STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA-alkylating agent temozolomide (TMZ) concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to TMZ-induced DNA damage due to elevated expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Here we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of TMZ resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or shRNA downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of IL-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens demonstrated significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (pSTAT3) (P < 0.001, r = 0.58). Importantly, the levels of both MGMT and pSTAT3 were increased in the recurrence compared to the primary lesion in paired identical tumors of 12 cases. Finally, we demonstrated that STAT3 inhibitor or STAT3 knockdown potentiated TMZ efficacy in TMZ-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with TMZ for TMZ-resistant GBM patients

Expression of O6-methylguanine DNA methyltransferase (MGMT) and immunohistochemical analysis of 12 pineal parenchymal tumors

Pineal parenchymal tumors (PPTs) are rare neoplasms which occupy less than 1% of primary central nervous system tumors. Because of their rare incidence, the previous reports on PPTs are limited in number and the useful molecular markers for deciding the histological grading and even selecting chemotherapy are undetermined. In this study, we conducted immunohistochemical analysis of 12 PPT specimens, especially for expression of O6-methylguanine DNA methyltransferase (MGMT) to assess whether temozolomide (TMZ) could serve as a possible alternative therapy for PPTs. We analyzed 12 PPTs consisting of 3 pineocytomas, 6 pineal parenchymal tumors of intermediate differentiation (PPTIDs), and 3 pineoblastomas. Immunohistochemical analysis was performed using antibody against MGMT, synaptophysin, neurofilament protein (NF), p53, and NeuN. Immunohistochemically, 11 out of 12 cases were positive for MGMT. The mean MIB-1 labeling index was less than 1% in pineocytoma, 3.5% in PPTID, and 10.5% in pineoblastoma. All 12 cases were positive for synaptophysin and 11 cases except 1 PPTID case showed positive for NF. Nuclear staining of NeuN was negative in all cases although cytoplasmic stain of NeuN was observed in 5 cases. No case was positive for p53. Eleven out of 12 cases of PPTs demonstrated MGMT expression, suggesting chemoresistancy to TMZ treatment. This is the first report showing MGMT expression in PPTs. In addition, MIB-1 labeling index correlated with WHO grade, although the immunoreactivity of synaptophysin, NF, NeuN, and p53 did not correlate with the histological grade

Low-lying strength in Sn photoneutron reactions

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Partially Ordered Preferences in Decision Trees: Computing Strategies with Imprecision in Probabilities

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Extra γ-ray strength for 116,117Sn arising from pygmy dipole resonance

Photoneutron cross sections were measured for 117Sn and 116Sn near neutron thresholds with quasi-monochromatic laser Compton scattering γ-rays. The measured cross sections for 117Sn and 116Sn are strongly enhanced from the threshold behavior expected for L=1 neutron emissions after E1 photoexcitation. This suggests the presence of extra γ-ray strength in the low-energy tail of the giant dipole resonance. The present cross sections were analyzed together with radiative neutron capture cross sections for 116Sn within the framework of the statistical model calculation. It is shown that the extra γ-ray strength can be interpreted as pygmy E1 resonance which was previously reported in the nuclear resonance fluorescence experiment for 116Sn and 124Sn. © 2010 American Institute of Physics.SCOPUS: cp.pinfo:eu-repo/semantics/publishe

Extra gamma-ray strength for 116,117Sn arising from pygmy dipole resonance

info:eu-repo/semantics/publishe