Relationship Between Platelets and the Clinical Efficacy of Umbilical Cord Mesenchymal Stem Cells for HBV-Related Acute-on-Chronic Liver Failure and Liver Cirrhosis: A Preliminary Clinical Study.

BACKGROUND: Previous studies have found that the production of platelets could enhance the therapeutic effects of stem cells. Nevertheless, there are still no articles reporting on the relationship between platelets and the clinical efficacy of umbilical cord mesenchymal stem cells (UCMSCs) for HBV-related acute-on-chronic liver failure (ACLF) and liver cirrhosis (LC). METHODS: In this retrospective observational study, patients who met the criteria were included. Patients were divided into subgroups according to the aims of this study. In the first part, the platelet count changes of ACLF and patients with LC after UCMSC therapy were compared and analyzed. Subgroup analysis based on UCMSC infusion times and patient age was also performed. In the second part, patients in the ACLF group and LC group were further divided into subgroups according to their platelet levels. Their clinical characteristics, demographics, and biochemical factors were compared. RESULTS: This study enrolled 64 patients with ACLF and 59 patients with LC. In both groups, platelet levels declined similarly. Compared with the short-course UCMSC treatment group (≤4 times), patients with ACLF and patients with LC with long-course UCMSC treatment (>4 times) showed an overall increasing trend. Younger patients with LC (<45 years) had significantly higher platelet levels than older patients with LC (≥45 years). However, this age difference was not present in the ACLF group. The median TBIL decrease and cumulative TBIL decrease were not significantly different between patients with high PLT and patients with low PLT after UCMSC transfusions. For patients with ACLF, the cumulative TBIL decrease and the median TBIL decrease were significantly greater than those of patients with LC at the same platelet level after UCMSC treatment. However, this difference was not observed at all time points. CONCLUSION: Trend of the platelet levels for HBV-related patients with ACLF and LC after UCMSC treatment did not parallel and varied according to treatment times and patients' age. Platelet levels did not affect the efficacy of MSCs for patients with ACLF or LC.

Can Epstein-Barr virus-deoxyribonucleic acid load after induction chemotherapy combined with American Joint Committee on Cancer stage determine the chemotherapy intensity of locally advanced nasopharyngeal carcinoma?

BACKGROUND: Induction chemotherapy (IC) comprising docetaxel, cisplatin, and fluorouracil (TPF), combined with concurrent chemoradiotherapy (CCRT) effectively improves the survival rate of locally advanced nasopharyngeal carcinoma (LA-NPC). Selecting patients whose risk of tumor recurrence and metastasis is high and the appropriate chemotherapy intensity is a concern. We combined tumor-node-metastasis staging with the load of Epstein-Barr virus (EBV) after IC to select the individualized chemotherapy strength. METHODS: The clinical data and prognostic factors of patients with stage III-IV LA-NPC treated with TPF IC combined with CCRT were analyzed retrospectively. The conventional treatment group received the standard three cycles TPF IC combined with CCRT. For the new treatment group, the cycles of IC were determined according to whether the EBV-DNA disappeared completely after a certain course of IC, if so, subsequent IC was stopped and the chemoradiotherapy stage was entered. Propensity score matching (PSM) was performed at a ratio of 1:1 to balance baseline characteristics. Survival outcomes and adverse events between the conventional treatment group and the new method treatment group were compared. RESULTS: The study included 256 patients, among whom 192 were matched successfully into 96 pairs. The patients were followed up for a median of 51 months. The proportions of patients receiving three, two, and one cycle of IC after PSM in the routine and new treatment cohorts were 93.8%, 3.1%, 3.1% versus 21.9%, 49.0%, 24.0%, respectively. However, their 3-year distant metastasis-free survival, local recurrence-free survival, progression-free survival, and overall survival did not differ significantly. The incidence of grade 3-4 neutropenia toxicity in CCRT decreased significantly in patients receiving the new treatment method compared with that in the conventional treatment group (p = 0.026). CONCLUSION: Combining TNM stage and EBV-DNA load after IC to determine the courses of IC in patients with LA-NPC did not alter the curative effect but decreased toxicity.

High Expression of POGK Predicts Poor Prognosis in Patients with Hepatocellular Carcinoma.

OBJECTIVE: Kruppel-associated box (KRAB) proteins reportedly play a dual role in neoplastic transformation. At present, little is known about the function of the proteins encoded by the human pogo transposable element derived with KRAB domain (POGK) gene. Herein, we evaluated the prognostic significance of POGK expression in patients with hepatocellular carcinoma (HCC). METHODS: The data of HCC patients was downloaded from The Cancer Genome Atlas (TCGA) database. To determine the relationship between POGK and clinical features, logistic regression was applied. Cox regression and Kaplan-Meier analyses were used to evaluate the correlation between POGK and survival rates. Gene ontology (GO) analysis and Gene set enrichment analysis (GSEA) were conducted to identify the enriched pathways and functions associated with POGK. RESULTS: A total of 374 HCC patients were identified in TCGA. POGK was significantly upregulated in HCC and correlated with tumor status (p = 0.036), race (p = 0.025), weight (p = 0.002), body mass index (p = 0.033), histologic grade (p < 0.001), and alpha-fetoprotein (p < 0.001). High POGK expression in HCC patients correlated with a poor outcome in terms of overall survival (p = 0.0018), progression-free survival (p = 0.0087), relapse-free survival (p = 0.045), and disease-specific survival (p = 0.014), according to Kaplan-Meier analysis. Receiver operating characteristic curve analysis showed that the area under the curve of POGK expression for HCC diagnosis was 0.891. GSEA showed that high POGK expression might activate mitotic prometaphase, kinesins, homologous DNA pairing and strand exchange, MET activates PTK2 signaling pathway, G1 to S cell cycle control, Aurora B pathway, ncRNAs involved in WNT signaling pathway, hepatitis C, and ncRNAs involved in the STAT3 signaling pathway. POGK expression correlated with the abundance of adaptive and innate immunocytes in HCC. CONCLUSION: High expression of POGK has high diagnostic and prognostic values in patients with HCC. Moreover, POGK expression is correlated with immune infiltration in HCC.

The relationship between zinc deficiency and infectious complications in patients with hepatitis B virus-related acute-on-chronic liver failure.

Background: The prevalence of zinc deficiency is high in patients with chronic liver disease, but few studies have hitherto explored the relationship between the serum zinc level and hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). This study aimed to assess the association between zinc deficiency and infectious complications, and model for end-stage liver disease (MELD) score in patients with HBV-related ACLF. Methods: Patients with HBV-related ACLF from the Department of Infectious Diseases of the Third Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between January 2019 and December 2019 were retrospectively analysed in this study. Their demographic, clinical, and laboratory data were retrieved from the hospital information system and analysed. The Student's t-test was used for normally distributed continuous variables between two groups and the Chi-square test was used for categorical data. Univariate and multivariate logistic regression analyses were applied to identify independent parameters. Results: A total of 284 patients were included in this study, including 205 liver cirrhosis and 79 non-cirrhosis patients. The proportion of patients with zinc deficiency was the highest (84.5%), followed by subclinical zinc deficiency (14.1%) and normal zinc level (1.4%). Patients in the zinc deficiency group had a higher MELD score than the subclinical zinc deficiency or normal zinc group (P = 0.021). Age, total bilirubin, and serum zinc level were independent factors for infection (Ps < 0.05). The serum zinc level in patients without complications at admission was significantly higher than that in patients with complications (P = 0.004). Moreover, the serum zinc level in patients with prothrombin time activity (PTA) of <20% was significantly lower than that in patients with 20% ≤ PTA < 30% (P = 0.007) and that in patients with 30% ≤ PTA < 40% (P < 0.001). Conclusions: Zinc deficiency is common in patients with HBV-related ACLF. Zinc deficiency is closely associated with infectious complications and MELD score in patients with HBV-related ACLF.

Molecular mechanism of the TGF­ß/Smad7 signaling pathway in ulcerative colitis.

Aberrant TGF­ß/Smad7 signaling has been reported to be an important mechanism underlying the pathogenesis of ulcerative colitis. Therefore, the present study aimed to investigate the effects of a number of potential anti­colitis agents on intestinal epithelial permeability and the TGF­ß/Smad7 signaling pathway in an experimental model of colitis. A mouse model of colitis was first established before anti­TNF­α and 5­aminosalicyclic acid (5­ASA) were administered intraperitoneally and orally, respectively. Myeloperoxidase (MPO) activity, histological index (HI) of the colon and the disease activity index (DAI) scores were then detected in each mouse. Transmission electron microscopy (TEM), immunohistochemical and functional tests, including Evans blue (EB) and FITC­dextran (FD­4) staining, were used to evaluate intestinal mucosal permeability. The expression of epithelial phenotype markers E­cadherin, occludin, zona occludens (ZO­1), TGF­ß and Smad7 were measured. In addition, epithelial myosin light chain kinase (MLCK) expression and activity were measured. Anti­TNF­α and 5­ASA treatments was both found to effectively reduce the DAI score and HI, whilst decreasing colonic MPO activity, plasma levels of FD­4 and EB permeation of the intestine. Furthermore, anti­TNF­α and 5­ASA treatments decreased MLCK expression and activity, reduced the expression of Smad7 in the small intestine epithelium, but increased the expression of TGF­ß. In mice with colitis, TEM revealed partial epithelial injury in the ileum, where the number of intercellular tight junctions and the expression levels of E­cadherin, ZO­1 and occludin were decreased, all of which were alleviated by anti­TNF­α and 5­ASA treatment. In conclusion, anti­TNF­α and 5­ASA both exerted protective effects on intestinal epithelial permeability in an experimental mouse model of colitis. The underlying mechanism may be mediated at least in part by the increase in TGF­ß expression and/or the reduction in Smad7 expression, which can inhibit epithelial MLCK activity and in turn reduce mucosal permeability during the pathogenesis of ulcerative colitis.

Prospective, multicentre, randomised controlled trial comparing the seroclearance of HBsAg between combination therapy of peg-interferon alpha and tenofovir with tenofovir monotherapy in nucleos(t)ide analogue-experienced patients with HBV-related liver fibrosis: a study protocol.

INTRODUCTION: Combination antiviral therapy of nucleos(t)ide analogue (NA) and pegylated interferon alpha (peg-IFN alpha) decrease hepatitis B virus (HBV) surface antigen (HBsAg) levels to achieve functional cure and improve long-term prognosis in chronic hepatitis B patients. However, for hepatitis B-related liver fibrosis, studies on combination of these two medicines are limited. This study was designed to compare the efficacy between peg-IFN alpha combined with tenofovir (TDF) and TDF monotherapy for the clearance of HBsAg in NA-experienced patients with HBV-related liver fibrosis. METHODS AND ANALYSIS: This study was designed to be a prospective, multicentre, open, randomised controlled study. A total of 272 patients with HBV-related liver fibrosis will be randomised into the combination therapy group or the monotherapy group at a 1:1 ratio. Participants in the combination group will receive subcutaneous injections of peg-IFN alpha 180 µg per week for 48 weeks combined with oral TDF 300 mg daily. Participants in the monotherapy group will receive 300 mg oral TDF daily alone. All participants will undergo long-term treatment with TDF and will be followed up at the outpatient department for 144 weeks after randomisation. Clinical symptoms, laboratory tests and examination indicators will be collected at each follow-up time point, and adverse events will be recorded. The primary endpoint is serological clearance rate of HBsAg at 48 weeks. ETHICS AND DISSEMINATION: The ethics committee of the Third Affiliated Hospital at Sun Yat-sen University approved this study (Approval Number: (2020)02-183-01). The results of the study will be presented at relevant meetings and published in an appropriate journal after the completion of the trial and the analysis of the data. TRIAL REGISTRATION NUMBER: NCT04640129.

The 96-week clinical outcomes after cessation of nucleos(t)ide analog treatment in chronic hepatitis B patients.

BACKGROUND: Chronic hepatitis B (CHB) patients have a high virological relapse rate after cessation of nucleos(t)ide analog (NA) treatment, but the clinical outcome remains unclear. This study aimed to investigate the 96-week clinical outcomes and the risk factors for relapse in CHB after cessation of NAs. METHODS: This study was a prospective trial; 74 eligible patients were enrolled. The patients underwent NA cessation and follow-up according to the 2012 Asian Pacific Association for the Study of the Liver Guideline. Symptoms, biochemical (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, urea nitrogen, creatinine), virological data (hepatitis B surface antigen [HBsAg], hepatitis B e antigen [HBeAg], hepatitis B e antibody [HBeAb], hepatitis B virus [HBV] DNA levels), and color Doppler ultrasound examination results were recorded and analysed. RESULTS: After NA cessation, 19 cases were HBsAg-negative without relapse during the 96-week follow-up. Of the 55 cases of HBsAg-positive after cessation, four types of clinical outcomes were observed. Twelve patients had no relapse during the 96-week follow-up (type A, 21.8%), 7 patients underwent virological relapses but spontaneously had a non-virological relapse (type B, 12.7%), 10 patients maintained virological relapse (type C, 18.2%), and 26 patients turned to clinical relapse, received NA retreatment, and achieved ALT normalization and negative conversion of HBV DNA within 12 months (type D, 47.3%). The 2-year overall cumulative rates of virological and clinical relapses were 58.1% and 24.3%, respectively. Independent factors associated with virological relapse were duration of negative HBV DNA, EOT (end of treatment) HBsAg, and original status of HBeAg. The EOT HBsAg was also an independent factor for clinical relapse. CONCLUSIONS: There are four types of clinical outcomes in patients with CHB after cessation of NA treatment. Further research is needed to explore the mechanism of different clinical outcomes. The EOT HBsAg level is an independent factor associated with both virological and clinical relapse.

Factors associated with non-compliance with breastfeeding recommendation: a retrospective survey in hepatitis B virus-infected mothers who had taken Nucleos(t)ide analogs during pregnancy.

BACKGROUND: We encourage Hepatitis B virus-infected mothers to breastfeed postpartum, even when continuing pregnancy category B nucleos(t)ide analogs (NAs) treatment. However, a large proportion of the Hepatitis B virus-infected mothers were noncompliant with this breastfeeding recommendation. This study aimed to investigate the factors associated with noncompliance with breastfeeding recommendation in Hepatitis B virus-infected mothers who had received NAs treatment during pregnancy. METHODS: A total of 155 mothers with chronic hepatitis B receiving NAs treatment for preventing mother-to-child transmission during the late gestation period were included and divided into exclusive breastfeeding (n = 63), mixed feeding (n = 34), and artificial feeding (n = 58) groups according to the postpartum feeding methods. Independent variables associated with feeding methods were analyzed using logistic regression analysis. RESULTS: Compared to the breastfeeding and mixed feeding groups, the artificial feeding group had significantly more multiparity, later postpartum timing of stopping NAs treatment, and a lower proportion of having knowledge of NAs medications (all P < 0.05). In addition, multivariable logistic regression analysis confirmed that multiparity, later postpartum timing of stopping NAs treatment, and lacking knowledge of medication were independent factors associated with noncompliance with breastfeeding recommendation. CONCLUSIONS: Hepatitis B virus-infected mothers who stopped NAs treatment at late postpartum period or had less knowledge of medication were more likely to be noncompliant with breastfeeding recommendation. Strengthening health education for participants taking NAs may be an important method to improve compliance with breastfeeding recommendation.

Joá yellow blotch-associated virus, a new alphanucleorhabdovirus from a wild solanaceous plant in Brazil.

We identified a novel plant rhabdovirus infecting native joá (Solanum aculeatissimum) plants in Brazil. Infected plants showed yellow blotches on the leaves, and typical enveloped bacilliform rhabdovirus particles associated with the nucleus were seen in thin sections by electron microscopy. The virus could be graft-transmitted to healthy joá and tomato plants but was not mechanically transmissible. RT-PCR using degenerate plant rhabdovirus L gene primers yielded an amplicon from extracted total RNA, the sequence of which was similar to those of alphanucleorhabdoviruses. Based on close sequence matches, especially with the type member potato yellow dwarf virus (PYDV), we adopted a degenerate-primer-walking strategy towards both genome ends. The complete genome of joá yellow blotch-associated virus (JYBaV) is comprised of 12,965 nucleotides, is less than 75% identical to that of its closest relative PYDV, and clusters with PYDV and other alphanucleorhabdoviruses in L protein phylogenetic trees, suggesting that it should be taxonomically classified in a new species in the genus Alphanucleorhabdovirus, family Rhabdoviridae. The genome organization of JYBaV is typical of the 'PYDV-like' subgroup of alphanucleorhabdoviruses, with seven genes (N-X-P-Y-M-G-L) separated by conserved intergenic regions and flanked by partly complementary 3' leader and 5' trailer regions.

Efficacy and Safety of Sofosbuvir-Based Direct-Acting Antiviral Agents Treatment for Patients with Genotype 3/6 Hepatitis C Virus Infection.

Aims: The aim is to evaluate the efficacy and safety of Sofosbuvir- (SOF-) based direct-acting antiviral agents (DAAs) treatment for patients with genotype (GT) 3/6 hepatitis C virus (HCV) infection. Methods: Patients infected with GT 3/6 HCV and treated with SOF-based DAAs were enrolled in this prospective, open, single-center, and real-world study. Drugs included Sofosbuvir (SOF), Velpatasvir (VEL), Daclatasvir (DCV), and Ribavirin (RBV). The treatment regimens included SOF + RBV for 24 weeks, SOF + DCV ± RBV for 12/24 weeks, and SOF/VEL ± RBV for 12 weeks. Results: A total of 54 patients were included. Age was 42.5 ± 10.4 years. Baseline HCV RNA was 6.29 ± 0.89log10 IU/mL. The numbers of GT 3a, 3b, and 6a patients were 10, 12, and 32, respectively. The numbers of chronic hepatitis, compensated cirrhosis, and decompensated cirrhosis patients were 39, 9, and 6, respectively. In patients with chronic hepatitis C and liver cirrhosis, sustained virological response 12 weeks after the end of treatment (SVR12) was 97.4% and 96.7%, respectively, and rapid virological response (RVR) was 75.0% and 57.1%, respectively. SVR12 of GT3a, GT3b, and GT6a was 100%, 83.3%, and 97%, respectively. ALT normality rate in chronic hepatitis group is higher than that in cirrhosis group at 4 weeks of treatment (89.7% versus 60.0%, p = 0.033) and at 12 weeks after EOT (94.9% versus 66.7%, p = 0.021). The overall incidence rate of adverse events was 44.4%, with fatigue being the most common (13.0%). Conclusion: SOF-based DAAs regimen can achieve ideal SVR12 for Chinese patients with both GT3a and GT6a HCV infection. The tolerance and safety of SOF-based DAAs regimen are good.

The safety of antiviral therapy and drug withdrawal for the prevention of mother-to-child transmission of HBV during pregnancy.

The efficacy of prenatal antiviral therapy (AVT) for preventing the vertical transmission of hepatitis B virus (HBV) is well demonstrated. However, data are limited regarding the safety of postpartum cessation of AVT, which may induce alanine aminotransferase (ALT) elevation. We aimed to investigate the necessity of prolonging maternal AVT after delivery. Chronic hepatitis B mothers at the immune-tolerant phase with HBV DNA levels >6 log10 IU/mL were prospectively enrolled and received AVT during the third trimester until delivery. Patients were offered to discontinue AVT either at delivery or postpartum week (PPW) 6. In addition, mothers who deferred AVT during pregnancy served as the control group. All mothers were followed until PPW 52 for clinical and virological parameters of hepatitis flares. Among 118 mothers recruited, 91 received AVT with 53 (group A) and 24 (group B) discontinue their treatment at delivery and PPW 6, respectively. Twenty-seven mothers who deferred AVT during pregnancy were followed as the control (group C). A total of 104 of 118 mothers who completed the study, 50% (52/104) had postpartum-elevated ALT levels, which were mild and moderate except 6 of 104 (5.77%) of patients had levels ≥5 times the upper limit of normal; 70% (36/52) of the ALT flares occurred within 12 weeks after delivery. In subgroup analyses, the frequency of ALT elevation was similar among the groups A vs B vs C (50.9% [27/53] vs 58.3% [14/24] vs 40.7% [11/27], respectively; P = .447), as well as the mean peak ALT level (108.4/74.1/126.7 U/L in groups A/B/C, respectively; P = .291). Although postpartum ALT flares were common for mothers with or without AVT during pregnancy, most cases of ALT elevation were mild to moderate. Our study observed that extending AVT to PPW 6 did not affect maternal outcomes and ATV should be discontinued at birth. Close monitoring is warranted as severe flares rarely occurred.

CD19+CD24hiCD38hi regulatory B cells: a potential immune predictive marker of severity and therapeutic responsiveness of hepatitis C.

OBJECTIVES: Hepatitis C virus (HCV) infection is associated with abnormal immune responses. Since regulatory T (Tregs) and B (Bregs) cells modulate the progression of infectious diseases, this study aimed at examining how these cells are involved with the development of HCV infection. METHODS: The frequencies of circulating Bregs and Tregs were characterized using flow cytometry. Both the association and dynamic changes of these cells with related clinical parameters were analyzed after Direct-Acting Antiviral (DAA) agent treatments. Additionally, both regulatory B and T and naïve B and T cells were sorted and stimulated with healthy or HCV sera in vitro. RESULTS: Bregs frequency in HCV-infected patients increased significantly and were positively correlated with levels of sera HCV RNA load, Alanine aminotransferase (AST) and total bilirubin (TBILI). Additionally, the increased Bregs returned to normal levels after DAA treatment. However, Tregs increased markedly in patients with HCV-cirrhosis and were significantly associated with Aspartate aminotransferase to Platelet Ratio Index (APRI) and Fibrosis 4 (FIB-4) scores. Furthermore, HCV sera doesn't expand either Tregs or Bregs, however, it does induce the IL-10 expression in B cells although it fails to induce FOXP3 expression in CD4+ T cells. CONCLUSIONS: Increased Bregs not only may be associated with poor viral eradication and liver injury but also may provide a predictive marker of HCV disease therapeutic efficacy following DAA-treatment. HCV sera may selectively induce Bregs. Tregs probably do not control disease status in the early stages but may contribute to the progression of liver fibrosis in the late stages of HCV infection.

An Immuno-Clinic score model for evaluating T cell immunity and predicting early antiviral therapy effectiveness in chronic hepatitis B.

We generated an Immuno-Clinic score (ICS) model to evaluate T cell immunity based on the clustering of antiviral cytokines and inhibitory molecules in 229 naïve chronic hepatitis B (CHB) patients. 126 patients receiving antiviral therapy were used to validate the model for predicting antiviral therapy effectiveness. Through receiver-operator characteristic curve analysis, the area under the curve, sensitivity, and specificity of the ICS model were 0.801 (95%CI 0.703-0.900), 0.727, and 0.722, respectively. The cut-off value was 0.442. Re-evaluation of T cell immunity in different phases of CHB showed that patients in the immune tolerant phase had the lowest percentage of ICS-high (15%), while patients in the inactive carrier phase had the highest percentage of ICS-high (92%). Patients in the immune active and gray zone phases had 17% and 56% ICS-high, respectively. Elevation of ICS as early as four weeks after treatment could predict the effectiveness of hepatitis B virus (HBV) DNA loss and normalization of alanine aminotransferase, while eight weeks after treatment could predict HBV surface antigen decline. Thus, this ICS model helps clinicians choose an optimal time for initiating antiviral therapy and predicting its efficacy.

Barriers to hepatitis C virus treatment in Guangdong Province.

BACKGROUND: The objective of this study is to analyze the causes of nontreatment among patients with hepatitis C virus (HCV) infection and increase the cure rate of chronic hepatitis C in Guangdong Province. METHODS: We performed both retrospective survey and prospective study in a cohort of 435 outpatients in our center to analyze the subjective and objective causes of HCV non-treatment. RESULTS: Among 1,931 patients, 435 did not receive anti-viral therapy (AVT), and, in 37 of these patients, the virus load was persistently negative. In the remaining 398 patients, HCV RNA repeatedly tested positive. The causes of nontreatment in these patients included economic constraints (n=77, 17.7%); old age, fear of treatment-related side effects, uncertainty (n=46, 10.6%); fear of potential adverse effects on fertility (n=37, 8.5%); fear of interferon side-effects (n=21, 4.8%); and dosing inconvenience during study or work (n=9, 2.1%). In addition, 137 patients (31.5%) had medical contraindications including decompensated hepatic cirrhosis (n=55, 12.6%), uncontrolled autoimmune diseases (e.g., autoimmune hepatitis and systemic lupus erythematosus) (n=19, 4.4%), renal dysfunction (n=21, 4.8%), thyroid disease (hyperthyroidism) (n=16, 3.7%), depression (n=14, 3.2%), uncontrolled diabetes (n=5, 1.1%), severe lung disease (e.g., active tuberculosis) (n=4, 0.9%), symptomatic heart disease (n=3, 0.7%), alcoholism (n=15, 3.4%), drug addiction (n=31, 7.1%), lack of physician recommendation (n=2, 0.5%), and unknown reasons (n=23, 5.3%). CONCLUSIONS: The low rate of AVT in HCV-infected patients is related to many factors. In Guangdong province, HCV patients do not receive AVT mainly due to economic constraints, patients' fear of side effects, and the presence of contraindications.

PAP-1 ameliorates DSS-induced colitis with involvement of NLRP3 inflammasome pathway.

BACKGROUND: Macrophages are a primary type of innate immune cells activated in colitis. Kv1.3 channel is one of the major potassium channels in macrophages. NLRP3 inflammasome is a downstream molecule of Kv1.3 channel. PAP-1, a specific Kv1.3 channel blocker, has been shown to have immune-regulatory effects. OBJECTIVE: To investigate the effect of PAP-1 on intestinal inflammation in DSS-induced colitis and explore its possible mechanism. METHODS: C57BL/6 mice were divided into four groups: normal control group, normal+PAP-1 injection group, DSS model group, DSS model+PAP-1 injection group. Experimental colitis was induced by 5% DSS treatment; mice were injected intraperitoneally with PAP-1 from the first day for 7 consecutive days; then all mice were sacrificed, followed by isolation of colon tissue, peritoneal macrophages and spleen macrophages. The anti-inflammatory effects of PAP-1 and the expression levels of Kv1.3, iNOS, pro-IL-1ß, IL-1ß and NLRP3 inflammasome were measured. RESULTS: PAP-1 reduced DSS-induced colonic pathological damage, DAI score, MPO activity and levels of IL-1, IL-6, TNF-a, IL-18. Compared with the DSS model group, the expression of Kv1.3, iNOS, NLRP3, ASC, caspase-1p20, pro-IL-1ß and IL-1ß in colon were decreased in the DSS-induced colitis mice with PAP-1 injection. PAP-1 also reduced the expression of Kv1.3, iNOS, NLRP3, caspase-1p20 and IL-1ß on macrophages in colitis mice. CONCLUSION: PAP-1 had protective effects on DSS-induced colitis, which might be ascribed to the regulation of NLRP3 inflammasome pathway. Therefore, we found that PAP-1 was useful as a therapeutic agent in IBD and suggested a potential important role of PAP-1 in NLRP3 inflammasome-associated diseases.

Resolvin D1 Resolve Inflammation in Experimental Acute Pancreatitis by Restoring Autophagic Flux.

BACKGROUND: Acute pancreatitis (AP) is a common acute gastrointestinal disorders. Increasing evidence indicated that autophagy is involved in the development of AP. Resolvin D1 is an endogenous pro-resolving lipid mediator, which can protect mice from cerulein-induced acute pancreatitis and facilitate autophagy in macrophage, but its mechanism remians unclear. AIMS: To investigate the effect of resolvin D1 on autophagy in mouse models of cerulein-induced AP. METHODS: C57BL/6 mice were randomly divided into control group, AP group and resolvin D1 group. The models of cerulein-induced AP were constructed by intraperitoneally cerulein. Resolvin D1 group was established by intraperitoneally resolvin D1 based on AP models, simultaneously, control group received normal saline. The severity of AP, the level of inflammatory cytokines, the number of autophagic vacuoles, and the expression of autophagy-related markers were evaluated among three groups. RESULTS: The AP models were established successfully. Compared to control group, the number of autophagic vacuoles and expressions of autophagy-related markers including Beclin-1, p62 and LC3-II were increased in AP models, In contrast, the degree of inflammation and levels of inflammatory cytokines in AP models were reduced after resolvin D1 treatment. Moreover, resolvin D1 attenuated the number of autophagic vacuoles and expressions of autophagy-related markers. CONCLUSIONS: Autophagic flux is impaired in cerulein-induced AP. Resolvin D1 ameliorate the severity of mice with cerulein-induced acute pancreatitis, possible attributing to its reducing impaired autophagy and restoring autophagic flux.

48-Week Outcome after Cessation of Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Patient and the Associated Factors with Relapse.

Background and Aims: We aimed to ascertain the feasibility and safety of NA cessation, the status of patients after cessation, and the predictive factors for relapse and subsequent retreatment. Methods: A total of 92 patients were enrolled in this prospective study. Patients were monitored every month for the first 3 months after cessation and every 3 months thereafter. Results: Sixty-two patients finished 48 weeks of follow-up. None died or developed liver failure, cirrhosis, or HCC. The 62 patients could be divided into 4 categories according to the 48-week clinical development of relapse. Virologic relapses occurred in 39 (62.9%) patients, with 72.7% occurring in the first 24 weeks in origin HBeAg positive patients and 82.4% in the first 12 weeks in origin HBeAg negative patients. Age (OR = 1.06, 95% CI = 1.02-1.10; p = 0.003), the HBsAg level (OR = 2.21, 95% CI = 1.47-3.32; p < 0.001), and positive origin HBeAg status (OR = 0.32, 95% CI = 0.14-0.74; p = 0.008) were predictive factors to virologic relapse. HBV DNA level (OR = 1.34, 95% CI = 1.13-1.58; p < 0.001) was predictive factor to retreatment. Conclusions: NA cessation is safe under supervision. Age, HBsAg level, and origin HBeAg status can be predictive factors for virologic relapse. The study was submitted to ClinicalTrials.gov Protocol Registration and Results System with the assigned NCT ID NCT02883647.

Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: A randomized controlled trial.

Mortality from hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) is high due to limited treatment options. Preclinical and clinical investigations have proved that treatment with mesenchymal stromal cells (MSCs) is beneficial for recovery from liver injury. We hypothesized that the outcome of HBV-related ACLF would be improved by MSC treatment. From 2010 to 2013, 110 patients with HBV-related ACLF were enrolled in this open-label, nonblinded randomized controlled study. The control group (n = 54) was treated with standard medical therapy (SMT) only. The experimental group (n = 56) was infused weekly for 4 weeks with 1.0 to 10 × 105 cells/kg allogeneic bone marrow-derived MSCs and then followed for 24 weeks. The cumulated survival rate of the MSC group was 73.2% (95% confidence interval 61.6%-84.8%) versus 55.6% (95% confidence interval 42.3%-68.9%) for the SMT group (P = 0.03). There were no infusion-related side effects, but fever was more frequent in MSC compared to SMT patients during weeks 5-24 of follow-up. No carcinoma occurred in any trial patient in either group. Compared with the control group, allogeneic bone marrow-derived MSC treatment markedly improved clinical laboratory measurements, including serum total bilirubin and Model for End-Stage Liver Disease scores. The incidence of severe infection in the MSC group was much lower than that in the SMT group (16.1% versus 33.3%, P = 0.04). Mortality from multiple organ failure and severe infection was higher in the SMT group than in the MSC group (37.0% versus 17.9%, P = 0.02). CONCLUSION: Peripheral infusion of allogeneic bone marrow-derived MSCs is safe and convenient for patients with HBV-related ACLF and significantly increases the 24-week survival rate by improving liver function and decreasing the incidence of severe infections. (Hepatology 2017;66:209-219).

24 versus 48 Weeks of Peginterferon Plus Ribavirin in Hepatitis C Virus Genotype 6 Chronically Infected Patients with a Rapid Virological Response: A Non-Inferiority Randomized Controlled Trial.

OBJECTIVES: The optimal treatment of hepatitis C virus (HCV) genotype 6 is unclear owing to its limited geographic distribution. Because of a high predictive value of rapid virological response (RVR) for sustained virological response (SVR), we conducted an open-label randomized controlled trial to compare 24- and 48-week peginterferon/ribavirin combination therapy for patients with HCV genotype 6 in Southern China who achieved an RVR. METHODS AND FINDINGS: Treatment-naive, non-cirrhotic patients with chronic hepatitis C genotype 6 were treated with pegylated interferon α-2a (180 µg/week) and ribavirin (800-1,200 mg, according to weight) for 4 weeks. Patients who achieved an RVR, which was defined as HCV RNA negativity at week 4 (<50 IU), were randomized to receive either an additional 20 or 44 weeks of treatment (24- and 48-week treatment groups, respectively). The primary outcome measure was SVR. From January 2011 to June 2014, 152(152/210, 72.4%) patients with HCV genotype 6a and RVR were randomized 1:1 to the 24- or 48-week treatment group. The SVR rates in the 24- and 48-week groups in the intention-to-treat analysis were 90.8% (69/76) and 88.2% (67/76), respectively; those in the per-protocol analysis were 95.7% (67/70) and 97.0% (64/66), respectively. More patients in the 48-week group had anemia (46.1% vs. 28.9%, P = 0.03), but other adverse events were comparable between the groups. The limitation of the present study was that only patients from Southern China were enrolled which may inhibit the extensive application of the findings. CONCLUSION: Twenty-four weeks of peginterferon/ribavirin combination therapy was non-inferior to 48 weeks in patients with HCV genotype 6a in Southern China who achieved an RVR. TRIAL REGISTRATION: ClinicalTrials.gov NCT01263860.