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The inhibitory activities of phaeosphaeride A (PPA), phaeosphaeride B, and four synthetic derivatives against phosphorylation of signal transducer and activator of transcription 3 (STAT3) and cell proliferation in cervical (HeLa) and breast (MDA-MB-231) cancer cells were evaluated. PPA inhibited IL-6-induced STAT3 phosphorylation and cell proliferation at similar concentrations. The structure-activity relationship studies revealed that the enantiomer of PPA was the most potent of the evaluated phaeosphaerides in both inhibiting STAT3 phosphorylation and cell growth. PPA clearly inhibited the IL-6-activated STAT3 signaling pathway. However, the presence or absence of activation of the STAT3 signaling pathway in cells showed no relationship to the antiproliferative activity. Notably, the possible covalent bond-forming ability of PPA was critical for its biological activities., 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 © 2024 Elsevier Ltd. All rights reserved.)

The RNA-binding protein HuD/ELAVL4 is essential for neuronal development and synaptic plasticity by governing various post-transcriptional processes of target mRNAs, including stability, translation, and localization. We previously showed that the linker region and poly(A)-binding domain of HuD play a pivotal role in promoting translation and inducing neurite outgrowth. In addition, we found that HuD interacts exclusively with the active form of Akt1, through the linker region. Although this interaction is essential for neurite outgrowth, HuD is not a substrate for Akt1, raising questions about the dynamics between HuD-mediated translational stimulation and its association with active Akt1. Here, we demonstrate that active Akt1 interacts with the cap-binding complex via HuD. We identify key amino acids in linker region of HuD responsible for Akt1 interaction, leading to the generation of two point-mutated HuD variants: one that is incapable of binding to Akt1 and another that can interact with Akt1 regardless of its phosphorylation status. In vitro translation assays using these mutants reveal that HuD-mediated translation stimulation is independent of its binding to Akt1. In addition, it is evident that the interaction between HuD and active Akt1 is essential for HuD-induced neurite outgrowth, whereas a HuD mutant capable of binding to any form of Akt1 leads to aberrant neurite development. Collectively, our results revisit the understanding of the HuD-Akt1 interaction in translation and suggest that this interaction contributes to HuD-mediated neurite outgrowth via a unique molecular mechanism distinct from translation regulation., (Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

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.)

Background: Desired longevity represents how strongly people esteem possible extensions of their own lifetime. The association between desired longevity and mortality risk has been reported in only one prospective study, which examined a small sample of older participants. We aimed to examine the hypothesis that desired longevity at middle-age predicted long-term survival., Methods: In the prospective cohort study, residents aged 40-64 years were asked how long they would like to live and asked to choose one from three options: longer than, as long as, or shorter than the life expectancy. We used Cox proportional hazards model to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality according to the three groups for desired longevity, treating the "longer than" group as the reference. We conducted mediation analysis to investigate the mechanism for the association between desired longevity and mortality., Results: We recruited 39,902 residents to the study. Risk of all-cause mortality was significantly higher in the "shorter than" group (HR 1.12; 95% CI, 1.04-1.21). The association was independent of sex, age, marital status, education, medical history, and health status. Regarding cause of death, mortality risk of cancer (HR 1.14; 95% CI, 1.00-1.29) and suicide (HR 2.15; 95% CI, 1.37-3.38) were also higher in the "shorter than" group. The unhealthy lifestyle mediated this association with all-cause mortality by 30.4%., Conclusion: Shorter desired longevity was significantly associated with an increased risk of all-cause mortality, and mortality from cancer and suicide. Lifestyle behaviors particularly mediated this association.

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.)

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.)

Translation initiation is the rate-limiting step of protein synthesis and is the main target of translation regulation. RNA-binding proteins (RBPs) are key mediators of the spatiotemporal control of translation and are critical for cell proliferation, development, and differentiation. We have previously shown that HuD, one of the neuronal RBPs, enhances cap-dependent translation through the direct interaction with eukaryotic initiation factor 4A (eIF4A) and poly(A) tail using a HeLa-derived in vitro translation system. We have also found that translation stimulation of HuD is essential for HuD-induced neurite outgrowth in PC12 cells. However, it remains unclear how HuD is involved in the regulation of translation initiation. Here, we report that HuD binds to eukaryotic initiation factor 3 (eIF3) via the eIF3b subunit, which belongs to the functional core of mammalian eIF3. eIF3 plays an essential role in recruiting the 40S ribosomal subunit onto mRNA in translation initiation. We hypothesize that the interaction between HuD and eIF3 stabilizes the translation initiation complex and increases translation efficiency. We also showed that the linker region of HuD is required for the interaction with eIF3b. Moreover, we found that eIF3b-binding region of HuD is conserved in all Hu proteins (HuB, HuC, HuD, and HuR). These data might also help to explain how Hu proteins stimulate translation in a cap- and poly(A)-dependent way.

Purpose: The association between dairy intake and mortality remains uncertain, and evidence for the Japanese population is scarce. We aimed to investigate the association between dairy intake and all-cause, cancer, and cardiovascular disease (CVD) mortality in Japanese adults., Methods: A total of 34,161 participants (16,565 men and 17,596 women) aged 40-64 years without a history of cancer, myocardial infarction, or stroke at baseline were included in the analysis, using data from the Miyagi Cohort Study initiated in 1990. Milk, yogurt, and cheese intake were obtained using a validated food frequency questionnaire. Total dairy intake was calculated as the sum of milk, yogurt, and cheese intake and then categorized by quartile. The outcomes were all-cause, cancer, and CVD mortality. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality risks., Results: During 750,016 person-years of follow-up, the total number of deaths was 6498, including 2552 deaths due to cancer and 1693 deaths due to CVD. There was no association between total dairy intake and all-cause, cancer, and CVD mortality for both men and women. We also examined the associations between subgroup dairy products and mortality. For milk and yogurt intake, our results suggest null associations. However, cheese intake was modestly associated with lower all-cause mortality in women; compared with non-consumers, the multivariable HRs (95%CIs) were 0.89 (0.81-0.98) for 1-2 times/month, 0.88 (0.78-1.00) for 1-2 times/week, and 0.89 (0.74-1.07) for 3 times/week or almost daily (p trend = 0.016)., Conclusion: Dairy intake was not associated with mortality in Japanese adults, except for limited evidence showing a modest association between cheese intake and a lower all-cause mortality risk in women., (© 2021. The Author(s).)

CCR4-NOT complex-mediated mRNA deadenylation serves critical functions in multiple biological processes, yet how this activity is regulated is not fully understood. Here, we show that osmotic stress induces MAPKAPK-2 (MK2)-mediated phosphorylation of CNOT2. Programmed cell death is greatly enhanced by osmotic stress in CNOT2-depleted cells, indicating that CNOT2 is responsible for stress resistance of cells. Although wild-type (WT) and non-phosphorylatable CNOT2 mutants reverse this sensitivity, a phosphomimetic form of CNOT2, in which serine at the phosphorylation site is replaced with glutamate, does not have this function. We also show that mRNAs have elongated poly(A) tails in CNOT2-depleted cells and that introduction of CNOT2 WT or a non-phosphorylatable mutant, but not phosphomimetic CNOT2, renders their poly(A) tail lengths comparable to those in control HeLa cells. Consistent with this, the CCR4-NOT complex containing phosphomimetic CNOT2 exhibits less deadenylase activity than that containing CNOT2 WT. These data suggest that CCR4-NOT complex deadenylase activity is regulated by post-translational modification, yielding dynamic control of mRNA deadenylation.

Nicotine administration enhances object recognition memory. However, target brain regions and cellular mechanisms underlying the nicotine effects remain unclear. In mice, the novel object recognition test revealed that systemic nicotine administration before training enhanced object recognition memory. Moreover, this effect was inhibited by infusion of retigabine, a selective voltage-dependent potassium 7 (Kv7) channel opener, into the medial prefrontal cortex (mPFC) before nicotine administration. Additionally, infusion of XE-991, a selective Kv7 channel blocker, into the mPFC before training enhanced object recognition memory. Therefore, Kv7 channels in the mPFC may be at least partly involved in nicotine-induced enhancement of object recognition memory., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Protein synthesis is tightly regulated at each step of translation. In particular, the formation of the basic cap-binding complex, eukaryotic initiation factor 4F (eIF4F) complex, on the 5' cap structure of mRNA is positioned as the rate-limiting step, and various cis-elements on mRNA contribute to fine-tune spatiotemporal protein expression. The cis-element on mRNAs is recognized and bound to the trans-acting factors, which enable the regulation of the translation rate or mRNA stability. In this review, we focus on the molecular mechanism of how the assembly of the eIF4F complex is regulated on the cap structure of mRNAs. We also summarize the fine-tuned regulation of translation initiation by various trans-acting factors through cis-elements on mRNAs., Competing Interests: The authors declare no conflict of interest.

Nicotine has been known to enhance recognition memory in various species. However, the brain region where nicotine acts and exerts its effect remains unclear. Since the medial prefrontal cortex (mPFC) is associated with memory, we examined the role of the mPFC in nicotine-induced enhancement of recognition memory using the novel object recognition test in male C57BL/6J mice. Systemic nicotine administration 10 min before training session significantly enhanced object recognition memory in test session that was performed 24 h after the training. Intra-mPFC infusion of mecamylamine, a non-selective nicotinic acetylcholine receptor (nAChR) antagonist, 5 min before nicotine administration blocked the effect of nicotine. Additionally, intra-mPFC infusion of dihydro-β-erythroidine, a selective α4β2 nAChR antagonist, or methyllycaconitine, a selective α7 nAChR antagonist, significantly suppressed the nicotine-induced object recognition memory enhancement. Finally, intra-mPFC infusion of nicotine 1 min before the training session augmented object recognition memory in a dose-dependent manner. These findings suggest that mPFC α4β2 and α7 nAChRs mediate the nicotine-induced object recognition memory enhancement.

Background: The Japanese government has recommended a 2-year endoscopic screening interval for gastric cancer. However, insufficient resources have constrained participation in endoscopic screening for gastric cancer. One way to avoid endoscopic screening harms and provide equal access is to define the appropriate screening interval., Methods: To expand screening interval from more than 2 years for low-risk group, a single-arm cohort of endoscopic screening started. At the baseline screening, the participants underwent endoscopic screening for gastric cancer, Helicobacter pylori ( H. pylori ) antibody test, and serum pepsinogen test (first year), and followed after 2 and 4 years (within the first 5 years). We also assessed H. pylori infection and atrophy status on images of upper gastrointestinal endoscopy at the baseline. A new screening model will be developed by dividing the participants into high-risk and low-risk groups based on demographics, history of H. pylori eradication, serological testing, and endoscopic diagnosis. The cumulative gastric cancer incidence after negative results at baseline are compared between the low-risk group on the 3rd screening round after 4 years from baseline and the total screening group on the 2nd screening round after 2 years. If the cumulative gastric cancer incidence in the low-risk group on the 3rd screening round is lower than that in the total screening group on the 2nd screening round, the screening interval can be expanded to 4 years in the low-risk group., Discussion: To reduce mortality from gastric cancer, a high participation rate of the target population is required. The screening interval of endoscopic screening can be changed if the individual risks for H. pylori infection are clarified. Our goal in this study is to obtain relevant data that can be used to improve the efficient use of endoscopic screening for gastric cancer by referring to individual risks in Japan., Trial Registration: UMIN000025839 (University Hospital Medical Information Network, Japan)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5949). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Purpose: The effects of immune checkpoint inhibitors have been reported to be linked with immune-related adverse events (irAEs). In patients with advanced non-small-cell lung cancer, who tested positive for programmed death-ligand 1 (PD-L1), pembrolizumab, an immune checkpoint inhibitor can be used as a treatment, and it was found to improve overall survival. However, there are only a few reports on the relationship between the therapeutic effects of pembrolizumab in patients with lung cancer and the irAEs of pembrolizumab. The purpose of this study was to determine the correlation between immune-related adverse events and the effects of pembrolizumab monotherapy in patients with non-small-cell lung cancer., Patients and Methods: From February 2017 to August 2019, we conducted a retrospective analysis of the effects of pembrolizumab treatment and immune-related adverse events in 94 patients with non-small-cell lung cancer treated with pembrolizumab only., Results: In 63 cases, irAEs were observed. The most common irAE was rash. PD-L1 positivity ≥ 50% tended to cause irAEs. The median progression-free survival (PFS) rates with and without irAEs were 371 days (95% CI, 184-NR) and 67 days (95% CI, 51-87 days), respectively. In a multivariate analysis, irAEs and Eastern Cooperative Oncology Group performance status (PS) were the factors related to PFS., Conclusion: In patients with lung cancer, who were treated with pembrolizumab monotherapy, the development of irAEs was likely indicative of the positive effects of pembrolizumab. This novel finding appears to be useful for clinicians who work with pembrolizumab for lung cancer treatment., Competing Interests: The authors have not received any funding for this study and report no conflicts of interest in this work., (© 2020 Noguchi et al.)

Eukaryotic gene expression can be spatiotemporally tuned at the post-transcriptional level by cis-regulatory elements in mRNA sequences. An important example is the AU-rich element (ARE), which induces mRNA destabilization in a variety of biological contexts in mammals and can also mediate translational control. Regulation is mediated by trans-acting factors that recognize the ARE, such as Tristetraprolin (TTP) and BRF1/ZFP36L1. Although both proteins can destabilize their target mRNAs through the recruitment of the CCR4-NOT deadenylation complex, TTP also directly regulates translation. Whether ZFP36L1 can directly repress translation remains unknown. Here, we used an in vitro translation system derived from mammalian cell lines to address this key mechanistic issue in ARE regulation by ZFP36L1. Functional assays with mutant proteins reveal that ZFP36L1 can repress translation via AU-Rich elements independent of deadenylation. ZFP36L1-mediated translation repression requires interaction between ZFP36L1 and CNOT1, suggesting that it might use a repression mechanism similar to either TPP or miRISC. However, several lines of evidence suggest that the similarity ends there. Unlike, TTP, it does not efficiently interact with either 4E-HP or GIGYF2, suggesting it does not repress translation by recruiting these proteins to the mRNA cap. Moreover, ZFP36L1 could not repress ECMV-IRES driven translation and was resistant to pharmacological eIF4A inhibitor silvestrol, suggesting fundamental differences with miRISC repression via eIF4A. Collectively, our results reveal that ZFP36L1 represses translation directly and suggest that it does so via a novel mechanism distinct from other translational regulators that interact with the CCR4-NOT deadenylase complex., Competing Interests: Declaration of competing interest We have no conflict of interest to declare., (Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

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.

Codon bias has been implicated as one of the major factors contributing to mRNA stability in several model organisms. However, the molecular mechanisms of codon bias on mRNA stability remain unclear in humans. Here, we show that human cells possess a mechanism to modulate RNA stability through a unique codon bias. Bioinformatics analysis showed that codons could be clustered into two distinct groups-codons with G or C at the third base position (GC3) and codons with either A or T at the third base position (AT3): the former stabilizing while the latter destabilizing mRNA. Quantification of codon bias showed that increased GC3-content entails proportionately higher GC-content. Through bioinformatics, ribosome profiling, and in vitro analysis, we show that decoupling the effects of codon bias reveals two modes of mRNA regulation, one GC3- and one GC-content dependent. Employing an immunoprecipitation-based strategy, we identify ILF2 and ILF3 as RNA-binding proteins that differentially regulate global mRNA abundances based on codon bias. Our results demonstrate that codon bias is a two-pronged system that governs mRNA abundance., (© 2019 The Authors.)

A 69-year-old woman underwent left upper lobectomy for left upper lobe lung adenocarcinoma. She later perceived a left visual field defect, and a brain metastasis was detected on head magnetic resonance imaging (MRI). Epidermal growth factor receptor (EGFR) testing identified two separate EGFR mutations: an L858R mutation in exon 21 and a de novo T790M mutation in exon 20. Treatment with osimertinib was started. After one month, head MRI showed that the brain metastasis had shrunk, and the visual field defect had also improved. In this case, first-line osimertinib was effective for treating brain metastasis of de novo T790M-positive lung cancer.

Mental disorders merge highly with thyroid diseases. Because of its regulatory effects on serotonin and noradrenalin, T3 has been linked closely to depression and anxiety. It has known that in many cases, the mental symptoms persist even after normalization of thyroid function by treatment. Psychosocial factors including stress have been associated with mental symptoms even after thyroid function normalization in Graves' disease and a combination of mental disorders have been related to the exacerbation of hyperthyroidism. These findings suggest that psychosomatic approaches based on the bio-psycho-social medical model are important for the treatment of mental disorders associated with Graves' disease., (© 2019 Published by Elsevier Inc.)

Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5'-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4 ; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5'-terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor β (PDGFRβ) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS , TP53 , eIF4A/4E-dependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among eIF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands., Competing Interests: Conflict of interest statement: H.S., S. Hashimoto, and A.H. are inventors on the patent application PCT/JP2019/10925., (Copyright © 2019 the Author(s). Published by PNAS.)

Rationale: N-[[1-(5-fluoropentyl)-1H-indazol-3-yl]carbonyl]-L-valine methyl ester (5F-AMB) is a synthetic cannabinoid that has been distributed recently. Although inhalation of 5F-AMB produces adverse effects, such as impaired memory and disturbed consciousness, in humans, the psychopharmacological effects of 5F-AMB in rodents have not been investigated., Objectives: We first examined the effects of intraperitoneal and intracerebroventricular injections of 5F-AMB on anxiety-like behavior and locomotor activity in the open field (OF) test and recognition memory in the novel object recognition test (NOR) in C57BL/6J mice. We also examined whether a cannabinoid 1 (CB1) receptor antagonist AM251 blocks the effects of 5F-AMB. We next examined the effects of 5F-AMB infusion into the medial prefrontal cortex (mPFC), a brain region associated with anxiety and memory, on these tests., Results: Intraperitoneal injection of 5F-AMB (0.3 mg/kg) dramatically decreased locomotor activity in the OF, and this effect was partially reversed by AM251 (3 mg/kg). Intracerebroventricular infusion of 5F-AMB (10 nmol) produced an anxiolytic effect in the OF and impaired acquisition, but not retrieval, of recognition memory in the NOR, and these effects were blocked by co-infusion of AM251 (1.8 nmol). Bilateral intra-mPFC infusion of 5F-AMB (10 pmol/side) similarly produced impaired recognition memory acquisition, but no anxiolytic effect., Conclusions: The results demonstrate that centrally administered 5F-AMB produces anxiolytic effect and impaired recognition memory acquisition via activation of CB1 receptors, while systemic 5F-AMB severely impaired locomotor activity. The mPFC is involved in 5F-AMB-induced impairment of recognition memory acquisition. However, other brain region(s) may contribute to the 5F-AMB-induced anxiolytic effect.

Lymphoproliferative disorders can occur in patients with autoimmune disorders who undergo long-term methotrexate therapy (MTX-LPD). Although the manifestations of MTX-LPD are diverse, little attention is paid to endobronchial involvement. We herein describe two patients with MTX-LPD who presented with parenchymal pulmonary tumors and endobronchial involvement of LPD; one had lymphomatoid gramulomatosis and the other LPD. The patients had no tumors adjacent to the endobronchial lesions. The endobronchial findings included multiple protruded mucosal lesions covered with white material, which was pathologically consistent with LPD. Recognition of the findings may help in making an earlier diagnosis of MTX-LPD in appropriate settings.

RNA-binding proteins (RBPs) are key regulators of posttranscriptional gene expression and control many important biological processes including cell proliferation, development, and differentiation. RBPs bind specific motifs in their target mRNAs and regulate mRNA fate at many steps. The AU-rich element (ARE) is one of the major cis-regulatory elements in the 3' untranslated region (UTR) of labile mRNAs. Many of these encode factors requiring very tight regulation, such as inflammatory cytokines and growth factors. Disruption in the control of these factors' expression can cause autoimmune diseases, developmental disorders, or cancers. Therefore, these mRNAs are strictly regulated by various RBPs, particularly ARE-binding proteins (ARE-BPs). To regulate mRNA metabolism, ARE-BPs bind target mRNAs and affect some factors on mRNAs directly, or recruit effectors, such as mRNA decay machinery and protein kinases to target mRNAs. Importantly, some ARE-BPs have stabilizing roles, whereas others are destabilizing, and ARE-BPs appear to compete with each other when binding to target mRNAs. The function of specific ARE-BPs is modulated by posttranslational modifications (PTMs) including methylation and phosphorylation, thereby providing a means for cellular signaling pathways to regulate stability of specific target mRNAs. In this review, we summarize recent studies which have revealed detailed molecular mechanisms of ARE-BP-mediated regulation of gene expression and also report on the importance of ARE-BP function in specific physiological contexts and how this relates to disease. We also propose an mRNP regulatory network based on competition between stabilizing ARE-BPs and destabilizing ARE-BPs.

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.

Many viruses strongly prefer to infect certain cell types, a phenomenon known as "tropism." Understanding tropism's molecular basis is important for the design of vaccines and antiviral therapy. A common mechanism involves viral protein interactions with cell-specific surface receptors, but intracellular mechanisms involving translation have also been described. In this report, we focus on Hepatitis A Virus (HAV) tissue tropism from the standpoint of the translational machinery. HAV genomic RNA, like other positive stranded RNA viruses, is devoid of a cap structure and its translation is driven by highly structured RNA sequences termed internal ribosome entry site (IRES) in the 5' untranslated region (UTR). Unlike most viral IRESs, HAV IRES-mediated translation requires eIF4E and the 3' end of HAV RNA is polyadenylated. However, the molecular mechanism of HAV IRES-mediated translation initiation remains poorly understood. We analyzed HAV-IRES-mediated translation in a cell-free system derived from either non-hepatic cells (HeLa) or hepatoma cells (Huh-7) that enables investigation of the contribution of the cap and the poly(A) tail. This revealed that HAV IRES-mediated translation activity in hepatoma cell extracts is higher as compared to extracts derived from a non-hepatic line. Our data suggest that HAV IRES-mediated translation is upregulated by a hepatic cell-specific activator in a poly(A) tail-independent manner.

Shortening and removal of the polyadenylate [poly(A)] tail of mRNA, a process called deadenylation, is a key step in mRNA decay that is mediated through the CCR4-NOT (carbon catabolite repression 4-negative on TATA-less) complex. In our investigation of the regulation of mRNA deadenylation in the heart, we found that this complex was required to prevent cell death. Conditional deletion of the CCR4-NOT complex components Cnot1 or Cnot3 resulted in the formation of autophagic vacuoles and cardiomyocyte death, leading to lethal heart failure accompanied by long QT intervals. Cnot3 bound to and shortened the poly(A) tail of the mRNA encoding the key autophagy regulator Atg7. In Cnot3 -depleted hearts, Atg7 expression was posttranscriptionally increased. Genetic ablation of Atg7 , but not Atg5 , increased survival and partially restored cardiac function of Cnot1 or Cnot3 knockout mice. We further showed that in Cnot3 -depleted hearts, Atg7 interacted with p53 and modulated p53 activity to induce the expression of genes encoding cell death-promoting factors in cardiomyocytes, indicating that defects in deadenylation in the heart aberrantly activated Atg7 and p53 to promote cell death. Thus, mRNA deadenylation mediated by the CCR4-NOT complex is crucial to prevent Atg7-induced cell death and heart failure, suggesting a role for mRNA deadenylation in targeting autophagy genes to maintain normal cardiac homeostasis., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

We herein describe the first known case of pleuritis caused by Mycobacterium kyorinense without pulmonary involvement. A 48-year-old man undergoing immunosuppressant therapy presented with cough and dyspnea. An accumulation of pleural fluid was noted; however, computed tomography revealed no pulmonary lesions. Cultures of the fluid yielded non-tuberculous mycobacteria, which was identified as Mycobacterium kyorinense. The patient recovered after 6 months of therapy with clarithromycin and moxifloxacin. Clinicians should be aware that Mycobacterium kyorinense can cause pleuritis without pulmonary involvement. When mycobacterial species are isolated from the pleural fluid, precise identification and drug susceptibility testing are warranted.

Recent progress in genomic research has raised expectations for the development of personalized preventive medicine, although genomics-related literacy of patients will be essential. Thus, enhancing genomics-related literacy is crucial, particularly for individuals with low genomics-related literacy because they might otherwise miss the opportunity to receive personalized preventive care. This should be especially emphasized when a lack of genomics-related literacy is associated with elevated disease risk, because patients could therefore be deprived of the added benefits of preventive interventions; however, whether such an association exists is unclear. Association between genomics-related literacy, calculated as the genomics literacy score (GLS), and the prevalence of non-communicable diseases was assessed using propensity score matching on 4646 participants (males: 1891; 40.7%). Notably, the low-GLS group (score below median) presented a higher risk of hypertension (relative risk (RR) 1.09, 95% confidence interval (CI) 1.03-1.16) and obesity (RR 1.11, 95% CI 1.01-1.22) than the high-GLS group. Our results suggest that a low level of genomics-related literacy could represent a risk factor for hypertension and obesity. Evaluating genomics-related literacy could be used to identify a more appropriate population for health and educational interventions.

Warfarin use often causes false-positive results in the dilute Russell viper venom time test (DRVVT). Thus, three sets of guidelines-those presented by the International Society on Haemostasis and Thrombosis (ISTH), the British Committee for Standards in Haematology (BCSH), and the Clinical and Laboratory Standards Institute (CLSI)-are advocated. We evaluated the clinical usefulness of the testing methods recommended in these three guidelines using laboratory samples. Of the 242 samples from patients using warfarin, 38 were positive for lupus anticoagulant (LA). After adding normal pooled plasma (NPP) as recommended in the ISTH, BCSH, and CLSI guidelines, the number of samples testing positive for LA decreased to 13, 18, and 19, respectively. The number of samples with inconsistent results between the activated partial thromboplastin time and mixing test, and the DRVVT following the ISTH, BCSH, and CLSI guidelines were four of 205 (1.9%), 15 of 242 (6.2%), and 17 of 242 (7.0%), respectively. In patients with an international normalized ratio (INR) ≥3.0, 11 of 37 (29.7%) and 12 of 37 (32.4%) samples showed inconsistent results according to the BCSH and CLSI guidelines, respectively. The accuracy of the DRVVT result may thus decrease in markedly anticoagulated patients.

RNA-binding proteins (RBPs) play important roles in the posttranscriptional regulation of gene expression, including mRNA stability, transport and translation. Fission yeast rnc1 + encodes a K Homology (KH)-type RBP, which binds and stabilizes the Pmp1 MAPK phosphatase mRNA thereby suppressing the Cl - hypersensitivity of calcineurin deletion and MAPK signaling mutants. Here, we analyzed the spatial regulation of Rnc1 and discovered a putative nuclear export signal (NES) Rnc1 , which dictates the cytoplasmic localization of Rnc1 in a Crm1-independent manner. Notably, mutations in the NES Rnc1 altered nucleocytoplasmic distribution of Rnc1 and abolished its function to suppress calcineurin deletion, although the Rnc1 NES mutant maintains the ability to bind Pmp1 mRNA. Intriguingly, the Rnc1 NES mutant destabilized Pmp1 mRNA, suggesting the functional importance of the Rnc1 cytoplasmic localization. Mutation in Rae1, but not Mex67 deletion or overproduction, induced Rnc1 accumulation in the nucleus, suggesting that Rnc1 is exported from the nucleus to the cytoplasm via the mRNA export pathway involving Rae1. Importantly, mutations in the Rnc1 KH-domains abolished the mRNA-binding ability and induced nuclear localization, suggesting that Rnc1 may be exported from the nucleus together with its target mRNAs. Collectively, the functional Rae1-dependent mRNA export system may influence the cytoplasmic localization and function of Rnc1., (© 2017 John Wiley & Sons Ltd.)

In mammals, spatiotemporal control of protein synthesis plays a key role in the post-transcriptional regulation of gene expression during cell proliferation, development and differentiation and RNA-binding proteins (RBPs) and microRNAs (miRNAs) are required for this phenomenon. RBPs and miRNAs control the levels of mRNA protein products by regulating mRNA stability and translation. Recent studies have shown that RBPs and miRNAs simultaneously regulate mRNA stability and translation, and that the differential functions of RBPs and miRNAs are dependent on their interaction partners. Here, we summarize the coupled- and uncoupled mechanisms by which trans-acting factors regulate mRNA stability and translation., (© The Authors 2016. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Recent epidemiological studies of the association between coffee consumption and the risk of bladder cancer have yielded conflicting results. The aim of the present study was to examine the association between coffee consumption and the incidence of bladder cancer on the basis of pooled data from two cohort studies carried out in Miyagi Prefecture, northeastern Japan. We delivered self-administered questionnaires inquiring about the frequency of coffee consumption and other lifestyle factors in 1990 for the Miyagi Cohort Study and in 1994 for the Ohsaki Cohort Study. We followed 73 346 individuals from both cohorts and identified 274 cases of bladder cancer during 17.6 years for the Miyagi Cohort Study and 13.3 years for the Ohsaki Cohort Study. The multivariate-adjusted hazard ratios (95% confidence intervals) of bladder cancer incidence for the individuals who drank coffee occasionally, 1-2 cups/day, and 3 or more cups/day compared with never drinkers were 1.22 (0.90-1.66), 0.88 (0.61-1.26), and 0.56 (0.32-0.99), respectively (Ptrend=0.04). The inverse association remained even after stratification for smoking status. These data indicate that there is a significant inverse association between coffee consumption and the risk of bladder cancer.

Erythroid abnormalities including anemia and polycythemia are often observed in the general clinical setting. Because recent studies reported that adiponectin negatively affects hematopoiesis, we performed a prospective observational study to assess the relationship between anemia and adiponectin, as well as other parameters, in 1029 Japanese subjects (477 men and 552 women) 40 years of age and older. Body measurements, blood tests, and nutrition intake studies were performed at baseline, and 5 to 7 years later (follow-up). Hemoglobin (Hb) and hematocrit (Hct) levels in men with high serum adiponectin levels were lower at follow-up than at baseline. Multiple regression analysis showed that age, body mass index, adiponectin, and glutamic-pyruvic transaminase were significantly associated with erythroid-related variables (red blood cells, Hb, and Hct) in both men and women (P <0.05). In a logistic regression analysis, adiponectin, fasting blood glucose, and β-natriuretic peptide were significant risk factors for anemia in men, and blood urea nitrogen and amylase were significant risk factors in women. Physical features and nutrient intake were not risk factors for anemia. Our study demonstrates, both clinically and epidemiologically, that a high serum adiponectin level decreases the amounts of erythroid-related variables and is a risk factor for anemia in Japanese men., Competing Interests: The authors have declared that no competing interests exist.

The Japanese government introduced endoscopic screening for gastric cancer in 2015 as a public policy based on the Japanese guidelines on gastric cancer screening. To provide appropriate endoscopic screening for gastric cancer in Japanese communities, we developed a quality assurance manual of endoscopic screening and recommend 10 strategies with their brief descriptions as follows: (i) Formulation of a committee responsible for implementing and managing endoscopic screening, and for deciding the suitable implementation methods in consideration of the local context; (ii) Development of an interpretation system that leads to a final judgement to standardize endoscopic examination and improve its accuracy; (iii) Preparation of management and reporting systems for adverse effects by the committee for safety management; (iv) Obtaining informed consent before operation following adequate explanations regarding the benefits and harms of endoscopic screening; (v) Avoidance of frequent screenings to reduce false-positive results and overdiagnosis. As a reference, the target age group is ≥50 years, and the screening interval is 2 years; (vi) Keeping the biopsy rate within 10% as post-biopsy bleeding may occur. Before endoscopic screening, any history of antithrombotic drug usage should be checked; (vii) Nonadministration of sedation in endoscopic screening for safety management; (viii) Adherence to proper endoscopic cleaning and disinfection to reduce infection; (ix) Use of a checklist to achieve optimal program preparation when municipal governments introduce endoscopic screening; (x) Identification of the aims and roles by referring to a checklist if primary care physicians decide to participate in endoscopic screening., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Recently, the approval of some molecularly targeted drugs has been questioned, due to differing opinions on their risks and benefits. The approval process remains a challenge in regulatory science., Methods: We analyzed the molecularly targeted drugs listed in the 2013 Medical Formulary. For the 21 identified drugs, 32 published Pharmaceuticals and Medical Devices Agency (PMDA) reports were open to the public. Data regarding clinical trials were extracted from these reports and assessed in order to clarify the characteristic examinations required for the approval of molecularly targeted drugs., Results: There was no correlation between the application year and the time between application and approval (p = 0.139). The median number of clinical trials in these reports was 5 (range 1-22). Phase III studies were not included in the assessment materials for 11 reports. A survival benefit was demonstrated for six of the 32 drugs. The PMDA issued approval terms, including all-case surveillance and additional clinical trials, for 24 of these 32 drugs., Conclusion: Molecularly targeted drugs were approved by the PMDA using a flexible process based on drug safety and efficacy. Doctors and patients who are administering or receiving these drugs should be fully informed about the lack of Japanese data assessment during these approval processes.

Background: It has been reported that there are regional differences in the incidence of acute myocardial infarction (AMI) in Japan. The purpose of this study was to investigate trends in regional differences in AMI incidence and dyslipidemia between coastal and inland areas., Methods: We investigated trends in AMI incidence and risk factors in 5325 first-ever AMI patients residing in a coastal area (n=1817), a rural inland area (n=1959), or an urban inland area (n=1549) for the periods 1994-2002, and 2003-2010, using data from the Yamagata AMI Registry., Results: Patients in the coastal area were significantly older than those in rural and urban inland areas and had a lower prevalence of dyslipidemia. The age-adjusted incidence rate of AMI was significantly lower in coastal and rural inland areas patients than those from urban inland area (males: 43.3, 42.2, and 51.3/10(5) person-years; females: 17.4, 20.0, and 23.7/10(5) person-years, respectively) during 2 observation periods. Due to a large increase in AMI incidence in younger males of the coastal area and a decrease in AMI incidence in late elderly females of the urban inland area, no significant regional differences in the age-adjusted incidence rates of AMI were observed during the 2003-2010 period in both genders. The increase in AMI incidence in males in the coastal area was associated with an increasing prevalence of dyslipidemia., Conclusion: There were no longer any regional differences observed in AMI incidence, which was considered to be associated with increased dyslipidemia especially in the coastal area., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Circulating microRNAs (miRNAs) have been detected in various types of cancer and have been proposed as novel biomarkers for diagnosis and treatment. Until recently, however, no studies had comprehensively examined circulating miRNAs in oral cancer. The current study used an ultra-sensitive genome-wide miRNA array to investigate changes in circulating miRNAs in plasma from five patients with oral cancer and ten healthy individuals. Results indicated that there were only a few circulating miRNAs, including miR-223, miR-26a, miR-126, and miR-21, that were up-regulated in patients with oral cancer. A subsequent validation test indicated that circulating miR-223 levels were significantly higher (~2-fold, P< 0.05) in patients with oral cancer (n = 31) than in those without cancer (n = 31). Moreover, miR-223 was found to be up-regulated in tumor-adjacent normal tissue compared to tumor tissue from patients with oral cancer. A gain-of-function assay was performed to explore the potential roles of circulating miR-223 in the development of oral cancer. Results revealed that miR-223 functions as a tumor suppressor by inhibiting cell proliferation and inducing apoptosis. In conclusion, this study suggested that circulating miR-223 may serve as a potential biomarker for diagnosis and that it may represent a novel therapeutic target for treatment of oral cancer.

Background: Twitter is a free social networking and microblogging service on the Internet. Medical professionals and patients have started to use Twitter in medicine. Twitter use by medical institutions can interactively and efficiently provide public health information and education for laypeople., Objective: This study examined Twitter usage by medical institutions., Methods: We reviewed all Japanese user accounts in which the names of medical institutions were described in the user's Twitter profile. We then classified medical institutions' tweets by content., Results: We extracted 168 accounts for medical institutions with ≥500 followers. The medical specialties of those accounts were dentistry and oral surgery (n=73), dermatology (n=12), cosmetic surgery (n=10), internal medicine (n=10), ophthalmology (n=6), obstetrics and gynecology (n=5), plastic surgery (n=2), and others (n=50). Of these, 21 accounts tweeted medical knowledge and 45 accounts tweeted guidance about medical practice and consultation hours, including advertisements. In the dentistry and oral surgery accounts, individual behavior or thinking was the most frequent (22/71, 31%) content. On the other hand, consultation including advertisements was the most frequent (14/23, 61%) in cosmetic surgery, plastic surgery, and dermatology., Conclusions: Some medical specialties used Twitter for disseminating medical knowledge or guidance including advertisements. This indicates that Twitter potentially can be used for various purposes by different medical specialties.

Obesity is associated with environmental factors; however, information about gene-environment interactions is lacking. We aimed to elucidate the effects of gene-environment interactions on obesity, specifically between genetic predisposition and various obesity-related lifestyle factors, using data from a population-based prospective cohort study. The genetic risk score (GRS) calculated from East Asian ancestry single-nucleotide polymorphisms was significantly associated with the body mass index (BMI) at baseline (P<0.001). Significant gene-environment interactions were observed for six nutritional factors, alcohol intake, metabolic equivalents-hour per day and the homeostasis model assessment ratio. The GRS altered the effects of lifestyle factors on BMI. Increases in the BMI at baseline per unit intake for each nutritional factor differed depending on the GRS. However, we did not observe significant correlations between the GRS and annual changes in BMI during the follow-up period. This study suggests that the effects of lifestyle factors on obesity differ depending on the genetic risk factors. The approach used to evaluate gene-environment interaction in this study may be applicable to the practice of preventive medicine.

Background: Mammography is the only proven method for breast cancer screening that reduces mortality, although it is inaccurate in young women or women with dense breasts. We investigated the efficacy of adjunctive ultrasonography., Methods: Between July, 2007, and March, 2011, we enrolled asymptomatic women aged 40-49 years at 42 study sites in 23 prefectures into the Japan Strategic Anti-cancer Randomized Trial (J-START). Eligible women had no history of any cancer in the previous 5 years and were expected to live for more than 5 years. Randomisation was done centrally by the Japan Clinical Research Support Unit. Participants were randomly assigned in 1:1 ratio to undergo mammography and ultrasonography (intervention group) or mammography alone (control group) twice in 2 years. The primary outcome was sensitivity, specificity, cancer detection rate, and stage distribution at the first round of screening. Analysis was by intention to treat. This study is registered, number UMIN000000757., Findings: Of 72,998 women enrolled, 36,859 were assigned to the intervention group and 36,139 to the control group. Sensitivity was significantly higher in the intervention group than in the control group (91·1%, 95% CI 87·2-95·0 vs 77·0%, 70·3-83·7; p=0·0004), whereas specificity was significantly lower (87·7%, 87·3-88·0 vs 91·4%, 91·1-91·7; p<0·0001). More cancers were detected in the intervention group than in the control group (184 [0·50%] vs 117 [0·32%], p=0·0003) and were more frequently stage 0 and I (144 [71·3%] vs 79 [52·0%], p=0·0194). 18 (0·05%) interval cancers were detected in the intervention group compared with 35 (0·10%) in the control group (p=0·034)., Interpretation: Adjunctive ultrasonography increases sensitivity and detection rate of early cancers., Funding: Ministry of Health, Labour and Welfare of Japan., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Desmoplastic small round cell tumor (DSRCT) is an aggressive mesenchymal tumor which primarily affects the abdomen. Even a multimodal approach rarely achieves durable remission and the optimal therapy for extended disease is unknown. We herein describe a rare case of DSRCT arising from the pleura in a 32-year-old man. Initial therapy, which included chemotherapy, surgery and radiotherapy, achieved a partial response for only two months. Although salvage chemotherapies had no effect, pazopanib treatment shrank the tumors and was well-tolerated on an outpatient basis. From the viewpoint of quality of life, pazopanib may therefore be a good therapeutic option for this aggressive disease.

The number of cancer survivors is increasing; however, optimal health management of cancer survivors remains unclear due to limited knowledge. To elucidate the risk of non-communicable diseases, and the effect of lifestyle habits on risk of non-communicable diseases, we compared cancer survivors and those who never had cancer (non-cancer controls) using a population-based prospective cohort study. The baseline survey of 2292 participants was carried out from 2004 to 2006, and the follow-up survey of 2124 participants was carried out in 2011. We compared the baseline characteristics and the risk of non-communicable diseases between cancer survivors and non-cancer controls. Analyzed participants included 124 cancer survivors (men/women, 57/67), and 2168 non-cancer controls (939/1229). Several lifestyle factors and nutritional intake significantly differed between survivors and non-cancer controls, although smoking status did not differ between the groups (P = 0.30). Univariate logistic regression analysis showed increased risk of death (odds ratio [OR], 3.64; 95% confidence interval [CI], 2.19-6.05) and heart disease (OR, 2.60; 95% CI, 1.06-6.39) in cancer survivors. Increased risk of heart disease was also significant (OR, 2.95; 95% CI, 1.05-8.26; P = 0.04) in the multivariate analysis of the smoking-related cancer subgroup. Current smoking significantly increased risk of death (OR, 2.42; 95% CI, 1.13-5.18). Specific management should be implemented for cancer survivors. More intense management against smoking is necessary, as continued smoking in cancer survivors may increase the risk of second primary cancer. Moreover, cancer survivors are at a high risk of heart disease; thus, additional care should be taken., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Data envelopment analysis (DEA) is a method of operations research that has not yet been applied in the field of obesity research. However, DEA might be used to evaluate individuals' susceptibility to obesity, which could help establish effective risk models for the onset of obesity. Therefore, we conducted this study to evaluate the feasibility of applying DEA to predict obesity, by calculating efficiency scores and evaluating the usefulness of risk models. In this study, we evaluated data from the Takahata study, which was a population-based cohort study (with a follow-up study) of Japanese people who are >40 years old. For our analysis, we used the input-oriented Charnes-Cooper-Rhodes model of DEA, and defined the decision-making units (DMUs) as individual subjects. The inputs were defined as (1) exercise (measured as calories expended) and (2) the inverse of food intake (measured as calories ingested). The output was defined as the inverse of body mass index (BMI). Using the β coefficients for the participants' single nucleotide polymorphisms, we then calculated their genetic predisposition score (GPS). Both efficiency scores and GPS were available for 1,620 participants from the baseline survey, and for 708 participants from the follow-up survey. To compare the strengths of the associations, we used models of multiple linear regressions. To evaluate the effects of genetic factors and efficiency score on body mass index (BMI), we used multiple linear regression analysis, with BMI as the dependent variable, GPS and efficiency scores as the explanatory variables, and several demographic controls, including age and sex. Our results indicated that all factors were statistically significant (p < 0.05), with an adjusted R2 value of 0.66. Therefore, it is possible to use DEA to predict environmentally driven obesity, and thus to establish a well-fitted model for risk of obesity.

It has long been hypothesized that personality is associated with breast cancer risk and survival. The present population-based prospective cohort study in Japan tested this hypothesis. To investigate the association of personality with breast cancer risk, a total of 15,107 women aged 40-64 years who completed the Eysenck Personality Questionnaire-Revised (EPQ-R) Short Form were followed from 1990 to 2007. To assess the association of personality with survival after breast cancer, 250 identified cases were further followed up from the date of diagnosis to 2008, and 45 all-cause deaths were documented. Study subjects were categorized into four groups based on the quartile points of scores ranging between 0 and 12 on each EPQ-R subscale (extraversion, neuroticism, psychoticism, and lie), and the hazard ratio (HR) for each category was computed using the lowest category as reference. Multivariate analysis revealed no association between any of the four personality subscales and the risk of breast cancer. In the analysis on survival, no significant association was found between any of these subscales and the risk of death, although breast cancer cases with a higher score of extraversion tended to have a lower risk of death (P for trend = 0.07; HR for highest score level = 0.38). Exclusion of 32 cases diagnosed in the first 3 years of follow-up did not largely change the results with regard to either breast cancer risk or survival. The present findings suggest that personality does not impact significantly on the development and progression of breast cancer.