Glioblastoma multiforme (GBM) is a malignant primary brain tumor. The 5-year relative survival rate of patients with GBM remains <30% on average despite aggressive treatments, and secondary therapy fails in 90% of patients. In chemotherapeutic failure, detoxification proteins are crucial to the activity of chemotherapy drugs. Usually, glutathione S-transferase (GST) superfamily members act as detoxification enzymes by activating xenobiotic metabolites through conjugation with glutathione in healthy cells. However, some overexpressed GSTs not only increase GST activity but also trigger chemotherapy resistance and tumorigenesis-related signaling transductions. Whether GSTM3 is involved in GBM chemoresistance remains unclear. In the current study, we found that T98G, a GBM cell line with pre-existing temozolomide (TMZ) resistance, has high glycolysis and GSTM3 expression. GSTM3 knockdown in T98G decreased glycolysis ability through lactate dehydrogenase A activity reduction. Moreover, it increased TMZ toxicity and decreased invasion ability. Furthermore, we provide next-generation sequencing–based identification of significantly changed messenger RNAs of T98G cells with GSTM3 knockdown for further research. GSTM3 was downregulated in intrinsic TMZ-resistant T98G with a change in the expression levels of some essential glycolysis-related genes. Thus, GSTM3 was associated with glycolysis in chemotherapeutic resistance in T98G cells. Our findings provide new insight into the GSTM3 mechanism in recurring GBM.

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Treatment guidelines recommend combination antifungal therapy with amphotericin B (AmB) as an induction therapy for cryptococcal meningitis. The objective of this study was to compare the survival benefit between 5-FC (flucytosine) and fluconazole as second-line drugs given in combination with AmB. We carried out a systematic review and meta-analysis of prospective controlled studies reporting early combination treatment for human immunodeficiency virus (HIV)-associated cryptococcal meningitis. We searched MEDLINE, EMBASE and the Cochrane Library up to October 2013. Randomised trials and prospective cohort studies were selected. The primary outcome was mortality in the first 14 and 70 days. The secondary outcome was early fungicidal activity (EFA) in the first 2 weeks. Four trials were included in our study. All included studies could be considered to be of fair quality in their methodology. The meta-analysis suggested that mortality was lower in patients who were given AmB and 5-FC at the 2 weeks point (Fig. 2); the overall reduction in mortality with the 5-FC combination group was 44% [risk ratio (RR) 0.56, 95% confidence interval (CI) 0.33-0.95, p = 0.03]. EFA was significantly shorter in patients receiving AmB plus 5-FC [mean difference (MD) -0.10 log10 colony-forming units (CFU) per day, 95 % CI -0.11-0.09, p < 0.00001]. Mortality was no different between the 5-FC and fluconazole groups at the 3 months time point (p = 0.15) (Fig. 4). Adverse events occurred with similar frequency between the two treatment groups. There was no statistically significant difference in the survival rate between AmB in combination with high-dose fluconazole and the current standard of AmB plus 5-FC therapy for HIV-associated cryptococcal meningitis.

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