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Ellis K.L.,Mount Sinai School of Medicine | Zhou Y.,Boston University | Beshansky J.R.,Tufts University | Ainehsazan E.,Molecular Cardiology Research Institute Center for Translational Genomics | And 4 more authors.
Pharmacogenomics Journal | Year: 2015

Modifiers of response to glucose, insulin and potassium (GIK) infusion may affect clinical outcomes in acute coronary syndromes (ACS). In an Immediate Myocardial Metabolic Enhancement During Initial Assessment And Treatment In Emergency Care (IMMEDIATE) trial's sub-study (n=318), we explored effects of 132 634 genetic variants on plasma glucose and potassium response to 12-h GIK infusion. Associations between metabolite-Associated variants and infarct size (n=84) were assessed. The 'G' allele of rs12641551, near ACSL1, as well as the 'A' allele of XPO4 rs2585897 were associated with a differential glucose response (P for 2 degrees of freedom test, P 2df ≤4.75 × 10-7) and infarct size with GIK (P 2df <0.05). Variants within or near TAS1R3, LCA5, DNAH5, PTPRG, MAGI1, PTCSC3, STRADA, AKAP12, ARFGEF2, ADCYAP1, SETX, NDRG4 and ABCB11 modified glucose response, and near CSF1/AHCYL1 potassium response (P 2df ≤4.26 × 10-7), but not outcomes. Gene variants may modify glucose and potassium response to GIK infusion, contributing to cardiovascular outcomes in ACS. © 2015 Macmillan Publishers Limited All rights reserved. Source


Ellis K.L.,Mount Sinai School of Medicine | Zhou Y.,Boston University | Beshansky J.R.,Tufts University | Ainehsazan E.,Mount Sinai School of Medicine | And 5 more authors.
Pharmacogenomics Journal | Year: 2015

The mechanistic effects of intravenous glucose, insulin and potassium (GIK) in cardiac ischemia are not well understood. We conducted a genetic sub-study of the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial to explore effects of common and rare glucose and insulin-related genetic loci on initial to 6-h and 6- to 12-h change in plasma glucose and potassium. We identified 27 NOTCH2/ADAM30 and 8 C2CD4B variants conferring a 40-57% increase in glucose during the first 6 h of infusion (P<5.96 × 10-6). Significant associations were also found for ABCB11 and SLC30A8 single-nucleotide polymorphisms (SNPs) and glucose responses, and an SEC61A2 SNP with a potassium response to GIK. These studies identify genetic factors that may impact the metabolic response to GIK, which could influence treatment benefits in the setting of acute coronary syndromes (ACS). © 2015 Macmillan Publishers Limited. Source


Baugh L.,Tufts University | Hinds P.,Molecular Oncology Research Institute | Huggins G.,Molecular Cardiology Research Institute Center for Translational Genomics | Georgakoudi I.,Tufts University | Black L.D.,Tufts University
Proceedings of the IEEE Annual Northeast Bioengineering Conference, NEBEC | Year: 2014

To understand the causes and progression of calcific aortic valve disease (CAVD), several in vitro models were studied using non-invasive imaging techniques. Explanted rat aortic valve leaflets were placed in culture medium to induce calcium nodule formation and valve interstitial cells (VICs) cultured from explanted rat valve leaflets were placed on collagen polyacrylamide (PAAM) gels of varying stiffness. The Second Harmonic Generation (SHG) signal and two-photon excited fluorescence (TPEF) generated by the collagen and calcium nodules, respectively, demonstrated that collagen fiber organization decreases with disease progression. Finally, using confocal fluorescence imaging, we found that average nodule size increases with substrate stiffness. © 2014 IEEE. Source


Arya M.A.,Molecular Cardiology Research Institute Center for Translational Genomics | Arya M.A.,Tufts University | Tai A.K.,Tufts University | Wooten E.C.,Molecular Cardiology Research Institute Center for Translational Genomics | And 4 more authors.
PLoS ONE | Year: 2013

The loss of muscle mass in alcoholic myopathy may reflect alcohol inhibition of myogenic cell differentiation into myotubes. Here, using a high content imaging system we show that ethanol inhibits C2C12 myoblast differentiation by reducing myogenic fusion, creating smaller and less complex myotubes compared with controls. Ethanol administration during C2C12 differentiation reduced MyoD and myogenin expression, and microarray analysis identified ethanol activation of the Notch signaling pathway target genes Hes1 and Hey1. A reporter plasmid regulated by the Hes1 proximal promoter was activated by alcohol treatment in C2C12 cells. Treatment of differentiating C2C12 cells with a gamma secretase inhibitor (GSI) abrogated induction of Hes1. On a morphological level GSI treatment completely rescued myogenic fusion defects and partially restored other myotube parameters in response to alcohol. We conclude that alcohol inhibits C2C12 myoblast differentiation and the inhibition of myogenic fusion is mediated by Notch pathway activation. © 2013 Arya et al. Source

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