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Smith A.H.,University of California at Berkeley | Marshall G.,University of Santiago de Chile | Yuan Y.,University of California at Berkeley | Steinmaus C.,University of California at Berkeley | And 8 more authors.
EBioMedicine | Year: 2014

Background: Arsenic trioxide is effective in treating promyelocytic leukemia, and laboratory studies demonstratethat arsenic trioxide causes apoptosis of human breast cancer cells. Region II in northern Chile experienced veryhigh concentrations of inorganic arsenic in drinking water, especially in the main city Antofagasta from 1958until an arsenic removal plant was installed in 1970.Methods:Weinvestigated breast cancermortality from1950 to 2010 amongwomen in Region II compared to RegionV, which had lowarsenicwater concentrations. Weconducted studies on human breast cancer cell lines andcompared arsenic exposure in Antofagasta with concentrations inducing apoptosis in laboratory studies. Findings: Before 1958, breast cancer mortality rates were similar, but in 1958-1970 the rates in Region II werehalf those in Region V (rate ratio RR= 0.51, 95% CI 0.40-0.66;p < 0.0001). Women under the age of 60 experienceda 70% reduction in breast cancer mortality during 1965-1970 (RR = 0.30, 0.17-0.54; p < 0.0001). Breastcancer cell culture studies showed apoptosis at arsenic concentrations close to those estimated to have occurredin people in Region II. Interpretation: We found biologically plausible major reductions in breast cancermortality during high exposureto inorganic arsenic in drinking waterwhich could not be attributed to bias or confounding. Werecommend clinicaltrial assessment of inorganic arsenic in the treatment of advanced breast cancer. © 2014 The Authors. Source

Pedrozo Z.,Southwestern Medical Center | Pedrozo Z.,Advanced Center for Chronic Diseases | Pedrozo Z.,University of Chile | Criollo A.,Southwestern Medical Center | And 15 more authors.
Circulation | Year: 2015

Background: L-type calcium channel activity is critical to afterload-induced hypertrophic growth of the heart. However, the mechanisms governing mechanical stress-induced activation of L-type calcium channel activity are obscure. Polycystin-1 (PC-1) is a G protein-coupled receptor-like protein that functions as a mechanosensor in a variety of cell types and is present in cardiomyocytes. Methods and Results-We subjected neonatal rat ventricular myocytes to mechanical stretch by exposing them to hypoosmotic medium or cyclic mechanical stretch, triggering cell growth in a manner dependent on L-type calcium channel activity. RNAi-dependent knockdown of PC-1 blocked this hypertrophy. Overexpression of a C-terminal fragment of PC-1 was sufficient to trigger neonatal rat ventricular myocyte hypertrophy. Exposing neonatal rat ventricular myocytes to hypo-osmotic medium resulted in an increase in α1C protein levels, a response that was prevented by PC-1 knockdown. MG132, a proteasomal inhibitor, rescued PC-1 knockdown-dependent declines in α1C protein. To test this in vivo, we engineered mice harboring conditional silencing of PC-1 selectively in cardiomyocytes (PC-1 knockout) and subjected them to mechanical stress in vivo (transverse aortic constriction). At baseline, PC-1 knockout mice manifested decreased cardiac function relative to littermate controls, and α1C L-type calcium channel protein levels were significantly lower in PC-1 knockout hearts. Whereas control mice manifested robust transverse aortic constriction-induced increases in cardiac mass, PC-1 knockout mice showed no significant growth. Likewise, transverse aortic constriction-elicited increases in hypertrophic markers and interstitial fibrosis were blunted in the knockout animals Conclusion-PC-1 is a cardiomyocyte mechanosensor that is required for cardiac hypertrophy through a mechanism that involves stabilization of α1C protein. © 2015 American Heart Association, Inc. Source

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