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We report the case of a 35-year-old pregnant woman (gravida 3, para 1) with antithrombin deficiency who was successfully treated with apixaban. She had a history of heparin-induced thrombocytopenia and venous thromboembolic events. Pregnancy was confirmed while the patient was having anticoagulant therapy for a persistent thrombus. Choice of anticoagulation during her pregnancy was limited because of her antithrombin deficiency: heparin was not an option because of her history of heparin-induced thrombocytopenia; antithrombin-dependent anticoagulant drugs were not an option because of her antithrombin deficiency, and she preferred outpatient management. Despite the fact that there are no reports of its use in pregnant women, we selected apixaban (10 mg/day), a direct Xa inhibitor, as the best solution. No progression of thrombus was noted during the pregnancy. The newborn baby had no external congenital anomalies, intracranial hemorrhage, or bleeding tendency. Thus, apixaban may be a candidate for anticoagulant therapy in pregnant women with a history of venous thromboembolic events and heparin-induced thrombocytopenia.

Background: The extracellular volume (ECV) calculated by T1 mapping, and tissue-tracking strain using cardiac magnetic resonance (CMR) are useful for assessing the left ventricular (LV) function. However, those parameters are controversial for assessing left atrial (LA) function. This study aimed to investigate the usefulness of CMR to evaluate the LA function using those parameters. Furthermore, those LA function parameters were compared in each LV function. Methods: A total of 65 consecutive patients who underwent contrast CMR were prospectively enrolled (age 55.7 ± 14. 6 years, males 67.7%). Among the 65 patients, there were 15 without hypertension, diabetes, or atrial fibrillation (Healthy group). The remaining 50 patients were divided into two groups according to a left ventricular ejection fraction (LVEF) of 50%. We assessed the correlations between the LV- and LA-CMR parameters among the three groups (LVEF

Although vascular injury during laparoscopic surgery is rare, it is occasionally reported. Previously, several physicians have reported cases of compartment syndrome resulting from a thrombus during gynecologic surgery. However, few reports describe thrombosis occurring in artery vessels as a result of applying angiopressure. Herein, we report the case of a 53-year-old woman with endometrioid carcinoma and a vascular injury that resulted in thrombus formation; this is the first such case to be reported. The complication was successfully treated by means of direct anastomosis following partial resection of the injured iliac artery. This is the first report of a case in which applying angiopressure for a vascular injury during laparoscopic pelvic lymphadenectomy led to an intra-arterial thrombus which was found and treated without sequelae.

Abstract Background Zrsr1 is a paternally expressed imprinted gene located in the first intron of Commd1, and the Zrsr1 promoter resides in a differentially methylated region (DMR) that is maternally methylated in the oocyte. However, a mechanism for the establishment of the methylation has remained obscure. Commd1 is transcribed in the opposite direction to Zrsr1 with predominant maternal expression, especially in the adult brain. Results We found Commed1 transcribed through the DMR in the growing oocyte. Zrsr1-DMR methylation was abolished by the prevention of Commd1 transcription. Furthermore, methylation did not occur at the artificially unmethylated maternal Zrsr1-DMR during embryonic development when transcription through the DMR was restored in the zygote. Loss of methylation at the maternal Zrsr1-DMR resulted in biallelic Zrsr1 expression and reduced the extent of the predominant maternal expression of Commd1. Conclusions These results indicate that the establishment of methylation at Zrsr1-DMR occurs in a transcription-dependent and oocyte-specific manner and caused Zrsr1 imprinting by repressing maternal expression. The predominant maternal expression of Commd1 is likely caused by transcriptional interference by paternal Zrsr1 expression.

Abstract: Alzheimer disease (AD) is a neurodegenerative disorder characterized by extracellular β-amyloid (Aβ) deposition. Although peripheral inflammation and cerebrovascular pathology are reported in AD, there is a lack of plasma biomarkers in this field. Because the contact system is triggered in patient plasma, we hypothesized that the hemostasis profile could be a novel biomarker in AD. Here, we assessed the clotting profile in plasma from AD patients and age-matched controls. Utilizing clinically relevant assays, thromboelastography and activated partial thromboplastin time, we found impaired clot initiation and formation rate in AD patient plasma. These coagulation end points correlated with cerebrospinal fluid neurofilament-light levels and cognition and were more profound in younger AD patients. Ex vivo intrinsic clotting of plasma from AD mice expressing human amyloid precursor protein (APP) was also delayed in an age-dependent manner, suggesting that this phenotype is related to APP, the parent protein of Aβ. Further analysis of coagulation factors in human plasma indicated that endogenous inhibitor(s) of factors XII and XI in AD plasma contribute to this delayed clotting. Together, these data suggest that delayed clotting in young AD patients is a novel biomarker and that therapies aimed to correct this phenotype might be beneficial in this patient population. Follow-up studies in additional AD patient cohorts are warranted to further evaluate these findings.

Abstract Introduction Accumulation of β‐amyloid is a pathological hallmark of Alzheimer's disease (AD). β‐Amyloid activates the plasma contact system leading to kallikrein‐mediated cleavage of intact high‐molecular‐weight kininogen (HKi) to cleaved high‐molecular‐weight kininogen (HKc). Increased HKi cleavage is observed in plasma of AD patients and mouse models by Western blot. For potential diagnostic purposes, a more quantitative method that can measure HKc levels in plasma with high sensitivity and specificity is needed. Methods HKi/c, HKi, and HKc monoclonal antibodies were screened from hybridomas using direct ELISA with a fluorescent substrate. Results We generated monoclonal antibodies recognizing HKi or HKc specifically and developed sandwich ELISAs that can quantitatively detect HKi and HKc levels in human. These new assays show that decreased HKi and increased HKc levels in AD plasma correlate with dementia and neuritic plaque scores. Discussion High levels of plasma HKc could be used as an innovative biomarker for AD.

Constipation is a frequent complication in patients with severe motor and intellectual disabilities (SMID). The aim of this study was to investigate changes in constipation symptoms and gut microbiota associated with the intake of malted rice amazake, a fermented food in Japan, in patients with SMID. Ten patients consumed the test food for six weeks, and their physical condition, dietary and medication status, and constipation assessment scale (CAS) were investigated. Comprehensive fecal microbiome analysis using the 16S rRNA sequence method was performed. The results showed a significant decrease in CAS, and a significant increase in Lactobacillales and decrease in Escherichia-Shigella after consuming malted rice amazake. To investigate the difference in the effects of malted rice amazake consumption, based on the characteristics of the original gut microbiota, the patients were grouped according to the similarity of their gut microbiota before the intervention; Firmicutes-rich Group 1 (n = 5), Actinobacteria-rich Group 2 (n = 4), and Proteobacteria-rich Group 3 (n = 1). The CAS decreased in Groups 1 and 2. The relative abundance of Bifidobacterium showed an increasing tendency both overall and in Group 1, but it was originally higher in Group 2. Our results suggest that malted rice amazake consumption reduces constipation symptoms and simultaneously changes the gut microbiota, but the changes may vary depending on the original composition of the gut microbiota.

Recent advances in next-generation sequencing and genome medicine have contributed to treatment decisions in patients with cancer. Most advanced gynecological cancers develop resistance to chemotherapy and have a poor prognosis. Therefore, we conducted genomic tests in gynecological tumors to examine the efficacy and clinical feasibility of genotype-matched therapy. Target sequencing was performed in 20 cases of gynecological cancers (cervical cancer, 6; endometrial cancer, 6; and ovarian cancer, 6). Both actionable and druggable genes were identified in 95% (19/20) of the cases. Among them, seven patients (35%) received genotype-matched therapy, which was effective in three patients. Of the three patients, one patient with a PTEN mutation received everolimus, another patient with a TSC2 mutation received everolimus and letrozole, and the patient with a BRIP1 mutation received olaparib. Subsequently, disease control in these three patients lasted for more than half a year. However, all patients relapsed between 9 and 13 months after the initiation of genotype-matched therapy. In this study, the response rate of genotype-matched therapy was 43% (3/7), which may have contributed to improved prognoses. Therefore, genotype-matched therapies may help patients with refractory gynecological cancers achieve better outcomes.

OBJECTS: Identification of biomarkers for Alzheimer's disease (AD) is important for its early diagnosis and prevention and a key in advancing our understanding of its pathophysiology. The aim of this study was to determine whether systemic inflammatory interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) as well as hypertension (HT), diabetes mellitus (DM), and body mass index (BMI) are predictors of AD. METHODS: We performed a 10-year follow-up study on 133 elderly who were institutionalized in a nursing home. The associations of IL-1ß and IL-6 at both rest and agitation, as well as HT, DM, and BMI at baseline, were analyzed with the incidences of vascular dementia (VD) and AD during a 10-year follow-up period. RESULTS: The Kaplan-Meier method with log-rank test and Cox regression analyses for the total of 133 subjects showed significantly higher incidences of both VD and AD in subjects with DM or HT at baseline. Resting IL-1ß or IL-6 value, or agitation score, was not significantly associated with the subsequent development of VD or AD. The analyses of 40 subjects who had shown agitation at least once in the previous 3 months demonstrated that IL-1ß and IL-6 values at the agitation stage were significantly associated with AD, but not with VD. CONCLUSION: Our results indicate that systemic inflammatory IL-1ß and IL-6 at the agitation stage are risk factors for the development of AD, but not VD. Inflammatory mechanisms for AD seem to be causal and specific to the development of AD. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective Alzheimer's disease (AD) is a neurodegenerative disorder that is the most common cause of dementia in the elderly and is frequently accompanied by emotional disorder, including agitation. Although evidence of neuroendocrine immune and inflammatory functions during emotional changes has been accumulated, the pathogenic mechanisms in the development of agitation accompanied by AD remain to be elucidated. Methods To clarify the involvement of neuroendocrine and immune and inflammatory systems in agitation in AD, we examined agitation levels, circadian rhythms of behavior, cortisol, interleukin-1β (IL-1β), and natural killer cell activity (NKCA) in controls without dementia and 16 AD patients who were recognized to be easily agitated in their nursing homes. These behavioral and blood indicators were assessed according to the progress of the stage of agitation in 16 AD patients (stable, pre-agitation, and agitation stages). Results Elevations in night behavior and blood cortisol, IL-1β and an reduced blood NKCA level in the evening were observed not only in the agitation stage, but also when stable in AD patients as compared to the control. Increased IL-1βand decreased NKCA occurred in both the morning and evening in pre-agitation and agitation stages in AD. Conclusions The increased IL-1βand decreased NKCA with the progress of agitation in AD suggest that inflammation produces agitation and aggravates AD. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

RATIONALE: IL-18 is a unique cytokine that enhances innate immunity and both Th1- and Th2-driven immune responses. Recent murine and human genetic studies have shown its role in the pathogenesis of asthma. OBJECTIVES: We conducted an association study in a Japanese population to discover variants of IL-18 that might have an effect on asthma susceptibility and/or progression and conducted functional analyses of the related variants. METHODS: The IL-18 gene locus was resequenced in 48 human chromosomes. Asthma severity was determined according to the 2002 Global Initiative for Asthma Guidelines. Association and haplotype analyses were performed using 1,172 subjects. MEASUREMENTS AND MAIN RESULTS: Although no polymorphisms differed significantly in frequency between the control and adult asthma groups, rs5744247 C>G was significantly associated with the severity of adult asthma (steps 1, 2 vs. steps 3, 4; P = 0.0034). We also found a positive association with a haplotype (P = 0.0026). By in vitro functional analyses, the rs5744247 variant was found to increase enhancer-reporter activity of the IL-18 gene in bronchial epithelial cells. Expression levels of IL-18 in response to LPS stimulation in monocytes were significantly greater in subjects homozygous for the susceptibility G allele at rs5744247 C>G. Furthermore, we found a significant correlation between the serum IL-18 level and the genotype of rs5744247 (P = 0.031). CONCLUSIONS: Although the association results need to be replicated by other studies, IL-18 variants are significantly associated with asthma severity, and the rs5744247 variant reflects higher transcriptional activity and higher expression of IL-18 in LPS-stimulated monocytes and a higher serum IL-18 level. [ABSTRACT FROM AUTHOR]

Endometriosis-harboring cancer-associated somatic mutations of PIK3CA and KRAS provides new opportunities for studying the multistep processes responsible for the functional and molecular changes in this disease. We aimed to establish a novel in vitro endometriosis model to clarify the functional behavior and molecular pathogenesis of this disorder. Immortalized HMOsisEC10 human ovarian endometriotic epithelial cell line was used in which KRAS and PIK3CA mutations were introduced. Migration, invasion, proliferation, and microarray analyses were performed using KRAS and PIK3CA mutant cell lines. In vitro assays showed that migration, invasion, and proliferation were significantly increased in KRAS and PIK3CA mutant cell lines, indicating that these mutations played causative roles in the aggressive behavior of endometriosis. Microarray analysis identified a cluster of gene signatures; among them, two significantly upregulated cancer-related genes, lysyl oxidase (LOX) and pentraxin3 (PTX3), were associated with cell proliferation, invasion, and migration capabilities. Furthermore, siRNA knockdown of the two genes markedly reduced the metastatic ability of the cells. These results suggest that endometriosis with KRAS or PIK3CA mutations can significantly enhance cell migration, invasion, and proliferation by upregulating LOX and PTX3. We propose that LOX and PTX3 silencing using small molecules could be an alternative therapeutic regimen for severe endometriosis.

Abstract: Optical simulation has been employed, for the first time, for rigorous evaluation of transmittance into the TiO2 nanocrystalline film, entering from the fluorine-doped SnO2 (F-SnO2) coated glass side, in dye sensitized solar cells. The refractive index of the TiO2 film with various porosities was determined theoretically, and was in agreement with the data obtained by ellipsometric measurements. The simulation clearly indicates that the transmittance into the TiO2 film is 85–90% at 450–800nm, on adjusting the porosity to 0.5–0.75. In contrast, transmittances experimentally determined for the TiO2 film deposited on F-SnO2 exhibits 70–83% at 450–800nm, under-estimating the transmittance by about 10% compared to the simulated results. The simulation method was further substantiated by observing the high IPCE value (∼85% at 530nm) for the solar cell using the same TiO2 film sensitized by ruthenium dye. [Copyright &y& Elsevier]

Aim: It is generally accepted that endurance exercise increases the expression of peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1 α), which governs the expression of oxidative metabolic enzymes. A previous report demonstrated that the regulation of mitochondrial protein expression in skeletal muscles in response to cold exposure depends on muscle fibre type. Cold exposure and endurance exercise are both metabolic challenges that require adjustments in mitochondrial energy metabolism, we hypothesized that the exercise-induced increase in oxidative enzymes and PGC-1 α expression is higher in fast-type than in slow-type muscle. Methods: Female ICR mice were individually housed in cages equipped with running wheel for 1, 2, 4, 6 or 8 weeks. The soleus, plantaris (PLA) and tibialis anterior (TA) muscles were then prepared from each mouse. The expression levels of PGC-1 α, mitochondrial proteins and GLUT4 were evaluated by Western blotting. Results: The expression level of PGC-1 α was increased only in the PLA muscle. Furthermore, the expression levels of all mitochondrial proteins and GLUT4 in the PLA muscle were increased. In the TA muscle, although there was no increase in PGC-1 α expression, the expression levels of mitochondrial proteins and GLUT4 were increased. Conclusions: These results suggest that muscle type-specific responses occur during endurance exercise, and that the increase in PGC-1 α expression is not the only factor that promotes oxidative capacity as a result of endurance exercise. [ABSTRACT FROM AUTHOR]

Background: Pilsicainide, a pure Na+ channel blocker, is a popular antiarrhythmic drug for the management of atrial tachyarrhythmias (AT), in Japan. However, serious drug-induced proarrhythmias (DIPs) may unexpectedly occur. We assessed the clinical background of AT patients presenting with DIPs caused by pilsicainide. Methods: This study retrospectively enrolled 874 consecutive patients (543 men, 63.6±15.3 years old, and 57.9±16.5 kg of body weight), who were orally administered pilsicainide for AT management. We evaluated the relationship between DIPs and serum pilsicainide concentration, renal dysfunction (estimate glomerular filtration rate, eGFR), and electrocardiogram (ECG) parameters. Results: Among the patients, 154 (17.6%) had renal dysfunction (eGFR

Malignant transformation of extraovarian endometriosis is rare, with the carcinogenesis mechanism unclear. To clarify the actionable variants of rare-site endometriosis-associated cancer (RSEAC), we performed whole-exome sequencing for the tumor, in two patients. The intestine was affected in both cases, although the histology was that of clear cell carcinoma and undifferentiated carcinoma, respectively. Therefore, the cases were referred to as endometriosis-associated intestinal tumors (EIATs). Actionable variants (all frameshift mutations) were identified in tumor suppressor genes ARID1A, PTEN, and p53; however, no oncogenic variants were identified. Both cases were microsatellite stable. The patient with undifferentiated carcinoma exhibited hypermutator and homologous recombination deficiency phenotypes. The dominant mutation signatures were signature 30 (small subset of breast cancers) and 19 (pilocytic astrocytoma) in patient 1, and signature 5 (small subset of breast cancers) and 3 (breast, ovarian, and pancreatic cancers) in patient 2. Immunohistochemistry revealed positive CD8 and PD-1 expression in both patients; patient 1 also showed positive PDL-1 expression. Our results suggest that RSEAC is associated with variants of tumor suppressor genes as epigenetic alterations. Mutation signature-based whole-exome sequencing could be useful to select an adjuvant chemotherapy regimen. High CD8 and PD-1 expression in RSEAC suggests that immune checkpoint inhibitors are useful for treatment.

Telomere length (TL) influences the development of lifestyle-related diseases, and neonatal TL may influence their prevalence. Various factors have been reported to affect neonatal TL. Although the fetus is exposed to multiple conditions in utero, the main factors affecting the shortening of neonatal TL are still not known. In this study, we sought to identify factors that influence fetal TL. A total of 578 mother-newborn pairs were included for TL analysis. TL was measured in genomic DNA extracted from cord blood samples using quantitative PCR. The clinical factors examined at enrollment included the following intrauterine environmental factors: maternal age, assisted reproductive technology (ART) used, body mass index (BMI), gestational diabetes mellitus (GDM), maternal stress, smoking, alcohol consumption, preterm delivery, small-for-gestational-age, neonatal sex, and placental weight. Univariate and multivariate regression analyses were used to verify the relationship between neonatal TL and these clinical factors. The median neonatal TL to single-copy gene ratio was 1.0. Pregnancy with ART was among the 11 factors associated with shorter neonatal TL. From multiple regression analysis, we determined that neonatal TL was significantly shorter for pregnancies in the ART group than in the other groups. We conclude that pregnancy with ART is associated with shorter neonatal TL.

Background: Lymphocyte telomere length is strongly correlated with patient prognosis in several malignant tumor types and is thought to be related to tumor immunity. However, this correlation has not been studied in gynecological cancers. We determined the prognostic significance of peripheral blood lymphocyte telomere length in gynecologic cancers. Methods: Telomere length of lymphocytes from patients with gynecological malignant tumors (ovarian cancer (OC), N = 72; cervical cancer (CC), N = 63; endometrial cancer (EC), N = 87) was examined by quantitative reverse-transcription PCR of isolated mononuclear cells. Kaplan–Meier and Cox proportional hazard analyses were used to determine the association between lymphocyte telomere length and clinicopathological factors. Results: The overall survival (OS) and progression-free survival (PFS) of patients were based on the dichotomized lymphocyte telomere length using the median as a threshold (OC: 0.75, CC: 1.94, and EC: 1.09). A short telomere length was significantly correlated with residual tumors (≥1 cm) in OC and with advanced stage (III and IV) of CC. In OC and CC, patients with shorter relative lymphocyte telomere length (RLT) had significantly poorer OS and PFS than patients with longer RLT (p = 0.002, p = 0.003, and p = 0.001, p = 0.001, respectively). However, in EC, RLT was not significantly associated with OS or PFS (p = 0.567 and p = 0.304, log-rank test). Multivariate analysis showed that shorter RLT was a significant independent prognostic factor of PFS and OS for OC (p = 0.03 and p = 0.04, respectively) and CC (p = 0.02 and p = 0.03, respectively). Conclusions: Patients with OC and CC with shorter lymphocyte telomeres have significantly reduced survival; therefore, the peripheral blood lymphocyte telomere length is a prognostic biomarker in OC and CC.

The inhibitory effects of 6-amidino-2-naphthyl 4-guanidinobenzoate (FUT-175) on the activities of factor B, factor &Dmacr; and cobra venom factor (CVF) · Bb were examined. FUT- 175 bound specifically to the Bb fragment of factor B or CVF · Bb. FUT-175 was a non-competitive inhibitor of the esterolysis of L-leucyI-L-alanyl-L-arginine naphthylester by factor B and CVF · Bb. FUT-175 also inhibited the haemolytic activity of factor B, the C3 convertase activity of CVF Rb and the factor B-cleaving activity of factor &Dmacr;. The concentration of FUT-175 causing 50% inhibition of these activities was 10-5-10-4M. [ABSTRACT FROM AUTHOR]

The frequency of KRAS/BRAF mutations associated with low-grade serous ovarian carcinoma (LGSC)/serous borderline tumors (SBTs) in Japan is unknown. We aimed to identify genetic variations in KRAS, BRAF, PIK3CA, and ERBB2 in LGSC/SBT/serous cystadenomas (SCAs) in a Japanese population. We performed a mutation analysis (by Sanger sequencing) of 33 cases of LGSC/SBT/SCA and 4 cases of LGSC with synchronous SBTs using microdissected paraffin-embedded sections. Immunohistochemistry of p53 and ARID1A was also performed. The frequency of oncogenic mutations in PIK3CA was 60.0% (6/10) in LGSCs, 63.6% (7/11) in SBTs, and 8.3% (1/12) in SCAs. All cases harbored wild-type KRAS. The frequency of BRAF mutations was 20.0% (2/10) in LGSCs, whereas all SBTs and SCAs harbored the wild-type allele. The frequency of ERBB2 mutations was 30.0% (3/10) in LGSCs, 0.0% (0/11) in SBTs, and 16.7% (2/12) in SCAs. ARID1A staining was positive in all cases. p53 staining was positive in 0% (0/10) LGSCs, 9.1% (1/11) SBTs, and 0.0% (0/12) SCAs. One LGSC case had two PIK3CA mutations (G1633A and G3149A) in both LGSC and SBT lesions, but a BRAF mutation was detected only in an LGSC lesion. These results suggest that, compared with the values in Western populations (16−54%), the KRAS mutation frequency in LGSCs/SBTs is lower and that of PIK3CA mutations in LGSCs/SBTs is much higher in Japanese populations. Therefore, the main carcinogenesis signaling pathways may be different between Japanese and Western LGSCs. Molecular therapies targeting the PIK3CA/AKT pathway may be effective in LGSCs in Japan.

Ovarian cancer has the worst prognosis among gynecological cancers. Thus, new ovarian cancer treatment strategies are needed. Currently, immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibody are attracting attention worldwide. The Food and Drug Administration approved the use of the PD-1 antibody pembrolizumab for solid cancers with microsatellite instability (MSI)-H or mismatch repair (MMR) deficiency in 2017. However, few studies on ovarian carcinoma have evaluated the relationship among MSI status, lymphocyte infiltration into the tumor, and the expression of immune checkpoint molecules by histologic type. We evaluated the expression of MMR proteins, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1/PD-1) by immunohistochemistry in 136 ovarian cancer patients (76, 13, 23, and 24 cases were high-grade serous, mucinous, endometrioid, and clear cell carcinoma, respectively) to investigate the effectiveness of immune checkpoint inhibitors. Only six cases (4.4%) had loss of MMR protein expression. There was no significant relationship between MSI status and age (p = 0.496), FIGO stage (p = 0.357), initial treatment (primary debulking surgery [PDS] or neoadjuvant chemotherapy) (p = 0.419), residual tumor after PDS or interval debulking surgery (p = 0.202), and expression of CD8 (p = 0.126), PD-L1 (p = 0.432), and PD-1 (p = 0.653). These results suggest that only a small number of MSI cases in ovarian cancer can be effectively treated with immune checkpoint inhibitor monotherapy. Therefore, to improve the prognosis of ovarian carcinoma, a combination therapy of immune checkpoint inhibitors and other anticancer drugs is necessary.

The inhibition of the hERG potassium channel is closely related to the prolonged QT interval, and thus assessing this risk could greatly facilitate the development of therapeutic compounds and the withdrawal of hazardous marketed drugs. The recent increase in SAR information about hERG inhibitors in public databases has led to many successful applications of machine learning techniques to predict hERG inhibition. However, most of these reports constructed their prediction models based on only one SAR database because the differences in the data format and ontology hindered the integration of the databases. In this study, we curated the hERG-related data in ChEMBL, PubChem, GOSTAR, and hERGCentral, and integrated them into the largest database about hERG inhibition by small molecules. Assessment of structural diversity using Murcko frameworks revealed that the integrated database contains more than twice as many chemical scaffolds for hERG inhibitors than any of the individual databases, and covers 18.2% of the Murcko framework-based chemical space occupied by the compounds in ChEMBL. The database provides the most comprehensive information about hERG inhibitors and will be useful to design safer compounds for drug discovery. The database is freely available at http://drugdesign.riken.jp/hERGdb/.

A threshold voltage (Vth) controllable multigate FinFET on a 10-nm-thick ultrathin BOX (UTB) SOI substrate have been investigated. It is revealed that the Vth of the FinFET on the UTB SOI substrate is effectively modulated thanks to the improved coupling between the Si channel and the back gate. We have also carried out analysis of the Vth controllability in terms of the size dependence such as the gate length (LG) and the fin width (TFin).

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.

Background: Class IC antiarrhythmic drugs, used to prevent paroxysmal atrial tachyarrhythmias (ATs), are well known to effectively unmask the electrocardiogram (ECG) pattern of Brugada syndrome. We used these drugs to investigate the prevalence and prognosis of patients with lone and paroxysmal ATs and Brugada-type ECGs. Methods and results: We enrolled 702 consecutive patients who were given class IC antiarrhythmic drugs (pilsicainide or propafenone) to inhibit paroxysmal ATs. We analyzed 12-lead ECGs before and after drug administration using a computerized ECG system. A Brugada-type ECG was defined as a coved pattern of ST segment elevation (>0.2 mV) in leads V1−V2. No patients had risk-stratifying factors of the syndrome. Forty-four patients (6.3%) had significant ST-segment elevation in leads V1−V2 after drug administration. Among these patients, a coved ECG pattern was observed in 10 (1.4%). The use of pilsicainide (n=9) was significantly (P=0.02) greater than that of propafenone (n=1). During the follow-up period of 85±19 months, none of the 10 patients had ventricular tachyarrhythmias. Conclusions: Manifestation of Brugada-type ECGs by class IC antiarrhythmic drugs is neither rare nor serious in patients with lone and paroxysmal ATs but without risk-stratifying factors for the syndrome.

This article examines the circulation and reception of the original Japanese shōjo manga text, Hana Yori Dango, through the three sites of Taiwan, Korea and Japan to both identify similarities and to investigate also specific differences between versions and how these differences relate to both cultural distancing and to cultural proximity. The distance-closeness binary is most informed by the historical relationship Japan has had under Western socio-politico-cultural subjugation that in turn has informed the colonial relationship both Taiwan and Korea have had with Japan. The remnant of these (ongoing) relationships has directed a subjective encoding onto versions of the text adapted in East Asia. Therefore, the appearance of similarity between versions is underscored by social, political and cultural differences contextualised locally and promoted globally as a polymorphous and multi-layered plurality.

AT-rich interactive domain 1A (ARID1A) and AT-rich interactive domain 1B (ARID1B) are subunits of the SWI/SNF chromatin complex. ARID1A is a tumor suppressor gene that is frequently mutated (46%) in ovarian clear cell carcinomas (OCCC). Loss of ARID1B in an ARID1A-deficient background eliminates the intact SWI/SNF complex, indicating that ARID1B is essential for the formation or stabilization of an intact SWI/SNF complex and, thus, the survival of ARID1A-mutant cancer cell lines. In this study, we investigated the clinicopathologic and prognostic relevance of ARID1B in OCCC by immunohistochemical analysis of 53 OCCC patient samples and loss-of-function experiments in OCCC cell lines. We also examined whether ARID1B could be a therapeutic target or prognostic biomarker in OCCC. siRNA-mediated knockdown of ARID1B in an ARID1A-mutant cell line significantly decreased cell growth, whereas concurrent depletion of both ARID1A and ARID1B was required to decrease wild type cell growth. In the immunohistochemical analyses, low ARID1B level was frequent in samples lacking ARID1A and was associated with shorter progression-free survival. This is the first report demonstrating that a low ARID1B level could be a marker of poor prognosis in OCCC. Moreover, the correlation between the loss of ARID1A immunoreactivity and reduced ARID1B levels indicates that ARID1B could be an attractive target for anti-cancer therapy.

Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2 (PMS2)). The disorder is associated with colorectal, endometrial, and other epithelial malignancies, but not cervical cancer. We report a woman with Lynch syndrome with synchronous cervical cancer. This is the first report of Lynch syndrome-related clear cell carcinoma of the cervix, which indicates the possibility of an association between cervical cancer and Lynch syndrome. Suitable genetic tests are required to determine whether common genetics can account for synchronous or subsequent malignancies in Lynch syndrome patients and their families. Such knowledge will also enhance our understanding of the genetic mechanisms governing the development of apparently unrelated cancers.

Nanopaper prepared from holocellulose pulp is one of the best substrates for flexible electronics because of its high thermal resistance and high clear transparency. However, the clearness of nanopaper decreases with increasing concentration of the starting cellulose nanofiber dispersion—with the use of a 2.2 wt % dispersion, for example—resulting in translucent nanopaper with a high haze of 44%. To overcome this problem, we show that the dilution of this high-concentration dispersion with water followed by sonication for 10 s reduces the haze to less than 10% while maintaining the high thermal resistance of the nanopaper. Furthermore, the combination of water dilution and a short sonication treatment improves the clearness of the nanopaper, which would translate into cost savings for the transportation and storage of this highly concentrated cellulose nanofiber dispersion. Finally, we demonstrate the improvement of the electrical conductivity of clear transparent nanopaper prepared from an initially high-concentration dispersion by dropping and heating silver nanowire ink on the nanopaper. These achievements will pave the way toward the realization of the mass production of nanofiber-based flexible devices.

The aims of this paper are to propose a new finishing process and show the feasibility of ultra-precision finishing of thin quartz wafers used for high-frequency devices. This particular application requires simultaneous improvement of surface roughness and thickness variation with minimal material removal. Consequently, the process must allow for the control of both super-fine finishing and localized material removal. This paper proposes a method using magnetic field-assisted finishing for the finishing of thin quartz wafers. The magnetic field-assisted finishing process enables localized material removal through control of the magnetic field distribution at the finishing area; and mirror finishing is achieved using magneto-rheological fluid-based slurry. This paper describes the processing principle, the development of the finishing equipment, and the required conditions to realize the principle. The finishing experiments demonstrate the feasibility of the proposed method to perform super-fine finishing of 60 μm thick quartz wafers, in which the control of the magnetic field allows for localization of the material removal to improve or maintain the thickness variation, as desired.

We aimed to clarify the usefulness of measuring the flow mediated dilatation (FMD) in patients with type 2 diabetes mellitus without and with coronary heart disease (CHD). The FMD was measured in 480 patients with type 2 diabetes and in 240 nondiabetic subjects. The FMD was significantly lower in the subjects with CHD (n = 145, 5.4±3.2%) than in those without CHD (n = 95, 6.9±3.5%) among the nondiabetic subjects. The FMD was also lower in the subjects both with CHD (n = 161, 5.6±2.8%) and without CHD (n = 319, 6.1±3.3%) among the patients with diabetes compared to those without both diabetes and CHD. The FMD showed a significant positive correlation with the estimated glomerular filtration rate (eGFR) in the diabetic patients without CHD, while there was no significant association in those with CHD. The FMD was significantly lower with the progressive stages of the GFR or albuminuria in the patients without CHD among those with diabetes, although the FMD was not different in those with CHD. In conclusion, the FMD is considered to be useful for the detection of atherosclerosis in patients with type 2 diabetes, even if overt macroangiopathy is not diagnosed.