Incidence and mortality of nasopharyngeal carcinoma: interim analysis of a cluster randomized controlled screening trial (PRO-NPC-001) in southern China.

BACKGROUND: Previous mass screening studies have shown that IgA antibodies against Epstein-Barr Virus (EBV) can facilitate early detection of nasopharyngeal carcinoma (NPC), but the impact of EBV-antibody screening for NPC-specific mortality remains unknown. PATIENTS AND METHODS: A prospective, cluster randomized, controlled trial for NPC screening (PRO-NPC-001) was conducted in 3 selected towns of Zhongshan City and 13 selected towns of Sihui City in southern China beginning in 2008. Serum samples of the screening group were tested for two previously selected anti-EBV antibodies. Subjects with serological medium risk were subsequently retested annually for 3 years, and those with serological high risk were referred to otorhinolaryngologists for diagnostic check-up. An interim analysis was carried out to evaluate the primary end points of the NPC-specific mortality and the early diagnostic rate, and the secondary end point of the NPC incidence, through linkage with the database of Zhongshan City. RESULTS: Among 70 296 total subjects, 29 413 screened participants (41.8% of the total subjects) in the screening group and 50 636 in the control group, 153 (43.3 per 100 000 person-year), 62 (55.3 per 100 000 person-year) and 99 (33.1 per 100 000 person-year) NPC cases were identified. The early diagnostic rates of NPC were significantly higher in the participants (79.0%, P < 0.0001) and the screening group (45.9%, P < 0.0001) compared with the control group (20.6%). Although no differences were found between NPC-specific mortality of the screening group and the control group [relative risk (RR)= 0.82, 95% confidence interval (CI) 0.37-1.79], lower NPC-specific mortality was noticed among participants from the screening group versus the control group (RR = 0.22, 95% CI 0.09-0.49). CONCLUSION: IgA antibodies against EBV can identify high-risk population and was effective in screening for early asymptomatic NPC. Although the mortality reduction was not significant in the primary end point, we noted encouraging evidence of a mortality reduction in screening participants in this interim analysis. CLINICAL TRIAL NUMBER: NCT00941538.

Drp1 is dispensable for apoptotic cytochrome c release in primed MCF10A and fibroblast cells but affects Bcl-2 antagonist-induced respiratory changes.

BACKGROUND AND PURPOSE: Dynamin-related protein 1 (Drp1) mediates mitochondrial fission and is thought to promote Bax/Bak-induced cytochrome c release during apoptosis. Conformationally active Bax, Bak and Bax/Bak-activating BH3-only proteins, such as Bim, are restrained by anti-apoptotic Bcl-2 proteins in cells that are 'primed for death'. Inhibition of Bcl-2/Bcl-xL/Bcl-w by the antagonist ABT-737 causes rapid apoptosis of primed cells. Hence, we determined whether Drp1 is required for cytochrome c release, respiratory alterations and apoptosis of cells that are already primed for death. EXPERIMENTAL APPROACH: We tested the Drp1 inhibitor mdivi-1 for inhibition of cytochrome c release in MCF10A cells primed by Bcl-2 overexpression. We measured ATP synthesis-dependent, -independent and cytochrome c-limited maximal oxygen consumption rates (OCRs) and cell death of immortalized wild-type (WT) and Drp1 knockout (KO) mouse embryonic fibroblasts (MEFs) treated with ABT-737. KEY RESULTS: Mdivi-1 failed to attenuate ABT-737-induced cytochrome c release. ABT-737 decreased maximal OCR measured in the presence of uncoupler in both WT and Drp1 KO MEF, consistent with respiratory impairment due to release of cytochrome c. However, Drp1 KO MEF were slightly less sensitive to this ABT-737-induced respiratory inhibition compared with WT, and were resistant to an initial ABT-737-induced increase in ATP synthesis-independent O2 consumption. Nevertheless, caspase-dependent cell death was not reduced. Pro-apoptotic Bax was unaltered, whereas Bak was up-regulated in Drp1 KO MEF. CONCLUSIONS AND IMPLICATIONS: The findings indicate that once fibroblast cells are primed for death, Drp1 is not required for apoptosis. However, Drp1 may contribute to ABT-737-induced respiratory changes and the kinetics of cytochrome c release.