Construction and validation of a survival prognostic model for stage III hepatocellular carcinoma: a real-world, multicenter clinical study.

OBJECTIVE: To construct a survival prediction model for patients with TNM stage III hepatocellular carcinoma (HCC) to guide the clinical diagnosis and treatment of HCC patients and improve prognosis. METHODS: Based on data from patients with stage III (AJCC 7th TNM stage) recorded by the American Institute of Cancer Research from 2010 to 2013, risk factors affecting the prognosis were screened by Cox univariate and multivariate regression, line plots was constructed, and the credibility of the model was verified by Boostrap method. ROC operating curves, calibration curves and DCA clinical decision curves were used to evaluate the model, and Kaplan-Meier was used for survival analysis was used to evaluate the efficacy of the model. External survival data from patients newly diagnosed with stage III hepatocellular carcinoma during 2014-2015 were used to validate and fit the model and to optimize the model. RESULTS: Age > 75 years vs.18-53 years [HR = 1.502; 95%CI(1.134-1.990)], stage IIIC vs. Stage IIIA [HR = 1.930; 95%CI(1.509-2.470)], lobotomy vs. non-surgery [HR = 0.295; 95%CI(0.228-0.383)], radiotherapy vs. non-radiotherapy [HR = 0.481; 95%CI(0.373-0.619)], chemotherapy vs. Non-chemotherapy [HR = 0.443; 95%CI(0.381-0.515)], positive serum AFP before treatment vs. negative [HR = 1.667; 95%CI(1.356-2.049)], the above indicators are independent prognostic factors for patients with stage III hepatocellular carcinoma, and the P values for the above results were less than 0.05. A joint prediction model was constructed based on age, TNM stage, whether and how to operate, whether to receive radiotherapy, whether to receive chemotherapy, pre-treatment serum AFP status and liver fibrosis score. The consistency index of the improved prognosis model was 0.725. CONCLUSIONS: The traditional TNM staging has limitations for clinical diagnosis and treatment, while the Nomogram model modified by TNM staging has good predictive efficacy and clinical significance.

Programmed cell death, from liver Ischemia-Reperfusion injury perspective: An overview.

Liver ischemia-reperfusion injury (LIRI) commonly occurs in liver resection, liver transplantation, shock, and other hemorrhagic conditions, resulting in profound local and systemic effects via associated inflammatory responses and hepatic cell death. Hepatocyte death is a significant component of LIRI and its mechanism was previously thought to be limited to apoptosis and necrosis. With the discovery of novel types of programmed cell death (PCD), necroptosis, ferroptosis, pyroptosis, autophagy, NETosis, and parthanatos have been shown to be involved in LIRI. Understanding the mechanisms underlying cell death following LIRI is indispensable to mitigating the widespread effects of LIRI. Here, we review the roles of different PCD and discuss potential therapy in LIRI.

Associations of exposure to bisphenol-A or parabens with markers of liver injury/function among US adults in NHANES 2011-2016.

BACKGROUND: Bisphenol-A (BPA) and parabens are common endocrine-disrupting compounds (EDCs) that are used extensively in consumer products worldwide and are widely found in the environment. OBJECTIVE: The purpose of this study was to comprehensively explore the correlations between urinary BPA/parabens levels and liver injury/function markers. METHODS: In this cross-sectional study, we used National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2016. The exposure variables were urinary BPA and four urinary parabens [methylparaben (MPB), ethylparaben (EPB), propylparaben (PPB), and butylparaben (BPB)], while the outcome variables were indicators of liver function/injury [alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ ALT, albumin (ALB), total protein (TP), total bilirubin (TBIL), alkaline phosphatase (ALP), and the fibrosis-4 index (FIB-4)]. Multiple linear regression and weighted quantile sum (WQS) regression analyses were applied to explore the relationships between the individual/combined exposure variables and the liver injury/function indicators, respectively. Furthermore, stratified analysis was employed to detect the associations influenced by age and sex. RESULTS: A total of 2,179 adults were eligible for the present analysis. Multivariate linear regression analysis revealed positive associations of EPB with AST, ALT, TP, and FIB-4 scores and negative associations of BPA with TP and ALB. The effects of urinary parabens on adverse outcomes in the liver (AST and ALT) were significant in the female and middle-aged subgroups. In addition, the WQS analysis revealed that the mixture of four compounds was negatively associated with ALB. BPA had the greatest effect on the serum ALB concentration (weight = 0.688). IMPACT: Our present study provided novel evidence of significant associations between BPA or certain parabens and numerous markers of liver injury/function indicators. We found that higher urinary BPA concentrations were associated with worse liver function. Exposure to high EPB/PPB ratios was significantly associated with biomarkers of liver injury.

Activation of cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis.

Inflammation plays an essential role in the development liver fibrosis.The Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a central cytoplasmic DNA sensor which can recognize cytoplasmic DNA, known to trigger stimulator of interferon genes (STING) and downstream proinflammatory factors. Here, we investigated the role of cGAS-STING signaling pathway in the pathogenesis of liver fibrosis.Differentially expressed genes (DEGs) in human liver tissue were identified using RNA-Seq analysis. As models of liver fibrosis, chronic Carbon tetrachloride (CCl4) exposure were applied in cGAS-knockout mice. LX-2 cells were co-cultured with human liver sinusoidal endothelial cells (LSECs) to explore the underlying mechanisms of hepatic sinusoidal microthrombosis in an inflammatory microenvironment. The endoscopic ultrasound-guided portal vein pressure gradient (EUS-PPG) method was used to analyze the associations between hepatic sinusoidal microthrombosis and PPG in patients with liver fibrosis and portal hypertension (PTH). The RNA-seq analysis results showed that DEGs were enriched in inflammation and endothelial cell activation. The upregulation of the cGAS-STING signaling exacerbated liver fibrosis and intrahepatic inflammation. It also exacerbated LSECs impairment and increased the contribution of hepatic sinusoidal microthrombosis to liver fibrosis in vivo and in vitro. Prothrombotic mediators and proinflammatory factors were associated with PPG in patients with liver fibrosis and portal hypertension. Therefore, activating cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis, which may lead to increased portal vein pressure.