Bid participates in genotoxic drug-induced apoptosis of HeLa cells and is essential for death receptor ligands' apoptotic and synergistic effects

Background: The BH3-only protein Bid is an important component of death receptor-mediated caspase activation. Bid is cleaved by caspase-8 or -10 into t-Bid, which translocates to mitochondria and triggers the release of caspase-activating factors. Bid has also been reported to be cleaved by other proteases. Methodology/Principal Findings: To test the hypothesis that Bid is a central mediator of stress-induced apoptosis, we investigated the effects of a small molecule Bid inhibitor on stress-induced apoptosis, and generated HeLa cells deficient for Bid. Stable knockdown of bid lead to a pronounced resistance to Fas/CD95- and TRAIL-induced caspase activation and apoptosis, and significantly increased clonogenic survival. While Bid-deficient cells were equally sensitive to ER stress-induced apoptosis, they showed moderate, but significantly reduced levels of apoptosis, as well as increased clonogenic survival in response to the genotoxic drugs Etoposide, Oxaliplatin, and Doxorubicin. Similar effects were observed using the Bid inhibitor BI6C9. Interestingly, Bid-deficient cells were dramatically protected from apoptosis when subtoxic concentrations of ER stressors, Etoposide or Oxaliplatin were combined with subtoxic TRAIL concentrations. Conclusions/Significance: Our data demonstrate that Bid is central for death receptor-induced cell death and participates in anti-cancer drug-induced apoptosis in human cervical cancer HeLa cells. They also show that the synergistic effects of TRAIL in combination with either ER stressors or genotoxic anti-cancer drugs are nearly exclusively mediated via an increased activation of Bid-induced apoptosis signalling

Legal Consequences of Apologizing

This article discusses the legal consequences of saying you are sorry, whether as an apology or an expression of sympathy. It discusses questions such as whether an apology is understood to be an admission of guilt, whether an apology fulfills any elements of a tort, how an apology can be useful for avoiding litigation, how an expression of sympathy should be worded to minimize the possibility that it could be misunderstood to be an admission of guilt, and why someone who is guilty of some error should apologize without concern that this would make their situation worse. It analyzes various apologies in the context of medical malpractice, attorney discipline, and correcting mistakes at trial

Systematics of heavy-ion fusion hindrance at extreme sub-barrier energies

The recent discovery of hindrance in heavy-ion induced fusion reactions at extreme sub-barrier energies represents a challenge for theoretical models. Previously, it has been shown that in medium-heavy systems, the onset of fusion hindrance depends strongly on the "stiffness" of the nuclei in the entrance channel. In this work, we explore its dependence on the total mass and the $Q$-value of the fusing systems and find that the fusion hindrance depends in a systematic way on the entrance channel properties over a wide range of systems.Comment: Submitted to Phys. Rev. Lett., 5 pages, 3 figure

Alcohol-attributable mortality in Switzerland in 2011--age-specific causes of death and impact of heavy versus non-heavy drinking.

BACKGROUND: Alcohol use causes high burden of disease and injury globally. Switzerland has a high consumption of alcohol, almost twice the global average. Alcohol-attributable deaths and years of life lost in Switzerland were estimated by age and sex for the year 2011. Additionally, the impact of heavy drinking (40+grams/day for women and 60+g/day for men) was estimated. METHODS: Alcohol consumption estimates were based on the Addiction Monitoring in Switzerland study and were adjusted to per capita consumption based on sales data. Mortality data were taken from the Swiss mortality register. Methodology of the Comparative Risk Assessment for alcohol was used to estimate alcohol-attributable fractions. RESULTS: Alcohol use caused 1,600 (95% CI: 1,472 - 1,728) net deaths (1,768 deaths caused, 168 deaths prevented) among 15 to 74 year olds, corresponding to 8.7% of all deaths (men: 1,181 deaths; women: 419 deaths). Overall, 42,627 years of life (9.7%, 95% CI: 40,245 - 45,008) were lost due to alcohol. Main causes of alcohol-attributable mortality were injuries at younger ages (15-34 years), with increasing age digestive diseases (mainly liver cirrhosis) and cancers (particularly breast cancers among women). The majority (62%) of all alcohol-attributable deaths was caused by chronic heavy drinking (men: 67%; women: 48 %). CONCLUSION: Alcohol is a major cause of premature mortality in Switzerland. Its impact, among young people mainly via injuries, among men mainly through heavy drinking, calls for a mix of preventive actions targeting chronic heavy drinking, binge drinking and mean consumption

Mortality risk and mental disorders: longitudinal results from the Upper Bavarian Study

The object of the study was the assessment of the mortality risk for persons with a mental disorder in an unselected representative community sample assessed longitudinally. Subjects from a rural area in Upper Bavaria (Germany) participated in semi-structured interviews conducted by research physicians in the 1970s (first assessment) and death-certificate diagnoses were obtained after an interval up to 13 years later. The sample consisted of 1668 community residents aged 15 years and over. Cox regression estimates resulted in an odds ratio of 1·35 (confidence interval 1·01 to 1·81) for persons with a mental disorder classified as marked to very severe. The odds ratio increased with increasing severity of mental illness from 1·04 for mild disorders, 1·30 for marked disorders, to 1·64 for severe or very severe disorders. The relative risk (odds ratio) for persons with a mental disorder only and no somatic disorder was 1·22, for persons with only a somatic disorder 2·00, and for those with both a mental and a somatic disorder 2·13. The presence of somatic illness was responsible for most of the excess mortality. Somatic disorders associated with excess mortality in mental disorders were diseases of the nervous system or sensory organs, diseases of the circulatory system, diseases of the gastrointestinal tract, and diseases of the skeleton, muscles and connective tissue (ICD-8). Thus, while mental illness alone had a limited effect on excess mortality, comorbidity with certain somatic disorders had a significant effec

Non-fatal injuries in three Central and Eastern European urban population samples: the HAPIEE study

Background: Despite high mortality from injuries and accidents, data on rates and distribution of non-fatal injuries in Central and Eastern European populations are scarce. Methods: Cross-sectional study of random population samples of 45–69-year-old men and women (n = 28 600) from Novosibirsk (Russia), Krakow (Poland) and six Czech towns, participating in the Health, Alcohol and Psychosocial factors In Eastern Europe (HAPIEE) study. Participants provided information on non-fatal injuries in the past 12 months, socio-economic characteristics, alcohol consumption and other covariates. Results: The period prevalence of non-fatal injuries in the last year among Czech, Russian and Polish men was 12.5, 9.4 and 5.3%, respectively; among women, the respective proportions were 9.9, 9.8 and 6.4%. Injury prevalence declined with age in men and increased with age in women. Higher injury prevalence was associated with being unmarried, material deprivation, higher drinking frequency and problem drinking. In the pooled data, the adjusted odds ratio (OR) for the highest versus lowest material deprivation category was 1.57 [95% confidence interval (CI) 1.38–1.79]; for problem drinking, the OR was 1.44 (95% CI 1.23–1.69). Alcohol did not mediate the link between socio-economic status and injury. Conclusion: Non-fatal injuries were associated with material deprivation, other socio-economic characteristics and with alcohol. These results not only underscore the universality of the inequality phenomenon, but also suggest that the mediating role of alcohol in social differentials in non-fatal injury remains an unresolved issue