Search

BACKGROUND AND AIMS: Cardiovascular disease risk is associated with coronary artery calcification and is mitigated by regular exercise. Paradoxically, elite endurance athletes, who have low risk, are likely to have more coronary calcification, raising questions about the optimal level of activity. METHODS: Female hyperlipidemic (Apoe-/-) mice with baseline aortic calcification were subjected to high-speed (18.5 m/min), low-speed (12.5 m/min), or no treadmill exercise for 9 weeks. 18F-NaF microPET/CT images were acquired at weeks 0 and 9, and echocardiography was performed at week 9. RESULTS: In controls, aortic calcium content and density increased significantly. Exercise regimens did not alter the time-dependent increase in content, but the increase in mean density was blunted. Interestingly, the low-speed regimen significantly reduced 18F-NaF uptake, a marker of surface area. Left ventricular (LV) systolic function was lower while LV diameter was greater in the low-speed group compared with controls or the high-speed group. In the low-speed group, vertebral bone density by CT decreased significantly, contrary to expectations. Male hyperlipidemic (Apoe-/-) mice were fed a Western diet and also subjected to low-speed or no exercise followed by imaging at weeks 0 and 9. In males, exercise also did not alter the time-dependent increase in aortic calcification. Exercise did not affect 18F-NaF uptake or bone mineral density, but it blunted the diet-induced LV hypertrophy seen in controls. CONCLUSIONS: These results suggest that, in mice, exercise has differential effects on aortic calcification, cardiac function, and skeletal bone mineral density.

BACKGROUND: Coronary calcification associates closely with cardiovascular risk, but its progress is accelerated in response to some interventions widely used to reduce risk. This paradox suggests that qualitative, not just quantitative, changes in calcification may affect plaque stability. To determine if the microarchitecture of calcification varies with aging, Western diet, statin therapy, and high intensity, progressive exercise, we assessed changes in a priori selected computed tomography radiomic features (intensity, size, shape, and texture). METHODS: Longitudinal computed tomography scans of mice (Apoe-/-) exposed to each of these conditions were autosegmented by deep learning segmentation, and radiomic features of the largest deposits were analyzed. RESULTS: Over 20 weeks of aging, intensity and most size parameters increased, but surface-area-to-volume ratio (a measure of porosity) decreased, suggesting stabilization. However, texture features (coarseness, cluster tendency, and nonuniformity) increased, suggesting heterogeneity and likely destabilization. Shape parameters showed no significant changes, except sphericity, which showed a decrease. The Western diet had significant effects on radiomic features related to size and texture, but not intensity or shape. In mice undergoing either pravastatin treatment or exercise, the selected radiomic features of their computed tomography scans were not significantly different from those of their respective controls. Interestingly, the total number of calcific deposits increased significantly less in the 2 intervention groups compared with the respective controls, suggesting more coalescence and/or fewer de novo deposits. CONCLUSIONS: Thus, aging and standard interventions alter the microarchitectural features of vascular calcium deposits in ways that may alter plaque biomechanical stability.

[Figure: see text].

The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitors erlotinib and osimertinib were tested separately in combination with the JAK2 inhibitor AZD1480. Combination therapy induced apoptosis of glioblastoma tumors in both flank and in patient-derived orthotopic xenograft models, providing a preclinical rationale to test analogous combinations in patients. SIGNIFICANCE: These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.