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Purpose: Glioblastoma (GBM) stands out as the most prevalent and aggressive intracranial tumor, notorious for its poor prognosis. The current standard-of-care for GBM patients involves surgical resection followed by radiotherapy, combined with concurrent and adjuvant chemotherapy using Temozolomide (TMZ). The effectiveness of TMZ primarily relies on the activity of O6-methylguanine DNA methyltransferase (MGMT), which removes alkyl adducts from the O6 position of guanine at the DNA level, thereby counteracting the toxic effects of TMZ. Method: In this study, we employed fusions of catalytically-inactive Cas9 (dCas9) to DNA methyltransferases (dCas9-DNMT3A) to selectively downregulation MGMT transcription by inducing methylation at MGMT promoter and K-M enhancer. Result: Our findings demonstrate a significant reduction in MGMT expression, leading to intensified TMZ sensitivity in the HEK293T cell line. Conclusion: This study serves as a proof of concept for the utilization of CRISPR-based gene suppression to overcome TMZ resistance and enhance the lethal effect of TMZ in glioblastoma tumor cells. [ABSTRACT FROM AUTHOR]

Previous studies have found an association between HLA‐B*1502 allele and lamotrigine‐induced Stevens‐Johnson syndrome (SJS)/ toxic epidermal necrosis (TEN) spectrum in Han Chinese populations. This study aims to investigate the association between HLA‐B*1502 and lamotrigine‐ or phenytoin‐ induced SJS/TEN in an Iranian population. The medical records of twenty‐eight lamotrigine‐induced SJS/TEN patients and twenty‐five lamotrigine‐tolerant controls as well as eight phenytoin‐induced SJS/TEN and twelve phenytoin‐tolerant controls were extracted between March 2013 and March 2019 from the university hospitals in Mashhad, Iran. The presence of HLA‐B*1502 allele was determined using real‐time polymerase chain reaction (PCR). Among lamotrigine‐induced patients with SJS/TEN, 11 (39.3%) patients tested positive for the HLA‐B*1502 while only 3 (12.0%) of the lamotrigine‐tolerant controls tested positive for this allele. The risk of lamotrigine‐induced SJS/TEN was significantly higher in patients with HLA‐B*1502, with an odds ratio (OR) of 4.74 [95% confidence interval (CI) 1.14–19.73, p = 0.032]. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of HLA‐B*1502 for lamotrigine‐induced SJS/TEN was 39.29%, 88.00%, 78.57% and 56.41%, respectively. The HLA‐B*1502 allele was present in 2 (25.0%) of phenytoin‐induced SJS/TEN cases and 5 (41.7%) of the phenytoin‐tolerant controls tested positive for HLA‐B*1502 allele. The risk of phenytoin‐induced SJS/TEN was not higher in the patients with HLA‐B*1502 (OR = 0.467 [95% confidence interval (CI) 0.065‐3.34, p = 0.642]). Lamotrigine‐induced SJS/TEN is associated with HLA‐B*1502 allele in an Iranian population but this is not the case for phenytoin‐induced SJS/TEN. [ABSTRACT FROM AUTHOR]