Predictive value of MGMT promoter methylation on the survival of TMZ treated IDH-mutant glioblastoma

Objective:O6 methylguanine-DNA methyltransferase(MGMT)promoter methylation is a biomarker widely used to predict the sensitivity of IDH-wildtype glioblastoma to temozolomide therapy.Given that the IDH status has critical effects on the survival and epigenetic features of glioblastoma,we aimed to assess the role of MGMT promoter methylation in IDH-mutant glioblastoma.Methods:This study included 187 IDH-mutant glioblastomas and used 173 IDH-wildtype glioblastomas for comparison.KaplanMeier curves and multivariate Cox regression were used to study the predictive effects.Results:Compared with IDH-wildtype glioblastomas,IDH-mutant glioblastomas showed significantly higher(P<0.0001)MGMT promoter methylation.We demonstrated that MGMT promoter methylation status,as determined by a high cutoff value(≥30%)in pyrosequencing,could be used to significantly stratify the survival of 50 IDH-mutant glioblastomas receiving temozolomide therapy(cohort A);this result was validated in another cohort of 25 IDH-mutant glioblastomas(cohort B).The median progression-free survival and median overall survival in cohort A were 9.33 and 13.76 months for unmethylated cases,and 18.37 and 41.61 months for methylated cases,and in cohort B were 6.97 and 9.10 months for unmethylated cases,and 23.40 and 26.40 months for methylated cases.In addition,we confirmed that the MGMT promoter methylation was significantly(P=0.0001)correlated with longer OS in IDH-mutant patients with GBM,independently of age,gender distribution,tumor type(primary or recurrent/secondary),and the extent of resection.Conclusions:MGMT promoter methylation has predictive value in IDH-mutant glioblastoma,but its cutoff value should be higher than that for IDH-wildtype glioblastoma.

The accumulation and toxicity of ZIF-8 nanoparticles in Corbicula fluminea

Metal-organic frameworks(MOFs)are promising new materials that have been intensively studied and possibly applied to various environmental remediation.However,little is known about the fate and risk of MOFs to living organisms in thewater environment.Here,the toxic effects of ZIF-8 nanoparticles(NPs)on benthic organisms were confirmed by sub-chronic toxicity experiments(7 and 14 days)using Corbicula fluminea as the model organism.With exposure doses ranging from 0 to 50 mg/L,ZIF-8 NPs induced oxidative stress behaviors similar to the hormesis effect in the tissues of C.fluminea.The oxidative stress induced by ZIF-8 NPs and the released Zn^(2+)was the crucial cause of the toxic effects.Besides,we also found that the ZIF-8 NPs and dissolved Zn^(2+)may result in different mechanisms of toxicity and accumulation depending on the dosages.The Zn^(2+)release rate of ZIF-8NPswas high at low dosages,leading to a higher proportion of Zn^(2+)taken up by C.fluminea than the particulate ZIF-8.Conversely,at high dosages,C.fluminea mainly ingested the ZIF-8 NPs and resulted in increased mortality.The results have important implications for understanding the fate and biological effects of ZIF-8 in natural aquatic environments.