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Summary: Cellular phenotypes of apoptosis, as well as the activation of apoptosis caspase cascades, are well described. However, sequences and locations of early biochemical effector events after apoptosis initiation are still only partly understood. Here, we use integrated modulation of protein interaction states-cellular thermal shift assay (IMPRINTS-CETSA) to dissect the cellular biochemistry of early stages of apoptosis at the systems level. Using 5 families of cancer drugs and a new CETSA-based method to monitor the cleavage of caspase targets, we discover the initial biochemistry of the effector stage of apoptosis for all the studied drugs being focused on the peripheral nuclear region rather than the cytosol. Despite very different candidate apoptosis-inducing mechanisms of the drug families, as revealed by the CETSA data, they converge into related biochemical modulations in the peripheral nuclear region. This implies a higher control of the localization of the caspase cascades than previously anticipated and highlights the nuclear periphery as a critical vulnerability for cancer therapies.

Aim: Here, we studied the incidence of acute cardiovascular toxicities in children treated for acute lymphoblastic leukaemia (ALL). Methods: We performed a population-based single-centre longitudinal retrospective cohort study in 70 children diagnosed and treated with anthracycline-containing therapy against ALL at Karolinska University Hospital during 2015–2019 with a follow-up period of at least three months. Cardiovascular surveillance for these patients included echocardiography with measurements of left ventricular ejection fraction (LVEF) and shortening fraction (LVSF), electrocardiography and non-invasive blood pressure monitoring. Results: No patient experienced a significant decrease in LVEF or LVSF during or early after primary cancer treatment including anthracyclines. Surveillance with LVEF and LVSF was unable to predict the trajectory to severe clinical heart failure in one patient following treatment. Pericardial effusion prior to therapy initiation occurred in 13.6% of the patients. The incidence of intracardiac thrombosis and arterial hypertension was 8.5%, and 20%, respectively. Conclusion: Early cardiovascular toxicities were common in this paediatric ALL cohort. We confirm that early routine LVEF and LVSF assessments were insufficient to identify patients at risk of subsequent treatment-related heart failure. This underlines the unmet need of more sensitive methods for cardiovascular surveillance in children treated for cancer to reduce the burden of cardiovascular morbidity and mortality.