Methyl vinyl ketone and its analogs covalently modify PI3K and alter physiological functions by inhibiting PI3K signaling.

Reactive carbonyl species (RCS), which are abundant in the environment and are produced in vivo under stress, covalently bind to nucleophilic residues such as Cys in proteins. Disruption of protein function by RCS exposure is predicted to play a role in the development of various diseases such as cancer and metabolic disorders, but most studies on RCS have been limited to simple cytotoxicity validation, leaving their target proteins and resulting physiological changes unknown. In this study, we focused on methyl vinyl ketone (MVK), which is one of the main RCS found in cigarette smoke and exhaust gas. We found that MVK suppressed PI3K-Akt signaling, which regulates processes involved in cellular homeostasis, including cell proliferation, autophagy, and glucose metabolism. Interestingly, MVK inhibits the interaction between the epidermal growth factor receptor and PI3K. Cys656 in the SH2 domain of the PI3K p85 subunit, which is the covalently binding site of MVK, is important for this interaction. Suppression of PI3K-Akt signaling by MVK reversed epidermal growth factor-induced negative regulation of autophagy and attenuated glucose uptake. Furthermore, we analyzed the effects of the 23 RCS compounds with structures similar to MVK and showed that their analogs also suppressed PI3K-Akt signaling in a manner that correlated with their similarities to MVK. Our study demonstrates the mechanism of MVK and its analogs in suppressing PI3K-Akt signaling and modulating physiological functions, providing a model for future studies analyzing environmental reactive species.

Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aß uptake in astrocytes.

The link between changes in astrocyte function and the pathological progression of Alzheimer's disease (AD) has attracted considerable attention. Interestingly, activated astrocytes in AD show abnormalities in their lipid content and metabolism. In particular, the expression of apolipoprotein E (ApoE), a lipid transporter, is decreased. Because ApoE has anti-inflammatory and amyloid ß (Aß)-metabolizing effects, the nuclear receptors, retinoid X receptor (RXR) and LXR, which are involved in ApoE expression, are considered promising therapeutic targets for AD. However, the therapeutic effects of agents targeting these receptors are limited or vary considerably among groups, indicating the involvement of an unknown pathological factor that modifies astrocyte and ApoE function. Here, we focused on the signaling lipid, sphingosine-1-phosphate (S1P), which is mainly produced by sphingosine kinase 2 (SphK2) in the brain. Using astrocyte models, we found that upregulation of SphK2/S1P signaling suppressed ApoE induction by both RXR and LXR agonists. We also found that SphK2 activation reduced RXR binding to the APOE promoter region in the nucleus, suggesting the nuclear function of SphK2/S1P. Intriguingly, suppression of SphK2 activity by RNA knockdown or specific inhibitors upregulated lipidated ApoE induction. Furthermore, the induced ApoE facilitates Aß uptake in astrocytes. Together with our previous findings that SphK2 activity is upregulated in AD brain and promotes Aß production in neurons, these results indicate that SphK2/S1P signaling is a promising multifunctional therapeutic target for AD that can modulate astrocyte function by stabilizing the effects of RXR and LXR agonists, and simultaneously regulate neuronal pathogenesis.

Attenuation of protein arginine dimethylation via S-nitrosylation of protein arginine methyltransferase 1.

Upregulation of nitric oxide (NO) production contributes to the pathogenesis of numerous diseases via S-nitrosylation, a post-translational modification of proteins. This process occurs due to the oxidative reaction between NO and a cysteine thiol group; however, the extent of this reaction remains unknown. S-Nitrosylation of PRMT1, a major asymmetric arginine methyltransferase of histones and numerous RNA metabolic proteins, was induced by NO donor treatment. We found that nitrosative stress leads to S-nitrosylation of cysteine 119, located near the active site, and attenuates the enzymatic activity of PRMT1. Interestingly, RNA sequencing analysis revealed similarities in the changes in expression elicited by NO and PRMT1 inhibitors or knockdown. A comprehensive search for PRMT1 substrates using the proximity-dependent biotin identification method highlighted many known and new substrates, including RNA-metabolizing enzymes. To validate this result, we selected the RNA helicase DDX3 and demonstrated that arginine methylation of DDX3 is induced by PRMT1 and attenuated by NO treatment. Our results suggest the existence of a novel regulatory system associated with transcription and RNA metabolism via protein S-nitrosylation.

Potential utility of pretreatment serum miRNAs for optimal treatment selection in advanced high-grade serous ovarian cancer.

OBJECTIVE: The primary treatment of patients with advanced ovarian cancer is selected from whether primary debulking surgery or neoadjuvant chemotherapy. We investigated whether pretreatment serum microRNA profiles are useful for selecting patients with advanced high-grade serous ovarian cancer who obtain better outcomes from undergoing primary debulking surgery or neoadjuvant chemotherapy. METHODS: Consecutive patients with clinical stage IIIB-IVB and serum microRNA data were selected. Patients who underwent primary debulking surgery or neoadjuvant chemotherapy were subjected to 1:1 propensity score matching before comparing their progression-free survival using Cox modelling. Progression-free probabilities for the selected microRNA profiles were calculated, and the estimated progression-free survival with the recommended primary treatment was determined and compared with the actual progression-free survival of the patients. RESULTS: Of the 108 patients with stage IIIB-IVB disease, the data of 24 who underwent primary debulking surgery or neoadjuvant chemotherapy were compared. Eleven and three microRNAs were independent predictors of progression-free survival in patients who underwent primary debulking surgery and neoadjuvant chemotherapy, respectively. Two microRNAs correlated significantly with complete resection of the tumours in primary debulking surgery. No differences were found between the actual and estimated progression-free survival in the primary debulking surgery and neoadjuvant chemotherapy groups (P > 0.05). The recommended and actual primary treatments were identical in 27 (56.3%) of the 48 patients. The median improved survival times between recommended and actual treatment were 11.7 and 32.6 months for patients with actual primary debulking surgery and neoadjuvant chemotherapy, respectively. CONCLUSIONS: Pretreatment microRNA profiles could be used to select subgroups of patients who benefited more from primary debulking surgery or neoadjuvant chemotherapy and might contribute to selecting the optimal primary treatment modality in advanced high-grade serous ovarian cancer patients.

Epigenetic Regulation of Carbonic Anhydrase 9 Expression by Nitric Oxide in Human Small Airway Epithelial Cells.

DNA methylation is a crucial epigenetic modification that regulates gene expression and determines cell fate; however, the triggers that alter DNA methylation levels remain unclear. Recently, we showed that S-nitrosylation of DNA methyltransferase (DNMT) induces DNA hypomethylation and alters gene expression. Furthermore, we identified DBIC, a specific inhibitor of S-nitrosylation of DNMT3B, to suppress nitric oxide (NO)-induced gene alterations. However, it remains unclear how NO-induced DNA hypomethylation regulates gene expression and whether this mechanism is maintained in normal cells and triggers disease-related changes. To address these issues, we focused on carbonic anhydrase 9 (CA9), which is upregulated under nitrosative stress in cancer cells. We pharmacologically evaluated its regulatory mechanisms using human small airway epithelial cells (SAECs) and DBIC. We demonstrated that nitrosative stress promotes the recruitment of hypoxia-inducible factor 1 alpha to the CA9 promoter region and epigenetically induces CA9 expression in SAECs. Our results suggest that nitrosative stress is a key epigenetic regulator that may cause diseases by altering normal cell function.

Characterization of pathological changes in the olfactory system of mice exposed to methylmercury.

Methylmercury (MeHg) is a well-known environmental neurotoxicant that causes severe brain disorders such as Minamata disease. Although some patients with Minamata disease develop olfactory dysfunction, the underlying pathomechanism is largely unknown. We examined the effects of MeHg on the olfactory system using a model of MeHg poisoning in which mice were administered 30 ppm MeHg in drinking water for 8 weeks. Mice exposed to MeHg displayed significant mercury accumulation in the olfactory pathway, including the nasal mucosa, olfactory bulb, and olfactory cortex. The olfactory epithelium was partially atrophied, and olfactory sensory neurons were diminished. The olfactory bulb exhibited an increase in apoptotic cells, hypertrophic astrocytes, and amoeboid microglia, mainly in the granular cell layer. Neuronal cell death was observed in the olfactory cortex, particularly in the ventral tenia tecta. Neuronal cell death was also remarkable in higher-order areas such as the orbitofrontal cortex. Correlation analysis showed that neuronal loss in the olfactory cortex was strongly correlated with the plasma mercury concentration. Our results indicate that MeHg is an olfactory toxicant that damages the central regions involved in odor perception. The model described herein is useful for analyzing the mechanisms and treatments of olfactory dysfunction in MeHg-intoxicated patients.

Therapeutic potential of 4-phenylbutyric acid against methylmercury-induced neuronal cell death in mice.

Methylmercury (MeHg) is an environmental neurotoxin that induces damage to the central nervous system and is the causative agent in Minamata disease. The mechanisms underlying MeHg neurotoxicity remain largely unknown, and there is a need for effective therapeutic agents, such as those that target MeHg-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which is activated as a defense mechanism. We investigated whether intraperitoneal administration of the chemical chaperone, 4-phenylbutyric acid (4-PBA), at 120 mg/kg/day can alleviate neurotoxicity in the brains of mice administered 50 ppm MeHg in drinking water for 5 weeks. 4-PBA significantly reduced MeHg-induced ER stress, neuronal apoptosis, and neurological symptoms. Furthermore, 4-PBA was effective even when administered 2 weeks after the initiation of exposure to 30 ppm MeHg in drinking water. Our results strongly indicate that ER stress and the UPR are key processes involved in MeHg toxicity, and that 4-PBA is a novel therapeutic candidate for MeHg-induced neurotoxicity.

MITOL prevents ER stress-induced apoptosis by IRE1α ubiquitylation at ER-mitochondria contact sites.

Unresolved endoplasmic reticulum (ER) stress shifts the unfolded protein response signaling from cell survival to cell death, although the switching mechanism remains unclear. Here, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) inhibits ER stress-induced apoptosis through ubiquitylation of IRE1α at the mitochondria-associated ER membrane (MAM). MITOL promotes K63-linked chain ubiquitination of IRE1α at lysine 481 (K481), thereby preventing hyper-oligomerization of IRE1α and regulated IRE1α-dependent decay (RIDD). Therefore, under ER stress, MITOL depletion or the IRE1α mutant (K481R) allows for IRE1α hyper-oligomerization and enhances RIDD activity, resulting in apoptosis. Similarly, in the spinal cord of MITOL-deficient mice, ER stress enhances RIDD activity and subsequent apoptosis. Notably, unresolved ER stress attenuates IRE1α ubiquitylation, suggesting that this directs the apoptotic switch of IRE1α signaling. Our findings suggest that mitochondria regulate cell fate under ER stress through IRE1α ubiquitylation by MITOL at the MAM.

Covalent N-arylation by the pollutant 1,2-naphthoquinone activates the EGF receptor.

The epidermal growth factor receptor (EGFR) is the most intensively investigated receptor tyrosine kinase. Several EGFR mutations and modifications have been shown to lead to abnormal self-activation, which plays a critical role in carcinogenesis. Environmental air pollutants, which are associated with cancer and respiratory diseases, can also activate EGFR. Specifically, the environmental electrophile 1,2-naphthoquinone (1,2-NQ), a component of diesel exhaust particles and particulate matter more generally, has previously been shown to impact EGFR signaling. However, the detailed mechanism of 1,2-NQ function is unknown. Here, we demonstrate that 1,2-NQ is a novel chemical activator of EGFR but not other EGFR family proteins. We found that 1,2-NQ forms a covalent bond, in a reaction referred to as N-arylation, with Lys80, which is in the ligand-binding domain. This modification activates the EGFR-Akt signaling pathway, which inhibits serum deprivation-induced cell death in a human lung adenocarcinoma cell line. Our study reveals a novel mode of EGFR pathway activation and suggests a link between abnormal EGFR activation and environmental pollutant-associated diseases such as cancer.

Alterations in UPR Signaling by Methylmercury Trigger Neuronal Cell Death in the Mouse Brain.

Methylmercury (MeHg), an environmental toxicant, induces neuronal cell death and injures specific areas of the brain. MeHg is known to induce oxidative and endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) pathway has a dual nature in that it regulates and protects cells from an overload of improperly folded proteins in the ER, whereas excessively stressed cells are eliminated by apoptosis. Oxidative stress/ER stress induced by methylmercury exposure may tilt the UPR toward apoptosis, but there is little in vivo evidence of a direct link to actual neuronal cell death. Here, by using the ER stress-activated indicator (ERAI) system, we investigated the time course signaling alterations of UPR in vivo in the most affected areas, the somatosensory cortex and striatum. In the ERAI-Venus transgenic mice exposed to MeHg (30 or 50 ppm in drinking water), the ERAI signal, which indicates the activation of the cytoprotective pathway of the UPR, was only transiently enhanced, whereas the apoptotic pathway of the UPR was persistently enhanced. Furthermore, detailed analysis following the time course showed that MeHg-induced apoptosis is strongly associated with alterations in UPR signaling. Our results suggest that UPR modulation could be a therapeutic target for treating neuropathy.

A case report of late-onset schizophrenia differentiated from a dementing disorder.

We report a case of late-onset schizophrenia that required differentiation from a dementing disorder. The patient was an 83-year-old woman who had experienced auditory hallucinations since she was 67 years old. The patient had slightly elevated total tau and slightly decreased amyloid ß1-42, cerebrospinal fluid biomarkers. This case was identified as late-onset schizophrenia. However, the results of cerebrospinal fluid biomarkers indicated that neurofibrillary tangles and neuronal death, which are characteristic of Alzheimer 's disease, may also have been present. Late-onset schizophrenia should be treated based on an appropriate differential diagnosis, including neuropathological consideration of dementing disorders.

Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain.

Methylmercury (MeHg), an environmental toxicant, induces neuronal cell death and injures a specific area of the brain. MeHg-mediated neurotoxicity is believed to be caused by oxidative stress and endoplasmic reticulum (ER) stress but the mechanism by which those stresses lead to neuronal loss is unclear. Here, by utilizing the ER stress-activated indicator (ERAI) system, we investigated the signaling alterations in the unfolded protein response (UPR) prior to neuronal apoptosis in the mouse brain. In ERAI transgenic mice exposed to MeHg (25 mg/kg, S.C.), the ERAI signal, which indicates activation of the cytoprotective pathway of the UPR, was detected in the brain. Interestingly, detailed ex vivo analysis showed that the ERAI signal was localized predominantly in neurons. Time course analysis of MeHg exposure (30 ppm in drinking water) showed that whereas the ERAI signal was gradually attenuated at the late phase after increasing at the early phase, activation of the apoptotic pathway of the UPR was enhanced in proportion to the exposure time. These results suggest that MeHg induces not only ER stress but also neuronal cell death via a UPR shift. UPR modulation could be a therapeutic target for treating neuropathy caused by electrophiles similar to MeHg.

S-Nitrosylation at the active site decreases the ubiquitin-conjugating activity of ubiquitin-conjugating enzyme E2 D1 (UBE2D1), an ERAD-associated protein.

S-Nitrosylation of protein cysteine thiol is a post-translational modification mediated by nitric oxide (NO). The overproduction of NO causes nitrosative stress, which is known to induce endoplasmic reticulum (ER) stress. We previously reported that S-nitrosylation of protein disulfide isomerase (PDI) and the ER stress sensor inositol-requiring enzyme 1 (IRE1) decreases their enzymatic activities. However, it remains unclear whether nitrosative stress affects ER-associated degradation (ERAD), a separate ER stress regulatory system responsible for the degradation of substrates via the ubiquitin-proteasomal pathway. In the present study, we found that the ubiquitination of a known ERAD substrate, serine/threonine-protein kinase 1 (SGK1), is attenuated by nitrosative stress. C-terminus of Hsc70-interacting protein (CHIP) together with ubiquitin-conjugating enzyme E2 D1 (UBE2D1) are involved in this modification. We detected that UBE2D1 is S-nitrosylated at its active site, Cys85 by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, in vitro and cell-based experiments revealed that S-nitrosylated UBE2D1 has decreased ubiquitin-conjugating activity. Our results suggested that nitrosative stress interferes with ERAD, leading to prolongation of ER stress by co-disruption of various pathways, including the molecular chaperone and ER stress sensor pathways. Given that nitrosative stress and ER stress are upregulated in the brains of patient with Parkinson's disease (PD) and of those with Alzheimer's disease (AD), our findings may provide further insights into the pathogenesis of these neurodegenerative disorders.

Differences in executive function among patients with schizophrenia, their unaffected first-degree relatives and healthy participants.

BACKGROUND: Patients with schizophrenia (SCZ) display impaired executive functions compared with healthy controls (HCs). Furthermore, unaffected first-degree relatives (FRs) of patients with SCZ independently perform worse executive functions than do HCs. However, few studies have investigated the differences in executive functions assessed among patients with SCZ, FRs, and HCs, and the findings are inconsistent. METHODS: We investigated diagnostic differences in executive functions, namely, (i) numbers of categories achieved (CA), (ii) total errors (TE) and (iii) %perseverative errors of Nelson types (%PEN), using the Wisconsin card sorting test (WCST) among patients with SCZ (n=116), unaffected FRs (n=62) and HCs (n=146) at a single institute. Correlations between these executive functions and clinical variables were investigated. RESULTS: Significant differences existed in all executive functions among diagnostic groups (CA, F2,319=15.5, p=3.71×10-7; TE, F2,319=16.2, p=2.06×10-7; and %PEN, F2,319=21.3, p=2.15×10-9). Patients with SCZ had fewer CA and more TE and %PEN than those of HCs (CA, Cohen's d=-0.70, p=5.49×10-8; TE, d=0.70, p=5.62×10-8; and %PEN, d=0.82, p=2.85×10-10) and FRs (TE, d=0.46, p=3.73×10-3 and %PEN, d=0.38, p=0.017). Of the three executive functions, CA and %PEN of FRs were intermediately impaired between patients with SCZ and HCs (CA, d=-0.41, p=0.011 and %PEN, d=0.41, p=0.012). In contrast, no significant difference in TE existed between FRs and HCs (d=0.22, p=0.18). Although CA and TE were affected by the duration of illness (p<0.017), %PEN was not affected by any clinical variable in patients with SCZ (p>0.017). CONCLUSIONS: Executive function, particularly %PEN, could be a useful intermediate phenotype for understanding the genetic mechanisms implicated in SCZ pathophysiology.

Efficacy of ascitic fluid cell block for diagnosing primary ovarian, peritoneal, and tubal cancer in patients with peritoneal carcinomatosis with ascites.

OBJECTIVE: To compare the efficacy of ascitic fluid cell block (ACB) with that of core needle biopsy (CNB) or the CA125/CEA ratio in diagnosing primary tubo-ovarian cancer in female patients with peritoneal carcinomatosis (PC) with ascites. METHODS: This retrospective study examined female patients with PC with ascites who had available results for ACB, peritoneal tumor CNB, and the CA125/CEA ratio. Several measures of the accuracy of ACB and the CA125/CEA ratio were calculated and compared, with CNB as the reference standard. RESULTS: Of 81 patients with available results, 57 were clinically diagnosed with primary tubo-ovarian cancer. Overall, 52, 47, and 64 patients were diagnosed via CNB, ACB, and CA125/CEA ratio > 25, respectively. CNB and ACB identified the cancer origin in 91.4% and 82.7% cases, respectively. The concordance ratio of the immunohistochemical findings between ACB and CNB was 93.6%. Two patients with inconclusive CNB results were diagnosed with primary tubo-ovarian cancer via ACB. The sensitivity, specificity, positive predictive value, negative predictive value, and positive likelihood ratio were 86.5%, 93.1%, 95.7%, 79.4%, and 12.5, respectively, for ACB and 94.2%, 48.3%, 76.6%, 82.4%, and 1.82, respectively, for CA125/CEA ratio > 25. CONCLUSIONS: ACB is not inferior to CNB in diagnosing primary tubo-ovarian cancer; the two methods complement each other. ACB can substitute CNB in diagnosing primary tubo-ovarian cancer in selected PC patients. ACB is superior to a CA125/CEA ratio of >25 in diagnosing primary tubo-ovarian cancer. ACB is effective, reliable, and convenient for diagnosing primary tubo-ovarian cancer in PC patients with ascites.

A case of cervical adenocarcinoma arising from endometriosis in the absence of human papilloma virus infection.

Endometriosis-related cervical neoplasms are rare, and their clinicopathological features and association with human papilloma virus infection are unclear. A postmenopausal woman with recently diagnosed cervical adenocarcinoma was referred to our hospital. After further investigation, we suspected a stage IIB neoplasm that originated from endometriosis of the cervix or left parametrium. A radical hysterectomy was performed, and pathological examination confirmed a stage IIB cervical endometrioid carcinoma arising from the endometriosis in the cervix to the left parametrium that invaded the cervix; human papilloma virus infection of tumor cells was not detected. Endometriosis-related neoplasms can occur in the cervix or parametrium and present as cervical cancer. The neoplasm described here was not associated with human papilloma virus infection.

Serum microRNA profile enables preoperative diagnosis of uterine leiomyosarcoma.

Uterine leiomyosarcoma (ULMS) is the major subtype of uterine sarcoma (US) and contributes to uterine cancer deaths. Although preoperative diagnosis of US remains challenging, frequent application of laparoscopic surgery for benign uterine leiomyomas (ULM) requires precise exclusion of US. MicroRNAs are stably present in the bloodstream, and the application of circulating miRNAs as disease biomarkers has been recognized. In the present study, we aimed to identify diagnostic biomarkers for distinguishing US from ULM by focusing on circulating miRNAs. All serum samples were collected preoperatively between 2009 and 2017, and all cases were histopathologically diagnosed. Whole miRNA profiles were obtained using a miRNA microarray. By analyzing expression levels of the miRNAs, candidate miRNAs were selected based on diagnostic performance in discriminating US from ULM, and a diagnostic model was then constructed. A total of 90 serum samples were analyzed, and clustering analyses revealed that the profiles of ULMS were distinct from those of controls. Based on leave-one-out cross-validation, seven miRNAs were selected as biomarker candidates. Based on model construction, the optimal model consisted of two miRNAs (miR-1246 and miR-191-5p), with an area under the receiver operating characteristic curve (AUC) for identifying ULMS of 0.97 (95% confidence interval [CI], 0.91-1.00). In contrast, serum lactate dehydrogenase had an AUC of only 0.64 (95% CI, 0.34-0.94). Seven serum miRNAs with high diagnostic performance for preoperative US screening were detected, and a promising diagnostic model for ULMS was generated.

Smoking Rates and Number of Cigarettes Smoked per Day in Schizophrenia: A Large Cohort Meta-Analysis in a Japanese Population.

Background: Cigarette smoking is consistently more common among schizophrenia patients than the general population worldwide; however, the findings of studies in Japan are inconsistent. Recently, the smoking rate has gradually decreased among the general population. Methods: We performed a meta-analysis of smoking status in a large Japanese cohort of (1) 1845 schizophrenia patients and 196845 general population and (2) 842 schizophrenia patients and 766 psychiatrically healthy controls from 12 studies over a 25-year period, including 301 patients and 131 controls from our study. Results: In our case-control sample, schizophrenia patients had a significantly higher smoking rate than healthy controls (P=.031). The proportion of heavy smokers (P=.027) and the number of cigarettes smoked per day (P=8.20×10-3) were significantly higher among schizophrenia patients than healthy controls. For the smokers in the schizophrenia group, atypical antipsychotics dosage was positively correlated with cigarettes per day (P=1.00×10-3). A meta-analysis found that schizophrenia patients had a higher smoking rate than the general population for both men (OR=1.53, P=.035; schizophrenia patients, 52.9%; general population, 40.1%) and women (OR=2.40, P=1.08×10-5; schizophrenia patients, 24.4%; general population, 11.8%). In addition, male schizophrenia patients had a higher smoking rate than male healthy controls (OR=2.84, P=9.48×10-3; schizophrenia patients, 53.6%; healthy controls, 32.9%), but the difference was not significant for women (OR=1.36, P=.53; schizophrenia patients, 17.0%; healthy controls,14.1%). Among both males and females, schizophrenia patients had a higher smoking rate than both the general population (OR=1.88, P=2.60×10-5) and healthy controls (OR=2.05, P=.018). These rates were not affected by the patients' recruitment year (P>.05). The cigarettes per day values of schizophrenia patients and the general population were 22.0 and 18.8, respectively. Conclusions: Schizophrenia patients are approximately 2 times more likely to smoke than the general population and healthy controls based on data collected over a decade in Japan.

Endometrial Carcinoma With an Unusual Morphology in a Patient With Cornelia de Lange Syndrome: A Case Study.

Cornelia de Lange syndrome (CdLS) is a cohesinopathy, which is characterized by multiple structural anomalies as well as mental and growth retardation. A 36-yr-old nulliparous woman with oligomenorrhea was referred to us due to a mass in the uterine corpus. She had been clinically diagnosed with CdLS during infancy based on her specific facial features as well as growth and intellectual retardation. Imaging examinations and an endometrial biopsy revealed endometrial endometrioid carcinoma and polycystic ovary syndrome (PCOS). She underwent a hysterectomy and bilateral salpingo-oophorectomy. The tumor was mainly located at the uterine isthmus and exhibited diffuse exophytic growth. Microscopically, the grade 1 endometrioid carcinoma consisted of extremely well-differentiated glands and showed myometrial invasion. Both swollen ovaries had a thick fibrous cortex and multiple follicles. To the best of our knowledge, this is the first case report of a gynecologic malignancy in an adult patient with CdLS. Several gene mutations have been reported to be causative of CdLS; however, a potential role of these mutations in the pathogenesis of PCOS and subsequent endometrial cancer remains controversial. In this case, PCOS seemed to underlie the endometrial carcinogenesis and then concurrent loss of PTEN and PAX2 expression, confirmed by immunohistochemistry, can facilitate tumor progression. Our case suggests that adult female patients with CdLS can have PCOS and subsequent endometrial carcinoma. As patients with CdLS often have difficulties recognizing and/or reporting menstrual disorder, their care providers should pay particular attention to menstrual cycle irregularities due to the risk of endometrial cancer.

Meta-analysis of physical activity and effects of social function and quality of life on the physical activity in patients with schizophrenia.

Schizophrenia patients have increased mortality and morbidity, mainly due to premature cardiovascular disease resulting from decreased physical activity (PA). However, which PA intensity is impaired in the patients and how factors such as social function and quality of life (QoL) are related to decreased PA is unknown. To assess PA, social function and QoL, the International Physical Activity Questionnaire (IPAQ), Social Functioning Scale (SFS) and Schizophrenia Quality of Life Scale (SQLS), respectively, were used in 109 schizophrenia patients and 69 healthy subjects. A meta-analysis comparing PA intensities (vigorous, moderate and light) assessed by the single PA measurement between schizophrenia patients and healthy subjects after including our case-control sample was performed. Furthermore, the effects of social function and QoL on each level of PA intensity were investigated in patients and controls. The meta-analysis in 212 schizophrenia patients and 132 healthy subjects revealed that patients showed lower total PA, particularly vigorous PA, than controls (I2 = 0, Hedges' g = - 0.41, P = 2.80 × 10-4). The decreased total PA was correlated with impaired total SFS scores (ß = 0.24, P = 2.86 × 10-3), withdrawal (ß = 0.23, P = 3.74 × 10-3) and recreation (ß = 0.23, P = 3.49 × 10-3) without significant heterogeneity between patients and controls. In contrast, the decreased total PA was affected by low independence-performance (ß = 0.22, P = 0.034), employment/occupation (ß = 0.27, P = 8.74 × 10-3), psychosocial (ß = - 0.24, P = 0.021) and motivation/energy (ß = - 0.26, P = 0.013), but only in patients. Similar findings were obtained for vigorous PA but not moderate or light PA. Our findings suggest that the impaired vigorous PA in schizophrenia patients may be mediated by schizophrenia-specific factors of social functioning and QoL. Understanding these factors has important implications for increasing PA participation in schizophrenia patients.