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As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC.

This study investigated the association between menstrual symptoms and the intention to leave work among female nurses in Japan.This cross-sectional study investigated female nurses (n = 317) at two university hospitals. The items measured were their characteristics (e.g., age, body mass index), "intention to leave" work, somatic symptoms related with menstruation, self-reported menstrual characteristics (e.g., pain), physical workloads (e.g., working hours and night shifts) and psychological workloads, measured with the Copenhagen Burnout Inventory (CBI), and the Job Content Questionnaire (JCQ). Participants with at least four somatic symptoms (e.g., cold, fatigue) which are present during their menstrual cycles were considered to have "somatic symptoms associated with menstruation." We also measured serum ovarian and gonadotropin-releasing hormones.Approximately 40% of women answered "intention to leave" work, and 17% had "somatic symptoms associated with menstruation." Multiple logistic regression analysis suggested that nurses reporting "somatic symptoms associated with menstruation" were more likely to have "intention to leave" work: the adjusted odds ratios (AOR, 95% confidence interval [CI]) were 2.15 (1.12-4.11) in the personal-burnout model, 2.23 (1.16-4.31) in the work-related burnout model, 2.91 (1.52-5.56) in the client-related burnout model; 2.96 (1.50-5.82) in the JCQ model. There was no association between serum and gonadotropin hormones and the intention to leave.Somatic symptoms with menstruation were associated with intention to leave work among female Japanese nurses. Intervention for somatic symptoms with menstruation might support nurses to continue work.

Long noncoding RNAs (lncRNAs) are important tissue-specific regulators of gene expression, and their dysregulation can induce aberrant gene expression leading to various pathological conditions, including cancer. Although many lncRNAs have been discovered by computational analysis, most of these are as yet unannotated. Herein, we describe the nature and function of a novel lncRNA detected downstream of the human parathyroid hormone (PTH) gene in both extremely rare ectopic PTH-producing retroperitoneal malignant fibrous histiocytoma and parathyroid tumors with PTH overproduction. This novel lncRNA, which we have named "PTH-AS," has never been registered in a public database, and here, we investigated for the first time its exact locus, length, transcription direction, polyadenylation, and nuclear localization. Microarray and Gene Ontology analyses demonstrated that forced expression of PTH-AS in PTH-nonexpressing human breast cancer T47D cells did not induce the ectopic expression of the nearby PTH gene but did significantly upregulate Janus kinase-signal transducer and activator of transcription pathway-related genes such as cancer-promoting interferon-related DNA damage resistance signature (IRDS) genes. Importantly, we show that PTH-AS expression not only enhanced T47D cell invasion and resistance to the DNA-damaging drug doxorubicin but also promoted lung metastasis rather than tumor growth in a mouse xenograft model. In addition, PTH-AS-expressing T47D tumors showed increased macrophage infiltration that promoted angiogenesis, similar to IRDS-associated cancer characteristics. Although the detailed molecular mechanism remains imperfectly understood, we conclude that PTH-AS may contribute to tumor development, possibly through IRDS gene upregulation.

Healthcare workers have a high risk of burnout. This study aimed to investigate if the numbers of physical symptoms are associated with burnout among healthcare workers. We conducted a cross-sectional survey at a large university in Tokyo, Japan, in 2016. Participants were 1080: 525 faculties and 555 hospital workers. We investigated 16 physical symptoms perceived more than once per week and examined the association between the number of physical symptoms and Copenhagen Burnout Inventory (CBI), work-related (WBO), personal (PBO), and client-related (CBO) burnout. All CBI scores were higher among hospital workers than among faculties: WBO (43 vs. 29), PBO (50 vs. 33), CBO (33 vs. 29). Moreover, the higher the number of physical symptoms perceived, the higher the degree of burnout scores became (trend p-values &lt, 0.001), except for CBO among faculties. Job strain (all except for CBO among hospital workers) and work–family conflict were associated with an increased risk of burnout. Being married (WBO and CBO among faculties), having a child (except for PBO and CBO among faculties), and job support (faculty and hospital workers with WBO and faculties with PBO) were associated with a decreased risk of burnout. Multiple physical symptoms might be useful for identifying high risk individuals for burnout.

Healthcare jobs are very popular among women, however in Japan, women readily quit working because of gender-role responsibilities. This study aimed to develop a workplace support checklist for women to continue to work. In 2017, we investigated 780 (female 74.8%) faculty members and healthcare professionals of one medical university in Japan. We asked them to score the extent to which they considered 35 items identified by a task team, to be related to continuous work support for female workers in healthcare. We carried out an exploratory factor analysis and extracted four domains with 16 items in all: &ldquo, Support for child rearing and home care&rdquo, (five items), &ldquo, Information dissemination&rdquo, Active promotion of women workers to higher positions&rdquo, (three items), and &ldquo, Consulting and counseling service&rdquo, (three items), with Cronbach&rsquo, s alpha values ranging from 0.88 to 0.92. We found that the first three factors were generally associated with reasonably relevant characteristics of being female, in their 30s, married, and members of faculty. We also found that women with &ldquo, Intention to leave&rdquo, the workplace underscored the importance of &ldquo, and &ldquo, These results suggest that the checklist is reliable and valid.

Background Physician-scientists are a vital segment of the healthcare workforce, but they may face significant challenges balancing and integrating clinical responsibilities, scientific research, and domestic responsibilities. This study investigates factors associated with burnout among highly successful early career physician-researchers in Japan. Method Among 1790 physician awardees of Grant-in-Aid for Young Scientists by the Japanese Ministry in 2014–2015, 490 participated in this cross-sectional survey in 2016 (usable response rate 23.8%). The primary outcome was psychological burnout, measured by the Copenhagen Burnout Inventory (i.e., personal burnout, work-related burnout, and patient-related burnout). “Workplace resources” in our study refers to the presence of career education in the workplace, promotion of gender equity, well-being consultation services on “career and work,” “research,” “harassment,” and/or “mental health,” as well as the presence of a role model in the workplace who has perceived good work-life balance. Results Among 408 physician-researchers (75% male, mean age 37 yrs), personal burnout scores were slightly higher in women than in men (mean score, 41.9 points vs. 36.7 points, difference, 5.2, 95% confidence interval, 0.5–9.9, p = 0.029), but work-related and patient-related burnout scores did not differ significantly between genders. Over half of women (64%) and men (58%) had a mentor (p = 0.374). In multivariable general linear regression models, personal burnout scores were higher for women (β = 4.98, p = 0.045), and lower among those who had a mentor (β = − 5.82, p = 0.010) and whose workplaces had well-being consultation services (β = − 0.79, p = 0.022). Work-related burnout scores were lower among those with larger amounts of grant funding (β = − 4.70, p = 0.013), a mentor (β = − 6.12, p = 0.002), well-being consultation services (β = − 0.78, p = 0.008) and a role model with a perceived good work-life balance (β = − 4.00, p = 0.038). Patient-related burnout scores were higher among physician-scientists aged older than 37 years (β = 6.25, p = 0.002) and those who had board certification (β = 9.01, p = 0.017), while these scores were lower among those had larger amounts of funding (β = − 5.01, p = 0.006) or a mentor (β = − 5.35, p = 0.006). Conclusions Workplace resources and mentorship appear to be associated with lower levels of psychological burnout for both men and women early career physician-scientists.

Background On 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET), diffuse uptake in the thyroid gland is often observed in patients with Hashimoto’s thyroiditis. In this study, we evaluated the factors associated with diffuse uptake by comparing Hashimoto’s thyroiditis patients with or without diffuse uptake in the thyroid. Methods A retrospective study was conducted of 18 patients with Hashimoto’s thyroiditis who underwent blood tests, thyroid ultrasonography, and FDG-PET during the period from 2014 to 2015. The patients were divided into two groups: one with diffuse thyroid uptake (group 1, n = 13) and one without diffuse thyroid uptake (group 2, n = 5). Clinical and laboratory parameters, including maximum standardized uptake in the thyroid (SUVmax), which was defined as the higher value obtained in either the right or left thyroid lobe, were compared in the two groups. Results The frequency of abnormal findings, such as a rough or heterogeneous pattern, was significantly higher in group 1 (p

Pheochromocytoma rupture is rare, and emergent adrenalectomy is associated with a high mortality. We herein report a patient with pheochromocytoma rupture who was stabilized by transcatheter arterial embolization (TAE) and subsequently underwent elective surgery. A 45-year-old man presented with the sudden onset of left lateral abdominal pain, headache, chest discomfort, high blood pressure, and adrenal hemorrhaging on enhanced abdominal computed tomography. TAE was performed under a provisional diagnosis of pheochromocytoma rupture. Following oral doxazosin, he underwent elective left adrenalectomy four and a half months after TAE. Stabilizing the hemodynamic status by TAE before adrenalectomy is a viable option for treating pheochromocytoma rupture.

Recently, the antiproliferative action of 1,25(OH)2D3 (1,25D3), an active metabolite of vitamin D3, in the management of prostate cancer has been argued rigorously. In this study, we found that at a physiological concentration, 25(OH)D3 (25D3), the precursor of 1,25D3 and an inactive form of vitamin D because of its much weaker binding activity to the vitamin D receptor (VDR) compared with 1,25D3, had a gene expression profile similar to that of 1,25D3 in prostate cancer LNCaP cells. By immunocytochemistry, western blotting, and CYP27B1 and/or VDR knockdown by small interfering RNAs, we found that 10−7 M 25D3, which is within its uppermost physiological concentration in the bloodstream, induced VDR nuclear import and robustly activated its target genes in the virtual absence of CYP27B1 expression. Comprehensive microarray analyses verified 25D3 bioactivity, and we found that 25D3 target gene profiles largely matched those of 1,25D3, while the presence a small subset of 25D3- or 1,25D3-specific target genes was not excluded. These results indicated that 25D3 shares bioactivity with 1,25D3 without conversion to the latter. Metallothionein 2A was identified as a 1,25D3-specific repressive target gene, which might be a prerequisite for 1,25D3, but not 25D3, to exert its anti-proliferative action in LNCaP cells.

OBJECTIVE To investigate factors including adherence to "maternal affection" and stereotypical gender roles associated with emotional exhaustion among hospital nurses. METHOD In 2014, among 2,690 workers recruited for this study, 891 participated with written informed consent. Of these, we investigated 464 hospital nurses. Adherence to maternal affection and emotional exhaustion were measured using valid and reliable scales developed by Egami (2005, 12 items) and Kubo (1992, 5 items), respectively. Stereotypical gender role was measured by asking "how much do you agree with the idea that women should stay home and men should work?". Workfamily conflict was measured in terms of the discrepancy in priority in life (i.e., a work or a private life) between the participant's ideal and the real world. RESULT The majority of our participants were women (86%), aged 39 or younger (80%), and single (70%). About one-quarter had workfamily conflict (26%) and agreed with the stereotypical gender role (28%). The mean scores of emotional exhaustion and adherence to maternal affection were 17.2 (out of 25) and 30.8 (out of 48), respectively. A stepwise multivariable model showed that being a woman (p=0.028), being young (p=0.022), being single (p=0.007), and having workfamily conflict (p

The purpose of this study is three-fold: (1) to compare harassment (sexual, gender, and academic harassment both directly and indirectly experienced - i.e. "directly harassed" and "have seen or heard of someone who experienced harassment", respectively) experienced by males and females, (2) to investigate whether such experiences correlate with burnout, and (3) to explore whether social support might mitigate any such relationship between harassment and burnout. This cross-sectional study was conducted at a private university in Japan in February 2014 and is based on a work-life balance survey obtained from 330 academic faculty members. We investigated the association between each of the six subcategories of harassment (direct and indirect forms of each of the three types) and burnout using general linear regression models; we then evaluated interactions between harassment and social support in these models. The prevalence of direct and indirect experiences of harassment was higher in females than in males for all three types of harassment. Males showed higher burnout scores if they had direct experiences of harassment. There were significant interactions between social support and the direct experience of harassment; high social support mitigated the effect size of direct harassment on burnout among males. Females showed higher burnout scores if they had indirect experiences of harassment. However, the same buffering effect of social support on burnout as observed in males was not observed in females. Direct harassment experiences increased the risk of burnout in males, and indirect harassment experiences increased burnout in females.

Recently, it was reported that 25(OH)D

Women in Japan face difficulties balancing work and personal life due to the gender division of labor, and medical professions are no exception. The purpose of this study was to investigate if the gender division of labor affects the intention to leave the workplace among the nursing profession. Among 328 female nurses working for three university-affiliated hospitals in Tokyo, Japan, above 70% were in their 20s and 30s and single, and agreed with the gender division of labor that men should be the breadwinner and women should assume family responsibilities. Adjusting for three types of Copenhagen burnout inventory, stepwise multivariable logistic regression models identified that being younger (all p-values &lt, 0.05), each domain of burnout score (each p &lt, 0.001 for work-, personal-, and client-related burnout) increased a risk of intention to leave, and high support decreased the risk (all p &lt, 0.001). Women who agreed with the gender division of labor were more likely to have intentions to leave (p = 0.003 but this association disappeared when adjusted. The findings of study demonstrate that perceptions toward gender division of labor are not a determinant of intention to leave the workplace but the young nurses and those who scored high on burnout were the most vulnerable population.

[Introduction] Immune checkpoint inhibitors (ICIs) are widely used for the treatment of several malignancies. Despite their effectiveness, they may cause immune-related adverse effects on endocrine organs. Here we describe three cases of isolated ACTH deficiency (IAD) that has occurred after ICI therapy. [Case presentation] Case 1: An 80-year-old female patient with advanced melanoma received nivolumab (NIVO) (3 mg/kg intravenously (IV) every two weeks) for 16 weeks, followed by ipilimumab (3 mg/kg IV every three weeks). After the third injection of ipilimumab, she was alert but complained of general fatigue and anorexia. Her laboratory tests revealed hyponatremia (Na 126 mEq/l), hypoglycemia (Glu 65 mg/dl), low ACTH (ACTH

Estrogen receptors (ER) are important transcription factors to relay signals from estrogen and to regulate proliferation of some of breast cancers. The cycling of estrogen-induced DNA binding and ubiquitin-linked proteolysis of ER potentiates ER-mediated transcription. Indeed, several transcriptional coactivators for ER-dependent transcription ubiquitinate ER. Histone acetyltransferase (HAT) Hbo1/KAT7/MYST2, involved in global histone acetylation, DNA replication, transcription, and cellular proliferation, promotes proteasome-dependent degradation of ERα through ubiquitination. However, molecular mechanism for ubiquitination of ERα by Hbo1 is unknown. Here we report the intrinsic ubiquitin E3 ligase activity of Hbo1 toward the ERα. The ligand, estradiol-17β, inhibited E3 ligase activity of Hbo1 for ERα in vitro, whereas hyperactive ERα mutants from metastatic breast cancers resistant to hormonal therapy, were better substrates for ERα ubiquitination by Hbo1. Hbo1 knock-down caused increase in ERα expression. Hbo1 is another ERα coactivator that ubiquitinates ERα.

Recently, it was reported that 25(OH)D3 (25D3) has physiological bioactivity in certain tissues derived from Cyp27b1 knockout mice. To investigate the function of 25D3 in the kidney as an informational crossroad of various calciotropic substances, we employed the CRISPR-Cas9 system to knock out Cyp27b1 in the mouse renal distal tubular mDCT cell line. Unlike the previously reported mice in which Cyp27b1 was targeted systemically, Cyp27b1 knockout mDCT cells did not produce any measurable 1α,25(OH)2D3 (1,25D3) after 25D3 administration. As was seen with treatment of Cyp27b1 knockout mDCT cells with ≥10−8 M of 1,25D3, the administration of 10-7 M of 25D3 translocated the vitamin D3 receptor (VDR) into the nucleus and promoted the expression of the representative 1,25D3-responsive gene Cyp24a1. The exhaustive target gene profiles of 25D3 were similar to those of 1,25D3. Subsequently, we confirmed that 25D3 induced the expression of the calcium reabsorption-related gene calbindin-D9K, in a way similar to 1,25D3. We also found that 1,25D3 and 25D3 induced the expression of the megalin gene. A chromatin immunoprecipitation assay identified two vitamin D response elements in the upstream region of the megalin gene that seemed to contribute to its expression. Together, we surmise that the ability of 25D3 to stimulate VDR target genes may provide a novel perspective for its role in certain tissues.

Objectives In academia, harassment may often occur and remain unrevealed in Japan, which discourages young researchers from pursuing their career. It is necessary to estimate and improve the perception of "academic harassment" among university faculties. Therefore, in this study, we aim to develop a scale of perception of academic harassment. Methods Prior to a quantitative survey, a task team consisting of medical doctors, researchers, nurses, hospital workers, and managers in general affairs division identified 36 items related to academic harassment. In February 2016, we sent a self-administered questionnaire to 1,126 academic faculty members who worked in a medical university located in Tokyo, Japan. We instructed them to score the extent to which they consider each item as related to academic harassment based on a Likert scale. We carried out maximum likelihood factor analyses with promax rotation and computed Cronbach's alpha to develop a scale and investigate the reliability of the scale. Results In total, 377 returned the questionnaires (response rate, 33.5%; male, 73.8%). In factor analyses, we removed 17 items owing to low factor loadings, and four factors were eventually extracted. The first factor was termed "Harassment in organization (7 items)" because it included conditions of forcing a particular person to work on chores or lectures for students that may prevent one's academic research outputs. The second factor was termed "Violence and denying personal character (4 items)". The third factor was termed "Research misconduct (5 items)" including conditions of excluding a particular person from the coauthor list of research outputs or pressuring a person to fabricate, falsify, or plagiarize research outputs. The fourth factor was termed "Research interference (3 items)" including a condition of interference with conference attendance. Cronbach's alpha values of these four factors ranged from 0.83 to 0.91, suggesting that the scale had high reliability. The means of these factors did not differ according to gender but were higher in participants aged 50 or older than in younger participants. Conclusions The results suggest that the scale of perception on academic harassment consisting of four factors with 19 items is valid and reliable to some extent.

OBJECTIVES To clarify the association between job stress and the number of physical symptoms among newly certified female nurses. METHODS In this cross-sectional self-administered survey, we investigated 313 female nurses working at three medical-university-affiliated hospitals in February 2016. We investigated working conditions including numbers of working and on-call hours, work-life balance, Job Content Questionnaire (JCQ) scores, and 16 physical symptoms perceived more often than once a week. RESULTS Among the 313 participants (mean age, 31.9), 57% were aged 21-29 years and 70% were single. Of the 16 physical symptoms investigated, fatigability was the most frequent complaint (66.1%), followed by lower back pain (44.7%). Univariate analysis showed that significant factors related to physical symptoms are job demands (p

Glucocorticoid production is regulated by adrenocorticotropic hormone (ACTH) via the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway in the adrenal cortex, but the changes in steroidogenesis associated with aging are unknown. In this study, we show that cell-autonomous steroidogenesis is induced by non-ACTH- mediated genotoxic stress in human adrenocortical H295R cells. Low-dose etoposide (EP) was used to induce DNA damage as a genotoxic stress, leading to cellular senescence. We found that steroidogenesis was promoted in cells stained with γH2AX, a marker of DNA damaged cells. Among stress-associated and p53-inducible genes, the expression of GADD45A and steroidogenesis-related genes was significantly upregulated. Immunofluorescence analysis revealed that GADD45A accumulated in the nuclei. Metabolite assay using cultured media showed that EP-treated cells were induced to produce and secrete considerable amounts of glucocorticoid. Knockdown of GADD45A using small interfering RNA markedly inhibited the EP-induced upregulation of steroidogenesis-related gene expression, and glucocorticoid production. A p38MAPK inhibitor, but not a PKA inhibitor, suppressed EP-stimulated steroidogenesis. These results suggest that DNA damage itself promotes steroidogenesis via one or more unprecedented non-ACTH-mediated pathway. Specifically, GADD45A plays a crucial role in the steroidogenic processes triggered by EP-stimulated genotoxic stress. Our study sheds new light on an alternate mechanism of steroidogenesis in the adrenal cortex.

To investigate factors including adherence to "maternal affection" and stereotypical gender roles associated with emotional exhaustion among hospital nurses.In 2014, among 2,690 workers recruited for this study, 891 participated with written informed consent. Of these, we investigated 464 hospital nurses. Adherence to maternal affection and emotional exhaustion were measured using valid and reliable scales developed by Egami (2005, 12 items) and Kubo (1992, 5 items), respectively. Stereotypical gender role was measured by asking "how much do you agree with the idea that women should stay home and men should work?". Workfamily conflict was measured in terms of the discrepancy in priority in life (i.e., a work or a private life) between the participant's ideal and the real world.The majority of our participants were women (86%), aged 39 or younger (80%), and single (70%). About one-quarter had workfamily conflict (26%) and agreed with the stereotypical gender role (28%). The mean scores of emotional exhaustion and adherence to maternal affection were 17.2 (out of 25) and 30.8 (out of 48), respectively. A stepwise multivariable model showed that being a woman (p=0.028), being young (p=0.022), being single (p=0.007), and having workfamily conflict (p0.001) were more likely to increase emotional exhaustion after adjusting for household income. Adherence to maternal affection and stereotypical gender role were not significantly associated with emotional exhaustion.This study demonstrated that adherence to "maternal affection" and stereotypical gender roles were not associated with psychological burnout. Special attention should be paid to hospital nurses who are women, young, or single, or who have workfamily conflict.

Recently, the antiproliferative action of 1,25(OH)

Background: As the population is aging, the indication for hepatocellular carcinoma (HCC) resection in patients aged over 80 years will increase. Japan is facing the most aging society worldwide. We examined the safety of hepatectomy in octogenarians and nonagenarians using large-scale data from the Diagnosis Procedure Combination database, a national administrative database in Japan. Method: We conducted a survey to collect data for all inpatients from 2007 and 2012. We identified 27,094 patients who underwent hepatectomy for HCC. Patients' age was divided into the following five categories: ≤59, 60-69, 70-79, 80-84, and ≥85 years (n = 5,099, 8,809, 10,805, 2,011, and 370, respectively). The primary outcomes of hepatectomy were in-hospital death within 90 days and complications. Logistic regression analyses were performed to analyze the impact of age on the outcomes with the adjustment of other individual-level factors. Results: The mortality and morbidity rates were 2.6 and 23.4%, respectively. Compared with patients in their 70s, the mortality rate was significantly lower in patients aged ≤59 years (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.26-0.45; p < 0.01) and in those in their 60s (OR, 0.63; 95% CI, 0.53-0.74; p < 0.01). However, no significant difference was observed in patients aged 80-84 years (OR, 1.03; 95% CI, 0.78-1.385; p = 0.844) and those aged ≥85 years (OR, 0.95; 95% CI, 0.50-1.79; p = 0.870). Based on the multivariate logistic regression analysis, age ≥70 years, male gender, low hospital volume, and surgical procedure were identified as independent predictors of mortality. Conclusions: The operative risk for hepatectomy gradually increases with age until patients are in their 70s, and it appears to reach a plateau among septuagenarian. Indeed, age over 70 years can also be a risk factor for HCC. By considering the aging risk, surgeons can attain good outcome after hepatectomy even in octo- and nonagenarian patients.

Background Accumulating evidence from medical workforce research indicates that poor work/life balance and increased work/home conflict induce psychological distress. In this study we aim to examine the existence of a priority gap between ideal and real lives, and its association with psychological burnout among academic professionals. Methods This cross-sectional survey, conducted in 2014, included faculty members (228 men, 102 women) at a single medical university in Tokyo, Japan. The outcome of interest was psychological burnout, measured with a validated inventory. Discordance between ideal- and real-life priorities, based on participants’ responses (work, family, individual life, combinations thereof), was defined as a priority gap. Results The majority (64%) of participants chose “work” as the greatest priority in real life, but only 28% chose “work” as the greatest priority in their conception of an ideal life. Priority gaps were identified in 59.5% of respondents. A stepwise multivariable general linear model demonstrated that burnout scores were associated positively with respondents’ current position (P

We modified and tested scaffold/matrix attachment region (S/MAR) episomal vectors. The new vectors would be useful in obtaining cells stably expressing fluorescent protein-tagged transgenes with small, mostly within 10-fold cell-to-cell fluctuations. In the vectors, the same transcript directs episomal replication and expression of transgene/antibiotic marker, and only antibiotic selection without any other extra steps was sufficient to obtain desired stable cells, including those expressing two different proteins simultaneously. Furthermore, the two test cases (expression of human growth hormone in AtT20 and four protein kinase C isoforms in HEK293) would prove to be useful in visualizing and analyzing regulatory processes involving these proteins.

The estrogen receptor (ER) is a key molecule for growth of breast cancers. It has been a successful target for treatment of breast cancers. Elucidation of the ER expression mechanism is of importance for designing therapeutics for ER-positive breast cancers. However, the detailed mechanism of ER stability is still unclear. Here, we report that histone acetyltransferase Hbo1 promotes destabilization of estrogen receptor α (ERα) in breast cancers through lysine 48-linked ubiquitination. The acetyltransferase activity of Hbo1 is linked to its activity for ERα ubiquitination. Depletion of Hbo1 and anti-estrogen treatment displayed a potent growth suppression of breast cancer cell line. Hbo1 modulated transcription by ERα. Mutually exclusive expression of Hbo1 and ERα was observed in roughly half of the human breast tumors examined in the present study. Modulation of ER stability by Hbo1 in breast cancers may provide a novel therapeutic possibility.

Thus far, only 23 cases of the ectopic production of parathyroid hormone (PTH) have been reported. We have characterized the genome-wide transcription profile of an ectopic PTH-producing tumor originating from a retroperitoneal histiocytoma. We found that the calcium-sensing receptor (CaSR) was barely expressed in the tumor. Lack of CaSR, a crucial braking apparatus in the presence of both intraparathyroid and, probably, serendipitous PTH expression, might contribute strongly to the establishment and maintenance of the ectopic transcriptional activation of the PTH gene in nonparathyroid cells. Along with candidate drivers with a crucial frameshift mutation or copy number variation at specific chromosomal areas obtained from whole exome sequencing, we identified robust tumor-specific cytochrome P450 family 24 subfamily A member 1 (CYP24A1) overproduction, which was not observed in other non–PTH-expressing retroperitoneal histiocytoma and parathyroid adenoma samples. We then found a 2.5-kb noncoding RNA in the PTH 3′-downstream region that was exclusively present in the parathyroid adenoma and our tumor. Such a co-occurrence might act as another driver of ectopic PTH-producing tumorigenesis; both might release the control of PTH gene expression by shutting down the other branches of the safety system (e.g., CaSR and the vitamin D3–vitamin D receptor axis)., We examined a genome-wide transcription profile of an ectopic PTH-producing tumor. Scarcity of CaSR, CYP24A1 overproduction, and an lncRNA near the PTH gene are candidate culprits of PTH ectopy.

Skull base metastasis from differentiated thyroid carcinoma including follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) is a rare clinical entity. Eighteen FTC cases and 10 PTC cases showing skull base metastasis have been reported. The most common symptom of skull base metastasis from FTC and PTC is cranial nerve dysfunction. Bone destruction and local invasion to the surrounding soft tissues are common on radiological imaging. Skull base metastases can be the initial clinical presentation of FTC and PTC in the presence of silent primary sites. The possibility of skull base metastasis from FTC and PTC should be considered in patients with the clinical symptoms of cranial nerve dysfunction and radiological findings of bone destruction. A variety of genetic alterations in thyroid tumors have been identified to have a fundamental role in their tumorigenesis. Molecular histochemical studies are useful for elucidating the histopathological features of thyroid carcinoma. Recent molecular findings may provide novel molecular-based treatment strategies for thyroid carcinoma.

We investigated relationships between the perception of organizational climate with gender equity and psychological health among 94 women and 211 men in a Japanese private university in 2015 using the Copenhagen Burnout Inventory (i.e., personal, work-related and student-related burnout). Perceptions of organizational climate with respect to gender equity were measured with two scales including organizational engagement with a gender equal society in the workplace (consisting of three domains of 'Women utilization', 'Organizational promotion of gender equal society' and 'Consultation service'); and a gender inequality in academia scale that had been previously developed. Multivariable linear models demonstrated significant statistical interactions between gender and perceptions of organizational climate; 'Women utilization' or lack of 'Inequality in academia' alleviated burnout only in women. In consequence of this gender difference, when 'Women utilization' was at a lower level, both personal (p=.038) and work-related (p=.010) burnout scores were higher in women, and the student-related burnout score was lower in women when they perceived less inequality in academia than in men (p=.030). As such, it is suggested organizational fairness for gender equity may be a useful tool to help mitigate psychological burnout among women in academia.

The aryl hydrocarbon receptor (AhR) is a transcription factor that is activated by xenobiotic substances such as dioxin. After activation, it binds to dioxin response elements of DNA, thereby inducing transcription of a variety of xenobiotic metabolizing enzymes. To investigate whether AhR-activating substances accumulate in patients with endocrine disorders, we tested serum samples for AhR-stimulating activity.Serum AhR-stimulating activity was evaluated by exposing the HepG2 cells transiently transfected with an AhR-responsive reporter plasmid to serum samples. On the basis of preliminary findings that implicated methimazole (MMI), wild-type and AhR-null mice were treated with MMI, and their plasma AhR-stimulating activities and thyroxine levels were quantified.In 28 randomly chosen patients, 7 out of 10 Graves' disease patients exhibited increased serum AhR-stimulating activity. The increased activity did not correlate with thyroid hormone status. However, we hypothesized that it might be caused by MMI. Subsequent analyses revealed that in 25 of 26 MMI-treated Graves' patients, serum samples collected after the MMI treatment had significantly higher AhR-stimulating activity compared to samples obtained when the same patients were not on MMI. By contrast, serum AhR-stimulating activity was unchanged in samples from the seven patients on propylthiouracil (PTU) compared to serum taken before the PTU treatment. In vitro experiments demonstrated that an MMI metabolite 3-methyl-2-thiohydantoin, but not MMI, activated AhR. MMI increased plasma AhR-stimulating activities and reduced plasma thyroxine concentrations, in both wild-type and AhR-deficient mice.Graves' patients taking MMI have increased serum AhR-stimulating activity, which is unrelated to thyroid hormone status, but correlates with MMI treatment. The AhR activation is likely caused by 3-methyl-2-thiohydantoin. Further studies are required to determine the potency of 3-methyl-2-thiohydantoin as an AhR activator and the significance of the differences between MMI and PTU observed in this study.

Combined in situ hybridization (ISH) and immunohistochemistry (IHC) under electron microscopy (EM-ISH & IHC) has sufficient ultrastructural resolution to provide two-dimensional images of subcellular localization of pituitary hormone and its mRNA in a pituitary cell. The advantages of semiconductor nanocrystals (Quantum dots; Qdots) and confocal laser scanning microscopy (CLSM) enable us to obtain three-dimensional images of the subcellular localization of pituitary hormone and its mRNA. Both EM-ISH & IHC and ISH & IHC using Qdots and CLSM are useful for understanding the relationship between protein and mRNA simultaneously in two or three dimensions. CLSM observation of rab3B and SNARE proteins such as SNAP-25 and syntaxin revealed that both rab3B and SNARE system proteins play an important role and work together as the exocytotic machinery in anterior pituitary cells. Another important issue is the intracellular transport and secretion of pituitary hormone. An experimental pituitary cell line, the GH3 cell, in which growth hormone (GH) is linked to enhanced yellow fluorescein protein (EYFP), has been developed. This stable GH3 cell secretes GH linked to EYFP upon being stimulated by Ca2+ influx or Ca2+ release from storage. This GH3 cell is useful for real-time visualization of the intracellular transport and secretion of GH. These three methods enable us to visualize consecutively the processes of transcription, translation, transport, and secretion of pituitary hormone.

Background and importance The case presented here describes the clinical evolution of a pituitary carcinoma from an atypical prolactinoma after temozolomide (TMZ) treatment. The mechanism of acquisition of TMZ resistance was analyzed. Clinical presentation A 60-year-old woman with atypical prolactinoma had been treated for 7 years with multiple therapies, including dopamine agonists, surgical intervention (5 times), conventional radiotherapy, and radiosurgery. The patient deteriorated as a result of tumor enlargement. Ten cycles of TMZ therapy, 200 mg/m for 5 days every 4 weeks, improved the patient's performance status and caused tumor shrinkage. Six months after discontinuation of TMZ, the tumor progressed into pituitary carcinoma with tumor regrowth and intraventricular dissemination. TMZ therapy was ineffective this time. A sixth surgery and salvage chemotherapy failed to improve the patient's condition, and she died 9 years after the first diagnosis. Throughout the treatment course, O6-methyl-guanine-DNA methyltransferase (MGMT) was immunonegative in the tumor specimens, including the TMZ-refractory pituitary carcinoma. Mutation of p53 was identified in both the atypical prolactinoma and pituitary carcinoma. In contrast, major differences were noted for mismatch repair protein MSH6 immunostaining: Although MSH6 was diffusely immunopositive in the atypical adenoma, it became immunonegative when the tumor evolved into TMZ-refractory pituitary carcinoma. Conclusion Loss of MSH6 occurred during the progression from an atypical prolactinoma to a pituitary carcinoma, which may have caused resistance to TMZ treatment. This case suggests that preserving MSH6 function is essential for responsiveness to TMZ treatment in MGMT-negative and p53-mutated atypical pituitary adenoma or pituitary carcinoma.

In situ hybridization (ISH) at the electron microscopic (EM) level is essential for elucidating the intracellular distribution and role of mRNA in protein synthesis. EM-ISH is considered to be an important tool for clarifying the intracellular localization of mRNA and the exact site of pituitary hormone synthesis on the rough endoplasmic reticulum. A combined ISH and immunohistochemistry (IHC) under EM (EM-ISH&IHC) approach has sufficient ultrastructural resolution, and provides two-dimensional images of the subcellular localization of pituitary hormone and its mRNA in a pituitary cell. The advantages of semiconductor nanocrystals (quantum dots, Qdots) and confocal laser scanning microscopy (CLSM) enable us to obtain three-dimensional images of the subcellular localization of pituitary hormone and its mRNA. Both EM-ISH&IHC and ISH & IHC using Qdots and CLSM are useful for understanding the relationships between protein and mRNA simultaneously in two or three dimensions. CLSM observation of rab3B and SNARE proteins such as SNAP-25 and syntaxin has revealed that both rab3B and SNARE system proteins play important roles and work together as the exocytotic machinery in anterior pituitary cells. Another important issue is the intracellular transport and secretion of pituitary hormone. We have developed an experimental pituitary cell line, GH3 cell, which has growth hormone (GH) linked to enhanced yellow fluorescein protein (EYFP). This stable GH3 cell secretes GH linked to EYFP upon stimulation by Ca2+ influx or Ca2+ release from storage. This GH3 cell line is useful for the real-time visualization of the intracellular transport and secretion of GH. These three methods from conventional immunohistochemistry and fluorescein imaging allow us to consecutively visualize the process of transcription, translation, transport and secretion of anterior pituitary hormone.

Combined medical treatment with long acting octreotide and cabergoline is now used with active patients with acromegaly and can reduce serum growth hormone (GH) and insulin-like growth factor-1 levels. In this article, we analyzed again the molecular aspects of the previously reported rare

Objectives This study aims to develop a scale of "women-doctor-friendly working conditions in a hospital setting". Methods A task team consisting of relevant people including a medical doctor and a hospital personnel identified 36 items related to women-doctor-friendly working conditions. From December in 2012 to January in 2013, we sent a self-administered questionnaire to 807 full-time employees including faculty members and medical doctors who worked for a university-affiliated hospital. We asked them to score the extent to which they think it is necessary for women doctors to balance between work and gender role responsibilities on the basis of the Likert scale. We carried out a factor analysis and computed Cronbach's alpha to develop a scale and investigated its construct validity and reliability. Results Of the 807 employees, 291 returned the questionnaires (response rate, 36.1%). The item-total correlation (between an individual item score and the total score) coefficient was in the range from 0.44 to 0.68. In factor analysis, we deleted six items, and five factors were extracted on the basis of the least likelihood method with the oblique Promax rotation. The factors were termed "gender equality action in an organization", "the compliance of care leave in both sexes and parental leave in men", "balance between life events and work", "childcare support at the workplace", and "flexible employment status". The Cronbach's alpha values of all the factors and the total items were 0.82-0.89 and 0.93, respectively, suggesting that the scale we developed has high reliability. Conclusions The result indicated that the scale of women-doctor-friendly working conditions consisting of five factors with 30 items is highly validated and reliable.

Combined in situ hybridization (ISH) and immunohistochemistry (IHC) under electron microscopy (EM-ISH&IHC) has sufficient ultrastructural resolution and provides two-dimensional images of subcellular localization of pituitary hormone and its mRNA in a pituitary cell. The advantages of semiconductor nanocrystals (Quantum dots, Qdots) and confocal laser scanning microscopy (CLSM) enable us to obtain three-dimensional images of subcellular localization of pituitary hormone and its mRNA. Both EM-ISH&IHC and ISH&IHC using Qdots and CLSM are useful for understanding the relation between protein and mRNA simultaneously in two or three dimensions. Another important issue is the intracellular transport and secretion of pituitary hormone. We have developed an experimental pituitary cell line, the GH3 cell, which has growth hormone (GH) linked to enhanced yellow fluorescein protein (EYFP). This stable GH3 cell secretes GH linked to EYFP upon stimulated by Ca2+ influx or Ca2+ release from storage. This GH3 cell is useful for real-time visualization of the intracellular transport and secretion of GH. These three methods enable us to visualize consecutively the process of transcription, translation, transport, and secretion of pituitary hormone.

To investigate, in real time, the transport and secretion of pituitary hormone, we have developed an experimental pituitary cell line, GH3 cell, which has secretory granules of growth hormone (GH) linked to enhanced yellow fluorescein protein (EYFP). This stable GH3 cell secretes secretory granules of GH linked to EYFP on stimulation by Ca2+ influx or Ca2 release from storage. This GH3 cell will be useful for the real-time visualization of the intracellular transport and secretion of GH.

The mechanisms of paradoxical TRH response in human somatotroph adenoma cells were investigated using intracellular calcium measurement and static incubation assay. Intracellular calcium measurement revealed that TRH induces a biphasic response: a transient increase followed by a sustained plateau. The transient phase was due to the calcium release from IP(3)-regulated intracellular calcium store and the subsequent sustained phase was due to the calcium influx through the voltage-gated calcium channels. The signal transduction mechanism of the calcium plateau involved protein kinase C. These calcium responses, especially the second phase, was responsible for the TRH-induced GH release.

Hypopituitarism is a well-known cause of secondary osteoporosis. However, patients receiving surgery for pituitary tumors or parasellar lesions have not been well studied for their bone sequel in Japan. We measured bone mineral density (BMD) and urinary type I collagen N-telopeptide (uNTX) in 35 postoperative patients including 25 with pituitary tumor (PT), 6 with craniopharyngioma (CP), and 4 others who had not been on sex hormone replacement, raloxifene, or bisphosphonate therapy. Compared with patients with PT, patients with CP had lower BMD and higher uNTX. Five out of 6 patients with CP had BMD lower than 80% of young adult mean (YAM), whereas 11 out of 22 patients with PT had BMD less than 80% of YAM. Patients with CP had significantly lower serum levels of gonadotropins, and they also tended to have lower serum levels of sex steroids, although statistically not significantly. Two postoperative patients with CP on sex steroid replacement, who were not included in the current analysis, had normal BMD. Of all the subjects, the prominent difference between patients with normal BMD and normal value of uNTX and patients with low BMD and elevated uNTX value was that the latter received higher dose of hydrocortisone replacement. The present study confirms postsurgical patients with pituitary or parasellar lesions, especially those with CP, are at high risk for osteopenia. In designing replacement therapy for those patients, it is important to consider bone by minimizing the dose of glucocorticoid, including sex steroids, and using other drugs that protect bone.

Glucocorticoids are important drugs in the treatment of variety diseases, but long-term period use can lead to various adverse effects, including osteoporosis. Glucocorticoid-induced osteoporosis is mainly caused by inhibition of osteoblastic bone formation, which results not only in decreased bone mineral density, but reduction of bone strength by trabecular thinning in bone microstructures. The evidence suggests that daily oral glucocorticoid doses higher than 5 mg prednisolone or equivalent increase the risk of fracture within 3-6 months after the start of therapy. High-dose inhaled glucocorticoids may also increase fracture risk. The diagnostic procedures are similar to those for primary osteoporosis, but the diagnostic threshold for bone mineral density needs to be higher than that for primary osteoporosis. Treatment with vitamin D, calcitonin, sex hormone replacement, and bisphosphonates has been shown to be effective, and bisphosphonates have been demonstrated to be the most valuable drugs for glucocorticoid-induced osteoporosis. There are several lines of evidence indicating that they are effective in preventing and treating low bone mineral density and in reducing fracture risk.

Recent advances in the radiological diagnosis in thyroid neoplasms have been achieved by high-resolution ultrasonography and color-Doppler, and the ultrasound-guided fine-needle aspiration biopsy and ultrasound-guided percutaneous ethanol injection therapy have been developed on the basis of these modalities. Ultrasonography and ultrasound-guided fine-needle aspiration biopsy have made minimally invasive thyroid surgery possible. The surgical procedures are classified into three main categories according to the approach, and each approach has its own advantages and disadvantages. Surgeons have to select the most suitable approach from one of these categories of approaches for each patient with a thyroid neoplasm.