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Background: Postherpetic pain (PHP) is difficult to control. Although Neurotropin® (NTP) and methylcobalamin (MCB) are often prescribed to treat the pain, the efficacy of combined treatment for PHP remains imcompletely understood., Objective: In this study, we investigate the combined effects of NTP and MCB on PHP in mice., Methods: NTP and MCB were administered from day 10-29 after herpes simplex virus type-1 (HSV-1) infection. The pain-related responses were evaluated using a paint brush. The expression of neuropathy-related factor (ATF3) and nerve repair factors (GAP-43 and SPRR1A) in the dorsal root ganglion (DRG) and neurons in the skin were evaluated by immunohistochemical staining. Nerve growth factor (NGF) and neurotrophin-3 (NT3) mRNA expression levels were evaluated using real-time PCR., Results: Repeated treatment with NTP and MCB after the acute phase inhibited PHP. Combined treatment with these drugs inhibited PHP at an earlier stage than either treatment alone. In the DRG of HSV-1-infected mice, MCB, but not NTP, decreased the number of cells expressing ATF3 and increased the number of cells expressing GAP-43- and SPRR1A. In addition, MCB, but not NTP, also increased and recovered non-myelinated neurons decreased in the lesional skin. NTP increased the mRNA levels of NTF3 in keratinocytes, while MCB increased that of NGF in Schwann cells., Conclusion: These results suggest that combined treatment with NTP and MCB is useful for the treatment of PHP. The combined effect may be attributed to the different analgesic mechanisms of these drugs., Competing Interests: Declaration of Competing Interest The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. This study was funded by Nippon Zoki Pharmaceutical Co., Ltd., (Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background and Aims: There is a lack of biliary epithelial molecular markers for primary sclerosing cholangitis (PSC). We analyzed candidates from disease susceptibility genes identified in recent genome-wide association studies (GWAS)., Methods: Expression levels of GWAS genes were analyzed in archival liver tissues of patients with PSC and controls. Immunohistochemical analysis was performed to evaluate expression levels in the biliary epithelia of PSC (N = 45) and controls (N = 12). Samples from patients with primary biliary cholangitis (PBC) were used as disease controls (N = 20)., Results: Hepatic expression levels of ATXN2, HHEX, PRDX5, MST1, and TNFRSF14 were significantly altered in the PSC group. We focused on the immune-related receptor, TNFRSF14. Immunohistochemistry revealed that high expression of TNFRSF14 in biliary epithelial cells was observed only in the PSC group. In addition, the expression of LIGHT, which encodes a TNFRSF14-activating ligand, was increased in PSC liver. Immunohistochemistry showed that high expression of LIGHT was more common in PSC biliary epithelia (53%) than in the PBC (15%) or control (0%) groups; moreover, it was positively associated with fibrotic progression, although it was not an independent prognostic factor., Conclusions: TNFRSF14 and LIGHT are promising candidate markers for PSC., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The occurrence of macrocyclic daphnane orthoesters (MDOs) with a 1-alkyl group originating from a C 14 aliphatic chain is extremely limited in the plant kingdom and has only been isolated from Edgeworthia chrysantha. In the present study, LC-ESI-MS/MS analysis was performed on different parts of E. chrysantha, including flower buds, flowers, leaves, and stems, and resulted in the identification of seven MDOs in all the four plant parts, including two previously unreported compounds 1 and 7. Further LC-MS guided isolation was carried out to afford compounds 1 and 7, and their structures were determined by various spectroscopic analyses. These compounds were also evaluated for anti-HIV activity, thus expanding insights into the structure-activity relationships for MDOs., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aims: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients., Methods: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients)., Results: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online., Conclusions: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country., Impact and Implications: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

In paralytic shellfish toxin-producing dinoflagellates, intracellular levels of saxitoxin and its analogues (STXs) are controlled by a balance between degradation and biosynthesis in response to marine environmental fluctuations and stresses. The purpose of this study was to demonstrate the utility of statistical analysis of in vivo labeling data for the dynamic analysis of variations in toxin production under stress. A toxic strain of the dinoflagellate Alexandrium pacificum (Group IV) was cultured in colchicine-containing 15 N-labeled sodium nitrate-medium and metabolite levels were analyzed over time by liquid chromatography-mass spectrometry. Quantitative values of all isotopomers of precursor amino acids, biosynthetic intermediates, and major STXs were subjected to statistical analysis. The decrease of the nitrogen incorporation rates for all compounds suggested that colchicine decreased nitrate assimilation upstream of glutamate biosynthesis. In colchicine-treated cultures, the per-cell content of total STX analogues did not change significantly over time; however, the production rate of each pathway varied greatly. De novo STX biosynthesis was decreased by colchicine until Day 3, while the salvage pathway was not. Subsequently, biosynthesis by both pathways was enhanced. This analysis of dynamic metabolism provides new insights into the complex mechanisms regulating STX metabolism in dinoflagellates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Obstructive colitis (OC) is a risk factor of anastomotic leakage in colorectal cancer resection. We aimed to clarify the relationship between the severity of OC and clinicopathological findings and to detect predictive factors of OC., Methods: We retrospectively reviewed 43 cases of colectomy after self-expandable metallic stent placement for left-sided colorectal cancer. Preoperative diagnosis of OC was made by multiple modalities (initial computed tomography (CT), presurgical CT, and colonoscopy). We classified OC macroscopically in resected specimens into five groups (Grade 0: none, 1: mild [mild edema], 2: moderate [severe edema, redness, erosion], 3: severe [ulceration, bleeding], 4: very severe [necrosis, perforation]), and investigated the relationship between the preoperative assessment, surgical findings and the severity of OC., Results: OC of Grade 2 or more (53.5%) was significantly correlated with severe edema in initial CT. There was no significant correlation between OC and anastomosis rate. The creation of covering stoma was significantly higher in the Grade 2 or more OC group. No leakage was observed in either group., Conclusions: Initial CT may be most useful for prediction of OC. It is important to make a preoperative diagnosis of OC by combining multiple modalities, which enables to determine the appropriate location for resection, anastomosis, and construction of a covering stoma., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

When assessing the risk from an underground environment that is contaminated by radioactive nuclides and hazardous chemicals and planning for remediation, the contaminant plume distribution and the associated uncertainty from measured data should be estimated accurately. While the release history of the contaminant plume may be unknown, the extent of the plume caused by a known source and the associated uncertainty can be calculated inversely from the concentration data using a geostatistical method that accounts for the temporal correlation of its release history and groundwater flow modeling. However, the preceding geostatistical approaches have three drawbacks: (1) no applications of the three-dimensional plume estimation using concentration data from multiple depths in real situations, (2) no constraints for the estimation of the plume distribution, which can yield negative concentration and large uncertainties, and (3) few applications to actual cases with multiple contaminants. To address these problems, the non-negativity constraint using Gibbs sampling was incorporated into the geostatistical method with groundwater flow modeling for contaminant plume estimation. This method was then tested on groundwater contamination in the Gloucester landfill in Ontario, Canada, using three-dimensional contaminant transport model and concentration data from multiple depths. The method was applied to three water soluble organic contaminants: 1,4-dioxane, tetrahydrofuran, and diethyl ether. The effectiveness of the proposed method was verified by the general agreement of the calculated plume distributions of the three contaminants with concentration data from 66 points in 1982 (linear correlation coefficient of about 0.7). In particular, the reproduced peak of 1,4-dioxane corresponding to the large disposal in 1978 was more accurate than the result of preceding minimum relative entropy-based studies. The same peak also appeared in the tetrahydrofuran and diethyl ether distributions approximately within the range of the retardation factor derived from the fraction of organic carbon., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to examine the clinical and histopathologic effects of neoadjuvant intra-arterial chemoradiotherapy (IACRT) using cisplatin in combination with oral S-1 (tegafur/gimeracil/oteracil potassium) on stage III and IV oral squamous cell carcinoma., Study Design: Thirty patients received infusions of superselective intra-arterial cisplatin 60 mg/m 2 by the Seldinger method and conventional external beam radiotherapy (total 40 Gy) combined with oral S-1 on the day of irradiation. Curative surgery and neck dissection were performed 4 to 6 weeks after IACRT. The clinical response of the primary lesion was evaluated approximately 4 weeks after IACRT. The surgically resected specimens were examined for histologic features according to the grading system for histologic evaluation and for residual tumor grade (RGrades)., Results: Histopathologic evaluation of the therapeutic effect was grade 2 in 10 patients and grade 3 in 16 patients. According to the distribution of RGrades, the remaining tumor cells were mostly in the central area of the primary lesion, as seen in 24 patients., Conclusions: These findings indicate that neoadjuvant IACRT with cisplatin and oral S-1 was an effective treatment, suggesting the possibility of reducing the extent of curative surgery based on RGrades., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: HBV causes hepatocellular carcinoma (HCC). While it was recently shown that the ability of HBV X protein (HBx) to impair the Smc5/6 (structural maintenance of chromosome 5/6) complex is important for viral transcription, HBx is also a potent driver of HCC. However, the mechanism by which HBx expression induces hepatocarcinogenesis is unclear., Methods: Degradation of the Smc5/6 complex and accumulation of DNA damage were observed in both in vivo and in vitro HBV infection models. Rescue experiments were performed using nitazoxanide (NTZ), which inhibits degradation of the Smc5/6 complex by HBx., Results: HBx-triggered degradation of the Smc5/6 complex causes impaired homologous recombination (HR) repair of DNA double-strand breaks (DSBs), leading to cellular transformation. We found that DNA damage accumulated in the liver tissue of HBV-infected humanized chimeric mice, HBx-transgenic mice, and human tissues. HBx suppressed the HR repair of DSBs, including that induced by the CRISPR-Cas9 system, in an Smc5/6-dependent manner, which was rescued by restoring the Smc5/6 complex. NTZ restored HR repair in, and colony formation by, HBx-expressing cells., Conclusions: Degradation of the Smc5/6 complex by HBx increases viral transcription and promotes cellular transformation by impairing HR repair of DSBs., Lay Summary: The hepatitis B virus expresses a regulatory protein called HBV X protein (or HBx). This protein degrades the Smc5/6 complex in human hepatocytes, which is essential for viral replication. We found that this process also plays a key role in the accumulation of DNA damage, which contributes to HBx-mediated tumorigenesis., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Twenty-five steroidal glycosides including eight undescribed compounds which were named as polygonatumosides H-O, were isolated from the 70 % EtOH extract of rhizomes of Polygonatum odoratum (Mill.) Druce (Asparagaceae). Their structures were elucidated by extensive spectroscopic analyses and chemical methods. The isolated compounds were evaluated cytotoxicity against three human cancer cell lines: human non-small cell lung cancer (A549), human epithelial colorectal adenocarcinoma (Caco2), and human hepatocellular carcinoma (HepG2) cells. Five compounds showed cytotoxicity against these cell lines with IC 50 values in the range of 1.7-30.8 μM., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Recent studies have revealed the pivotal role of complement activation in the pathogenesis of antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). This study investigated the clinicopathologic and prognostic significance of glomerular C3 deposition in the renal histopathology of patients with ANCA-GN., Methods: We retrospectively identified 142 patients with ANCA-GN from 6 hospitals in Japan (2004-2020). C3 deposition was defined as C3 staining ≥1+ on a scale of 0 to 2+ using direct immunofluorescence (IF). The primary composite end points included a 30% reduction in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), and death. We compared clinicopathologic features and long-term outcomes between patients with and without C3 deposition., Results: C3 deposition was observed in 56 of 142 kidney biopsy samples (39.4%). Patients with C3 deposition had a lower serum C3 level ( P  = 0.002). During a median follow-up of 2.9 (interquartile range: 0.2-5.7) years, 69 events occurred and the cumulative event-free survival rate at 5 years was significantly lower in the C3-positive group than in the C3-negative group (log-rank: P  = 0.002). In multivariable analysis, C3 deposition was significantly associated with the composite end points after adjusting for age, sex, baseline eGFR, serum C3 level, treatment, and the percentage of normal glomerulus, cellular crescents, global sclerosis, and interstitial damage (adjusted hazard ratio [HR] = 2.02, 95% confidence interval: 1.20-3.40, P  = 0.008)., Conclusion: This study revealed that ANCA-GN patients with glomerular C3 deposition on IF had worse renal and overall survival rates., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background & Aims: This study was conducted to investigate the nutritional status and longitudinal dietary intake during the course of chemotherapy, and their relationships with the survival in patients with unresectable pancreatic cancer., Methods: A prospective cohort study was conducted in 38 patients with unresectable pancreatic cancer receiving chemotherapy between January 2018 and November 2019. Subjective global assessment was used to assess the nutritional status, and the dietary intake was assessed monthly, for up to 12 months, using a brief self-administered diet history questionnaire. The primary outcome was overall survival, and the secondary outcome was progression-free survival. Cox regression analysis was performed to identify independent prognostic factors., Results: Moderate or severe malnutrition was found in 34.2% of the participants. Daily protein intake was significantly higher in the survivor group than in the deceased group at one month after the initiation of chemotherapy (1.4 ± 0.7 g/kg/day vs. 0.9 ± 0.5 g/kg/day, p = 0.019), while the baseline nutritional intakes were similar between the two groups. Univariate analysis identified weight loss >3.5%, energy intake <25 kcal/kg/day, protein intake <1.1 g/kg/day, and malnutrition as possible poor prognostic factors. Multivariate analysis identified protein intake <1.1 g/kg/day (hazard ratio [HR]: 9.03, 95%CI: 1.45-56.32, p = 0.018) as an independent poor prognostic factor., Conclusions: Insufficient protein intake was identified as an independent poor prognostic factor in patients with unresectable pancreatic cancer receiving chemotherapy. Improving the dietary protein intake could be a useful therapeutic approach in patients with advanced pancreatic cancer receiving chemotherapy., Competing Interests: Conflicts of interest YN have received grants or contracts from Taiho Pharmaceutical, Yakult Honsha, Eisai, Sumitomo Dainippon Pharma. They had no role in designing the study, data collection or analysis, interpretation of the data, or writing the manuscript., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

SxtA is the enzyme that catalyses the first step of saxitoxin biosynthesis. We developed an immunofluorescent method to detect SxtA using antibodies against SxtA peptides. Confocal microscopy revealed the presence of abundant, sub-cellularly localized signal in cells of toxic species and its absence in non-toxic species. Co-localization of SxtA with Rubisco II and ultra-structural observation by transmission electron microscopy strongly suggested the association of SxtA with chloroplasts. We also characterized a non-toxic sub-clone of Alexandrium catenella (Group I) to elucidate the mutation responsible for its loss of toxicity. Although sxtA4 gene copy number was indistinguishable in toxic and non-toxic sub-clones, mRNA and protein expression were significantly reduced in the non-toxic sub-clone and we uncovered sequence variation at the 3' untranslated region (3'UTR) of sxtA4 mRNA. We propose that differences in the sxtA4 mRNA 3'UTR lead to down-regulation of STX biosynthesis post-transcriptionally, thereby explaining the differences in toxicity amongst different A. catenella (Group I) sub-clones., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: End-stage renal disease is associated with an increased risk of atherosclerotic vascular disease (AVD). We investigated whether low plantar skin perfusion pressure (SPP), a useful indicator of peripheral arterial disease (PAD), predicts systemic AVD events and mortality in outpatients undergoing maintenance haemodialysis (HD)., Methods: A total of 206 HD patients were enrolled and followed for 5 years. They were divided into 3 groups according to measured SPP: group 1 (G1), SPP >70 mmHg (n = 123); G2, SPP 50-70 mmHg (n = 61); and G3, SPP <50 mmHg (n = 22)., Results: During the follow-up period (median, 4.2 years), 56 AVD events (27.2%) and 68 deaths (33.0%) occurred. In G1, G2, and G3, the event-free survival rates were 74%, 55% and 19%, respectively, for AVD events (p < 0.01) and 73%, 54% and 26%, respectively, for mortality (p < 0.01). A Cox multivariate analysis showed that lower SPP was an independent predictor for AVD events [hazard ratio (HR) 3.12, 95% confidence interval (CI) 1.45-6.77, p < 0.01 for G3 vs. G1] and mortality (HR 3.06, 95% CI 1.57-5.98, p < 0.01 for G3 vs. G1). Furthermore, the addition of the SPP value to a model with established risk factors improved the predictability of increasing the net reclassification improvement (NRI; 0.463, p < 0.01) and integrated discrimination improvement (IDI; 0.039, p < 0.01) for AVD events. Similar results were obtained for mortality., Conclusions: Low plantar SPP can stratify risk and improve the predictability of both systemic AVD events and mortality in the maintenance HD population., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Naldemedine is a peripherally acting μ-opioid receptor antagonists (PAMORAs) indicated for the treatment of opioid-induced constipation (OIC). We investigated the preventive effect of naldemedine on morphine-induced nausea and vomiting in ferrets and conducted a pharmacokinetic/pharmacodynamic (PK/PD) analysis., Main Methods: The antiemetic effect of naldemedine was evaluated as the frequency and time of retching (rhythmic abdominal contractile motion) and vomiting (throwing up vomit or similar reactions) caused by morphine in ferrets. After a single oral administration of naldemedine to ferrets, the plasma concentrations of naldemedine and morphine were measured by liquid chromatography-tandem mass spectrometry., Key Findings: Naldemedine showed a potent and dose-dependent anti-emetic effects against morphine-induced emetic responses, for up to 6 h. The dose of naldemedine that produced half the maximal effect (ED 50 ) value for anti-emetic effect of naldemedine in the morphine-treated ferrets was 0.033 mg/kg. The PK/PD analysis revealed that the antiemetic effect was related to the plasma naldemedine concentration, with a half maximal effective concentration that produces half the maximal effect (EC 50 ) of 3.51 ng/mL. The plasma concentration producing an antiemetic effect was almost 200-fold lower than that inducing an anti-analgesic effect in rats., Significance: Naldemedine showed potent inhibition of morphine-induced vomiting for up to 6 h after dosing. These data suggest that naldemedine possesses antiemetic properties and could be effective against opioid-induced nausea and vomiting (OINV)., Competing Interests: Declaration of competing interest Some of the authors (TK, KK, MH, TM) are employee of Shionogi & Co., Ltd., a manufacture of naldemedine. TS has received funding from Shionogi & Co., Ltd., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the efficient suppression of hepatitis B virus (HBV) replication by nucelos(t)ide analogs, HBV RNA expression usually continues even during nucleots(t)ide analog therapy because episomal covalently closed circular DNA (ccDNA), which is the template for HBV RNA transcription, cannot be eliminated. Here, we found that the common sequences of all HBV RNAs and that encoding the X protein (HBx) have similarities with the sequences of a host cellular microRNA (miRNA), miR129-5p. HBx inhibits miR129-5p function, resulting in increased expression of ZBTB20, a target gene of miR129-5p. ZBTB20 activates transcription and increases cell-surface epidermal growth factor receptor (EGFR) levels, promoting the cell growth rate, and this effect was reversed through ZBTB20 knockdown. mir129-5p levels in Ago2-containing complexes were reduced by expression of HBx, suggesting that the viral RNA sequestered miR129-5p from Ago2-containing complexes. These results indicate the possibility that HBV RNA may maintain pathogenicity even through nucleos(t)ide analog therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Obesity-related glomerulopathy (ORG) is a slowly progressive kidney disease occurring in association with obesity. It is characterized histopathologically by glomerulomegaly, likely caused by single-nephron hyperfiltration that has not been demonstrated in humans because of technical difficulty in measuring single-nephron glomerular filtration rate (SNGFR) in the clinical setting., Methods: Total glomerular number per kidney, with or without global glomerulosclerosis, was estimated by the combination of cortical volume assessment via unenhanced computed tomography and biopsy-based stereology. Mean glomerular volume was calculated from the measured area of glomerular tufts. Both SNGFR and single-nephron urinary protein excretion (SNUPE) were estimated by dividing values for estimated glomerular filtration rate and urinary protein excretion by the number of nonsclerotic glomeruli. Living kidney donors were used as healthy controls., Results: A total of 48 ORG patients with average nonsclerotic glomerular numbers of 456,000 ± 235,000 per kidney were included. The values for SNGFR in ORG patients with chronic kidney disease (CKD) stages 1 and 2 were higher than for nonobese and obese controls (97 ± 43 vs. 59 ± 21 vs. 64 ± 21 nl/min, respectively, P  = 0.001). Nonsclerotic glomerular number decreased with advancing stages of renal functional impairment. The presence of ORG with more advanced CKD stages was associated with lower SNGFR and marked elevation in SNUPE levels, with no difference in the mean glomerular volume between the stages., Conclusions: These results provide functional evidence for single-nephron hyperfiltration in patients with ORG, and identify compensatory failure to maintain effective SNGFR as a feature of advanced-stage ORG., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background: Stent thrombosis (ST) is a rare but serious complication after deployment of a drug-eluting stent. The features of ST after implantation of an everolimus-eluting stent (EES) have not been fully elucidated., Methods: A comprehensive survey of real-world adverse event reporting with conditions for approval under the Pharmaceuticals and Medical Devices Act identified 490 cases of ST with EES. A total of 370 patients with definite ST after EES implantation [287 with early (E)ST (within 30 days), 54 with late (L)ST (31-365 days), and 29 with very late (VL)ST (over 1 year)] were divided into an EST group and an LST/VLST group to compare the patients and lesions characteristics., Results: The frequency of patients with hemodialysis and in-stent restenosis (ISR) lesions were significantly higher in the LST/VLST group than in the EST group (hemodialysis, 22.9% vs 2.7%, p = 0.0001; ISR lesions, 25.9% vs 9.4%, p = 0.0001). Characteristic demographic factors for LST/VLST versus EST identified by multivariable model were hemodialysis and ISR lesions (hemodialysis: odds ratio 7.348, 95% confidence interval 2.458-21.968, p = 0.0001; ISR lesions: odds ratio, 2.490, 95% confidence interval 1.100-5.638, p = 0.027). The in-hospital death rates from ST were not significantly different between the EST group and the LST/VLST group (EST, 15% vs LST/VLST, 21.7%, p = 0.147)., Conclusions: Patient-related and lesion-related characteristics were significantly different between EST and LST/VLST. Data collection from adverse event reporting could be a helpful strategy for evaluation of this serious but rare complication., (Copyright © 2019. Published by Elsevier Ltd.)

Three-dimension quantitative structure activity relationship (3D-QSAR) was one of the major statistical techniques to investigate the correlation of biological activity with structural properties of candidate molecules, and the accuracy of statistic greatly depended on molecular alignment methodology. Exhaustive conformational search and successful conformational superposition could extremely improve the predictive accuracy of QSAR modeling. In this work, we proposed a solution to optimize QSAR prediction by multiple-conformational alignment methods, with a set of 40 flexible PTP1B inhibitors as case study. Three different molecular alignment methods were used for the development of 3D-QSAR models listed as following: (1) docking-based alignment (DBA); (2) pharmacophore-based alignment (PBA) and (3) co-crystallized conformer-based alignment (CCBA). Among these three alignments, it was indicated that the CCBA was the best and the fastest strategy in 3D-QSAR development, with the square correlation coefficient (r 2 ) and cross-validated squared correlation coefficient (q 2 ) of comparative molecular field analysis (CoMFA) were 0.992 and 0.694; the r 2 and q 2 of comparative molecular similarity indices analysis (CoMSIA) were 0.972 and 0.603, respectively. The alignment methodologies used here not only generated a robust QSAR model with useful molecular field contour maps for designing novel PTP1B inhibitors, but also provided a solution for constructing accurate 3D-QSAR model for various disease targets. Undoubtedly, such attempt in QSAR analysis would greatly help us to understand essential structural features of inhibitors required by its target, and so as to discover more promising chemical derivatives., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Diabetes is one of the metabolic disorders in the world. It is the prime reason of mortality and morbidity owing to hyperglycemia which is link with numerus obstacles. Artemisia argyi is commonly used as an ingredient in healthy foods as well as an herbal medicine in Asian countries. The present research aims to evaluate the hypoglycemic effects of A. argyi and reveal its the potentially active constituents. The chemical composition was identified by HPLC-DAD-Q-TOF-MS, and fractionation was performed by extraction. The fractions were assessed by the blood glucose level, oral glucose tolerance and small intestinal α-glucosidase inhibitory tests, and an analysis of the total phenolic content (TPC), antioxidant and α-glucosidase inhibitory activities. In our efforts to characterize the compounds responsible for hypoglycemic effect, bioactivity-guided fraction of the MeOH extract and chemical investigation of its active EtOAc fraction led to the successful identification of caffeoylquinic acids, which were elucidated by molecular docking, using the crystal structure of S. cerevisiae isomaltase (PD code: 3AXI). In summary, this bio-guided search revealed that caffeoylquinic acids from A. argyi as potential active constituents displayed with hypoglycemic activity, which provided a basis for further study of pharmacological activity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Liver diseases affect millions of people worldwide. In most developed countries, the incidence of viral hepatitis is waning as a result of modern advances in disease prevention, diagnosis, and therapies. Expanded programmes for systematic immunisation against hepatitis B virus have also significantly brought down the number of new cases in many countries, including China. In contrast, with the improvement in living standards, the prevalence of metabolic liver diseases including non-alcoholic fatty liver disease and alcohol-related liver disease is set to rise, ultimately leading to more cases of end-stage liver diseases (liver failure, cirrhosis, and liver cancer). Over the past 30 years, visionary governments of major nations have provided strong incentives for basic/clinical research, vaccination programmes, and drug discovery and development in the field of hepatology. To get rid of her unflattering title as the "leader in liver diseases", China has also made a serious effort to initiate nationwide preventive measures for liver diseases, global partnerships, and mentoring programmes for young hepatologists. Instrumental to such progress is the continuous support of the National Natural Science Foundation of China (NSFC), which has helped hepatology to thrive in virtually all research directions within the country. In this article, we seek to provide stimulating glimpses into the evolving liver disease epidemiology, institutional research profiles, funding landscape, and drug development trends in China, with an attempt to compare her status and achievements with those of the United States, European countries, and Japan., (Copyright © 2019 European Association for the Study of the Liver. All rights reserved.)

Selective estrogen receptor modulators (SERMs) act as either agonist or antagonist of estrogen receptor (ER) in a tissue selective manner and have been used in several diseases such as breast cancer, postmenopausal syndrome, osteoporosis, and cardiovascular diseases. However, current SERMs may also increase the risk of serious side effects and trigger drug resistance. Herein, a screening program, that was designed to search for novel SERMs, resulted in the identification of a series of 2-arylbenzofuran-containing compounds that are ligands for ERα, when applying the Gaussia-luciferase reporter assay. One of these compounds, 10-dehydrooxyglycyuralin E (T9) was chemically synthesized. T9 showed anti-estrogenic/proliferative activity in ERα-positive breast cancer cells. Pretreatment of T9 prevented the mRNA expression of GREB1, which is an estrogen response gene. Furthermore, by an in silico docking simulation study we demonstrated that T9 showed interactions directly to ERα. Taken together, these results demonstrated that T9 is a candidate of SERMs and a useful seed compound for the foundation of the selective activity of SERMs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bacterial peritonitis, an infection of the ascitic fluid, can be classified etiologically as spontaneous or secondary bacterial peritonitis. The former is mainly caused by portal hypertension and its subsequent effects, whereas the latter is caused by the direct dissemination of bacteria into the peritoneal cavity. Previous reports have described some distinguishing features of these two entities. Here, we report the first known case of bacterial peritonitis with Aeromonas hydrophilia and Escherichia coli in a patient with malignant ascites associated with pancreatic carcinoma who exhibited features of both spontaneous and secondary peritonitis. Our report suggests that clinicians should also consider bacterial peritonitis in patients with malignant ascites who present with ostensibly cancer-related symptoms., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Tripartite motif family-like 2 (TRIML2), a member of the TRIM proteins family, is closely related to Alzheimer's disease, however, no studies of TRIML2 have been published in the cancer research literature. In the current study, we investigated the expression level of TRIML2 and its molecular mechanisms in human oral squamous cell carcinoma (OSCC); reverse transcriptase-quantitative polymerase chain reaction, immunoblot analysis, and immunohistochemistry showed that TRIML2 is up-regulated significantly in OSCCs in vitro and in vivo. TRIML2 knockdown OSCC cells showed decreased cellular proliferation by cell-cycle arrest at G1 phase that resulted from down-regulation of CDK4, CDK6, and cyclin D1 and up-regulation of p21 Cip1 and p27 Kip1 . Surprisingly, resveratrol, a polyphenol, led to not only down-regulation of TRIML2 but also cell-cycle arrest at G1 phase similar to TRIML2 knockdown experiments. Taken together, we concluded that TRIML2 might play a significant role in tumoral growth and that resveratrol may be a new drug for treating OSCC by interfering with TRIML2 function., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background & Aims: It remains controversial whether direct-acting antivirals (DAAs) accelerate the recurrence of hepatitis C-related hepatocellular carcinoma (HCC) after curative therapy. This study aimed to evaluate HCC recurrence after DAA treatment of chronic hepatitis C., Methods: We enrolled patients with a history of successful radiofrequency ablation treatment for hepatitis C-related HCC who received antiviral therapy with DAAs (DAA group: 147 patients) or with interferon (IFN)-based therapy (IFN group: 156 patients). We assessed HCC recurrence rates from the initiation of antiviral therapy using the Kaplan-Meier method and evaluated risk factors for HCC recurrence by multivariate Cox proportional hazard regression analysis. The recurrence pattern was categorized as follows: intrahepatic recurrence with a single tumor <2 cm (stage 0), a single tumor or up to 3 tumors ≤3 cm (stage A), multinodular (stage B), and extrahepatic metastasis or macrovascular invasion (stage C)., Results: The recurrence rates at 1 and 2 years were 39% and 61% in the IFN group and 39% and 60% in the DAA group, respectively (p = 0.43). Multivariate analysis identified higher lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, a history of multiple HCC treatments, and a shorter interval between HCC treatment and initiation of antiviral therapy as independent risk factors for HCC recurrence. HCC recurrence in stage 0, A, B, and C was found in 56 (41%), 60 (44%), 19 (14%), and 1 (0.7%) patients in the IFN group and 35 (44%), 32 (40%), 11 (14%), and 2 (2.5%) patients in the DAA group, respectively (p = 0.70)., Conclusions: HCC recurrence rates and patterns after initiation of antiviral therapy did not differ between patients who received IFN-based therapy and DAA therapy., Lay Summary: We detected no significant difference in early hepatocellular carcinoma (HCC) recurrence rates and patterns between patients who received interferon-based and direct-acting antiviral therapy after HCC treatment. High lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, short recurrence-free period, and a history of multiple HCC treatments were independent risk factors for early HCC recurrence after the initiation of antiviral therapy., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Candida lusitaniae is an uncommon cause of candidiasis in humans. Ocular manifestations of C. lusitaniae infection have not been reported. C. lusitaniae is either intrinsically resistant to amphotericin B or can acquire such resistance. We describe a case of bilateral endophthalmitis due to C. lusitaniae bloodstream infection in a liver transplant patient with rectal cancer. The patient suffered fungemia and endophthalmitis and was treated with liposomal amphotericin B. The isolate was identified as C. lusitaniae by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, the system based on biochemical tests, and sequencing of the internal transcribed spacer region. The minimal inhibitory concentrations were 0.06 μg/mL for amphotericin B and 2.0 μg/mL for fluconazole. Repeat blood cultures were negative and the endophthalmitis improved following treatment with liposomal amphotericin B. However, the treatment was changed to fluconazole due to nephrotoxicity. No recurrence occurred after completion of treatment., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Strains of a dinoflagellate from the Salton Sea, previously identified as Protoceratium reticulatum and yessotoxin producing, have been reexamined morphologically and genetically and Pentaplacodinium saltonense n. gen. et sp. is erected to accommodate this species. Pentaplacodinium saltonense differs from Protoceratium reticulatum (Claparède et Lachmann 1859) Bütschli 1885 in the number of precingular plates (five vs. six), cingular displacement (two widths vs. one), and distinct cyst morphology. Incubation experiments (excystment and encystment) show that the resting cyst of Pentaplacodinium saltonense is morphologically most similar to the cyst-defined species Operculodinium israelianum (Rossignol, 1962) Wall (1967) and O. psilatum Wall (1967). Collections of comparative material from around the globe (including Protoceratium reticulatum and the genus Ceratocorys) and single cell PCR were used to clarify molecular phylogenies. Variable regions in the LSU (three new sequences), SSU (12 new sequences) and intergenic ITS 1-2 (14 new sequences) were obtained. These show that Pentaplacodinium saltonense and Protoceratium reticulatum form two distinct clades. Pentaplacodinium saltonense forms a monophyletic clade with several unidentified strains from Malaysia. LSU and SSU rDNA sequences of three species of Ceratocorys (C. armata, C. gourreti, C. horrida) from the Mediterranean and several other unidentified strains from Malaysia form a well-supported sister clade. The unique phylogenetic position of an unidentified strain from Hawaii is also documented and requires further examination. In addition, based on the V9 SSU topology (bootstrap values >80%), specimens from Elands Bay (South Africa), originally described as Gonyaulax grindleyi by Reinecke (1967), cluster with Protoceratium reticulatum. The known range of Pentaplacodinium saltonense is tropical to subtropical, and its cyst is recorded as a fossil in upper Cenozoic sediments. Protoceratium reticulatum and Pentaplacodinium saltonense seem to inhabit different niches: motile stages of these dinoflagellates have not been found in the same plankton sample., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Alterations in glomerular filtration can considerably influence the dynamics and functions of the Bowman capsule. Despite the potentially important role in maintaining normal renal functions, few studies have focused on Bowman capsule volume in normal human kidneys., Methods: We analyzed specimens from biopsies performed 1 hour after kidney transplantation from living donors without apparent renal disease. The measurements of all cross-sectional areas of the Bowman capsules and glomerular capillaries were used to estimate the mean Bowman capsule volume (BV) and glomerular capillary volume (GV) in each subject. The G/B ratio was defined as the ratio of GV to BV. The morphometric findings were examined in relation to the clinical findings in donors just before kidney transplantation., Results: We analyzed 37 adults with a mean creatinine clearance of 111 ml/min. The mean BV and GV of these subjects were 6.10 ± 2.46 × 10 6 μm 3 and 3.83 ± 1.52 × 10 6 μm 3 , respectively. Both the BV and GV varied up to 6-fold and were significantly higher in elderly, obese, or hypertensive subjects in comparison to nonelderly, nonobese, or normotensive subjects, whereas the renal function of each subgroup was similar. The G/B ratio (0.63 ± 0.05) was unaffected, and BV and GV were strongly correlated regardless of these clinical factors ( r  = 0.980 [95% confidence interval = 0.961-0.990], P  < 0.001)., Conclusion: In the normal adult kidney, there may be an optimal BV to GV ratio for maintaining effective filtration in a variety of clinical situations, including advanced age, obesity, and hypertension.

Purpose: Precise genetic diagnosis of inherited bone marrow failure syndromes (IBMFS), a heterogeneous group of genetic disorders, is challenging but essential for precise clinical decision making., Methods: We analyzed 121 IBMFS patients using a targeted sequencing covering 184 associated genes and 250 IBMFS patients using whole-exome sequencing (WES)., Results: We achieved successful genetic diagnoses for 53 of 121 patients (44%) using targeted sequencing and for 68 of 250 patients (27%) using WES. In the majority of cases (targeted sequencing: 45/53, 85%; WES: 63/68, 93%), the detected variants were concordant with, and therefore supported, the clinical diagnoses. However, in the remaining 13 cases (8 patients by target sequencing and 5 patients by WES), the clinical diagnoses were incompatible with the detected variants., Conclusion: Our approach utilizing targeted sequencing and WES achieved satisfactory diagnostic rates and supported the efficacy of massive parallel sequencing as a diagnostic tool for IBMFS.Genet Med advance online publication 19 January 2017.

Background & Aims: Primary biliary cholangitis (PBC) is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. CD4 + T cells play a pivotal role in immunological dysfunction observed in PBC, and therefore, microRNA (miRNA) and mRNA expression were analysed in CD4 + T cells, to investigate PBC pathogenesis and identify novel therapeutic targets., Methods: Integral miRNA and mRNA analysis of 14 PBC patients and ten healthy controls was carried out using microarray and quantitative real-time polymerase chain reaction (qRT-PCR), with gene set enrichment analysis. The functional analyses of miRNA were then assessed using reporter and miRNA-overexpression assays., Results: The integral analysis of miRNA and mRNA identified four significantly downregulated miRNAs (miR-181a, -181b, -374b, and -425) related to the T cell receptor (TCR) signalling pathway in CD4 + T cells of PBC. N-Ras, a regulator of the TCR signalling pathway, was found to be targeted by all four identified miRNAs. In addition, in vitro assays confirmed that decreased miR-425 strongly induced inflammatory cytokines (interleukin [IL]-2 and interferon [IFN]-γ) via N-Ras upregulation in the TCR signalling pathway., Conclusion: The decreased expression of four miRNAs that dysregulate TCR signalling in PBC CD4 + T cells was identified. miR-425 was demonstrated as an inflammatory regulator of PBC via N-Ras upregulation. Therefore, the restoration of decreased miR-425 or the suppression of N-Ras may be a promising immunotherapeutic strategy against PBC., Lay Summary: Primary biliary cholangitis (PBC) is an autoimmune liver disease, but the causes are unknown. MicroRNAs are molecules known to regulate biological signals. In this study, four microRNAs were identified as being decreased in PBC patients, leading to activation of T cell receptor signalling pathways, involved in inflammation. One particular target, N-Ras, could be an attractive and novel immunotherapeutic option for PBC., Transcript Profiling: Microarray data are deposited in GEO (GEO accession: GSE93172)., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a prototypical NKG2D ligand. Because immune cells, such as natural killer (NK) cells, recognize virally infected or transformed cells and eliminate them through the interaction between NKG2D receptors on NK cells and NKG2D ligands on pathogenic cells, MICA expression levels are associated with NK cell-mediated immunity. Here, we report that an engineered clustered regularly interspaced short palindromic repeats-Cas9-related complex targeting MICA gene promoter sequences activates transcription of the MICA gene from its endogenous locus. Inhibiting microRNA function, which targets the 3' untranslated region of the MICA gene, enhances this activation. These results demonstrate that the combination of Cas9-based transcriptional activators and simultaneous modulation of microRNA function may be a powerful tool for enhancing MICA protein expression and efficient anti-pathogenic cell immunity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Nonocclusive mesenteric ischemia (NOMI) is induced by intestinal vasospasm without thromboembolic occlusion and is associated with high morbidity and mortality. The estimated overall incidence of autopsy-verified fatal NOMI is 2.0 cases/100,000 person-years; however, no pediatric or adolescent cases have yet been reported. An 18-year-old female was diagnosed with B-cell precursor acute lymphoblastic leukemia at the age of 10 years. Our patient received three allogeneic hematopoietic stem cell transplantations but experienced hematological relapse after each. She received combination therapy of prednisolone, L-asparaginase, vincristine, and bortezomib after the third relapse. On Day 16 after the initiation of chemotherapy, she developed NOMI; therefore, we performed a right-sided hemicolectomy on Day 27. Nonocclusive mesenteric ischemia should be considered during the differential diagnosis of intestinal complications after chemotherapy, even in pediatric and adolescent patients., (Copyright © 2014. Published by Elsevier B.V.)

Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disorder that includes two distinct disease categories: ulcerative colitis and Crohn's disease. Epidemiological, genetic, and experimental studies have revealed many important aspects of IBD. Genetic susceptibility, inappropriate immune responses, environmental changes, and intestinal microbiota are all associated with the development of IBD. However, the exact mechanisms of the disease and the interactions among these pathogenic factors are largely unknown. Here we introduce recent findings from experimental colitis models that investigated the interactions between host genetic susceptibility and gut microbiota. In addition, we discuss new strategies for the treatment of IBD, focusing on the complex interactions between microbiota and host epithelial and immune cells., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To examine the efficacy of third-line Helicobacter pylori eradication therapy with esomeprazole, amoxicillin, and sitafloxacin for patients with clarithromycin- and metronidazole-based first- and second-line therapy failure., Methods: Thirty patients with first- and second-line H. pylori eradication failure were treated prospectively with esomeprazole 20mg twice daily, amoxicillin 750mg twice daily, and sitafloxacin 100mg twice daily for 7 days. After 8-12 weeks, the outcome of eradication therapy was assessed by 13 C-urea breath test or stool antigen test., Results: All 30 patients completed the study. Eradication was successful in 25 patients and the eradication rate was 83% in the intention-to-treat and per-protocol analyses. No specific or significant adverse events were recorded in the 30 patients. Patient characteristics such as sex, body mass index, and pepsinogen I/II ratio did not differ between patients who were treated successfully and those who were not treated successfully., Conclusions: Third-line H. pylori eradication therapy with esomeprazole, amoxicillin, and sitafloxacin is as safe and effective as previously reported sitafloxacin-based triple therapy., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Twelve triterpenoid saponins, including seven compounds (i.e., armerosides A-G) hitherto unknown, were isolated from whole plants of Silene armeria. Their structures were established based on extensive spectroscopic analyses and chemical methods. From a biosynthetic perspective, C-23 oxidation of the sapogenin appears to be a key factor in the glycosylation pathway., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Obesity-related glomerulopathy is an established secondary glomerular disease that may occur in obese individuals with a body mass index (BMI) of ≥30 kg/m 2 . However, patients with moderate obesity (BMI ≤ 30 kg/m 2 ) may also develop this disease., Methods: A total of 20 patients with grade 1 obesity (25 ≤ BMI < 30 kg/m 2 ) with persistent proteinuria, without evidence of other renal diseases, were analyzed retrospectively. These patients were compared with 20 patients with grade 2 or higher obesity (BMI ≥ 30 kg/m 2 ) with persistent proteinuria. Biopsies of 31 kidney transplant donors as healthy controls were used to compare histologic parameters., Results: Similar to the grade 2 or higher obesity group, the grade 1 obesity group had a male predominance (85%) and showed a high incidence of hypertension (80%). Urinary protein excretion and renal outcome parameters were comparable between the groups. Patients with grade 1 obesity showed typical histologic features of obesity-related glomerulopathy: low glomerular density with glomerulomegaly. The glomerular density and mean glomerular volume in the grade 1 group, the grade 2 or higher group, and the kidney transplant donors with grade 1 obesity were 1.6 ± 0.8 versus 1.4 ± 0.6 versus 3.0 ± 1.1 (per mm 2 ) and 6.1 ± 2.1 versus 6.4 ± 1.6 versus 2.9 ± 0.8 (×10 6 μm 3 ), respectively., Discussion: A glomerulopathy similar to obesity-related glomerulopathy can occur in moderately obese individuals. Renal factor(s), such as low glomerular density, may thus underlie susceptibility to this disease entity as well as BMI.

Immune cells, such as natural killer (NK) cells, recognize virally infected and transformed cells, and eliminate them through the interaction between NKG2D receptors on NK cells and NKG2D ligands on pathogenic cells. Shedding of NKG2D ligands is thought to be a type of counter-mechanism employed by pathogenic cells to evade from NKG2D-mediated immune surveillance. MHC class I polypeptide-related sequence A (MICA) is a prototypical NKG2D ligand. We previously reported that, in soluble form, MICA expression levels are significantly associated with hepatitis virus-induced hepatocellular carcinoma. Here, we report a MICA shedding assay that utilizes membrane-bound MICA tagged at its N-terminus with a nano-luciferase reporter to quantify MICA shedding into culture media. Using this method, we screened a compound library and identified putative regulators of MICA shedding that have the potential to enhance the immune reaction by simultaneously increasing cell surface MICA levels and decreasing soluble MICA levels. This shedding assay may be useful for screening regulators of cell surface molecule shedding., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) using a fully-covered self-expandable metal stent (SEMS) is increasingly used as an alternative to failed endoscopic retrograde cholangiopancreatography. An EUS-CDS fistula can provide endoscopists with a new approach route for intrahepatic bile ducts. Here, we present successful placement of multiple SEMS for intrahepatic biliary obstruction via an EUS-CDS fistula., (Copyright © 2015 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

In mammalian livers, sexual dimorphisms are observed in tissue-specific functions and diseases such as hepatocellular carcinoma. We identified sex-dependent differentially methylated regions (S-DMRs) which had been previously been characterized as growth hormone- STAT5 dependent. In this study, we performed genome-wide screening and identified ten additional hypomethylated S-DMR gene regions in male livers. Of these S-DMRs, Uggt2 and Sarnp were hypomethylated in both male and female livers compared to brain and embryonic stem (ES) cells. Similarly, Adam2, Uggt2, and Scp2 were hypomethylated in female embryonic germ (EG) cells and not in male EG cells, indicating that these S-DMRs are liver-specific male hypo-S-DMRs. Interestingly, the five S-DMRs were free from STAT5 chromatin immunoprecipitation (ChIP) signals, suggesting that S-DMRs are independent of the growth hormone-STAT5-pathway. Instead, the DNA methylation statuses of the S-DMRs of Adam2, Snx29, Uggt2, Sarnp, and Rnpc3 genes were under the control of testosterone. Importantly, the hypomethylated S-DMRs of the Adam2 and Snx29 regions showed chromatin decondensation. Epigenetic factors could be responsible for the sexual dimorphisms in DNA methylation status and chromatin structure, as the expression of Dnmt1, Dnmt3b, and Tet2 genes was lower in male mice compared to female mice and TET2 expression recovered following orchidectomy by testosterone treatment. In conclusion, we identified novel male-specific hypomethylated S-DMRs that contribute to chromatin decondensation in the liver. S-DMRs were tissue-specific and the hypomethylation is testosterone-dependent., (Copyright © 2015. Published by Elsevier Inc.)

Background & Aims: Obesity defined by body mass index (BMI) significantly increases the risk of hepatocellular carcinoma (HCC). In contrast, not only obesity but also underweight is associated with poor prognosis in patients with HCC. Differences in body composition rather than BMI were suggested to be true determinants of prognosis. However, this hypothesis has not been demonstrated conclusively., Methods: We measured skeletal muscle index (SMI), mean muscle attenuation (MA), visceral adipose tissue index, subcutaneous adipose tissue index, and visceral to subcutaneous adipose tissue area ratios (VSR) via computed tomography in a large-scale retrospective cohort of 1257 patients with different stages of HCC, and comprehensively analyzed the impact of body composition on the prognoses., Results: Among five body composition components, low SMI (called sarcopenia), low MA (called intramuscular fat [IMF] deposition), and high VSR (called visceral adiposity) were significantly associated with mortality, independently of cancer stage or Child-Pugh class. A multivariate analysis revealed that sarcopenia (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.18-1.96; p=0.001), IMF deposition (HR, 1.34; 95% CI, 1.05-1.71; p=0.020), and visceral adiposity (HR, 1.35; 95% CI, 1.09-1.66; p=0.005) but not BMI were significant predictors of survival. The prevalence of poor prognostic body composition components was significantly higher in underweight and obese patients than in normal weight patients., Conclusions: Sarcopenia, IMF deposition, and visceral adiposity independently predict mortality in patients with HCC. Body composition rather than BMI is a major determinant of prognosis in patients with HCC., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)