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Mammalian target of rapamycin (mTOR) has a key role in the regulation of an array of cellular function. We found that rapamycin, an inhibitor of mTOR complex 1 (mTORC1), attenuated endoplasmic reticulum (ER) stress-induced apoptosis. Among three major branches of the unfolded protein response, rapamycin selectively suppressed the IRE1–JNK signaling without affecting PERK and ATF6 pathways. ER stress rapidly induced activation of mTORC1, which was responsible for induction of the IRE1–JNK pathway and apoptosis. Activation of mTORC1 reduced Akt phosphorylation, which was an event upstream of IRE–JNK signaling and consequent apoptosis. In vivo , administration with rapamycin significantly suppressed renal tubular injury and apoptosis in tunicamycin-treated mice. It was associated with enhanced phosphorylation of Akt and suppression of JNK activity in the kidney. These results disclosed that, under ER stress conditions, mTORC1 causes apoptosis through suppression of Akt and consequent induction of the IRE1–JNK pathway.

Objective: To clarify the effects of isoflavone intake on bone resorption and bone formation. Methods: We identified randomized controlled trials related to urinary deoxypyridinoline (Dpyr, a bone resorption marker) and serum bone-specific alkaline phosphatase (BAP, a bone formation marker) listed on MEDLINE (January 1966-April 2006), the Cochrane Controlled Trials Register, EMBASE (1985-January 2006), Science Citation Index and PUBMED (updated till April 2006). Results: Nine studies with a total of 432 subjects were selected for meta-analysis. The urinary Dpyr concentration in subjects who consumed isoflavones decreased significantly by -2.08 nmol/mmol (95% confidence interval (CI): -3.82 to -0.34 nmol/mmol) in comparison with that in subjects who did not consume isoflavones. Isoflavone intake vs placebo intake significantly increased serum BAP by 1.48 microgram/l (95% CI: 0.22-2.75 microgram/l). Decreases in the urinary Dpyr concentration with isoflavone intake of <90 mg/day and with treatment lasting less than 12 weeks were -2.34 nmol/mmol (95% CI: -4.46 to -0.22 nmol/mmol) and -2.03 nmol/mmol (95% CI: -3.20 to -0.85 nmol/mmol), respectively. Conclusions: Isoflavone intervention significantly inhibits bone resorption and stimulates bone formation. These favorable effects occur even if <90 mg/day of isoflavones are consumed or the intervention lasts less than 12 weeks.

Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3–2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower ‘Reward Dependence’ score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1 . These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.

The unfolded protein response (UPR) is involved in a diverse range of pathologies triggered by endoplasmic reticulum (ER) stress. Endeavor to seek selective regulators of the UPR is a promising challenge towards therapeutic intervention in ER stress-related disorders. In the present report, we describe aberrant, differential and bidirectional regulation of the UPR by 3′-deoxyadenosine (cordycepin) towards cell survival. 3′-Deoxyadenosine blocked ER stress-induced apoptosis via inhibiting the IRE1–JNK pro-apoptotic pathway. 3′-Deoxyadenosine also inhibited apoptosis through reinforcement of the pro-survival eIF2 α signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2 α , and dephosphorylation of eIF2 α by salubrinal mimicked the anti-apoptotic effect of 3′-deoxyadenosine. Unexpectedly, although 3′-deoxyadenosine caused activation of eIF2 α , it inhibited downstream pro-apoptotic events including induction of ATF4 and expression of CHOP. Cooperation of adenosine transporter and A3 adenosine receptor, but not A1/A2 receptors, mediated the pluripotent effects of 3′-deoxyadenosine. In mice, ER stress caused activation of JNK, expression of CHOP and induction of apoptosis in renal tubules. The apoptosis was significantly attenuated by administration with 3′-deoxyadenosine, and it was correlated with blunted induction of JNK and CHOP in the kidney. These results disclosed atypical pro-survival regulation of the UPR by 3′-deoxyadenosine, which may be advantageous for the treatment of intractable, ER stress-related disorders.

It is still controversial as to how the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). This meta-analysis was aimed to investigate the impact of NIFTP on the ROM in each TBSRTC category. We accessed three electronic databases including PubMed, Web of Science, and Scopus to search for relevant data from January, 2016 to July, 2018. Relative risk and meta-analysis of proportions using the DerSimonian-Laird method, and each corresponding 95% confidence interval (CI) was pooled using a random-effect model. A total of 14 studies consisting of 14,153 resected nodules were included for meta-analyses. Overall, there was a significant reduction in ROM in all TBSRTC categories following the NIFTP reclassification, except TBSRTC category I. The largest absolute and relative decrease in ROM was observed in TBSRTC category V (16%; 95% CI = 8 to 24) and category III (32%; 95% CI = 24 to 39), respectively. There was a positive correlation between the rate of NIFTP and resection rate (r = 0.83; = .02). The decreases in ROM were more prominent in Western than in Asian cohorts. We confirmed the decrease in ROM due to the NIFTP reclassification for most of TBSRTC categories, which was more significant in Western than in Asian practice. The incidence of NIFTP was higher in institutions where surgical resection rates were high in patients with indeterminate cytology nodules. = atypia of undetermined significance/follicular lesion of undetermined significance; = confidence interval; = fine-needle aspiration; = follicular neoplasm/suspicious for follicular neoplasm; = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; = noninvasive follicular variant of papillary thyroid carcinoma; = risk of malignancy; = relative risk; = suspicious for malignancy; = The Bethesda System for Reporting Thyroid Cytopathology.

FOLFOX is widely used to treat patients with advanced colorectal cancer (CRC). However, dose-limiting toxicity after continuous oxaliplatin administration can lead to peripheral neuropathy. Several agents, including opioids, that have been employed to treat oxaliplatin-induced peripheral neuropathy (OIPN) have been examined in clinical settings regarding their protective and therapeutic effects. We investigated the efficacy and tolerability of oxycodone for OIPN and subsequently with FOLFOX therapy in CRC patients. Controlled-release (CR) oxycodone was concomitantly administered to 29 patients (OXY group), whereas the additional 35 patients (non-OXY group) were not given oxycodone during the FOLFOX treatment course. Most patients experienced grade 1 or 2 sensory neuropathy. Grade 3 sensory neuropathy was observed in two patients in the non-OXY group. All patients in the OXY group completed the scheduled FOLFOX therapy, whereas FOLFOX therapy was discontinued in ten patients in the non-OXY group due to severe peripheral neuropathy. The median numbers of FOLFOX cycles in the OXY and non-OXY groups were 13 and 7, respectively (P < 0.05). The median cumulative oxaliplatin doses were 1072.3 mg/m2 in the OXY group and 483.0 mg/m2 in the non-OXY group (P < 0.05). Overall survival was longer among patients in OXY group (49 months vs. 35 months, P=0.14). Our findings indicate that CR oxycodone might attenuate the severity of OIPN and extend the use of FOLFOX therapy.

The tumour lacked fibrosarcoma-like pattern, and mitotic figures with low Ki-67 labelling index. [...]the eosinophilic cells might be a pleomorphic element with heterologous differentiation rather than the dedifferentiated counterpart.

•Compared to the Western countries, the scientific evidences of effectiveness of HPV-based cervical cancer screening is limited in Japan.•We initiated a randomized trial entitled CervIcal cancer screening Trial by Randomization of HPV testing intervention for Upcoming Screening (CITRUS).•Insights from CITRUS will provide future prospects for cervical cancer screening focused on the use of HPV testing. To assess the efficacy of screening with concurrent liquid-based cytology and human papillomavirus (HPV) testing for primary cervical cancer screening, we initiated a randomized trial entitled CervIcal cancer screening Trial by Randomization of HPV testing intervention for Upcoming Screening (CITRUS). Between June 2013 and March 2015, women aged 30–64 years of age who participated in a regular cervical cancer screening program (every 2 years) were invited to enrollment of our study. After giving their informed consent, 18,402 women were randomly assigned to liquid-based cytology as the control group (n=9145) or to HPV DNA testing with liquid-based cytology as the intervention group (n=9257). We subsequently compared the incidence rate of cervical intraepithelial neoplasia (CIN), the rate of false positive tests and the rate of overdiagnosis, as well as assessing the risks and benefits of receiving screening for women in both groups. The primary outcome of our study was the incidence of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) during the study period of around 6 years. In the control group, 97.9% of women were NILM, and 2.06% ASC-US or worse (ASC-US+). In the intervention group, 87.13% of women were NILM/HPV negative, 0.72% ASC-US/HPV negative, 10.34% NILM/HPV positive, 0.69% ASC-US/HPV positive, 0.90% worse than ASC-US/either HPV. Positive HPV testing was not linearly related to age in our study. Insights from CITRUS will provide future prospects for cervical cancer screening focused on the use of HPV testing in Japan. Clinical trial registration number: NCT01895517, UMIN000010843, TRIUC1312.

The expression of thyroid transcription factor-1 in normal and neoplastic tissues and cell lines of the human lung was investigated using immunohistochemistry and in situ hybridization in conjunction with reverse transcription polymerase chain reaction. In normal lung tissues, immunoproducts of thyroid transcription factor-1 were observed in the nuclei of alveolar cells and bronchiolar cells. Interestingly, in distal bronchioles, immunohistochemistry and in situ hybridization revealed that thyroid transcription factor-1 was present not only in nonciliated cells (Clara cells) but also in ciliated cells and basal cells. In neoplastic tissues, thyroid transcription factor-1 was demonstrated in adenocarcinomas and small cell lung carcinomas with high frequency: 96% and 89% of cases, respectively. Thyroid transcription factor-1 was not detected in squamous cell carcinomas and large cell carcinomas. The strong immunoreactivity of thyroid transcription factor-1 or simultaneous expressions of thyroid transcription factor-1 and surfactant protein A tended to correlate with the differentiation phenotypes in adenocarcinomas; they were more frequently present in the well-differentiated type than were moderately and/or poorly differentiated types. By reverse transcription polymerase chain reaction, expression of thyroid transcription factor-1 messenger RNA was observed in squamous cell carcinomas in addition to in adenocarcinomas and small cell lung carcinomas, and this finding was confirmed in the cell lines from squamous cell carcinomas. Only one case of 99 adenocarcinomas that originated in various organs other than lung and thyroid immunohistochemically expressed thyroid transcription factor-1. Our results suggest that thyroid transcription factor-1 can play an important role for the maintenance and/or differentiation process in bronchiolar and alveolar cells. Thyroid transcription factor-1 expression associates with histologic types and/or differentiation of lung cancers and can be a valuable marker for the better understanding of their biological nature and pathological behavior.

This paper describes an electrically powered prosthetic system controlled by electromyography (EMG) signal detected from the skin surface of the human body. The research of electrically powered prosthetic systems is divided into two main subjects. One is the design of the joint mechanism. We propose the use of an adaptive joint mechanism based on the tendon‐driven architecture. This mechanism includes mechanical torque–velocity converters and a mechanism to assist the proximal joint torque by distal actuators. The other subject is the recognition of the EMG signal. For the discrimination of many patterns and nonlinear properties of the EMG signal, we propose a controller based on a simple pattern recognition information process. The system also drives 12 servomotors to move the adaptive joint mechanism. In this paper, we show the proposed system and describe the mechanical design of the prosthetic hand. The experimental results show that the electrically powered devices can be controlled using the proposed method.