Search

Background: It has been suggested that the association between body mass index and breast cancer risk differs between Asian women and Western women. We aimed to assess the associations between body mass index and breast cancer incidence in East Asian women., Methods: Pooled analyses were performed using individual participant data of 319,189 women from 13 cohort studies in Japan, Korea, and China. Participants' height and weight were obtained by measurement or self-reports at cohort baseline. Breast cancer was defined as code C50.0-C50.9 according to the International Classification. Using a Cox proportional hazards model, hazard ratios of breast cancer were estimated for each body mass index category, with the reference group set as the group with a body mass index of 21 to < 23 kg/m 2 . The hazard ratio for a 5 kg/m 2 increase in body mass index was also calculated., Results: During a mean 16.6 years of follow-up, 4819 women developed breast cancer. Similar to Westerners, a steady increase in breast cancer risk with increasing body mass index was observed in postmenopausal women, but the slope of the risk increase appeared to slow at a body mass index of 26-28 kg/m 2 . In premenopausal women, the inverse association seen in Westerners was not observed. The risk of developing breast cancer after 50 years of age increased slightly with increasing body mass index, which was more pronounced in the older birth cohort. There was no significant association between body mass index and the risk of developing breast cancer before 50 years of age, but the risk estimates changed from positive to negative as the birth cohort got younger., Conclusions: In East Asia, the role of body mass index in breast cancer in premenopausal women may be changing along with the increase in obesity and breast cancer. The increased risk of postmenopausal breast cancer with a higher body mass index was as robust as that of Western women., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in accordance with the Declaration of Helsinki. Each participating study was approved by the relevant institutional ethical review boards. The protocol for the ACC analysis was approved by the institutional review board of the National Cancer Center, Japan. The requirement for consent from several cohort studies was waived due to the justification for lack of consent at the time of the survey, the difficulty in obtaining new consent, and the public necessity of the research. Consent for publication All authors reviewed and approved the final version for submission. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Disulfide formation generally involves a two-electron oxidation reaction between cysteine residues. Additionally, disulfide formation is an essential post-translational modification for the structural maturation of proteins. This oxidative folding is precisely controlled by an electron relay network constructed by protein disulfide isomerase (PDI), with a CGHC sequence as the redox-active site, and its family enzymes. Creating reagents that mimic the functions of these enzymes facilitates folding during chemical protein synthesis. In this study, we aimed to imitate a biological electron relay system using cyclic diselenide compounds as surrogates for endoplasmic reticulum oxidoreductin 1 (Ero1), which is responsible for the re-oxidation of PDI. Oxidized PDI (PDI ox ) introduces disulfide bonds into substrate proteins, resulting in its conversion to reduced PDI (PDI red ). The PDI red is then re-oxidized to PDI ox by a coexisting cyclic diselenide compound, thereby restoring the function of PDI as a disulfide-forming agent. The produced diselenol state is readily oxidized to the original diselenide state with molecular oxygen, continuously sustaining the PDI catalytic cycle. This artificial electron relay system regulating enzymatic PDI function effectively promotes the oxidative folding of disulfide-containing proteins, such as insulin - a hypoglycemic formulation - by enhancing both yield and reaction velocity., (© 2024 Wiley-VCH GmbH.)

Objectives: To evaluate changes in the age at menarche in Asian populations., Study Design: Retrospective cohort study., Methods: We included 548,830 women from six countries in Asia. The data were sourced from 20 cohorts participating in the Asia Cohort Consortium (ACC) and two additional cohort studies: Japan Multi-institutional Collaborative Cohorts (J-MICC), and Japan Nurse Health Study (JNHS) with data on age at menarche. Joinpoint regression was used to evaluate changes in age at menarche by birth year and by country., Results: The study includes data from cohorts in six Asian countries namely, China, Iran, Japan, Korea, Malaysia and Singapore. Birth cohorts ranged from 1873 to 1995. The mean age of menarche was 14.0 years with a standard deviation (SD) of 1.4 years, ranged from 12.6 to 15.5 years. Over 100 years age at menarche showed an overall decrease in all six countries. China showed a mixed pattern of decrease, increase, and subsequent decrease from 1926 to 1960. Iran and Malaysia experienced a sharp decline between about 1985 and 1990, with APC values of -4.48 and -1.24, respectively, while Japan, South Korea, and Singapore exhibited a nearly linear decline since the 1980s, notably with an APC of -3.41 in Singapore from 1993 to 1995., Conclusions: Overall, we observed a declining age at menarche, while the pace of the change differed by country. Additional long-term observation is needed to examine the contributing factors of differences in trend across Asian countries. The study could serve as a tool to strengthen global health campaigns., (Copyright © 2024 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Family history of lung cancer (FHLC) has been widely studied but most prospective cohort studies have primarily been conducted in non-Asian countries. We assessed the association between FHLC with risk of lung cancer (LC) incidence and mortality in a population of East Asian individuals. A total of 478,354 participants from 11 population-based cohorts in the Asia Cohort Consortium were included. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 7,785 LC incident cases were identified. FHLC (any LC subtype) was associated with an increased risk of LC incidence (HR = 1.45, 95% CI = 1.30-1.63). The positive association was observed in men and women (HR = 1.44, 95% CI = 1.26-1.66 in men; HR = 1.47, 95% CI = 1.22-1.79 in women), and in both never-smokers and ever-smokers (HR = 1.43, 95% CI = 1.18-1.73 in never-smokers; HR = 1.46, 95% CI =1.27-1.67 in ever-smokers). FHLC was associated with an increased risk of lung adenocarcinoma (HR = 1.63, 95% CI: 1.36-1. 94), squamous cell carcinoma (HR = 1.88, 95% CI: 1.46-2.44), and other non-small cell LC (HR = 1.94, 95% CI: 1.02-3.68). However, we found no evidence of significant effect modification by sex, smoking status, and ethnic groups. In conclusion, FHLC was associated with increased risk of LC incidence and mortality, and the associations remained consistent regardless of sex, smoking status and ethnic groups among the East Asian population., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust., (© 2024 UICC.)

Importance: The global burden of obesity is increasing, as are colorectal cancer (CRC) incidence and mortality., Objectives: To assess the association between body mass index (BMI) and risks of incident CRC and CRC-related death in the Asian population., Design, Setting, and Participants: This cohort study includes data pooled from 17 prospective cohort studies included in The Asia Cohort Consortium. Cohort enrollment was conducted from January 1, 1984, to December 31, 2002. Median follow-up time was 15.2 years (IQR, 12.1-19.2 years). Data were analyzed from January 15, 2023, through January 15, 2024., Exposure: Body mass index, calculated as weight in kilograms divided by height in meters squared., Main Outcomes and Measures: The primary outcomes were CRC incidence and CRC-related mortality. The risk of events is reported as adjusted hazard ratios (AHRs) and 95% CIs for incident CRC and death from CRC using the Cox proportional hazards regression model., Results: To assess the risk of incident CRC, 619 981 participants (mean [SD] age, 53.8 [10.1] years; 52.0% female; 11 900 diagnosed incident CRC cases) were included in the study, and to assess CRC-related mortality, 650 195 participants (mean [SD] age, 53.5 [10.2] years; 51.9% female; 4550 identified CRC deaths) were included in the study. A positive association between BMI and risk of CRC was observed among participants with a BMI greater than 25.0 to 27.5 (AHR, 1.09 [95% CI, 1.03-1.16]), greater than 27.5 to 30.0 (AHR, 1.19 [95% CI, 1.11-1.29]), and greater than 30.0 (AHR, 1.32 [95% CI, 1.19-1.46]) compared with those with a BMI greater than 23.0 to 25.0 (P < .001 for trend), and BMI was associated with a greater increase in risk for colon cancer than for rectal cancer. A similar association between BMI and CRC-related death risk was observed among participants with a BMI greater than 27.5 (BMI >27.5-30.0: AHR, 1.18 [95% CI, 1.04-1.34]; BMI >30.0: AHR, 1.38 [95% CI, 1.18-1.62]; P < .001 for trend) and was present among men with a BMI greater than 30.0 (AHR, 1.87 [95% CI, 1.49-2.34]; P < .001 for trend) but not among women (P = .15 for trend) (P = .02 for heterogeneity)., Conclusions and Relevance: In this cohort study that included a pooled analysis of 17 cohort studies comprising participants across Asia, a positive association between BMI and CRC incidence and related mortality was found. The risk was greater among men and participants with colon cancer. These findings may have implications to better understand the burden of obesity on CRC incidence and related deaths in the Asian population.

Proteins form native structures through folding processes, many of which proceed through intramolecular hydrophobic effect, hydrogen bond and disulfide-bond formation. In vivo , protein aggregation is prevented even in the highly condensed milieu of a cell through folding mediated by molecular chaperones and oxidative enzymes. Chemical approaches to date have not replicated such exquisite mediation. Oxidoreductases efficiently promote folding by the cooperative effects of oxidative reactivity for disulfide-bond formation in the client unfolded protein and chaperone activity to mitigate aggregation. Conventional synthetic folding promotors mimic the redox-reactivity of thiol/disulfide units but do not address client-recognition units for inhibiting aggregation. Herein, we report thiol/disulfide compounds containing client-recognition units, which act as synthetic oxidoreductase-mimics. For example, compound βCD W SH/SS bears a thiol/disulfide unit at the wide rim of β-cyclodextrin as a client recognition unit. βCD W SH/SS shows promiscuous binding to client proteins, mitigates protein aggregation, and accelerates disulfide-bond formation. In contrast, positioning a thiol/disulfide unit at the narrow rim of β-cyclodextrin promotes folding less effectively through preferential interactions at specific residues, resulting in aggregation. The combination of promiscuous client-binding and redox reactivity is effective for the design of synthetic folding promoters. βCD W SH/SS accelerates oxidative protein folding at highly condensed sub-millimolar protein concentrations., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: The family history of gastric cancer holds important implications for cancer surveillance and prevention, yet existing evidence predominantly comes from case-control studies. We aimed to investigate the association between family history of gastric cancer and gastric cancer risk overall and by various subtypes in Asians in a prospective study., Methods: We included 12 prospective cohorts with 550,508 participants in the Asia Cohort Consortium. Cox proportional hazard regression was used to estimate study-specific adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between family history of gastric cancer and gastric cancer incidence and mortality, then pooled using random-effects meta-analyses. Stratified analyses were performed for the anatomical subsites and histological subtypes., Results: During the mean follow-up of 15.6 years, 2258 incident gastric cancers and 5194 gastric cancer deaths occurred. The risk of incident gastric cancer was higher in individuals with a family history of gastric cancer (HR 1.44, 95% CI 1.32-1.58), similarly in males (1.44, 1.31-1.59) and females (1.45, 1.23-1.70). Family history of gastric cancer was associated with both cardia (HR 1.26, 95% CI 1.00-1.60) and non-cardia subsites (1.49, 1.35-1.65), and with intestinal- (1.48, 1.30-1.70) and diffuse-type (1.59, 1.35-1.87) gastric cancer incidence. Positive associations were also found for gastric cancer mortality (HR 1.30, 95% CI 1.19-1.41)., Conclusions: In this largest prospective study to date on family history and gastric cancer, a familial background of gastric cancer increased the risk of gastric cancer in the Asian population. Targeted education, screening, and intervention in these high-risk groups may reduce the burden of gastric cancer., (© 2024. The Author(s).)

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70-0.96) and 0.78 (95% CI = 0.65-0.94). The protective association of parity and lung cancer incidence was greater among ever-smokers (HR = 0.66, 95% CI = 0.49-0.87) than in never-smokers (HR = 0.90, 95% CI = 0.74-1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time., (© 2024 UICC.)

Compounds harboring high acidity and oxidizability of thiol groups permit tuning the redox equilibrium constants of CxxC sites of members of the protein disulphide isomerase (PDI) family and thus can be used to accelerate folding processes and increase the production of native proteins by minimal loading in comparison to glutathione.

It has been postulated that being breastfed in infancy affects not only health status in childhood but also disease risk in adulthood. To investigate the association of being breastfed with the risks of adult colorectal cancer and benign tumor, we conducted a case-control study including 1190 colorectal cancer and 1585 benign tumor cases and 5301 controls, admitted to a single hospital in Miyagi Prefecture, Japan, between 1997 and 2013. History of having been breastfed was assessed using a self-administered questionnaire, and odds ratios (ORs) were estimated using unconditional logistic regression. There was no association between being breastfed and colorectal cancer risk (breastfed versus formula-only fed, OR = 1.21; 95% CI 0.87-1.67). There was also no association with the risk of benign tumor (OR = 1.04). On the other hand, analyses stratified by sex and birth year found heterogeneous associations. Women born after 1950 who had been breastfed tended to have increased risks of colorectal cancer (OR = 1.58) and benign tumor (OR = 1.51) relative to those who had been formula-only fed, although not statistically significant. In men born after 1950, being breastfed was associated with a significantly decreased risk of benign tumor (OR = 0.57; 95% CI 0.33-0.98)., (© 2024. The Author(s).)

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m 2 ); normal (18.5-22.9 kg/m 2 ); overweight (23-24.9 kg/m 2 ); and obese (25+ kg/m 2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis., (© 2023 UICC.)

Introduction: Although lung cancer prediction models are widely used to support risk-based screening, their performance outside Western populations remains uncertain. This study aims to evaluate the performance of 11 existing risk prediction models in multiple Asian populations and to refit prediction models for Asians., Methods: In a pooled analysis of 186,458 Asian ever-smokers from 19 prospective cohorts, we assessed calibration (expected-to-observed ratio) and discrimination (area under the receiver operating characteristic curve [AUC]) for each model. In addition, we developed the "Shanghai models" to better refine risk models for Asians on the basis of two well-characterized population-based prospective cohorts and externally validated them in other Asian cohorts., Results: Among the 11 models, the Lung Cancer Death Risk Assessment Tool yielded the highest AUC (AUC [95% confidence interval (CI)] = 0.71 [0.67-0.74] for lung cancer death and 0.69 [0.67-0.72] for lung cancer incidence) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model had good calibration overall (expected-to-observed ratio [95% CI] = 1.06 [0.90-1.25]). Nevertheless, these models substantially underestimated lung cancer risk among Asians who reported less than 10 smoking pack-years or stopped smoking more than or equal to 20 years ago. The Shanghai models were found to have marginal improvement overall in discrimination (AUC [95% CI] = 0.72 [0.69-0.74] for lung cancer death and 0.70 [0.67-0.72] for lung cancer incidence) but consistently outperformed the selected Western models among low-intensity smokers and long-term quitters., Conclusions: The Shanghai models had comparable performance overall to the best existing models, but they improved much in predicting the lung cancer risk of low-intensity smokers and long-term quitters in Asia., (Copyright © 2023. Published by Elsevier Inc.)

Background: The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a differential pattern of associations exists between certain factors and breast cancer risk based on birth cohorts., Methods: This was a cohort study using pooled data from 12 cohort studies. We analysed associations between reproductive (menarche age, menopause age, parity and age at first delivery) and lifestyle (smoking and alcohol consumption) factors and breast cancer risk. We obtained hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard regression analysis on the 1920s, 1930s, 1940s and 1950s birth cohorts., Results: Parity was found to lower the risk of breast cancer in the older but not in the younger birth cohort, whereas lifestyle factors showed associations with breast cancer risk only among the participants born in the 1950s. In the younger birth cohort group, the effect size was lower for parous women compared to the other cohort groups (HR [95% CI] 0.86 [0.66-1.13] compared to 0.60 [0.49-0.73], 0.46 [0.38-0.56] and 0.62 [0.51-0.77]). Meanwhile, a higher effect size was found for smoking (1.45 [1.14-1.84] compared to 1.25 [0.99-1.58], 1.06 [0.85-1.32] and 0.86 [0.69-1.08]) and alcohol consumption (1.22 [1.01-1.48] compared to 1.10 [0.90-1.33], 1.15 [0.96-1.38], and 1.07 [0.91-1.26])., Conclusion: We observed different associations of parity, smoking and alcohol consumption with breast cancer risk across various birth cohorts., (© 2024. The Author(s).)

Background: Previous studies have shown that socioeconomic factors are associated with cancer incidence and stage at diagnosis; however, relevant findings in Japan are limited. We examined the association between socioeconomic status and cancer incidence, stage at diagnosis, and detection status by screening, as assessed using the areal deprivation index (ADI), in population-based cancer registry data., Methods: A total of 79,816 cases, including stomach, colorectal, lung, female breast, and cervical cancer diagnosed in Miyagi Prefecture between 2005 and 2010, were analyzed. After calculating the ADI at the place of residence in each case, we examined the association between quintiles of ADI and age-adjusted incidence rates of all stages and advanced stages by sex and site using Poisson regression analysis. The association between the ADI and the proportion of screen-detected cancers was also examined using logistic regression analysis., Results: The age-adjusted incidence rates of all sites and lung cancer in men and lung cancer and cervical cancer in women tended to increase significantly in areas with a higher ADI. The age-adjusted incidence rates of advanced-stage cancers were significantly higher for all sites and lung cancer in both sexes, and for stomach and colorectal cancer in men. The proportion of screen-detected cancer tended to be significantly lower in areas with a higher ADI for stomach and colorectal cancer in men., Conclusion: Our results indicate that socioeconomic disparities may affect cancer incidence and early diagnosis in Japan. These results suggest the importance of cancer control measures targeting people with low socioeconomic status in Japan.

Objective: Endometrial cancer has been increasing worldwide, and is one of the most common female hormone-related cancers. The purpose of this study was to examine the association between sleep duration and risk of endometrial cancer among Japanese women., Methods: We conducted a pooled analysis of two prospective studies conducted among residents of Miyagi Prefecture in rural northern Japan. A total of 36,537 women aged 40-79 years participated in the Miyagi Cohort Study in 1990 and in the Ohsaki Cohort Study in 1994. The participants responded to a self-administered questionnaire that including sleep duration. Sleep duration was assessed at the baseline using a self-administered questionnaire. The participants entered the mean integer number representing the hours of sleep taken per day during the previous year. We divided the participants into three groups (≤6 h, 7-8 h, or ≥9 h). Cox proportional hazards regression analysis was used to estimate the multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for endometrial cancer incidence., Results: During 745,993 person-years of follow-up, we identified 146 incident cases of endometrial cancer. Compared with women who slept 7-8 h per day, the multivariate HR (95%CI) for endometrial cancer incidence was 1.07 (0.72-1.60) for those who slept 6 h or less, and 1.05 (0.57-1.93) for those who slept 9 h or longer (p-trend=0.57)., Conclusion: In analysis of two population -based prospective cohort studies conducted among Japanese women, we found no significant associations between sleep duration and the incidence of endometrial cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Importance: Despite evidence of an association between reproductive factors and endometrial cancer risk, prospective studies have been conducted mainly in non-Asian countries., Objective: To assess the association between reproductive factors, such as number of deliveries, age at menarche, or menopause, and endometrial cancer risk., Design, Setting, and Participants: This cohort study used pooled individual data from 13 prospective cohort studies conducted between 1963 and 2014 in the Asia Cohort Consortium. Participants were Asian women. Data analysis was conducted from September 2019 to April 2023., Exposures: Reproductive factors were assessed using a questionnaire in each cohort., Main Outcomes and Measures: The main outcome was time to incidence of endometrial cancer. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% CIs., Results: A total of 1005 endometrial cancer cases were detected among 332 625 women (mean [SD] age, 54.3 [10.4] years) during a mean (SD) of 16.5 (6.4) years of follow-up. Increasing number of deliveries was associated with a decreased endometrial cancer risk in a dose-response manner (≥5 deliveries vs nulliparous [reference]: HR, 0.37; 95% CI, 0.26-0.53; P for trend < .001). Compared with menarche at younger than 13 years, menarche at 17 years or older had an HR of 0.64 (95% CI, 0.48-0.86; P for trend < .001). Late menopause (age ≥55 years) showed an HR of 2.84 (95% CI, 1.78-4.55; P for trend < .001) compared with the youngest age category for menopause (<45 years). Age at first delivery, hormone therapy, and breastfeeding were not associated with endometrial cancer risk., Conclusions and Relevance: This large pooled study of individual participant data found that late menarche, early menopause, and a higher number of deliveries were significantly associated with a lower risk of endometrial cancer. These convincing results from Asian prospective studies add to the growing body of evidence for the association between reproductive factors and endometrial cancer.

Some laboratory studies have shown that fucoidan, which is contained in seaweed extract, has inhibitory effects on the invasion and angiogenesis of tumor cells; however, the association between seaweed consumption and prostate cancer incidence remains unclear. The purpose of the present study was to examine the association between seaweed consumption and the risk of prostate cancer incidence in the Japanese population. Data from 19 311 men in the Miyagi Cohort Study who were 40-64 years old at baseline in 1990 were examined. Seaweed consumption was assessed at baseline using a self-administered food frequency questionnaire. The participants were divided into three categories based on seaweed consumption at baseline. During 24.5 years of follow-up, we identified 815 incident cases of prostate cancer. Multivariate analysis showed that seaweed consumption was not associated with prostate cancer incidence. The multivariate hazard ratios and 95% confidence intervals for prostate cancer incidence in the highest tertile versus the other tertiles were 0.76 (0.60-0.96) and 0.78 (0.61-0.99) ( P -trend = 0.15). Furthermore, the null association was independent of whether their clinical stage was localized or advanced. In this population-based prospective cohort study conducted in Japan, we found no significant association between seaweed consumption and the incidence of prostate cancer., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

We report the first example of a synthetic thiol-based compound that promotes oxidative protein folding upon 1-equivalent loading to the disulfide bonds in the client protein to afford the native form in over 70% yield. N -Methylation is a central post-translational processing of proteins in vivo for regulating functions including chaperone activities. Despite the universally observed biochemical reactions in nature, N -methylation has hardly been utilized in the design, functionalization, and switching of synthetic bioregulatory agents, particularly folding promotors. As a biomimetic approach, we developed pyridinylmethanethiols to investigate the effects of N -methylation on the promotion of oxidative protein folding. For a comprehensive study on the geometrical effects, constitutional isomers of pyridinylmethanethiols with ortho -, meta -, and para -substitutions have been synthesized. Among the constitutional isomers, para -substituted pyridinylmethanethiol showed the fastest disulfide-bond formation of the client proteins to afford the native forms most efficiently. N -Methylation drastically increased the acidity and enhanced the oxidizability of the thiol groups in the pyridinylmethanethiols to enhance the folding promotion efficiencies. Among the isomers, para -substituted N -methylated pyridinylmethanethiol accelerated the oxidative protein folding reactions with the highest efficiency, allowing for protein folding promotion by 1-equivalent loading as a semi-enzymatic activity. This study will offer a novel bioinspired molecular design of synthetic biofunctional agents that are semi-enzymatically effective for the promotion of oxidative protein folding including biopharmaceuticals such as insulin in vitro by minimum loading., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: The purpose of the present study was to investigate the association between personality and the risk of IHD mortality among Great East Japan Earthquake (GEJE) survivors, and to investigate whether personality traits affected the increase in IHD mortality observed after the GEJE., Methods: We analyzed data for 29,065 men and women in the Miyagi Cohort Study who were 40-64 years old at baseline. We divided the participants into quartiles based on scores for each of the four personality subscales (extraversion, neuroticism, psychoticism, and lie), using the Japanese version of the Eysenck Personality Questionnaire-Revised Short Form. We divided the eight years before and after the GEJE event (11 March 2011) into two period, and examined the relationship between personality traits and the risk of IHD mortality. Cox proportional hazards analysis was used to estimate the multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of IHD mortality according to each personality subscale category., Results: In the four years before the GEJE, neuroticism was significantly associated with an increased risk of IHD mortality. Compared with the lowest category for neuroticism, the multivariate-adjusted HR (95% CI) for IHD mortality in the highest category was 2.19 (1.03-4.67) (p-trend = 0.12). In contrast, no statistically significant association between neuroticism and IHD mortality was observed in the four years after the GEJE., Conclusion: This finding suggests that the observed increase in IHD mortality after the GEJE can be attributed to risk factors other than personality., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: The impact of dairy consumption on thyroid cancer is unclear. The purpose of this study was to elucidate the association between dairy consumption and the risk of thyroid cancer in Japanese people., Methods: The association between dairy consumption and the risk of thyroid cancer in Japanese people was examined by conducting a pooled analysis of two prospective studies of residents in Miyagi Prefecture, Japan. Data from 64,340 men and women aged 40-79 years registered in the Miyagi Cohort Study in 1990 and in the Ohsaki Cohort Study in 1994 were analyzed. Dairy consumption was assessed at baseline using a self-administered food frequency questionnaire and was divided into quartiles based on the weight (in grams) of total dairy consumption per day., Results: During 1,075,018 person-years of follow-up, there were 190 incident cases of thyroid cancer (29 men and 161 women). The hazard ratios (HRs) and 95% confidence intervals (CIs) for thyroid cancer incidence in the highest quartile of dairy consumption compared with the lowest quartile were 0.83 (95% CIs 0.28-2.43, P-trend = 0.823) for men and 0.67 (95% CIs 0.42-1.06, P-trend = 0.056) for women. After stratification for BMI, a decreased risk was observed in women with BMI ≥ 25 kg/m 2 (HRs: 0.37, 95% CIs 0.18-0.79, P-trend = 0.010)., Conclusion: Dairy consumption is inversely associated with the risk of thyroid cancer in women with BMI ≥ 25 kg/m 2 ., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Cigarette smoking, alcohol drinking and obesity are known to be risk factors for colorectal cancer. These factors may affect survival after diagnosis, but evidence has been inconsistent. We investigated subsite-specific associations between prediagnosis smoking, alcohol drinking and body mass index and survival in colorectal cancer., Methods: Subjects were 1300 patients (colon 778; rectum 502; concurrent 20) with histologically confirmed colorectal cancer diagnosed during 1997-2013 at a single institution in Japan. Histories of smoking and alcohol drinking, height and prediagnosis weight were assessed using a self-administered questionnaire. Using Cox proportional hazards model, hazard ratios and 95% confidence intervals of mortality were estimated., Results: During a median follow-up period of 6.7 years, 479 deaths were documented. Ever-smoking was associated with an increased risk of all-cause death among patients with colon cancer (hazard ratio: 1.47; 95% confidence interval: 1.07-2.02 compared with never-smoking). According to colon subsite, this increased risk was clear in patients with proximal colon cancer (hazard ratio: 2.09; 95% confidence interval: 1.28-3.40). There was no association between smoking and rectal cancer survival. Alcohol drinking was not associated with survival for either colon or rectal cancer. Among patients with rectal cancer, higher body mass index was associated with a lower risk of all-cause (Ptrend = 0.0006) and disease-specific death (Ptrend = 0.02). For colon cancer, lower body mass index tended to be associated with a higher risk of all-cause death (Ptrend = 0.05)., Conclusions: The results indicate that lifestyles identified as risk factors for colorectal cancer may impact differently on patient survival according to anatomic subsite., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This study was performed to investigate the association between body mass index (BMI) and gastric cancer in East and Southeast Asia where most of gastric cancer is non-cardia gastric cancer., Methods: On the basis of 8,997 gastric cancer cases among the Asia Cohort Consortium participants from China, Japan, Korea, and Singapore (N = 538,835), we assessed gastric cancer risk according to BMI by calculating hazard ratios (HR) and 95% confidence intervals (CI) using the Cox proportional hazard regression model., Results: A U-shaped associations between BMI and gastric cancer risk were observed. Gastric cancer risks in underweight group (&lt;18.5 kg/m2) and in obesity group (≥27.5 kg/m2) were higher than reference BMI group (23-24.9 kg/m2; HR, 1.15; 95% CI, 1.05-1.25 for underweight; HR, 1.12; 95% CI, 1.03-1.22 for obesity, respectively). The associations of underweight and obesity with gastric cancer risk were consistent in the analyses for non-cardia gastric cancer, intestinal-type gastric cancer, and late-onset gastric cancer. No significant association of underweight and obesity with the risk of cardia gastric cancer, diffuse-type gastric cancer, and early-onset gastric cancer was observed. In addition, we found that the U-shaped association between BMI and gastric cancer risk remained in nonsmokers, while only underweight was related to increased gastric cancer risk in smokers., Conclusions: BMI has a U-shaped association with gastric cancer risk in East and Southeast Asian population, especially for the non-cardia gastric cancer, intestinal-type gastric cancer, and late-onset gastric cancer., Impact: Future studies with consideration of anatomic location and histology of gastric cancer are needed to establish the association of underweight as well as obesity with gastric cancer risk., (©2022 American Association for Cancer Research.)

Background: The association between body mass index (BMI) and oesophageal cancer (OC) has been consistently negative among Asians, whereas different associations based on histological OC subtypes have been observed in Europeans and North Americans. We examined the association between BMI and OC mortality in the Asia Cohort Consortium., Methods: We performed a pooled analysis to evaluate the association between BMI and OC mortality among 842 630 Asians from 18 cohort studies. Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs., Results: A wide J-shaped association between BMI and overall OC mortality was observed. The OC mortality risk was increased for underweight (BMI <18.5 kg/m2: HR = 2.20, 95% CI 1.80-2.70) and extreme obesity (BMI ≥35 kg/m2: HR = 4.38, 95% CI 2.25-8.52) relative to the reference BMI (23-25 kg/m2). This association pattern was confirmed by several alternative analyses based on OC incidence and meta-analysis. A similar wide J-shaped association was observed in oesophageal squamous cell carcinoma (OSCC). Smoking and alcohol synergistically increased the OC mortality risk in underweight participants (HR = 6.96, 95% CI 4.54-10.67) relative to that in reference BMI participants not exposed to smoking and alcohol., Conclusion: Extreme obesity and being underweight were associated with an OC mortality risk among Asians. OC mortality and BMI formed a wide J-shaped association mirrored by OSCC mortality. Although the effect of BMI on OSCC and oesophageal adenocarcinoma mortality can be different in Asians, further research based on a large case-control study is recommended., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between coffee and tea consumption and mortality in Asian populations., Methods: We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model., Results: In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% [95% confidence interval (CI) 17%, 29%] and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption., Conclusions: In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Importance: Marital status has been shown to be associated with mortality, but evidence in Asian populations is limited., Objective: To examine the association of marital status with total and cause-specific mortality., Design, Setting, and Participants: This cohort study included individual participant data from 16 prospective studies in the Asia Cohort Consortium conducted between 1963 and 2015. Asian participants with complete information on marital and vital status were included. Study-specific hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards model and then pooled using a random-effects meta-analysis. The analysis began in February 2021 and ended in August 2021., Exposures: Marital status., Main Outcomes and Measures: All-cause and cause-specific mortality., Results: Of 623 140 participants (326 397 women [52.4%] and 296 743 men [47.6%]; mean [SD] age, 53.7 [10.2] years; mean [SD] follow-up time, 15.5 [6.1] years), 123 264 deaths were ascertained. Compared with married individuals, those who were unmarried had pooled HRs of 1.15 (95% CI, 1.07-1.24) for total mortality, 1.12 (95% CI, 1.03-1.22) for cerebrovascular disease mortality, 1.20 (95% CI, 1.09-1.31) for coronary heart disease mortality, 1.17 (95% CI, 1.07-1.28) for circulatory system diseases mortality, 1.06 (95% CI, 1.01-1.11) for cancer mortality, 1.14 (95% CI, 1.05-1.23) for respiratory diseases mortality, and 1.19 (95% CI, 1.05-1.34) for external causes of death. Positive associations with total mortality were also observed for those who were single (HR, 1.62; 95% CI, 1.41-1.86), separated (HR, 1.35; 95% CI, 1.13-1.61), divorced (HR, 1.38; 95% CI, 1.13-1.69), and widowed (HR, 1.09; 95% CI, 1.04-1.13). In subgroup analyses, the positive association persisted across baseline health conditions, and the risk of death was more pronounced among men or people younger than 65 years., Conclusions and Relevance: This large pooled cohort study of individual participant data provides strong evidence that being unmarried, as well as belonging to the unmarried subcategories, was positively associated with total and cause-specific mortality. Investment of targeted social support services might need to be considered in light of the mortality differences between married and unmarried individuals.

Background: Although previous meta-analyses have suggested a dose-response relationship between body mass index (BMI) and thyroid cancer risk, limited evidence has been presented about Asian populations. To assess this association among Asian populations, where underweight is more prevalent than in other regions, a pooled analysis from the Asia Cohort Consortium was conducted. Methods: Baseline height and weight were measured in five cohorts and self-reported in eight cohorts. Thyroid cancer incidence was ascertained by linkage to local cancer registries. Cohorts were treated as a stratum in the Cox proportional hazard model to estimate the pooled hazard ratios (HRs) and corresponding confidence intervals (CIs) from the estimates for each cohort. All analyses were stratified by sex. Results: A total of 538,857 men and women from 13 cohorts from mainland China, Korea, Japan, and Singapore were included in the analysis. During a mean of 15.1 years of follow-up, 1132 thyroid cancer cases were ascertained. Using a BMI of 18.5-22.9 kg/m 2 as a reference, an elevated risk of thyroid cancer was observed for groups with a BMI between 25 and 29.9 kg/m 2 (HR: 1.31, [CI: 0.95-1.80]) and a BMI of 30 kg/m 2 and greater (HR: 1.84, [CI: 0.89-3.81]) in men. Thyroid cancer risk was elevated in women with a BMI of 23-24.9 kg/m 2 (HR: 1.26, [CI: 1.07-1.48]). The HRs for 5-U increment of BMI showed a linear association among men (HR: 1.25, [CI 1.10-1.55]) but not among women (HR: 1.07, [CI: 0.97-1.18]). Although the overall thyroid cancer risk was lower among underweight men and women, the papillary cancer risk may be elevated among underweight men (HR: 2.24, [CI: 0.75-6.66]). Conclusion: While higher BMI is associated with an elevated risk of thyroid cancer in both men and women, the association of underweight BMI may differ by sex and histological subtype.

P5, also known as PDIA6, is a PDI family member involved in the ER quality control. Here, we revealed that P5 dimerizes via a unique adhesive motif contained in the N-terminal thioredoxin-like domain. Unlike conventional leucine zipper motifs with leucine residues every two helical turns on ∼30-residue parallel α helices, this adhesive motif includes periodic repeats of leucine/valine residues at the third or fourth position spanning five helical turns on 15-residue anti-parallel α helices. The P5 dimerization interface is further stabilized by several reciprocal salt bridges and C-capping interactions between protomers. A monomeric P5 mutant with the impaired adhesive motif showed structural instability and local unfolding, and behaved as aberrant proteins that induce the ER stress response. Disassembly of P5 to monomers compromised its ability to inactivate IRE1α via intermolecular disulfide bond reduction and its Ca 2+ -dependent regulation of chaperone function in vitro. Thus, the leucine-valine adhesive motif supports structure and function of P5., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

P5 is one of protein disulfide isomerase family proteins (PDIs) involved in endoplasmic reticulum (ER) protein quality control that assists oxidative folding, inhibits protein aggregation, and regulates the unfolded protein response. P5 reportedly interacts with other PDIs via intermolecular disulfide bonds in cultured cells, but it remains unclear whether complex formation between P5 and other PDIs is involved in regulating enzymatic and chaperone functions. Herein, we established the far-western blot method to detect non-covalent interactions between P5 and other PDIs and found that PDI and ERp72 are partner proteins of P5. The enzymatic activity of P5-mediated oxidative folding is up-regulated by PDI, while the chaperone activity of P5 is stimulated by ERp72. These findings shed light on the mechanism by which the complex formations among PDIs drive to synergistically accelerate protein folding and prevents aggregation. This knowledge has implications for understanding misfolding-related pathology.

Importance: The association between long sleep duration and mortality appears stronger in East Asian populations than in North American or European populations., Objectives: To assess the sex-specific association between sleep duration and all-cause and major-cause mortality in a pooled longitudinal cohort and to stratify the association by age and body mass index., Design, Setting, and Participants: This cohort study of individual-level data from 9 cohorts in the Asia Cohort Consortium was performed from January 1, 1984, to December 31, 2002. The final population included participants from Japan, China, Singapore, and Korea. Mean (SD) follow-up time was 14.0 (5.0) years for men and 13.4 (5.3) years for women. Data analysis was performed from August 1, 2018, to May 31, 2021., Exposures: Self-reported sleep duration, with 7 hours as the reference category., Main Outcomes and Measures: Mortality, including deaths from all causes, cardiovascular disease, cancer, and other causes. Sex-specific hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression with shared frailty models adjusted for age and the key self-reported covariates of marital status, body mass index, smoking status, alcohol consumption, physical activity, history of diabetes and hypertension, and menopausal status (for women)., Results: For 322 721 participants (mean [SD] age, 54.5 [9.2] years; 178 542 [55.3%] female), 19 419 deaths occurred among men (mean [SD] age of men, 53.6 [9.0] years) and 13 768 deaths among women (mean [SD] age of women, 55.3 [9.2] years). A sleep duration of 7 hours was the nadir for associations with all-cause, cardiovascular disease, and other-cause mortality in both men and women, whereas 8 hours was the mode sleep duration among men and the second most common sleep duration among women. The association between sleep duration and all-cause mortality was J-shaped for both men and women. The greatest association for all-cause mortality was with sleep durations of 10 hours or longer for both men (hazard ratio [HR], 1.34; 95% CI, 1.26-1.44) and women (HR, 1.48; 95% CI, 1.36-1.61). Sex was a significant modifier of the association between sleep duration and mortality from cardiovascular disease (χ25 = 13.47, P = .02), cancer (χ25 = 16.04, P = .007), and other causes (χ25 = 12.79, P = .03). Age was a significant modifier of the associations among men only (all-cause mortality: χ25 = 41.49, P < .001; cancer: χ25 = 27.94, P < .001; other-cause mortality: χ25 = 24.51, P < .001)., Conclusions and Relevance: The findings of this cohort study suggest that sleep duration is a behavioral risk factor for mortality in both men and women. Age was a modifier of the association between sleep duration in men but not in women. Sleep duration recommendations in these populations may need to be considered in the context of sex and age.

The management of chronic disseminated intravascular coagulation( DIC) caused by aortic dissection has not yet been established. We report the successful treatment of a case of aortic dissection with a patent false lumen using danaparoid sodium for acute exacerbation of chronic DIC. 2,000 U danaparoid sodium per day has been stabilizing the coagulative and fibrinolytic parameters and has been relieving bleeding tendencies with no side effects for a long term.

Associations of coffee and tea consumption with lung cancer risk have been inconsistent, and most lung cancer cases investigated were smokers. Included in this study were over 1.1 million participants from 17 prospective cohorts. Cox regression analyses were conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Potential effect modifications by sex, smoking, race, cancer subtype and coffee type were assessed. After a median 8.6 years of follow-up, 20 280 incident lung cancer cases were identified. Compared with noncoffee and nontea consumption, HRs (95% CIs) associated with exclusive coffee drinkers (≥2 cups/d) among current, former and never smokers were 1.30 (1.15-1.47), 1.49 (1.27-1.74) and 1.35 (1.15-1.58), respectively. Corresponding HRs for exclusive tea drinkers (≥2 cups/d) were 1.16 (1.02-1.32), 1.10 (0.92-1.32) and 1.37 (1.17-1.61). In general, the coffee and tea associations did not differ significantly by sex, race or histologic subtype. Our findings suggest that higher consumption of coffee or tea is associated with increased lung cancer risk. However, these findings should not be assumed to be causal because of the likelihood of residual confounding by smoking, including passive smoking, and change of coffee and tea consumption after study enrolment., (© 2020 UICC.)

ERp57, a member of the protein disulfide isomerase family, is a ubiquitous disulfide catalyst that functions in the oxidative folding of various clients in the mammalian endoplasmic reticulum (ER). In concert with ER lectin-like chaperones calnexin and calreticulin (CNX/CRT), ERp57 functions in virtually all folding stages from co-translation to post-translation, and thus plays a critical role in maintaining protein homeostasis, with direct implication for pathology. Here, we present mechanisms by which Ca 2+ regulates the formation of the ERp57-calnexin complex. Biochemical and isothermal titration calorimetry analyses revealed that ERp57 strongly interacts with CNX via a non-covalent bond in the absence of Ca 2+ . The ERp57-CNX complex not only promoted the oxidative folding of human leukocyte antigen heavy chains, but also inhibited client aggregation. These results suggest that this complex performs both enzymatic and chaperoning functions under abnormal physiological conditions, such as Ca 2+ depletion, to effectively guide proper oxidative protein folding. The findings shed light on the molecular mechanisms underpinning crosstalk between the chaperone network and Ca 2+ .

Background: Little is known about the health harms associated with low-intensity smoking in Asians who, on average, smoke fewer cigarettes and start smoking at a later age than their Western counterparts., Methods: In this pooled analysis of 738 013 Asians from 16 prospective cohorts, we quantified the associations of low-intensity (<5 cigarettes/day) and late initiation (≥35 years) of smoking with mortality outcomes. HRs and 95% CIs were estimated for each cohort by Cox regression. Cohort-specific HRs were pooled using random-effects meta-analysis., Findings: During a mean follow-up of 11.3 years, 92 068 deaths were ascertained. Compared with never smokers, current smokers who consumed <5 cigarettes/day or started smoking after age 35 years had a 16%-41% increased risk of all-cause, cardiovascular disease (CVD), respiratory disease mortality and a >twofold risk of lung cancer mortality. Furthermore, current smokers who started smoking after age 35 and smoked <5 cigarettes/day had significantly elevated risks of all-cause (HRs (95% CIs)=1.14 (1.05 to 1.23)), CVD (1.27 (1.08 to 1.49)) and respiratory disease (1.54 (1.17 to 2.01)) mortality. Even smokers who smoked <5 cigarettes/day but quit smoking before the age of 45 years had a 16% elevated risk of all-cause mortality; however, the risk declined further with increasing duration of abstinence., Conclusions: Our study showed that smokers who smoked a small number of cigarettes or started smoking later in life also experienced significantly elevated all-cause and major cause-specific mortality but benefited from cessation. There is no safe way to smoke-not smoking is always the best choice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Complicated and sophisticated protein homeostasis (proteostasis) networks in the endoplasmic reticulum (ER), comprising disulfide catalysts, molecular chaperones, and their regulators, help to maintain cell viability. Newly synthesized proteins inserted into the ER need to fold and assemble into unique native structures to fulfill their physiological functions, and this is assisted by protein disulfide isomerase (PDI) family. Herein, we focus on recent advances in understanding the detailed mechanisms of PDI family members as guides for client folding and assembly to ensure the efficient production of secretory proteins.

Second-generation antipsychotics are widely used to medicate patients with schizophrenia, but may cause metabolic side effects such as diabetes, which has been considered to result from obesity-associated insulin resistance. Olanzapine is particularly well known for this effect. However, clinical studies have suggested that olanzapine-induced hyperglycemia in certain patients cannot be explained by such a generalized mechanism. Here, we focused on the effects of olanzapine on insulin biosynthesis and secretion by mouse insulinoma MIN6 cells. Olanzapine reduced maturation of proinsulin, and thereby inhibited secretion of insulin; and specifically shifted the primary localization of proinsulin from insulin granules to the endoplasmic reticulum. This was due to olanzapine's impairment of proper disulfide bond formation in proinsulin, although direct targets of olanzapine remain undetermined. Olanzapine-induced proinsulin misfolding and subsequent decrease also occurred at the mouse level. This mechanism of olanzapine-induced β-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine., Competing Interests: SN, ST, MO, KI, MK, SK, KI, HU, TI, RM, ST, YI, KI, TA, TN, KM No competing interests declared, (© 2020, Ninagawa et al.)

Oxidative protein folding occurs primarily in the mammalian endoplasmic reticulum, enabled by a diverse network comprising more than 20 members of the protein disulfide isomerase (PDI) family and more than five PDI oxidases. Although the canonical disulfide bond formation pathway involving Ero1α and PDI has been well-studied so far, the physiological roles of the newly identified PDI oxidases, glutathione peroxidase-7 (GPx7) and -8 (GPx8), are only poorly understood. We here demonstrated that human GPx7 has much higher reactivity with H 2 O 2 and hence greater PDI oxidation activity than human GPx8. The high reactivity of GPx7 is due to the presence of a catalytic tetrad at the redox-active site, which stabilizes the sulfenylated species generated upon the reaction with H 2 O 2 Although it was previously postulated that GPx7 catalysis involved a highly reactive peroxidatic cysteine that can be sulfenylated by H 2 O 2 , we revealed that a resolving cysteine instead regulates the PDI oxidation activity of GPx7. We also determined that GPx7 formed complexes preferentially with PDI and P5 in H 2 O 2 -treated cells. Altogether, these results suggest that human GPx7 functions as an H 2 O 2 -dependent PDI oxidase in cells, whereas PDI oxidation may not be the central physiological role of human GPx8., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Kanemura et al.)

We report a case of a 48-year-old man with polycystic kidney disease (PKD), who was emergently transported to our institution by ambulance because of thoracic aortic rupture of Stanford type B acute aortic dissection. PKD is a congenital disease associated with hypertension( 60%) and cerebrovascular disease (20%). Few reports have described sudden death due to the rupture of an abdominal aortic aneurysm and acute aortic dissection. In this case, emergency hemi-arch replacement was performed successfully. His postoperative course was uneventful, and he was discharged on the 15th postoperative day.

Malignant pleural mesothelioma (MPM) is an asbestos-related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin-1 receptor (IL-1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro-inflammatory cytokine IL-1β and the IL-1R in MPM cells. Stimulation by IL-1β promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor-associated macrophages (TAMs) as the major source of IL-1β in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos-activated inflammasome in TAMs induced the production of IL-1β, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL-1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL-1β/IL-1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973)., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Dietary factors may affect the prognosis of digestive tract cancer, but evidence has been sparse. We investigated the association between pretreatment intake of 6 Japanese foods (including soy food, miso [soybean paste] soup and seaweed) and the risk of death among patients with histologically confirmed major digestive tract cancers (stomach, 1931; colon, 793; rectum, 510) diagnosed during 1997-2013 at a single institution in Japan. Pretreatment dietary intake was assessed using a food frequency questionnaire, and the patients were followed until December 2016. The Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Among the patients with stomach cancer, frequent intake of soy food was inversely associated with the risk of all-cause (P trend for four frequency groups = 0.01; HR = 0.72, 95% CI: 0.50-1.04 for highest vs lowest group) and stomach cancer (P trend  = 0.03; HR = 0.63, 95% CI: 0.40-0.99) death. A similar inverse association was also found for intake of miso soup. In contrast, frequent seaweed intake was inversely associated with the risk of all-cause death among the patients with colon cancer (P trend  = 0.03). Rectal cancer patients who had frequently consumed seaweed tended to have a lower risk of rectal cancer death (P trend  = 0.02). These findings indicate that pretreatment intake of Japanese foods such as soybean products and seaweed may have favorable effects on patient survival of stomach and colorectal cancer, although this needs to be confirmed by further research., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

It is already known that adult height is a factor associated with an increased risk of colon cancer and postmenopausal breast cancer, pancreatic cancer, premenopausal breast cancer, and ovarian cancer. However, the association between adult height and lung cancer incidence remains unclear. The purpose of the present study was to examine the association between adult height and the risk of lung cancer incidence in the Japanese population. We analyzed data for 43,743 men and women who were 40-64 years old at the baseline in 1990. We divided the participants into quintiles based on height at the baseline. Cox proportional hazards analysis was used to estimate the multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of lung cancer according to adult height, after adjustment for potential confounders. We identified 1,101 incident case of lung cancer during 24.5 years of follow-up. The multivariate HRs and 95% CIs for the highest category relative to the lowest were 1.48 (1.15-1.91) in men and 1.35 (0.91-1.99) in women. Furthermore, the association between adult height and the incidence of lung cancer was found the significant increased risk among ever smokers in men, but not never smokers. We also observed that adult height tend to be associated with an increased risk of small cell lung cancer and squamous cell carcinoma. This prospective cohort study has demonstrated a positive association between adult height and the risk of lung cancer incidence among men, especially those who have ever smoked.

How and when disulfide bonds form in proteins relative to the stage of their folding is a fundamental question in cell biology. Two models describe this relationship: the folded precursor model, in which a nascent structure forms before disulfides do, and the quasi-stochastic model, where disulfides form prior to folding. Here we investigated oxidative folding of three structurally diverse substrates, β2-microglobulin, prolactin, and the disintegrin domain of ADAM metallopeptidase domain 10 (ADAM10), to understand how these mechanisms apply in a cellular context. We used a eukaryotic cell-free translation system in which we could identify disulfide isomers in stalled translation intermediates to characterize the timing of disulfide formation relative to translocation into the endoplasmic reticulum and the presence of non-native disulfides. Our results indicate that in a domain lacking secondary structure, disulfides form before conformational folding through a process prone to nonnative disulfide formation, whereas in proteins with defined secondary structure, native disulfide formation occurs after partial folding. These findings reveal that the nascent protein structure promotes correct disulfide formation during cotranslational folding., (© 2020 Robinson et al.)

In mammalian cells, nearly one-third of proteins are inserted into the endoplasmic reticulum (ER), where they undergo oxidative folding and chaperoning assisted by approximately 20 members of the protein disulfide isomerase family (PDIs). PDIs consist of multiple thioredoxin-like domains and recognize a wide variety of proteins via highly conserved interdomain flexibility. Although PDIs have been studied intensely for almost 50 years, exactly how they maintain protein homeostasis in the ER remains unknown, and is important not only for fundamental biological understanding but also for protein misfolding- and aggregation-related pathophysiology. Herein, we review recent advances in structural biology and biophysical approaches that explore the underlying mechanism by which PDIs fulfil their distinct functions to promote productive protein folding and scavenge misfolded proteins in the ER, the primary factory for efficient production of the secretome., (Copyright © 2019 Elsevier B.V. All rights reserved.)