Lecithin-cholesterol acyltransferase is a potential tumor suppressor and predictive marker for hepatocellular carcinoma metastasis

BACKGROUND Hepatocellular carcinoma(HCC)is a major cause of cancer mortality worldwide,and metastasis is the main cause of early recurrence and poor prognosis.However,the mechanism of metastasis remains poorly understood.AIM To determine the possible mechanism affecting HCC metastasis and provide a possible theoretical basis for HCC treatment.METHODS The candidate molecule lecithin-cholesterol acyltransferase(LCAT)was screened by gene microarray and bioinformatics analysis.The expression levels of LCAT in clinical cohort samples was detected by quantitative realtime polymerase chain reaction and western blotting.The proliferation,migration,invasion and tumor-forming ability were measured by Cell Counting Kit-8,Transwell cell migration,invasion,and clonal formation assays,respectively.Tumor formation was detected in nude mice after LCAT gene knockdown or overexpression.The immunohistochemistry for Ki67,E-cadherin,N-cadherin,matrix metalloproteinase 9 and vascular endothelial growth factor were performed in liver tissues to assess the effect of LCAT on HCC.Gene set enrichment analysis(GSEA)on various gene signatures were analyzed with GSEA version 3.0.Three machine-learning algorithms(random forest,support vector machine,and logistic regression)were applied to predict HCC metastasis in The Cancer Genome Atlas and GEO databases.RESULTS LCAT was identified as a novel gene relating to HCC metastasis by using gene microarray in HCC tissues.LCAT was significantly downregulated in HCC tissues,which is correlated with recurrence,metastasis and poor outcome of HCC patients.Functional analysis indicated that LCAT inhibited HCC cell proliferation,migration and invasion both in vitro and in vivo.Clinicopathological data showed that LCAT was negatively associated with HCC size and metastasis(HCC size≤3 cm vs 3-9 cm,P<0.001;3-9 cm vs>9 cm,P<0.01;metastatic-free HCC vs extrahepatic metastatic HCC,P<0.05).LCAT suppressed the growth,migration and invasion of HCC cell lines via PI3K/AKT/mTOR signaling.Our results indicated that the logistic regression model based on LCAT,TNM stage and the serum level of α-fetoprotein in HCC patients could effectively predict high metastatic risk HCC patients.CONCLUSION LCAT is downregulated at translational and protein levels in HCC and might inhibit tumor metastasis via attenuating PI3K/AKT/mTOR signaling.LCAT is a prognostic marker and potential therapeutic target for HCC.

Seven amino acid peptide mimic from HVR1 of HCV influences cytokine profile of immune cells

Objective:To investigate the actions of cytokine profile in the immune cells by a seven amino acid peptide mimic from HVR1 of HCV (GQTYTSG,named 7P).Methods:The peripheral blood mononuclear cells (PBMCs) from 17 healthy blood donors were stimulated with 7P,and the cytokine levels in CD4+CD8-,CD4-CD8+ T cells,NK,NKT cells were analyzed by the intracellular cytokine staining.Results:The frequency of cells which secreted interferon-γ (IFN-γ) was found to be significantly increased in all cells,interleukin-10(IL-10) was significantly increased in CD4+CD8-,CD4-CD8+ T cells but decreased in NK,NKT cells,and tumor necrosis factor-α (TNF-α) was decreased in CD4+CD8-,CD4-CD8+ but increased in NK cells.Conclusion:7P could induce a cytokine profile in different immune cells in vitro and there was some difference between the CD4+CD8-,CD4-CD8+ T cells which represented the adaptive immunity cells and NK,NKT cells which represented the innate immunity cells.This kind of variation of cytokine profile might contribute to anti-virus and anti-inflammatory immune reaction.

the rtA181 Mutation Produces Similar Clinical and Cellular Characteristics in Patients infected with Hepatitis B Virus Genotypes B and C

Objective To investigate the association between HBV genotypes and characteristics of rt A181 mutation. Methods Total of 85 chronic hepatitis B(CHB) patients who appeared rt A181 mutation after nucleos(t)ide analogs(NAs) therapy were enrolled in this study. Levels of serum ALT, AST, HBV DNA and HBs Ag titers were monitored during therapy. HBV reverse transcriptase genes were amplified and sequenced to identify genotypes and resistance mutations. Virions and HBs Ag in Hep G2 cell with rt A181 mutation were also compared between genotypes B and C. Results The majority of sera contained HBV genotypes B(15.7%) and C(84.3%). There were no significant difference of rt A181 mutant patterns between genotypes(P > 0.05). After emergence of rt A181 mutation, serum ALT, AST, HBV DNA levels and HBs Ag titers were decreased than that at baseline(P < 0.05), while these characteristics were not different between genotypes B and C(P > 0.05). In cellular experiment, there were no significant differences between genotypes B and C not only in HBV virions but also in HBs Ag titres(P > 0.05). Conclusions No differences of clinical characteristics and cellular results were found in rt A181 mutation of HBV genotypes B and C.

Transjugular intrahepatic portosystemic shunt with radioactive seed strand for main portal vein tumor thrombosis with cirrhotic portal hypertension

BACKGROUND Patients with hepatocellular carcinoma complicated with main portal vein tumor thrombosis(mPVTT) and cirrhotic portal hypertension(CPH) have an extremely poor prognosis, and there is a lack of a clinically effective treatment paradigm.AIM To evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt(TIPS)combined with radioactive seed strand for the treatment of mPVTT patients with CPH.METHODS The clinical data of 83 consecutive patients who underwent TIPS combined with 125I seed strand placement for mPVTT and CPH from January 2015 to December 2018 were retrospectively reviewed. Procedure-related data(success rate, relief of portal vein pressure and CPH symptoms,and adverse events), PVTT response, and patient survival were assessed through a 2-year followup.RESULTS The success rate was 100.0% without perioperative death or procedure-related severe adverse events. The mean portal vein pressure was significantly decreased after the procedure(22.25 ± 7.33mmHg vs 35.12 ± 7.94 mmHg, t = 20.61, P < 0.001). The symptoms of CPH were all effectively relieved within 1 mo. The objective response rate of PVTT was 67.5%. During a mean follow-up of 14.5 ± 9.4 mo(range 1-37 mo), the cumulative survival rates at 6, 12 and 24 mo were 83.1%, 49.7%,and 21.8%, respectively. The median survival time was 12.0 ± 1.3 mo(95% confidence interval: 9.5-14.5). In multivariate Cox regression analysis, body mass index, Child-Pugh grade, cTNM stage,and PVTT response were independent prognostic factors(P < 0.05).CONCLUSION TIPS combined with radioactive seed strand might be effective and safe in treating mPVTT patients with CPH.

Performance of Hepatitis Delta Virus(HDV)RNA Testing for the Diagnosis of Active HDV Infection:Systematic Review and Meta-analysis

Background and Aims:Hepatitis delta virus(HDV)is a defective virus and causes severe liver disease.Several HDV RNA assays have been developed,however the diagnostic efficacy remains unclear.This systematic review and metaanalysis aims to evaluate the diagnostic accuracy of HDV RNA assays to aid in the diagnosis of active hepatitis D.Methods:The PubMed,Embase,and Cochrane Library databases were systematically searched from the beginning to June 31,2022.Information on the characteristics of the literature and data on sensitivity,specificity,and area under curve(AUC)of the receiver operating characteristic(ROC)were extracted.Stata 14.0 was used for meta-analysis of the combined sensitivity,specificity,positive likelihood ratio,and negative likelihood ratio.Results:A total of 10 studies were included in the meta-analysis.The summary sensitivity,specificity,positive likelihood ratio,negative likelihood ratio,and diagnostic odds ratio of HDV RNA assays for HDV diagnosis were 0.92(95%CI:0.87-0.95),0.90(95%CI:0.86-0.93),7.74(95%CI:5.31-11.29),0.10(95%CI:0.06-0.18)and 99.90(95%CI:47.08-211.99),respectively.The AUC of the pooled ROC curve was 0.95(95%CI:0.92-0.96).Conclusions:The results show that HDV RNA assays had high diagnostic performance.However,that is limited by the number and quality of studies.Standard protocols for the development of assays by manufacturers and larger studies on the use of the assays are needed.

Tenofovir disoproxil fumarate therapy in patients with chronic hepatitis B and advanced fibrosis or compensated cirrhosis

Background and aims:Tenofovir disoproxil fumarate(TDF)is the first-line therapy for chronic hepatitis B.This interim analysis presents the efficacy and safety data for TDF at Week 144 in patients with chronic hepatitis B and advanced fibrosis or compensated cirrhosis from China.Methods:Patients were assessed for incidence of newly diagnosed hepatocellular carcinoma(HCC)and disease progression,liver stiffness measurement(LSM),virological suppression(serum hepatitis B virus DNA<20 IU/mL),alanine aminotransferase normalization,hepatitis B e antigen(HBeAg)loss and seroconversion,histological liver fibrosis score,and safety at Week 144.Results:Overall,197 patients were enrolled.At Week 144,the incidence of newly diagnosed HCC was observed in 2.1%patients,and the incidence of disease progression was observed in 3.6%patients.The mean(standard deviation)change in LSM from baseline was
5.1(5.85)kPa.Serum hepatitis B virus DNA<20 IU/mL was observed in 94.1%patients,alanine aminotransferase normalization in 33.5%patients,HBeAg loss in 35.6%patients,and HBeAg seroconversion in 14.4%patients.Among patients with stage F3 or F4 fibrosis at baseline by LSM,38.3%patients regressed to stage F0/1,and 22.0%of patients regressed to stage F2 at Week 144.Overall,67.7%patients experienced≥1 adverse events,13.8%patients experienced TDF-related adverse events,and 16.4%patients experienced serious(none were TDF-related).Conclusions:At Week 144 of TDF treatment,low incidence of HCC and disease progression were reported.Virological suppression was observed in 94.1%patients,which was associated with fibrosis regression.No new safety events were identified.