RUNX1 promotes liver fibrosis progression through regulating TGF-ß signalling.

Liver fibrosis is caused by chronic liver injury. There are limited treatments for it, and the pathogenesis is unclear. Therefore, there is an urgent need to explore the pathogenesis of liver fibrosis, and to try to identify new potential therapeutic targets. For this study we used the carbon tetrachloride abdominal injection induced liver fibrosis animal model in mice. Primary hepatic stellate cell isolation was performed by a density-gradient separation method, and this was followed by immunofluorescence stain analyses. Signal pathway analysis was performed by dual-luciferase reporter assay and western blotting. Our results showed that RUNX1 was upregulated in cirrhotic liver tissues compared with normal liver tissues. Besides, overexpression of RUNX1 caused more severe liver fibrosis lesions than control group under CCl4 -induced conditions. Moreover, α-SMA expression in the RUNX1 overexpression group was significantly higher than in the control group. Interestingly, we found that RUNX1 could promote the activation of TGF-ß/Smads in a dual-luciferase reporter assay. Thus we demonstrated that RUNX1 could be considered as a new regulator of hepatic fibrosis by activating TGF-ß/Smads signalling. Based on this, we concluded that RUNX1 may be developed as a new therapeutic target in the treatment of liver fibrosis in the future. In addition, this study also provides a new insight about the aetiology of liver fibrosis.

Risk Factors for Mortality in Severe Fever with Thrombocytopenia Syndrome Patients with Central Nervous System Complications.

BACKGROUND Severe fever with thrombocytopenia syndrome (SFTS) is a zoonotic viral hemorrhagic fever caused by the SFTS virus (SFTSV), which is a newly identified tick-borne bunyavirus, recently named Dabie bandavirus. In rural China, SFTSV or Dabie bandavirus is commonly transmitted by Haemaphysalis longicornis, the Asian longhorned tick. In recent years, SFTS has been of great concern due to its high morbidity and mortality. The present study investigated the risk factors for mortality in patients with SFTS complicated by central nervous system involvement. MATERIAL AND METHODS We studied 69 SFTS patients hospitalized between 2013 and 2020. We analyzed the laboratory test results and clinical data through univariate and multivariate regression. RESULTS Neurological complications occurred in 59 patients in the survival group and 10 in the mortality group. No significant gender difference was found between the 2 groups. No significant difference was found in age, hospitalization duration, or occurrence of encephalitis between the 2 groups. The mean duration of hospitalization and course of the disease in the mortality group were significantly shorter than those in the survival group (P<0.01). The mean values of platelet count, potassium, and sodium in the mortality group were significantly lower, while the mean values of aspartate aminotransferase, lactic dehydrogenase, creatine kinase-MB (CK-MB) and procalcitonin were higher than those in the survival group. Low platelet count and high CK-MB were independent risk factors for mortality in patients. For each unit increase in platelet count, the risk of mortality decreased by 24.2%, and for each unit increase in CK-MB, the probability of mortality increased by 118.6%. CONCLUSIONS Decreased platelets and increased CK-MB were independent risk factors for mortality in encephalitis patients. SFTS patients with encephalitis should be monitored for changes in these 2 indicators.

The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease.

Fatty liver disease associated with metabolic dysfunction is of increasing concern in mainland China, the world's most populous country. The incidence of fatty liver disease is highest in China, surpassing the incidence in European countries and the USA. An international consensus panel recently published an influential report recommending a novel definition of fatty liver disease associated with metabolic dysfunction. This recommendation includes a switch in name from non-alcoholic fatty liver disease (NAFLD) to metabolic (dysfunction)-associated fatty liver disease (MAFLD) and adoption of a set of positive criteria for disease diagnosis that are independent of alcohol intake or other liver diseases. Given the unique importance of this proposal, the Chinese Society of Hepatology (CSH) invited leading hepatologists and gastroenterologists representing their respective provinces and cities to reach consensus on alternative definitions for fatty liver disease from a national perspective. The CSH endorses the proposed change from NAFLD to MAFLD (supported by 95.45% of participants). We expect that the new definition will result in substantial improvements in health care for patients and advance disease awareness, public health policy, and political, scientific and funding outcomes for MAFLD in China.

Prognostic factors of adult tuberculous meningitis in intensive care unit: a single-center retrospective study in East China.

BACKGROUND: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis worldwide. Data on critically ill TBM patients in the intensive care unit (ICU) of China are lacking. We tried to identify prognostic factors of adult TBM patients admitted to ICU in China. METHODS: We conducted a retrospective study on adult TBM in ICU between January 2008 and April 2018. Factors associated with unfavorable outcomes at 28 days were identified by logistic regression. Factors associated with 1-year mortality were studied by Cox proportional hazards modeling. RESULTS: Eighty adult patients diagnosed with TBM (age 38.5 (18-79) years, 45 (56 %) males) were included in the study. An unfavorable outcome was observed in 39 (49 %) patients and were independently associated with Acute Physiology and Chronic Health Evaluation (APACHE) II > 23 (adjusted odds ratio (aOR) 5.57, 95 % confidence interval (CI) 1.55-19.97), Sequential Organ Failure Assessment (SOFA) > 8 (aOR 9.74, 95 % CI 1.46-64.88), and mechanical ventilation (aOR 18.33, 95 % CI 3.15-106.80). Multivariate Cox regression analysis identified two factors associated with 1-year mortality: APACHE II > 23 (adjusted hazard ratio (aHR) 4.83; 95 % CI 2.21-10.55), and mechanical ventilation (aHR 9.71; 95 % CI 2.31-40.87). CONCLUSIONS: For the most severe adult TBM patients of Medical Research Council (MRC) stage III, common clinical factors aren't effective enough to predict outcomes. Our study demonstrates that the widely used APACHE II and SOFA scores on admission can be used to predict short-term outcomes, while APACHE II could also be used to predict long-term outcomes of adult patients with TBM in ICU.

High hepatitis C virus cure rates with approved interferon-free direct-acting antivirals among diverse mainland Chinese patients including genotypes 3a and 3b.

BACKGROUND AND AIM: Globally, China has the highest chronic hepatitis C (CHC) burden, but its real-world direct-acting antiviral (DAA) data are limited. Our aim is to investigate the real-world outcome of China Food and Drug Administration-approved DAA therapies across mainland China including those with genotype (GT) 3. METHODS: The REAL-C is a multinational real-world interferon-free DAA-treated CHC registry of several mainland China and other Asian centers. We evaluated the sustained virological response rate 12 weeks after end of treatment (SVR12), adverse events, and treatment effect on liver function and fibrosis (fibrosis-4 index). RESULTS: We analyzed 859 DAA-treated CHC patients (6/1/2017-5/30/2019) from 12 mainland China centers (three municipalities and nine provinces): median age 52, 49.9% male, 33.1% cirrhosis, 95% treatment naïve, and 2.5% HBsAg+ . The most common GT was GT1b (523, 62.2%), followed by GT2a (156, 18.5%), GT3b (74, 8.8%), GT3a (41, 4.9%), and GT6 (37, 4.4%). SVR12 rates were 98.0% overall (95% confidence interval 96.9-98.8%), 98.1% for GT1b, 96.8% GT2a, 100% GT3a, 97.3% GT3b, and 100% GT6. Baseline cirrhosis and male sex but not prior treatment history, renal dysfunction, age, and GTs were associated with SVR12. For both cirrhotic and non-cirrhotic patients, there were significant improvement in liver function tests, alpha fetoprotein, and fibrosis-4 index with SVR12. Serious adverse events were rare (1.1%) with only nine patients discontinuing therapy prematurely and anemia being the most common adverse event (13.1%, mostly with ribavirin). CONCLUSIONS: In real-world Chinese patients with diverse GTs, Chinese Food and Drug Administration-approved interferon-free DAAs were well tolerated, provided high cure rates (98.0% overall) including GT3a/3b, and led to improvement of liver function.

Risk Factors of Neurological Complications in Severe Fever Patients with Thrombolytic Syndrome: A Single-Center Retrospective Study in China.

BACKGROUND Severe fever with thrombocytopenia syndrome is a serious insect-borne infectious disease caused by the Huaiyangshanbanyang virus. We conducted a retrospective study to identify risk factors for neurological complications caused by the virus. MATERIAL AND METHODS We included 121 patients who had severe fever with thrombocytopenia syndrome and were admitted to our hospital from 2013 to 2020. Patients' laboratory test results and clinical data were collected. Univariate and multivariate regression were used for statistical analysis. RESULTS Patients with neurological complications had higher mortality rates and longer hospital stays and disease duration than did patients without neurological complications. The neurological symptoms with the highest incidence rates were involuntary tremors (tongue and mandible), cognitive disorder, and limb tremors. Patients with neurological complications had a higher incidence of abnormal heart rhythms. Subcutaneous bleeding, pulmonary rales, percentage of neutrophils, increased lactate dehydrogenase and C-reactive protein levels, and decreased chloride ion concentration were closely related to the occurrence of neurological complications. The significant decrease in chloride ion concentration within 1 to 5 days of disease onset may be a risk factor for predicting the occurrence of neurological complications in patients with severe fever with thrombocytopenia syndrome. CONCLUSIONS Early monitoring of subcutaneous bleeding, pulmonary rales, electrocardiogram changes, and biochemical indicators in patients with severe fever with thrombocytopenia syndrome can predict the occurrence of neurological complications.

Radiofrequency ablation versus repeat resection for recurrent hepatocellular carcinoma (≤ 5 cm) after initial curative resection.

OBJECTIVES: Recurrence rate is up to 70% at 5 years for hepatocellular carcinoma (HCC) after initial resection, but the management of recurrent HCC remains unclear. To compare the efficacy and safety of radiofrequency ablation (RFA) and repeat resection as the first-line treatment in recurrent HCC. METHODS: This multicenter retrospective study analyzed 290 patients who underwent RFA (n = 199) or repeat resection (n = 91) between January 2006 and December 2016 for locally recurrent HCC (≤ 5 cm) following primary resection. We compared the overall survival (OS), progression-free survival (PFS), and complications between the two treatment groups for the total cohort and the propensity score matched (PSM) cohort. RESULTS: The 1-, 3-, and 5-year OS (90.7%, 69.04%, 55.6% vs. 87.7%, 62.9%, 38.1%, p = 0.11) and PFS (56.5%, 27.9%, 14.6% vs. 50.2%, 21.9%, 19.2%, p = 0.80) were similar in the RFA group and the repeat resection group. However, RFA was superior to repeat resection in complication rate and hospital stay (p ≤ 0.001). We observed similar findings in the PSM cohort of 48 pairs of patients and when OS and PFS were measured from the time of the primary resection. The OS of the RFA group was significantly better than repeat resection group among those with 2 or 3 recurrent tumor nodules in both the total cohort (p = 0.009) and the PSM cohort (p = 0.018). CONCLUSION: RFA has the same efficacy as repeat resection in recurrent HCC patients, but with fewer complications. RFA is more efficient and safer than repeat resection in patients with 2 or 3 recurrent tumor nodules. KEY POINTS: • Recurrence rate is up to 70% at 5 years for hepatocellular carcinoma (HCC) after initial resection. • RFA has the same efficacy as repeat resection in recurrent HCC patients, but with fewer complications. • RFA may be preferred for those with 2 or 3 recurrent HCC nodules.

Expression and prognostic significance of epithelial tissue-specific transcription factor ESE3 in hepatocellular carcinoma.

BACKGROUND: Epithelium-specific ETS 3 (ESE3) is down-regulated frequently in several malignancies and involved in carcinogenesis and progression. However, ESE3 expression pattern and its relationship with clinical features and prognosis in hepatocellular carcinoma (HCC) are still largely unknown. METHODS: ESE3 expression was analyzed by quantitative real-time PCR and western blotting in HCC cell lines, and then, it was analyzed by immunohistochemistry in HCC tissues and peritumoral normal tissues from total 94 HCC patients. The relationship between ESE3 expression and clinical features was investigated to illustrate the potential prognostic value in HCC. ESE3 roles on HCC progression were evaluated in vitro and vivo by MTT assay and mice tumor model, respectively. RESULTS: ESE3, mainly located in the cytoplasm, was remarkably down-regulated in HCC tissues and cell lines. Low ESE3 expression was positively associated with tumor progression and metastasis features. Kaplan-Meier analysis demonstrated that low ESE3 expression contributed to poor recurrence-free survival (RFS) and overall survival (OS) (both p < 0.01) of patients, and maintained its prognostic value in predicting poor RFS and OS of "Early-stage" HCC patients regardless of clinical features being studied. Multivariate survival analysis was also identified ESE3 as an independent prognostic factor for RFS (p = 0.05 for marginal significance) and OS (p = 0.031). ESE3 expression restoration in cells led to a significant inhibition in HepG2 cell proliferation in vitro and vivo (both p < 0.001). CONCLUSIONS: Down-regulated ESE3 expression in HCC tissues could serve as a potential therapeutic target against HCC and appears to be as a poor prognostic indicator for prognosis, especially in "Early-stage" HCC patients.

HBeAg induces the expression of macrophage miR-155 to accelerate liver injury via promoting production of inflammatory cytokines.

Activation of Kupffer cells (KCs) induced that inflammatory cytokine production plays a central role in the pathogenesis of HBV infection. The previous studies from our and other laboratory demonstrated miRNAs can regulate TLR-inducing inflammatory responses to macrophage. However, the involvement of miRNAs in HBV-associated antigen-induced macrophage activation is still not thoroughly understood. Here, we evaluated the effects and mechanisms of miR-155 in HBV-associated antigen-induced macrophage activation. First, co-culture assay of HepG2 or HepG2.2.15 cells and RAW264.7 macrophages showed that HepG2.2.15 cells could significantly promote macrophages to produce inflammatory cytokines. Furthermore, we, respectively, stimulated RAW264.7 macrophages, mouse primary peritoneal macrophages, or healthy human peripheral blood monocytes with HBV-associated antigens, including HBcAg, HBeAg, and HBsAg, and found that only HBeAg could steadily enhance the production of inflammatory cytokines in these cells. Subsequently, miRNAs sequencing presented the up- or down-regulated expression of multiple miRNAs in HBeAg-stimulated RAW264.7 cells. In addition, we verified the expression of miR-155 and its precursors BIC gene with q-PCR in the system of co-culture or HBeAg-stimulated macrophages. Meanwhile, the increased miR-155 expression was positively correlation with serum ALT, AST, and HBeAg levels in AHB patients. Although MAPK, PI3K, and NF-κB signal pathways were all activated during HBeAg treatment, only PI3K and NF-κB pathways were involved in miR-155 expression induced by HBeAg stimulation. Consistently, miR-155 over-expression inhibited production of inflammatory cytokines, which could be reversed by knocking down miR-155. Moreover, we demonstrated that miR-155 regulated HBeAg-induced cytokine production by targeting BCL-6, SHIP-1, and SOCS-1. In conclusion, our data revealed that HBeAg augments the expression of miR-155 in macrophages via PI3K and NF-κB signal pathway and the increased miR-155 promotes HBeAg-induced inflammatory cytokine production by inhibiting the expression of BCL-6, SHIP-1, and SOCS-1.

VEGFR-1 activation-induced MMP-9-dependent invasion in hepatocellular carcinoma.

AIM: VEGFR-1 can promote invasion through epithelial-mesenchymal transition induction in hepatocellular carcinoma (HCC). This study aims to elucidate VEGFR-1 impact on proteolytic enzymes profile involved with invasion. MATERIALS & METHODS: The effect on cell invasion was evaluated by invasive and migration assays with and without VEGFR-1 activation. The mechanism was investigated by real-time PCR, western blot and gelatin zymography using inhibitors for MMP-9. In total, 95 HCC patients were enrolled for its clinical value evaluation. RESULTS: VEGFR-1 activation induced invasion in HCC cells with an increase in the expression and activity of MMP-9 and Snail. MMP-9 blockage effectively inhibited VEGFR-1-induced invasion. High coexpression of both in HCC predicted a worse clinical outcome. CONCLUSION: Data show a novel VEGFR-1 activation-to-MMP-9 mechanism promoting HCC invasion.

[Clinical significance of cysteinyl leukotriene receptor expression in primary hepatocellular carcinoma].

OBJECTIVE: To investigate expression of the cysteinyl leukotriene receptor (CysLT1R) in hepatocellular carcinoma (HCC) tissues and determine its clinical significance. METHODS: Cancerous and paraneoplastic liver tissues were collected from 30 patients with HCC and from 12 patients with liver hemangioma patients (controls). Real-time PCR and immunohistochemistry were used to evaluate the expression of CysLT1R in these tissues and assess the relationship with clinical pathological features. T-test,?Fisher's exact test and Kaplan-Meier survival analysis were used for statistical analysis. RESULTS: The expression of CysLT1R in adjacent liver tissues (100%) was higher than that in the HCC (43.33%, P = 0.000) and normal liver tissues (41.67%, P = 0.000). The level of CysLT1R mRNA was also higher in paraneoplastic liver tissues (0.0339+/-0.0221) than in the paired HCC tissues (0.0127+/-0.0116, t = 2.911, P = 0.008) and normal liver tissues (0.0154+/-0.0123, t = -2.310, P = 0.033). There was no difference between the levels in HCC and normal liver tissues (P more than 0.05). Higher level of CysLT1R mRNA, higher level of serum alpha-fetoprotein, and higher tumor stage (III-IV) were associated with poor prognosis (respectively 4.372, P = 0.037; 24.187, P = 0.000; 8.75, P = 0.003). However, no evident relationship between the expression of CysLT1R and other clinical features was observed. Conclusions Overexpression of CysLT1R may contribute to the occurrence and progression of HCC.

Regulatory role of CD4(+)CD25 (+)Foxp3 (+) regulatory T cells on IL-17-secreting T cells in chronic hepatitis B patients.

BACKGROUND: Both interleukin (IL)-17-secreting CD4(+) T (Th17) and CD4(+)CD25(+)Foxp3(+) T regulatory (Treg) cells have been shown to be associated with disease progression or liver damage in chronic hepatitis B (CHB) patients. However, the relationship between Treg cells and IL-17-secreting T cells in hepatitis B virus (HBV) infections is unclear. METHODS: The frequencies of Treg cells and IL-17-secreting T cells in hepatitis B e antigen (HBeAg)-positive CHB patients and healthy subjects were measured by flow cytometric analysis. The role of Treg cells on the differentiation of Ag-specific IL-17-secreting T cells was determined by removing the Treg cells from peripheral blood mononuclear cells (PBMCs) in HBeAg-positive CHB patients. RESULTS: The frequencies of both Th17 (1.71 ± 0.58 vs. 1.08 ± 0.36 %; P < 0.01) and Treg cells (8.92 ± 4.11 vs. 6.45 ± 1.56 %; P < 0.01) were increased in the peripheral blood of HBeAg-positive CHB patients compared with healthy controls, but in not the IL-17-secreting CD8(+) T (Tc17) cells. The frequency of Treg cells was significantly associated with that of Th17 cells (r = 0.625, P = 0.001) in CHB patients. Spearman analysis showed a positive correlation between the frequency of Treg cells and HBV DNA load (r = 0.508, P = 0.008), as well as between the frequency of Th17 cells and serum alanine aminotransferase level (r = 0.516, P = 0.007). The deletion of Treg cells significantly enhanced both Th17 and Tc17 cell development in PBMCs following recombinant HBV core antigen stimulation. CONCLUSIONS: Our data indicate a clear inverse relationship between Th17 cells and Treg cells and that Treg cells can inhibit Th17 cell development in CHB patients.

Impact of Onset Time, Number, Type, and Sequence of Extrahepatic Organ Failure on Prognosis of Acute-on-chronic Liver Failure.

Background and Aims: The impact of the characteristics of extrahepatic organ failure (EHOF) including the onset time, number, type, and sequence on the prognosis of acute-on-chronic liver failure (ACLF) patients remains unknown. This study aimed to identify the association between the characteristics of EHOF and the prognosis of ACLF patients. Methods: ACLF subjects enrolled at six hospitals in China were included in the analysis. The risk of mortality based on the characteristics of EHOF was evaluated. Survival of study groups was compared by Kaplan-Meier analysis and log-rank tests. Results: A total of 736 patients with ACLF were included. EHOF was observed in 402 patients (54.6%), of which 295 (73.4%) developed single EHOF (SEHOF) and 107 (26.6%) developed multiple EHOF (MEHOF). The most commonly observed EHOF was coagulation failure (47.0%), followed by renal (13.0%), brain (4.9%), respiratory (4.3%), and circulatory (2.3%) failure. Survival analysis found that MEHOF or SEHOF patients with brain failure had a worse prognosis. However, no significant outcome was found in the analysis of the effect of onset time and sequence of failed organs on prognosis. Patients were further divided into three risk subgroups by the EHOF characteristics. Kaplan-Meier analysis showed that risk stratification resulted in the differentiation of patients with different risks of mortality both in the training and validation cohorts. Conclusions: The mortality of ACLF patients was determined by the number and type, but not the onset time and sequence of EHOF. Risk stratification applicable to clinical practice was established.

Predicting the 28-day prognosis of acute-on-chronic liver failure patients based on machine learning.

BACKGROUND: We aimed to establish a prognostic predictive model based on machine learning (ML) methods to predict the 28-day mortality of acute-on-chronic liver failure (ACLF) patients, and to evaluate treatment effectiveness. METHODS: ACLF patients from six tertiary hospitals were included for analysis. Features for ML models' development were selected by LASSO regression. Models' performance was evaluated by area under the curve (AUC) and accuracy. Shapley additive explanation was used to explain the ML model. RESULTS: Of the 736 included patients, 587 were assigned to a training set and 149 to an external validation set. Features selected included age, hepatic encephalopathy, total bilirubin, PTA, and creatinine. The eXtreme Gradient Boosting (XGB) model outperformed other ML models in the prognostic prediction of ACLF patients, with the highest AUC and accuracy. Delong's test demonstrated that the XGB model outperformed Child-Pugh score, MELD score, CLIF-SOFA, CLIF-C OF, and CLIF-C ACLF. Sequential assessments at baseline, day 3, day 7, and day 14 improved the predictive performance of the XGB-ML model and can help clinicians evaluate the effectiveness of medical treatment. CONCLUSIONS: We established an XGB-ML model to predict the 28-day mortality of ACLF patients as well as to evaluate the treatment effectiveness.

[Quantifiable changes in HBeAg expression predict therapeutic efficacy of peg-interferon alfa-2a in patients with HBeAg-positive chronic hepatitis B].

OBJECTIVE: To investigate whether quantifiable changes in serum levels of hepatitis B e antigen (HBeAg) in response to 24 weeks of pegylated-interferon alfa-2a (Peg-IFN-a 2a) treatment are predictive of therapeutic efficacy at 48 weeks of treatment in HBeAg-positive chronic hepatitis B (CHB) patients and to investigate the efficacy of using an individualized antiviral treatment strategy. METHODS: Ninety-six HBeAg-positive CHB patients with detectable HBeAg at week 24 of Peg-IFN-a 2a treatment were categorized according to the quantitative change in HBeAg (vs. pre-treatment baseline): group A, HBeAg decline more than 2 log; group B, HBeAg decline between 1 - 2 log; group C, HBeAg decline less than 1 log, which was then randomly divided into two sub-groups: C1 and C2. Group A, B, and C1 patients continued the original therapy for an additional 24 weeks, while group C2 patients were supplemented with lamivudine (3TC + Peg-IFN-a 2a) for the additional 24 weeks of treatment. All patients underwent liver biopsy at the end of treatment (week 48), and HBV covalently-closed circular (ccc)DNA was quantified as a measure of therapeutic efficacy. A, B, and C1 between-group multiple comparisons were made by the Nemenyi test; C1 and C2 between-group comparison was made by the Mann-Whitney U test. The significance of between-group differences in decreased HBV cccDNA vs. HBeAg/anti-HBe seroconversion was made by the Chi-squared test. RESULTS: At week 48, the mean decrease of serum HBV cccDNA in each group was: A, 5.8 log10 copy/ml; B, 3.8 log10 copy/ml; C1, 2.8 log10 copy/ml; C2, 5.7 log10 copy/ml. Statistically significant differences were observed for group A vs. B and C1 (P less than 0.01) and C1 vs. C2 (P less than 0.01); however, the difference between group B and C1 did not reach statistical significance (P = 0.19). The mean decrease of HBeAg in each group was: A, 2.7 log10 S/CO; B, 1.9 log10 S/CO; C1, 0.9 log10 S/CO; C2, 1.6 log10 S/CO. Statistically significant differences were observed for group A vs. B and C1 (P less than 0.01) and C1 vs. C2 (P less than 0.01). The rate of patients who achieved undetectable HBV DNA in each group was: A, 87.5%; B, 34.5%; C1, 17.4%; C2, 85.0%. Statistically significant differences were observed for group A vs. B and C1 (P less than 0.01) and C1 vs. C2 (P less than 0.01). The HBeAg seroconversion rates were: A, 75.0%; B, 24.1%; C1, 13.0%; C2, 25.0%. Statistically significant differences were observed only for group A vs. B and C1 (P less than 0.01). Finally, group A achieved greater reduction in levels of cccDNA in liver tissues than B or C1 (P less than 0.01); however, the differences between B and C1 and between C1 and C2 did not reach statistical significance. CONCLUSION: CHB patients who showed an HBeAg decline of more than 2 log at week 24 of Peg-IFN-a 2a treatment had better treatment outcome at week 48 than those who showed HBeAg decline less than 2 log at week 24. Augmenting the Peg-IFN-a 2a treatment with 3TC can improve the clinical response. A change of quantifiable HBeAg at week 24 of Peg-IFN-a 2a treatment may be a useful predictor of therapeutic efficacy of a 48-week antiviral regimen.

A novel laboratory-based nomogram for assessing infection presence risk in acute-on-chronic liver failure patients.

Accurate assessment of infection presence risk level, timely diagnosis, and effective control are critical for decreasing mortality of Acute­on­chronic liver failure (ACLF). We aimed to develop and validate a novel diagnostic model to accurately assess infection presence risk level in ACLF patients. 185 ACLF patients with/without infection were enrolled, and their demographic, physical findings, immune-inflammatory, hepatic function, metabolism, and coagulation-fibrinolysis indicators were analyzed. Regression analysis was performed to identify the independent diagnostic parameters, which were further used to establish diagnostic models with a nomogram for visual. An area under receiver operating characteristic curve (AUROC), calibration plots, clinical impact curves, decision curve analysis, and net reclassification index were used to evaluate and identify the best model. An external validating cohort was introduced to verify the diagnostic accuracy. We screened out white blood cell (WBC) count, LYM%, blood urea nitrogen (BUN), and D-dimer for assessing infection presence risk levels in ACLF patients. WBD (WBC + BUN + D-dimer) was established and proposed as a novel diagnostic model for infection presence risk levels assessment in ACLF patients with an AUROC of 0.803 (95%CI 0.723-0.883), 0.885 (95%CI 0.786-0.984) in training and external cohorts, respectively. In stratification analysis by ACLF etiology and stages, WBD achieved an AUROC of 0.791 (95%CI 0.691-0.891) and 0.873 (95%CI 0.78-0.966) in HBV-related and early-stage patients, respectively. Whereas a higher AUROC of 0.905 (95%CI 0.807-1.00) in the early-stage of HBV-related ACLF patients indicated its optimum application scope. WBD, a novel laboratory-based nomogram, can serve as a decision-making support tool for clinicians to assess infection presence risk levels in ACLF patients.

An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir.

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Identification of Immune-Related Prognostic Markers in Gastric Cancer.

Gastric cancer (GC) is a malignant tumor with a high fatality rate. Poor prognosis is the main cause of death caused by GC. In this study, the gene expression difference between GC and the control group was analyzed. Differentially expressed genes (DEGs) related to immunity were screened for enrichment analysis. The differences in immune cell infiltration and immune function between GC and normal were identified. Cox regression analysis and survival analysis were used to determine the prognostic genes of GC in TCGA and GSE62254. The potential prognostic role of genes was further evaluated by risk score. Difference genes in GC were analyzed in TCGA. Candidate genes in TCGA and GSE62254 are analyzed, and prognostic genes are determined. The potential prognostic role of genes was further evaluated by risk score. The immune-related prognostic markers in GC were determined. FABP4, LBP, LCN1, CMA1, INHBA, ANGPTL1, ACKR1, GHR, and OGN may be used as markers for monitoring the prognosis of GC in the future.

SARS-CoV-2 and Emerging Variants: Unmasking Structure, Function, Infection, and Immune Escape Mechanisms.

As of April 1, 2022, over 468 million COVID-19 cases and over 6 million deaths have been confirmed globally. Unlike the common coronavirus, SARS-CoV-2 has highly contagious and attracted a high level of concern worldwide. Through the analysis of SARS-CoV-2 structural, non-structural, and accessory proteins, we can gain a deeper understanding of structure-function relationships, viral infection mechanisms, and viable strategies for antiviral therapy. Angiotensin-converting enzyme 2 (ACE2) is the first widely acknowledged SARS-CoV-2 receptor, but researches have shown that there are additional co-receptors that can facilitate the entry of SARS-CoV-2 to infect humans. We have performed an in-depth review of published papers, searching for co-receptors or other auxiliary membrane proteins that enhance viral infection, and analyzing pertinent pathogenic mechanisms. The genome, and especially the spike gene, undergoes mutations at an abnormally high frequency during virus replication and/or when it is transmitted from one individual to another. We summarized the main mutant strains currently circulating global, and elaborated the structural feature for increased infectivity and immune evasion of variants. Meanwhile, the principal purpose of the review is to update information on the COVID-19 outbreak. Many countries have novel findings on the early stage of the epidemic, and accruing evidence has rewritten the timeline of the outbreak, triggering new thinking about the origin and spread of COVID-19. It is anticipated that this can provide further insights for future research and global epidemic prevention and control.