Acute suppurative terminal cholangitis: Clinical characteristics of a new subtype of acute cholangitis.

BACKGROUND: Acute suppurative terminal cholangitis (ASTC) is rarer than acute obstructive cholangitis and is not well studied. To explore this subtype of acute cholangitis, we described our clinical experience with ASTC. METHODS: We performed a retrospective review of patients with ASTC admitted to our center from September 2014 to August 2020. We analyzed their clinical characteristics, including etiology, clinical manifestations, imaging features, treatment and prognosis. RESULTS: A total of 32 ASTC patients were included in the analysis. The majority of the patients had a history of biliary operations, and clinical manifestations were occult and atypical. The positive rate of bacterial culture was 46.9%. All the patients had typical imaging features on computed tomography and magnetic resonance imaging. Treatment with effective antibiotics was provided as soon as diagnosis was established. After treatment, most patients had a good outcome. Elevated levels of total bilirubin, aspartate aminotransferase, procalcitonin and gamma-glutamyltransferase were the characteristics of critically ill patients and were associated with relatively poor prognosis. CONCLUSIONS: Our results demonstrated that ASTC should be recognized as a new subtype of acute cholangitis, and that earlier diagnosis and more personalized treatments are needed.

RING finger and WD repeat domain 3 regulates proliferation and metastasis through the Wnt/ß-catenin signalling pathways in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) exhibits high invasiveness and mortality rates, and the molecular mechanisms of HCC have gained increasing research interest. The abnormal DNA damage response has long been recognized as one of the important factors for tumor occurrence and development. Recent studies have shown the potential of the protein RING finger and WD repeat domain 3 (RFWD3) that positively regulates p53 stability in response to DNA damage as a therapeutic target in cancers. AIM: To investigate the relationship between HCC and RFWD3 in vitro and in vivo and explored the underlying molecular signalling transduction pathways. METHODS: RFWD3 gene expression was analyzed in HCC tissues and adjacent normal tissues. Lentivirus was used to stably knockdown RFWD3 expression in HCC cell lines. After verifying the silencing efficiency, Celigo/cell cycle/apoptosis and MTT assays were used to evaluate cell proliferation and apoptosis. Subsequently, cell migration and invasion were assessed by wound healing and transwell assays. In addition, transduced cells were implanted subcutaneously and injected into the tail vein of nude mice to observe tumor growth and metastasis. Next, we used lentiviral-mediated rescue of RFWD3 shRNA to verify the phenotype. Finally, the microarray, ingenuity pathway analysis, and western blot analysis were used to analyze the regulatory network underlying HCC. RESULTS: Compared with adjacent tissues, RFWD3 expression levels were significantly higher in clinical HCC tissues and correlated with tumor size and TNM stage (P < 0.05), which indicated a poor prognosis state. RFWD3 silencing in BEL-7404 and HCC-LM3 cells increased apoptosis, decreased growth, and inhibited the migration in shRNAi cells compared with those in shCtrl cells (P < 0.05). Furthermore, the in vitro results were supported by the findings of the in vivo experiments with the reduction of tumor cell invasion and migration. Moreover, the rescue of RFWD3 shRNAi resulted in the resumption of invasion and metastasis in HCC cell lines. Finally, gene expression profiling and subsequent experimental verification revealed that RFWD3 might influence the proliferation and metastasis of HCC via the Wnt/ß-catenin signalling pathway. CONCLUSION: We provide evidence for the expression and function of RFWD3 in HCC. RFWD3 affects the prognosis, proliferation, invasion, and metastasis of HCC by regulating the Wnt/ß-catenin signalling pathway.

Ubiquitin-specific protease 3 facilitates cell proliferation by deubiquitinating pyruvate kinase L/R in gallbladder cancer.

Ubiquitin-specific protease 3 (USP3), a kind of cysteine protease, is a crucial family member of deubiquitinating enzymes. USP3 is aberrantly expressed in several tumors, which may contribute to cancer progression. However, the role of USP3 in gallbladder cancer (GBC) is still unknown. In the current study, we detected the expression of USP3 in GBC tissues, measured its contribution to the cell proliferation in GBC progression, and further studied the underlying mechanism of USP3 in GBC through pyruvate kinase L/R (PKLR; a kind of glycolytic enzyme). We found that the expression of USP3 in GBC tissues were higher than that of adjacent tissues, and the protein levels of USP3 and PKLR were positively correlated. Additionally, overexpressed USP3 significantly promoted cell proliferation in vitro and tumor growth in vivo, while the silencing of USP3 inhibited proliferation and tumor growth. Glycolysis in GBC cells ws promoted by the USP3 overexpression and inhibited bye USP3 downregulation. Moreover, the loss of USP3 promoted the ubiquitination and weakened the stability of PKLR. Results of the rescue assay confirmed that PKLR knockdown suppressed USP3-induced oncogenic activity in USP3 overexpressed GBC cells. These findings imply that USP3 is an essential positive regulator in GBC progression, and USP3-PKLR plays a vital role in the progression and metabolism of GBC.

SOD3 deficiency induces liver fibrosis by promoting hepatic stellate cell activation and epithelial-mesenchymal transition.

Hepatic stellate cell (HSC) activation plays an important role in the pathogenesis of liver fibrosis, and epithelial-mesenchymal transition (EMT) is suggested to potentially promote HSC activation. Superoxide dismutase 3 (SOD3) is an extracellular antioxidant defense against oxidative damage. Here, we found downregulation of SOD3 in a mouse model of liver fibrosis induced by carbon tetrachloride (CCl4 ). SOD3 deficiency induced spontaneous liver injury and fibrosis with increased collagen deposition, and further aggravated CCl4 -induced liver injury in mice. Depletion of SOD3 enhanced HSC activation marked by increased α-smooth muscle actin and subsequent collagen synthesis primarily collagen type I in vivo, and promoted transforming growth factor-ß1 (TGF-ß1)-induced HSC activation in vitro. SOD3 deficiency accelerated EMT process in the liver and TGF-ß1-induced EMT of AML12 hepatocytes, as evidenced by loss of E-cadherin and gain of N-cadherin and vimentin. Notably, SOD3 expression and its pro-fibrogenic effect were positively associated with sirtuin 1 (SIRT1) expression. SOD3 deficiency inhibited adenosine monophosphate-activated protein kinase (AMPK) signaling to downregulate SIRT1 expression and thus involving in liver fibrosis. Enforced expression of SIRT1 inhibited SOD3 deficiency-induced HSC activation and EMT, whereas depletion of SIRT1 counteracted the inhibitory effect of SOD3 in vitro. These findings demonstrate that SOD3 deficiency contributes to liver fibrogenesis by promoting HSC activation and EMT process, and suggest a possibility that SOD3 may function through modulating SIRT1 via the AMPK pathway in liver fibrosis.

Complete resection of the gastric antrum decreased incidence and severity of delayed gastric emptying after pancreaticoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) is the main complication after pancreaticoduodenectomy (PD), but the mechanism is still unclear. The aim of this study was to elucidate the role of complete resection of the gastric antrum in decreasing incidence and severity of DGE after PD. METHODS: Sprague-Dawley rats were divided into three groups: expanded resection (ER group), complete resection (CR group), and incomplete resection (IR group) of the gastric antrum. The tension (g) of remnant stomach contraction was observed. We analyzed the histological morphology of the gastric wall by different excisional methods after distal gastrectomy. Moreover, patients underwent PD at our department between January 2012 and May 2016 were included in the study. These cases were divided into IR group and CR group of the gastric antrum, and the clinical data were retrospectively analyzed. RESULTS: The ex vivo remnant stomachs of CR group exhibited much greater contraction tension than others (P < 0.05). The contraction tension of the remnant stomach increased with increasing acetylcholine concentration, while remained stable at the concentration of 10 × 10-5 mol/L. Furthermore, 174 consecutive patients were included and retrospectively analyzed in the study. The incidence of DGE was significantly lower (3.5% vs. 21.3%, P < 0.01) in CR group than in IR group. In addition, hematoxylin-eosin staining analyses of the gastric wall confirmed that the number of transected circular smooth muscle bundles were higher in IR group than in CR group (8.24 ± 0.65 vs. 3.76 ± 0.70, P < 0.05). CONCLUSIONS: The complete resection of the gastric antrum is associated with decreased incidence and severity of DGE after PD. Gastric electrophysiological and physiopathological disorders caused by damage to gastric smooth muscles might be the mechanism underlying DGE.

Specific alterations in gut microbiota are associated with prognosis of Budd-Chiari syndrome.

Gut microbiota is associated with liver diseases. However, gut microbial characteristics of Budd-Chiari syndrome (B-CS) have not been reported. Here, by MiSeq sequencing, gut microbial alterations were characterized among 37 health controls, 20 liver cirrhosis (LC) patients, 31 initial B-CS patients (B-CS group), 33 stability patients after BCS treatment (stability group) and 23 recurrent patients after BCS treatment (recurrence group). Gut microbial diversity was increased in B-CS versus LC. Bacterial community of B-CS clustered with controls but separated from LC. Operational taxonomic units (OTUs) 421, 502 (Clostridium IV) and 141 (Megasphaera) were unique to B-CS. Genera Escherichia/Shigella and Clostridium XI were decreased in B-CS versus controls. Moreover, nine genera, mainly including Bacteroides and Megamonas, were enriched in B-CS versus LC. Notably, Megamonas could distinguish B-CS from LC with areas under the curve (AUCs) of 0.7904. Microbial function prediction revealed that L-amino acid transport system activity was decreased in B-CS versus both LC and controls. Furthermore, OTUs 27 (Clostridium XI), 137 (Clostridium XIVb) and 40 (Bacteroides) were associated with B-CS stability. Importantly, genus Clostridium XI was enriched in stability group versus both recurrence group and B-CS group. Also, PRPP glutamine biosynthesis was reduced in stability group versus recurrence group, but was enriched in stability group versus B-CS group. In conclusion, specific microbial alterations associated with diagnosis and prognosis were detected in B-CS patients. Correction of gut microbial alterations may be a potential strategy for B-CS prevention and treatment.

Total closure of pancreatic section for end-to-side pancreaticojejunostomy decreases incidence of pancreatic fistula in pancreaticoduodenectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a serious complication and results in prolonged hospitalization and high mortality. The present study aimed to evaluate the safety and effectiveness of total closure of pancreatic section for end-to-side pancreaticojejunostomy in pancreaticoduodenectomy (PD). METHODS: This was a prospective randomized clinical trial comparing the outcomes of PD between patients who underwent total closure of pancreatic section for end-to-side pancreaticojejunostomy (Group A) vs those who underwent conventional pancreaticojejunostomy (Group B). The primary endpoint was the incidence of pancreatic fistula. Secondary endpoints were morbidity and mortality rates. RESULTS: One hundred twenty-three patients were included in this study. The POPF rate was significantly lower in Group A than that in Group B (4.8% vs 16.7%, P<0.05). About 38.3% patients in Group B developed one or more complications; this rate was 14.3% in Group A (P<0.01). The wound/abdominal infection rate was also much higher in Group B than that in Group A (20.0% vs 6.3%, P<0.05). Furthermore, the average hospital stays of the two groups were 18 days in Group A, and 24 days in Group B, respectively (P<0.001). However, there was no difference in the probability of mortality, biliary leakage, delayed gastric emptying, and pulmonary infection between the two groups. CONCLUSION: Total closure of pancreatic section for end-to-side pancreaticojejunostomy is a safe and effective method for pancreaticojejunostomy in PD.

Physical Activity and the Risk of Gallstone Disease: A Systematic Review and Meta-analysis.

BACKGROUND: The role of physical activity in preventing gallstone disease independent of its effect on the body weight has not been well established. We performed a systematic review and meta-analysis of cohort and case-control studies to analyze this potential association. METHODS: We searched PubMed and EMBASE to identify all published studies in English through April 2016. We pooled the relative risks (RRs) or odds ratios (ORs) and corresponding 95% confidence intervals (CIs) from individual studies using a random-effects model to investigate associations between physical activity and the risk of gallstone disease. RESULTS: A total of 16 studies comprising 19 independent reports of approximately 260,000 participants met the inclusion criteria, including 6 case-control studies and 13 cohort studies. In a pooled analysis of cohort studies, physical activity (in a comparison of the highest-level and the lowest-level groups) was associated with a reduced risk of gallstone disease (RR=0.85; 95% CI, 0.78-0.92; I=79.5%). For men, the RR was 0.76 (95% CI, 0.60-0.97), and for women, the RR was similar (RR=0.77; 95% CI, 0.66-0.91). In a dose-response analysis, the RR of gallstone disease was 0.87 (95% CI, 0.83-0.92; I=1.0%) per 20 metabolic equivalent-hours of recreational physical per week. In comparison, case-control studies yielded a stronger significant risk reduction for gallstone disease (OR=0.64; 95% CI, 0.46-0.90; I=76.6%). CONCLUSIONS: This study suggests an inverse association between physical activity and gallstone disease in both men and women; however, these findings should be interpreted cautiously because of study heterogeneity.

Investigation for role of tissue factor and blood coagulation system in severe acute pancreatitis and associated liver injury.

This study aims to investigate the molecular mechanisms underlying the pathogenesis of severe acute pancreatitis (SAP) and SAP-associated liver injury, we performed an association analysis of the functions of tissue factor (TF) and blood coagulation system in both SAP patients and mouse SAP model. Our results showed that serum TF and tissue factor-microparticle (TF-MP) levels were highly up-regulated in both SAP patients and SAP mouse model, which was accompanied by the dysfunction of blood coagulation system. Besides, TF expression was also highly up-regulated in the Kupffer cells (KCs) of SAP mouse model. After inhibiting KCs in SAP mouse model, the amelioration of blood coagulation system functions was associated with the decrease in serum TF and TF-MPs levels, and the reduction of SAP-associated liver injury was associated with the decrease of TF expression in KCs. In conclusion, the dis-regulated TF expression and associated dysfunction of blood coagulation system are critical factors for the pathogenesis of SAP and SAP-associated liver injury. TF may serve as a potential and effective target for treating SAP and SAP-associated liver injury.

Epithelial-mesenchymal transition in liver fibrosis.

Liver fibrosis is the result of a sustained wound healing response to sustained chronic liver injury, which includes viral, alcoholic and autoimmune hepatitis. Hepatic regeneration is the dominant outcome of liver damage. The outcomes of successful repair are the replacement of dead epithelial cells with healthy epithelial cells, and reconstruction of the normal hepatic structure and function. Prevention of the development of epithelial-mesenchymal transition (EMT) may control and even reverse liver fibrosis. EMT is a critical process for an epithelial cell to undergo a conversion to a mesenchymal phenotype, and is believed to be an inflammation-induced response, which may have a central role in liver fibrosis. The origin of fibrogenic cells in liver fibrosis remains controversial. Numerous studies have investigated the origin of all fibrogenic cells within the liver and the mechanism of the signaling pathways that lead to the activation of EMT programs during numerous chronic liver diseases. The present study aimed to summarize the evidence to explain the possible role of EMT in liver fibrosis.

Aspirin might reduce the incidence of pancreatic cancer: A meta-analysis of observational studies.

Although there is evidence that non-steroidal anti-inflammatory drugs (NSAIDs) might be able to prevent pancreatic cancer, the findings from epidemiological studies have been inconsistent. In this paper, we conducted a meta-analysis of observational studies to examine this possibility. We searched PubMed and Embase for observational (cohort or case-control) studies examining the consumption of aspirin and other NSAIDs and the incidence of or mortality rates associated with pancreatic cancer. Twelve studies including approximately 258,000 participants in total were analysed. The administration of aspirin significantly reduced the incidence of pancreatic cancer (8 studies; odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.62 to 0.96; I(2) = 74.2%) but not the mortality associated with it (2 studies; OR = 0.94; 95% CI = 0.73 to 1.22). Specifically, frequent aspirin use was associated with reduced pancreatic cancer incidence (OR = 0.57; 95% CI = 0.39 to 0.83 for high frequency; OR = 0.57; 95% CI = 0.38 to 0.84 for medium frequency). The summary ORs regarding the incidence of pancreatic cancer and either non-aspirin NSAIDs use (OR = 1.08; 95% CI = 0.90 to 1.31) or overall NSAIDs use (OR = 0.97; 95% CI = 0.86 to 1.10) were not significant. In conclusion, aspirin use might reduce the incidence of pancreatic cancer; however, this finding should be interpreted with caution because of study heterogeneity.