The Impact of Pazopanib on the Cardiovascular System

Background: Pazopanib was FDA-approved in 2009 and has become the first line of treatment for renal cell carcinoma. Pazopanib is a tyrosine kinase inhibitor that slows tumor growth and angiogenesis by its action on vascular endothelial and platelet-derived growth factor receptors. Unfortunately, the efficacy of this drug is limited by its cardiovascular toxicity, including hypertension. Goal: Gain a greater understanding of the mechanism of these side effects in order to: 1) identify patients who are at higher risk; 2) develop strategies to mitigate cardiovascular toxicity; and 3) aid in future drug development. Hypothesis: The hypertensive effects of pazopanib are due to sustained activation of the renin-angiotensin-aldosterone system (RAAS). Methods: Wild type mice were dosed with 30 mg/kg of pazopanib twice daily for 42 days. Cardiac-specific beta-II spectrin knockout mice and flox control mice were dosed with 100 mg/kg once daily for 22 days, and an additional cohort was co-treated with Lisinopril (RAAS inhibitor). Blood pressures were monitored throughout treatment. Electrophysiological studies were conducted on isolated cardiomyocytes. Results: Pazopanib treatment led to an increase in blood pressure in all mice that received pazopanib. After 42 days, precursors to ventricular arrhythmias, such as delayed afterdepolarizations and prolonged action potential duration, were detected in cardiomyocytes. In mice that received 100 mg/kg of pazopanib, lisinopril co-treatment attenuated pazopanib-induced blood pressure rise and enlargement of the heart. Discussion: These results support our hypothesis regarding the involvement of the RAAS pathway, and validate the use of lisinopril for mitigating the hypertensive effects of pazopanib. Notably, the mechanism by which various tyrosine kinase inhibitors lead to hypertension may vary. Conclusion: Lisinopril is effective at attenuating the hypertensive effects of pazopanib, and it is worth determining whether the cardioprotective qualities of lisinopril are dependent upon blood pressure.Pelotonia Undergraduate Research Fellowship ProgramAcademic Major: Biochemistr

Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes

To assess the safety and efficacy of dual sodium–glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes

Precision Medicine in Diabetes: A Consensus Report From the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

The convergence of advances in medical science, human biology, data science, and technology has enabled the generation of new insights into the phenotype known as "diabetes." Increased knowledge of this condition has emerged from populations around the world, illuminating the differences in how diabetes presents, its variable prevalence, and how best practice in treatment varies between populations. In parallel, focus has been placed on the development of tools for the application of precision medicine to numerous conditions. This Consensus Report presents the American Diabetes Association (ADA) Precision Medicine in Diabetes Initiative in partnership with the European Association for the Study of Diabetes (EASD), including its mission, the current state of the field, and prospects for the future. Expert opinions are presented on areas of precision diagnostics and precision therapeutics (including prevention and treatment), and key barriers to and opportunities for implementation of precision diabetes medicine, with better care and outcomes around the globe, are highlighted. Cases where precision diagnosis is already feasible and effective (i.e., monogenic forms of diabetes) are presented, while the major hurdles to the global implementation of precision diagnosis of complex forms of diabetes are discussed. The situation is similar for precision therapeutics, in which the appropriate therapy will often change over time owing to the manner in which diabetes evolves within individual patients. This Consensus Report describes a foundation for precision diabetes medicine, while highlighting what remains to be done to realize its potential. This, combined with a subsequent, detailed evidence-based review (due 2022), will provide a roadmap for precision medicine in diabetes that helps improve the quality of life for all those with diabetes.This article is freely available via Open Access. Click on the publisher URL to access it via the publisher's site.R01 HD094150/HD/NICHD NIH HHS/United States DP3 DK111906/DK/NIDDK NIH HHS/United States U01 DK105535/DK/NIDDK NIH HHS/United States R01 DK104942/DK/NIDDK NIH HHS/United States U54 DK118612/DK/NIDDK NIH HHS/United States R21 AI142483/AI/NIAID NIH HHS/United States R01 DK122586/DK/NIDDK NIH HHS/United States P30 DK026687/DK/NIDDK NIH HHS/United States WT_/Wellcome Trust/United Kingdom R01 DK052431/DK/NIDDK NIH HHS/United States UL1 TR001873/TR/NCATS NIH HHS/United States R01 DK104351/DK/NIDDK NIH HHS/United Statesaccepted version, submitted versio

Regulation of skeletal muscle oxidative capacity and insulin signaling by the Mitochondrial Rhomboid Protease PARL

Type 2 diabetes mellitus (T2DM) and aging are characterized by insulin resistance and impaired mitochondrial energetics. In lower organisms, remodeling by the protease pcp1 (PARL ortholog) maintains the function and lifecycle of mitochondria. We examined whether variation in PARL protein content is associated with mitochondrial abnormalities and insulin resistance. PARL mRNA and mitochondrial mass were both reduced in elderly subjects and in subjects with T2DM. Muscle knockdown of PARL in mice resulted in malformed mitochondrial cristae, lower mitochondrial content, decreased PGC1&alpha; protein levels, and impaired insulin signaling. Suppression of PARL protein in healthy myotubes lowered mitochondrial mass and insulin-stimulated glycogen synthesis and increased reactive oxygen species production. We propose that lower PARL expression may contribute to the mitochondrial abnormalities seen in aging and T2DM.<br /

Hospital quality indicators are not unidimensional: A reanalysis of Lieberthal and Comer.

ObjectiveTo evaluate the dimensionality of hospital quality indicators treated as unidimensional in a prior publication.Data source/study designPooled cross-sectional 2010-2011 Hospital Compare data (10/1/10 and 10/1/11 archives) and the 2012 American Hospital Association Annual Survey.Data extractionWe used 71 indicators of structure, process, and outcomes of hospital care in a principal component analysis of Ridit scores to evaluate the dimensionality of the indicators. We conducted an exploratory factor analysis using only the indicators in the Centers for Medicare &amp; Medicaid Services' Hospital Value-Based Purchasing.Principal findingsThere were four underlying dimensions of hospital quality: patient experience, mortality, and two clinical process dimensions.ConclusionsHospital quality should be measured using a variety of indicators reflecting different dimensions of quality. Treating hospital quality as unidimensional leads to erroneous conclusions about the performance of different hospitals

Hospital quality indicators are not unidimensional: A&nbsp;reanalysis&nbsp;of Lieberthal and Comer.

ObjectiveTo evaluate the dimensionality of hospital quality indicators treated as unidimensional in a prior publication.Data source/study designPooled cross-sectional 2010-2011 Hospital Compare data (10/1/10 and 10/1/11 archives) and the 2012 American Hospital Association Annual Survey.Data extractionWe used 71 indicators of structure, process, and outcomes of hospital care in a principal component analysis of Ridit scores to evaluate the dimensionality of the indicators. We conducted an exploratory factor analysis using only the indicators in the Centers for Medicare &amp; Medicaid Services' Hospital Value-Based Purchasing.Principal findingsThere were four underlying dimensions of hospital quality: patient experience, mortality, and two clinical process dimensions.ConclusionsHospital quality should be measured using a variety of indicators reflecting different dimensions of quality. Treating hospital quality as unidimensional leads to erroneous conclusions about the performance of different hospitals