| アブストラクト | Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from the US Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), we analyzed 12 million patient reports to identify drugs inversely correlated with gastrointestinal bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in patients with diabetes and those targeting PPARgamma-related mechanisms were associated with decreased AEC phenotypes (P < 0.0001). Electronic health records (EHRs) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARgamma agonists. Murine knockout models of AEC phenotypes were used to construct a gene-regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARgamma, HIF1alpha, VEGF, and TGFbeta1. In vitro analysis of human AEC tissues showed lower expression of PPARgamma and TGFbeta1 compared with controls (0.55 +/- 0.07 and 0.49 +/- 0.05). National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) RNA-Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC. |
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| 投稿者 | Sarangdhar, Mayur; Yacyshyn, Mary B; Gruenzel, Andrew R; Engevik, Melinda A; Harris, Nathaniel L; Aronow, Bruce J; Yacyshyn, Bruce R |
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| 組織名 | Department of Biomedical Informatics, Cincinnati Children's Hospital Medical;Center, Cincinnati, Ohio, USA.;Department of Pediatrics, University of Cincinnati College of Medicine,;Cincinnati, Ohio, USA.;Division of Digestive Diseases, University of Cincinnati College of Medicine,;Department of Pharmacology and Systems Physiology, University of Cincinnati,;Department of Anesthesiology, Cleveland Clinic, Cleveland, Ohio, USA.;Department of Pathology, Baylor College of Medicine, Houston, Texas, USA.;Division of Gastroenterology, Hepatology and Nutrition, University of Louisville,;Louisville, Kentucky, USA. |
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