Background: Liver cirrhosis is a major global health burden worldwide due to its high risk of morbidity and mortality. Role of terlipressin for the management of liver cirrhosis–related complications has been recognized during recent years. This article aims to develop evidence-based clinical practice guidance on the use of terlipressin for liver cirrhosis–related complications. Methods: Hepatobiliary Study Group of the Chinese Society of Gastroenterology of the Chinese Medical Association and Hepatology Committee of the Chinese Research Hospital Association have invited gastroenterologists, hepatologists, infectious disease specialists, surgeons, and clinical pharmacists to formulate the clinical practice guidance based on comprehensive literature review and experts’ clinical experiences. Results: Overall, 10 major guidance statements regarding efficacy and safety of terlipressin in liver cirrhosis were proposed. Terlipressin can be beneficial for the management of cirrhotic patients with acute variceal bleeding and hepatorenal syndrome (HRS). However, the evidence regarding the use of terlipressin in cirrhotic patients with ascites, post-paracentesis circulatory dysfunction, and bacterial infections and in those undergoing hepatic resection and liver transplantation remains insufficient. Terlipressin-related adverse events, mainly including gastrointestinal symptoms, electrolyte disturbance, and cardiovascular and respiratory adverse events, should be closely monitored. Conclusion: The current clinical practice guidance supports the use of terlipressin for gastroesophageal variceal bleeding and HRS in liver cirrhosis. High-quality studies are needed to further clarify its potential effects in other liver cirrhosis–related complications.
Abstract Background Cholangiocarcinoma (CCA) is a biliary epithelial malignant tumor with an increasing incidence worldwide. Therefore, further understanding of the molecular mechanisms of CCA progression is required to identify new therapeutic targets. Methods The expression of RPL35A in CCA and para-carcinoma tissues was detected by immunohistochemical staining. IP-MS combined with Co-IP identified downstream proteins regulated by RPL35A. Western blot and Co-IP of CHX or MG-132 treated CCA cells were used to verify the regulation of HSPA8 protein by RPL35A. Cell experiments and subcutaneous tumorigenesis experiments in nude mice were performed to evaluate the effects of RPL35A and HSPA8 on the proliferation, apoptosis, cell cycle, migration of CCA cells and tumor growth in vivo. Results RPL35A was significantly upregulated in CCA tissues and cells. RPL35A knockdown inhibited the proliferation and migration of HCCC-9810 and HUCCT1 cells, induced apoptosis, and arrested the cell cycle in G1 phase. HSPA8 was a downstream protein of RPL35A and overexpressed in CCA. RPL35A knockdown impaired HSPA8 protein stability and increased HSPA8 protein ubiquitination levels. RPL35A overexpression promoted CCA cell proliferation and migration. HSPA8 knockdown inhibited CCA cell proliferation and migration, and reversed the promoting effect of RPL35A. Furthermore, RPL35A promoted tumor growth in vivo. In contrast, HSPA8 knockdown suppressed tumor growth, while was able to restore the effects of RPL35A overexpression. Conclusion RPL35A was upregulated in CCA tissues and promoted the progression of CCA by mediating HSPA8 ubiquitination.
BACKGROUNDTransjugular intrahepatic portosystemic shunt (TIPS), splenectomy plus esophagogastric devascularization (SED) and endoscopic therapy + non-selective β-blockers (ET + NSBB) are widely applied in secondary prevention of recurrent gastroesophageal variceal bleeding in patients with liver cirrhosis.These different treatments, however, have not been compared in patients with idiopathic noncirrhotic portal hypertension (INCPH). AIMTo compare the outcomes of TIPS, SED and ET + NSBB in the control of variceal rebleeding in patients with INCPH. METHODSThis retrospective study recruited patients from six centers across China.
Objective To evaluate the efficacy of intraoperative ultrasonography (IOUS) on primary and repeated hepatectomies for hepatocellular carcinoma (HCC).Methods 430 patients underwent 555 operations for HCC.New tumors detected by IOUS at the primary and repeated hepatectomies were retrospectively analyzed.The long-term outcomes were also studied.Results IOUS had the highest sensitivity in the routinely used imaging examinations.The detection rate by each imaging modality decreased slightly but uniformly at the second hepatectomy.IOUS detected 56 new tumors in 30 patients (7.1％) at the primary hepatectomy and 13 new tumors in 8 (7.3％) at the second.The average size of tumor detected was 8.7±3.8 and 9.0±5.2 mm at the primary and second resections,respectively.The preoperative surgical plan was changed due to the IOUS findings alone in 24 patients (5.6％) at the primary hepatectomy,and in 7 (6.4％) at the second.Although recurrence was frequent in patients with new tumors detected at the primary hepatectomy,long-term survival after appropriate treatment for recurrence was similar to those patients without new tumors detected.Conlusions Despite recent progress in imaging modalities,IOUS is still the most sensitive examination.The same degree of precaution is necessary to detect new tumors using IOUS in repeated hepatectomy.Patients with new tumors detected by IOUS are at high risk for recurrence so that regular check-up is important to improve patient survival.
Key words:
Intraoperative ultrasonography; Hepatocellular carcinoma; Hepatectomies
Introduction Gastro-oesophageal variceal bleeding is one of the most common and severe complications with high mortality in cirrhotic patients who developed portal hypertension. Hepatic venous pressure gradient (HVPG) is a globally recommended golden standard for the portal pressure assessment and an HVPG ≥16 mm Hg indicates a higher risk of death and rebleeding. This study aims to compare the effectiveness and safety of splenectomy and pericardial devascularisation (laparoscopic therapy) plus propranolol and endoscopic therapy plus propranolol for variceal rebleeding in cirrhotic patients with HVPG between 16 and 20 mm Hg. Methods and analysis This is a multicenter, randomised, controlled clinical trial. Participants will be 1:1 assigned randomly into either laparoscopic or endoscopic groups. Forty participants whose transjugular HVPG lies between 16 and 20 mm Hg with a history of gastro-oesophageal variceal bleeding will be recruited from three sites in China. Participants will receive either endoscopic therapy plus propranolol or laparoscopic therapy plus propranolol. The primary outcome measure will be the occurrence of gastro-oesophageal variceal rebleeding. Secondary outcome measures will include overall survival, occurrence of hepatocellular carcinoma, the occurrence of venous thrombosis, the occurrence of adverse events, quality of life and tolerability of treatment. Outcome measures will be evaluated at baseline, 12 weeks, 24 weeks, 36 weeks, 48 weeks and 60 weeks. Multivariate COX regression model will be introduced for analyses of occurrence data and Kaplan-Meier analysis with the log-rank test for intergroup comparison. Ethics and dissemination Ethical approval was obtained from all three participating sites. Primary and secondary outcome data will be submitted for publication in peer-reviewed journals and widely disseminated. Trial registration number NCT03783065 ; Pre-results. Trial status Recruitment for this study started in December 2018 while the first participant was randomised in January 2019. Recruitment is estimated to stop in October 2019.
Abstract Background and Aim Arginine is a nonessential amino acid for humans and mice because it can be synthesized from citrulline by argininosuccinate synthetase ( ASS ) and argininosuccinate lyase. Hepatocellular carcinoma ( HCC ) is believed to be auxotrophic for arginine through the lack of expression of ASS . However, there are also some ASS ‐positive HCC cells. Therefore, the aim of this article was to study the levels of arginine and the expression of ASS in patients with HCC . Methods Thirty patients with HCC who had undergone HCC surgery were enrolled in the study. Serum arginine levels were determined with an automatic amino acid analyzer. ASS expression was examined by W estern blot and immunohistochemistry. Methylation specific polymerase chain reaction and methylation sequencing were performed to detect the methylation of DNA encoding ASS . Results There was a decrease of arginine in HCC patients compared with that of healthy control. High expression of ASS was found in the adjacent tissues by W estern blot and immunohistochemistry. Little ASS expression was found in most HCC tissues, but there were also some HCC tissues that expressed low levels of ASS . Methylation of the DNA encoding ASS was obviously higher in HCC tissues than that in paired adjacent tissues. Conclusions ASS expression is decreased significantly in HCC tissues. The downregulation of arginine and ASS expression may be a self‐defense action of the body against malignant tumors, and the decreased arginine and ASS levels in HCC patients are an advantage for the arginine deiminase treatment.
Abstract Recent studies suggest that Src family kinase (SFK) plays important roles in systemic sclerosis and pulmonary fibrosis. However, how SFKs contributed to the pathogenesis of liver fibrosis remains largely unknown. Here, we investigated the role of Fyn, a member of SFK, in hepatic stellate cell (HSC) activation and liver fibrosis, and evaluated the anti-fibrotic effects of Saracatinib, a clinically proven safe Fyn inhibitor. Fyn activation was examined in human normal and fibrotic liver tissues. The roles of Fyn in HSC activation and liver fibrosis were evaluated in HSC cell lines by using Fyn siRNA and in Fyn knockout mice. The effects of Saracatinib on HSC activation and liver fibrosis were determined in primary HSCs and CCl 4 induced liver fibrosis model. We showed that the Fyn was activated in the liver of human fibrosis patients. TGF-β induced the activation of Fyn in HSC cell lines. Knockdown of Fyn significantly blocked HSC activation, proliferation, and migration. Fyn deficient mice were resistant to CCl 4 induced liver fibrosis. Saracatinib treatment abolished the activation of Fyn, downregulated the Fyn/FAK/N-WASP signaling in HSCs, and subsequently prevented the activation of HSCs. Saracatinib treatment significantly reduced the severity liver fibrosis induced by CCl 4 in mice. In conclusions, our findings supported the critical role of Fyn in HSC activation and development of liver fibrosis. Fyn could serve as a promising drug target for liver fibrosis treatment. Fyn inhibitor Saracatinib significantly inhibited HSC activation and attenuated liver fibrosis in mouse model.
Aim: To investigate the clinical significance of cyclic adenosine monophosphate-responsive element-binding (CREB) and phosphorylated CREB (pCREB) expression in human hepatocellular carcinoma (HCC). Materials and methods: Immunohistochemistry and Western blot analyses were performed to detect the expression and subcellular localizations of CREB and pCREB proteins in 130 pairs of HCC and adjacent nonneoplastic liver tissues. Results: Both immunohistochemistry and Western blot analyses showed that the expression levels of CREB and pCREB proteins in HCC tissues were significantly higher than those in the adjacent nonneoplastic liver tissues (both P <0.001). In addition, the combined upregulation of CREB and pCREB proteins (CREB-high/pCREB-high) was significantly associated with serum α-fetoprotein ( P =0.02), tumor stage ( P <0.001), and tumor grade ( P =0.01). Moreover, HCC patients with CREB-high/pCREB-high expression showed shortest 5-year disease-free survival and 5-year overall survival (both P <0.001). Furthermore, the multivariate survival analysis found that the combined upregulation of CREB and pCREB proteins may be an independent unfavorable prognostic factor for both 5-year disease-free survival and 5-year overall survival (both P =0.01) in HCC. Conclusion: Our data indicate for the first time that the activation of the CREB protein may be associated with tumor progression in HCC, and may serve as a valuable marker of prognosis for patients with this malignancy. Keywords: hepatocellular carcinoma, cyclic AMP-responsive element-binding protein, tumor progression, prognosis
In recent years it was found that the synthesis and biological activity of ribosomes are closely associated with tumor cell growth, tumorigenesis, and malignant transformation. However, the role of regulator of ribosome synthesis 1 (RRS1) in hepatocellular carcinoma (HCC) has not yet been reported. In the present study, we aimed to examine the potential role of RRS1 in tumor cell growth by using a lentivirus-mediated RNA interference (RNAi) system in the HCC cell line SMMC-7721 in vitro. Compared with that of the negative control group (Lv-shCon), the mRNA and protein expression levels of RRS1 in SMMC-7721 cells transfected with Lv-shRRS1 were significantly decreased. Further experiments found that silencing of RRS1 gene expression in SMMC-7721 cells significantly suppressed cell proliferation, inhibited colony formation capacity, increased apoptosis and arrested cells in the G1 phase. These results suggest that the RRS1 gene plays a critical role in cell proliferation, colony formation, cell apoptosis and cell cycle distribution in human HCC cells, and that silencing of RRS1 by RNAi is a promising therapeutic approach for the treatment of HCC, and should be further developed.
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