Dilated cardiomyopathy and end-stage heart failure result in multiple defects in cardiac excitation-contraction coupling. Via complementation of a genetically based mouse model of dilated cardiomyopathy, we now provide evidence that progressive chamber dilation and heart failure are dependent on a Ca2+ cycling defect in the cardiac sarcoplasmic reticulum. The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure. Inhibition of phospholamban-SERCA2a interaction via in vivo expression of a phospholamban point mutant dominantly activated the contractility of ventricular muscle cells. Thus, interfering with phospholamban-SERCA2a interaction may provide a novel therapeutic approach for preventing the progression of dilated cardiomyopathy.

Purpose: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adenoand squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer.Experimental Design: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-na€ ve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC.Results: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio !2.0 or average gene copy number per nucleus !6.0 or !10% of tumor cells containing !15 MET copies). The remaining cases can be subdivided into intermediate-(6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations.Conclusion: MET amplification is not a mutually exclusive genetic event in therapy-na€ ve non-small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors. Clin Cancer Res; 21(4); 907-15. Ó2014 AACR.

The increased expression of the Na(+)-Ca2+ exchanger is a possible explanation for the increased inotropic potency of the Na+ channel activator BDF 9148 in failing human myocardium. The increase in exchanger molecules could be of functional relevance for the modulation of cardiac contractility by agents that increase the intracellular Na+ concentration. Enhancement of Na(+)-Ca2+ exchanger activity might be a powerful mechanism for increasing cardiac contractility in chronic heart failure.

The enhanced sensitivity of failing human myocardium toward cardiac glycosides may be, at least in part, attributed to a reduced protein expression and activity of the sarcolemmal Na+,K+-ATPase without a change in Na+-Ca2+ exchanger protein expression.