15-keto-PGE2 acts as switched agonist of EP receptors

Prostaglandin E2 (PGE2) is well-known as an endogenous proinflammatory prostanoid synthesized from arachidonic acid by the activation of cyclooxygenase-2. E type prostanoid (EP) receptors are cognates for PGE2 that have four main subtypes: EP1 to EP4. Of these, the EP2 and EP4 prostanoid receptors have been shown to couple to Gαs-protein and can activate adenylyl cyclase to form cAMP. Studies suggest that EP4 receptors are involved in colorectal homeostasis and cancer development, but further work is needed to identify the roles of EP2 receptors in these functions. After sufficient inflammation has been evoked by PGE2, it is metabolized to 15-keto-PGE2. Thus, 15-keto-PGE2 has long been considered an inactive metabolite of PGE2. However, it may have an additional role as a biased and/or partial agonist capable of taking over the actions of PGE2 to gradually terminate reactions. Here, using cell-based experiments and in silico simulations, we show that PGE2-activated EP4 receptor–mediated signaling may evoke the primary initiating reaction of the cells, which would take over the 15-keto-PGE2–activated EP2 receptor–mediated signaling after PGE2 is metabolized to 15-keto-PGE2. The present results shed light on new aspects of 15-keto-PGE2, which may have important roles in passing on activities to EP2 receptors from PGE2-stimulated EP4 receptors as a “switched agonist.” This novel mechanism may be significant for gradually terminating PGE2-evoked inflammation and/or maintaining homeostasis of colorectal tissues/cells functions

Sociodemographic factors affecting not receiving COVID-19 vaccine in Japan among people who originally intended to vaccinate: a prospective cohort study

ObjectiveVaccine hesitancy is a major issue for acquiring herd immunity. However, some individuals may go unvaccinated owing to inhibitory factors other than vaccine hesitancy. If there is even a small number of such people, support is needed for equitable vaccine distribution and acquiring herd immunity. We investigated sociodemographic factors that affected not undergoing COVID-19 vaccination in Japan among individuals who had strong intention to vaccinate before beginning the vaccination.MethodsWe conducted this prospective cohort study on workers aged 20–65 years from December 2020 (baseline), to December 2021 using a self-administered questionnaire survey. There were 27,036 participants at baseline and 18,560 at follow-up. We included 6,955 participants who answered yes to this question at baseline: “Would you like to receive a COVID-19 vaccine as soon as it becomes available?” We applied multilevel logistic regression analyses to examine the association between sociodemographic factors and being unvaccinated at follow-up.ResultsIn all, 289 participants (4.2%) went unvaccinated. The odds ratios (ORs) for being unvaccinated were significantly higher for participants aged 30–39 and 40–49 than those aged 60–65 years. Being divorced, widowed, or single, having low income, and having COVID-19 infection experience also had higher ORs.DiscussionWe found that some participants who initially had strong intention to vaccinate may have gone unvaccinated owing to vaccine side effects and the financial impact of absenteeism due to side effects. It is necessary to provide information repeatedly about the need for vaccination as well as social support to ensure that those who intend to vaccinate are able to do so when aiming for acquiring herd immunity through vaccination against COVID-19 as well as other potential infection pandemics in the future

Association between shift work and the risk of death from biliary tract cancer in Japanese men

Background: There is increasing evidence suggesting that shift work involving night work may increase cancer risk. Methods: We examined the association between working rotating shifts and the risk of death from biliary tract cancer among Japanese men who participated in the Japan Collaborative Cohort Study. Of the 46, 395 men recruited, 22, 224 men aged 40-65 at baseline (1988-1990) who reported working full-time or were self-employed were included in the present analysis. The study subjects were followed through December 31, 2009. Information regarding occupation and lifestyle factors was collected using a self-administered questionnaire. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95 % confidence interval (CI) for the risk of death from biliary tract cancer in relation to shift work. Results: During a mean 17-year follow-up, we observed 94 biliary tract cancer deaths, including 23 deaths from gallbladder cancer and 71 deaths from extrahepatic bile duct cancer. Overall, shift work was associated with a statistically non-significant increase in the risk of biliary tract cancer, with an HR of 1.50 (95 % CI: 0.81-2.77), among rotating shift workers. When the analysis was limited to extrahepatic bile duct cancer, a significant association appeared, with a multivariable-adjusted HR of 1.93 (95 % CI: 1.00-3.72) for rotating shift workers. Conclusion: Our data indicate that shift work may be associated with increased risk of death from extrahepatic bile duct cancer in this cohort of Japanese men. The association with gallbladder cancer remains unclear because of the small number of deaths

ジョウチョウカンマク ドウミャクセイ ジュウニシチョウ ヘイソクショウ SMA syndrome ニ タイスル フククウキョウカ ジュウニシチョウ クウチョウ フンゴウジュツ

Superior mesenteric artery (SMA) syndrome is a rare disorder, recognized as nausea, vomiting, weight loss, and postprandial abdominal pain due to compression and obstruction of the third portion of the duodenum by the SMA. If conservative treatment fails, then duodenojejunostomy or lysis of the ligament of Treitz is indicated. Recently, laparoscopic techniques have been described. This is the first case report, to our knowledge, of performance of a laparoscopic duodenojejunostomy for treatment of SMA syndrome in Japan. A 17-year-old female with a diagnosis of SMA syndrome was prepared for surgery after having failed conservative management. Laparoscopic duodenojejunostomy was performed through the mesenterium of the transverse colon. Postoperative course was uneventful. A gastografin study obtained on postoperative day 6 demonstrated no leakage of the anastomosis and free flow of contrast medium through the duodenojejunostomy. Laparoscopic duodenojejunostomy is safe and effective and a viable method for treatment of SMA syndrome

Downregulation of microRNA-100/microRNA-125b

A majority of early colorectal cancers (CRCs) with submucosal invasion undergo surgical operation, despite a very low incidence of lymph node metastasis. Our study aimed to identify microRNAs (miRNAs) specifically responsible for lymph node metastasis in submucosal CRCs. MicroRNA microarray analysis revealed that miR-100 and miR-125b expression levels were significantly lower in CRC tissues with lymph node metastases than in those without metastases. These results were validated by quantitative real-time PCR in a larger set of clinical samples. The transfection of a miR-100 or miR-125b inhibitor into colon cancer HCT116 cells significantly increased cell invasion, migration, and MMP activity. Conversely, overexpression of miR-100 or miR-125b mimics significantly attenuated all these activities but did not affect cell growth. To identify target mRNAs, we undertook a gene expression array analysis of miR-100-silenced HCT116 cells as well as negative control cells. The Ingenuity Pathway Analysis, TargetScan software analyses, and subsequent verification of mRNA expression by real-time PCR identified mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 receptor (IGF1R) as direct, and Fas and X-linked inhibitor-of-apoptosis protein (XIAP) as indirect candidate targets for miR-100 involved in lymph node metastasis. Knockdown of each gene by siRNA significantly reduced the invasiveness of HCT116 cells. These data clearly show that downregulation of miR-100 and miR-125b is closely associated with lymph node metastasis in submucosal CRC through enhancement of invasion, motility, and MMP activity. In particular, miR-100 may promote metastasis by upregulating mTOR, IGF1R, Fas, and XIAP as targets. Thus, miR-100 and miR-125b may be novel biomarkers for lymph node metastasis of early CRCs with submucosal invasion

Marital status and mortality among Japanese men and women: the Japan Collaborative Cohort Study

<p>Abstract</p> <p>Background</p> <p>Several studies have indicated a significant association between marital status and mortality risks. However, most of these studies have compared married and unmarried people without differentiating among single, divorced and widowed status. Moreover, gender differences in mortality rates associated with marital status have not been sufficiently clarified. With significant increases in the percentages of divorced and widowed people and a corresponding drop in the marriage rate in Japan during the past two or three decades, it can be expected that these changes will have a significant impact on mortality rates.</p> <p>Methods</p> <p>This investigation used a prospective study of a total of 94,062 Japanese men and women aged 40–79 who completed self-administered questionnaires at baseline and during a followed-up of 9.9-years.</p> <p>Results</p> <p>Compared with married men, never-married men showed higher risks of mortality from cardiovascular disease [relative risk (RR) = 3.05, 95% confidence interval (CI) 2.03–4.60], respiratory disease (RR = 2.43, 95%CI 1.27–4.63), external causes (RR = 2.18, 95%CI 1.05–4.54) and all causes (RR = 1.91, 95%CI 1.51–2.42) after adjustment for potentially confounding variables. For never-married women, there was a smaller but significantly higher risk of mortality from all causes (RR = 1.46, 95%CI 1.15–1.84). Divorced and widowed men showed moderately higher risks of mortality from cardiovascular disease, external causes and all causes compared with married men, but such a trend was not observed in women.</p> <p>Conclusion</p> <p>Single status was associated with a higher risk of mortality than was married status for both men and women. Divorce and widowhood were associated with elevated risk for men, but not for women. These findings suggest single, divorce and widowhood status constitute potentially adverse health effects.</p

A prospective cohort study of neighborhood stress and ischemic heart disease in Japan: a multilevel analysis using the JACC study data

<p>Abstract</p> <p>Background</p> <p>A body of research has shown that neighborhood environment may have an effect on a variety of health outcomes, including cardiovascular disease. One explanation for the mechanism of the effect of neighborhood on cardiovascular disease is psychosocial pathways. Direct evidence for an effect of neighborhood on cardiovascular disease with adjustment for perceived stress at the individual level has not been obtained, however. The Japan Collaborative Cohort Study for the Evaluation of Cancer Risk provides a unique dataset which has aggregated area-based cohorts from 45 areas throughout Japan. The purpose of the present study was to examine the contextual effect of area-level stress on ischemic heart disease using data from a large prospective cohort in Japan.</p> <p>Methods</p> <p>A baseline survey of 110,792 residents of 45 areas aged 40-79 years was conducted between 1988 and 1990. Analysis was restricted to subjects from the 33 of 45 areas providing information about self-rated stress (32183 men and 45896 women). Multilevel Poisson regression models were employed in a two-level structure of individuals nested within the 33 areas. Area-level stress was calculated by sex as the number of persons who rated their stress level as high divided by the total number of subjects in that area. Mortality rate ratios (MRRs) per 1 percentage point increase in area-level stress were estimated with adjustment for compositional individual factors.</p> <p>Results</p> <p>During 15 years of follow-up (1,116,895 person-years), 936 deaths due to ischemic heart disease were recorded. Area-level stress varied from 6% to 22%. In the multivariable models, MRRs of area-level stress were 1.06 (95% confidence interval: 1.00-1.12, p = 0.043) in men and 1.07 (95% confidence interval: 1.00-1.14, p = 0.057) in women.</p> <p>Conclusions</p> <p>Area-level stress affects the likelihood of death due to ischemic heart disease of individuals in men. The present findings may suggest that stress should be considered not only within the individual but also within the neighborhood context.</p