Glioma stem-like cells (GSCs) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells and it is re-emerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phosphokinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment.

No abstract

Purpose Alzheimer’s disease (AD) is a neurodegenerative disorder that manifests as abnormal behavior and a progressive decline in memory. Although the pathogenesis of AD is due to the excessive deposition of amyloid β protein (Aβ) outside the neurons in the brain, evidence suggests that tau proteins may be a better target for AD therapy. In neurodegenerative diseases, a decrease in autophagy results in the failure to eliminate abnormally deposited or misfolded proteins. Therefore, induction of autophagy may be an effective way to eliminate tau proteins in the treatment of AD. We investigated the effects of polyethylene glycol (PEG)-ceramide nanomicelles on autophagy and on tau proteins in N2a, a murine neuroblastoma metrocyte cell line. Methods Ceramide is a sphingolipid bioactive molecule that induces autophagy. PEG-ceramide is a polymer that is composed of the hydrophobic chain of ceramide and the hydrophilic chain of PEG-2000. In this study, we prepared PEG-ceramide nanomicelles that were 10–20 nm in size and had nearly neutral zeta potential. Results The results show that PEG-ceramide nanomicelles caused an increase in the LC3-II/LC3-I ratio, while p62 protein levels decreased. Confocal microscopy revealed a significant increase in the number of dots corresponding to autophagosomes and autolysosomes, which indicated autophagic activation. Moreover, PEG-ceramide nanomicelles induced tau degradation in N2a cells through autophagy. Conclusion In summary, we have confirmed that PEG-ceramide nanomicelles enhanced autophagic flux and degraded overexpressed human tau proteins in N2a cells by regulating the autophagy pathway. Thus, PEG-ceramide nanomicelles show great promise as agents to induce autophagy and degrade tau proteins in the treatment of AD.

BackgroundThe findings of epidemiologic studies on the association between fiber intake and prostate cancer risk remain conflicting. We aimed to examine this association by conducting a meta-analysis of epidemiological studies.MethodsRelevant studies were identified by PubMed (1966 to March 2015) and Embase (1974 to March 2015) database search through March 2015. We included epidemiological studies that reported relative risks (RRs) or odds ratios (ORs) with 95 % confidence intervals (CIs) for the association between dietary fiber intake and prostate cancer risk. Random effects models were used to calculate the summary risk estimates.ResultsFor the highest compared with the lowest dietary fiber intake, a significantly decreased risk with prostate cancer was observed in case-control studies (OR = 0.82; 95 % CI, 0.68–0.96), but not in cohort studies (RR = 0.94; 95 % CI, 0.77–1.11). The combined risk estimate of all studies was 0.89 (95 % CI, 0.77, 1.01). A significant heterogeneity was observed across studies (p = 0.005). There was no evidence of significant publication bias based on Begg’s funnel plot (p = 0.753) or Egger’s test (p = 0.946).ConclusionsThis meta-analysis suggests the absence of evidence for association between dietary fiber intake and prostate cancer risk.