Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy

Resistance to platinum chemotherapy is a long-standing problem in the management of lung adenocarcinoma. Using a whole-genome synthetic lethal RNA interference screen, we identified activin signaling as a critical mediator of innate platinum resistance. The transforming growth factor-β (TGFβ) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGFβ-activated kinase 1 (TAK1), rather than through the SMAD family of transcription factors. Inhibition of activin receptor signaling or blockade of activin A and GDF11 by the endogenous protein follistatin overcame this resistance. Consistent with the role of activin signaling in acute renal injury, both therapeutic interventions attenuated acute cisplatin-induced nephrotoxicity, its major dose-limiting side effect. This cancer-specific enhancement of platinum-induced cell death has the potential to dramatically improve the safety and efficacy of chemotherapy in lung cancer patients.Kieren D. Marini … Luciano G. Martelotto … et al

Correlacionando tipos de cultura organizacional com estratégias de remuneração utilizando a tipologia de Charles Handy

Este estudo identificou as correlações entre as estratégias de remuneração e a tipologia de cultura organizacional proposta por Handy (2003) baseada nas dimensões do grau de formalização e centralização que identifica a cultura: Zeus (poder), Apolo (papéis), Atena (tarefa), e Dionísio (pessoa). A pesquisa foi aplicada a gestores de remuneração de 76 empresas associadas ao Grupo de Permuta de Informações Salariais (Grupisa), e os questionários com um construto composto por doze componentes da remuneração organizacional foram analisados utilizando Correlação de Pearson e Regressão Múltipla. Concluímos que as variáveis de remuneração se correlacionam de forma diferente com cada um dos tipos de cultura: (i) organizações "Zeus" devem enfatizar os fatores comportamentais em todas as esferas do sistema de remuneração; (ii) para as organizações "Apolo" a ênfase deve ser aplicada nas oportunidades de crescimento e desenvolvimento, (iii) nas organizações "Atena" o foco deve ser nas recompensas financeiras, e, (iv) organizações "Dionísio" devem dar ênfase à qualidade da remuneração

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used