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F usion genes involving ZNF384 have recently been identified in Bcell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384. Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic

SummaryGenotyping of TPMT prior to 6-mercaptopurine (6-MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6-MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6-MP toxicity-related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6-MP dose reduction, therapy interruption and event-free survival. The allele frequency of rs116855232 was 0Á16, and leucopenia was more common in carriers of the T allele (odds ratio, 7Á20; 95% confidence interval, 2Á49-20Á80; P = 2Á7 9 10 À4). As leucopenia results in 6-MP dose reduction, we observed average doses during maintenance therapy of 40Á7, 29Á3 and 8Á8 mg/m 2 for patients with CC, CT and TT genotypes, respectively (P < 0Á001). Hepatotoxicity was observed only in CC genotype patients. Event-free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6-MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity-related locus in Asians to date. Considerations for clinical application may be warranted.

Although the inverse association between coffee consumption and risk of diabetes has been reported numerous times, the role of caffeine intake in this association has remained unclear. We evaluated the consumption of coffee and other beverages and food containing caffeine in relation to the incidence of diabetes. The study participants were 5897 men and 7643 women in a community-based cohort in Takayama, Japan. Consumption of coffee, green tea, oolong tea, black tea and chocolate snacks were measured with a semi-quantitative FFQ in 1992. At the follow-up survey in 2002, the development of diabetes and the time of diagnosis were reported. To assess the association, age, smoking status, BMI, physical activity, education in years, alcohol consumption, total energy intake, fat intake and women's menopausal status were adjusted. Among men who consumed one cup per month to six cups per week and among those who consumed one cup per d or more, the associated hazard ratios were 0·69 (95 % CI 0·50, 0·97) and 0·69 (95 % CI 0·49, 0·98) compared with those who drank little to no coffee, with a P value for trend of 0·32. The hazard ratios for women with the same coffee consumption patterns were 1·08 (95 % CI 0·74, 1·60) and 0·70 (95 % CI 0·44, 1·12), with a P value for trend of 0·03. The association between estimated total caffeine intake and risk of diabetes was insignificant both among men and among women. The results imply that coffee consumption decreased the risk of developing diabetes. The protective effect may exist aside from the influence of caffeine intake.

Dietary supplementation with branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, has shown potential benefits for the metabolic profile. However, higher blood BCAA levels have been associated with insulin resistance. To our knowledge, there has been no study on dietary BCAAs and the risk of diabetes. We examined the association between BCAA intake and risk of diabetes in a population-based cohort study in Japan. A total of 13,525 residents of Takayama City, Japan, who enrolled in a cohort study in 1992 responded to a follow-up questionnaire seeking information about diabetes in 2002. Diet at baseline was assessed by means of a validated food frequency questionnaire. A high intake of BCAAs in terms of percentage of total protein was significantly associated with a decreased risk of diabetes in women after controlling for covariates; the hazard ratio for the highest tertile versus the lowest was 0.57 (95% confidence interval: 0.36, 0.90; P-trend = 0.02). In men, leucine intake was significantly marginally associated with the risk of diabetes; the hazard ratio for the highest tertile versus the lowest was 0.70 (95% confidence interval: 0.48, 1.02; P-trend = 0.06). Data suggest that a high intake of BCAAs may be associated with a decrease in the risk of diabetes.

BackgroundSeveral studies have reported the prevalence of tinnitus among general populations; however, most of these studies were conducted in Europe or the United States. We estimated the prevalence of tinnitus among the general adult population in Japan.MethodsThe subjects were participants in the Takayama Study, a population-based cohort study. In 2002, a total of 14 423 adults (6450 men and 7973 women) aged 45 to 79 years responded to a self-administered questionnaire that inquired about history of tinnitus, which was defined as episodes lasting longer than 5 minutes, excluding those occurring immediately after noise exposure. Respondents were also asked about the loudness and severity of tinnitus.ResultsOverall, 11.9% of the subjects reported having tinnitus; the percentage was somewhat higher among men (13.2%) than women (10.8%). The prevalence of tinnitus increased with age in both sexes. Approximately 0.4% of the overall population reported that tinnitus had a severe effect on their ability to lead a normal life. Medical history of hypertension or ischemic heart diseases, use of steroid or antihypertensive medication, and employment as a factory worker or machine operator were associated with tinnitus status in both men and women.ConclusionsTinnitus is relatively common in Japan. Although the use of various definitions of tinnitus in different studies makes it difficult to compare prevalence among populations, the present prevalence estimate was similar to those in studies in Europe and the United States.

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Although a growing body of evidence suggests a link between diabetes and cancer, it is not clear whether diabetes independently increases the risk of cancer. We conducted a comprehensive assessment of the association between pre-existing diabetes and total and site-specific cancer risk based on a pooled analysis of eight cohort studies in Japan (>330 000 subjects). We estimated a summary hazard ratio by pooling study-specific hazard ratios for total and site-specific cancer by using a random-effects model. A statistically increased risk was observed for cancers at specific sites, such as colon (hazard ratio; HR = 1.40), liver (HR = 1.97), pancreas (HR = 1.85) and bile duct (HR = 1.66; men only). Increased risk was also suggested for other sites, and diabetes mellitus was associated with an overall 20% increased risk in total cancer incidence in the Japanese population. The association between these two diseases has important implications for reiterating the importance of controlling lifestyle factors and may suggest a possible strategy for cancer screening among patients with diabetes. Studies continuously investigating the risk factors for diabetes are also important. (Cancer Sci 2013; 104: 1499-1507 I n Japan, as in other countries, the increasing prevalence of diabetes presents a serious public health problem. The estimated numbers of persons with diabetes in 1997, 2002 and 2007 were 6.9 million (prevalence 5.5%), 7.4 million (prevalence 5.4%) and 8.9 million (prevalence 7.1%), respectively.( 1) A growing body of evidence suggests a link between diabetes and cancer. A recent meta-analysis showed that people with diabetes are at elevated risk for cancers of the liver,biliary tract,pancreas, (4) stomach,colorectum, (6) kidney,bladder, (8) breast (9) and endometrium, (10) but at decreased risk for prostate cancer.(11) Research suggests that hyperinsulinemia acting through aberrations in the insulin-like growth factor pathways or steroid hormone metabolism is involved in mitogenic actions. However, whether diabetes independently increases the risk of these cancers or whether cancer and diabetes simply share common risk factors, such as obesity or physical inactivity, is not clear; many of the studies included in the meta-analysis did not necessarily control for other lifestyle factors. Moreover, evidence from other cancer sites and the impact of diabetes on total cancer have not been elucidated completely. (12)(13)(14) In the present study, we conducted a comprehensive assessment of the association between pre-existing diabetes and total and site-specific cancer by means of a pooled analysis of eight cohort studies in Japan (>330 000 subjects). Patients and MethodsStudy population. In 2006, the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan initiated a pooling project using original data from major cohort studies to evaluate the association between lifestyle and major forms of cancer and mortality in Japanese people. The following a priori inclusion criteria were set f...