The calcineurin pathway has been reported to be essential for the development of azole resistance in Candida albicans. The depletion or ectopic overexpression of RTA2 increased or decreased susceptibility of C. albicans to azoles, respectively. CaCl 2 -induced activation of the calcineurin pathway in wildtype C. albicans promoted resistance to azoles, while the Ca 2+ chelator (EGTA), calcineurin inhibitors (FK506 and cyclosporin A) and the deletion of RTA2 blocked the resistance-promoting effects of CaCl 2 . Furthermore, we found that RTA2 was upregulated in a calcineurin-dependent manner. The depletion of RTA2 also made the cell membrane of C. albicans liable to be destroyed by azoles and RTA2 over-expression attenuated the destroying effects. Finally, the disruption of RTA2 caused an increased accumulation of dihydrosphingosine (DHS), one of the two sphingolipid long-chain bases, by decreasing release of DHS. In conclusion, our findings suggest that RTA2 is involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in C. albicans.

The present randomised phase II study was an effort to evaluate single-agent gemcitabine as a first-line systemic treatment of Asian patients with unresectable hepatocellular carcinoma (HCC). Gemcitabine was given via intravenous infusion at 1250 mg m À2 on days 1 and 8 of 3-week cycles. Patients were randomised to receive gemcitabine as a 30-min intravenous infusion (standard schedule) or at a fixed dose rate (FDR) of 10 mg m À2 min À1 . A total of 50 patients were enrolled in the study, of whom 48 received study therapy. One patient on standard schedule had a partial response, for an overall response rate of 2.1% (95% CI: 0.05 -11.1%). The median time to progression and survival time were 46 and 97 days, respectively. The overall rates of Grade 3 or 4 haematological and nonhaematological toxicities were 39.6 and 64.6%, respectively, with no significant difference between the two treatment arms. There were no drug-related deaths and severe clinical toxicities were rare. Both schedules of gemcitabine were safe and toxicity was well manageable in this patient population. However, gemcitabine seems no more active than other cytotoxic agents when used alone for systemic treatment of advanced HCC.

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