Translational Medical Research Commons^™

Design Of The Strive-Ipf Trial-Study Of Therapeutic Plasma Exchange, Rituximab, And Intravenous Immunoglobulin For Acute Exacerbations Of Idiopathic Pulmonary Fibrosis, Tejaswini Kulkarni, Gerard Criner, Daniel Kass, Ivan Rosas, Mary Beth Scholand, Daniel Dilling, Ross Summer, Steven Duncan

Division of Pulmonary and Critical Care Medicine Faculty Papers

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) affect a significant proportion of patients with IPF. There are limited data to inform therapeutic strategies for AE-IPF, despite its high mortality. We discuss the rationale and design of STRIVE-IPF, a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF exacerbations.

METHODS: The STRIVE-IPF trial will randomize 51 patients among five sites in the United States. The inclusion criteria have been designed to select a study population …

Regulation Of Airway Smooth Muscle Cell Proliferation By Diacylglycerol Kinase: Relevance To Airway Remodeling In Asthma, Miguel Angel Hernandez-Lara, Santosh K Yadav, Sushrut D. Shah, Mariko Okumura, Yuichi Yokoyama, Raymond B. Penn,, Taku Kambayashi, Deepak A. Deshpande

Center for Translational Medicine Faculty Papers

Airway remodeling in asthma involves the hyperproliferation of airway smooth muscle (ASM) cells. However, the molecular signals that regulate ASM growth are not completely understood. Gq-coupled G protein-coupled receptor and receptor tyrosine kinase signaling regulate ASM cell proliferation via activation of phospholipase C, generation of inositol triphosphate (IP3) and diacylglycerol (DAG). Diacylglycerol kinase (DGK) converts DAG into phosphatidic acid (PA) and terminates DAG signaling while promoting PA-mediated signaling and function. Herein, we hypothesized that PA is a pro-mitogenic second messenger in ASM, and DGK inhibition reduces the conversion of DAG into PA resulting in inhibition of ASM cell proliferation. We …

Ogr1-Dependent Regulation Of The Allergen-Induced Asthma Phenotype, Ajay P Nayak, Deepak A. Deshpande, Phd, Sushrut D. Shah, Dominic R Villalba, Roslyn Yi, Nadan Wang, Raymond B. Penn

Division of Pulmonary and Critical Care Medicine Faculty Papers

The proton-sensing receptor, ovarian cancer G protein-coupled receptor (OGR1), has been shown to be expressed in airway smooth muscle (ASM) cells and is capable of promoting ASM contraction in response to decreased extracellular pH. OGR1 knockout (OGR1KO) mice are reported to be resistant to the asthma features induced by inhaled allergen. We recently described certain benzodiazepines as OGR1 activators capable of mediating both procontractile and prorelaxant signaling in ASM cells. Here we assess the effect of treatment with the benzodiazepines lorazepam or sulazepam on the asthma phenotype in wild-type (WT) and OGR1KO mice subjected to inhaled house dust mite (HDM; …

Mitochondrial Quality Control In Age-Related Pulmonary Fibrosis., Willy Roque, Karina Cuevas-Mora, Freddy Romero

Center for Translational Medicine Faculty Papers

Idiopathic pulmonary fibrosis (IPF) is age-related interstitial lung disease of unknown etiology. About 100,000 people in the U.S have IPF, with a 3-year median life expectancy post-diagnosis. The development of an effective treatment for pulmonary fibrosis will require an improved understanding of its molecular pathogenesis and the "normal" and "pathological' hallmarks of the aging lung. An important characteristic of the aging organism is its lowered capacity to adapt quickly to, and counteract, disturbances. While it is likely that DNA damage, chronic endoplasmic reticulum (ER) stress, and accumulation of heat shock proteins are capable of initiating tissue repair, recent studies point …

Protocol For Ground Glass Opacity, Elissa Goldman

Phase 1

Rationale: Pure ground glass opacities (GGO), identified incidentally or on lung cancer screening, may indicate pre-invasive subtypes of lung adenocarcinoma. These neoplasms typically demonstrate indolent patterns of growth, and Fleischner Society guidelines recommend up to five years of serial imaging. Our aim was to determine the frequency of diagnosed lung adenocarcinoma arising from GGO detected beyond 5 years of CT surveillance.

Methods: We reviewed all pathologic diagnoses of lung adenocarcinoma (n=442) between 2016 and 2018 of a tertiary academic hospital and National Cancer Institute-designated cancer center to identify all cancers that arose from ground glass opacities detected on CT scan. …

Retrospective Review Of Fluoroscopic Swallowing Studies And Outcomes At An Academic Health Center, Rachel Strock, Priyha Mahesh, Baskaran Sundaram, Md, Gregory C. Kane, Md

Phase 1

Introduction: Aspiration is often associated with underlying medical conditions and can cause pneumonia or death. Aspiration risk can be assessed via video fluoroscopic swallowing study (VFSS) or barium swallow (BaSw). We aimed to assess the diagnoses and clinical course of patients who were evaluated for potential aspiration through VFSS or BaSw to determine if there is a degree of aspiration that increases the risk of developing pneumonia and/or death.

Methods: We conducted a retrospective chart review of 374 patients in TJUH who were evaluated via VFSS or BaSw from January 1 to June 30, 2017. We recorded the degree and …

Treatment Of Persistent Air Leaks Using Endobronchial Valves, Michael Zimmerman, Cole Zingas, Achala Donuru, Scott W. Cowan, Nathaniel Evans Iii, Boyd Hehn

Phase 1

Introduction: Persistent air leaks (PAL) are from bronchopleural fistula resulting from communication between the bronchial tree and pleural space. Endobronchial valves (EBVs) are unidirectional valves placed bronchoscopically preventing airflow to the diseased lung lobe. For non-operable patients with PALs, EBVs offer a potential non-invasive treatment approach to stop air leak and allow lung healing. The purpose of this study is to retrospectively analyze EBV placement to treat non-operable adult patients with PALs.

Methods: We retrospectively analyzed all adult patients that underwent EBV placement for PAL treatment at our institution from January 2016 to June 2019. All patients failed conservative …

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 …

Apoptosis Signal-Regulating Kinase 1 Inhibition Attenuates Human Airway Smooth Muscle Growth And Migration In Chronic Obstructive Pulmonary Disease., Mathew S. Eapen, Anudeep Kota, Howard Vindin, Kielan D. Mcalinden, Dia Xenaki, Brian G. Oliver, Deepak A. Deshpande, Sukhwinder Singh Sohal, Pawan Sharma

Center for Translational Medicine Faculty Papers

Increased airway smooth muscle (ASM) mass is observed in chronic obstructive pulmonary disease (COPD), which is correlated with disease severity and negatively affects lung function in these patients. Thus, there is clear unmet clinical need for finding new therapies which can target airway remodeling and disease progression in COPD. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) activated by various stress stimuli, including reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) and is known to regulate cell proliferation. ASM cells from COPD patients are hyperproliferative to mitogens in vitro. …