Translational Medical Research Commons^™

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 …

Why A New Journal?, Julio A. Ramirez

The University of Louisville Journal of Respiratory Infections

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Time To Clinical Stability In Patients With Ventilator-Associated Pneumonia Due To Methicillin-Resistant Staphylococcus Aureus Treated With Linezolid Versus Vancomycin: Results From The Impact-Hap Study, Paula Peyrani, Timothy L. Wiemken, Marcus J. Zervos, Daniel H. Kett, Thomas M. File Jr., Gary E. Stein, Kimbal D. Ford, Julio A. Ramirez

The University of Louisville Journal of Respiratory Infections

Background: Time to clinical stability is a well-defined early clinical outcome in hospitalized patients with community-acquired pneumonia, but it has not been evaluated in patients with ventilator-associated pneumonia (VAP). The objective of this study was to compare time to clinical stability in patients with MRSA VAP treated with linezolid versus vancomycin.

Methods: This was a secondary analysis of the IMPACT-HAP study database. VAP was defined according to CDC criteria. MRSA VAP was considered when MRSA was isolated from a tracheal aspirate or bronchoalveolar lavage. A patient was considered to reach clinical stability the day that the following four criteria were …

Neutrophil Function In Elderly Patients Hospitalized With Community- Acquired Pneumonia, Jorge Perez San Juan, Lisandra Rodriguez Hernandez, Timothy L. Wiemken, Robert R. Kelley, Rafael Fernandez-Botran, Martin Gnoni, Paula Peyrani, Madhavi J. Rane, Forest W. Arnold, Julio A. Ramirez, Silvia Uriarte, Jose Bordon

The University of Louisville Journal of Respiratory Infections

Background: Advanced age is associated with immunosenescence as well as increased risk for poor outcomes during episodes of community-acquired pneumonia (CAP). Data on neutrophil function in hospitalized elderly patients with CAP is lacking. In this study we compared neutrophil function in elderly and non-elderly hospitalized patients with CAP.

Methods: Prospective study of healthy controls (HC) and patients hospitalized with CAP nonelderly (NE-CAP) and elderly (E-CAP). Blood samples were obtained on the day of hospitalization. The following neutrophil functional assays were performed: degranulation of secretory vesicles (CD35), degranulation of specific granules (CD66b), phagocytosis, and hydrogen peroxide (H₂O₂) …

A Review Of Macrolide Based Regimens For Community-Acquired Pneumonia, Forest W. Arnold, Leslie A. Beavin

The University of Louisville Journal of Respiratory Infections

Community-acquired pneumonia (CAP) has significant morbidity and mortality. The Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines recommend two antimicrobial regimens for hospitalized patients with CAP, one of which includes a macrolide, and one of which does not. Both regimens have antimicrobial properties, but macrolides also possess immunomodulatory properties. Macrolides, however, may also have potential arrhythmia adverse effects. The purpose of this review is to provide an update of studies evaluating outcomes for patients with CAP treated with or without a macrolide-based regimen. Two recent randomized controlled trials conflict with each other regarding the benefit versus noninferiority of including …

Translational Models For Vascular Cognitive Impairment: A Review Including Larger Species, Atticus H. Hainsworth, Stuart M. Allan, Johannes Boltze, Catriona Cunningham, Chad Farris, Elizabeth Head, Masafumi Ihara, Jeremy D. Isaacs, Raj N. Kalaria, Saskia A. M. J. Lesnik Oberstein, Mark B. Moss, Björn Nitzsche, Gary A. Rosenberg, Julie W. Rutten, Melita Salkovic-Petrisic, Aron M. Troen

Pharmacology and Nutritional Sciences Faculty Publications

Background: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited.

Methods: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, …

The Ethics Of Offering Futile Treatment, Rebekah L. Eddy, Viktoria Krajnc, Lauren Smith

Clinical Research in Practice: The Journal of Team Hippocrates

It important to acknowledge our own emotional biases and be cognizant of how we present evidence-based options to patients and their families, so that they may provide truly informed consent.

Stem Cell Therapy For End Stage Copd: A Cautionary Tale Of Direct-To-Consumer Advertising, Blake J. Arthurs, Scott Yaekle

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. 2013;143(6):1590-1598. doi: 10.1378/chest.12-2094

It Is Reasonable To Recommended Intrapleural Alteplase For Loculated Pleural Effusions, Tricia Fernandez

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Thommi G, Shehan J, Robison K, Christensen M, Backemeyer L, McLeay M. A double blind randomized cross over trial comparing rate of decortication and efficacy of intrapleural instillation of alteplase vs placebo in patients with empyemas and complicated parapneumonic effusions. Respir Med. 2012;17(2):716-723. doi: 10.1016/j.rmed.2012.02.005

Combination Octreotide, Midodrine, And Albumin May Improve Survival In Patients With Hepatorenal Syndrome, But The Evidence Is Weak, Jacob Szafranski

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Skagen C, Einstein M, Lucey MR, Said A. Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome. J Clin Gastroenterol. 2009 Aug;43(7):680-5. doi: 10.1097/MCG.0b013e318188947c

We Have No Real Evidence Related To Anticoagulation Plus Aspirin For Stroke Prevention In Atrial Fibrillation, Yuxiang Wang

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J. 2006;152:967-973. doi: 10.1016/j.ahj.2006.06.024

Manage Terminal Ileum Diverticulitis Comparably To Diverticulitis Elsewhere, James Yip

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Park HC, Lee BH. The management of terminal ileum diverticulitis. Am Surg. 2009 Dec;75(12):1199-202.

From The Editor, James Peter Meza

Clinical Research in Practice: The Journal of Team Hippocrates

With this issue of the Journal, we expand types of submissions to include generalizable knowledge in the form of brief reports and original research.

Endothelium In The Pharyngeal Arches 3, 4 And 6 Is Derived From The Second Heart Field., Xia Wang, Dongying Chen, Kelley Chen, Ali Jubran, Annjosette Ramirez, Sophie Astrof

Center for Translational Medicine Faculty Papers

Oxygenated blood from the heart is directed into the systemic circulation through the aortic arch arteries (AAAs). The AAAs arise by remodeling of three symmetrical pairs of pharyngeal arch arteries (PAAs), which connect the heart with the paired dorsal aortae at mid-gestation. Aberrant PAA formation results in defects frequently observed in patients with lethal congenital heart disease. How the PAAs form in mammals is not understood. The work presented in this manuscript shows that the second heart field (SHF) is the major source of progenitors giving rise to the endothelium of the pharyngeal arches 3 - 6, while the endothelium …

Unique Breast Cancer Features Within The Vietnamese Population, Polly Niravath, Melissa Bondy, Susan G. Hilsenbeck

Journal of Health Disparities Research and Practice

BACKGROUND: Breast cancer is known to be a heterogeneous disease across women, and even within individual tumors. However, relatively little is known about heterogeneity across cultures. There has been some evidence to suggest that Asian women are more likely to have HER2+ breast cancer than their Caucasian counterparts.

PURPOSE: The aim of this study was to further investigate the unique pattern of breast cancer incidence and subtype in the Vietnamese population.

METHODS: We retrospectively collected data on all Vietnamese women diagnosed with invasive breast cancer at the Lester & Sue Smith Breast Center in Houston, Texas over a four year …

Small Rna Zippers Lock Mirna Molecules And Block Mirna Function In Mammalian Cells., Lingyu Meng, Cuicui Liu, Jinhui Lü, Qian Zhao, Shengqiong Deng, Guangxue Wang, Jing Qiao, Chuyi Zhang, Lixiao Zhen, Ying Lu, Wenshu Li, Yuzhen Zhang, Richard G. Pestell, Huiming Fan, Yi-Han Chen, Zhongmin Liu, Zuoren Yu

Department of Cancer Biology Faculty Papers

MicroRNAs (miRNAs) loss-of-function phenotypes are mainly induced by chemically modified antisense oligonucleotides. Here we develop an alternative inhibitor for miRNAs, termed 'small RNA zipper'. It is designed to connect miRNA molecules end to end, forming a DNA-RNA duplex through a complementary interaction with high affinity, high specificity and high stability. Two miRNAs, miR-221 and miR-17, are tested in human breast cancer cell lines, demonstrating the 70∼90% knockdown of miRNA levels by 30-50 nM small RNA zippers. The miR-221 zipper shows capability in rescuing the expression of target genes of miR-221 and reversing the oncogenic function of miR-221 in breast cancer …