable, and this may be due to muscle inflammation susceptibility. Metformin reduces inflammation, so we hypothesized that metformin would augment the muscle response to PRT in healthy women and men aged 65 and older. In a randomized, double-blind trial, participants received 1,700 mg/day metformin (N = 46) or placebo (N = 48) throughout the study, and all subjects performed 14 weeks of supervised PRT. Although responses to PRT varied, placebo gained more lean body …

Reflection: Reducing Long-Term Mortality In Suicidal Adolescents, Nina R. Bihani

Clinical Research in Practice: The Journal of Team Hippocrates

A transformative method to reducing mortality in suicidal adolescents involves a novel approach of educating and empowering their loved ones.

Reduced Doses Of Direct Oral Anticoagulation Are Safe In Atrial Fibrillation Patients With Mild Thrombocytopenia, Matthew Gross

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Janion-Sadowska A, Papuga-Szela E, Łukaszuk R, et al. Non–Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation and Thrombocytopenia. Journal of Cardiovascular Pharmacology. 2018;72(3):153-160. doi: 10.1097/fjc.0000000000000607

Nsaid Use Increases Risk Of Miscarriage In Early Pregnancy, Leigh Durudogan

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Li D, Ferber J, Odouli R, Quesenberry C. Use of nonsteroidal anti-inflammatory drugs during pregnancy and the risk of miscarriage. Am J Ob Gyn. 2018; 219(3): 275.e1–275.e8. doi: 10.1016/j.ajog.2018.06.002.

Fecal Microbiota Therapy In Recurrent And Refractory Clostridium Difficile Infections Has Been Associated With Positive Results In Immunocompromised Patients, Eric Applebach

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. The American Journal of Gastroenterology, 2014;109(7):1065-71. doi: 10.1038/ajg.2014.133

Intravenous Iodinated Contrast Is Not Associated With Acute Kidney Injury In Adult Patients With Nephrotic Syndrome, Andrew Bacyinski

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Tao SM, Kong X, Schoepf UJ, et al. Acute kidney injury in patients with nephrotic syndrome undergoing contrast-enhanced CT for suspected venous thromboembolism: a propensity score-matched retrospective cohort study. European Radiology. 2018;28(4):1585-1593. doi: 10.1007/s00330-017-5109-0

Getting Sexual And Gender Minority Health “Into The Brick And Mortar”: A Mixed Methods Implementation Study, Mandi Pratt-Chapman

Doctor of Philosophy in Translational Health Sciences Dissertations

Sexual and gender minorities (SGM) have unique health risks and health care needs, but medical students receive little training on SGM health (Obedin-Maliver, et al., 2011). This mixed methods study sought to learn from curricular champions in diverse settings to apply lessons learned at the George Washington University (GW). Exploratory models that included eight potential predictor variables for six criterion variables were tested using multiple linear regression. Criterion variables were: knowledge, attitudes, and clinical preparedness measured by the Lesbian, Gay, Bisexual, and Transgender Development of Clinical Skills Scale (LGBT-DOCSS; Bidell, 2017); attitudes measured by the Attitudes Toward LGBT Patients Scale …

Carvedilol Is Not Superior To Metoprolol For Heart Failure Patients When Given At Equivalent Doses, Adam Gorman

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Lazarus DL, Jackevicius CA, Behlouli H, et al. Population-Based Analysis of Class Effect of β Blockers in Heart Failure. The American Journal of Cardiology 2011;107(8):1196-1202. doi: 10.1016/j.amjcard.2010.12.017.

Weighing Harms, Benefits, And Alternatives For A Young Man With A Recent Flare Of Ulcerative Colitis, Louise B. Welsh

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Sandborn WJ, Su C, Sands B, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2017 May 4;376(18):1723-1736. doi: 10.1056/NEJMoa1606910

Thrombosis Prevention In Atrial Fibrillation With Concomitant Cirrhosis: Oral Anticoagulation May Not Be Worth The Risks, Madeline Berschback

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Kuo L, Chao TF, Liu CJ, et al. Liver cirrhosis in patients with atrial fibrillation: Would oral anticoagulation have a net clinical benefit for stroke prevention? J Am Heart Assoc. 2017;6(6):e005307. doi: 10.1161/jaha.116.005307

Andexanet Alfa Is An Effective Reversal Agent For Factor Xa Inhibitors In Patients That Develop Intracranial Hemorrhage, Joseph Friedli

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-1141. doi: 10.1056/NEJMoa1607887.

Cannabidiol Is Beneficial In Management Of Drug-Resistant Dravet Syndrome, Nikita Desai

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Devinsky O, Cross H, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017;376(21):2011-2020. doi: 10.1056/NEJMoa1611618.

Agenesis Of The Corpus Callosum Is Associated With Developmental Delay And Intellectual Disability, Quinton J. Mandle

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Romaniello R, Marelli S, Giorda R, et al. Clinical characterization, genetics, and long-term follow-up of a large cohort of patients with agenesis of the corpus callosum. Journal of Child Neurology, 2016;32(1):60-71. doi: 10.1177/0883073816664668.

Ranolazine Decreases Weekly Anginal Episodes In Patients With Chronic Stable Angina And Type 2 Diabetes, Hisham Kaddurah

Clinical Research in Practice: The Journal of Team Hippocrates

The author reflects on the meaningful difference between statistical and clinical significance.

Tevar Should Be Considered In Select Patients With Uncomplicated Stanford Type B Aortic Dissection, Mordechai G. Sadowsky

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Nienaber CA, Kische S, Rousseau H, et al. Endovascular repair of type B aortic dissection: long-term results of the randomized investigation of stent grafts in aortic dissection trial. Circ Cardiovasc Interv, 2013;6(4):407-16. doi: 10.1161/circinterventions.113.000463.

Insights Into The Hiv Latency And The Role Of Cytokines., Joseph Hokello, Adhikarimayum Lakhikumar Sharma, Manjari Dimri, Mudit Tyagi

Center for Translational Medicine Faculty Papers

Human immunodeficiency virus-1 (HIV-1) has the ability to infect latently at the level of individual CD4+ cells. Latent HIV-1 proviruses are transcriptionally silent and immunologically inert, but are still capable of reactivating productive lytic infection following cellular activation. These latent viruses are the main obstacle in the eradication of HIV-1, because current HIV-1 treatment regimens are ineffective against them. Normal immunological response against an antigen activates CD4+ naïve T cells. The activated CD4+ naïve T cells undergo cell cycle, resulting in further transformation and profound proliferation to form effector CD4+ T-cells. Notably, in HIV-1 infected individuals, some of the effector …

Fatty Acid Metabolites Combine With Reduced Β Oxidation To Activate Th17 Inflammation In Human Type 2 Diabetes, Dequina A. Nicholas, Elizabeth A. Proctor, Madhur Agrawal, Anna C. Belkina, James M. Van Nostrand, Leena Panneerseelan-Bharath, Albert R. Jones Iv, Forum Raval, Blanche C. Ip, Min Zhu, Jose M. Cacicedo, Chloe Habib, Nestor Sanez-Rueda, Leah Persky, Patrick G. Sullivan, Barbara E. Corkey, Caroline M. Apovian, Philip A. Kern, Douglas A. Lauffenburger, Barbara S. Nikolajczyk

Clinical and Translational Science Faculty Publications

Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondrial function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation. However, glycolysis was not critical for …

Mechanisms Of Simvastatin Myotoxicity: The Role Of Autophagy Flux Inhibition., Arya Emami, Shahla Shojaei, Simone C. Da Silva Rosa, Mahmoud Aghaei, Ehsan Samiei, Amir Reza Vosoughi, Forouh Kalantari, Philip Kawalec, James Thliveris, Pawan Sharma, Amir A. Zeki, Mohsen Akbari, Joseph W. Gordon, Saeid Ghavami

Center for Translational Medicine Faculty Papers

Statins are some of the most widely used drugs worldwide, but one of their major side effects is myotoxicity. Using mouse myoblast (C2C12) and human alveolar rhabdomyosarcoma cell lines (RH30) in both 2-dimensional (2D) and 3-dimensional (3D) cell culture, we investigated the mechanisms of simvastatin's myotoxicity. We found that simvastatin significantly reduced cell viability in C2C12 cells compared to RH30 cells. However, simvastatin induced greater apoptosis in RH30 compared to C2C12 cells. Simvastatin-induced cell death is dependent on geranylgeranyl pyrophosphate (GGPP) in C2C12 cells, while in RH30 cells it is dependent on both farnesyl pyrophosphate (FPP) and GGPP. Simvastatin inhibited …

Developing Drug Therapies: Cognitive Damage In Mice Following Brain Radiation, Rachel Yuska

The Journal of Purdue Undergraduate Research

Pediatric brain cancer patients are at a high risk for radiation-induced cognitive impairment due to white matter changes in the brain. Half of six-month radiotherapy survivors develop significant changes in white matter. Previous research has shown that a mouse model can be used to show similar cognitive and behavioral deficits in human patients. The purpose of this work is to evaluate the effectiveness of two drug therapies, Donepezil and 3,3-Diindolylmethane (DIM), that could be used to either protect the brain from radiation injury or cure the cognitive injury and behavioral deficits that result from whole-brain irradiation. This project consisted of …

P53r245w Mutation Elicits Metastatic Phenotype In Pten Deficient Prostate Cancer, Ky Pham

Dissertations and Theses (Open Access)

Trp53 mutations are the most frequent genetic alterations in prostate cancer and are associated with more aggressive disease and worse overall survival. The majority of Trp53 mutations in prostate cancer are missense mutations, resulting in amino acid substitutions with profound effect. In addition to the loss of wild type function, missense mutations in Trp53 result in a gain-of-function (GOF) phenotype. This GOF phenotype confers biologic advantages to the tumor cells, enabling them to metastasize and invade distant organs. In this study, we generated mice carrying a conditional prostate-specific p53R245W mutant and Pten deletion to access the role of this common …

Spg7 Targets The M-Aaa Protease Complex To Process Mcu For Uniporter Assembly, Ca2 Influx, And Regulation Of Mitochondrial Permeability Transition Pore Opening, Stephen Hurst, Ariele Baggett, György Csordás, Shey-Shing Sheu

Center for Translational Medicine Faculty Papers

The mitochondrial matrix ATPase associated with diverse cellular activities (m-AAA) protease spastic paraplegia 7 (SPG7) has been recently implicated as either a negative or positive regulatory component of the mitochondrial permeability transition pore (mPTP) by two research groups. To address this controversy, we investigated possible mechanisms that explain the discrepancies between these two studies. We found that loss of the SPG7 gene increased resistance to Ca²-induced mPTP opening. However, this occurs independently of cyclophilin D (cyclosporine A insensitive) rather it is through decreased mitochondrial Ca² concentrations and subsequent adaptations mediated by impaired formation of functional mitochondrial Ca …

Matrix Metalloproteinase Activity In The Lung Is Increased In Hermansky-Pudlak Syndrome., Ross Summer, Rachana Krishna, Deleila Schriner, Karina Cuevas-Mora, Dominic Sales, Rachel Para, Jesse Roman, Carl Nieweld, Bernadette R. Gochuico, Freddy Romero

Center for Translational Medicine Faculty Papers

BACKGROUND: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction and can sometimes lead to a highly aggressive form of pulmonary fibrosis that mimics the fatal lung condition called idiopathic pulmonary fibrosis (IPF). Although the activities of various matrix metalloproteinases (MMPs) are known to be dysregulated in IPF, it remains to be determined whether similar changes in these enzymes can be detected in HPS.

RESULTS: Here, we show that transcript and protein levels as well as enzymatic activities of MMP-2 and -9 are markedly increased in the lungs of mice carrying the HPS …