Translational Medical Research Commons^™

Cyclin D1-Mediated Microrna Expression Signature Predicts Breast Cancer Outcome, Guangxue Wang, Michael Gormley, Jing Qiao, Qian Zhao, Min Wang, Gabriele Disante, Shengqiong Deng, Lin Dong, Timothy G. Pestell, Xiaoming Ju, Mathew C. Casimiro, Sankar Addya, Adam Ertel, Ayden Tozeren, Qinchuan Li, Zuoren Yu, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood.

Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes.

Results: Hierarchical clustering of …

Α-Catenin-Dependent Cytoskeletal Tension Controls Yap Activity In The Heart., Alexia Vite, Caimei Zhang, Roslyn Yi, Sabrina Emms, Glenn L. Radice

Center for Translational Medicine Faculty Papers

Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. At the same time, the N-cadherin/catenin cell adhesion complex accumulates at the cell termini, creating a specialized type of cell-cell contact called the intercalated disc (ICD). To investigate the relationship between ICD maturation and proliferation, αE-catenin (Ctnna1) and αT-catenin (Ctnna3) genes were deleted to generate cardiac-specific α-catenin double knockout (DKO) mice. DKO mice exhibited aberrant N-cadherin expression, mislocalized actomyosin activity and increased cardiomyocyte proliferation that was dependent on Yap activity. To assess effects on tension, cardiomyocytes were cultured on deformable polyacrylamide hydrogels of varying stiffness. When …

Human Body Composition And Immunity: Visceral Adipose Tissue Produces Il-15 And Muscle Strength Inversely Correlates With Nk Cell Function In Elderly Humans, Ahmad Al-Attar, Steven R. Presnell, Jody L. Clasey, Douglas E. Long, R. Grace Walton, Morgan Sexton, Marlene E. Starr, Philip A. Kern, Charlotte A. Peterson, Charles T. Lutz

Clinical and Translational Science Faculty Publications

Natural killer (NK) lymphocyte-mediated cytotoxicity and cytokine secretion control infections and cancers, but these crucial activities decline with age. NK cell development, homeostasis, and function require IL-15 and its chaperone, IL-15 receptor alpha (IL-15Rα). Macrophages and dendritic cells (DC) are major sources of these proteins. We had previously postulated that additional IL-15 and IL-15Rα is made by skeletal muscle and adipose tissue. These sources may be important in aging, when IL-15-producing immune cells decline. NK cells circulate through adipose tissue, where they may be exposed to local IL-15. The objectives of this work were to determine (1) if human muscle, …

The Pharmacogene Variation (Pharmvar) Consortium: Incorporation Of The Human Cytochrome P450 (Cyp) Allele Nomenclature Database, Andrea Gaedigk, Magnus Ingelman-Sundberg, Neil A. Miller, J Steven Leeder, Michelle Whirl-Carrillo, Teri E. Klein

Manuscripts, Articles, Book Chapters and Other Papers

The Human Cytochrome P450 (CYP) Allele Nomenclature Database, a critical resource to the pharmacogenetics and genomics communities, will be transitioning to the Pharmacogene Variation (PharmVar) Consortium. In this report we provide a summary of the current database, provide an overview of the PharmVar consortium and highlight the PharmVar database which will serve as the new home for pharmacogene nomenclature.

Disparities In Healthcare Coverage And Utilization After Expanded Dependent Coverage, Tina Hernandez-Boussard, Doug E. Morrison, Lu Tian, Sanjay Basu

Journal of Health Disparities Research and Practice

Background. A goal of expanding insurance coverage is reducing racial disparities in healthcare utilization, however the effects of such expansions under the affordable care act (ACA) on disparities remain unclear. The 2010 dependent coverage expansion provided an opportunity to evaluate disparities following a major coverage expansion.

Objectives. We sought to understand changes in emergency department (ED)utilization following a major insurance expansion, the 2010 dependent coverage expansion.

Research Design. We present changes in coverage and utilization among young adults (19-25 years old) before and after the dependent coverage expansion, compared to a control group (26-31 years old) unaffected …

Patient-Provider Race And Sex Concordance: New Insights Into Antibiotic Prescribing For Acute Bronchitis, Jake R. Morgan, Mari-Lynn Drainoni, Cindy Christiansen, Tamar F. Barlam

Journal of Health Disparities Research and Practice

Objective: To examine whether patient and provider concordance by sex or race predicts antibiotic prescribing for acute bronchitis.

Study setting: General Internal Medicine and Family Medicine adult clinics at a large safety-net hospital.

Study design: We used a logistic model of prescribing as a function of race and sex concordance.

Data extraction: Data were extracted from de-identified patient records for those with an acute bronchitis visit between 2008 and 2010.

Principal findings: 71% (95% CI 68%-73%) of visits resulted in an antibiotic prescription. Patients in race-concordant visits were 17% (95% CI 8%-25%) less likely to receive …

Calidad De Vida: An Exploratory Investigation Of Latino Breast Cancer Survivors And Intimate Partners, Sejal Barden, Daniel Gutierrez, Jessica Gonzalez, Shainna Ali

Journal of Health Disparities Research and Practice

Advances in addressing psychosocial issues related to cancer treatment and prevention are not reaching all survivors equally. Latina breast cancer survivors and intimate partners are underrepresented in psychosocial interventions, and there is a scarcity of research on the influence of cancer on Latino couples’ quality of life. The purpose of this manuscript is to present findings from a trans-linguistic, dyadic qualitative research study aimed at exploring the influence of cancer on quality of life for Latina breast cancer survivors and their intimate partners. Results highlight several areas that are helpful and hindering to supporting survivorship.

Acute Pressor Response To Psychosocial Stress Is Dependent On Endothelium‐Derived Endothelin‐1, Brandon M. Fox, Bryan K. Becker, Analia S. Loria, Kelly A. Hyndman, Chunhua Jin, Hannah Clark, Robin Johns, Masashi Yanagisawa, David M. Pollock, Jennifer S. Pollock

Pharmacology and Nutritional Sciences Faculty Publications

Background

Acute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor.

Methods and Results

Adult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in …

Coronary Stents—The Role Of Experience And Evidence In Making Clinical Decisions, Elise Anderson, Aria Ganz-Waple, Nikola Rakic, Eric Blake, Destiny Kellam, Nadeen Mansour, David Aguilar, Jessica A. Johns, Jerry Chen

Clinical Research in Practice: The Journal of Team Hippocrates

The authors reflect on the charge placed on future medical practitioners given evolving standards of care.

Intra-Articular Tranexamic Acid During Total Knee Arthroplasty, Ahmed F. Khan

Clinical Research in Practice: The Journal of Team Hippocrates

An informed consent conversation regarding bleeding risk prior to total knee arthroplasty in an elderly patient with chronic kidney disease.

Mechanical Pleurodesis Is Not A Contraindication To Lung Transplantation, Alexa Thibodeau

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Shigemura N, Bhama J, Gries CJ, et al. Lung transplantation in patients with prior cardiothoracic surgical procedures. American Journal of Transplantation. 2012;12(5):1249-1255. doi: 10.1111/j.1600-6143.2011.03946.x

Closure Of Patent Foramen Ovale Or Medical Therapy Alone Are Both Appropriate Choices For Preventing Recurrent Cryptogenic Strokes, Kevin Juan Zhang

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Carroll JD, Saver JL, Thaler DE, et al. Closure of Patent Foramen Ovale versus Medical Therapy after Cryptogenic Stroke. N Engl J Med, 2013;368(12):1092-1100. doi:10.1056/nejmoa1301440.

Multiple Doctors, Different Recommendations For Multiloculated Pyogenic Hepatic Abscesses, Eric Gr Kim

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Hope WW, Vrochides DV, Newcomb WL, Mayo-Smith WW, Iannitti DA. Optimal treatment of hepatic abscess. The American Surgeon. 2008 Feb;74(2):178-82. doi: 10.1016/j.jamcollsurg.2010.03.004

Cognitive Behavioral Therapy For Patients With Psychogenic Non-Epileptic Seizures, Andrew Brown

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Goldstein L., Chalder T., et al. Cognitive-behavioral therapy for psychogenic non-epileptic seizures: A pilot RCT. Neurology. 2010;74(24):1986-1994. doi: 10.1212/WNL.0b013e3181e39658

From The Editor: Demonstrating Implementation Of Clinical Research Into Clinical Practice, James Peter Meza

Clinical Research in Practice: The Journal of Team Hippocrates

The editor stresses that learning to apply scientific research to clinical decision-making is not a formulaic endeavor.

Rad Gtpase Deletion Atenuates Post-Ischemic Cardiac Dysfunction And Remodeling, Janet R. Manning, Lakshman Chelvarajan, Bryana R. Levitan, Catherine Nicole Kaminski Withers, Prabhakara R. Nagareddy, Christopher M. Haggerty, Brandon K. Fornwalt, Erhe Gao, Himi Tripathi, Ahmed Abdel-Latif, Douglas A. Andres, Jonathan Satin

Physiology Faculty Publications

The protein Rad interacts with the L-type calcium channel complex to modulate trigger Ca²⁺ and hence to govern contractility. Reducing Rad levels increases cardiac output. Ablation of Rad also attenuated the inflammatory response following acute myocardial infarction. Future studies to target deletion of Rad in the heart could be conducted to establish a novel treatment paradigm whereby pathologically stressed hearts would be given safe, stable positive inotropic support without arrhythmias and without pathological structural remodeling. Future investigations will also focus on establishing inhibitors of Rad and testing the efficacy of Rad deletion in cardioprotection relative to the time of …

Microrna 1207-3p In Prostate Cancer, Dibash Das

Dissertations, Theses, and Capstone Projects

Prostate cancer (PCa) is the most commonly diagnosed male cancer and the second leading cause of cancer-related death for men in the United States. Understanding the molecular mechanisms involved in progression from the asymptomatic androgen-dependent PCa to the lethal castration resistant prostate cancer (CRPC) is a major challenge. MicroRNAs (miRNAs), are known to be dysregulated in PCa. MicroRNA-1207-3p (miR-1207-3p) is encoded by the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of miR-1207-3p in PCa is unclear. We have discovered that miR-1207-3p is significantly underexpressed in PCa cell lines …

Implementation Of A Low-Cost Unna Boot Alternative As Adjunctive Treatment For Kaposi Sarcoma, Alexander Robert Mills, Edith Tonui, Sonak Pastakia, Rakhi Karwa, Phelix Were

Engagement & Service-Learning Summit

There are 6 million people living with HIV; 70% reside in Sub-Saharan Africa (SSA). Furthermore, 1.1 million deaths occur due to opportunistic infections (OIs) that can be minimized with antiretroviral therapy. In Kenya, Kaposi Sarcoma (KS) is an especially debilitating OI that presents with dermatologic lesions; magnifying the stigma that patients with HIV face physically and psychosocially. Dermatology research is underway to determine the effectiveness of an unna boot (medicated, layered compression dressing) to speed the healing of these lesions with anecdotal success. Commercially available unna boot products are too expensive and not readily available in SSA. Clinicians from Purdue …

Beta-Catenin Cleavage Enhances Transcriptional Activation, Tatiana Goretsky, Emily M. Bradford, Qing Ye, Olivia F. Lamping, Tomas Vanagunas, Mary Pat Moyer, Patrick C. Keller, Preetika Sinh, Josep M. Llovet, Tianyan Gao, Qing-Bai She, Linheng Li, Terrence A. Barrett

Internal Medicine Faculty Publications

Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat⁵⁵²). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat⁵⁵², increased to the exclusion of full size (FS) forms of β-catenin. LMW β-catenin lacks both termini, leaving residues in the armadillo repeat intact. Further experiments showed that TCF4 predominantly binds LMW pβ-Cat⁵⁵² in the nucleus of inflamed and …

Two Case Examples Of Reaching The Hard-To-Reach: Low Income Minority And Lgbt Individuals, Tricia K. Gatlin, Michael J. Johnson

Journal of Health Disparities Research and Practice

‘Hard-to-reach’ is a term primarily used by researchers to describe groups of people who have been historically difficult to find or contact. It is important for the public interest to include hard-to-reach groups in research because excluding certain sub-populations diminishes the ability to identify groups that potentially have the highest burden of illness and to develop an understanding of why group differences exist. Thus, the purposes of this paper are to: 1) describe the challenges in recruiting hard-to-reach population in two separate research studies; 2) discuss the strategies that were used to overcome those challenges; and 3) provide recommendations for …

Examining Differences In Hpv Awareness And Knowledge And Hpv Vaccine Awareness And Acceptability Between U.S. Hispanic And Island Puerto Rican Women, Daisy Y. Morales-Campos Phd, Robin Vanderpool

Journal of Health Disparities Research and Practice

Background: In 2015, only 42% of Puerto Rican (PR) girls aged 13-17 and 44% of U.S. Hispanic girls aged 13-17 were vaccinated with all three Human Papillomavirus (HPV) vaccine doses. These percentages were far lower than the Healthy People 2020 goal of 80% of girls aged 13-15 completing the vaccine series. The purpose of this study was to examine potential differences in HPV awareness and knowledge and HPV vaccine awareness and acceptability between a population-based sample of U.S. Hispanic and island Puerto Rican women.

Methods: We restricted our analyses to female respondents from the Health Information National Trends Survey (HINTS) …

Self-Reported Vs. Measured Height, Weight, And Bmi In Young Adults, Melissa D. Olfert, Makenzie L. Barr, Camille M. Charlier, Oluremi A. Famodu, Wenjun Zhou, Anne E. Mathews, Carol Byrd-Bredbenner, Sarah E. Colby

Faculty & Staff Scholarship

Self-reported height and weight, if accurate, provide a simple and economical method to track changes in body weight over time. Literature suggests adults tend to under-report their own weight and that the gap between self-reported weight and actual weight increases with obesity. This study investigates the extent of discrepancy in self-reported height, weight, and subsequent Body Mass Index (BMI) versus actual measurements in young adults. Physically measured and self-reported height and weight were taken from 1562 students. Male students marginally overestimated height, while females were closer to target. Males, on average, closely self-reported weight. Self-reported anthropometrics remained statistically correlated to …

The Role Of Ceramide In Neutrophil Elastase Induced Inflammation In The Lungs, Sophia Karandashova

Theses and Dissertations

Alterations to sphingolipid metabolism are associated with increased pulmonary inflammation, but the impact of inflammatory mediators, such as neutrophil elastase (NE), on airway sphingolipid homeostasis remains unknown. NE is a protease associated CF lung disease progression, and can be found in up to micromolar concentrations in patient airways. While sphingolipids have been investigated in the context of CF, the focus has been on loss of cystic fibrosis transmembrane conductance regulator (CFTR) function. Here, we present a novel observation: oropharyngeal aspiration of NE increases airway ceramides in mice. Using a previously characterized mouse model of NE-induced inflammation, we demonstrate that NE …

Electrotransfer Of Different Control Plasmids Elicits Different Antitumor Effectiveness In B16.F10 Melanoma, Masa Bosnjak, Tanjo Jesenko, Urska Kamensek, Gregor Sersa, Jaka Lavrencak, Loree Heller, Maja Cemazar

Bioelectrics Publications

Several studies have shown that different control plasmids may cause antitumor action in different murine tumor models after gene electrotransfer (GET). Due to the differences in GET protocols, plasmid vectors, and experimental models, the observed antitumor effects were incomparable. Therefore, the current study was conducted comparing antitumor effectiveness of three different control plasmids using the same GET parameters. We followed cytotoxicity in vitro and the antitumor effect in vivo after GET of control plasmids pControl, pENTR/U6 scr and pVAX1 in B16.F10 murine melanoma cells and tumors. Types of cell death and upregulation of selected cytosolic DNA sensors and cytokines were …

Design And Analysis Of A 3d-Printed, Thermoplastic Elastomer (Tpe) Spring Element For Use In Corrective Hand Orthotics, Kevin Thomas Richardson

Theses and Dissertations--Mechanical and Aerospace Engineering

This thesis proposes an algorithm that determine the geometry of 3D-printed, custom-designed spring element bands made of thermoplastic elastomer (TPE) for use in a wearable orthotic device to aid in the physical therapy of a human hand exhibiting spasticity after stroke. Each finger of the hand is modeled as a mechanical system consisting of a triple-rod pendulum with nonlinear stiffness at each joint and forces applied at the attachment point of each flexor muscle. The system is assumed quasi-static, which leads to a torque balance between the flexor tendons in the hand, joint stiffness and the design force applied to …

Scalable Feature Selection And Extraction With Applications In Kinase Polypharmacology, Derek Jones

Theses and Dissertations--Computer Science

In order to reduce the time associated with and the costs of drug discovery, machine learning is being used to automate much of the work in this process. However the size and complex nature of molecular data makes the application of machine learning especially challenging. Much work must go into the process of engineering features that are then used to train machine learning models, costing considerable amounts of time and requiring the knowledge of domain experts to be most effective. The purpose of this work is to demonstrate data driven approaches to perform the feature selection and extraction steps in …

Age-Dependent Changes In Oxygen Supply And Demand Of Rat Spinotrapezius Muscle, Sami C. Dodhy

Theses and Dissertations

Because of the aerobic nature of cellular metabolism in mammalian organisms, a continuous supply of oxygen is necessary to maintain normal physiological function. As organisms age, their metabolic rates generally decline and there are accompanying alterations in the structure and function of the microcirculation, as this part of the cardiovascular system is especially important for oxygen exchange. The overall Oxygen Transport System can be considered as being composed of two complementary components: one for Oxygen Demand and one for Oxygen Supply. The purpose of the current work is to describe the age-dependent changes in both oxygen demand and oxygen supply …

Reducing Sepsis Mortality: A Cloud-Based Alert Approach, Janet A. Zink

Theses and Dissertations

The aim of this study is to examine the impact of a cloud-based CDS alerting system for SIRS, a precursor to sepsis, and sepsis itself, on adult patient and process outcomes at VCU Health System. The two main hypotheses are: 1) the implementation of cloud-based SIRS and sepsis alerts will lead to lower sepsis-related mortality and lower average length of stay, and 2) the implementation of cloud-based SIRS and sepsis alerts will lead to more frequent ordering of the Sepsis PowerPlan and more recording of sepsis diagnoses. To measure these outcomes, a pre-post study was conducted. A pre-implementation group diagnosed …

Effects Of The Na-Cl Co-Transporter (Ncc) In Western Diet Induced Metabolic And Cardiac Dysfunction, Zachary S. Cutter

Theses and Dissertations

Interleukin-18 (IL-18) is a pro-inflammatory cytokine known to be involved in maintaining metabolic homeostasis; however, also capable of inducing cardiac dysfunction. Additionally, IL-18, has been shown to bind to a novel receptor, the Na-Cl Co-transporter (NCC). We hypothesized that NCC mediates IL-18 metabolic and cardiac signaling in mice. Using male C57BL/6J mice, we compared the metabolic and cardiac function changes after at least 8 weeks of high-saturated fat high sugar diet (Western Diet) in NCC knockout (NCCKO), IL-18 knockout (IL-18KO), and wild-type mice. We show that NCCKO mice have significantly increased body weight gain from baseline, no difference in fasting …

Type 1 Diabetes Alters Lipid Handling And Metabolism In Human Fibroblasts And Peripheral Blood Mononuclear Cells, Albert R. Jones Iv, Emily L. Coleman, Nicholas R. Husni, Jude T. Deeney, Forum Raval, Devin Steenkamp, Hans Dooms, Barbara S. Nikolajczyk, Barbara E. Corkey

Clinical and Translational Science Faculty Publications

Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca²⁺ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα). These data indicate that metabolic and signal transduction defects present in T1D can be elicited ex vivo in isolated cells. Changes that precede T1D, including inflammation, may activate atypical responses in people that are genetically predisposed to T1D. To identify such cellular differences …