A mutational signature and ARID1A mutation associated with outcome in hepatocellular carcinoma.

OBJECTIVE: The prognosis of hepatocellular carcinoma (HCC) is poor and there is no stable and reliable molecular biomarker for evaluation. This study attempted to find reliable prognostic markers from tumor mutational profiles. METHODS: A total of 362 HCC samples with whole-exome sequencing were collected as discovery datasets, and 200 samples with targeted sequencing were used for validation of the relevant results. All HCC samples were obtained from previously published studies. Bayesian non-negative matrix factorization was used to extract mutational signatures, and multivariate Cox regression models were utilized to identify the prognostic role of mutational factors. Gene set enrichment analysis was employed to discover potential signaling pathways associated with specific mutational groups. RESULTS: In the HCC discovery dataset, a total of four mutational signatures (i.e., signatures 4, 6, 16, and 22) were extracted, of which signature 16 characterized by T>C mutations was observed to be associated with favorable HCC prognosis, and this correlation was also found in the validation dataset. Further analysis showed that patients with ARID1A mutations exhibited inferior survival outcomes in both discovery and validation datasets. Mechanistic exploration revealed that the presence of signature 16 was associated with better immune infiltration and tumor immunogenicity, while patients with ARID1A mutations were away from these favorable immunological features. CONCLUSION: By integrating somatic mutation data and clinical information of HCC, this study identified that signature 16 and ARID1A mutations were associated with better and worse outcomes respectively, providing a basis for prognosis prediction and clinical treatment strategies of HCC.

Construction of an Oxidative Stress Risk Model to Analyze the Correlation Between Liver Cancer and Tumor Immunity.

BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally. Despite advancements in immunotherapy, the prognosis for patients with HCC continues to be poor. As oxidative stress plays a significant role in the onset and progression of various diseases, including metabolism-related HCC, comprehending its mechanism in HCC is critical for effective diagnosis and treatment. METHODS: This study utilized the TCGA dataset and a collection of oxidative stress genes to determine the expression of oxidative stress-related genes in HCC and their association with overall survival using diverse bioinformatics methods. A novel prognostic risk model was developed, and the TCGA cohort was divided into high-risk and low-risk groups based on each tumor sample's risk score. Levels of immune cell infiltration and the expression of immune checkpoint-related genes in different risk subgroups were analyzed to investigate the potential link between tumor immunity and oxidative stress-related features. The expression of model genes in actual samples was validated through immunohistochemistry, and their mRNA and protein expression levels were measured in cell cultures. RESULTS: Four oxidative stress-related genes (EZH2, ANKZF1, G6PD, and HMOX1) were identified and utilized to create a predictive risk model for HCC patient overall survival, which was subsequently validated in an independent cohort. A significant correlation was found between the expression of these prognostic genes and the infiltration of tumor immune cells. Elevated expression of EZH2, ANKZF1, G6PD, and HMOX1 was observed in both HCC tissues and cell lines. CONCLUSION: The combined assessment of EZH2, ANKZF1, G6PD, and HMOX1 gene expression can serve as a model to evaluate the risk of oxidative stress in HCC. Furthermore, there is a notable correlation between the expression of these risk model genes and tumor immunity.

An analysis of sintilimab combined with ruxolitinib as compassionate therapy for 12 adults with EBV-associated hemophagocytic lymphohistiocytosis.

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a severe hyperinflammatory illness that affects adults and is caused by an EBV infection. Without allogeneic hematopoietic stem cell transplantation (allo-HSCT), the overall survival of adult patients with EBV-HLH is unsatisfactory, necessitating the development of innovative therapeutic approaches. The clinical records of twelve EBV-HLH patients who received sintilimab therapy combined with ruxolitinib on a compassionate basis at the First Affiliated Hospital of Soochow University were retrospectively examined in this investigation. All the patients responded without fever, but three patients relapsed within a week. Among the nine patients achieving complete response (CR), 55.6% (5/9) maintained CR for >4.5 months, and 33.3% (3/9) relapsed following CR. Neither patients with no response (NR) nor relapsed patients were fit for allo-HSCT, and all died soon after discharge. Six patients had clinical CR with a median follow-up of 5 (4.4-14.7) months. There were no documented severe negative effects. Additional information on this innovative treatment for adult EBV-HLH is provided in our report.

Utility of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in predicting acute-on-chronic liver failure survival.

This study explored the predictive value of the monocyte-to-lymphocyte ratio (MLR) and platelet-lymphocyte ratio (PLR) in patients with acute-on-chronic liver failure (ACLF). A retrospective analysis was carried out on 40 patients with ACLF from January 2018 and August 2019 in our hospital. The patient's clinical information during hospitalization was collected, and their survivals were followed for 3 months. MLR and PLR values of patients were compared, and the correlation between liver function indicators and prognosis was analyzed. We observed that MLR levels in the survival and death groups were 0.521 (0.311, 0.827) and 0.741 (0.442, 1.121), respectively. MLR levels were markedly enhanced in the death group compared to the survival group (P = 0.021). The receiver operating characteristic curve (ROC) exhibited that the area under the ROC curve and 95% confidence interval for the survival group was 0.641 (0.528-0.757). Survival analysis demonstrated that the 3-month survival of the high MLR group was markedly lower than that of the low MLR group (P = 0.001). Multivariate regression exposed that MLR and PLR were independent prognostic factors for ACLF. MLR and PLR could be prospective prognosticative markers of ACLF.

The Role of Oxidative Stress in the Development and Therapeutic Intervention of Hepatocellular Carcinoma.

Oxidative stress (OS) is a condition in which the body has an unbalanced oxidative and antioxidant effect. Oxidative stress has emerged as a critical component in the onset and progression of numerous diseases, including liver cancer and chronic liver disease caused by the hepatitis C virus and hepatitis B virus. Reactive oxygen species (ROS) are the most prevalent reactive chemical species involved in the oxidative stress response during the progression of the disease. Oxidative stress has a unique role in the development of hepatocellular carcinoma (HCC), and excessive ROS production is a common occurrence in liver illnesses of various etiologies. In response to various deleterious stimuli, the liver shows manifestations of lipid accumulation, oxidative damage, inflammatory infiltration, and immune response, which interact with each other in a mutually reinforcing manner, collectively exacerbating liver damage and malignant transformation. The intracellular buildup of ROS is a two-edged sword for tumor advancement. ROS are tumorigenic, and low amounts of ROS can trigger different signaling pathways that promote proliferation, survival, and migration, among other aspects. However, excessive oxidative stress can induce tumor cell death. Understanding the mechanisms of oxidative stress in hepatocellular carcinogenesis is beneficial for the prevention and surveillance of hepatocellular carcinoma in humans. An improved knowledge of the impacts and potential implications of oxidative stress regulation in therapeutic strategies will likely allow us to find new therapeutic targets for cancer. Oxidative stress also plays a significant role in the treatment of hepatocellular carcinoma and the mechanisms of drug resistance involved. This paper reviews recent studies on oxidative stress in HCC that are more reliable and important, and provides a more comprehensive view of the development of the treatment of HCC based on the relevant summaries of the effect of oxidative stress on the treatment.

Cuproptosis-related lncRNAs predict the prognosis and immune response in hepatocellular carcinoma.

Cuproptosis has been recently used to indicate unique biological processes triggered by Cu action as a new term. This study aimed to explore the relationship between cuproptosis-related lncRNA and hepatocellular carcinoma (HCC) with regard to immunity and prognosis. RNA sequencing and the clinical data were downloaded from the TCGA database. The cuproptosis-related genes were sorted out through literature study. The cuproptosis-related IncRNA signature was identified by Cox regression analysis and the least absolute shrinkage and selection operator analysis. The K-M survival analysis, receiver operating characteristic analysis, and C-index analysis were adopted to evaluate the prognostic prediction performance of the signature. The functional enrichment, immune infiltration and tumor mutation analysis were further analyzed. Subsequently, we predicted the differences in chemosensitivity from tumor gene expression levels for some chemotherapy drugs. The prognostic signature consisting of 5 overall survival-related CUPlncRNAs. It showed an extraordinary ability to predict the prognoses of patients with HCC. The signature can predict the abundance of immune cell infiltration, immune functions, expression of immune checkpoint inhibitors, m6A genes, which was supported by the GO biological process and KEGG analysis. And it may also have a guiding effect in the sensitivity of different chemotherapeutic drugs and tumor mutation burden. We constructed a new cuproptosis-related lncRNA signature for HCC patients. The model can be used for prognostic prediction and immune evaluation, providing a reference for immunotherapies and targeted therapies.

Cluster of Differentiation 24 Polymorphism Has No Significant Association with Chronic Hepatitis B Virus Infection in the Chinese Han Population: A Family-Based Association Study.

Objective: Studies have shown that cluster of differentiation (CD) 24 gene polymorphism is associated with several diseases. Among these, chronic hepatitis B (CHB) infection has not been investigated. This study aimed to assess the function of CD24 in CHB. Methods: The study included 478 cases of CHB and 318 cases without CHB from 230 families that underwent genotyping. Polymerase chain reaction-restriction fragment length polymorphism was performed to assess the single nucleotide polymorphism (SNP) P170 of the CD24 gene. The detected genotypes were TT, CT, and CC. Then, family based-association analysis was carried out to investigate the association between CD24 gene polymorphism and susceptibility to CHB. Results: In the 478 patients with CHB, the frequencies of CD24 P170 T and C alleles were 35.5% and 64.5%, respectively, and the frequencies of CD24 P170 CC, CT, and TT genotypes were 39.3%, 50.4% and 10.3%, respectively. In a CD24 single-locus analysis by a family-based association test of P170 polymorphisms, T and C were not significantly associated with CHB in the additive (Z = 0.169, P = 0.866; Z = -0.169, P = 0.866, respectively), dominant (Z = 0.522, P = 0.602; Z = 0.428, P = 0.669, respectively), or recessive (Z = -0.428, P = 0.669; Z = -0.522, P = 0.602, respectively) models. Transmission-disequilibrium (TD) and sib-transmission disequilibrium (STD) tests revealed no excess of T or C alleles from heterozygous parents to their children with the disease or higher frequencies of these alleles in patients compared with their normal siblings (χ 2 = 0.06, P = 0.897). Conclusion: The study findings suggest that the SNP P170 of CD24 has no significant association with susceptibility to the HB virus and related phenotypes in Chinese patients.

SU5, a new Auraptene analog with improved metabolic stability, ameliorates nonalcoholic fatty liver disease in methionine- and choline-deficient diet-fed db/db mice.

Farnesoid X receptor (FXR) has been considered as a promising target for nonalcoholic steatohepatitis (NASH), while existing FXR agonists suffer from serious side effects. Thus, it is very necessary to identify novel FXR agonists with good safety. Auraptene (AUR) is a new FXR agonist with excellent safety and extensive pharmacological activities, while the lactone of AUR is vulnerable to esterolysis. In this study, the lactone of AUR was converted to metabolically stable amide moiety, and the obtained analog SU5 revealed comparable activity and better metabolic stability than that of AUR. In NASH model, SU5 showed stronger efficacy than AUR on fatty liver by upregulating gene expressions related to FXR in vivo. Moreover, SU5 improved lipid metabolism by downregulating the gene expressions of lipid synthesis, while upregulating the gene expressions of fatty acid ß-oxidation and triglyceride metabolism. Besides, the inflammation-related genes were significantly decreased in SU5-treated group. These positive results highlighted the pharmacological potential of SU5 for the treatment of NASH.

Lower levels of interleukin-35 in patients with prophase of liver failure are associated with progression to liver failure.

BACKGROUND: Cytokines play critical roles in the inflammatory processes underlying liver failure. The relevance of interleukin-35 (IL-35), an anti-inflammatory cytokine, in liver failure remains uncharacterized. This study was conducted to investigate whether the IL-35 level in patients with prophase of liver failure (PLF) is associated with prognosis and the possible mechanism of immune regulation for IL-35. METHODS: This retrospective study enrolled 42 patients with PLF at the Department of Infection, First Affiliated Hospital of Soochow University between January 2016 and December 2018. Thirty patients with hepatitis and 30 healthy controls were also enrolled. We divide patients with prophase of liver failure into improvement group who recovered quickly (n=33) and deteriorate group who deteriorated to overt liver failure (n=9). Serum IL-35 level was measured by enzyme-linked immunosorbent assay (ELISA). The ratio of regulatory T cells to T-helper type-17 cells (Treg/Th17) in peripheral blood was determined by flow cytometry. RESULTS: Serum IL-35 level was higher in patients with PLF who showed subsequent improvement than in patients with PLF who showed deterioration to overt liver failure. The Treg/Th17 ratio was higher in patients with PLF who showed improvement than in patients with PLF who developed overt liver failure. The serum IL-35 level and Treg/Th17 ratio were positively correlated in patients with PLF. CONCLUSIONS: High serum IL-35 level is associated with better prognosis in patients with PLF.

CircFAM13B promotes the proliferation of hepatocellular carcinoma by sponging miR-212, upregulating E2F5 expression and activating the P53 pathway.

BACKGROUND: Most of the biological functions of circular RNAs (circRNAs) and the potential underlying mechanisms in hepatocellular carcinoma (HCC) have not yet been discovered. METHODS: In this study, using circRNA expression data from HCC tumor tissues and adjacent tissues from the Gene Expression Omnibus database, we identified out differentially expressed circRNAs and verified them by qRT-PCT. Functional experiments were performed to evaluate the effects of circFAM13B in HCC in vitro and in vivo. RESULTS: We found that circFAM13B was the most significantly differentially expressed circRNA in HCC tissue. Subsequently, in vitro and in vivo studies also demonstrated that circFAM13B promoted the proliferation of HCC. Further studies revealed that circFAM13B, a sponge of miR-212, is involved in the regulation of E2F5 gene expression by competitively binding to miR-212, inhibits the activation of the P53 signalling pathway, and promotes the proliferation of HCC cells. CONCLUSIONS: Our findings revealed the mechanism underlying the regulatory role played by circFAM13B, miR-212 and E2F5 in HCC. This study provides a new theoretical basis and novel target for the clinical prevention and treatment of HCC.

Steroids Enable Mesenchymal Stromal Cells to Promote CD8+ T Cell Proliferation Via VEGF-C.

Mesenchymal stromal cells (MSCs) function as a formidable regulator of inflammation and tissue homeostasis and expanded MSCs are shown to be effective in treating various inflammatory diseases. Their therapeutic effects require the existence of certain inflammatory cytokines. However, in the absence of sufficient proinflammatory stimuli or in the presence of anti-inflammatory medications, MSCs are animated to promote immune responses and unable to alleviate inflammatory disorders. In this study, it is demonstrated that steroid co-administration interferes the efficacy of MSCs in treating acute graft-versus-host disease (aGvHD). Molecular analysis reveals that vascular endothelial growth factor C (VEGF-C) is highly induced in MSCs by steroids and TNFα and VEGF-C in turn promotes CD8+ T cell response. This immune promoting effect is abolished by blockade or specific genetic ablation of VEGFR3 in CD8+ T cells. Additionally, administration of VEGF-C alone exacerbates aGvHD progression through eliciting more vigorous CD8+ T cell activation and proliferation. Further studies demonstrate that VEGF-C augments the PI3K/AKT signaling process and the expression of downstream genes, such as Cyclin D1. Thus, the data demonstrate that steroids can reverse the immunosuppressive effect of MSCs via promoting VEGF-C-augmented CD8+ T cell response and provide novel information for designing efficacious MSC-based therapies.

IL-21 Is Associated With Virological Relapse of HBeAg Positive Chronic Hepatitis B After Discontinuance of Entecavir.

BACKGROUND: To investigate the association between interleukin-21 (IL-21) expression level and virological relapse (VR) of HBeAg positive chronic hepatitis B (CHB) after discontinuance of entecavir (ETV). METHODS: The serum IL-21 level of 112 CHB patients was measured at 0, 12, 24, 52, and 104 weeks after ETV discontinuance. ELISA was used for the measurement of serum IL-21 level. VR was defined as two continuous examinations with an interval of 1 month with both showing HBV DNA >10 000 copies/mL after drug discontinuance. RESULTS: The serum IL-21 levels at 0, 12, 24, 52, and 104 weeks after discontinuance of ETV were significantly higher in the durable virological remission (DVR) group than in the VR group (all P < .01). The area under the ROC curve (AUC) was 0.728 (95% CI: 0.630-0.827, P < .001), while the best cut-off value was 49.8 pg/mL. Multivariate Cox model showed that the factors affecting the relapse included age, followed by HBsAg level at the serological conversion of HBeAg and serum IL-21 level (all P < .05). CONCLUSION: Serum IL-21 level at ETV discontinuance is an independent risk factor for CHB relapse. IL-21 acts as an immunomodulatory factor in maintaining DVR in HBeAg positive CHB patients after ETV discontinuance.

Role of the microRNA­214/Bax axis in the progression of acute liver failure.

Acute liver failure (ALF) is a fatal liver disease characterized by severe hepatocyte destruction. MicroRNAs (miRNAs/miRs) have been reported to serve a key role in a number of liver diseases. Therefore, the aim of the present study was to investigate the role and underlying mechanism of miR­214 in ALF. ALF murine and hepatocyte models were established using D­galactosamine (D­GalN) and lipopolysaccharide (LPS) or D­GalN + tumor necrosis factor (TNF)­α, respectively. The expression levels of miR­214 and Bax were detected by reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and/or western blotting. Furthermore, an automatic biochemical analyzer was used to measure the levels of aspartate aminotransferase (AST) or alanine aminotransferase (ALT). The levels of TNF­α and interleukin (IL)­6 were detected by ELISA and RT­qPCR. In addition, TUNEL staining and flow cytometry were used to analyze cell apoptosis, and the protein expression of caspase­3 was determined by western blotting. It was identified that the levels of AST and ALT were increased and that hepatocyte apoptosis was enhanced in the D­GalN/LPS­stimulated group compared with the control. Furthermore, higher expression of caspase­3 was observed in the D­GalN/LPS­stimulated group. In addition, it was demonstrated that miR­214 was downregulated, while Bax was upregulated in D­GalN/LPS­stimulated mice and D­GalN/TNF­α­stimulated BNLCL2 cells. Moreover, in D­GalN/TNF­α­stimulated BNLCL2 cells, miR­214 overexpression suppressed apoptosis and decreased TNF­α and IL­6 levels, and these effects were reversed by the Bax plasmid. It was also identified that overexpression of miR­214 significantly decreased Bax mRNA and protein expression levels in vitro. Collectively, the present results suggested that miR­214 inhibited hepatocyte apoptosis during ALF development via targeting Bax, thus indicating that miR­214 may be a potential target for ALF treatment.

Nitroglycerin ameliorates liver injury and regulates adaptive immunity in mice.

This study aimed to assess the protective effect of nitroglycerin, a commonly used drug in cardiovascular diseases, on mice with acute liver injury induced by carbon tetrachloride (CCl4 ). The mice were randomly divided into three groups: control, CCl4 , and CCl4 + nitroglycerin. They were killed at 0, 6, 12, 24, and 48 h after treatment. Blood and liver tissue samples were collected for analysis. Analysis of the amounts of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), hepatic glutathione (GSH), and malondialdehyde (MDA) showed that nitroglycerin protected against CCl4 -induced acute liver injury. Liver histological analysis provided further evidence of the protective effect of nitroglycerin. Furthermore, we found that nitroglycerin suppressed the increase of T helper 17 (Th17) cells in CCl4 -induced acute liver injury mice. The results indicate that nitroglycerin is a potential candidate for hepatic disease.

MiR-195 regulates CD40 to maintain Th17/Treg balance in rats with non-alcoholic fatty liver disease.

PURPOSE: This study aims to explore the relationship between miR-195 and CD40 and its effect on Th17/Treg balance in rats with non-alcoholic fatty liver disease (NAFLD). METHODS: We established rat models of NAFLD and made seven groups, Normal group (without modeling), Model group (model rats), NC group (model rats injected with negative control vector), miR-195 OE group (model rats injected with miR-195 mimic), anti-miR-195 group (model rats injected with miR-195 inhibitor), Si-CD40 group (model rats injected with CD40 silencing vector), and anti-miR-195+Si-CD40 group (model rats injected with miR-195 inhibitor and CD40 silencing vector). Dual-luciferase reporter gene assay verified the targeting relationship between miR-195 and CD40. The mRNA and protein expression levels of miR-195, CD40 as well as Th17/Treg associated cytokines in the liver tissues were detected. The pathological changes of liver tissues were detected, and the liver lesion scoring was carried out. The liver coefficient was calculated. The levels of liver function related indices, and Th17/Treg associated cytokines and inflammatory factors in serum were determined. The proportions of Th17/Treg cells in serum were determined by flow cytometry. RESULTS: Compared with Normal group, miR-195 expression level in liver tissues of rats in other six groups was significantly reduced (all P < 0.05); the serum levels of AST, ALT, GGT, IL-17, TNF-α, IL-23, IL-6, IL-8, TC, TG, HDL, and LDL, and the Th17/Treg ratio, as well as the mRNA and protein expression levels of CD40, RORyt, IL-17, TNF-α, IL-23, and IL-8 in liver tissues were significantly increased (all P < 0.05); while the mRNA and protein expression levels of Foxp3, and IL-10 level were significantly reduced (all P < 0.05). Compared with Model group, the above parameters showed an opposite trend in miR-195 OE group and Si-CD40 group were significantly reduced (all P < 0.05). Moreover, anti-miR-195 group could aggravate the imbalance of Th17/Treg cells in rats with NAFLD and promote inflammatory response. Compared with anti-miR-195 group, the combined treatment in anti-miR-195+Si-CD40 group can partially avoid the imbalance of Th17/Treg cells, and inhibit inflammatory response. CONCLUSION: Overexpression of miR-195 can reduce the Th17/Treg ratio to maintain Th17/Treg balance by inhibiting CD40 expression in rats with NAFLD.

Neutrophil-lymphocyte ratio as an early new marker in AIV-H7N9-infected patients: a retrospective study.

Background: Avian AIV-H7N9 influenza progresses rapidly and has a high fatality rate. However, it lacks an early effective biomarker to predict disease severity and fatal outcomes successfully. Our study aimed to explore whether the neutrophil-to-lymphocyte ratio (NLR) taken within 24 h after admission can predict disease severity and fatality in AIV-H7N9-infected patients. Methods: We retrospectively studied 237 AIV-H7N9-infected patients from multiple centers from 2013 to 2015. We used univariate analysis and multivariate analysis to compare clinical variables between the survival and fatal groups to evaluate the prognostic value. Results: The NLR taken within 24 h after admission in the fatal group was significantly higher than that in the survival group (P<0.01). Our study found that NLR was independently associated with fatality. The area under the curve (AUC) of the NLR was 0.70, and moreover, when the NLR =19.94, the specificity was 100%, and the sensitivity was 28.4%. The fatality in the NLR ≥19.94 group was significantly increased relative to the patients with an NLR <19.94 (P<0.05). Conclusion: The NLR is potentially a predictive prognostic biomarker in patients infected with the AIV-H7N9 influenza virus.

Forkhead box o3a suppresses lipopolysaccharide-stimulated proliferation and inflammation in fibroblast-like synoviocytes through regulating tripartite motif-containing protein 3.

Fibroblast-like synoviocytes (FLS), synovial tissue-specific cells, are key effector cells during the pathogenesis of rheumatoid arthritis (RA). Our previous study has shown that tripartite motif-containing protein 3 (TRIM3) overexpression inhibits the proliferation and cytokine secretion of RA FLS. Experiments with gene knockout mice have suggested the important roles of forkhead box o3a (Foxo3a) in RA pathogenesis. The present study aimed to investigate the correlation between Foxo3a and TRIM3 during RA pathogenesis. The expression of Foxo3a and TRIM3 was reduced in RA synovial tissues in comparison to healthy controls, and Foxo3a messenger RNA (mRNA) expression in RA synovial tissues correlated positively with TRIM3 mRNA expression. We found that stimulation with lipopolysaccharide (LPS) caused the downregulation of Foxo3a and TRIM3 in FLS. Foxo3a or TRIM3 overexpression significantly attenuated the promoting effects of LPS on cell proliferation and the release of tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1ß. In addition, Foxo3a suppressed the inhibitory effects of LPS on the mRNA and protein levels of TRIM3, as well as the activity of TRIM3 promoter. Foxo3a or TRIM3 overexpression attenuated collagen-induced arthritis in rats. Furthermore, knockdown of TRIM3 significantly suppressed the effects of Foxo3a overexpression on LPS-activated FLS. In summary, our findings suggested that Foxo3a exerted inhibitory effects on LPS-induced proliferation and inflammation through increasing TRIM3 transcription. The decreased expression of Foxo3a may contribute to the RA pathogenesis.

Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure.

OBJECTIVE: The definition of acute-on-chronic liver failure (ACLF) based on cirrhosis, irrespective of aetiology, remains controversial. This study aimed to clarify the clinicopathological characteristics of patients with hepatitis B virus-related ACLF (HBV-ACLF) in a prospective study and develop new diagnostic criteria and a prognostic score for such patients. DESIGN: The clinical data from 1322 hospitalised patients with acute decompensation of cirrhosis or severe liver injury due to chronic hepatitis B (CHB) at 13 liver centres in China were used to develop new diagnostic and prognostic criteria. RESULTS: Of the patients assessed using the Chronic Liver Failure Consortium criteria with the exception of cirrhosis, 391 patients with ACLF were identified: 92 with non-cirrhotic HBV-ACLF, 271 with cirrhotic HBV-ACLF and 28 with ACLF with cirrhosis caused by non-HBV aetiologies (non-HBV-ACLF). The short-term (28/90 days) mortality of the patients with HBV-ACLF were significantly higher than those of the patients with non-HBV-ACLF. Total bilirubin (TB) ≥12 mg/dL and an international normalised ratio (INR) ≥1.5 was proposed as an additional diagnostic indicator of HBV-ACLF, and 19.3% of patients with an HBV aetiology were additionally diagnosed with ACLF. The new prognostic score (0.741×INR+0.523×HBV-SOFA+0.026×age+0.003×TB) for short-term mortality was superior to five other scores based on both discovery and external validation studies. CONCLUSIONS: Regardless of the presence of cirrhosis, patients with CHB, TB ≥12 mg/dL and INR ≥1.5 should be diagnosed with ACLF. The new criteria diagnosed nearly 20% more patients with an HBV aetiology with ACLF, thus increasing their opportunity to receive timely intensive management.

Elevated serum prostaglandin E2 predicts the risk of infection in hepatitis B virus-related acute-on-chronic liver failure patients.

OBJECTIVE: To evaluate the serum Prostaglandin E2 (PGE2) level in Acute-on-chronic liver failure (ACLF) and determine its predicative value for infection. METHODS: From April 2014 to April 2015, ninety-one patients with hepatitis B virus and ACLF but without infection were enrolled into this prospective study that was carried out at our Hospital. Twenty patients with stable chronic hepatitis B were enrolled from the outpatient department and twenty healthy control subjects without any disease were enrolled from hospital staff. Serum PGE2 levels were determined using ELISA at enrollment. Clinical and laboratory parameters were collected. Receiver operating characteristic (ROC) curves were used to determine optimal cut-off values to predict infection. RESULTS: Significantly higher PGE2 levels were found in patients with ACLF in comparison with healthy controls and patients with stable CHB (P < 0.0001). In ACLF patients, PGE2 levels were significantly higher in patients that eventually developed infection than those without this complication (P < 0.0001). ROC analysis showed that serum PGE2 (area under the ROC curve, 0.83) could predict infection in patients with ACLF with sensitivity of 78.4% and specificity of 81.5% using a threshold of 141 pg/mL. CONCLUSIONS: Serum PGE2 is associated with the susceptibility to secondary infections for patients with ACLF. Increased PGE2 serum levels may serve as a potential biomarker for developing infections in ACLF patients.