Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

The chemotherapeutic agent doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10% of pediatric cancer survivors will 10–20 years later develop severe dilated cardiomyopathy (DCM), whereby the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidence, we first argue why a dilated phenotype can occur when little apoptosis is detected. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream of mitochondrial outer membrane permeabilisation (MOMP). This lack of MOMP induction is proposed to alter the metabolic phenotype, induce hypertrophic remodeling, and lead to functional cardiac impairment even in the absence of cardiomyocyte apoptosis. We discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosis-primed cancer cells and propose computational system biology as a tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DC

The Making of the Japanese Physicist

The image of a hi-tech samurai has often been invoked to describe Japan’s post-World War II economic success. But such references to the role of Japan’s warrior class go back to the beginning of the twentieth century. “Scratch a Japanese of the most advanced ideas, and he will show a samurai”1—so wrote Inazō Nitobe in his classic text, Bushido: The Soul of Japan, first published in 1900 and then in a revised form in 1905, the year of Japan’s victory in the Russo-Japanese War (1904–1905). Nitobe, who studied politics and international relations at Johns Hopkins University in Baltimore during the years 1884–1887, develops an argument, along the lines that “What Japan was she owed to the samurai.”2 He suggests that the samurai became an ideal for the Japanese and that the spirit of bushidō permeated all social classes