Translational Medical Research Commons^™

A 49-Year-Old Woman With Chronic Skin Lesions, Acute Mental Status Changes And New Pulmonary Infiltrate: Case Discussion From The University Of Louisville Hospital, Bhavani Puskur, Youssef Khafateh, Srikant Ramachandruni, Veronica Corcino, Mark Burns, Forest W. Arnold

The University of Louisville Journal of Respiratory Infections

No abstract provided.

Clinical Research: Educational Videos - The Process Of Clinical Research: Step-By-Step From Idea To Publication, Julio A. Ramirez

The University of Louisville Journal of Respiratory Infections

Clinical research can be defined as the creation and dissemination of new knowledge with the goal to improve outcomes in patients with a particular health problem. In this short video, Dr. Julio Ramirez, from the University of Louisville, offers an overview of the process of clinical research and describe how an investigator moves from the generation of an idea to the publication of study findings.

Timelines Of Translational Science: From Technology Initiation To Fda Approval, Laura M. Mcnamee, Michael Jay Walsh, Fred D. Ledley

Natural & Applied Sciences Faculty Publications

While timelines for clinical development have been extensively studied, there is little data on the broader path from initiation of research on novel drug targets, to approval of drugs based on this research. We examined timelines of translational science for 138 drugs and biologicals approved by the FDA from 2010±2014 using an analytical model of technology maturation. Research on targets for 102 products exhibited a characteristic (S-curve) maturation pattern with exponential growth between statistically defined technology initiation and established points. The median initiation was 1974, with a median of 25 years to the established point, 28 years to first clinical …

Cyclin B1 Mediates The Effect Of Uchl1 In Promoting Cell Cycle Progression In Uterine Papillary Serous Carcinoma, Suet Ying Kwan

Dissertations and Theses (Open Access)

Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer with poor survival rates and a high risk of recurrence. The rarity of UPSC poses challenges to the discovery of novel targeted therapies. Therefore, the purpose of this dissertation was to identify novel therapeutic targets that could aid in the management of UPSC. To do so, we began with the relatively large cohort of UPSC cases in the TCGA data set, which was used to identify differentially expressed genes between UPSC and low-grade endometrioid endometrial carcinoma (EEC) and normal tissue.

We identified Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1 …

Molecular Determinants Of Residual Disease In Ovarian Cancer, Kshipra M. Gharpure

Dissertations and Theses (Open Access)

The standard treatment for high grade serous ovarian cancer is primary cytoreductive surgery followed by adjuvant chemotherapy. Residual disease followed by surgery is associated with adverse overall and progression-free survival as well as poor response to adjuvant chemotherapy. Accurate identification of patients at high risk of residual disease will help avoid unnecessary surgeries and help in triaging these patients to neoadjuvant chemotherapy prior to interval surgical debulking. In this study, we address this clinical issue by identifying and validating molecular biomarkers that can predict the likelihood of residual disease in ovarian cancer patients. Using publically available databases and microarray datasets, …

Integrative Analysis Of Omics Data In Adult Glioma And Other Tcga Cancers To Guide Precision Medicine, Xin Hu, Xin Hu

Dissertations and Theses (Open Access)

Transcriptomic profiling and gene expression signatures have been widely applied as effective approaches for enhancing the molecular classification, diagnosis, prognosis or prediction of therapeutic response towards personalized therapy for cancer patients. Thanks to modern genome-wide profiling technology, scientists are able to build engines leveraging massive genomic variations and integrating with clinical data to identify “at risk” individuals for the sake of prevention, diagnosis and therapeutic interventions. In my graduate work for my Ph.D. thesis, I have investigated genomic sequencing data mining to comprehensively characterise molecular classifications and aberrant genomic events associated with clinical prognosis and treatment response, through applying high-dimensional …

Developing Novel Approaches To Improve Response To T Cell Based Cancer Immunotherapy, Rina M. Mbofung

Dissertations and Theses (Open Access)

Recently, T cell based immunotherapies have moved to the forefront of cancer immunotherapy with the success of Adoptive T cell therapy (ACT) and Immune checkpoint blockade.ACT, where patients are treated with tumour infiltrating T cells (TILs), conferred a clinical response rate of ~50%. Treatment with anti-CTLA4 and anti –PD1 therapy, conferred response rates of up to 50%, greatly improving the overall survival of patients with advanced melanoma amongst other cancer types. Despite the encouraging outcomes, there are relatively low response rates coupled with the delay of weeks to months before tumour shrinkage can be appreciated. Thus, understanding what tumour intrinsic …

Targeting Autophagy To Improve Efficacy Of Cdk4/6 Inhibition In Breast Cancer, Smruthi Vijayaraghavan

Dissertations and Theses (Open Access)

Deregulation of the cell cycle machinery is a hallmark of cancer, leading to aberrant proliferation and tumorigenesis. The crucial role of the CDK4/6-Cyclin D pathway has led to the development and FDA approval (palbociclib, ribociclib) of CDK4/6 inhibitors for the treatment of advanced estrogen receptor positive breast cancer. However, three major clinical challenges remain: i) adverse events leading to discontinuation of therapy and ii) lack of reliable biomarkers to identify responsive patients and iii) acquired resistance to CDK4/6 inhibitors. Previous in vitro studies have shown that palbociclib mediated CDK4/6 inhibition induces G1 arrest and senescence in ER+ breast cancer cells, …

Low Molecular-Weight Heparin Is Better Than Warfarin For Prevention Of Recurrent Venous Thromboembolism In Cancer Patients, Sarah Choi

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Lee AYY, Levin MN, Bake RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-153. doi: 10.1056/NEJMoa025313

Metformin To Augment Strength Training Effective Response In Seniors (Masters): Study Protocol For A Randomized Controlled Trial, Doug E. Long, Bailey D. Peck, Jenny L. Martz, S. Craig Tuggle, Heather M. Bush, Gerald Mcgwin, Philip A. Kern, Marcas M. Bamman, Charlotte A. Peterson

Clinical and Translational Science Faculty Publications

Background: Muscle mass and strength are strong determinants of a person's quality of life and functional independence with advancing age. While resistance training is the most effective intervention to combat age-associated muscle atrophy (sarcopenia), the ability of older adults to increase muscle mass and strength in response to training is blunted and highly variable. Thus, finding novel ways to complement resistance training to improve muscle response and ultimately quality of life among older individuals is critical. The purpose of this study is to determine whether a commonly prescribed medication called metformin can be repurposed to improve the response to resistance …

The Impact Of The Patient-Centered Medical Home On Health Disparities In Adults: A Systematic Review Of The Evidence, J. Nwando Olayiwola 2062970, Sonali Sheth, Victor Mleczko, Anna L. Choi, Anjana E. Sharma

Journal of Health Disparities Research and Practice

Introduction: The objective of this study was to review the empirical evidence on Patient-Centered Medical Home (PCMH) impact on health disparities in adults.

Methods: We searched PubMed, Scopus, and Google Scholar to identify studies on PCMH/health homes and health disparities published in English between January 1, 2009 and December 31, 2014. Articles met inclusion criteria if they investigated at least one component of PCMH or health homes in vulnerable populations, defined by PROGRESS-PLUS criteria, and reported differences in one of five clinical quality measures.

Results: 964 articles were identified through database searching and subsequent snowballing. 60 articles underwent full text …

Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction And Promotes Acute Lung Injury, Dilip Shah, Freddy Romero, Zhi Guo, Jianxin Sun, Jonathan C. Li, Caleb Kallen, Ulhas P. Naik, Ross Summer

Center for Translational Medicine Faculty Papers

Conclusion

• Lung endothelial dysfunction in DIO mice coincides with increased endoplasmic reticulum (ER) stress.
• Fatty acids in obese serum induce ER stress in the pulmonary endothelium leading to pulmonary endothelial cell dysfunction.
• Reducing protein load in the endoplasmic reticulum of pulmonary endothelial cells might protect against ARDS in obese individuals.

Bitter Taste Receptor Agonists Mitigate Features Of Allergic Asthma In Mice., Pawan Sharma, Roslyn Yi, Ajay P Nayak, Nadan Wang, Francesca Tang, Morgan J. Knight, Shi Pan, Brian Oliver, Deepak A. Deshpande

Department of Medicine Faculty Papers

Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in …

Autophagy And Airway Fibrosis: Is There A Link?, Pawan K. Sharma, Anudeep Kota, Deepak A. Deshpande, Mehra Haghi, Brian G. Oliver

Center for Translational Medicine Faculty Papers

In the past decade, an emerging process named “autophagy” has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital …

Modeling Timelines For Translational Science In Cancer; The Impact Of Technological Maturation, Laura M. Mcnamee, Fred D. Ledley

Natural & Applied Sciences Faculty Publications

This work examines translational science in cancer based on theories of innovation that posit a relationship between the maturation of technologies and their capacity to generate successful products. We examined the growth of technologies associated with 138 anticancer drugs using an analytical model that identifies the point of initiation of exponential growth and the point at which growth slows as the technology becomes established. Approval of targeted and biological products corresponded with technological maturation, with first approval averaging 14 years after the established point and 44 years after initiation of associated technologies. The lag in cancer drug approvals after the …

Clinical & Translational Research In Pneumonia: Defining A Research Agenda For Today And Tomorrow, Julio A. Ramirez

The University of Louisville Journal of Respiratory Infections

From the Editor in Chief

The reason for this special supplement of the Journal is to inform readers of a scientific research conference supported by the National Institutes of Health (NHI). The NIH Research Conference Grant (R13) supports high quality scientific conferences in areas that are important to the NIH's mission and to the public health. We just received notification that the National Heart, Lung, and Blood Institute (NHLBI) has approved the application for an international research conference entitled: DzClinical & Translational Research in Pneumonia: Defining a Research Agenda for Today and Tomorrowdz. The conference will be held on Wednesday, …

A Novel Hybrid Imaging System To Aid In Surgical Decision Making, Lawrence Yip, Madeleine Van De Kleut, Ivan Kosik, Astrid Chamson-Reig, Jeffrey Jl Carson

Western Research Forum

Background:

Breast cancer accounts for 25% of all cancer cases among women. In breast-conserving surgery, a common treatment, the tumour is excised with a healthy tissue margin. However, detection of the margin can be difficult. Current techniques to guide excision are often insufficient, and re-excision can occur up to 25% of the time.

Methods:

Photoacoustic imaging is a hybrid imaging modality that combines the advantages of optical imaging and ultrasound while using safe non-ionizing light. This project involves the development of a novel imaging system with a new scanner design to overcome common limitations and provide images to aid in …

Chemogenetic Stimulation Of The Hypoglossal Neurons Improves Upper Airway Patency, Thomas Curado, Kenneth Fishbein, Huy Pho, Michael Brennick, Olga Dergacheva, David Mendelowitz, +Several Additional Authors

Pharmacology and Physiology Faculty Publications

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. DREADD (rAAV5-hSyn-hM3(Gq)-mCherry) and control virus (rAAV5-hSyn-EGFP) were stereotactically administered to the hypoglossal nucleus of C57BL/6J mice. In 6–8 weeks genioglossus EMG and dynamic MRI …

Correcting The Trajectory Of Stroke Therapeutic Research, Keith R. Pennypacker, Gregory J. Bix, Justin F. Fraser

Neurology Faculty Publications

No abstract provided.

Clinical Outcomes Of Community-Acquired Pneumonia In Patients With Diabetes Mellitus, Siddartha Bandhary, Bolivar Y. Contreras-Mora, Ruby Gupta, Patricia Fernandez, Patricio Jimenez, Paula Peyrani, Timothy L. Wiemken, Steven Burdette, Julio A. Ramirez, Hadi Harati, Jose Bordon

The University of Louisville Journal of Respiratory Infections

Background: Studies have found admission hyperglycemia as a predictor of poor outcomes in Community acquired Pneumonia (CAP), whereas others have not. The objective of this study was to evaluate the impact of diabetes mellitus (DM) on mortality as well as Length of stay (LOS) and Time to clinical stability (TCS) of hospitalized patients with CAP.

Materials and Methods: Adult patients hospitalized with CAP enrolled at Community-Acquired Pneumonia Organization (CAPO) database with DM were categorized as admission blood glucose ≥ 250 mg/dL (diabetes mellitus blood sugar (BG) > 250) and admission blood glucose ≤ 250 mg/dL (DM BG ≤ 250). CAP outcomes …