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We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

Background −Cardiac glycosides initiate an increase in force of contraction by inhibiting the sarcolemmal sodium pump (Na + ,K + -ATPase), thereby decreasing Ca 2+ extrusion by the Na + -Ca 2+ exchanger, which increases the cellular content of Ca 2+ . In patients with heart failure the sensitivity toward cardiac glycosides is enhanced. Methods and Results −Because the inotropic effect of cardiac glycosides may be a function of the sodium pump and Na + -Ca 2+ exchanger (NCE) expression levels, the present study aimed to investigate protein expression of both transporters (immunoblot with specific antibodies against the sodium pump catalytic α 1 -, α 2 -, α 3 -, and glycoprotein β 1 -isoforms and against NCE) in left ventricle from failing (heart transplantations, New York Heart Association class IV, n=21) compared with nonfailing (donor hearts, NF, n=22) human myocardium. The density of 3 H-ouabain–binding sites (B max ) and the Na + ,K + -ATPase activity were also measured. In NYHA class IV, protein levels of Na + ,K + -ATPase α 1 - (0.62±0.06 of control), α 3 - (0.70±0.09), and β 1 - (0.61±0.04) but not α 2 -isoforms were significantly reduced ( P + ,K + -ATPase activity (NF: 1.9±0.29; NYHA class IV: 1.1±0.17 μmol ATP/min per milligram of protein) and the 3 H-ouabain binding sites (B max NF: 15.9±1.9 pmol/mg protein; NYHA class IV: 9.7±1.5) were reduced in NYHA class IV and correlated significantly to each other ( r 2 =0.73; P 1 -subunit expression. In left ventricular papillary muscle strips from NYHA class IV compared with nonfailing tissue the Na + -channel modulator BDF 9198 exerted an increase in force of contraction with unchanged effectiveness but enhanced potency. Conclusions −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 + -Ca 2+ exchanger protein expression.

Cardiac contraction is dependent on a rapid alteration of the intracellular Ca(2+) concentration, especially the Ca(2+) released during systole. In end-stage heart failure, cardiac contractility is depressed due to alterations in the structure and function of proteins or protein complexes. Over recent years, new insights have been obtained regarding the regulation of the intracellular Ca(2+) homeostasis and its pathophysiological alteration in end-stage heart failure. This review focuses on the mechanisms involved in the release of Ca(2+) from the sarcoplasmic reticulum (SR) during systole via the ryanodine receptors and the Ca(2+)-uptake into the SR by the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a). In addition, new therapeutic options will be introduced which may be of importance for the treatment of heart failure patients.