Search

Reactive oxygen species impair the blood vessels, leading to the initiation of atherosclerosis, and migration and proliferation of vascular smooth muscle cells and neovascularization by endothelial cells of vasa vasorum are essential for atherosclerosis development. Obg-like ATPase 1 (OLA1), a negative regulator in cellular responses to oxidative stress, binds to breast cancer susceptibility gene 1 (BRCA1), which protects vascular endothelial and smooth muscle cells against reactive oxygen species. However, it is not known whether OLA1 is genetically correlated with atherosclerosis. Here, we conducted two independent population-based case-control studies to explore the effects of variants in

High-risk pregnancies, such as pregnancies with gestational diabetes mellitus (GDM), are becoming more common and as such, have become important public health issues worldwide. GDM increases the risks of macrosomia, premature infants, and preeclampsia. Although placental dysfunction, including fibrosis is associated with the development of GDM, factors that link these observations remain unknown. Prothymosin α (ProTα) is expressed in the placenta and is involved in cell proliferation and immunomodulation. It also plays an important role in insulin resistance and fibrosis. However, the role of ProTα in GDM is still unclear. In the present study, we found that fibrosis-related protein expressions, such as type I collagen (Col-1) were significantly increased in the placentae of ProTα transgenic mice. With elevated fibrosis-related protein expressions, placental weights significantly increased in GDM group. In addition, placental and circulating ProTα levels were significantly higher in patients with GDM (n=39), compared with the healthy group (n=102), and were positively correlated with Col-1 expression. Mice with streptozotocin (STZ)-induced GDM had increased ProTα, fasting blood glucose, Col-1, and placental weight, whereas plasma insulin levels were decreased. ProTα overexpression enhanced nuclear factor κB (NFκB) activation to increase fibrosis-related protein expressions in 3A-Sub-E trophoblasts, while treatment with an NFκB inhibitor reversed the effect of ProTα on fibrosis-related protein expressions. We further investigated whether ProTα is regulated by hyperglycemia-induced reactive oxygen species (ROS). In conclusion, ProTα increases the amount of placental connective tissue and thus contributes to the pathogenesis of placental fibrosis in GDM. Therefore, ProTα may be a novel therapeutic target for GDM.

Background & aims: Transarterial chemoembolization (TACE) is the standard of care for intermediate stage hepatocellular carcinoma (HCC) patients. Variceal bleeding is a life-threatening complication and may alter the initial treatment plan. This study was aimed to elucidate the risk factors for variceal bleeding in HCC patients receiving TACE treatment. Methods: From 2005 to 2016, a total of 1233 treatment-naive HCC patients receiving first time TACE treatment in Chang Gung Memorial Hospital, Linkou medical center were recruited. Pre-TACE status including baseline characteristics, prior history of ascites, and parameters for liver function evaluation were analyzed. All the variables were compared between patients with and without variceal bleeding. Results: Among the 1233 patients, the median age was 63.7 (range 25.8–91.5) years old, and 73.5% were male. Variceal bleeding events were documented in 19 patients (1.5%) within 3 months post TACE treatment. Patients with younger age, cirrhosis, pre-treatment ascites and advanced fibrosis status (higher MELD score, CTP score, ALBI grade, FIB-4 and APRI score) were more likely to encounter post-treatment variceal bleeding. Multivariate Cox regression analysis revealed existence of ascites (adjusted HR: 4.859 (1.947–12.124), p = 0.001), and higher FIB-4 score (adjusted HR: 4.481 (1.796–11.179), p = 0.001) were the independent predictive factors for variceal bleeding. Patients with post-TACE variceal bleeding are more likely to encounter tumor progression (42.1% vs. 20.3%, p = 0.039) and mortality owing to GI bleeding (15.8% vs. 3%, p = 0.032). Conclusion: The incidence of post-TACE variceal bleeding was 1.5%. Patients with post-TACE variceal bleeding have poorer TACE treatment response. The pre-treatment ascites and FIB-4 score are the independent predictors for post-TACE variceal bleeding. Keywords: Ascites, Gastrointestinal bleeding, Mortality, Portal hypertension, Treatment response

HCV-specific T cells are few and exhausted in patients with chronic hepatitis C (CHC). Whether these T cells are responsible for the liver damage and fibrosis is still debated. However, cluster of differentiation 38-positive (CD38Lymphocytes from peripheral blood were obtained from 108 patients with CHC and 43 healthy subjects. Immunophenotyping, functional assays, T-cell receptor (TCR) repertoire, and cytotoxic assay of CD38The percentage of CD38The TCR-independent, cytokine-responsive bystander CD38

Hepatic steatosis is a major cause of chronic liver disease. Two-dimensional (2D) ultrasound is the most widely used non-invasive tool for screening and monitoring, but associated diagnoses are highly subjective.To develop a scalable deep learning (DL) algorithm for quantitative scoring of liver steatosis from 2D ultrasound images.Using multi-view ultrasound data from 3310 patients, 19513 studies, and 228075 images from a retrospective cohort of patients received elastography, we trained a DL algorithm to diagnose steatosis stages (healthy, mild, moderate, or severe) from clinical ultrasound diagnoses. Performance was validated on two multi-scanner unblinded and blinded (initially to DL developer) histology-proven cohorts (147 and 112 patients) with histopathology fatty cell percentage diagnoses and a subset with FibroScan diagnoses. We also quantified reliability across scanners and viewpoints. Results were evaluated using Bland-Altman and receiver operating characteristic (ROC) analysis.The DL algorithm demonstrated repeatable measurements with a moderate number of images (three for each viewpoint) and high agreement across three premium ultrasound scanners. High diagnostic performance was observed across all viewpoints: Areas under the curve of the ROC to classify mild, moderate, and severe steatosis grades were 0.85, 0.91, and 0.93, respectively. The DL algorithm outperformed or performed at least comparably to FibroScan control attenuation parameter (CAP) with statistically significant improvements for all levels on the unblinded histology-proven cohort and for "= severe" steatosis on the blinded histology-proven cohort.The DL algorithm provides a reliable quantitative steatosis assessment across view and scanners on two multi-scanner cohorts. Diagnostic performance was high with comparable or better performance than the CAP.

The embryonic stem cell marker Oct4 is expressed in several human cancers and is positively correlated with a poor outcome in cancer patients. However, its physiological role in cancer progression remains poorly understood. Tumor cells block apoptosis to escape cell death so that they can proliferate indefinitely, leading to ineffective therapy for cancer patients. In this study, we investigated whether Oct4 regulates the apoptosis pathway and contributes to poor prognosis in patients with lung adenocarcinoma. Our results revealed that Oct4 expression is correlated with Stat1 expression in lung adenocarcinoma patients and Oct4 is directly bound to the Stat1 promoter to transactivate Stat1 in lung adenocarcinoma cells. Expression of the Stat1 downstream gene Mcl-1 increased in Oct4-overexpressing cancer cells, while Stat1 knockdown in Oct4-overexpressing cancer cells sensitized them to cisplatin-induced apoptosis. Furthermore, Oct4 promoted Stat1 expression and tumor growth, whereas silencing of Stat1 reduced Oct4-induced tumor growth in human lung tumor xenograft models. Taken together, we demonstrate that Oct4 is a pro-survival factor by inducing Stat1 expression and that the Oct4/Stat1/Mcl-1 axis may be a potential therapeutic target for lung adenocarcinoma.

Background and aims Sorafenib is the first proved target therapy that shows significant survival benefit in advanced hepatocellular carcinoma. This study was aimed to investigate whether add-on sorafenib be beneficial for those experienced transarterial chemoembolization refractoriness. Methods From 2005 to 2016, a total of 656 treatment-naive hepatocellular carcinoma patients receiving transarterial chemoembolization treatment were recruited. Transarterial chemoembolization refractoriness was defined as progressive disease after two consecutive of transarterial chemoembolization treatment within 6 months. Patient's baseline characteristics, tumor burden, and parameters for liver function evaluation during treatment were analyzed. All the variables were compared between patients with and without transarterial chemoembolization refractoriness, as well as with and without add-on sorafenib. Results Among the 656 patients, the median age was 62.5 (range 27.3-91.5) years old, and 74.5% were male. Transarterial chemoembolization refractoriness events were documented in 202 patients (30.8%). After multivariate logistic regression analysis, tumor size ≧5 cm, baseline alpha-fetoprotein level ≧200 mg/dl, elevation of alpha-fetoprotein ≧20%, and elevation of Child-Turcotte-Pugh score ≧2 points after first transarterial chemoembolization were the independent predictive factors for transarterial chemoembolization refractoriness. Twenty-two patients (10.9%) received add-on sorafenib treatment and 146 (72.3%) patients continued transarterial chemoembolization treatment alone. After 1:2 propensity score matching, patients with add-on sorafenib therapy had significantly longer median overall survival than transarterial chemoembolization treatment alone (23.1 vs. 11.0 months, log-rank P = 0.001). Conclusion The tumor size, baseline alpha-fetoprotein, and elevation of alpha-fetoprotein and Child-Turcotte-Pugh score after first transarterial chemoembolization were the predictors for transarterial chemoembolization refractoriness. For patients with transarterial chemoembolization refractoriness, add-on sorafenib achieved better survival benefit than transarterial chemoembolization treatment alone.

Background: Secondary prevention of hepatocellular carcinoma (HCC) among patients with chronic hepatitis C (CHC) who achieve sustained virologic response (SVR) with interferon-based therapy has been proved effective. However, tertiary prevention with PegIFN/RBV therapy of HCC recurrence seems limited effect in CHC-HCC patients post curative therapies. This study aims to investigate the timing and impact of PegIFN/RBV treatment on prevention of HCC recurrence in patients after RFA treatment. Methods: From 2013 to 2016, a total of 137 CHC-HCC patients from a 508 patient based cohort receiving complete RFA treatment in Chang Gung Memorial Hospital, Linkou Medical Center were retrospectively recruited. Pre-RFA patient demographics were analyzed by cox regression analysis for prediction on tumor recurrence. Statistics analysis was performed with SPSS V.20 (IBM, USA). Results: The mean age of the 137 patients were 69.6 year-old and 71.5% of patients were cirrhotic. After propensity score matching, one hundred and two patients were enrolled into the analysis. Fifty-one patients (50%) received PegIFN/RBV therapy and twenty-seven patients (52.9%) achieved SVR. Patients who could achieve SVR had lower tumor recurrence rate than non-SVR and untreated groups (29.6% vs. 66.7% vs. 49.0%, P = 0.030). The effect is more prominent in those achieve SVR prior to compared with after RFA despite not reach statistically significant (26.1% vs. 50.0%, P = 0.334). Conclusion: Timely treatment with SVR achievement has the lowest tumor recurrence rate in CHC-HCC patients. Secondary prevention might be even more important than tertiary prevention in CHC patients, especially regarding prevention of post RFA HCC recurrence. Keywords: Radiofrequency ablation, Haptocellular carcinoma, Peginterferon and ribavirin, Prognosis

Diffuse alveolar hemorrhage (DAH) in systemic lupus erythematosus (SLE) is associated with significant mortality, requiring a thorough understanding of its complex mechanisms to develop novel therapeutics for disease control. Activated p53-dependent apoptosis with dysregulated long non-coding RNA (lncRNA) expression is involved in the SLE pathogenesis and correlated with clinical activity. We examined the expression of apoptosis-related p53-dependent lncRNA, including H19, HOTAIR and lincRNA-p21 in SLE-associated DAH patients. Increased lincRNA-p21 levels were detected in circulating mononuclear cells, mainly in CD4+ and CD14+ cells. Higher expression of p53, lincRNA-p21 and cell apoptosis was identified in lung tissues. Lentivirus-based short hairpin RNA (shRNA)-transduced stable transfectants were created for examining the targeting efficacy in lncRNA. Under pristane stimulation, alveolar epithelial cells had increased p53, lincRNA-p21 and downstream Bax levels with elevated apoptotic ratios. After pristane injection, C57/BL6 mice developed DAH with increased pulmonary expression of p53, lincRNA-p21 and cell apoptosis. Intra-pulmonary delivery of shRNA targeting lincRNA-p21 reduced hemorrhage frequencies and improved anemia status through decreasing Bax expression and cell apoptosis. Our findings demonstrate increased p53-dependent lncRNA expression with accelerated cell apoptosis in the lungs of SLE-associated DAH patients, and show the therapeutic potential of targeting intra-pulmonary lncRNA expression in a pristane-induced model of DAH.

Non-inferior antiviral efficacy and better renal safety have been reported in chronic hepatitis B patients with tenofovir alafenamide (TAF) treatment. The experience in real-world clinical practice is limited.We aimed to explore the efficacy after 1-year TAF treatment.A total of 148 patients (42 HBeAg-positive and 106 HBeAg-negative) with TAF treatment ≥1 year were included. Virological suppression (20 IU/mL or undetectable), HBsAg level, alanine aminotransferase (ALT) normalization (≤36 U/L), and estimated glomerular filtration rate (eGFR) were analyzed at 1 year. Multivariate logistic regression analysis was performed to determine the associated factors for virological suppression and ALT normalization.Virological suppression was achieved in 83% and the 1-year median decline of hepatitis B virus DNA was 5.18 log IU/mL. ALT normalization occurred in 75.7%. HBsAg level decreased at a median of 0.27 log IU/mL with significant difference from baseline (P .001). Baseline ALT (odds ratio [OR] 1.005, 95% confidence interval [CI] 1.000-1.010, P = .036) and hepatitis B virus DNA (OR 0.222, 95% CI 0.079-0.621, P = .004) were significant factors for 1-year virological suppression. Age (OR 1.064, 95% CI 1.003-1.130, P = .041) was associated with ALT normalization. Significant changes were observed in creatinine (mean increase 0.03 mg/dL, P = .011) and eGFR (mean decrease 2.6 mL/min/1.73 m2, P = .004) after 1-year TAF treatment.One-year TAF treatment came to good virological response, modest ALT normalization rate and significant HBsAg decline. The observation of significant changes in eGFR warranted further studies.

Patients with chronic hepatitis B (CHB) are at an increased risk of disease progression. The influence of hepatic steatosis (HS) to liver fibrosis was controversial. We aim to investigate the association between HS and liver fibrosis and explore the predicting factors for advanced fibrosis.CHB patients undergoing liver biopsy with complete assessments of HS, necroinflammation grade [histological activity index (HAI) score], and fibrosis stage were retrospectively recruited. Logistic regression analysis was performed to determine the factors associated with advanced liver fibrosis.In this cohort of 672 patients, 342 (50.9%) had HS and 267 (39.4%) were of advanced liver fibrosis. Age [odds ratio (OR) 1.026, 95% confidence interval (CI) 1.007-1.046, p = 0.008], body mass index (BMI, OR 1.091, 95% CI 1.026-1.159, p = 0.005), genotype (C vs. B) (OR 2.790, 95% CI 1.847-4.214, p 0.001), platelet (OR 0.986, 95% CI 0.982-0.991, p 0.001), and HAI score (OR 1.197, 95% CI 1.114-1.285, p 0.001) were independent factors for advanced liver fibrosis in multivariate logistic regression analysis. HAI score was also a significantly associated factor for significant liver fibrosis in non-cirrhotic subpopulation (OR 1.578, 95% CI 1.375-1.810, p 0.001). HS was not related to advanced/significant liver fibrosis in overall/non-cirrhotic population (p 0.05).Significant or advanced liver fibrosis is associated with grade of necroinflammation but not with HS in CHB patients.

Supplemental Digital Content is available in the text, Abrupt alanine aminotransferase (ALT) elevation during direct-acting antiviral agents (DAA) treatment is an uncommon but noticeable adverse event in chronic hepatitis C (CHC) patients, which may lead to early termination of treatment. This study aims to investigate the incidence, outcome and predictors of the on-treatment ALT elevation during DAA therapy. CHC patients treated with DAA regimen in Chang Gung Memorial Hospital, Linkou branch during March 2015 to March 2019 were recruited. Prospective scheduled ALT assessment at baseline, 2nd, 4th, 8th, and 12th/24th weeks were recorded. Pretherapy host and viral factors were compared between patients with and without on-treatment ALT elevation. Multivariate logistic regression was used for independent factors for on-treatment ALT elevation. A total of 1563 CHC patients treated with grazoprevir/elbasvir, glecaprevir/pibrentasvir and sofosbuvir-based regimen were analyzed. On-treatment ALT elevation occurred in 10.9% patients while those treated with glecaprevir/pibrentasvir had the least possibility (5.4%). Only 1.4% patients had ≥grade 3 ALT elevation events. The presence of such events had no impact on sustained virological response 12 rates. Hepatitis B virus coinfection (aOR: 3.599, P

A biocomposite coating comprising chitosan and ZnO deposited on a porous Ti oxide is developed to avoid orthopedic and dental implant-related infections. The coating comprised of an inner layer of nanoporous TiO2 and the outer layer of the chitosan matrix with ZnO nanoparticles. Microbiological tests show that chitosan coating is effective against Escherichia coli (E. coli), however, its ability to inhibit bacterial adhesion is very limited. A 1.2-fold increase in the antibacterial activity of chitosan/ZnO coating against E. coli was detected as compared to the chitosan coating alone, and the chitosan/ZnO efficiently inhibited biofilm formation. In addition, the chitosan/ZnO coating exhibited improved bioactivity compared to the chitosan coating. The improvement in antibacterial properties and bioactivity of the chitosan/ZnO coating is attributed to the release of Zn2+ ions. The critical force of scratching the chitosan/ZnO coating was approximately twice that of the chitosan coating. The potentiodynamic polarization results confirmed that the corrosion resistance of the implant with ZnO/chitosan/Ti structure was improved. In addition, cytocompatibility evaluation indicated that the chitosan/ZnO coating has good cytocompatibility in MG-63 cells as compared to pure Ti.

Background The impact of hepatic steatosis (HS) on treatment response following nucleos(t)ide analogue (NA) treatment for chronic hepatitis B (CHB) patients has not been clearly elucidated. We aimed to investigate the difference in HBeAg seroclearance between NA-treated HBeAg-positive CHB patients with and without HS. Methods We retrospectively recruited HBeAg-positive CHB patients receiving liver biopsy and NA monotherapy. The baseline clinical characteristics and cumulative incidence of HBeAg seroclearance were compared between patients with and without HS and age/gender-matched subgroup analysis was performed. Results A total of 196 patients were enrolled from 2003 April to 2016 October. The mean age was 39.6 ± 11.2 years, 142 (72.4%) were males and 94 (48%) had histological evidence of HS. Median treatment duration and follow-up period were 24.3 months and 54.9 months, respectively. HBeAg seroclearance was achieved in 56/102 (54.9%) and 54/94 (57.4%) patients with and without HS, respectively (p = 0.830). The 5-year cumulative incidence of HBeAg seroclearance in patients with and without HS was 62.8 and 67.7% in overall population (p = 0.398) and 62.4 and 66.9% in age/gender-matched subgroups (p = 0.395), respectively. The rate of HBeAg seroclearance was comparable between patients with or without HS in different NA monotherapy (all p > 0.05). Conclusions HS had no significant impact on HBeAg seroclearance in HBeAg-positive CHB patients with NA monotherapy during long-term follow-up.

Background Chemokines/cytokines play important roles in the pathogenesis of chronic hepatitis C (CHC). However, their clinical characteristics and implications in treatment responses to pegylated interferon plus ribavirin treatment (PegIFN/RBV) have not been fully illustrated yet. In this study, we intended to investigate the possible predictability of serum chemokines/cytokines on the treatment response in Taiwanese of CHC, genotype-1 (GT-1). Methods 60 Patients with GT-1 CHC infection who had been treated with PegIFN/RBV were enrolled, including 27 (45%) with sustained virological response (SVR), 11 (18%) with relapse after 48 weeks of treatment and 22 (37%) non-response (NR). Clinical parameters, seven chemokines/cytokines, CCL3, CCL4, CXCL9, CXCL10, CXCL11, IL-10 and IFN-γ, and genotypes of rs12979860, the single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) were analyzed for their relationship to treatment response. Results Baseline serum levels of CXCL10, CXCL11, CCL3 and CCL4 were significantly higher in NR group while comparing with non-NR group. (CXCL10: p = 0.001; CXCL11: p

Adjuvant pegylated interferon plus ribavirin treatment (PegIFN/RBV) reduces recurrence and prolongs survival in early stage hepatocellular carcinoma (HCC) patients with chronic hepatitis C (CHC) infection receiving resection or ablation. However, the impact of antiviral therapy in intermediate and advanced stage of CHC-HCC patients is uncertain. This study aimed to investigate the impact PegIFN/RBV treatment on recurrence-free interval and survival in patients with HCC receiving transarterial chemoembolization (TACE). From 2010 to 2013, 274 CHC patients from a 1073 patient-based cohort composed of freshly diagnosed HCC and receiving TACE treatment the Chang Gung Memorial Hospital, Linkou Medical Center were recruited. Propensity score matching (PSM) (age, gender, AST to Platelet Ratio Index (APRI), tumour size, tumour number and Child-Turcotte-Pugh score) with the ratio 1:2 for patients with and without PegIFN/RBV treatment was performed. Statistics were performed with SPSS V.20 (IBM, USA). After matching, 153 patients were analysed and 27 patients (17.6%) achieved sustained virologic response (SVR). The 2-year cumulative overall survival rate and recurrence-free survival rate among patients with SVR, non-SVR, and untreated were 85.2% vs 58.3% vs 69.6% (P=.001) and 73.3% vs 53.8% vs 58.5% (P=.013). By Cox regression analysis, non-SVR, untreated, increase CTP score and nonresponder to TACE were independent factors related to mortality. The SVR achieved by PegIFN/RBV treatment markedly improves survival and reduces tumour recurrence in CHC-HCC patients receiving TACE treatment after complete response.

Background: A lower neutrophil–to–lymphocyte ratio (NLR) was found to be associated with better clinical outcomes in hepatitis B-related liver cirrhosis and hepatocellular carcinoma. We aimed to identify pre-therapeutic variables capable of predicting NLR changes in patients with hepatitis B receiving peginterferon therapy. Patients and Methods: The baseline clinicopathological data were analyzed to correlate with NLR changes before and 1 year after peginterferon treatment in 71 patients with hepatitis B. Results: Univariate analysis revealed that pre-treatment NLR itself negatively predicted NLR changes following peginterferon treatment (odds ratio(OR)=0.320, p=0.013). Further analysis identified pre-treatment NLR, hemoglobin and hepatitis B surface antigen level as independent predictors for NLR changes (adjusted p=0.028, 0.005, and 0.028, respectively). A predictive score composed of these three factors had an area under the curve of 76.5% (p

AIM To explore factors associated with persistent hepatitis B virus (HBV) infection in a cohort of hepatocellular carcinoma (HCC)-affected families and then investigate factors that correlate with individual viral load among hepatitis B surface antigen (HBsAg)-positive relatives. METHODS We evaluated non-genetic factors associated with HBV replication in relatives of patients with HCC. Relatives of 355 HCC cases were interviewed using a structured questionnaire. Demographics, relationship to index case, HBsAg status of mothers and index cases were evaluated for association with the HBV persistent infection or viral load by generalized estimating equation analysis. RESULTS Among 729 relatives enrolled, parent generation (P = 0.0076), index generation (P = 0.0044), mothers positive for HBsAg (P = 0.0007), and HBsAg-positive index cases (P = 5.98 × 10-8) were associated with persistent HBV infection. Factors associated with HBV viral load were evaluated among 303 HBsAg-positive relatives. Parent generation (P = 0.0359) and sex (P = 0.0007) were independent factors associated with HBV viral load. The intra-family HBV viral load was evaluated in families clustered with HBsAg-positive siblings. An intra-family trend of similar HBV viral load was found for 27 of 46 (58.7%) families. Male offspring of HBsAg-positive mothers (P = 0.024) and older siblings were associated with high viral load. CONCLUSION Sex and generation play important roles on HBV viral load. Maternal birth age and nutritional changes could be the reasons of viral load difference between generations.

Polycystic kidney disease (PKD) is characterized by the expansion of fluid-filled cysts in the kidney, which impair the function of kidney and eventually leads to end-stage renal failure. It has been previously demonstrated that transgenic overexpression of prothymosin α (ProT) induces the development of PKD; however, the underlying mechanisms remain unclear. In this study, we used a mouse PKD model that sustains kidney-specific low-expression of Pkd1 to illustrate that aberrant up-regulation of ProT occurs in cyst-lining epithelial cells, and we further developed an in vitro cystogenesis model to demonstrate that the suppression of ProT is sufficient to reduce cyst formation. Next, we found that the expression of ProT was accompanied with prominent augmentation of protein acetylation in PKD, which results in the activation of downstream signal transducer and activator of transcription (STAT) 3. The pathologic role of STAT3 in PKD has been previously reported. We determined that this molecular mechanism of protein acetylation is involved with the interaction between ProT and STAT3; consequently, it causes the deprivation of histone deacetylase 3 from the indicated protein. Conclusively, these results elucidate the significant role of ProT, including protein acetylation and STAT3 activation in PKD, which represent potential for ameliorating the disease progression of PKD.—Chen, Y.-C., Su, Y.-C., Shieh, G.-S., Su, B.-H., Su, W.-C., Huang, P.-H., Jiang, S.-T., Shiau, A.-L., Wu, C.-L. Prothymosin α promotes STAT3 acetylation to induce cystogenesis in Pkd1-deficient mice.

We examined the seroprevalence change of anti-hepatitis D virus (HDV) antibodies in Taiwan from 2006 to 2019. A total of 1147 patients who had chronic hepatitis B virus (HBV) infection were assessed. Of them, 51 (4.4%) were positive for anti-HDV antibodies. Comparison between anti-HDV-positive and negative groups was performed to examine clinical and virological factors related to anti-HDV positivity. It was found that the median HBV-DNA concentration was 1.6 × 105 IU/mL (range, 15 000 IU/mL, the year-to-year (calculated every 2 years) seropositive rates of anti-HDV were 10.0%, 7.9%, 0.7%, 0.3%, 0%, 0%, and 0% (P

This study provided an eco-friendly manufacturing method for Ti implants by combining machining and surface treatment processes. Ti was machined by electrical discharge machining (EDM) in a water-based dielectric in order to reduce environmental impact and improve operational health. The feasibility of this eco-friendly EDM was evaluated by tested the bioactivity and cytocompatibility of the EDM-treated Ti and the commercially micro-arc oxidation (MAO)-treated Ti was used as a control group. Pulsed MAO and EDM treatments were applied on Ti in an aqueous solution containing hydroxyapatite (HA) with the same concentration (30 g/L) under the same voltage and treatment period. The two surface modification processes were compared from the aspects of surface composition, coating structure, and coating adhesion. Furthermore, in vitro bioactivity and cellular biocompatibility of the MAO- and EDM-treated Ti films were tested. Both treatments produced Ti oxide containing Ca and P on Ti, and the EDM-formed film possessed more Ca, with its Ca/P value closer to HA, as compared to the MAO-formed film. The MAO-formed films had micropores and nanopores in the middle region and film/substrate interface, respectively. Pores only existed on the surface of the EDM-formed films. The MAO-formed films were fractured, but the EDM-formed films maintained their original structure under tensile stress, tested according to the ASTM C633 standard. The bioactivity of the EDM-treated surface was higher than that of the MAO-treated and untreated Ti surface. After 24 h cell incubation, the EDM-treated surface exhibited a significantly higher number of cells than untreated Ti and the MAO-treated surface.

The pathological role of vitamin K2 in Alzheimer’s disease (AD) involves a definite link between impaired cognitive functions and decreased serum vitamin K levels. Vitamin K2 supplementation may have a protective effect on AD. However, the mechanism underlying vitamin K2 protection has not been elucidated. With the amyloid-β (Aβ) cascade hypothesis, we constructed a clone containing the C-terminal fragment of amyloid precursor protein (β-CTF/APP), transfected in astroglioma C6 cells and used this cell model (β-CTF/C6) to study the protective effect of vitamin K2 against Aβ cytotoxicity. Both cellular and biochemical assays, including cell viability and reactive oxygen species (ROS), assays assay, and Western blot and caspase activity analyses, were used to characterize and unveil the protective role and mechanism of vitamin K2 protecting against Aβ-induced cytotoxicity. Vitamin K2 treatment dose-dependently decreased the death of neural cells. The protective effect of vitamin K2 could be abolished by adding warfarin, a vitamin K2 antagonist. The addition of vitamin K2 reduced the ROS formation and inhibited the caspase-3 mediated apoptosis induced by Aβ peptides, indicating that the mechanism underlying the vitamin K2 protection is likely against Aβ-mediated apoptosis. Inhibitor assay and Western blot analyses revealed that the possible mechanism of vitamin K2 protection against Aβ-mediated apoptosis might be via regulating phosphatidylinositol 3-kinase (PI3K) associated-signaling pathway and inhibiting caspase-3-mediated apoptosis. Our study demonstrates that vitamin K2 can protect neural cells against Aβ toxicity.

Accelerated cell apoptosis with dysregulated long noncoding RNAs is the crucial pathogenesis in lupus nephritis (LN). Pro-apoptotic lincRNA-p21 was studied in LN patients, cell lines with lentivirus-mediated overexpression and CRISPR interference (CRISPRi)-conducted repression, and a mouse model. Clinical samples were from patients and age/sex-matched controls. Expression of lincRNA-p21 and endogenous RNA target miR-181a, were examined in mononuclear and urine cells. Guide RNA sequences targeting lincRNA-p21 were cloned into CRISPRi with dCas9/ Kr&uuml, ppel-associated box (KRAB) domain. LincRNA-p21-silened transfectants were investigated for apoptosis and miR-181a expression. LincRNA-p21-overexpressed cells were evaluated for apoptosis and p53-related down-stream molecules. Balb/C mice were injected with pristane to induce LN and examined for apoptosis and lincRNA-p21. Higher lincRNA-p21 levels were found in LN mononuclear and urine cells, positively correlated with activity. There were lower miR-181a levels in LN mononuclear cells, negatively correlated with activity. Doxorubicin-induced apoptotic cells had up-regulated lincRNA-p21 levels. CRISPRi with dCas9/KARA domain showed efficient repression ability on transcription initiation/elongation. CRISPRi-conducted lincRNA-p21-silenced transfectants displayed reduced apoptosis with up-regulated miR-181a levels, whereas lentivirus-mediated lincRNA-p21-overexpressed cells revealed enhanced apoptosis with up-regulated downstream PUMA/Bax expression. LN mice had glomerular apoptosis with progressive increased lincRNA-p21 levels. Our results demonstrate up-regulated lincRNA-p21 expression in LN, implicating a potential diagnostic marker and therapeutic target.

Although targeted agents are recommended as the first-line treatments for advanced hepatocellular carcinoma (aHCC), systemic chemotherapy or hepatic arterial infusion chemotherapy (HAIC) are still being used in Asian countries. Beside economic considerations, it was found that targeted drugs could not significantly prolong overall survival in aHCC patients with distant metastasis. In addition, chemotherapy could achieve complete response in a small proportion of patients. Here, we aimed to investigate whether combination of three previously identified single nucleotide polymorphism (SNP) predictors (GALNT14-rs9679162, WWOX-rs13338697, and rs6025211) could guide our choice between systemic chemotherapy, HAIC, and targeted agents in aHCC patients. A cohort of 237 real-world aHCC patients (171 receiving systemic chemotherapy followed by various anticancer treatments including sorafenib; 66 receiving HAIC) were included for outcome analysis. By combining the three SNP markers with or without addition of two clinical criteria (tumor diameter8 cm, neutrophils80%), small groups of patients were found to harbor high complete response rates to systemic chemotherapy (35.3% if the 3-SNP signature alone matched; 60.0% if clinical criteria also matched). Subsequent sorafenib treatment for chemotherapy non-responders was associated with longer overall survival (P 0.001). In HAIC-treated patients, GALNT14-rs9679162 genotype "GG" was associated with longer overall survival (P = 0.019, median survival 10.5 months). In conclusion, pre-test for the 3-SNP signature in aHCC patients could identify potential systemic chemotherapy or HAIC responders. Chemotherapy non-responders still benefited from subsequent sorafenib treatment. Accordingly, we propose a roadmap for aHCC patients when chemotherapy or HAIC is to be used.

Ustekinumab is used to treat moderate-to-severe psoriasis by blocking the interleukin-12/23 pathway, which is also essential against intracellular pathogens. Because there is a high prevalence of hepatitis B viral infection in Taiwan, the expected risk of reactivation is higher among ustekinumab-treated patients. We performed this study to investigate the risk of hepatitis reactivation.Patients with psoriasis treated with ustekinumab from October 2011 to June 2016 were enrolled in a prospective cohort study. All patients were tested for hepatitis B serology and serum viral DNA at baseline. For those positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibodies (anti-HBc) testing for HBV DNA was conducted at least annually. An increase of HBV DNA 2 log scale or emergence of HBV DNA were defined as reactivation. The primary outcome of this study was HBV reactivation.Ninety-three psoriasis patients receiving ustekinumab were included. The average duration of treatment and follow-up was 24 ± 12 months. There were 39 patients classified as naïve to HBV or vaccinated, and none of these patients had HBV reactivation. Among the remaining 54 patients classified as inactive HBV carriers, resolved HBV infection, or isolated anti-HBc positivity, only 3 patients experienced virologic reactivation, and none had liver failure.The study outcomes indicate that ustekinumab could be safe for psoriasis patients since none developed persistent hepatitis or acute liver failure during therapy. However, the re-appearance of plasma HBV DNA requires appropriate monitoring of HBV viral load during ustekinumab treatment.

Epithelial-to-mesenchymal transition (EMT) is a highly orchestrated process motivated by the nature of physical and chemical compositions of the tumor microenvironment (TME). The role of the physical framework of the TME in guiding cells toward EMT is poorly understood. To investigate this, breast cancer MDA-MB-231 and MCF-7 cells were cultured on nanochips comprising tantalum oxide nanodots ranging in diameter from 10 to 200 nm, fabricated through electrochemical approach and collectively referred to as artificial microenvironments. The 100 and 200 nm nanochips induced the cells to adopt an elongated or spindle-shaped morphology. The key EMT genes, E-cadherin, N-cadherin, and vimentin, displayed the spatial control exhibited by the artificial microenvironments. The E-cadherin gene expression was attenuated, whereas those of N-cadherin and vimentin were amplified by 100 and 200 nm nanochips, indicating the induction of EMT. Transcription factors, snail and twist, were identified for modulating the EMT genes in the cells on these artificial microenvironments. Localization of EMT proteins observed through immunostaining indicated the loss of cell-cell junctions on 100 and 200 nm nanochips, confirming the EMT induction. Thus, by utilizing an in vitro approach, we demonstrate how the physical framework of the TME may possibly trigger or assist in inducing EMT in vivo. Applications in the fields of drug discovery, biomedical engineering, and cancer research are expected.

BACKGROUND Clinical factors associated with hepatocellular carcinoma (HCC) have been extensively studied in antiviral treatment-naive patients with chronic hepatitis B virus (HBV) infection but not in treatment-experienced patients. Owing to the wide availability of antiviral agents that effectively suppress HBV replication, we investigated HCC risk factors in treatment-experienced patients. METHODS In a cohort of 330 patients who underwent pretherapeutic liver biopsy, we analyzed the HCC incidence in relationship to clinical parameters. Ultra-deep sequencing of the viral genome was performed on 11 entecavir-treated and pegylated interferon (peginterferon)-treated patients. RESULTS Initial univariate/multivariate explorations indicated that cirrhosis and antiviral treatment were independently associated with HCC occurrence. The peginterferon-experienced patients had a lower HCC incidence than the nucleos(t)ide analogue-treated patients (P = .011). The peginterferon and entecavir monotherapy groups also differed in HCC incidence (P = .018). Results of analysis of baseline-matched subgroups concurred with cohort analysis (P = .009 for comparison of peginterferon-experienced vs nucleotide analogue-treated patients; P = .022 for comparison of peginterferon- vs entecavir-treated patients). Viral loads of entecavir-treated patients were constantly suppressed to levels lower than those of peginterferon-treated patients (P < .001). Oncogenic surface antigen truncation mutations were detected in entecavir-treated patients with HCC but not in peginterferon-treated patients (P = .015). CONCLUSIONS Treatment by peginterferon was associated with a lower HCC incidence than nucleos(t)ide-analogue treatment in chronic HBV infection.

Proteolytic cleavage of the hemagglutinin (HA) of influenza virus by host trypsin-like proteases is required for viral infectivity. Some serine proteases are capable of cleaving influenza virus HA, whereas some serine protease inhibitors (serpins) inhibit the HA cleavage in various cell types. Kallikrein-related peptidase 1 (KLK1, also known as tissue kallikrein) is a widely distributed serine protease. Kallistatin, a serpin synthesized mainly in the liver and rapidly secreted into the circulation, forms complexes with KLK1 and inhibits its activity. Here, we investigated the roles of KLK1 and kallistatin in influenza virus infection. We show that the levels of KLK1 increased, whereas those of kallistatin decreased, in the lungs of mice during influenza virus infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. In contrast, kallistatin inhibited KLK1-mediated HA cleavage and reduced viral production. Cells transduced with the kallistatin gene secreted kallistatin extracellularly, which rendered them more resistant to influenza virus infection. Furthermore, lentivirus-mediated kallistatin gene delivery protected mice against lethal influenza virus challenge by reducing the viral load, inflammation, and injury in the lung. Taking the data together, we determined that KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting the cleavage of the HA peptide and inflammatory responses. This study provides a proof of principle for the potential therapeutic application of kallistatin or other KLK1 inhibitors for influenza. Since proteolytic activation also enhances the infectivity of some other viruses, kallistatin and other kallikrein inhibitors may be explored as antiviral agents against these viruses.

Commonly used non-invasive fibrosis scores usually included serum transaminase levels in the equations, including Aspartate transaminase to Platelet Ratio Index (APRI) and fibrosis-4 (FIB-4). Transaminases fluctuated significantly in chronic hepatitis B patients with exacerbations, leading to unsteady score values. As such, here, we aim to develop a transaminase-free score suitable for pretherapeutic evaluation of fibrosis stages.Firstly, 1082 treatment-naïve chronic hepatitis B patients were enrolled and divided into modeling (n = 541) and verification (n = 541) cohorts. Secondly, 265 patients having received liver biopsy, with known Ishak fibrosis stages, were included for independent correlation.Cross-sectional analysis of 1082 patients revealed age-dependent variation of association between virological factors and cirrhosis. A fibrosis score including Anti-hepatitis B e antibody, Basal core promoter (BCP) A1762T mutation, and Platelet count Index (named ABPI) was derived from the modeling cohort. ABPI performed better than APRI and FIB-4 in the verification cohort for identifying cirrhotic patients (comparison of area under the receiver operating characteristic curves: ABPI vs APRI and FIB-4 = 0.785 vs 0.563 [P 0.001] and 0.700 [P = 0.026], respectively). The performance of ABPI was even better in young ( 40 years old) hepatitis B patients (area under the receiver operating characteristic curves: 0.856 vs 0.402 [P 0.001] and 0.599 [P = 0.009], respectively). Finally, in the independent cohort of 265 patients with known Ishak fibrosis stages, it was found that ABPI effectively distinguished between Ishak fibrosis stages 3 and 3 and between 4 and 4 (P 0.001 for each).We developed a transaminase-free fibrosis score (ABPI) utilizing basal core promoter A1762T data, which outperformed APRI and FIB-4.

CD4+Foxp3+ regulatory T cells (Tregs) are the main immune suppressors with subpopulation of inflamed-tissue related memory Tregs (mTregs) and non-related resting Treg (rTregs). Previously, Treg was proposed to be the cause of chronicity of hepatitis B virus (HBV) infection but with controversies. We then investigated the role of mTregs in distinct immune phases of chronic HBV infection, especially the non-inflammatory versus inflammatory phases. It was found mTregs but not rTregs increased only in the inflammatory phase and correlated with serum alanine aminotransferase (ALT) level. These mTregs accumulated in the inflamed liver, expressed significantly higher Tim-3, CCR4, CCR5 and fewer CCR7, and possessed potent suppressive function. These mTregs mainly originated from natural Tregs because of high Helios expression. Hierarchical clustering analysis showed higher frequency of mTreg was concordant with higher serum ALT and galectin-9 levels. Furthermore, galectin-9 could expand mTregs through galectin-9/Tim-3 interaction. In conclusion, increased mTregs are found only in inflammatory phase of chronic HBV infection. Galectin-9, associated with liver inflammation, contributes to the expansion of mTregs through galectin-9/Tim-3 interaction. Therefore, this expansion of mTregs only reflects as an immune regulatory mechanism to limit the on-going liver damages rather than the cause of chronicity of HBV infection.

Aim A genome-wide association study (GWAS) had identified a single nucleotide polymorphism (SNP), GALNT14-rs9679162, capable of predicting chemotherapy responses in advanced hepatocellular carcinoma (HCC). Here, we revisited the GWAS database to search for necessary SNPs that could improve our outcome prediction. Methods A cohort of 116 HCC patients receiving split-dose chemotherapy composed of 5-fluorouracil, mitoxantrone and cisplatin was enrolled. The GALNT14-rs9679162 together with four other leading candidate SNPs (rs6025211, rs715171, LOC105369482-rs1955024 and WWOX-rs13338697) was genotyped and correlated with time-to-tumor progression (TTP) and overall survival (OS). Results GALNT14-rs9679162-TT genotype remained an effective predictor for favorable TTP and OS (P = 0.012 and 0.002). Additionally, it was found that WWOX-rs13338697-CT genotype was associated with unfavorable TTP (P = 0.031), independent of GALNT14-rs9679162 genotype (adjusted P = 0.045), and rs6025211-CT genotype was associated with unfavorable OS (P = 0.014), independent of GALNT14-rs9679162 genotype (adjusted P = 0.025). Combinations of these SNPs stratified patients into three groups with differential treatment outcomes. Patients with GALNT14-rs9679162-TT/WWOX-rs13338697-non-CT genotypes achieved the most favorable treatment outcomes (n = 19; median TTP, median OS and response rate were 3.9 months, 6.8 months and 4/19 [21.1%], respectively); whereas patients with GALNT14-rs9679162-non-TT/rs6025211-CT genotypes associated with the most unfavorable treatment outcomes (n = 40; median TTP, median OS and response rate were 1.9 months, 3.5 months and 1/40 [2.5%], respectively). The remaining patients constituted a third subgroup with intermediate clinical outcomes. Conclusions Three genetic variants, GALNT14-rs9679162, WWOX-rs13338697 and rs6025211, stratified advanced HCC patients into three groups with differential treatment outcomes.

Cisplatin is a known nephrotoxic agent requiring vigorous hydration before use. However, aggressive hydration could be life-threatening. Therefore, in cirrhotic patients with advanced hepatocellular carcinoma (HCC) under cisplatin-based chemotherapy, the risk of nephrotoxicity increased. Because previous studies showed that long-term telbivudine treatment improved renal function in chronic hepatitis B virus (HBV) infected patients, we conducted a case-control study to evaluate the clinical outcome of telbivudine preemptive therapy in HBV-related advanced HCC patients treated by combination chemotherapy comprising 5-fluorouracil, mitoxantrone and cisplatin (FMP).From June 2007 to March 2012, 60 patients with HBV-related advanced HCC, all receiving the same FMP chemotherapy protocol, were enrolled. Of them, 20 did not receive any antiviral therapy, whereas the remaining 40 patients (sex and age matched) received telbivudine preemptive therapy.Progressive decrease of aminotransferase levels (p0.05) and progressive increase of viral clearance rates (p0.001) were found in telbivudine-treated group. No drug resistance developed during the course of treatment. When compared with non-antiviral-treated patients, a significantly higher post-therapeutic estimated glomerular filtration rate (eGFR) was found in the telbivudine-treated group (p0.001). In patients with initial eGFR100 ml/min (n = 34), the median overall survival was significantly longer in the telbivudine-treated group (12.1 vs. 4.9 months; p = 0.042).Preemptive use of telbivudine significantly prevented eGFR deterioration caused by cisplatin-based chemotherapy in HBV-related advanced HCC. In patients with initially sufficient eGFR level, telbivudine treatment was associated with a longer overall survival.

The glycine zipper motif at the C-terminus of the β-amyloid (Aβ) peptide have been shown to strongly influence the formation of neurotoxic aggregates. A previous study showed that the G37L mutation dramatically reduces the Aβ toxicity in vivo and in vitro. However, the primary cause and mechanism of the glycine zipper motif on Aβ properties remain unknown. To gain molecular insights into the impact of glycine zipper on Aβ properties, we substituted the residue 37 of Glycine by Valine and studied the structural and biochemical properties of G37V mutation, Aβ42(37V), by using in vitro and in silico approaches. Unlike G37L mutation, the G37V mutation reduced toxicity substantially but did not significantly accelerate the aggregation rate or change the content of secondary structures. Further TEM analyses showed that the G37V mutation formed an ellipse-like aggregate rather than a network-like fibril as wild type or G37L mutation of Aβ42 form. This different aggregation morphology may be highly linked with the reduction of toxicity. To gain the insight for the different properties of Aβ42(37V), we studied the structure of Aβ42 and G37V mutation using the replica exchange molecular dynamics simulation. Our results demonstrate that although the overall secondary structure population is similar with Aβ42 and Aβ42(G37V), Aβ42(G37V) shows an increase in the β-turn and β-hairpin at residues 36-37 and the flexibility of the Asp23-Lys28 salt bridge. These unique structural features may be the possible reason to account for the ellipse-like morphology.

Background and Purpose— Although there has been extensive research on the effectiveness of repetitive transcranial magnetic stimulation (rTMS) to improve patients’ motor performance after experiencing chronic stroke, explicit findings on the coupling of different rTMS protocols are meager. We designed this sham-controlled randomized study to investigate the potential for a consecutive suppressive-facilitatory TMS protocol to improve motor outcomes after chronic stroke. Methods— Fifty-four chronic hemiplegic stroke patients were allocated across 4 groups to undergo 20 daily sessions of (1) 1 Hz rTMS over the contralesional primary motor cortex (M1) and then intermittent theta burst stimulation over the ipsilesional M1 (group A); (2) contralesional sham stimulation and then ipsilesional real intermittent theta burst stimulation (group B); (3) contralesional real 1 Hz rTMS and then ipsilesional sham stimulation (group C); or (4) bilateral sham-control procedures (group D). We tested cortical excitability and motor activity assessments at the baseline, postpriming rTMS, and postconsequent rTMS periods. Results— At post, group A showed greater muscle strength, Fugl-Meyer Assessment (FMA), Wolf Motor Function test, and reaction time improvement in comparison with group B ( P P =0.001≈0.003). Correlation analyses in group A revealed a close relation between contralesional map area decrement and Wolf Motor Function test gain ( P =0.005; r =−0.75), and also revealed ipsilesional map area increment and reaction time decrement ( P =0.02; r =−0.87). We detected no such relations in the other 3 groups. Conclusions— Our clinical trials established an extended timeframe during which conditioning could be safely continued and produced more favorable outcomes in facilitating motor performance and ameliorating interhemispheric imbalance than those obtained from single-course rTMS modulation alone.

Background Aggregation of amyloid-beta (Aβ) has been proposed as the main cause of Alzheimer's disease (AD). Vitamin K deficiency has been linked to the pathogenesis of AD. Therefore, 15 synthesized vitamin K3 (VK3) analogues were studied for their anti-amyloidogenic activity. Methods Biological and spectroscopic assays were used to characterize the effect of VK3 analogues on amyloidogenic properties of Aβ, such as aggregation, free radical formation, and cell viability. Molecular dynamics simulation was used to calculate the binding affinity and mode of VK3 analogue binding to Aβ. Results Both numerical and experimental results showed that several VK3 analogues, including VK3-6, VK3-8, VK3-9, VK3-10, and VK3-224 could effectively inhibit Aβ aggregation and conformational conversion. The calculated inhibition constants were in the μM range for VK3-10, VK3-6, and VK3-9 which was similar to the IC50 of curcumin. Cell viability assays indicated that VK3-9 could effectively reduce free radicals and had a protective effect on cytotoxicity induced by Aβ. Conclusions The results clearly demonstrated that VK3 analogues could effectively inhibit Aβ aggregation and protect cells against Aβ induced toxicity. Modified VK3 analogues can possibly be developed as effective anti-amyloidogenic drugs for the treatment of AD. General significance VK3 analogues effectively inhibit Aβ aggregation and are highly potent as anti-amyloidogenic drugs for therapeutic treatment of AD.

Patients with liver cirrhosis are susceptible to infections with high short-term mortalities. One CD97-related EGF-TM7 molecule, EMR2 (EGF-like molecule containing mucin-like hormone receptor 2), had been shown to regulate human neutrophil function, potentiate systemic inflammation. Nevertheless, EMR2 could also suppress neutrophil survival. Studying the role of EMR2 on neutrophil would be intriguing. 48 healthy volunteers and 100 cirrhotic patients were enrolled. Neutrophils were isolated from peripheral blood and cell surface markers were measured by flow cytometry.EMR2 expression levels correlated with CTP scores and increased further in patients with infections. These EMR2-expressed neutrophils were with activated phenotype, but with deranged functions like increased resting oxidative burst and impaired phagocytosis ability. Ligation of EMR2 could increase the phagoburst capacity but not the phagocytosis ability. Furthermore, neutrophils with higher EMR2 expression were more apoptotic and lost the LPS-induced neutrophil survival. Finally, EMR2 expressions on neutrophils correlated with infections and their levels greater than 25 had an AUC = 0.708 for predicting mortality. In conclusion, EMR2 expression levels correlated with CTP scores and increased further in cirrhotic patients with infections. These high EMR2-expressed neutrophils had activated phenotype but with deranged functions. Higher levels of these EMR2-expressed neutrophils correlated with infectious complications and predict mortality.

Formation of intracellular plaques and small oligomeric species of amyloid β (Aβ) peptides inside neurons is a hallmark of Alzheimer's disease. The most abundant Aβ species in the brain are Aβ1-40 and Aβ1-42, which are composed, respectively, of 40 and 42 residues. Aβ1-42 differs from Aβ1-40 only in two residues, Ile41 and Ala42, yet it shows remarkably faster aggregation and greater neurotoxicity than Aβ1-40. Thus, it is crucial to understand the relative contributions of Ile41 and Ala42 to these distinct behaviors. To achieve this, secondary structures of the Aβ1-41 monomer, which contribute to aggregation propensity, were studied by all-atom molecular dynamics simulation in an implicit solvent and compared to those of Aβ1-40 and Aβ1-42. We find that the secondary structure populations of Aβ1-41 are much closer to those of Aβ1-40 than to those of Aβ1-42, suggesting that Aβ1-41 and Aβ1-40 are likely to have similar aggregation properties. This prediction was confirmed through a thioflavin-T aggregation assay. Thus, our finding indicates that the hydrophobic residue at position 42 is the major contributor to the increased fibril formation rates and consequently neurotoxicity of Aβ peptides.

Acute hepatitis C exacerbations can occur in cancer patients carrying hepatitis C virus (HCV) when receiving systemic chemotherapy. However, clinical studies evaluating these complications remain rare due to the lack of clinically proven effective and tolerable anti-HCV treatments at late cancer stages. Furthermore, no data were available regarding hepatitis C exacerbation in advanced hepatocellular carcinoma (HCC) patients receiving chemotherapy. To address this issue, 48 patients with HCV-related advanced HCC, who underwent systemic chemotherapy using 5- fluorouracil, cisplatin, and mitoxantrone from 2008 to 2014 were analyzed. Nine patients developed acute hepatitis exacerbations defined by HCV-RNA elevation ≥10-fold and alanine transaminase (ALT) elevation ≥5-fold of the upper normal limit. Six were genotype 1b and 3 were genotype 2. Three patterns of clinical courses were observed including single episode of exacerbation (n = 5), fluctuated flares (n = 3), and delayed exacerbation (n = 1). Hepatic failure developed in five patients. Patients with acute exacerbations were less likely to have pretreatment ascites (11.1% vs. 53.8%; P = 0.028) and displayed a lower baseline ALT (44.1 ± 28.5 U/L vs. 72.6 ± 19.2 U/L; P = 0.007). Paradoxically, despite a high risk of hepatic failure, occurrence of hepatitis C exacerbation was associated with a favorable overall survival (P = 0.027; 22.8 vs. 5.4 months). In conclusion, hepatitis C exacerbation can occur in HCC patients receiving chemotherapy, leading to liver failure. However, the flare was associated with a better overall survival, possibly due to its association with a better baseline liver function. J. Med. Virol. 89:153-160, 2017. © 2016 Wiley Periodicals, Inc.

Cancer cells initially characterized as sensitive to chemotherapy may acquire resistance to chemotherapy and lead to tumor recurrence through the expansion of drug-resistant population. Acquisition of drug resistance to conventional chemotherapy is a major obstacle in the treatment of recurrent cancer. Here we investigated whether anticancer drugs induced Oct4 expression, thereby contributing to acquired drug resistance and tumor recurrence in bladder cancer. We identified a positive correlation of Oct4 expression with tumor recurrence in 122 clinical specimens of superficial high-grade (stages T1-2) bladder transitional cell carcinoma (TCC). Increased Oct4 levels in bladder tumors were associated with short recurrence-free intervals in the patients. Chemotherapy induced Oct4 expression in bladder cancer cells. Notably, treatment with cisplatin increased CD44-positive bladder cancer cells expressing Oct4, representing cancer stem-like cell subpopulation. Forced expression of Oct4 reduced, whereas knockdown of Oct4 enhanced, drug sensitivity in bladder cancer cells. Furthermore, tumor cells overexpressing Oct4 responded poorly to cisplatin in vivo. In regard to clinical relevance, inhibition of Oct4 by all-trans retinoic acid (ATRA) synergistically increased sensitivity to cisplatin in bladder cancer cells. Furthermore, the combination of cisplatin and ATRA was superior to cisplatin alone in suppressing tumor growth. Therefore, our results provide evidence that Oct4 increases drug resistance and implicate that inhibition of Oct4 may be a therapeutic strategy to circumvent drug resistance.

Background & Aims Of the hepatitis B e antigen–negative chronic hepatitis B patients with more than 1 year of sustained hepatitis B virus (HBV) suppression during therapy, the 1-year clinical relapse rate after cessation of entecavir therapy was 45%, of which 25.6% occurred within 6 months. The events after cessation of another preferred drug tenofovir were investigated. Methods A retrospective-prospective study was conducted in 85 hepatitis B e antigen–negative chronic hepatitis B patients with sustained HBV suppression who had stopped tenofovir therapy and were monitored every 1 to 3 months for a median duration of 39 weeks (range, 4–133 wk). Results Clinical relapse occurred in 38 patients, 57.9% and 86.8% within 3 and 6 months, respectively, with an estimated 1-year cumulative incidence of 52%. The optimal duration of therapy and consolidation therapy were calculated to be 3 and 2 years, respectively. Of the relapsers, 81.6% and 57.9% showed an alanine aminotransferase level greater than 5 and 10 times the upper limit of normal, respectively, 23.7% showed a bilirubin level of 2 mg/dL or greater, and 2 developed hepatic decompensation. Relapsers had significantly higher pretherapy baseline hepatitis B surface antigen level, more prior anti-HBV therapy experience, later alanine aminotransferase level normalization, and a shorter duration of treatment and consolidation therapy. Cox regression analyses showed that treatment for more than 3 years combined with consolidation therapy for more than 2 years was an independent significant manageable factor of clinical relapse (adjusted hazard ratio, 0.387; P = .008). With this combination, the clinical relapse rate was reduced to 30%. Conclusions Clinical relapses occurred mostly within 6 months, with high alanine aminotransferase and serum bilirubin levels. Closer monitoring, monthly in the first 3 to 6 months, with timely re-treatment is mandatory for a safe cessation of tenofovir therapy.

β-amyloid peptide (Aβ) aggregation has been thought to be associated with the pathogenesis of Alzheimer’s disease. Recently, we showed that L17A/F19A substitutions may increase the structural stability of wild-type and Arctic-type Aβ40 and decrease the rates of structural conversion and fibril formation. However, the underlying mechanism for the increase of structural stability as a result of the alanine substitutions remained elusive. In this study, we apply nuclear magnetic resonance and circular dichroism spectroscopies to characterize the Aβ40 structure, demonstrating that L17A/F19A substitutions can augment the α-helicity of the residues located in the α/β-discordant segment (resides 15 to 23) of both wild-type and Arctic-type Aβ40. These results provide a structural basis to link the α-helicity of the α/β-discordant segment with the conformational conversion propensity of Aβ.

The spindle assembly checkpoint (SAC) is essential for ensuring the proper attachment of kinetochores to the spindle and, thus, the precise separation of paired sister chromatids during mitosis. The SAC proteins are recruited to the unattached kinetochores for activation of the SAC in prometaphase. However, it has been less studied whether activation of the SAC also requires the proteins that do not localize to the kinetochores. Here, we show that the nuclear protein RED, also called IK, a down-regulator of human leukocyte antigen (HLA) II, interacts with the human SAC protein MAD1. Two RED-interacting regions identified in MAD1 are from amino acid residues 301-340 and 439-480, designated as MAD1(301-340) and MAD1(439-480), respectively. Our observations reveal that RED is a spindle pole-associated protein that colocalizes with MAD1 at the spindle poles in metaphase and anaphase. Depletion of RED can cause a shorter mitotic timing, a failure in the kinetochore localization of MAD1 in prometaphase, and a defect in the SAC. Furthermore, the RED-interacting peptides MAD1(301-340) and MAD1(439-480), fused to enhanced green fluorescence protein, can colocalize with RED at the spindle poles in prometaphase, and their expression can abrogate the SAC. Taken together, we conclude that RED is required for kinetochore localization of MAD1, mitotic progression, and activation of the SAC.

Serum levels of hepatitis B surface antigen (HBsAg) decrease gradually during chronic hepatitis B virus infection. We investigated the association between levels of HBsAg and HBsAg seroclearance.We studied data from 46 patients who underwent spontaneous seroclearance of HBsAg (median age at seroclearance, 48 y; 87% male; 76% infected with genotype B). There were 46 controls matched for age, sex, and hepatitis B virus genotype, and e antigen status with persistently normal levels of alanine aminotransferase and seropositive for HBsAg. Levels of HBsAg were assessed in serum specimens collected 5 years 3 years, and 1 year before HBsAg seroclearance (or before the last examination, for controls).The decrease in HBsAg level was significant and accelerated within the 3 years before HBsAg seroclearance; there was no significant decrease in serum level of HBsAg among controls (P.0001). The positive predictive value (PPV) for HBsAg seroclearance within 1 year was 36% among patients with HBsAg levels of 200 IU/mL, increasing to 44%, 54%, and 67% among patients with HBsAg levels of 100 IU/mL, 50 IU/mL, or 10 IU/mL, respectively; the negative predictive value (NPV) for these levels was 96% or greater. The combination of HBsAg level less than 200 IU/mL and a decrease of 1 or more log(10) IU/mL in a preceding 2-year period had PPVs of 97% and 100% for HBsAg seroclearance at 1 and 3 years, respectively; the NPVs were 100% and 92%, respectively.The decrease in the level of HBsAg accelerates during the 3 years before HBsAg seroclearance. Levels of HBsAg of 200 IU/mL or less have high NPVs for HBsAg seroclearance; PPVs increase to 97% to 100% when combined with a 1 log IU/mL or more decrease in level of HBsAg over a 2-year period.

We examined the characteristic changes of hepatitis B virus (HBV) in antiviral drug treatment–naive patients referred for pretreatment evaluation in Taiwan during 2008–2012. Over time, we observed substantial decreases in the prevalence of HBV e antigen (HBeAg) and increasing prevalence of the precore G1899A mutation and HBV-DNA levels in HBeAg-positive patients.

Emerging evidence shows that the translocation of apoptosis related factors on cellular organelles, such as mitochondria, endoplasmic reticulum, Golgi apparatus and nucleus, has a crucial role in the apoptotic process. We characterized the effect of paclitaxel (Sigma®) on Golgi involved apoptosis in human hormone refractory prostate cancer.FACScan™ flow cytometric analysis was used to determine cell cycle distribution and the subG1 (apoptosis) population. Protein expression and localization were detected by Western blot, confocal microscopic examination and the sucrose gradient separation technique.Paclitaxel induced Golgi apparatus disassembly and interaction between Golgi complexes and mitochondria. Discontinuous sucrose gradient fractionation was used to determine and collect Golgi containing fractions. Data revealed that paclitaxel induced an increase of Cdk1 activity and DR5 expression on the Golgi complex that was associated with increased cleavage of caspase-8, a DR5 downstream factor, and caspase-3 into catalytically active fragments. Data were validated by confocal immunofluorescence microscopy. Golgi associated effects were inhibited by the Cdk1 inhibitor roscovitine (Sigma), suggesting a critical role for Golgi-Cdk1. Also, paclitaxel caused an increase of nuclear but not of Golgi associated PKC-δ activity. The selective PKC-δ inhibitor rottlerin (Sigma) completely inhibited the increase of Golgi-Cdk1 activity, suggesting that nuclear PKC-δ served as an upstream regulator of Golgi-Cdk1.Data suggest that paclitaxel induces nuclear translocation and activation of PKC-δ, which in turn causes Golgi-Cdk1 activation, leading to Golgi associated DR5 up-regulation, and caspase-8 and 3 activation. Golgi mediated signaling cascades facilitate mitochondria involved apoptotic pathways and at least partly explain the anticancer activity of paclitaxel action.

Poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, plays a crucial role in the regulation of DNA repair. PARP-1 hyperactivation causes DNA damage and cell death. The underlying mechanism is complicated and is through diverse pathways. The understanding of responsible signaling pathways may offer implications for effective therapies. After concentration-response determination of N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG, a PARP-1 activating agent and an environmental mutagen) in human hormone-refractory prostate cancers, the data showed that concentrations below 5μM did not change cell survival but cause a time-dependent up-regulation of intracellular adhesion molecule-1 (ICAM-1) in mRNA, total protein and cell surface levels. Detection of phosphorylation and degradation of IκB-α and nuclear translocation of NF-κB showed that MNNG induced the activation of NF-κB that was responsible for the ICAM-1 up-regulation since PDTC (a NF-κB inhibitor) significantly abolished this effect. However, higher concentrations (e.g., 10μM) of MNNG induced a 61% detachment of the cells which were apoptosis associated with the activation of AMP-activated protein kinase (AMPK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Further identification showed that both AMPK and JNK other than p38 MAPK functionally contributed to cell death. The remaining 39% attached cells were survival associated with high ICAM-1 expression. In conclusion, the data suggest that NF-κB-dependent up-regulation of ICAM-1 plays a key role on cell attachment and survival; whereas, activation of AMPK and JNK participates in cytotoxic signaling pathways in detached cells caused by PARP-1 activation.

Background and aim Hepatic decompensation is a severe on-treatment adverse event for chronic hepatitis C treated with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD). Till now, few papers regarding on-treatment hepatic decompensation have been reported. The study aims to analyze the general feature and predictive factors of on-treatment hepatic decompensation in hepatitis C virus (HCV) genotype 1b-infected patients with advanced fibrosis and compensated cirrhosis who receive treatment with PrOD. Methods A real-word cohort enrolled 189 HCV genotype 1b patients with advanced fibrosis and compensated cirrhosis treated with 12-week PrOD. Clinical and laboratory data were analyzed between patients with and without on-treatment hepatic decompensation. Results The sustained virologic response rate at 12 weeks after treatment was 97.3% in HCV subtype 1b patients with advanced fibrosis and cirrhosis. On-treatment hyperbilirubinemia (total bilirubin >2 mg/dL) occurred in 27 (14.3%) patients, and the incidence of the increase of total and direct form bilirubin was significantly different during treatment between patients with Child-Turcotte-Pugh score 5 and score 6. Five (18.5%) hyperbilirubinemia patients progressed to hepatic decompensation. Older age (adjusted OR: 1.2, 95% CI: 1.0–1.4) and albumin ≤3.6 g/dL (adjusted OR: 10.4, 95% CI: 1.3–81.2) may be two predictors for on-treatment hepatic decompensation by multivariate analysis. Conclusions PrOD is an effective direct-acting antiviral agent for antiviral therapy in HCV genotype 1b patients with advanced fibrosis and cirrhosis. Hyperbilirubinemia is possibly the early warning feature of on-treatment hepatic decompensation. This serious adverse event of on-treatment hepatic decompensation is not common. Older age and low baseline albumin level may be predictive factors.

Androgen refractory prostate cancer is a major clinical challenge. Treatment approaches to prostate cancer are based on various mechanisms that cause malignant cell apoptosis. Of these strategies the anticancer effect of triggering death receptors is well substantiated.Several pharmacological and biochemical assays were used to characterize the apoptotic signaling pathways of the natural dihydrochalcone cryptocaryone in prostate cancer cells.Cryptocaryone induced antiproliferative and apoptotic effects in human androgen independent prostate cancer cells. It induced caspase-8 and 3 activation but did not change total protein levels of death receptors and their ligands. DR5 surface expression was moderately increased by cryptocaryone. Confocal immunofluorescence examination showed that cryptocaryone induced Fas clustering and the association of downstream signaling molecules, including FADD and procaspase-8. DR4 and DR5 aggregation was also induced by cryptocaryone. Data were confirmed by protein profile analysis of detergent resistant membranes showing that Fas, DR4, DR5, FADD and procaspase-8 levels were increased 1.3, 3.5, 4.1, 13.1 and 4.1-fold, respectively, in the lipid raft compartment. Cryptocaryone mediated clustering of death receptors and associated molecules was also detected in nonraft compartments. The distribution between lipid raft and nonraft compartments was validated by the cholesterol depleting agent methyl-beta-cyclodextrin. Cryptocaryone significantly potentiated FasL induced apoptosis in PC-3 cells.We suggest that cryptocaryone has anticancer activity via the stimulation of death receptor and associated molecule clustering, leading to caspase-8 and 3 activation, and apoptosis in prostate cancer cells.

Chemical investigation of the acetonic extract of the leaves and twigs of Taxus sumatrana (Taxaceae) led to the isolation of four new taxane diterpene esters, taiwantaxins A-D (1-4, resp.). Their structures were determined primarily on the basis of 1D- and 2D-NMR techniques as well as MS. Compound 1 is a rearranged taxane diterpenoid possessing an opened oxetane ring moiety containing C(4), C(5), and C(20). The metabolites 2 and 3 belong to a 5/6/6 taxene system having a rare five-membered gamma-lactone ring comprising C(8), C(9), C(10), and C(19). Compound 4 is an example of a taxane diterpene containing a 6/8/6 ring system with a tetrahydrofuran ring comprising C(2), C(3), C(4), and C(20). The 11(15-->1)abeo-taxane diterpenoids, taiwantaxins A-C (1-3, resp.) are lacking an O-bearing functionality at either C(13) or C(14). Compound 2 showed significant cytotoxic activity against human PC-3 tumor cells.

Objective This study presents a conceptual model to investigate the healthcare technology management (HTM) competency required by healthcare IS professionals and the impact of such competency in gaining strategic advantages through information technology (IT) by development of partnerships with people from different divisions of healthcare organizations. Methods First, a scale to measure HTM competency was developed and validated, then it was used to collect the large-scale survey data. Second, the partial least squares (PLS) method was used to empirically test the conceptual model and hypotheses through the large-scale survey data collected. Results The empirical results support the proposed structure for HTM competency encompassing the four skills/knowledge domains: healthcare organization overview, external knowledge networking, healthcare technology integration, and management and interpersonal. The findings indicate that HTM competency positively influences the attitudes of information system (IS) professionals towards their willingness to develop partnerships with healthcare professionals. Conclusions The findings improve our understanding of the concept of HTM competency and its influence on IT–healthcare partnerships. The conceptual model of HTM is of particular value to those concerned with skills/knowledge training and competency development for IS professionals in healthcare organizations. Healthcare organizations can develop HTM profiles for individual IS professionals in accordance with their own organization contexts. Executive management can take advantage of such HTM profiles to assist in making succession-planning decisions by evaluating the competency levels and development needs of their employees.