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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.)

Small-cell lung cancer (SCLC) is characterized by one of neuroendocrine tumors, and is a clinically aggressive cancer due to its rapid growth, early dissemination, and rapid acquisition of multidrug resistance to chemotherapy. Moreover, the standard chemotherapeutic regimen in SCLC has not changed for three decades despite of the dramatic therapeutic improvement in non-SCLC. The development of a novel therapeutic strategy for SCLC has become a pressing issue. We found that expression of Eph receptor A2 (EphA2) is upregulated in three of 13 SCLC cell lines and five of 76 SCLC tumor samples. Genetic inhibition using siRNA of EphA2 significantly suppressed the cellular proliferation via induction of cell cycle arrest in SBC-5 cells. Furthermore, small molecule inhibitors of EphA2 (ALW-II-41-27 and dasatinib) also exclusively inhibited proliferation of EphA2-positive SCLC cells by the same mechanism. Collectively, EphA2 could be a promising candidate as a therapeutic target for SCLC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: It is unclear whether alcohol consumption may impact survival after breast cancer diagnosis. To clarify the association between pretreatment alcohol consumption and survival in breast cancer patients, a prospective patient cohort study was conducted., Methods: The cohort comprised 1,420 breast cancer patients diagnosed during 1997-2013 at a single institute in Japan. Alcohol drinking and other lifestyle factors were assessed by questionnaire survey at the initial admission. The patients were followed until December 31, 2016. The crude associations of pretreatment alcohol intake with survival were evaluated by Kaplan-Meier analysis. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) controlled by confounders., Results: During a median follow-up period of 8.6 years, 261 all-cause and 193 breast cancer-specific deaths were documented. Survival curves showed that ever-drinkers tended to have better survival than never-drinkers (breast cancer-specific survival, log-rank p = 0.0381). Better survival was also observed for light drinkers with an intake of <5.0 g per day. In the Cox model, ever-drinking was associated with a decreased risk of all-cause (HR: 0.75; 95% CI: 0.54-1.05) and breast cancer-specific death (HR: 0.68; 95% CI: 0.46-0.99). Light drinkers had a lower risk of breast cancer-specific death (frequency of drinking, HR = 0.57 for occasional or 1-2 times per week and 0.72 for 3-7 times per week; amount of alcohol consumed per day, HR = 0.57 for <5.0 g and 0.68 for ≥5.0 g compared with never-drinking). In terms of hormone receptor status, a significantly decreased risk of death associated with ever-drinking was observed among women with receptor-negative cancer (ER-/PR-, HR = 0.41; 95% CI: 0.20-0.84 for breast cancer-specific death)., Conclusions: Pretreatment, i.e., pre-diagnosis alcohol consumption is unlikely to have an adverse effect on survival after breast cancer diagnosis. Light alcohol consumption may have a beneficial effect on patient survival., Competing Interests: The authors have declared that no competing interests exist.

Background: Reproductive factors may influence breast cancer progression and patient survival; however, evidence has been limited., Methods: The associations of reproductive factors with tumor characteristics and patient survival were analyzed among 1468 breast cancer patients diagnosed during 1997-2013 at a single institute in Japan. The patients were followed until 2016. During a median follow-up period of 8.6 years, 272 all-cause and 199 breast cancer deaths were documented., Results: In case-case comparisons, later age at menarche was inversely associated with advanced tumors. Nulliparous patients tended to have receptor-positive [estrogen receptor (ER)+ or progesterone receptor (PR)+] tumors. Conversely, the Cox proportional-hazards model including adjustment for tumor characteristics revealed U-shaped relationship between parity number and the risk of all-cause death among the patients overall [hazard ratio (HR) = 2.10 for nulliparous, 1.28 for 2, and 1.50 for ≥ 3 vs. one child]. According to hormone receptor, later age at menarche and later age at last birth were positively associated with the risk of all-cause death among patients with ER- and PR- cancer (menarche, HR = 2.18 for ≥ 15 vs. ≤ 12 years, p trend  = 0.03; last birth, HR = 3.10 for ≥ 35 vs. ≤ 29 years, p trend  = 0.01). A shorter time since last birth was associated with the risk of death among receptor-positive patients (HR = 5.72 for ≤ 4 vs. ≥ 10 years, p trend  = 0.004)., Conclusion: The results indicate that the timing of menarche and parity have significant effects on patient survival, providing clues for understanding the association between women's life course and breast cancer outcome.

Background: To date, few epidemiologic studies have been conducted to elucidate lifestyle-related risk factors for multiple myeloma in Asia. We investigated the association of body mass index (BMI), smoking, and alcohol intake with the risk of multiple myeloma mortality through a pooled analysis of more than 800,000 participants in the Asia Cohort Consortium., Methods: The analysis included 805,309 participants contributing 10,221,623 person-years of accumulated follow-up across Asia Cohort Consortium cohorts. HRs and 95% confidence intervals (95% CI) for the association between BMI, smoking, and alcohol at baseline and the risk of multiple myeloma mortality were assessed using a Cox proportional hazards model with shared frailty., Results: We observed a statistically significant dose-dependent association between BMI categories and the risk of multiple myeloma mortality (<18.5 kg/m 2 : HR = 0.80, 95% CI: 0.52-1.24; 18.5-24.9 kg/m 2 : reference; 25.0-29.9 kg/m 2 : HR = 1.17, 95% CI: 0.94-1.47; ≥30 kg/m 2 : HR = 1.61, 95% CI: 0.99-2.64, P trend = 0.014). By sex, this association was more apparent in women than in men (P for heterogeneity between sexes = 0.150). We observed no significant associations between smoking or alcohol consumption and risk of multiple myeloma mortality., Conclusions: This study showed that excess body mass is associated with an increased risk of multiple myeloma mortality among Asian populations. In contrast, our results do not support an association between smoking or alcohol consumption and the risk of multiple myeloma mortality in Asian populations., Impact: This study provides important evidence on the association of BMI, smoking, and alcohol with the risk of multiple myeloma mortality in Asian populations., (©2019 American Association for Cancer Research.)

Objective: To study the association of educational level and risk of death from all causes, cardiovascular disease (CVD) and cancer among Asian populations., Design: A pooled analysis of 15 population-based cohort studies., Setting and Participants: 694 434 Asian individuals from 15 prospective cohorts within the Asia Cohort Consortium., Interventions: None., Main Outcome Measures: HRs and 95% CIs for all-cause mortality, as well as for CVD-specific mortality and cancer-specific mortality., Results: A total of 694 434 participants (mean age at baseline=53.2 years) were included in the analysis. During a mean follow-up period of 12.5 years, 103 023 deaths were observed, among which 33 939 were due to cancer and 34 645 were due to CVD. Higher educational levels were significantly associated with lower risk of death from all causes compared with a low educational level (≤primary education); HRs and 95% CIs for secondary education, trade/technical education and ≥university education were 0.88 (0.85 to 0.92), 0.81 (0.73 to 0.90) and 0.71 (0.63 to 0.80), respectively (p trend =0.002). Similarly, HRs (95% CIs) were 0.93 (0.89 to 0.97), 0.86 (0.78 to 0.94) and 0.81 (0.73 to 0.89) for cancer death, and 0.88 (0.83 to 0.93), 0.77 (0.66 to 0.91) and 0.67 (0.58 to 0.77) for CVD death with increasing levels of education (both p trend <0.01). The pattern of the association among East Asians and South Asians was similar compared with ≤primary education; HR (95% CI) for all-cause mortality associated with ≥university education was 0.72 (0.63 to 0.81) among 539 724 East Asians (Chinese, Japanese and Korean) and 0.61 (0.54 to 0.69) among 154 710 South Asians (Indians and Bangladeshis)., Conclusion: Higher educational level was associated with substantially lower risk of death among Asian populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Time-resolved direct observations of proteins in action provide essential mechanistic insights into biological processes. Here, we present mechanisms of action of protein disulfide isomerase (PDI)-the most versatile disulfide-introducing enzyme in the endoplasmic reticulum-during the catalysis of oxidative protein folding. Single-molecule analysis by high-speed atomic force microscopy revealed that oxidized PDI is in rapid equilibrium between open and closed conformations, whereas reduced PDI is maintained in the closed state. In the presence of unfolded substrates, oxidized PDI, but not reduced PDI, assembles to form a face-to-face dimer, creating a central hydrophobic cavity with multiple redox-active sites, where substrates are likely accommodated to undergo accelerated oxidative folding. Such PDI dimers are diverse in shape and have different lifetimes depending on substrates. To effectively guide proper oxidative protein folding, PDI regulates conformational dynamics and oligomeric states in accordance with its own redox state and the configurations or folding states of substrates.

Importance: Asia is home to the largest diabetic populations in the world. However, limited studies have quantified the association of diabetes with all-cause and cause-specific mortality in Asian populations., Objectives: To evaluate the association of diabetes with all-cause and cause-specific mortality in Asia and to investigate potential effect modifications of the diabetes-mortality associations by participants' age, sex, education level, body mass index, and smoking status., Design, Setting, and Participants: This pooled analysis incorporated individual participant data from 22 prospective cohort studies of the Asia Cohort Consortium conducted between 1963 and 2006. A total of 1 002 551 Asian individuals (from mainland China, Japan, South Korea, Singapore, Taiwan, India, and Bangladesh) were followed up for more than 3 years. Cohort-specific hazard ratios and 95% confidence intervals for all-cause and cause-specific mortality were estimated using Cox regression models and then pooled using random-effects meta-analysis. Analysis was conducted between January 10, 2018, and August 31, 2018., Exposures: Doctor-diagnosed diabetes, age, sex, education level, body mass index, and smoking status., Main Outcomes and Measures: All-cause and cause-specific mortality., Results: Of 1 002 551 participants (518 537 [51.7%] female; median [range] age, 54.0 [30.0-98.0] years), 148 868 deaths were ascertained during a median (range) follow-up of 12.6 (3.0-38.9) years. The overall prevalence of diabetes reported at baseline was 4.8% for men and 3.6% for women. Patients with diabetes had a 1.89-fold risk of all-cause death compared with patients without diabetes (hazard ratio [HR], 1.89; 95% CI, 1.74-2.04), with the highest relative risk of death due to diabetes itself (HR, 22.8; 95% CI, 18.5-28.1), followed by renal disease (HR, 3.08; 95% CI, 2.50-3.78), coronary heart disease (HR, 2.57; 95% CI, 2.19-3.02), and ischemic stroke (HR, 2.15; 95% CI, 1.85-2.51). The adverse diabetes-mortality associations were more evident among women (HR, 2.09; 95% CI, 1.89-2.32) than among men (HR, 1.74; 95% CI, 1.62-1.88) (P for interaction < .001) and more evident among adults aged 30 to 49 years (HR, 2.43; 95% CI, 2.08-2.84) than among adults aged 70 years and older (HR, 1.51; 95% CI, 1.40-1.62) (P for interaction < .001). A similar pattern of association was found between diabetes and cause-specific mortality, with significant variations noted by sex and age., Conclusions and Relevance: This study found that diabetes was associated with increased risk of death from several diseases among Asian populations. Development and implementation of diabetes management programs are urgently needed to reduce the burden of diabetes in Asia.

Importance: Understanding birth cohort-specific tobacco smoking patterns and their association with total and cause-specific mortality is important for projecting future deaths due to tobacco smoking across Asian populations., Objectives: To assess secular trends of tobacco smoking by countries or regions and birth cohorts and evaluate the consequent mortality in Asian populations., Design, Setting, and Participants: This pooled meta-analysis was based on individual participant data from 20 prospective cohort studies participating in the Asia Cohort Consortium. Between September 1, 2017, and March 31, 2018, a total of 1 002 258 Asian individuals 35 years or older were analyzed using Cox proportional hazards regression analysis and random-effects meta-analysis. The pooled results were presented for mainland China; Japan; Korea, Singapore, and Taiwan; and India., Exposures: Tobacco use status, age at starting smoking, number of cigarettes smoked per day, and age at quitting smoking., Main Outcomes and Measures: Country or region and birth cohort-specific mortality and the population attributable risk for deaths from all causes and from lung cancer., Results: Of 1 002 258 participants (51.1% women and 48.9% men; mean [SD] age at baseline, 54.6 [10.4] years), 144 366 deaths (9158 deaths from lung cancer) were ascertained during a mean (SD) follow-up of 11.7 (5.3) years. Smoking prevalence for men steadily increased in China and India, whereas it plateaued in Japan and Korea, Singapore, and Taiwan. Among Asian male smokers, the mean age at starting smoking decreased in successive birth cohorts, while the mean number of cigarettes smoked per day increased. These changes were associated with an increasing relative risk of death in association with current smoking in successive birth cohorts of pre-1920, 1920s, and 1930 or later, with hazard ratios for all-cause mortality of 1.26 (95% CI, 1.17-1.37) for the pre-1920 birth cohort, 1.47 (95% CI, 1.35-1.61) for the 1920s birth cohort, and 1.70 (95% CI, 1.57-1.84) for the cohort born in 1930 or later. The hazard ratios for lung cancer mortality were 3.38 (95% CI, 2.25-5.07) for the pre-1920 birth cohort, 4.74 (95% CI, 3.56-6.32) for the 1920s birth cohort, and 4.80 (95% CI, 3.71-6.19) for the cohort born in 1930 or later. Tobacco smoking accounted for 12.5% (95% CI, 8.4%-16.3%) of all-cause mortality in the pre-1920 birth cohort, 21.1% (95% CI, 17.3%-24.9%) of all-cause mortality in the 1920s birth cohort, and 29.3% (95% CI, 26.0%-32.3%) of all-cause mortality for the cohort born in 1930 or later. Tobacco smoking among men accounted for 56.6% (95% CI, 44.7%-66.3%) of lung cancer mortality in the pre-1920 birth cohort, 66.6% (95% CI, 58.3%-73.5%) of lung cancer mortality in the 1920s birth cohort, and 68.4% (95% CI, 61.3%-74.4%) of lung cancer mortality for the cohort born in 1930 or later. For women, tobacco smoking patterns and lung cancer mortality varied substantially by countries and regions., Conclusions and Relevance: In this study, mortality associated with tobacco smoking continued to increase among Asian men in recent birth cohorts, indicating that tobacco smoking will remain a major public health problem in most Asian countries in the coming decades. Implementing comprehensive tobacco-control programs is warranted to end the tobacco epidemic.

Although cigarette smoking is a major risk factor for lung cancer, genetic susceptibility may also affect lung cancer risk. To explore the role of genetic risk, this case-control study investigated the association between family history of cancer at several sites and lung cancer risk. A total of 1,733 lung cancer cases and 6,643 controls were selected from patients aged 30 years and over admitted to a single hospital in Japan between 1997 and 2009. Information on family history of cancer was collected using a self-administered questionnaire and odds ratios (ORs) were estimated by unconditional logistic regression. Family history of lung cancer in first-degree relatives was associated with an increased risk of lung cancer among both sexes. According to histology and type of relatives, a parental history of lung cancer was significantly associated with an increased risk of female adenocarcinoma (OR = 1.72). Stratification by smoking status revealed that this significant positive association in women was limited to ever-smokers (OR = 4.13). In men, a history of lung cancer in siblings was significantly associated with an increased risk of small cell carcinoma (OR = 2.28) and adenocarcinoma (OR = 2.25). Otherwise, positive associations between history of breast (OR = 1.99) and total (OR = 1.71) cancers in siblings and the risk of male adenocarcinoma were observed. These results suggest that inherited genetic susceptibility may contribute to the development of lung cancer. In men, shared exposure to environmental factors among siblings may also be responsible for the increase in lung cancer risk.

Disulfide-rich peptides are highly abundant in nature and their study has provided fascinating insight into protein folding, structure and function. Venomous cone snails belong to a group of organisms that express one of the largest sets of disulfide-rich peptides (conotoxins) found in nature. The diversity of structural scaffolds found for conotoxins suggests that specialized molecular adaptations have evolved to ensure their efficient folding and secretion. We recently showed that canonical protein disulfide isomerase (PDI) and a conotoxin-specific PDI (csPDI) are ubiquitously expressed in the venom gland of cone snails and play a major role in conotoxin folding. Here, we identify cone snail endoplasmic reticulum oxidoreductin-1 ( Conus Ero1) and investigate its role in the oxidative folding of conotoxins through reoxidation of cone snail PDI and csPDI. We show that Conus Ero1 preferentially reoxidizes PDI over csPDI, suggesting that the reoxidation of csPDI may rely on an Ero1-independent molecular pathway. Despite the preferential reoxidation of PDI over csPDI, the combinatorial effect of Ero1 and csPDI provides higher folding yields than Ero1 and PDI. We further demonstrate that the highest in vitro folding rates of two model conotoxins are achieved when all three enzymes are present, indicating that these enzymes may act synergistically. Our findings provide new insight into the generation of one of the most diverse classes of disulfide-rich peptides and may improve current in vitro approaches for the production of venom peptides for pharmacological studies.

Background: Age at first birth has been increasing among women in developed countries. Meanwhile, endometrial cancer has also been increasing worldwide, being one of the most common female hormone-related cancers. The purpose of this study was to examine the association between age at first birth and the risk of endometrial cancer among Japanese women, and to examine the hypothesis that the recent increase in endometrial cancer incidence can be partly explained by the trend for increasing age at first birth. Methods: We conducted a pooled analysis of two prospective studies among residents in Miyagi Prefecture in rural northern in Japan. The Miyagi Cohort Study started in 1990 and included 21,455 parous women. The Ohsaki Cohort Study started in 1994 and included 17,287 parous women. The subjects responded to a self-administrated questionnaire including reproductive factors such as age at first birth. Incident cases of cancer were identified through linkage to the Miyagi Prefectural Cancer Registry, which covers the study area. Results: In a consortium of two prospective studies with 598,933 person-years, we identified 105 incident case of endometrial cancer. Compared with women aged 22 years or less at first birth, multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of endometrial cancer were 0.79 (0.49-1.26) for women aged 23 to 25 years at first birth, and 0.53 (0.28-1.00) for those aged 26 years and older (p-trend <0.05). Conclusion: This pooled analysis of two prospective studies does not support the hypothesis that the recent increase in the incidence of endometrial cancer can be partly explained by the increase in the age at first birth., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The misfolding, amyloid aggregation, and fibril formation of intrinsically disordered proteins/peptides (or amyloid proteins) have been shown to cause a number of disorders. The underlying mechanisms of amyloid fibrillation and structural properties of amyloidogenic precursors, intermediates, and amyloid fibrils have been elucidated in detail; however, in-depth examinations on physiologically relevant contributing factors that induce amyloidogenesis and lead to cell death remain challenging. A large number of studies have attempted to characterize the roles of biomembranes on protein aggregation and membrane-mediated cell death by designing various membrane components, such as gangliosides, cholesterol, and other lipid compositions, and by using various membrane mimetics, including liposomes, bicelles, and different types of lipid-nanodiscs. We herein review the dynamic effects of membrane curvature on amyloid generation and the inhibition of amyloidogenic proteins and peptides, and also discuss how amyloid formation affects membrane curvature and integrity, which are key for understanding relationships with cell death. Small unilamellar vesicles with high curvature and large unilamellar vesicles with low curvature have been demonstrated to exhibit different capabilities to induce the nucleation, amyloid formation, and inhibition of amyloid-β peptides and α-synuclein. Polymorphic amyloidogenesis in small unilamellar vesicles was revealed and may be viewed as one of the generic properties of interprotein interaction-dominated amyloid formation. Several mechanical models and phase diagrams are comprehensively shown to better explain experimental findings. The negative membrane curvature-mediated mechanisms responsible for the toxicity of pancreatic β cells by the amyloid aggregation of human islet amyloid polypeptide (IAPP) and binding of the precursors of the semen-derived enhancer of viral infection (SEVI) are also described. The curvature-dependent binding modes of several types of islet amyloid polypeptides with high-resolution NMR structures are also discussed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cigarette smoking and alcohol drinking may affect the prognosis of stomach cancer, but evidence has been inconsistent. We investigated the associations between pretreatment smoking and alcohol drinking and the risk of all-cause and stomach cancer death among 1,576 patients with histologically confirmed stomach cancer diagnosed during 1997-2010 at a single hospital in Japan. Histories of smoking and alcohol drinking were assessed using a self-administered questionnaire. The patients were followed until December 31, 2013. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During 9,625.1 person-years, 670 all-cause and 419 stomach cancer deaths were documented. Among the patients overall, ever-drinking was significantly associated with an increased risk of all-cause death (HR: 1.25; 95% CI: 1.03-1.51), but not stomach cancer death. Positive linear associations with the frequency of drinking (p trend  = 0.02) and the amount of alcohol consumed per day (p trend  = 0.03) were observed for the risk of all-cause death. Ever-smoking was not related to either the risk of all-cause or stomach cancer death. Conversely, among the patients who underwent curative resection, a significant positive association was found between ever-smoking and the risk of stomach cancer death (HR: 2.44; 95% CI: 1.17-5.08). A positive association was also found for earlier age at start of smoking (p trend  = 0.0046). Pretreatment smoking and alcohol drinking have significant effects on stomach cancer survival. Lifestyle adjustments throughout life may improve survival., (© 2018 UICC.)

Background: Most previous studies evaluating the association between leisure-time physical activity (LTPA) and risk of death were conducted among generally healthy individuals of European ancestry. We investigated the association of LTPA with all-cause and cause-specific mortality among East Asian populations, including healthy individuals and those with existing chronic diseases, which has been less well characterized., Methods: We performed pooled analyses among 467 729 East Asian individuals recruited in nine prospective cohorts included in the Asia Cohort Consortium. Cox proportional hazards regressions were used to derive hazard ratios (HRs) and 95% confidence intervals (CIs) associated with LTPA after adjusting for age, sex, education and marital and smoking status., Results: During a mean follow-up period of 13.6 years, 65 858 deaths were identified. Compared with those who reported no or less than 1 h of LTPA per week, an inverse association was observed between the amount of LTPA and all-cause and cause-specific mortality (P for trend < 0.001). The strength of the inverse association was stronger for death due to cardiovascular diseases and causes other than cancer deaths. An inverse association of LTPA with total mortality was observed among individuals with a severe and often life-threatening disease: cancer, stroke or coronary heart disease [hazard ratio (HR) = 0.81, 95% CI = 0.73-0.89 for high vs low LTPA) and those with other chronic diseases such as diabetes or hypertension (HR = 0.86, 95% CI = 0.80-0.93 for high vs low LTPA). No clear modifying effects by sex, body mass index or smoking status were identified., Conclusions: Regular participation in LTPA is associated with reduced mortality in middle-aged and elder Asians regardless pre-existing health conditions., (© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

We present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron star systems, which are the most promising targets for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and [Formula: see text] credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5-[Formula: see text] requires at least three detectors of sensitivity within a factor of [Formula: see text] of each other and with a broad frequency bandwidth. When all detectors, including KAGRA and the third LIGO detector in India, reach design sensitivity, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone.

Background: Mesothelioma of peritoneal origin has wider variation in treatment outcomes than mesothelioma of pleural origin, likely because peritoneal mesothelioma comprises borderline malignant variants and aggressive malignant peritoneal mesothelioma (MPeM). This study retrospectively evaluates the efficacy of first-line systemic pemetrexed and cisplatin chemotherapy in MPeM., Research Design and Methods: Twenty-four patients with histologically proven MPeM were treated with pemetrexed plus cisplatin as a first-line systemic chemotherapy. The response was evaluated radiologically according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Twenty-two patients underwent 18 F-fluorodeoxyglucose positron emission tomography/(FDG-PET)/computed tomography(CT) at baseline, and 13 were eligible for metabolic assessment., Results: Two complete responses and 9 partial responses were achieved. Overall response rate and disease control rate were 45.8% and 91.7%, respectively. Median progression-free survival and median overall survival were 11.0 months and 15.8 months, respectively. Wet- type MPeM had significantly longer survival (40.9 months median) than other clinical types (15.5 months) (P = 0.045). The baseline maximum standardized uptake value in 22 patients was 8.93 (range, 2.5-16.77)., Conclusions: Systemic pemetrexed plus cisplatin is active for MPeM. Disparity with the outcome of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) needs to receive more emphasis, since peritoneal mesothelioma has a 5-year survival rate of 50%.

Aims/hypothesis: The aims of the study were to evaluate the association between type 2 diabetes and the risk of death from any cancer and specific cancers in East and South Asians., Methods: Pooled analyses were conducted of 19 prospective population-based cohorts included in the Asia Cohort Consortium, comprising data from 658,611 East Asians and 112,686 South Asians. HRs were used to compare individuals with diabetes at baseline with those without diabetes for the risk of death from any cancer and from site-specific cancers, including cancers of the oesophagus, stomach, colorectum, colon, rectum, liver, bile duct, pancreas, lung, breast, endometrium, cervix, ovary, prostate, bladder, kidney and thyroid, as well as lymphoma and leukaemia., Results: During a mean follow-up of 12.7 years, 37,343 cancer deaths (36,667 in East Asians and 676 in South Asians) were identified. Baseline diabetes status was statistically significantly associated with an increased risk of death from any cancer (HR 1.26; 95% CI 1.21, 1.31). Significant positive associations with diabetes were observed for cancers of the colorectum (HR 1.41; 95% CI 1.26, 1.57), liver (HR 2.05; 95% CI 1.77, 2.38), bile duct (HR 1.41; 95% CI 1.04, 1.92), gallbladder (HR 1.33; 95% CI 1.10, 1.61), pancreas (HR 1.53; 95% CI 1.32, 1.77), breast (HR 1.72; 95% CI 1.34, 2.19), endometrium (HR 2.73; 95% CI 1.53, 4.85), ovary (HR 1.60; 95% CI 1.06, 2.42), prostate (HR 1.41; 95% CI 1.09, 1.82), kidney (HR 1.84; 95% CI 1.28, 2.64) and thyroid (HR 1.99; 95% CI 1.03, 3.86), as well as lymphoma (HR 1.39; 95% CI 1.04, 1.86). Diabetes was not statistically significantly associated with the risk of death from leukaemia and cancers of the bladder, cervix, oesophagus, stomach and lung., Conclusions/interpretation: Diabetes was associated with a 26% increased risk of death from any cancer in Asians. The pattern of associations with specific cancers suggests the need for better control (prevention, detection, management) of the growing epidemic of diabetes (as well as obesity), in order to reduce cancer mortality.

ERp44 retrieves some endoplasmic reticulum (ER)-resident enzymes and immature oligomers of secretory proteins from the Golgi. Association of ERp44 with its clients is regulated by pH-dependent mechanisms, but the molecular details are not fully understood. Here we report high-resolution crystal structures of human ERp44 at neutral and weakly acidic pH. These structures reveal key regions in the C-terminal tail (C tail) missing in the original crystal structure, including a regulatory histidine-rich region and a subsequent extended loop. The former region forms a short α-helix (α16), generating a histidine-clustered site (His cluster). At low pH, the three Trx-like domains of ERp44 ("a," "b," and "b'") undergo significant rearrangements, likely induced by protonation of His157 located at the interface between the a and b domains. The α16-helix is partially unwound and the extended loop is disordered in weakly acidic conditions, probably due to electrostatic repulsion between the protonated histidines in the His cluster. Molecular dynamics simulations indicated that helix unwinding enhances the flexibility of the C tail, disrupting its normal hydrogen-bonding pattern. The observed pH-dependent conformational changes significantly enlarge the positively charged regions around the client-binding site of ERp44 at low pH. Mutational analyses showed that ERp44 forms mixed disulfides with specific cysteines residing on negatively charged loop regions of Ero1α. We propose that the protonation states of the essential histidines regulate the ERp44-client interaction by altering the C-tail dynamics and surface electrostatic potential of ERp44., Competing Interests: The authors declare no conflict of interest.

Purpose: It has been hypothesized that intratumoral estrogens may play important roles in the growth of breast cancer. However, few studies have investigated such intratumoral hormones, or their association with risk factors of breast cancer., Methods: In this cross-sectional study, hormone levels in paired serum and tumor tissue samples from 146 postmenopausal women with breast cancer were measured by liquid chromatography-tandem mass spectrometry and compared between estrogen/progesterone (ER/PgR) subtypes. The associations of risk factors including body mass index (BMI) and other lifestyle factors with these hormone levels were investigated using analysis of covariance., Results: The level of estradiol (E2) in tumor tissue was extremely high in women with ER+ (geometric mean 95.6 pg/g) relative to women with ER-/PgR- (8.9 pg/g), whereas serum E2 level did not differ much between the two groups (3.1 and 2.8 pg/ml, respectively). Serum levels of precursors for E2, including testosterone (T) and androstenedione (Adione), and tissue Adione level, were high among women with ER+. After adjustment for confounding variables, BMI was found to be positively associated with tissue levels of E2, estrone (E1), T, and Adione among women with ER+ (P trend  < 0.0001 for E2; 0.0016 for E1; 0.0002 for T; and 0.03 for Adione)., Conclusion: The data suggest that tissue E2 is related to the growth of receptor-positive breast cancer and that risk factors such as BMI affect tissue levels of E2 and its precursors. Understanding of hormonal environments within tumor tissue may be important for elucidating hormonal etiology of breast cancer and improving the prognosis of patients.

Purpose: Efficient monitoring of tumor responsiveness to chemotherapy is essential to mitigate high mortality risks and cytotoxic effects of chemotherapeutics. However, there is no consensus on the most suitable diagnostic technique/parameters for assessing response to chemotherapy in malignant pleural mesothelioma (MPM). We compared the tumor responsiveness of MPM patients as assessed using modified RECIST (mRECIST) criteria and integrated 18F-FDG-PET/CT., Methods: Histologically confirmed MPM patients (N=82) who were treated with three cycles of cisplatin and pemetrexed, or carboplatin and pemetrexed, were included. mRECIST and integrated 18F-FDG-PET/CT were used to evaluate MPM tumor response to chemotherapy. Metabolic non-responders were defined as those with a 25% or greater increase in SUVmax compared with the previous value. Time to progression (TTP) and overall survival (OS) were compared between metabolic-responders and non-responders., Results: After three cycles of chemotherapy, 62(75.6%) of the patients were classified as having SD, 15 (18%) with partial remission (PR), and 5 (6%) with progressive disease (PD), based on mRECIST criteria. The cumulative median OS was 728.0days (95% confidence interval [CI]: 545.9-910.1) and cumulative median TTP was 365.0days (95% CI: 296.9-433.1). For the 82 patients, the disease control rate was 93.9%, whereas the metabolic response rate was only 71.9% (p<0.001). All PD and PR patients were found to be metabolic responders on 18F-FDG-PET/CT; however, among the 62mRECIST SD patients, 18 (29%) were classified as metabolic non-responders. The median TTP for metabolic responders was 13.7 months, while it was 10.0 months for non-responders(p<0.001). Metabolic responders had a trend toward longer OS, although the difference did not reach statistical significance (metabolic responders:33.9 months; non-responders: 21.6 months; p>0.05)., Conclusion: Several mRECIST-confirmed SD MPM patients may be classified as metabolic non-responders on18F-FDGPET/CT. Metabolic response is significantly correlated with the median TTP, suggesting it should be included in the evaluation of the response to chemotherapy in MPM patients classified as mRECIST SD, to identify non-responders., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

In the mammalian endoplasmic reticulum, oxidoreductin-1α (Ero1α) generates protein disulfide bonds and transfers them specifically to canonical protein-disulfide isomerase (PDI) to sustain oxidative protein folding. This oxidative process is coupled to the reduction of O 2 to H 2 O 2 on the bound flavin adenine dinucleotide cofactor. Because excessive thiol oxidation and H 2 O 2 generation cause cell death, Ero1α activity must be properly regulated. In addition to the four catalytic cysteines (Cys 94 , Cys 99 , Cys 104 , and Cys 131 ) that are located in the flexible active site region, the Cys 208 -Cys 241 pair located at the base of another flexible loop is necessary for Ero1α regulation, although the mechanistic basis is not fully understood. The present study revealed that the Cys 208 -Cys 241 disulfide was reduced by PDI and other PDI family members during PDI oxidation. Differential scanning calorimetry and small angle X-ray scattering showed that mutation of Cys 208 and Cys 241 did not grossly affect the thermal stability or overall shape of Ero1α, suggesting that redox regulation of this cysteine pair serves a functional role. Moreover, the flexible loop flanked by Cys 208 and Cys 241 provides a platform for functional interaction with PDI, which in turn enhances the oxidative activity of Ero1α through reduction of the Cys 208 -Cys 241 disulfide. We propose a mechanism of dual Ero1α regulation by dynamic redox interactions between PDI and the two Ero1α flexible loops that harbor the regulatory cysteines., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

To compare the efficacy of antipsychotics (APs) for delirium treatment in patients with cancer, 27 patients treated with 1 of the 4 APs, haloperidol (HPD), risperidone (RIS), olanzapine (OLZ), and quetiapine (QTP), were divided into 2 groups: long half-life (T1/2; HPD, RIS, and OLZ) versus short T1/2 (QTP) or the multiacting receptor-targeted APs (MARTAs; OLZ and QTP) versus the non-MARTA (HPD and RIS). The symptom severity was evaluated by the memorial delirium rating scale (MDAS) on days 0, 3, and 7 following intervention. Significant improvements in total MDAS scores were found in all groups on day 3. However, on day 7, only the short T1/2 group and MARTA group showed significant improvement. Consideration of an AP's pharmacological properties may be helpful for improving the outcomes of pharmacological delirium intervention in patients with cancer., (© The Author(s) 2014.)

Endoplasmic reticulum (ER) oxidoreductin 1α (Ero1α) is a disulfide producer in the ER of mammalian cells. Besides four catalytic cysteines (Cys(94), Cys(99), Cys(394), Cys(397)), Ero1α harbors four regulatory cysteines (Cys(104), Cys(131), Cys(208), Cys(241)). These cysteines mediate the formation of inhibitory intramolecular disulfide bonds, which adapt the activation state of the enzyme to the redox environment in the ER through feedback signaling. Accordingly, disulfide production by Ero1α is accelerated by reducing conditions, which minimize the formation of inhibitory disulfides, or by mutations of regulatory cysteines. Here we report that reductive stimulation enhances Ero1α activity more potently than the mutation of cysteines. Specifically, mutation of Cys(208)/Cys(241) does not mechanistically mimic reductive stimulation, as it lowers the turnover rate of Ero1α in presence of a reducing agent. The Cys(208)/Cys(241) pair therefore fulfills a function during catalysis that reaches beyond negative regulation. In agreement, we identify a reciprocal crosstalk between the stabilities of the Cys(208)-Cys(241) disulfide and the inhibitory disulfide bonds involving Cys(104) and Cys(131), which also controls the recruitment of the H2O2 scavenger GPx8 to Ero1α. Two possible mechanisms by which thiol-disulfide exchange at the Cys(208)/Cys(241) pair stimulates the catalytic turnover under reducing conditions are discussed., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

ISO 15189:2003 was published as an International Standard in 2003 by Technical Committee ISO/TC212 of the International Organization for Standardization (ISO). This international standard based on ISO 9001 specifies requirements for competence and quality that are specific to medical laboratories. With the publication of this standard, we will have to markedly change our concept. We have to adopt methods to manage the causes of errors in measurement processes rather than methods to manage only the results of measurements. The new concept of the Quality Management System (QMS) which manages the result of measurements is summarized. With the publication of ISO 15189, the definition of the quality assurance of examination results became clearer and stricter. This report describes the contents of ISO 15189 and the method of enforcing it.

Oxidative folding in the endoplasmic reticulum (ER) involves ER oxidoreductin 1 (Ero1)-mediated disulfide formation in protein disulfide isomerase (PDI). In this process, Ero1 consumes oxygen (O2) and releases hydrogen peroxide (H2O2), but none of the published Ero1 crystal structures reveal any potential pathway for entry and exit of these reactants. We report that additional mutation of the Cys(208)-Cys(241) disulfide in hyperactive Ero1α (Ero1α-C104A/C131A) potentiates H2O2 production, ER oxidation, and cell toxicity. This disulfide clamps two helices that seal the flavin cofactor where O2 is reduced to H2O2. Through its carboxyterminal active site, PDI unlocks this seal by forming a Cys(208)/Cys(241)-dependent mixed-disulfide complex with Ero1α. The H2O2-detoxifying glutathione peroxidase 8 also binds to the Cys(208)/Cys(241) loop region. Supported by O2 diffusion simulations, these data describe the first enzymatically controlled O2 access into a flavoprotein active site, provide molecular-level understanding of Ero1α regulation and H2O2 production/detoxification, and establish the deleterious consequences of constitutive Ero1 activity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background/aims: Phosphatidylinositol (PI) regulates a variety of cell processes. The present study investigated the antitumor action of 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol)(DOPI) and 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-myo-inositol)(DPPI) on human malignant pleural mesothelioma (MPM) cell lines such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells., Methods: MTT assay, TUNEL staining, flow cytometry using propidium iodide (PI) and annexin V (AV), enzymatic caspase assay, and nuclear staining using DAPI were carried out, and mitochondrial membrane potentials and intracellular distribution of apoptosis-inducing factor (AIF) were monitored in cells with and without the siRNA silencing the Bid-targeted gene., Results: Both DOPI and DPPI reduced cell viability for all the investigated MPM cell lines in a concentration (0.01-100 µM)-dependent manner. DOPI and DPPI significantly increased TUNEL-positive cells and the population of PI-negative/AV-positive and PI-positive/AV-positive cells, corresponding to early apoptosis and late apoptosis/secondary necrosis, respectively. DOPI and DPPI perturbed mitochondrial membrane potentials in MSTO-211H cells, but no significant activation of caspase-3, -4, -8, and -9 was obtained. DOPI and DPPI upregulated expression of Bid in MSTO-211H cells. DOPI and DPPI significantly increased nuclear localization of AIF without affecting expression of the mRNAs and proteins in MSTO-211H cells, which was inhibited by knocking-down Bid. In the DAPI staining, nuclear fragmentation and condensation were found., Conclusion: The results of the present study indicate that DOPI and DPPI facilitate Bid-mediated AIF release from the mitochondria, to accumulate AIF in the nucleus and induce caspase-independent apoptosis of MPM cells., (© 2015 S. Karger AG, Basel.)

A comprehensive review of physics at an [Formula: see text] linear collider in the energy range of [Formula: see text] GeV-3 TeV is presented in view of recent and expected LHC results, experiments from low-energy as well as astroparticle physics. The report focusses in particular on Higgs-boson, top-quark and electroweak precision physics, but also discusses several models of beyond the standard model physics such as supersymmetry, little Higgs models and extra gauge bosons. The connection to cosmology has been analysed as well.

Bisphenol A (BPA) is an endocrine disruptor that may have adverse effects on human health. We recently isolated protein-disulfide isomerase (PDI) as a BPA-binding protein from rat brain homogenates and found that BPA markedly inhibited PDI activity. To elucidate mechanisms of this inhibition, detailed structural, biophysical, and functional analyses of PDI were performed in the presence of BPA. BPA binding to PDI induced significant rearrangement of the N-terminal thioredoxin domain of PDI, resulting in more compact overall structure. This conformational change led to closure of the substrate-binding pocket in b' domain, preventing PDI from binding to unfolded proteins. The b' domain also plays an essential role in the interplay between PDI and ER oxidoreduclin 1α (Ero1α), a flavoenzyme responsible for reoxidation of PDI. We show that BPA inhibited Ero1α-catalyzed PDI oxidation presumably by inhibiting the interaction between the b' domain of PDI and Ero1α; the phenol groups of BPA probably compete with a highly conserved tryptophan residue, located in the protruding β-hairpin of Ero1α, for binding to PDI. Consistently, BPA slowed down the reoxidation of PDI and caused the reduction of PDI in HeLa cells, indicating that BPA has a great impact on the redox homeostasis of PDI within cells. However, BPA had no effect on the interaction between PDI and peroxiredoxin-4 (Prx4), another PDI family oxidase, suggesting that the interaction between Prx4 and PDI is different from that of Ero1α and PDI. These results indicate that BPA, a widely distributed and potentially harmful chemical, inhibits Ero1-PDI-mediated disulfide bond formation., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

The mammalian endoplasmic reticulum (ER) contains a diverse oxidative protein folding network in which ERp46, a member of the protein disulfide isomerase (PDI) family, serves as an efficient disulfide bond introducer together with Peroxiredoxin-4 (Prx4). We revealed a radically different molecular architecture of ERp46, in which the N-terminal two thioredoxin (Trx) domains with positively charged patches near their peptide-binding site and the C-terminal Trx are linked by unusually long loops and arranged extendedly, forming an opened V-shape. Whereas PDI catalyzes native disulfide bond formation by the cooperative action of two mutually facing redox-active sites on folding intermediates bound to the central cleft, ERp46 Trx domains are separated, act independently, and engage in rapid but promiscuous disulfide bond formation during early oxidative protein folding. Thus, multiple PDI family members likely contribute to different stages of oxidative folding and work cooperatively to ensure the efficient production of multi-disulfide proteins in the ER., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The Great East Japan earthquake and tsunami caused immense damage over a wide area of eastern Japan. Hence, many survivors are at high risk for posttraumatic stress disorder (PTSD). This randomized, observer-blinded, controlled trial examined the efficacy and safety of the traditional Japanese herbal formula saikokeishikankyoto (SKK) in the treatment of PTSD among survivors of this disaster. Forty-three participants with an Impact of Event Scale-Revised (IES-R) score ≥ 25 were randomized into SKK (n = 21) and control (n = 22) groups. The primary endpoint was the change in IES-R scores from baseline till after 2 weeks of treatment. Intergroup statistical comparisons were performed. The magnitude of changes in total IES-R scores differed significantly between the two groups (P < 0.001). Post hoc analysis showed that the total IES-R score improved significantly in the SKK group from 49.6 ± 11.9 to 25.5 ± 17.0 (P < 0.001). Subscale scores improved significantly in the SKK group (avoidance, P = 0.003; hyperarousal, P < 0.001; intrusion, P < 0.001). Two-week treatment with SKK significantly improved IES-R scores among PTSD patients. This traditional medicine may be a valid choice for the treatment of psychological and physical symptoms in PTSD patients.

The aim of this study was to examine the effects of oral administration of kampo medical formulas on ocular blood flow (OBF). A crossover protocol was used to randomly administer five grams of yokukansan, tokishakuyakusan (TSS), keishibukuryogan, or hachimijiogan to 13 healthy blinded subjects (mean age: 37.3 ± 12.3 years). The mean blur rate, a quantitative OBF index obtained with laser speckle flowgraphy, was measured at the optic nerve head before and 30 minutes after administration. Blood pressure (BP) and intraocular pressure (IOP) were also recorded. No significant changes were observed in mean BP or IOP after the administration of any of the kampo medical formulas. There was a significant increase in OBF 30 minutes after administration of TSS (100% to 103.6 ± 6.9%, P < 0.01). Next, TSS was administered to 19 healthy subjects (mean age: 32.0 ± 11.0 years) and OBF was measured before and 15, 30, 45, and 60 minutes after administration. Plain water was used as a control. OBF increased significantly after TSS administration compared to control (P < 0.01) and also increased from 30 to 60 minutes after administration compared to baseline (P < 0.05). These results suggest that TSS can increase OBF without affecting BP or IOP in healthy subjects.

Poststroke patients with functional constipation, assessed by the Rome III criteria, from 6 hospitals were recruited in a study on the effects of the traditional Japanese medicine Daikenchuto (DKT) on constipation. Thirty-four patients (17 men and 17 women; mean age: 78.1 ± 11.6 years) were randomly assigned to 2 groups; all patients received conventional therapy for constipation, and patients in the DKT group received 15 g/day of DKT for 4 weeks. Constipation scoring system (CSS) points and the gas volume score (GVS) (the measure of the intestinal gas volume calculated from plain abdominal radiographs) were recorded before and after a 4-week observation period. The total score on the CSS improved significantly in the DKT group compared to the control (P < 0.01). In addition, scores for some CSS subcategories (frequency of bowel movements, feeling of incomplete evacuation, and need for enema/disimpaction) significantly improved in the DKT group (P < 0.01, P = 0.049, and P = 0.03, resp.). The GVS was also significantly reduced in the DKT group compared to the control (P = 0.03). DKT in addition to conventional therapy is effective in treating functional constipation in poststroke patients. This study was a randomized controlled trial and was registered in the UMIN Clinical Trial Registry (no. UMIN000007393).

Purpose: The primary aim of this study was to clarify the effect of sublingual scopolamine on the intensity of nausea., Patients and Methods: This was an open uncontrolled study, and the study participants were cancer patients consecutively admitted to a palliative care unit in Japan. When the patients had nausea, they were administered a solution of scopolamine at 0.15 mg sublingually. The intensities of nausea were assessed using the 6-point Numerical Rating Scale (NRS 0 = no nausea to 5 = worst nausea) before and 15, 30, and 60 min after administration. Primary endpoints were (1) changes in the NRS of nausea and (2) percentage of patients who achieved a decrease in NRS of 1 or more points 15 min after treatment., Results: Twenty-six patients were recruited for this study. The median NRS significantly decreased from 3.0 (range, 1-5) to 1.5 (0-5) after 15 min, and 84 % (n = 21) of the patients achieved a decrease in NRS of 1 or more points after 15 min. In addition, the median NRS significantly decreased from 3.0 (before) to 0 (30 min) and 0 (60 min). The percentage of patients who achieved a decrease in NRS over 1 point was 96 % (n = 25) in 30 min and 100 % (n = 26) in 60 min. Fifteen percent (n = 4) showed drowsiness. No other adverse effects were reported., Conclusion: Sublingually administered scopolamine may be effective for managing nausea in terminally ill cancer patients. Randomized controlled trials are promising.

Background: Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to cytoreductive surgery along with intraperitoneal chemotherapy. Therefore, early diagnosis of DMPM is very important. Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis. DMPM involves the malignant transformation of mesothelial cells, which originate from mesenchymal cells, similar to lung fibroblasts. Here, we investigated serum levels of HMGB1 in patients with MPM and compared them with those of a population that had been exposed to asbestos without developing MPM., Study: The serum concentrations of HMGB1 were measured in 13 DMPM patients and 45 individuals with benign asbestos-related diseases., Result: We demonstrated that the patients with DMPM had significantly higher serum levels of HMGB1 compared with the population who had been exposed to asbestos but did not develop DMPM., Conclusion: Our data suggest that serum HMGB1 concentration is a useful serum marker for DMPM.

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to conventional chemotherapy and radiotherapy. Therefore, diagnosing MPM early is very important. Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis. MPM involves the malignant transformation of mesothelial cells, which originate from mesenchymal cells similar to lung fibroblasts. Here, we investigated serum levels of HMGB1 in patients with MPM and compared them with those of a population that had been exposed to asbestos without developing MPM., Methods: HMGB1 production from MPM cell lines was measured using ELISA. Serum HMGB1 levels were also examined in 61 MPM patients and 45 individuals with benign asbestos-related diseases., Results: HMGB1 concentrations of 2 out of 4 MPM cell lines were higher than that of normal mesothelial cell line, Met-5A. We demonstrated that patients with MPM had significantly higher serum levels of HMGB1 than the population who had been exposed to asbestos but had not developed MPM. The difference in overall survival between groups with serum HMGB1 levels that were lower and higher than assumed cut-off values was significant., Conclusions: Our data suggest that serum HMGB1 concentration is a useful prognostic factor for MPM.

Objective. We investigated the relationship between superior mesenteric artery blood flow volume (SMA BFV) and autonomic nerve activity in acupuncture stimulation of lower limb points through heart rate variability (HRV) evaluations. Methods. Twenty-six healthy volunteers underwent crossover applications of bilateral manual acupuncture stimulation at ST36 or LR3 or no stimulation. Heart rate, blood pressure, cardiac index, systemic vascular resistance index, SMA BFV, and HRV at rest and 30 min after the intervention were analyzed. Results. SMA BFV showed a significant increase after ST36 stimulation (0% to 14.1% ± 23.4%, P = 0.007); very low frequency (VLF), high frequency (HF), low frequency (LF), and LF/HF were significantly greater than those at rest (0% to 479.4% ± 1185.6%, P = 0.045; 0% to 78.9% ± 197.6%, P = 0.048; 0% to 123.9% ± 217.1%, P = 0.006; 0% to 71.5% ± 171.1%, P = 0.039). Changes in HF and LF also differed significantly from those resulting from LR3 stimulation (HF: 78.9% ± 197.6% versus -18.2% ± 35.8%, P = 0.015; LF: 123.9% ± 217.1% versus 10.6% ± 70.6%, P = 0.013). Conclusion. Increased vagus nerve activity after ST36 stimulation resulted in increased SMA BFV. This partly explains the mechanism of acupuncture-induced BFV changes.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy, thus early diagnosis of MPM is extremely critical. CT scans have limited accuracy in the differentiation between benign and malignant pleural disease. Several studies have reported that 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) plays an important role in the assessment of thoracic malignancy such as lung cancer. Here, we investigated the clinical utility of PET in patients with MPM. The maximum SUV (SUVmax) of 18F-FDG was measured in 47 MPM patients and 29 non-MPM patients including those with pleural thickening. We demonstrated that patients with MPM had significantly higher SUVmax levels than a population with non-malignant pleural disease. The Kaplan-Meier method revealed significant differences in overall survival between groups with SUVmax levels lower and higher than the assumed cut-off. Our data suggest that SUVmax levels are useful as an aid for diagnosis and prognosis of MPM.

Background: Whether effect-site concentrations of propofol (Cep) at loss of consciousness and return of consciousness (LOC and ROC, respectively) in elderly women using Diprifusor are similar is unclear. We investigated whether differences in initial target Cep (Ctarget) alter similarities between Cep values at LOC and ROC., Materials and Methods: In this study, female patients (n = 58, age = 72.5 ± 1.1 years) undergoing knee arthroplasty were administered propofol with Diprifusor. Cep at LOC and ROC were estimated for different Ctarget values (3.0-4.5 μg/ml). Pearson's correlation coefficient analysis and simple regression were performed to assess the relationship between Cep at LOC and ROC for each Ctarget. Differences in correlation coefficients of regression lines obtained from each Ctarget group were determined using the t-test., Results: The different Ctarget groups did not show significant differences in total propofol levels and in Cep values at LOC or ROC. However, Cep at ROC was significantly higher than Cep at LOC when Ctarget was 4.0 and 4.5 μg/ml, whereas these Cep values were not significantly different in low Ctarget groups. Strong positive correlations were observed between Cep at LOC and ROC for all Ctarget groups. Regression coefficients for the different Ctarget groups were not significantly different. Compared to low (≤3.5 μg/ml) Ctarget groups, high Ctarget groups showed significantly shorter time until LOC. Induction quality was not significantly different among the groups., Conclusions: In elderly women, Cep values at LOC are strong predictors of Cep at ROC when Ctarget is 3.0-4.5 μg/ml. High Ctarget groups (≥4.0 μg/ml) exhibited shorter induction times with normal cardiovascular stability.

The patient was a 57-year-old woman with malignant pleural mesothelioma. She had a past history of anxiety neurosis but not had any history of otological diseases. On admission to our hospice (day 1), she complained of dyspnea and wheezing associated with the progression of her underlying disease. After we started oral betamethasone (2 mg/d), dyspnea was alleviated and the frequency of wheezing was reduced. On day 3, she began to experience musical hallucinations that were manifested in opera/piano concert music and a child's voice. The episodes of musical hallucinations occurred approximately 10 times a day and disappeared spontaneously within several minutes. She had not experienced these symptoms before. We reduced the dose of betamethasone to 1 mg/d, but the musical hallucinations continued. Then on day 11, we switched betamethasone (1 mg/d) to prednisolone (10 mg/d) and we then gradually tapered off prednisolone. The frequency of musical hallucinations decreased and she ceased to experience musical hallucinations on day 29. However, on day 40, her dyspnea was aggravated again, so we started treatment with prednisolone (5 mg/d). Dyspnea was alleviated and no musical hallucinations occurred. On Day 51, dyspnea was worsened and we switched prednisolone to betamethasone (4 mg/d), which she hoped to use. The betamethasone alleviated the dyspnea but she developed musical hallucinations that were similar to the previous episodes. The musical hallucinations disappeared spontaneously 4-5 days later without changing the betamethasone. Musical hallucinations never occurred thereafter. She later died due to the exacerbation of disease.

Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion of blood and blood components. TRALI is reported to be the most common cause of transfusion-associated death. TRALI has increasingly become known in the medical community. However, TRALI has been overlooked frequently because of poor knowledge of medical staffs. We report two cases of TRALI after massive transfusion due to massive bleeding during cardiovascular surgery. In the perioperative period, the diagnosis of TRALI is difficult to make because of coexistence of various factors leading to hypoxia. Thus, in this report, we discuss the management of these two cases focusing upon the differential diagnosis of TRALI.

We propose an extended version of the standard model, in which neutrino oscillation, dark matter, and the baryon asymmetry of the Universe can be simultaneously explained by the TeV-scale physics without assuming a large hierarchy among the mass scales. Tiny neutrino masses are generated at the three-loop level due to the exact Z2 symmetry, by which the stability of the dark matter candidate is guaranteed. The extra Higgs doublet is required not only for the tiny neutrino masses but also for successful electroweak baryogenesis. The model provides discriminative predictions especially in Higgs phenomenology, so that it is testable at current and future collider experiments.