Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified. METHODS: In silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM's effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment. RESULTS: We defined "a pro-tumor cirrhotic-ECM" which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors' institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1. CONCLUSIONS: Cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.

Isolation and characterization of exosomes for cancer research.

Exosomes are a subset of extracellular vesicles that carry specific combinations of proteins, nucleic acids, metabolites, and lipids. Mounting evidence suggests that exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including cancer development. Exosomes are released by various cell types under both normal and pathological conditions, and they can be found in multiple bodily fluids. Moreover, exosomes carrying a wide variety of important macromolecules provide a window into altered cellular or tissue states. Their presence in biological fluids renders them an attractive, minimally invasive approach for liquid biopsies with potential biomarkers for cancer diagnosis, prediction, and surveillance. Due to their biocompatibility and low immunogenicity and cytotoxicity, exosomes have potential clinical applications in the development of innovative therapeutic approaches. Here, we summarize recent advances in various technologies for exosome isolation for cancer research. We outline the functions of exosomes in regulating tumor metastasis, drug resistance, and immune modulation in the context of cancer development. Finally, we discuss prospects and challenges for the clinical development of exosome-based liquid biopsies and therapeutics.

Identification and Validation of Key Genes Associated With Systemic Sclerosis-Related Pulmonary Hypertension.

Systemic sclerosis-associated with pulmonary arterial hypertension (SSc-PAH) is still a major cause of SSc related deaths. Early diagnosis and prompt treatment are crucial to reduce the mortality of patients with SSc-PAH. To screen the candidate biomarkers and potential therapeutic targets for SSc-PAH, we analyzed the data set (GSE33463 and GSE19617) for confirming key genes in peripheral blood mononuclear cells from SSc-PAH patients. A total of 105 SSc patients from gene expression omnibus (GEO) were included as discovery cohort (n = 69) and duplication cohort (n = 36) for screening hub genes by weighted gene co-expression network analysis (WGCNA). Furthermore, an independent validation cohort (n = 40), including healthy controls, SSc and SSc-PAH patients, was used for further validation by quantitative real-time polymerase chain reaction. The results showed that four key genes, including IFIT2, IFIT3, RSAD2, and PARP14, may serve as potential biomarkers in SSc-PAH. Also, they could be independent risk factors for SSc-PAH. In conclusion, the four key genes can be expected to become the potential therapeutic targets and early biomarkers for accurate therapy and diagnosis of SSc-PAH in the future, which also provides promising insights into the pathogenesis of SSc-PAH at the molecular level.

MetS Risk Score: A Clear Scoring Model to Predict a 3-Year Risk for Metabolic Syndrome.

Although several risk factors for metabolic syndrome (MetS) have been reported, there are few clinical scores that predict its incidence. Therefore, we created and validated a risk score for prediction of 3-year risk for MetS. Three-year follow-up data of 4395 initially MetS-free subjects, enrolled for an annual physical examination from Wenzhou Medical Center were analyzed. Subjects at enrollment were randomly divided into the training and the validation cohort. Univariate and multivariate logistic regression models were employed for model development. The selected variables were assigned an integer or half-integer risk score proportional to the estimated coefficient from the logistic model. Risk scores were tested in a validation cohort. The predictive performance of the model was tested by computing the area under the receiver operating characteristic curve (AUROC). Four independent predictors were chosen to construct the MetS risk score, including BMI (HR=1.906, 95% CI: 1.040-1.155), FPG (HR=1.507, 95% CI: 1.305-1.741), DBP (HR=1.061, 95% CI: 1.002-1.031), HDL-C (HR=0.539, 95% CI: 0.303-0.959). The model was created as -1.5 to 4 points, which demonstrated a considerable discrimination both in the training cohort (AUROC=0.674) and validation cohort (AUROC=0.690). Comparison of the observed with the estimated incidence of MetS revealed satisfactory precision. We developed and validated the MetS risk score with 4 risk factors to predict 3-year risk of MetS, useful for assessing the individual risk for MetS in medical practice.

Lifestyle interventions for patients with nonalcoholic fatty liver disease: a network meta-analysis.

Lifestyle interventions remain the first-line therapy for nonalcoholic fatty liver disease (NAFLD). This study aims to evaluate the individual impact of exercise and/or dietary interventions on the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), homeostasis model of assessment for insulin resistance index (HOMA-IR), and BMI. Randomized-controlled trials from patients diagnosed with NAFLD were included in the meta-analysis if they reported the associations between changes in ALT, AST, HOMA-IR, or BMI and types of lifestyle interventions. Nineteen eligible articles were included. Compared with observation, aerobic exercise training (AEx) plus diet [weighted mean difference (WMD)=-25.85; 95% confidence interval (CI): -43.90 to -7.80], AEx (WMD=-8.81; 95% CI: -20.22-2.60) and diet (WMD=-11.85; 95% CI: -47.65-24.95) showed significant efficacy in the improvement of ALT levels. Also AST, AEx plus diet showed a significant tendency to reduce AST levels. In addition, progressive resistance training (WMD=-1.70; 95% CI: -5.61-2.21) led to the most obvious reduction in HOMA-IR compared with observation, but appeared to show no significant effect in BMI (WMD=0.27; 95% CI: -0.48 to -0.07), whereas AEx plus diet (WMD=-0.96; 95% CI: -1.54 to -0.38 and WMD=-1.96; 95% CI: -2.79 to -1.12) showed great efficacy both in the improvement of HOMA-IR and BMI. AEx plus diet is the most effective intervention in the management of patients with NAFLD. Dietary intervention may be more effective in the improvements of aminotransferases, whereas exercise shows superiority in improving insulin sensitivity and reduction of BMI.

NAFL screening score: A basic score identifying ultrasound-diagnosed non-alcoholic fatty liver.

BACKGROUND: Several non-invasive diagnostic scores for non-alcoholic fatty liver (NAFL) have been developed, but the clinical application is limited because of their complexity. AIM: To develop and validate an easy-to-calculate scoring system to identify ultrasound-diagnosed NAFL. METHODS: 48,489 patients from 2 centers were included in this study. Multivariable logistic regression models were employed for model development. Ultrasonography was applied to diagnose NAFL. The selected variables were assigned an integer score proportional to the estimated coefficient from the logistic regression analysis, namely NAFL Screening Score (NSS). The ability of the NSS to identify NAFL was assessed by analyzing the area under the receiver operating characteristic curve (AUROC) and was tested in an independent validation cohort. Additionally, the performance of NSS was compared with existing models. RESULTS: NSS was developed as a basic score comprising of age, body mass index (BMI), triglyceride (TG), ALT/AST, fasting plasma glucose (FPG) and uric acid (UA) in both sexes. NSS showed a relatively good discriminative power (AUROC=0.825 for males, 0.861 for females in the validation cohort) in comparison with other models. The optimal cut-off point was 32 for males and 29 for females. CONCLUSION: We developed and validated NSS, an easy-to-use score sheet identify ultrasound-diagnosed NAFL. NSS may be clinically useful for initial diagnosing NAFL.

Comparative efficacy of vasoconstrictor therapies for type 1 hepatorenal syndrome: a network meta-analysis.

INTRODUCTION: The outcome of a comparative efficacy and safety of vasoconstrictor therapies for treatment of patients with type 1 hepatorenal syndrome (HRS-1) remain inconclusive. Areas covered: We searched literature databases for randomized controlled trials (RCTs) until 31 January 2016, and included ten eligible RCTs. In conclusion, terlipressin was the most efficacious vasoconstrictor drug for HRS-1, but had a higher probability of causing AEs. Norepinephrine was an attractive alternative to terlipressin and associated with less AEs. Expert commentary: To date, most previous traditional meta-analyses included trials with a limited population and compared terlipressin alone or with albumin against no intervention or albumin. Since different HRS types have different diagnoses and show different responses to vasoconstrictors, it may be questionable to combine data from patients with type 1 and type 2 HRS, which has been reported for most previous meta-analyses. Thus, performing a high-quality network meta-analysis of the existing literature is a valuable way to interrogate published data and to draw conclusions which may inform on the best interventional strategy.

Development of a prognostic nomogram for cirrhotic patients with upper gastrointestinal bleeding.

BACKGROUND AND AIM: Upper gastrointestinal bleeding (UGIB) is a complication with a high mortality rate in critically ill patients presenting with cirrhosis. Today, there exist few accurate scoring models specifically designed for mortality risk assessment in critically ill cirrhotic patients with upper gastrointestinal bleeding (CICGIB). Our aim was to develop and evaluate a novel nomogram-based model specific for CICGIB. PATIENTS AND METHODS: Overall, 540 consecutive CICGIB patients were enrolled. On the basis of Cox regression analyses, the nomogram was constructed to estimate the probability of 30-day, 90-day, 270-day, and 1-year survival. An upper gastrointestinal bleeding-chronic liver failure-sequential organ failure assessment (UGIB-CLIF-SOFA) score was derived from the nomogram. Performance assessment and internal validation of the model were performed using Harrell's concordance index (C-index), calibration plot, and bootstrap sample procedures. UGIB-CLIF-SOFA was also compared with other prognostic models, such as CLIF-SOFA and model for end-stage liver disease, using C-indices. RESULTS: Eight independent factors derived from Cox analysis (including bilirubin, creatinine, international normalized ratio, sodium, albumin, mean artery pressure, vasopressin used, and hematocrit decrease>10%) were assembled into the nomogram and the UGIB-CLIF-SOFA score. The calibration plots showed optimal agreement between nomogram prediction and actual observation. The C-index of the nomogram using bootstrap (0.729; 95% confidence interval: 0.689-0.766) was higher than that of the other models for predicting survival of CICGIB. CONCLUSION: We have developed and internally validated a novel nomogram and an easy-to-use scoring system that accurately predicts the mortality probability of CICGIB on the basis of eight easy-to-obtain parameters. External validation is now warranted in future clinical studies.

Stratified Platelet-to-lymphocyte Ratio: A Novel Target for Prognostic Prediction of Hepatocellular Carcinoma after Curative Liver Resection.

Background and Aims: Platelet-to-lymphocyte ratio (PLR) has been shown to predict prognosis of cancers. We aimed to evaluate the prognostic value of stratification of PLR in patients after curative liver resection (CLR) for hepatocellular carcinoma (HCC). Methods: A total of 1804 patients who underwent CLR for suspected HCC between January 2007 and January 2014 were screened for the study. All of the patients were categorized into equal tertiles according to the number of patients and the distribution of PLR. Prognostic significance was determined for overall survival (OS) and was assessed using Kaplan-Meier analysis. Univariate and multivariate Cox proportional hazard regression analyses were evaluated for association of all independent parameters with disease prognosis. Results: The optimal cut-off points of preoperative PLR were: (T1) 11.98-75.00, (T2) 75.00-113.33 and (T3) 113.33-567.50. There were obvious differences in each PLR tertile with mortality within 36 months of CLR (plog-rank < 0.001). Multivariable analysis suggested that the level of PLR (HR = 1.004, 95%CI: 1.001-1.008, p = 0.006), portal vein thrombosis (HR = 3.406, 95%CI: 1.185-9.794, p = 0.023), number of nodules (HR = 1.810, 95%CI: 1.345-2.437, p < 0.001), Child-Turcotte-Pugh score (HR = 1.741, 95%CI: 1.129-2.684, p = 0.012) and microvascular invasion (HR = 2.730, 95%CI: 1.777-4.196, p < 0.001) were significant predictors of mortality. Kaplan-Meier analysis of overall survival (OS) demonstrated that each PLR tertile showed a progressively worse OS and apparent separation (plog-rank = 0.016). The highest 5-year OS rate following CLR (58%) was revealed in tertile 1. In contrast, the lowest 5-year OS rate (30%) was revealed in tertile 3. Conclusion: Stratified preoperative PLR could strengthen the predictive power for OS in HCC patients with CLR.

Serum alkaline phosphatase, a risk factor for non-alcoholic fatty liver, but only for women in their 30s and 40s: evidence from a large cohort study.

BACKGROUND: Several risk factors are able to predict non-alcoholic fatty liver (NAFL) development, but the predictive value of serum alkaline phosphatase (ALP) remains uncertain. Our aim is to investigate the association between serum ALP levels and NAFL. METHODS: 21,331 NAFL-free subjects were included. Sex-specific ALP quartiles (Q1 to Q4) were defined. With Q1 used as reference, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated across each quartile. RESULTS: After adjusting for confounding variables, values in Q2, Q3 and Q4 had HRs (95%CIs) of 1.16 (0.94-1.43), 1.38 (1.13-1.69), 1.51 (1.24-1.83) in females and 0.99 (0.90-1.09), 1.04 (0.95-1.14), 0.96 (0.87-1.05) in males, respectively. A subgroup analysis of age factors in females, from Q2 to Q4, adjusted HRs (95%CIs) were 1.31 (0.81-1.99), 1.86 (1.23-2.81), 2.44 (1.60-3.71) in their 30 s, 1.13 (0.83-1.54), 1.17 (0.85-1.62), 1.65 (1.22-2.25) in their 40 s, and 0.95 (0.51-1.78), 0.91 (0.52-1.62), 0.89 (0.53-1.52) in their 50 s. CONCLUSIONS: Higher serum ALP levels are considered a significant predictor for NAFL development in females aged 30 to 50.

The NAFL Risk Score: A simple scoring model to predict 4-y risk for non-alcoholic fatty liver.

BACKGROUND: Although several risk factors for non-alcoholic fatty liver (NAFL) have been reported, there are few clinical scores that predict its incidence in the long term. We developed and validate a scoring model for individual prediction of 4-y risk for NAFL. METHODS: Four-year follow-up data of 8226 initially NAFL-free subjects enrolled for an annual physical examination from Wenzhou Medical Center were analyzed. These subjects are randomly split into the training and the validation cohort. Univariate and multivariable logistic regression models were employed for model development. The selected variables were assigned an integer or half-integer risk score proportional to the estimated coefficient from the logistic model. Risk scores were tested in a validation cohort. We also compared the predictive performance of with that of the NAFLD Index by computing the area under the receiver operating characteristic curve (AUROC). RESULTS: The NAFL Risk Score was developed as 0 to 18 points comprising of BMI, TG×GGT, ALT/AST, LDL-C/HDL-C and UA in both sexes. Comparison of the observed with the estimated incidence of NAFL at both cohorts showed satisfactory precision. In addition, the NAFL Risk Score showed relatively good discriminative power (AUROC=0.739 for males, 0.823 for females) compared with the NAFLD Index (AUROC=0.661 for males, 0.729 for females) in these Chinese subjects. CONCLUSIONS: We developed and validated the NAFL Risk Score, a new scoring model to predict 4-y risk for NAFL. The NAFL Risk Score may be clinically simple and useful for assessing individual risk for NAFL.

Systematic Review with Network Meta-Analysis: Antidiabetic Medication and Risk of Hepatocellular Carcinoma.

Antidiabetic medication may modify the incidence of hepatocellular carcinoma (HCC). We aimed to compare the use of different antidiabetic strategies and the incidence of HCC. PubMed, Embase.com and Cochrane Library databases were searched up to 31 October 2015 and randomized controlled trials (RCTs), cohort studies or case-control studies were included for our analyses. A total of thirteen studies enrolling 481358 participants with 240678 HCC cases who received at least two different strategies were retrieved in this analysis. Direct comparisons showed that use of metformin (risk ratio [RR] 0.49, 95% CI 0.25-0.97) was associated with a significant risk reduction of HCC, while insulin (RR = 2.44, 95% CI 1.10- 5.56) may significantly increase the risk. Indirect evidence also suggested that insulin (RR = 2.37, 95% CI 1.21-4.75) was associated with a significantly increased risk of HCC. Additionally, metformin was effective in reducing the risk of HCC when compared with sulphonylurea (RR = 0.45, 95% CI 0.27-0.74) and insulin (RR = 0.28, 95% CI 0.17-0.47). Notably, metformin was hierarchically the best when compared with other antidiabetic therapies for the prevention of HCC. In summary, available evidence suggests that metformin was the most effective strategy to reduce HCC risk when compared with other antidiabetic interventions.

Comparative efficacy of oral nucleotide analogues for the prophylaxis of hepatitis B virus recurrence after liver transplantation: a network meta-analysis.

BACKGROUND: Prophylactic nucleos(t)ide anologues against hepatitis B virus (HBV) recurrence after liver transplantation (LT) include lamivudine, entecavir, tenofovir, adefovir. Since the most effective strategies for post-LT remain inconclusive, we aimed to compare 6 different treatment options (lamivudine, entecavir, tenofovir, adefovir, lamivudine plus adefovir, lamivudine plus tenofovir) in terms of HBV recurrence after LT using network meta-analysis. METHODS: The search identified seventeen studies involving 6 different prophylactic regimens covering 7274 patients. RESULTS: Compared with entecavir, lamivudine plus tenofovir (OR 2.00, 95%CI 0.02-183.29), lamivudine plus adefovir, (OR 2.83, 95%CI 0.18-33.57), tenofovir (OR 1.11, 95%CI 0.22-5.80), adefovir (OR 3.78, 95%CI 0.59-22.16), lamivudine (OR 4.62, 95%CI 1.75-11.39) were associated with an increased risk of HBV recurrence. CONCLUSION: Entecavir resulted with the highest probability (31%) as the best prophylactic option on reducing the risk of HBV recurrence. Entecavir is the preferred oral NAs treatment compared to other five different prophylactic regimens in the prevention of HBV recurrence after LT.

Systematic Review and Network Meta-Analysis of Randomized Controlled Trials: Comparative Effectiveness and Safety of Direct-Acting Antiviral Agents for Treatment-Naive Hepatitis C Genotype 1.

All possible direct-acting antiviral agent (DAA) regimens for treatment-naive hepatitis C genotype 1 were evaluated by many randomized controlled trials (RCTs). However, the optimum regimen remains inconclusive. We aim to compare interventions in terms of sustained virological response at 12 (SVR12) and 24 (SVR24) weeks after the end of treatment and adverse effects (AEs) (fatigue, headache, nausea, insomnia). PubMed, Embase, and the Cochrane Library were searched for RCTs until July 31, 2015. We estimated odds ratios (ORs) between treatments on clinical outcomes. Twenty-two eligible RCTs were included. Compared with peginterferon-ribavirin (PR), daclatasvir plus PR (OR 8.90, P < 0.001), faldaprevir plus PR (OR 3.72, P < 0.001), simeprevir plus PR (OR 3.59, P < 0.001), sofosbuvir plus PR (OR 4.69, P < 0.001) yield a significant effect in improving SVR12. Consistently, simeprevir plus PR (OR 3.49, P < 0.001), sofosbuvir plus PR (OR 4.51, P < 0.001), daclatasvir plus PR (OR 4.77, P < 0.001) also improved the rates of SVR24 significantly compared with PR. With respect to AEs, compared with PR, ledipasvir plus sofosbuvir plus PR (OR 2.13, P < 0.001) confer a significant AE in nausea, whereas daclatasvir plus PR (OR 0.20, P < 0.001 and OR 0.18, P < 0.001, respectively) lowered the incidence of fatigue and nausea significantly when compared with ledipasvir plus sofosbuvir plus PR. Daclatasvir plus PR was the most effective in SVR12 and SVR24, but caused an increased AEs profile (headache and insomnia). Combined ledipasvir with sofosbuvir or combination of PR was associated with higher incidence of fatigue and nausea.