Risk of bladder cancer in male Japanese workers exposed to ortho-toluidine and other aromatic amines.

PURPOSE: Nine bladder cancer (BCa) cases were reported among aromatic amine-exposed male workers at a factory manufacturing organic dye/pigment intermediates in Japan. We aimed to evaluate the characteristics of aromatic amine-exposed workers by cross-sectional observation, and the risk of BCa by assessing the standardized incidence ratio (SIR). METHODS: In the cross-sectional study, our subjects were: 9 BCa patients, 36 aromatic amine-exposed non-patients, and 79 non-exposed workers from 3 factories. We evaluated the subjects' medical history, urinalysis, qualitative determination of nuclear matrix protein 22, and urinary cytology. For SIR assessment, 98 aromatic amine-exposed workers from 1 factory were included, and the Japanese general male population was used as a referent population. Since no direct aromatic amine-exposure data were available, we calculated surrogate exposure levels using information on job sites, exposure potency, and duration. RESULTS: Coexistent aromatic amines were ortho-toluidine (OT), aniline, para-toluidine, ortho-anisidine, 2,4-xylidine, and ortho-chloroaniline. The prevalence rates of cystitis and bladder lesion-related symptoms in both BCa patients and aromatic amine-exposed non-patient workers were significantly higher than those of non-exposed workers. Overall, the SIR for BCa in OT-exposed workers was 56.8 (95% CI 27.7-104.3) and apparent dose-response relationships were revealed between the SIR and the surrogate exposure level in the 0-10-year lagged analyses. Overall, SIRs in other aromatic amine-exposed workers were also significantly high but no or unclear dose-response relationships were observed. CONCLUSIONS: We conclude that OT may be responsible for the increased risk of BCa. Regular monitoring of bladder lesion-related symptoms is essential for the early identification of BCa.

The incidence and mortality rates of neuroblastoma cases before and after the cessation of the mass screening program in Japan: A descriptive study.

In 2003, Japan's Ministry of Health, Labour and Welfare halted the neuroblastoma (NB) mass screening program, running since 1985. This study aimed to examine whether NB incidence and mortality changed before and after the program halted. This is a descriptive population-based study. We used data from the Monitoring of Cancer Incidence in Japan (MCIJ) project, Vital Statistics of Japan, and Japanese CANcer Survival Information for Society (J-CANSIS). Incidence rate, cumulative incidence rate, mortality rate, cumulative mortality rate, and relative 5-year survival for NB were calculated. Children were divided into two birth cohort groups, consisting of children born before, or after the cessation of the NB mass screening program. We compared the two cohorts, with regards to the cumulative incidence and mortality rates at 5 years old. The incidence rate was lower after the cessation of the NB mass screening program. There was no substantial change in the mortality rate, and no significant variation in the relative 5-year survival between groups. The cumulative incidence rate in the latter cohort was significantly lower than that in the former cohort (rate ratio: 0.39, 95% CI: 0.25-0.61, p < 0.001). No significant difference in the cumulative mortality rate between the two cohorts was observed (rate ratio: 0.99, 95% CI: 0.80-1.22, p = 0.93). The NB incidence rate decreased markedly and the mortality rate did not substantially change after the cessation of the NB mass screening program. The NB mass screening program probably caused overdiagnosis, and its effectiveness was not clear.

Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation.

A polarity complex of PAR-3, PAR-6, and atypical protein kinase C (aPKC) functions in various cell polarization events. PAR-3 directly interacts with Tiam1/Taim2 (STEF), Rac1-specific guanine nucleotide exchange factors, and forms a complex with aPKC-PAR-6-Cdc42*GTP, leading to Rac1 activation. RhoA antagonizes Rac1 in certain types of cells. However, the relationship between RhoA and the PAR complex remains elusive. We found here that Rho-kinase/ROCK/ROK, the effector of RhoA, phosphorylated PAR-3 at Thr833 and thereby disrupted its interaction with aPKC and PAR-6, but not with Tiam2. Phosphorylated PAR-3 was observed in the leading edge, and in central and rear portions of migrating cells having front-rear polarity. Knockdown of PAR-3 by small interfering RNA (siRNA) impaired cell migration, front-rear polarization, and PAR-3-mediated Rac1 activation, which were recovered with siRNA-resistant PAR-3, but not with the phospho-mimic PAR-3 mutant. We propose that RhoA/Rho-kinase inhibits PAR complex formation through PAR-3 phosphorylation, resulting in Rac1 inactivation.