Systems analysis of cancer cell heterogeneity in caspase-dependent apoptosis subsequent to mitochondrial outer membrane permeabilization.

Deregulation of apoptosis is a hallmark of carcinogenesis. We here combine live cell imaging and systems modeling to investigate caspase-dependent apoptosis execution subsequent to mitochondrial outer membrane permeabilization (MOMP) in several cancer cell lines. We demonstrate that, although most cell lines that underwent MOMP also showed robust and fast activation of executioner caspases and apoptosis, the colorectal cancer cell lines LoVo and HCT-116 Smac(-/-), similar to X-linked inhibitor of apoptosis protein (XIAP)-overexpressing HeLa (HeLa XIAP(Adv)) cells, only showed delayed and often no caspase activation, suggesting apoptosis impairment subsequent to MOMP. Employing APOPTO-CELL, a recently established model of apoptosis subsequent to MOMP, this impairment could be understood by studying the systemic interaction of five proteins that are present in the apoptosis pathway subsequent to MOMP. Using APOPTO-CELL as a tool to study detailed molecular mechanisms during apoptosis execution in individual cell lines, we demonstrate that caspase-9 was the most important regulator in DLD-1, HCT-116, and HeLa cells and identified additional cell line-specific co-regulators. Developing and applying a computational workflow for parameter screening, systems modeling identified that apoptosis execution kinetics are more robust against changes in reaction kinetics in HCT-116 and HeLa than in DLD-1 cells. Our systems modeling study is the first to draw attention to the variability in cell specific protein levels and reaction rates and to the emergent effects of such variability on the efficiency of apoptosis execution and on apoptosis impairment subsequent to MOMP

Optimal Medical Therapy With or Without Surgical Revascularization and Long-Term Outcomes in Ischemic Cardiomyopathy

OBJECTIVES: Optimal medical therapy in patients with heart failure and coronary artery disease is associated with improved outcomes. However, whether this association is influenced by the performance of coronary artery bypass grafting is less well established. Thus, the aim of this study was to determine the possible relationship between coronary artery bypass grafting and optimal medical therapy and its effect on the outcomes of patients with ischemic cardiomyopathy. METHODS: The Surgical Treatment for Ischemic Heart Failure trial randomized 1212 patients with coronary artery disease and left ventricular ejection fraction 35% or less to coronary artery bypass grafting with medical therapy or medical therapy alone with a median follow-up over 9.8 years. For the purpose of this study, optimal medical therapy was collected at baseline and 4 months, and defined as the combination of 4 drugs: angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, beta-blocker, statin, and 1 antiplatelet drug. RESULTS: At baseline and 4 months, 58.7% and 73.3% of patients were receiving optimal medical therapy, respectively. These patients had no differences in important parameters such as left ventricular ejection fraction and left ventricular volumes. In a multivariable Cox model, optimal medical therapy at baseline was associated with a lower all-cause mortality (hazard ratio, 0.78; 95% confidence interval, 0.66-0.91; P = .001). When landmarked at 4 months, optimal medical therapy was also associated with a lower all-cause mortality (hazard ratio, 0.82; 95% confidence interval, 0.62-0.99; P = .04). There was no interaction between the benefit of optimal medical therapy and treatment allocation. CONCLUSIONS: Optimal medical therapy was associated with improved long-term survival and lower cardiovascular mortality in patients with ischemic cardiomyopathy and should be strongly recommended