Cardiac Structure and Function in Men with Prostate Cancer Receiving Androgen-Deprivation Therapy and the Effects of Recreational Small-Sided Football Training:A Randomized Controlled Trial

Purpose: Androgen deprivation therapy (ADT) is a cornerstone in prostate cancer (PCa) management that prolongs PCa-free and overall survival, but effects of ADT on human cardiac function have not been investigated. We used echocardiography to examine cardiac structure and function in patients with prostate cancer receiving ADT and to determine whether an exercise intervention can elicit cardiac adaptations in these subjects. Methods: Forty-three patients with prostate cancer receiving ADT were randomized to 12 weeks football training (ST group;n = 20) or usual care (control [CO] group;n = 23). Cardiac function was assessed at baseline and after 12 weeks by comprehensive echocardiography. Peak oxygen consumption, blood pressure and peripheral microvascular function was also measured. Results: At baseline, no considerable echocardiographic abnormalities were observed. In the ST group, increases in left ventricular diastolic function variables including E/A ratio (P = 0.03), E’ (P = 0.016), E’TDIcolor (P = 0.040) and in left atrial diameter (P = 0.001) were observed after 12 weeks. In addition, diastolic blood pressure (P = 0.027) and resting heart rate (P 0.001) were reduced after ST. In the CO group, no significant changes were observed in the examined variables after 12 weeks. Despite within group changes in the ST group, no significant differences were observed after 12 weeks between groups in echocardiographic variables, peak oxygen consumption, blood pressure and peripheral microvascular function. Conclusion: In men with prostate cancer receiving ADT, echocardiography showed no abnormalities in cardiac structure and function. Twelve weeks of ST failed to elicit significant cardiovascular adaptations and ADT may blunt cardiovascular adaptations to short-term exercise training.

Deregulation of tumor suppressive ASXL1−PTEN/AKT axis in myeloid malignancies

Mutations of epigenetic regulators are pervasive in human tumors.ASXL1 is frequently mutated in myeloid malignancies.We previously found that ASXL1 forms together with BAP1 a complex that can deubiquitinylate mono-ubiquitinylated lysine 119 on histone H2A(H2AK119ub1),a Polycomb repressive mark.However,a complete mechanistic understanding of ASXL1 in transcriptional regulation and tumor suppression remains to be defined.Here,we find that depletion of Asxl1 confers murine 32D cells to IL3-independent growth at least partly due to sustained activation of PI3K/AKT signaling.Consistently,Asxl1 is critical for the transcriptional activation of Pten,a key negative regulator of AKT activity.Then we confirm that Asxl1 is specifically enriched and required for H2AK119 deubiquitylation at the Pten promoter.Interestingly,ASXL1 and PTEN expression levels are positively correlated in human blood cells and ASXL1 mutations are associated with lower expression levels of PTEN in human myeloid malignancies.Furthermore,malignant cells with ASXL1 downregulation or mutations exhibit higher sensitivity to the AKT inhibitor MK2206.Collectively,this study has linked the PTEN/AKT signaling axis to deregulated epigenetic changes in myeloid malignancies.It also provides a rationale for mechanism-based therapy for patients with ASXL1 mutations.