The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis

BACKGROUND: Patients with metastatic tumors to the brain have a very poor prognosis. Increased metastatic potential has been associated with the fibrinolytic system. We investigated the role of the fibrinolytic enzyme plasmin in tumor cell migration across brain endothelial cells and growth of brain metastases in an experimental metastatic melanoma model. METHODS: Metastatic tumors to the brain were established by direct injection into the striatum or by intracarotid injection of B16F10 mouse melanoma cells in C57Bl mice. The role of plasminogen in the ability of human melanoma cells to cross a human blood-brain barrier model was studied on a transwell system. RESULTS: Wild type mice treated with the plasmin inhibitor epsilon-aminocaproic acid (EACA) and plg(-/- )mice developed smaller tumors and survived longer than untreated wild type mice. Tumors metastasized to the brain of wild type mice treated with EACA and plg(-/- )less efficiently than in untreated wild type mice. No difference was observed in the tumor growth in any of the three groups of mice. Human melanoma cells were able to cross the human blood-brain barrier model in a plasmin dependent manner. CONCLUSION: Plasmin facilitates the development of tumor metastasis to the brain. Inhibition of the fibrinolytic system could be considered as means to prevent tumor metastasis to the brain

Transjugular intrahepatic portosystemic shunt trends in China: A brief review

Transjugular intrahepatic portosystemic shunt (TIPS) is now considered as a major treatment option for cirrhotic patients with portal hypertension. Globally, it is getting markedly increase attention, and a similar phenomenon is occurring in China. On average, the number of TIPS procedures is increasing at a rate of 15% per year. Published research papers are also continuously growing every year. Similar but unique compared to western countries, most Chinese physicians follow Chinese specialized guidelines when treating patients with portal hypertension. In this review, we briefly introduce the history of TIPS in China, the present and the future of TIPS in China

Effect of transjugular intrahepatic portosystemic shunt combined with splenic artery embolization on hepatic hemodynamics and liver function in patients with liver cirrhosis

ObjectiveTo investigate the effect of transjugular intrahepatic portosystemic shunt (TIPS) combined with splenic artery embolization (SAE) on hepatic hemodynamics, liver function, and prognosis in patients with liver cirrhosis. MethodsA total of 24 patients who underwent TIPS in the Department of Gastroenterology in Drum Tower Hospital from September 2014 to June 2015 were enrolled and divided into TIPS group (14 patients) and TIPS-SAE group (10 patients) according to whether TIPS was used in combination with SAE. Color Doppler was used to measure the diameter, blood flow rate, and blood flow volume of the hepatic artery and portal vein before and after treatment; liver function parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) were measured before and after surgery; the incidence of postoperative complications such as hepatic encephalopathy (HE) and splenic abscess was observed in the two groups. The Wilcoxon rank sum test was used for comparison of parameters before and after treatment within each group, and the Mann-Whitney U test was used for comparison of parameters between the two groups. ResultsAt 5 days after surgery, the TIPS-SAE group showed significant increases in hepatic artery blood flow rate ［200.00(168.25-224.75) vs 91.35(76.00-113.25), Z=2.803, P=0.005］, portal vein blood flow rate ［60.30(49.85-75.70 ) vs 28.30(21.20-30.00), Z=2.666, P=0.008］, and hepatic artery blood flow volume ［188.00(172.00-232.00) vs 79.10(61.15-89.75), Z=2.803, P=0.005］, a significant reduction in portal vein pressure ［29.50(24.50-34.00) vs 38.00(34.00-41.75), Z=-2.668, P=0.008］, and significant increases in ALT ［61.30(28.55-139.60) vs 21.10(14.00-26.95), Z=2.429, P=0.015］, AST ［43.70(22.67-106.27) vs 23.20(20.97-36.87), Z=2.599, P=0.009］, and TBil ［31.75(17.95-36.92) vs 15.35(13.10-18.62), Z=2.803, P=0.005］. The TIPS-SAE group showed a significantly higher level of AST at 30 days after surgery［49.00(12.10~58.35)U/L vs 23.20(20.97~36.87)U/L］(t=2.100,P=0.036). At 30 days after surgery, the TIPS group showed a significantly higher level of TBil than the TIPS-SAE group ［35.00(24.00-51.25) vs 1830(12.55-31.00), Z=-2.371, P=0.017］. At three month after surgery, one patient in the TIPS group developed HE (grade 2), and in the TIPS-SAE group, one patient experienced HE (grade 3) and 2 experienced splenic abscess. ConclusionAfter TIPS, hepatic artery infusion is significantly increased. SAE cannot further increase liver perfusion after TIPS; however, it may aggravate postoperative liver impairment within a short time and cannot improve the prognosis of patients

Current research status of mechanisms of the development and progression of liver fibrosis

Liver fibrosis is the intermediate process in the progression of various chronic liver diseases to liver cirrhosis, and its serious complications affect the prognosis of patients with chronic liver diseases. However, so far, there remain no effective drugs for the treatment of liver fibrosis. This article investigates the development and progression of liver fibrosis from the aspects of signaling pathways and molecular mechanisms and briefly introduces the latest research advances in the roles of signaling pathways, including transforming growth factor-β/Smad pathway, platelet-derived growth factor pathway, leptin signaling pathway, and connective tissue growth factor pathway, chemokines, neuroendocrine factors, and angiogenesis in the development of liver fibrosis, so as to enhance the knowledge of the development of liver fibrosis and provide a theoretical basis for the research on molecular-targeted drugs based on the pathogenesis of liver fibrosis

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Promotes Hepatic Stellate Cells Migration via Canonical NF-κB/MMP9 Pathway.

In the liver, the signal and function of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) have mainly been assessed in association with liver regeneration. However, the effects of TWEAK on liver fibrosis have not been fully elucidated. To investigate the effects of TWEAK on human hepatic stellate cells (HSCs) and to explore the relevant potential mechanisms, human HSCs line-LX-2 were cultured with TWEAK. Cell migration was detected by transwell assay; cell viability was evaluated by Cell Counting Kit-8; the expression of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13 gene was identified by quantitative real-time polymerase chain reaction and western blotting; the activity of matrix metalloproteinases (MMPs) was tested by enzyme-linked immuno sorbent assay; small interfering RNA transfection was applied for depletion of MMP9 and p65. The result of transwell assay revealed that TWEAK promoted LX-2 migration. Subsequently, our data testified that the expression and activity of MMP9 was induced by TWEAK in LX-2 cells, which enhanced the migration. Furthermore, our findings showed that TWEAK upregulated the phosphorylation of IκBα and p65 protein to increase MMP9 expression in LX-2 cells. Meanwhile, the alpha-smooth muscle actin, vimentin and desmin expression were upregulated following TWEAK treatment. The results in the present study revealed that TWEAK promotes HSCs migration via canonical NF-κB/MMP9 pathway, which possibly provides a molecular basis targeting TWEAK for the therapy of liver fibrosis

High-density lipoprotein cholesterol for the prediction of mortality in cirrhosis with portal vein thrombosis: a retrospective study

Abstract Background Lipid profiles disorders frequently occur in patients with chronic liver diseases, and the mortality of cirrhosis complicated with portal vein thrombosis (PVT) remains high. Research identifying simple and objective prognosis indicators for cirrhotic PVT has been limited. The aim of the present study was to investigate the association between lipid profiles and liver function, which may help predict the 1-year mortality in non-malignant cirrhosis with PVT. Methods A retrospective cohort of 117 subjects with non-malignant cirrhotic PVT was conducted. The primary indicators of lipid profiles included triglyceride, cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol. Correlations of lipid profiles with liver function tests, the Child-Turcotte-Pugh (CTP) score and the model for end-stage liver disease (MELD) score were investigated. The relationship between lipid profiles and 1-year mortality was assessed using the area under the receiver operating characteristic curves (AUROC). Logistic regression models were established to confirm the association between HDL-C and mortality. Results The level of HDL-C was significantly decreased in non-survivors (p < 0.01) and patients with more severe liver damage stages (CTP p < 0.001; MELD p < 0.001). There was no significant difference in the HDL-C level among patients with different severities of PVT (p = 0.498). The level of HDL-C was positively correlated with albumin (p < 0.001, R = 0.438) and platelet (p = 0.022, R = 0.212) levels. The level of HDL-C was negatively correlated with bilirubin (p < 0.001, R = − 0.319), C-reactive protein (p < 0.001, R = − 0.342), the aspartate aminotransferase to alanine aminotransferase ratio (p < 0.0.1, R = − 0.237), the CTP score (p < 0.001, R = − 0.397) and the MELD score (p < 0.001, R = − 0.406). The 1-year mortality rate was 12.8%. The AUROC of HDL-C for the prediction of 1-year mortality in this population was 0.744 (p < 0.01, 95%CI 0.609–0.879). The level of HDL-C was independently associated with mortality by multivariate logistic regression models. Conclusions The HDL-C level significantly decreases with the deterioration of liver function, which may serve as a potential indicator for the prognosis of non-malignant cirrhotic patients with PVT

Agreement between Wedged Hepatic Venous Pressure and Portal Pressure in Hepatic Sinusoidal Obstruction Syndrome

Background: Wedge hepatic vein pressure (WHVP) accurately estimates the portal pressure (PP) in chronic sinusoidal portal hypertension patients. Whether this applies to patients with acute portal hypertension due to hepatic sinusoidal obstruction syndrome (HSOS) is unclear. Our aim was to assess the agreement between WHVP and PP in patients with HSOS by comparing them to decompensated cirrhosis patients. Methods: From December 2013 to December 2021, patients with pyrrolidine alkaloid-induced HSOS (PA-HSOS) receiving hepatic venous pressure gradient (HVPG) measurement and transjugular intrahepatic portosystem shunt (TIPS) were retrospectively collected and matched with those of patients with virus- or alcohol-related cirrhosis as a cirrhosis group. Pearson’s correlation (R), intraclass correlation coefficient (ICC), scatter plots, and the Bland–Altman method were performed for agreement evaluation. Results: A total of 64 patients were analyzed (30 PA-HSOS and 34 cirrhosis groups). The correlation between WHVP and PP was moderate in the PA-HSOS group (R: 0.58, p = 0.001; ICC: 0.68, p = 0.002) but good in the cirrhosis group (R: 0.81, p p p = 0.156), respectively, and an overestimation of PP was more common in the PA-HSOS group (33.3% vs. 2.9%, p = 0.004). HVPG and portal pressure gradient (PPG) consistency was poor in both groups (R: 0.51 vs. 0.26; ICC: 0.65 vs. 0.41; p < 0.05). Conclusions: WHVP in patients with PA-HSOS did not estimate PP as accurately as in patients with virus- or alcohol-related cirrhosis, which was mainly due to PP overestimation