The transcriptional heterogeneity and cellular ecosystem diversity of HCC await further exploration. Single-cell and bulk RNA sequencing data from HCC cells are analyzed to generate a LASSO model for HCC prognostication. CCK-8, scratch assay, flow cytometry, and ROS assays are used to validate how TREM1 may affect HCC cell biological behaviors in vitro. qPCR, western blot analysis, immunohistochemistry, and flow cytometry are applied in a xenograft model to test the effects of TREM1 knockdown on carcinogenesis and the tumor microenvironment. A single-cell atlas of the multicellular ecosystem comprising 13 cell types in HCC is constructed. On the basis of ligand-receptor marker genes specifically extracted from the cell populations, a prognostic model is defined and subsequently validated in additional clinical cohorts. For the first time, a heterogeneous immune microenvironment is observed between low- and high-risk patients, primarily involving macrophages, CD4+ T cells, M1 macrophages, and regulatory T (Treg) cells. Sufficient evidence validates the positive effects of TREM1 on HCC cell proliferation, migration, and apoptosis. Additionally, TREM1 positively modulates the levels of the proinflammatory cytokines IL-1β, TNF-α, and MCP-1. TREM1 downregulation alters the proportions of M1 macrophages and Tregs in the tumor tissue from our HCC xenograft model. Eventually, the Nrf2/Keap1 signaling pathway, which is related to oxidative stress, is shown to be a key pathway downstream of TREM1 downregulation. In summary, we construct a novel prognostic model for HCC on the basis of ligand-receptor marker genes and investigate the role of TREM1 in HCC progression and its impact on the TME.

Summary Background and Aims We aimed to define gender‐specific, optimal alanine aminotransferase (ALT) cut‐off values for the prediction of significant liver histological changes (SLHC) in Chinese patients with grey zone (GZ) chronic hepatitis B (CHB) and normal ALT. Methods In a retrospective study, we included 1101 consecutive patients with GZ CHB and normal ALT assigned to training or internal validation cohorts. We included an independent cohort of 842 patients for external validation. We performed receiver operating characteristic (ROC) curve, smoothed curve fitting, and threshold effect analyses to determine optimal ALT cut‐off values. Area under the curve (AUC) values were calculated to assess their predictive performance. Results A proportion of 79.3% of patients with GZ CHB and normal ALT (≤40 U/L) had SLHC. ROC curve analysis initially identified optimal ALT cut‐off values of 29 U/L (male) and 22 U/L (female). After smoothed curve fitting and threshold effect analyses, new optimal cut‐off values were 27 U/L for males and 24 U/L for females. AUCs for these values were 0.836 (male) and 0.833 (female) in the internal validation cohort, and 0.849 (male) and 0.844 (female) in the external validation cohort. The accuracy and discriminative ability of the newly defined ALT cut‐off values were greater than those of the current recommendations. Conclusion This study established novel optimal ALT cut‐off values for more precise prediction of SLHC among Chinese patients with GZ CHB and normal ALT levels. This may help identify individuals who will benefit from timely antiviral therapy.

PURPOSE:To assess the predictive value of liver stiffness measurement (LSM) and three bleeding risk scoring systems for esophagogastric varices bleeding (EGVB) in patients with hepatitis B cirrhosis during hospitalization. METHODS:In this study, 210 patients who had hepatitis B cirrhosis were selected as the subjects. They were categorized into two groups based on whether EGVB occurred during hospitalization: a bleeding group (70 cases) and a non-bleeding group (140 cases). Logistic regression was used to analyze the factors related to the occurrence of EGVB, and the diagnostic performance was evaluated using a receiver operating characteristic (ROC) curve. RESULTS:Significant differences were observed between the two groups in systolic blood pressure, platelet count, albumin, urea nitrogen, LSM, pre-endoscopic Rockall score (PRS), Glasgow-Blatchford score (GBS), and AIMS65 score (P < 0.05). The correlation analysis showed that LSM had significant positive relationship with PRS, GBS and AIMS65 score. Logistic regression analysis revealed that LSM and GBS score were independent risk factors for EGVB occurrence during hospitalization. ROC curve analysis showed that the combined prediction model of LSM and GBS score had the best prediction performance for EGVB occurrence, with an ROC curve area of 0.811, which was significantly better than the three risk scoring systems (P < 0.05), but similar to the predicted value of LSM (P = 0.335). CONCLUSIONS:The combination of LSM and GBS score can significantly improve the predictive efficacy of EGVB occurrence in patients with hepatitis B cirrhosis during hospitalization, which has important clinical significance for patients' prognosis.

Background and Aims:To determine whether liver stiffness measurement (LSM) indicates liver inflammation in chronic hepatitis B (CHB) with different upper limits of normal (ULNs) for alanine aminotransferase (ALT).Methods:We grouped 439 CHB patients using different ULNs for ALT: cohort I, ≤40 U/L (439 subjects); cohort II, ≤35/25 U/L (males/females; 330 subjects); and cohort III, ≤30/19 U/L (males/females; 231 subjects). Furthermore, 84 and 96 CHB patients with normal ALT (≤40 U/L) formed the external and prospective validation groups, respectively. We evaluated the correlation between LSM and biopsy-confirmed liver inflammation, and determined diagnostic accuracy using area under the curve (AUC). A noninvasive LSM-based model was developed using multivariate logistic regression.Results:Fibrosis-adjusted LSM values significantly increased with increasing inflammation. The AUCs of LSM in cohorts I, II, and III were 0.799, 0.796, and 0.814, respectively, for significant inflammation (A≥2) and 0.779, 0.767, and 0.770, respectively, for severe inflammation (A=3). Cutoff LSM values in all cohorts for A≥2 and A=3 were 6.3 and 7.5 kPa, respectively. Internal, external, and prospective validations showed high diagnostic accuracy of LSM for A≥2 and A=3, and no significant differences in AUCs among the four groups. LSM and globulin independently predicted A≥2. The AUC of an LSM-globulin model for A≥2 exceeded those of globulin, ALT, and AST, but was similar to that of LSM.Conclusions:LSM predicted liver inflammation and guided the indication of antiviral therapy for CHB in patients with normal ALT.

A proportion of chronic hepatitis B virus (HBV) carriers with normal alanine transaminase (ALT) present with significant liver histological changes (SLHC). To construct a noninvasive nomogram model to identify SLHC in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. The training cohort consisted of 732 chronic HBV carriers who were stratified into four sets according to different ULNs for ALT: chronic HBV carriers I, II, III, and IV. The external validation cohort comprised 277 chronic HBV carriers. Logistic regression and least absolute shrinkage and selection operator analyses were applied to develop a nomogram model to predict SLHC. A nomogram model‐HBGP (based on hepatitis B surface antigen, gamma‐glutamyl transpeptidase, and platelet count) demonstrated good performance in diagnosing SLHC with area under the curve (AUCs) of 0.866 (95% confidence interval [CI]: 0.839−0.892) and 0.885 (95% CI: 0.845−0.925) in the training and validation cohorts, respectively. Furthermore, HBGP displayed high diagnostic values for SLHC with AUCs of 0.866 (95% CI: 0.839−0.892), 0.868 (95% CI: 0.838−0.898), 0.865 (95% CI: 0.828−0.901), and 0.853 (95% CI: 0.798−0.908) in chronic HBV carriers I, II, III, and IV, respectively. Additionally, HBGP showed greater ability in predicting SLHC compared with the existing predictors. HBGP has shown high predictive performance for SLHC, and thus may lead to an informed decision on the initiation of antiviral treatment.

Background and Aims: Aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) are widely used to assess liver fibrosis in chronic hepatitis B virus (HBV) infection. Currently, the definition of normal alanine aminotransferase (ALT) is controversial. We aimed to examine the diagnostic value of APRI and FIB-4 in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. Methods: 581 chronic HBV carriers were divided into the following four groups based on different ULNs for ALT: chronic HBV carriers I, II, III, and IV. Furthermore, 106 chronic HBV carriers formed an external validation group. Predictive values of APRI and FIB-4 were elucidated using the area under the curve (AUC). A liver fibrosis-predictive model-GPSA (named for its measure of gamma glutamyl transpeptidase, platelet count, HBsAg and albumin) was developed using multivariate logistic regression analysis. Results: In chronic HBV carriers I, the AUCs of APRI and FIB-4 were 0.680 and 0.609 for significant fibrosis and 0.678 and 0.661 for cirrhosis, respectively. The AUCs of GPSA for significant fibrosis in the training group, internal group, and external validation group were 0.877, 0.837, and 0.871, respectively. The diagnostic value of GPSA differed among chronic HBV carriers I, II, III, and IV, with AUCs for significant fibrosis being 0.857, 0.853, 0.868, and 0.905 and AUCs for cirrhosis being 0.901, 0.905, 0.886, and 0.913, respectively. GPSA showed a higher diagnostic value than APRI and FIB-4 for predicting significant fibrosis in the four groups. Conclusions: The GPSA model allows for accurate diagnosis of liver fibrosis in chronic HBV carriers with different ULN for ALT.

BACKGROUND:The microbes and metabolomics of microbiota dysbiosis in the gut in the different phases of hepatitis B virus (HBV) infection are not fully understood.AIM:To investigate the specific gut microbiota and metabolites of the immune-tolerant (IT) and immune-active (IA) phases of chronic hepatitis B (CHB).METHODS:Clinical fecal samples from healthy individuals and patients in the IT and IA phases of HBV infection were collected. Next, non-target metabolomics, bioinformatics, and 16S rDNA sequencing analyses were performed.RESULTS:A total of 293 different metabolites in 14 phyla, 22 classes, 29 orders, 51 families, and 190 genera were identified. The four phyla of Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria were the most abundant, accounting for 99.72%, 99.79%, and 99.55% in the healthy controls, IT-phase patients, and IA-phase patients, respectively. We further identified 16 genera with different richness in the IT phase and IA phase of HBV infection. Of the 134 named metabolites, 57 were upregulated and 77 were downregulated. A total of 101 different metabolic functions were predicted in this study, with 6 metabolic pathways having the highest enrichments, namely carbohydrate metabolism (14.85%), amino acid metabolism (12.87%), lipid metabolism (11.88%), metabolism of cofactors and vitamins (11.88%), xenobiotic biodegradation (9.9%), and metabolism of terpenoids and polyketides (7.92%).CONCLUSION:These findings provide observational evidence of compositional alterations of the gut microbiome and some related metabolites in patients with IT-phase or IA-phase HBV infection. Further studies should investigate whether microbiota modulation can facilitate the progression of CHB and the cause-effect relationship between the gut microbiota and CHB.

BACKGROUND:Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) in the immune-tolerant (IT) phase is significantly associated with high risk for hepatocellular carcinoma, suggesting requirement for antiviral therapy, particularly for those with histological liver injury. This study aimed to establish a non-invasive panel to assess significant liver fibrosis in IT chronic hepatitis B.PATIENTS AND METHODS:One hundred and thirteen IT-phase CHB patients were retrospectively recruited and divided into two histopathological groups according to their histological profiles: necroinflammatory score <4 (N <4)/fibrosis score ⩽1 (F0-1), and necroinflammatory score ⩾4 (N ⩾4)/fibrosis score ⩾2 (F2-4). Multivariate analysis was conducted to assess the predictive value of the non-invasive model for significant liver fibrosis.RESULTS:IT-phase CHB patients with N <4/F0-1 had significantly higher HBsAg levels than those with N ⩾4/F2-4. The optimal HBsAg level of log 4.44 IU/mL for significant liver fibrosis (F ⩾2) gave an area under the curve (AUC) of 0.83, sensitivity of 81.1%, specificity of 81.6%, positive predictive value (PPV) of 68.2%, and negative predictive value (NPV) of 89.9%. An IT model with HBsAg and gamma glutamyl transpeptidase (GGT) in combination was established, and it had an AUC of 0.86, sensitivity of 86.5%, specificity of 81.6%, PPV of 69.6, NPV of 92.5, and accuracy of 83.2% to predict F ⩾2 in the IT-phase CHB patients. Notably, the IT model exhibited higher predictive value than the existing aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 score, and GGT to platelet ratio.CONCLUSION:The established IT model combining HBsAg and GGT has good performance in predicting significant liver fibrosis in IT-phase CHB patients.

BACKGROUND:Transient elastography (FibroScan) is a new and non-invasive test, which has been widely recommended by the guidelines of chronic hepatitis B virus (HBV) management for assessing hepatic fibrosis staging. However, some confounders may affect the diagnostic accuracy of the FibroScan device in fibrosis staging.AIM:To evaluate the diagnostic value of the FibroScan device and the effect of hepatic inflammation on the accuracy of FibroScan in assessing the stage of liver fibrosis in patients with HBV infection.METHODS:The data of 416 patients with chronic HBV infection who accepted FibroScan, liver biopsy, clinical, and biological examination were collected from two hospitals retrospectively. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic performance of FibroScan for assessing the stage of liver fibrosis. Any discordance in fibrosis staging by FibroScan and pathological scores was statistically analyzed. Logistic regression and ROC analyses were used to analyze the accuracy of FibroScan in assessing the stage of fibrosis in patients with different degrees of liver inflammation. A non-invasive model was constructed to predict the risk of misdiagnosis of fibrosis stage using FibroScan.RESULTS:In the overall cohort, the optimal diagnostic values of liver stiffness measurement (LSM) using FibroScan for significant fibrosis (≥ F2), severe fibrosis (≥ F3), and cirrhosis (F4) were 7.3 kPa [area under the curve (AUC) = 0.863], 9.7 kPa (AUC = 0.911), and 11.3 kPa (AUC = 0.918), respectively. The rate of misdiagnosis of fibrosis stage using FibroScan was 34.1% (142/416 patients). The group of patients who showed discordance between fibrosis staging using FibroScan and pathological scores had significantly higher alanine aminotransferase and aspartate aminotransferase levels, and a higher proportion of moderate to severe hepatic inflammation, compared with the group of patients who showed concordance in fibrosis staging between the two methods. Liver inflammation activity over 2 (OR = 3.53) was an independent risk factor for misdiagnosis of fibrosis stage using FibroScan. Patients with liver inflammation activity ≥ 2 showed higher LSM values using FibroScan and higher rates of misdiagnosis of fibrosis stage, whereas the diagnostic performance of FibroScan for different fibrosis stages was significantly lower than that in patients with inflammation activity < 2 (all P < 0.05). A non-invasive prediction model was established to assess the risk of misdiagnosis of fibrosis stage using FibroScan, and the AUC was 0.701.CONCLUSION:Liver inflammation was an independent risk factor affecting the diagnostic accuracy of FibroScan for fibrosis stage. A combination of other related non-invasive factors can predict the risk of misdiagnosis of fibrosis staging using FibroScan.

BACKGROUND:The presence of significant liver fibrosis in hepatitis B virus (HBV)-infected individuals with persistently normal serum alanine aminotransferase (PNALT) levels is a strong indicator for initiating antiviral therapy. Serum ceruloplasmin (CP) is negatively correlated with liver fibrosis in HBV-infected individuals.AIM:To examine the potential value of serum CP and develop a noninvasive index including CP to assess significant fibrosis among HBV-infected individuals with PNALT.METHODS:Two hundred and seventy-five HBV-infected individuals with PNALT were retrospectively evaluated. The association between CP and fibrotic stages was statistically analyzed. A predictive index including CP [Ceruloplasmin hepatitis B virus (CPHBV)] was constructed to predict significant fibrosis and compared to previously reported models.RESULTS:Serum CP had an inverse correlation with liver fibrosis (r = -0.600). Using CP, the areas under the curves (AUCs) to predict significant fibrosis, advanced fibrosis, and cirrhosis were 0.774, 0.812, and 0.853, respectively. The CPHBV model was developed using CP, platelets (PLT), and HBsAg levels to predict significant fibrosis. The AUCs of this model to predict significant fibrosis, advanced fibrosis, and cirrhosis were 0.842, 0.920, and 0.904, respectively. CPHBV was superior to previous models like the aspartate aminotransferase (AST)-to-PLT ratio index, Fibrosis-4 score, gamma-glutamyl transpeptidase-to-PLT ratio, Forn's score, and S-index in predicting significant fibrosis in HBV-infected individuals with PNALT.CONCLUSION:CPHBV could accurately predict liver fibrosis in HBV-infected individuals with PNALT. Therefore, CPHBV can be a valuable tool for antiviral treatment decisions.

Background: Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) in the immune-tolerant (IT) phase is significantly associated with high risk for hepatocellular carcinoma (HCC), suggesting requirement for antiviral therapy particularly for those with histological liver injury. This study aimed to develop a noninvasive model to predict significant liver fibrosis among IT-phase CHB patients.Methods: 113 IT-phase CHB patients were retrospectively recruited and divided into two histopathological groups according to their histological profiles: necroinflammatory score <4 (N<4)/fibrosis score ≥1 (F0-1), and necroinflammatory score ≥4 (N≥4)/ fibrosis score ≥2 (F2-4). Multivariate analysis was conducted to assess the predictive value of the noninvasive model for significant liver fibrosis.Findings: IT-phase CHB patients with N<4/F0-1 had significantly higher HBsAg levels than those with N≥4/F2-4. The optimal HBsAg level of log 4.44 IU/mL for significant liver fibrosis (F≥2) gave an AUC of 0.83, sensitivity of 81.1%, specificity of 81.6%, positive predictive value (PPV) of 68.2%, and negative predictive value (NPV) of 89.9%. An IT-model with HBsAg and GGT in combination was established, and it had an AUC of 0.86, sensitivity of 86.5%, specificity of 81.6%, PPV of 69.6, NPV of 92.5, and accuracy (AC) of 83.2% to predict F≥2 in the IT-phase CHB patients. Notably, the IT-model exhibited higher predictive value than the existing aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 score, and GGT to platelet ratio.Interpretation: The established IT-model combing HBsAg and GGT has good performance in predicting significant liver fibrosis in IT-phase CHB patients. Funding: This study was supported by the Science and Technology Department of Fujian [2018J01164], and Professor Academic Development Fund of Fujian Medical University [2015j01460].Declaration of Interest: All authors declare no conflict of interest.Ethical Approval: The study protocol was reviewed and approved by the Institutional Review Board (IRB) of the First Affiliated Hospital of Fujian Medical University, and the need for informed consent from each patient was waived due to its retrospective nature.

Aims: To evaluate the significance of serum ceruloplasmin (CP) to diagnosis hepatic steatosis (HS) in Chronic hepatitis B (CHB) patients. Methods: A total of 360 CHB patients with HS (n = 136) or without HS (n=224) were included. Relationships between CP and HS degrees were analyzed by Spearman rank correlation. HS predictive models including CP were constructed using multivariate logistic regression analysis and compared to other HS predicting indexes. Results: Serum CP were significantly higher in CHB patients with HS than in patients without HS (P < 0.001) and were positively correlated with HS degree (r = 0.487, P < 0.001). The area under the receiver-operating characteristic curves (AUCs) of using CP to predict HS (S >= 1), moderate and severe steatosis (S >= 2) and severe steatosis (S = 3) were 0.758, 0.794 and 0.883, respectively. Multivariate analysis showed that CP, age, high density lipoprotein (HDL) and hemoglobin were independent predictors of HS, and CP, body mass index and HDL were independent predictors of moderate and severe HS. Two novel indexes for predicting HS of CHB patients were generated. The AUC of HSCHB-1 (for S >= 1) and HSCHB-2 (for S >= 2) were 0.881 and 0.916 in the training group, and 0.865 and 0.841 in the validation group, respectively. HSCHB-1 was superior to HS index (P < 0.001), fatty liver disease index (P= 0.0043) and steatosis index of patients with hepatitis B virus infection (P=0.0029) in predicting HS in CHB patients. Conclusions: HS of CHB patients was positively associated with serum CP. HSCHB-1 and HSCHB-2 with inclusion of CP are two novel models for predicting HS in CHB patients. (C) 2019 Elsevier Masson SAS. All rights reserved.

目的 构建慢病毒表达载体介导siRNA沉默Id-1,观察其对人肝癌HepG2细胞裸鼠皮下移植瘤生长的抑制作用及其对ERK1/2信号通路的影响. 方法 构建合成特异性针对Id-1基因的siRNA慢病毒载体,转染肝癌HepG2细胞系,经半定量RT-PCR鉴定筛选沉默效果最佳的细胞系,于倒置荧光显微镜(×400)下观察转染前后细胞的形态学变化.取细胞浓度为5×106 mL1的干扰效率最佳的稳定转染细胞系、稳定转染空载体病毒细胞系及正常HepG2细胞系悬液各0.2 mL,分别注射到转染实验组、阴性对照组及空白对照组的裸鼠右腋皮下,每周测量肿瘤体积及裸鼠体质量,绘制肿瘤生长曲线,28d后处死裸鼠,制作肿瘤组织标本,行常规病理检查,采用半定量RT-PCR及Western-blot方法检测肿瘤组织Id-1,ERK1/2的mRNA和蛋白的表达水平及p-ERK1/2的蛋白表达水平. 结果 倒置荧光显微镜显示,转染前后细胞形态学变化不明显.经半定量RT PCR筛选出Id-1基因的siRNA慢病毒载体的最佳细胞系为sh31,与稳定转染空载体病毒细胞系相比,目的基因Id-1的表达降低了80％0以上,与未干扰的HepG2细胞相比降低了60％;转染细胞皮下接种后,转染组最终瘤体大小明显小于阴性对照组和空白对照组(P＜0.05).半定量RT-PCR显示,转染组肿瘤组织的Id-1及ERK1/2 mRNA分别为(0.389±0.058)及(0.475±0.079),均明显低于阴性对照组[(0.845±0.113),(0.977±0.082)]和空白对照组[(0.917±0.083),(0.978±0.056)](均为P＜0.05).Western-blot检测显示,转染组的Id-1及p-ERK1/2蛋白均明显低于阴性对照组和空白对照组(P＜0.05). 结论 Id 1基因特异性siRNA的慢病毒表达载体通过靶向抑制Id-1的表达,明显抑制人肝癌细胞HepG2裸鼠皮下移植瘤的生长,推测Id 1可能通过调节ERK1/2 MAPK信号通路参与肝癌的发生发展.

Objective To investigate the distribution of serum hepatitis B surface antigen（HBs Ag）levels in patients with hepatitis B virus（HBV）-related hepatocellular carcinoma（HCC）.Methods A total of 226 cases of HBV-related HCC were collected from June 2009 to December 2013.Demographic characteristics of patients

Stem cells and cancer cells express a common subset of antigens called oncofetal antigens. Theoretically, vaccination with stem cells is effective at boosting the preexisting anticancer immune response. Herein we describe the efficacy of two stem cell-based vaccines in the prophylaxis and treatment of subcutaneous hepatic tumors transplanted into mice. C57BL/6j mice were vaccinated weekly with either hepatic stem cells (HSCs) or embryonic stem cells (ESCs) for three weeks, followed by a subcutaneous challenge with Hepa 1-6 cells at one week (group 1) or four weeks (group 2) after vaccination. No tumor formation was observed in HSC-vaccinated mice when challenged within one week after vaccination (group 1), but tumors formed in 10% of mice in the ESC-vaccinated group and in 60% of mice in the unvaccinated group. When the long-term memory response was examined (group 2), only 10% of HSC-vaccinated mice and 20% of ESC-vaccinated mice developed macroscopic hepatocarcinomas compared to 60% of the unvaccinated mice. Besides their function as prophylactic vaccines, administration of either HSC or ESC could be a potential treatment for cancer. In mice with subcutaneous hepatocarcinomas, complete clearance of tumor burden was observed in 80% of mice receiving HSC vaccination, but 40% of ESC-vaccinated mice presented with tumors that did not increase in size over time. These data support that HSC is a superior vaccine candidate for durable antitumor protection in this hepatocarcinoma model.

Objective:To explore the correlation of neutrophil-to-lymphocyte ratio(NLR) with the clinicopathological characteristics and prognosis of early primary hepatocellular carcinoma(HCC).Methods:The clinical data of 1 1 3 patients with early HCC and 110 patients with hepatitis B cirrhosis were collected.The expression of alpha-fetoprotein(AFP),copy number of hepatitis B virus(HBV)-DNA,pathological grade of HCC tissues,NLR and other pathological indicators between the two groups were compared.The differences in disease-free survival rate and overall survival rate were analyzed between the different levels of NLR(NLR < 3.65 vs NLR >3.65).The factors influencing the occurrence of HCC were analyzed by logistic regression,while the factors influencing the postoperative recurrence of HCC were analyzed by COX regression.Results:A significant difference in NLR was found between HCC and hepatitis B cirrhosis groups(f = 3.546,P < 0.05).Spearman correlation analysis showed that NLR was negatively correlated with the pathological differentiation degree of HCC(r =-0.408,P < 0.001).Logrank analysis showed that the postoperative disease-free survival rate of HCC patients was significantly different according to the different NLR(χ~2= 40.838,P < 0.001),but the overall survival rate was not significantly different(χ~2 = 0.046,P > 0.05).Multivariate logistic regression analysis showed that the occurrence of HCC had been influenced by NLR,alanine transaminase(ALT) and γ-glutamyl transferase(γ-CCT).COX regression analysis showed that NLR was correlated with the recurrence of HCC(odds ratio = 2.271,P < 0.01).Conclusion:NLR is correlated with the occurrence of HCC.The higher the NLR,the lower the differentiation degree of HCC,and the higher the recurrence rate of HCC patients in 3 years after surgery.But the overall survival rate of HCC patients in 3 years after operation is not associated with NLR.

AIMTo develop a non-invasive model to evaluate significant fibrosis and cirrhosis by investigating the association between serum ceruloplasmin (CP) levels and liver fibrosis in chronic hepatitis B (CHB) patients with normal or minimally raised alanine aminotransferase (ALT).METHODSSerum samples and liver biopsy were obtained from 193 CHB patients with minimally raised or normal ALT who were randomly divided into a training group (n = 97) and a validation group (n = 96). Liver histology was evaluated by the METAVIR scoring system. Receiver operator characteristic curves were applied to the diagnostic value of CP for measuring liver fibrosis in CHB patients. Spearman rank correlation analyzed the relationship between CP and liver fibrosis. A noninvasive model was set up through multivariate logistic regression analysis.RESULTSSerum CP levels individualized various fibrosis stages via area under the curve (AUC) values. Multivariate analysis revealed that CP levels were significantly related to liver cirrhosis. Combining CP with serum GGT levels, a CG model was set up to predict significant fibrosis and liver cirrhosis in CHB patients with normal or minimally raised ALT. The AUC, sensitivity, specificity, positive predictive value, and negative predictive value were 0.84, 83.1%, 78.6%, 39.6%, and 96.5% to predict liver cirrhosis, and 0.789, 80.26%, 68.38%, 62.25%, and 84.21% to predict significant fibrosis. This model expressed a higher AUC than FIB-4 (age, ALT, aspartate aminotransferase, platelets) and GP (globulin, platelets) models to predict significant fibrosis (P = 0.019 and 0.022 respectively) and revealed a dramatically greater AUC than FIB-4 (P = 0.033) to predict liver cirrhosis.CONCLUSIONThe present study showed that CP was independently and negatively associated with liver fibrosis. Furthermore, we developed a novel promising model (CG), based on routine serum markers, for predicting liver fibrosis in CHB patients with normal or minimally raised ALT.

肝纤维化及其终末病变肝硬化已严重危害全球人类健康,虽然慢性肝病的治疗手段和抗肝纤维化药物的研究已取得了很大进展,肝移植依然是最有效的治疗方案,但器官的紧缺却是一个现实问题.目前寻找有效的干预手段进行抗肝纤维化治疗已越来越受到大家的关注.近些年,大量基础及临床研究均证实在一定条件下利用骨髓间充质干细胞(MSCs)可以抑制肝星状细胞活化诱导其凋亡,实现肝纤维化逆转.随着干细胞技术的快速发展,基于骨髓间充质干细胞(MSCs)的细胞疗法在肝纤维化治疗领域的研究与应用已成为一个充满生命力的新方向.本文将对肝纤维化及基于MSCs的治疗机制进展及其应用进行综述.

Objective To evaluate the effects of antiviral therapy in prevention of tumor recurrence after curative resection in patients with hepatitis B virus (HBV) related hepatocarcinoma. Methods The data of 78 HBV related hepatocellular carcinoma patients having underwent hepatocarcinoma curative resection were retrospectively analyzed. The patients were divided into 2 groups according to the treatment method and the serum replication level of HBV DNA: 45 patients received antiviral therapy after hepatocarcinoma curative resection (treatment group), including 28 cases of preoperative HBV DNA high replication level (HBV DNA ≥ 107 copies/L), and 17 cases of preoperative HBV DNA low replication level (HBV DNA < 107 copies/L); 33 cases only received hepatocarcinoma curative resection (control group), including 20 cases of preoperative HBV DNA high replication level, and 13 cases of preoperative HBV DNA low replication level. The median follow-up time was 11 months, and the tumor recurrence was observed. The Kaplan-Meier method was used to calculate the tumor-free survival rate, and Cox regression model was used in multi-factor prognostic analysis. Results In the follow-up period, the tumor recurrence rates in treatment group were 84.4% (38/45), in control group were 93.9% (31/33), and there was no statistical difference (P >0.05). The tumorfree survival rates at 6, 12, 18 and 24 months after operation in patients with HBV high replication level of treatment group were 78.6%, 46.4%, 32.1% and 10.7%, and in patients with HBV low replication level of treatment group were 82.4%, 64.7%, 47.1% and 35.3%; these in patients with HBV high replication level of control group were 50.0%, 15.0%, 5.0% and 0, and in patients with HBV low replication level of control group were 92.3%, 46.2%, 30.8% and 15.4%. The tumor-free survival rates in patients with HBV high replication level of control group were significantly lower than those in patients with HBV low replication level of treatment group and patients with HBV low replication level of control group, and there were statistical differences (P 0.05). Multivariate analysis result showed that preoperative serum HBV DNA ≥ 107 copies/L, lack of antiviral therapy after operation and tumor low differentiation were independent risk factors for tumor recurrence after operations (OR = 1.987, 2.119 and 2.539; P <0.05 or <0.01). Conclusions The serum HBV high replication levels and lack of antiviral therapy after operation are independent factors in influencing tumor recurrence in HBV related hepatocarcinoma patients after operation. It might be better that patients with HBV high replication level should receive an antiviral therapy as early as possible after operation. Key words: Hepatitis B virus; Hepatocellular carcinoma; Recurrence; Antiviral therapy

There are approximately 240 million patients with chronic hepatitis B virus (HBV) infection worldwide. Up to 40% of HBV-infected patients can progress to liver cirrhosis, hepatocellular carcinoma or chronic end-stage liver disease during their lifetime. This, in turn, is responsible for around 650000 deaths annually worldwide. Repeated hepatitis flares may increase the progression of liver fibrosis, making the accurate diagnosis of the stage of liver fibrosis critical in order to make antiviral therapeutic decisions for HBV-infected patients. Liver biopsy remains the "gold standard" for diagnosing liver fibrosis. However, this technique has recently been challenged by the development of several novel noninvasive tests to evaluate liver fibrosis, including serum markers, combined models and imaging techniques. In addition, the cost and accessibility of imaging techniques have been suggested as additional limitations for invasive assessment of liver fibrosis in developing countries. Therefore, a noninvasive assessment model has been suggested to evaluate liver fibrosis, specifically in HBV-infected patients, owing to its high applicability, inter-laboratory reproducibility, wide availability for repeated assays and reasonable cost. The current review aims to present the status of knowledge in this new and exciting field, and to highlight the key points in HBV-infected patients for clinicians.