CLU blocks HDACI-mediated killing of neuroblastoma

Clusterin is a ubiquitously expressed glycoprotein with multiple binding partners including IL-6, Ku70, and Bax. Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing cytochrome c, and triggering apoptosis. Because increased clusterin expression correlates with aggressive behavior in tumors, clusterin inhibition might be beneficial in cancer treatment. Our recent findings indicated that, in neuroblastoma cells, cytoplasmic Bax also binds to Ku70; when Ku70 is acetylated, Bax is released and can initiate cell death. Therefore, increasing Ku70 acetylation, such as by using histone deacetylase inhibitors, may be therapeutically useful in promoting cell death in neuroblastoma tumors. Since clusterin, Bax, and Ku70 form a complex, it seemed likely that clusterin would mediate its anti-apoptotic effects by inhibiting Ku70 acetylation and blocking Bax release. Our results, however, demonstrate that while clusterin level does indeed determine the sensitivity of neuroblastoma cells to histone deacetylase inhibitor-induced cell death, it does so without affecting histone deacetylase-inhibitor-induced Ku70 acetylation. Our results suggest that in neuroblastoma, clusterin exerts its anti-apoptotic effects downstream of Ku70 acetylation, likely by directly blocking Bax activation

Four-Dimensional Magnetic Resonance Imaging Assessment of Intracranial Aneurysms: A State-of-the-Art Review

Treatment of unruptured intracranial aneurysms can reduce the risk of subarachnoid hemorrhage and its associated morbidity and mortality. However, current methods to predict the risk of rupture and optimize treatment strategies for intracranial aneurysms are limited. Assessment of intra-aneurysmal flow using 4-dimensional magnetic resonance imaging (4D MRI) is a novel tool that could be used to guide therapy. A systematic search of the literature was performed to provide a state-of-the-art review on 4D MRI assessment of unruptured intracranial aneurysms. A total of 18 studies were available for review. Eccentric flow on 4D MRI is associated with a greater aspect ratio and peak wall shear stress (WSS). WSS, vorticity, and peak velocity are greater in saccular than fusiform aneurysms. Unstable aneurysms are associated with greater WSS, peak wall stress, and flow jet angle and may exhibit wall enhancement. In comparison to computational fluid dynamics (CFD), 4D MRI has a lower spatial resolution and reports lower WSS and velocity magnitudes, but these parameters equalize when spatial resolution is matched. 4D MRI demonstrates the intra-aneurysmal hemodynamic changes associated with flow diversion, including significantly decreased flow velocity. Thus, 4D MRI is a novel, noninvasive imaging tool used for the evaluation of hemodynamics within intracranial aneurysms. Hemodynamic indices derived from 4D MRI appear to correlate well with the simulated (CFD) values and may be used to measure the success of endovascular therapies and risk factors for aneurysm growth and rupture