Citrullinaemia (CTLN) is an autosomal recessive disease caused by deficiency of argininosuccinate synthetase (ASS). Adult-onset type II citrullinaemia (CTLN2) is characterized by a liver-specific ASS deficiency with no abnormalities in hepatic ASS mRNA or the gene ASS (refs 1-17). CTLN2 patients (1/100,000 in Japan) suffer from a disturbance of consciousness and coma, and most die with cerebral edema within a few years of onset. CTLN2 differs from classical citrullinaemia (CTLN1, OMIM 215700) in that CTLN1 is neonatal or infantile in onset, with ASS enzyme defects (in all tissues) arising due to mutations in ASS on chromosome 9q34 (refs 18-21). We collected 118 CTLN2 families, and localized the CTLN2 locus to chromosome 7q21.3 by homozygosity mapping analysis of individuals from 18 consanguineous unions. Using positional cloning we identified a novel gene, SLC25A13, and found five different DNA sequence alterations that account for mutations in all consanguineous patients examined. SLC25A13 encodes a 3.4-kb transcript expressed most abundantly in liver. The protein encoded by SLC25A13, named citrin, is bipartite in structure, containing a mitochondrial carrier motif and four EF-hand domains, suggesting it is a calcium-dependent mitochondrial solute transporter with a role in urea cycle function.

Background Unlike many North American and European countries, Japan has observed a continuous increase in cancer incidence over the last few decades. We examined the most recent trends in population-based cancer incidence and mortality in Japan. Methods National cancer mortality data between 1958 and 2018 were obtained from published vital statistics. Cancer incidence data between 1985 and 2015 were obtained from high-quality population-based cancer registries maintained by three prefectures (Yamagata, Fukui, and Nagasaki). Trends in age-standardized rates (ASR) were examined using Joinpoint regression analysis. Results For males, all-cancer incidence increased between 1985 and 1996 (annual percent change [APC] +1.1%; 95% confidence interval [CI], 0.7–1.5%), increased again in 2000–2010 (+1.3%; 95% CI, 0.9–1.8%), and then decreased until 2015 (−1.4%; 95% CI, −2.5 to −0.3%). For females, all-cancer incidence increased until 2010 (+0.8%; 95% CI, 0.6–0.9% in 1985–2004 and +2.4%; 95% CI, 1.3–3.4% in 2004–2010), and stabilized thereafter until 2015. The post-2000 increase was mainly attributable to prostate in males and breast in females, which slowed or levelled during the first decade of the 2000s. After a sustained increase, all-cancer mortality for males decreased in 1996–2013 (−1.6%; 95% CI, −1.6 to −1.5%) and accelerated thereafter until 2018 (−2.5%; 95% CI, −2.9 to −2.0%). All-cancer mortality for females decreased intermittently throughout the observation period, with the most recent APC of −1.0% (95% CI, −1.1 to −0.9%) in 2003–2018. The recent decreases in mortality in both sexes, and in incidence in males, were mainly attributable to stomach, liver, and male lung cancers. Conclusion The ASR of all-cancer incidence began decreasing significantly in males and levelled off in females in 2010.

Cervical cancer screening rate is extremely low and the governmental recommendation of HPV vaccine has been suspended for 5 years in Japan. Here, we utilized data from the Osaka Cancer Registry, collected between 1976 and 2012, to evaluate cervical cancer trends in Japan. Age-adjusted incidence, relative survival, and conditional survival rates were calculated using multiple imputation methods and period analyses in 25,826 cervical cancer cases. Association of survival rates and clinical factors, including patients' age, clinical stage, and treatment procedures, were also analyzed. A trend for significantly decreasing age-adjusted incidence of cervical cancer (per 100,000) began in 1976 but reversed after 2000, increasing significantly to date (annual percent change ¼ 3.8, 95% confidence interval, 2.7-4.8; age-adjusted rate: 28.0 in 1976, 9.1 in 2000, 14.1 in 2012). The 10-year relative survival rate improved significantly after 2002, especially in cases of "localized" and "adjacent organs" disease; this was likely due to the introduction of concurrent chemotherapy and radiation. The conditional 5-year relative survival rate improved significantly yearly until the fourth survival year. In the surgery-based group, we observed no age-dependent differences in outcomes. Unexpectedly, however, prognosis for younger age groups was poorer in the radiation-based treatment group. These results indicate that although relative survival rates have recently increased, treatment for more advanced cases with distant metastasis requires further improvement. In addition, this study is the first to suggest that age might be an important predictor of radiotherapy resistance in cervical cancer. Significance: A large-cohort analysis of cervical cancer cases reveals that age-adjusted incidence in Japan has increased since 2000 and that age may negatively correlate with resistance to radiotherapy.

In Japan, the serious adverse events after human papillomavirus (HPV) vaccination were widely reported in the media. The Ministry of Health, Labour and Welfare of Japan (MHLW) announced the suspension of the governmental recommendation of HPV vaccine in 2013, and the inoculation rate has since sharply declined. The estimated inoculation rate for each birth fiscal year (FY) announced by the MHLW and the actual numbers for each birth FY surveyed by local governments were very different. In particular, the cumulative vaccination rate of girls born in FY2000 was regarded to be as high as 42.9% by the Council of the MHLW. However, this estimation included a confusion. When the suspension of the governmental recommendation was announced in FY2013, the girls born in FY2000 turned 13 years old, the targeted starting age of the HPV vaccination. The vaccination rate of this generation is considered to be quite low. The numbers were recalculated in this study. This study revealed that the real vaccination rate is only 14.3%. Female individuals born in or after FY2000 have been confirmed to be exposed to the same cervical cancer risk as before the HPV vaccine was introduced in Japan.

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