No abstract

Two Re‐Os dating reference material molybdenites were prepared. Molybdenite JDC and molybdenite HLP are from a carbonate vein‐type molybdenum‐(lead)‐uranium deposit in the Jinduicheng‐Huanglongpu area of Shaanxi province, China. The samples proved to be homogeneous, based on the coefficient of variation of analytical results and an analysis of variance test. The sampling weight was 0.1 g for JDC and 0.025 g for HLP. An isotope dilution method was used for the determination of Re and Os. Sample decomposition and pre‐concentration of Re and Os prior to measurement were accomplished using a variety of methods: acid digestion, alkali fusion, ion exchange and solvent extraction. Negative thermal ionisation mass spectrometry and inductively coupled plasma‐mass spectrometry were used for the determination of Re and 187Os concentration and isotope ratios. The certified values include the contents of Re and Os and the model ages. For HLP, the Re content was 283.8 ± 6.2 μg g−1, 187Os was 659 ± 14 ng g−1 and the Re‐Os model age was 221.4 ± 5.6 Ma. For JDC, the Re content was 17.39 ± 0.32 μg g−1, 187Os was 25.46 ± 0.60 ng g−1 and the Re‐Os model age was 139.6 ± 3.8 Ma. Uncertainties for both certified reference materials are stated at the 95% level of confidence. Three laboratories (from three countries: PR. China, USA, Sweden) joined in the certification programme. These certified reference materials are primarily useful for Re‐Os dating of molybdenite, sulfides, black shale, etc.

PURPOSE Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation. METHODS This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway–activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2. RESULTS Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]). CONCLUSION Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

SUV measured in patients with esophageal cancer, reflecting the metabolic activity of tumor and malignancy, could serve as a prognostic factor. Considering that the FDG-PET can add important information of metabolism in detection and staging to conventional imaging modality, we anticipate that SUV could be used in patients with esophageal carcinoma.

Background Temozolomide (TMZ) resistance in glioblastoma multiforme (GBM) is mediated by the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT). MGMT promoter methylation (occurs in about 40% of patients) is associated with loss of MGMT expression (MGMT−) that compromises DNA repair, leading to a favorable response to TMZ therapy. The 60% of patients with unmethylated MGMT (MGMT+) GBM experience resistance to TMZ; in these patients, understanding the mechanism of MGMT-mediated repair and modulating MGMT activity may lead to enhanced TMZ activity. Here, we report a novel mode of regulation of MGMT protein activity by poly(ADP-ribose) polymerase (PARP). Methods MGMT-PARP interaction was detected by co-immunoprecipitation. PARylation of MGMT and PARP was detected by co-immunoprecipitation with anti-PAR antibody. O6-methylguanine (O6-MetG) adducts were quantified by immunofluorescence assay. In vivo studies were conducted in mice to determine the effectiveness of PARP inhibition in sensitizing GBM to TMZ. Results We demonstrated that PARP physically binds with MGMT and PARylates MGMT in response to TMZ treatment. In addition, PARylation of MGMT by PARP is required for MGMT binding to chromatin to enhance the removal of O6-MetG adducts from DNA after TMZ treatment. PARP inhibitors reduced PARP-MGMT binding and MGMT PARylation, silencing MGMT activity to repair O6-MetG. PARP inhibition restored TMZ sensitivity in vivo in MGMT-expressing GBM. Conclusion This study demonstrated that PARylation of MGMT by PARP is critical for repairing TMZ-induced O6-MetG, and inhibition of PARylation by PARP inhibitor reduces MGMT function rendering sensitization to TMZ, providing a rationale for combining PARP inhibitors to sensitize TMZ in MGMT-unmethylated GBM.