Translational Medical Research Commons^™

Pepducins As A Potential Treatment Strategy For Asthma And Copd., Reynold A. Panettieri, Tonio Pera, Stephen B B. Liggett, Jeffrey L. Benovic, Raymond B. Penn

Center for Translational Medicine Faculty Papers

Current therapies to treat asthma and other airway diseases primarily include anti-inflammatory agents and bronchodilators. Anti-inflammatory agents target trafficking and resident immunocytes and structural cells, while bronchodilators act to prevent or reverse shortening of airway smooth muscle (ASM), the pivotal tissue regulating bronchomotor tone. Advances in our understanding of the biology of G protein-coupled receptors (GPCRs) and biased agonism offers unique opportunities to modulate GPCR function that include the use of pepducins and allosteric modulators. Recent evidence suggests that small molecule inhibitors of Gα _q as well as pepducins targeting G _q -coupled receptors can broadly inhibit contractile agonist-induced ASM …

New Targets For Resolution Of Airway Remodeling In Obstructive Lung Diseases., Ajay P. Nayak, Deepak A. Deshpande, Raymond B. Penn

Center for Translational Medicine Faculty Papers

Airway remodeling (AR) is a progressive pathological feature of the obstructive lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). The pathology manifests itself in the form of significant, progressive, and (to date) seemingly irreversible changes to distinct respiratory structural compartments. Consequently, AR correlates with disease severity and the gradual decline in pulmonary function associated with asthma and COPD. Although current asthma/COPD drugs manage airway contraction and inflammation, none of these effectively prevent or reverse features of AR. In this review, we provide a brief overview of the features and putative mechanisms affecting AR. We further discuss recently proposed …

First Results On Survival From A Large Phase 3 Clinical Trial Of An Autologous Dendritic Cell Vaccine In Newly Diagnosed Glioblastoma, Linda M. Liau, Keyoumars Ashkan, David D. Tran, Jian L. Campian, John E. Trusheim, Charles S. Cobbs, Jason A. Heth, Michael Salacz, Sarah Taylor, Stacy D. D'Andre, Fabio M. Iwamoto, Edward J. Dropcho, Yaron A. Moshel, Kevin A. Walter, Clement P. Pillainayagam, Robert Aiken, Rekha Chaudhary, Samuel A. Goldlust, Daniela A Bota, Paul Duic, Jai Grewal, Heinrich Elinzano, Steven A. Toms, Kevin O. Lillehei, Tom Mikkelsen, Tobias Walbert, Steven R. Abram, Andrew J. Brenner, Steven Brem, Matthew G. Ewend, John L. Villano

Internal Medicine Faculty Publications

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax^®-L) to standard therapy for newly diagnosed glioblastoma.

Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).

Results: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months …

First Results On Survival From A Large Phase 3 Clinical Trial Of An Autologous Dendritic Cell Vaccine In Newly Diagnosed Glioblastoma., Linda M. Liau, Keyoumars Ashkan, David D. Tran, Jian L. Campian, John E. Trusheim, Charles S. Cobbs, Jason A. Heth, Michael Salacz, Sarah Taylor, Stacy D. D'Andre, Fabio M. Iwamoto, Edward J. Dropcho, Yaron A. Moshel, Kevin A. Walter, Clement P. Pillainayagam, Robert Aiken, Rekha Chaudhary, Samuel A. Goldlust, Daniela A. Bota, Paul Duic, Jai Grewal, Heinrich Elinzano, Steven A. Toms, Kevin O. Lillehei, Tom Mikkelsen, Tobias Walbert, Steven R. Abram, Andrew J. Brenner, Steven Brem, Matthew G. Ewend, Simon Khagi, Jana Portnow, Lyndon J. Kim, William G. Loudon, Reid C. Thompson, David E Avigan, Karen L. Fink, Francois J. Geoffroy, Scott Lindhorst, Jose Lutzky, Andrew E. Sloan, Gabriele Schackert, Dietmar Krex, Hans-Jorg Meisel, Julian Wu, Raphael P Davis, Christopher Duma, Arnold B. Etame, David Mathieu, Santosh Kesari, David Piccioni, Manfred Westphal, David S. Baskin, Pamela Z. New, Michel Lacroix, Sven-Axel May, Timothy J. Pluard, Victor Tse, Richard M. Green, John L. Villano, Michael Pearlman, Kevin Petrecca, Michael Schulder, Lynne P Taylor, Anthony E. Maida, Robert M. Prins, Timothy F. Cloughesy, Paul Mulholland, Marnix L. Bosch

Department of Medical Oncology Faculty Papers

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax

METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).

RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly …

The Association Of Kangaroo Mother Care, Energy Conservation, And Bonding In Preterm Neonates, Dorothy Forde

Dissertations

Purpose:To examine the association of kangaroo mother care (KMC) on energy utilization and bonding as evidenced by reduced biochemical markers of adenosine triphosphate (ATP) degradation, hypoxanthine (Hx), xanthine (Xa), and uric acid (UA), and (allantoin), a measure of oxidative stress in preterm infants 24-36 weeks gestation. A secondary objective was to compare specific physiological parameters using bedside monitoring and perfusion and oxygenation of the gut using near-infrared spectroscopy (NIRS) during 1 hour of KMC compared to incubator care.

Study design: A randomized controlled trial (RCT) examining the effects of 1-hour of KMC or 1-hour incubator care on urinary markers …

Food Insecurity And Pre-Hypertension, Pre-Diabetes In Adult Women: Results From The 2007-2010 National Health And Nutrition Examination Survey, Michelle L. Redmond, Phd, Ms, Fanglong Dong, Phd, Philip Twumasi-Ankrah, Phd, Robert B. Hines, Phd, Mph, Lisette T. Jacobson, Phd, Mpa, Ma, Elizabeth Ablah, Phd, Mph, Judy Johnston, Ms, Rd/Ld, Tracie C. Collins, Md, Mph, Mhcds

Journal of Health Disparities Research and Practice

Background

Being food insecure is generally defined as the limited or uncertain availability of safe and nutritious foods and is linked to poor nutrition and fully progressed diet-sensitive chronic diseases. However, little is known about the association between food insecurity and pre-clinical disease such as pre-hypertension and pre-diabetes. This study sought to examine the associations between food insecurity and pre-clinical disease among a racially/ethnically diverse population of women.

Methods

Using data from 2007-2010 NHANES, we examined associations between food security and pre-clinical disease among women 18-65 years. Chi-square tests were used to examine differences in demographic variables. Bivariate and multivariable …

Selective Generation Of Dopaminergic Precursors From Human Fibroblasts By Direct Lineage Conversion, Miao He

Theses & Dissertations

Transplantation of dopaminergic precursors (DPs) is a promising therapeutic strategy of Parkinson’s disease (PD). However, limited cell source for dopaminergic precursors has become a major obstacle for transplantation therapy. In the first part of the study, we demonstrated that Foxa2 is superior to Lmx1a in inducing dopaminergic neuronal differentiation from induced neural progenitor cells (iNPCs). Based on the results above and some other published results, our group demonstrated that mouse fibroblasts can be reprogrammed into induced dopaminergic precursors (iDPs) through ectopic expression of transcription factors Brn2, Sox2 and Foxa2(1). In the current study, we hypothesized that similar strategy …

A Study Of Acoustically Activated Nanodroplets, Songita Choudhury

Theses & Dissertations

Current treatment of acute myocardial infarction (AMI), which is the main pathophysiological event leading to death in the United States, has advanced considerably with the introduction of emergent percutaneous interventions, but there remains an urgent need for novel techniques to rapidly and accurately detect infarcted or ischemic tissue that results from AMI. Ultrasound contrast agents, also known as microbubbles (MB), have become commonplace in echocardiography. However, MBs are purely intravascular tracers and unable to cross endothelial barriers due to size. The limitations of MBs, namely size and short circulation times within the human body, led to the development of phase-change …

Muc4 Based Immunotherapy For Pancreatic Cancer, Kasturi Banerjee

Theses & Dissertations

Pancreatic Cancer (PC) is a lethal disease claiming approximately 45000 lives in the US in 2018, and it establishes an elaborate immunosuppressive tumor microenvironment that aids in disease pathogenesis. Immunotherapy has emerged as a strategy to target tumor cells by reprogramming patient’s immune system. Challenges present in PC immunotherapy are: i) identifying a tumor-associated antigen that could be targeted, ii) identifying adjuvants that could efficiently deliver antigens, iii) eliciting robust anti-tumor responses and iv) overcoming peripheral tolerance and immunosuppression elicited by the tumor.

Firstly, we detected circulating autoantibodies to MUC4 present in PC patients and observed that IgM autoantibodies to …

Strain Differences In Susceptibility To Cisplatin-Induced Renal Fibrosis, Gabrielle B. Oropilla

College of Arts & Sciences Senior Theses

Cisplatin is a potent chemotherapeutic; the dose-limiting side effect of this drug is nephrotoxicity, causing acute kidney injury (AKI) in 30% of adult patients. Patients with cisplatin-induced AKI are more likely to develop end stage renal diseases, particularly chronic kidney disease (CKD), which is marked by the development of fibrosis. Currently, there are no therapeutic interventions for cisplatin-induced kidney injury, which may be due to limitations in the mouse model used to study this type of injury. We have previously developed a repeated dosing regimen of cisplatin (mice treated with 7 mg/kg once a week for 4 weeks, mice sacrificed …

Intestinal Permeability And Microbial Dysbiosis In Acute Coronary Syndrome (Miacs Study), Tarik Z. Alhmoud

Biomedical Sciences ETDs

Background: Acute Coronary Syndrome (ACS) is a leading cause of morbidity and mortality. Metabolic syndrome and obesity are major risk factors for atherosclerosis and ACS. Dysbiosis plays an important role in metabolic syndrome and obesity. Studies show a markedly increased risk of heart attacks in patients with high levels of the pro-atherogenic metabolite trimethylamine-N-Oxide (TMAO). TMAO is produced by the intestinal microbial flora through metabolism of dietary phospholipids; Gram-negative bacteria (Phylum Proteobacteria) is the major source of TMAO metabolism. Patients with obesity and metabolic syndrome have a defective intestinal tight-junctional (TJ) barrier, which allows paracellular permeation of luminal antigens such …

Genomic Evolution Of Chemoresistance In Triple-Negative Breast Cancer Delineated By Single Cell Sequencing, Charissa Kim

Dissertations and Theses (Open Access)

Triple-negative breast cancer (TNBC) is an aggressive subtype that displays extensive intratumor heterogeneity and frequently (46%) develops resistance to neoadjuvant chemotherapy (NAC). Currently, the genomic basis of chemoresistance remains poorly understood. An important question is whether resistance to chemotherapy is driven by the selection of rare pre-existing subclones with genomic mutations and transcriptional programs that confer resistance to chemotherapy (adaptive resistance) or by the spontaneous induction of new mutations and expression changes that confer a resistant phenotype (acquired resistance). To investigate this question we applied single cell DNA and RNA sequencing methods and deep-exome sequencing to longitudinal time-point samples collected …

Efficacy Of Antibiotic Treatments For Klebsiella And Esbl Pneumonia, Harry Snow

Clinical and Translational Science Center Scholarly Output

There is a dearth of knowledge and studies about empiric antibiotic treatment for Extended Spectrum-β-Lactamase (ESBL) bacterial pneumonia.

This study is meant to improve quality of evidence to “medium” levels from the current level of “very-low” quality.

Improved methods for treating Klebsiella Pneumoniae infection.

Primary outcome:Mortality

Aim:To assess differences in patient survival probability due to different antibiotic regimens, considering all classes of antibiotics.

Genotype-Specific Insertion Of Cytotoxic Genetic Elements Into Cancer Cells, Ryan Englander

University Scholar Projects

The new gene editing system CRISPR/Cas9, composed of a complex composed of a guide RNA and the Cas9 endonuclease, promises to revolutionize biological research and potentially allow clinicians to directly modify patient DNA in vivo. While its applications in the treatment of genetic diseases and in modifying immune cells for immunotherapy are currently being explored, CRISPR/Cas9’s potential utility as a modular system for targeting tumor-specific mutated sequences has not as of yet been explored. While CRISPR/Cas9 is specific enough to target small insertions and deletions or gross chromosomal rearrangements, it is not specific enough to reliably restrict editing to …

Cognitive Changes Following Multiple-Modality Exercise And Mind-Motor Training In Older Adults With Subjective Cognitive Complaints: The M4 Study, Narlon Cassio Boa Sorte Silva, Dawn P. Gill, Adrian M. Owen, Teresa Liu-Ambrose, Vladimir Hachinski, Ryosuke Shigematsu, Robert Petrella

Lifestyle Research Team

Background

We investigated the effects of multiple-modality exercise with additional mind-motor training on cognition in community-dwelling older adults with subjective cognitive complaints.

Methods

Participants (n = 127, mean age 67.5 [7.3] years, 71% women) were randomized to receive 45 minutes of multiple-modality exercise with additional 15 minutes of either mind-motor training (M4, n = 63) or control (balance, range of motion and breathing exercises [M2, n = 64]). In total, both groups exercised 60 minutes/day, 3 days/week, for 24 weeks. Standardized global cognitive functioning (GCF), concentration, reasoning, planning, and memory were assessed at 24 weeks and after a 28-week no-contact …

Extending The Phenotypic Spectrum Of Sengers Syndrome: Congenital Lactic Acidosis With Synthetic Liver Dysfunction., David B Beck, Kristina Cusmano-Ozog, Nickie Andescavage, Eyby Leon

Pathology Faculty Publications

Sengers syndrome is a rare autosomal recessive mitochondrial disease characterized by lactic acidosis, hypertrophic cardiomyopathy and bilateral cataracts. We present here a case of neonatal demise, within the first day of life, who initially presented with severe lactic acidosis, with evidence of both chorioamnionitis and cardiogenic shock. Initial metabolic labs demonstrated a severe lactic acidosis prompting genetic testing which revealed a homozygous pathogenic variant for Sengers syndrome in

Visualization Of Fibronectin Assembly Using Crispr And Fluorescence Imaging, Brenda French, Sophie Astrof

Sigma Xi Student Research Day

Objectives

Surprisingly, the mechanisms of fibronectin assembly remain largely unknown. This project aims to elucidate the process by which fibronectin assembles through fluorescent labeling. Fluorescent tags allow for the visualization of fibronectin to clarify how this extracellular matrix protein may influence migration and signaling.

Adult Patients Living With Human Immunodeficiency Virus Hospitalized For Community-Acquired Pneumonia In The United States: Incidence And Outcomes, Leslie A. Beavin, Stephen P. Furmanek, Paula Peyrani, Anupama Raghuram, Forest W. Arnold, Mark Burns, Julio A. Ramirez

The University of Louisville Journal of Respiratory Infections

Background: Community-acquired pneumonia (CAP) is a common infectious reason for hospitalization of adults in the United States (US), including those with Human Immunodeficiency Virus (HIV). While there are studies detailing the incidence and outcomes for all adults with CAP we are not aware of a recent study detailing incidence and outcomes in adult HIV patients hospitalized with CAP. The objectives of this study were (1) to define the current incidence and outcomes of adult HIV patients hospitalized with CAP in Louisville, Kentucky, and (2) to estimate the burden of CAP in the US HIV adult population.

Methods: This was a …

A Software Tool For Automated Upload Of Large Clinical Datasets Using Redcap And The Capo Database, William A. Mattingly, Christopher Sinclair, Danna Williams, Matthew Grassman, Stephen Furmanek, Kimberley Buckner, Mohammad Tahboub

The University of Louisville Journal of Respiratory Infections

Introduction: Obtaining clinical data from healthcare sources is necessary for conducting clinical research. New technologies now allow for connecting a research database to Electronic Medical Records remotely, allowing the automatic import of clinical research data. In this paper we design and evaluate a REDCap extension to import clinical records from an external health database.

Methods: Many hospital EHRs are designed to use secure file transfer protocol (SFTP) repositories for data communication. We develop a REDCap plugin to connect to an external SFTP file repository for the import of clinical record data. We use the CAPO instance of REDCap and a …

Bacteremic Pneumococcal Pneumonia: A Longitudinal Study In 279 Adult Patients From A Single Center, Jorge H. Gentile, Claudia Hernandez, Monica D. Sparo, Edgardo M. Rodriguez, Carolina Ceriani, Florencia Bruggesser

The University of Louisville Journal of Respiratory Infections

Background: Bacteremic pneumococcal pneumonia (BPP) is the most common clinical presentation of invasive pneumococcal disease (IPD). Although it has been extensively studied, there is little knowledge in our region in relation to burden of disease, demographic and outcome features.

Methods: We conducted a prospective, longitudinal, observational study from 1989 to 2015 in adult patients with BPP, in order to deepen our knowledge of the characteristics of this disease in our community hospital in Tandil, Argentina.

Results: 279 patients were included. The mean incidence was 2.8/1000 admissions with a sharp decrease in the last two years, reaching 0.8/1000 admissions. Mean patient …