Left-sided portal hypertension caused by peripancreatic lymph node tuberculosis misdiagnosed as pancreatic cancer: a case report and literature review.

BACKGROUND: Left-sided portal hypertension (LSPH) is an extremely rare clinical syndrome, and it is the only form of curable portal hypertension. It is primarily caused by pancreatic disease, and is associated with complications that cause spleen vein compression. Specific symptoms are often lacking, rendering it difficult to diagnose. Splenectomy is the main treatment for cases complicated by variceal bleeding, and the effects of treatment primarily depend on the condition of the primary disease. CASE PRESENTATION: The patient was a 29-year-old woman who was admitted to the hospital for repeated hematemesis and black stool. She had been misdiagnosed with pancreatic cancer 7 years prior. Combined imaging and endoscopic examination indicated varicose gastric fundus veins, a pancreatic mass, and enlarged peripancreatic lymph nodes. Laboratory investigations revealed reduced erythrocyte, platelet, and leukocyte counts, the interferon gamma release assay was positive, and liver function was normal. Abdominal exploration, splenectomy, varicose vein dissection, and lesion resection were performed via laparotomy. Postoperative biopsy analysis confirmed the diagnosis of lymph node tuberculosis. Based on the above-described factors, LSPH caused by peripancreatic lymph node tuberculosis was a diagnosed. CONCLUSIONS: Herein we describe the first reported case of LSPH caused by peripancreatic lymph node tuberculosis. When left portal hypertension occurs simultaneously, peripancreatic lymph node tuberculosis is often misdiagnosed as pancreatic cancer. Further studies are necessary to develop a more favorable diagnostic method for pancreas masses and more advantageous therapy for LSPH, especially in cases caused by mechanical compression.

Acetyl-3-Aminoethyl Salicylate Ameliorates Hepatic Ischemia/Reperfusion Injury and Liver Graft Survival Through a High-Mobility Group Box 1/Toll-Like Receptor 4-Dependent Mechanism.

In liver transplant cases, severe hepatic ischemia/reperfusion injury (HIRI) is a strong predictor of adverse liver graft and overall outcomes. During HIRI, high-mobility group box 1 (HMGB1) promotes hepatocellular death and proinflammatory cytokine secretion by toll-like receptor 4 (TLR4). Because salicylates inhibit HMGB1/TLR4 interaction, we hypothesized that salicylates may ameliorate HIRI-induced liver damage by inhibiting HMGB1/TLR4 axis activation. Using a murine model of HIRI, we found that the salicylate acetyl-3-aminoethyl salicylic acid (ac3AESA) reduced serum alanine aminotransferase and aspartate aminotransferase as well as Suzuki scores and apoptotic cell counts after HIRI. Ac3AESA also down-regulated hepatocellular HMGB1 and TLR4 expression, phosphorylated inhibitor of κBα, extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, cleaved caspase 3, and cleaved caspase 1 levels after HIRI. Ac3AESA reduced liver Kupffer cell transcription of proinflammatory mediators tumor necrosis factor α (TNF-α), interleukin (IL) 6, IL1ß, chemokine (C-X-C motif) ligand (CXCL) 1, CXCL2, and CXCL8 after HIRI. Ac3AESA also dose-dependently reduced in vitro release of Kupffer cell TNF-α. Employing a murine orthotopic liver transplantation model, we found daily ac3AESA administration up to day 10 after transplant improved liver graft survival, suppressed allograft damage, and down-regulated HMGB1/TLR4 signaling. These benefits to survival and allograft health were maintained for cold ischemia times of 12 and 18 hours. Notably, TLR4 knockout eliminated all foregoing ac3AESA-induced effects. In conclusion, ac3AESA partially rescues the negative effects of HIRI and prolongs liver graft survival in a TLR4-dependent manner.

Exogenous vascular endothelial growth factor delivery prior to endothelial precursor cell transplantation in orthotopic liver transplantation-induced hepatic ischemia/reperfusion injury.

Vascular endothelial growth factor (VEGF) promotes angiogenesis in vivo. We hypothesized that exogenous delivery of VEGF prior to bone marrow-derived endothelial precursor cell (EPC) transplantation may improve orthotopic liver transplantation (OLT)-induced hepatic ischemia/reperfusion injury (HIRI). OLT between Sprague Dawley donor rats and inbred LEW Wistar recipient rats was performed in 6 experimental groups to comparatively assess the effects of the VEGF gene: an untreated normal control group, a surgical control group, a liposomal control group, a VEGF group receiving only the liposome-encapsulated VEGF plasmid, an EPC group receiving only EPCs, and an EPC+VEGF group receiving the liposome-encapsulated VEGF plasmid followed by EPCs. VEGF plasmid delivery to liver tissue, endogenous VEGF, and vascular endothelial growth factor receptor (VEGFR) expression, liver transaminase levels, hepatocellular injury levels, apoptosis, apoptotic biomarkers, hepatotrophic mitogens, angiogenesis, and nitric oxide synthase (NOS) activity were assayed after OLT. Exogenous VEGF gene delivery prior to EPC transplantation significantly increased endogenous VEGF and VEGFR expression, significantly reduced liver transaminase levels, significantly reduced hepatocellular injury levels, significantly reduced hepatic apoptosis levels, and significantly reduced several apoptotic biomarkers (ie, B cell lymphoma 2-associated X protein/B cell lymphoma 2 ratio, caspase 3 activity, and heat shock protein 70 expression) in post-OLT-induced HIRI. Moreover, VEGF gene delivery prior to EPC transplantation significantly increased hepatotrophic mitogen expression (ie, epidermal growth factor, heparin-binding epidermal growth factor-like growth factor, hepatocyte growth factor, and transforming growth factor α), angiogenesis, and NOS activity in post-OLT-induced HIRI. In conclusion, exogenous liposomal delivery of the VEGF gene prior to bone marrow-derived EPC transplantation may be an effective strategy in decreasing OLT-induced HIRI. Liver Transplantation 23 804-812 2017 AASLD.

Intercellular adhesion molecular-1, Fas, and Fas ligand as diagnostic biomarkers for acute allograft rejection of pancreaticoduodenal transplantation in pigs.

BACKGROUND: The early diagnosis of pancreas allograft dysfunction is crucial for the management and long-term survival of transplanted pancreases. We investigated whether intercellular adhesion molecular-1 (ICAM-1), Fas, and Fas ligand (FasL) can be used as novel biomarkers of acute pancreaticoduodenal allograft dysfunction in pigs. METHODS: Forty outbred landraces were randomly divided into three groups. In the control group (8 pigs), a sham operation was performed but no drugs were administered. In groups 1 and 2 (8 pairs each), pancreaticoduodenal transplantation was performed, with the latter administered immunosuppressive drugs and the former not administered drugs. The expression of ICAM-1, Fas, and FasL mRNA in the peripheral vein blood was assessed by flow cytometry and RT-PCR, pre-transplant and on days 1, 3, 5, and 7 after transplantation. Simultaneously, the levels of glucose, insulin, and glucagon in the serum of the recipients were evaluated. The allograft pancreas tissue was obtained to assess the pathological damage and the expression of Fas and FasL by immunohistochemistry. RESULTS: On the first 7 days after transplantation, ICAM-1, Fas, and FasL mRNA expression in the blood leukocytes of the recipient increased significantly in groups 1 and 2 compared with the control group (P < 0.01). However, the levels in group 2 were significantly lower than those in group 1 (P < 0.05). Interestingly, the FasL expression increased but the Fas expression decreased gradually in the graft pancreas tissue during the first week after transplantation in both groups 1 and 2 compared with the control group (P < 0.05). The levels of serous glucose, insulin, and glucagon in groups 1 and 2 obviously changed on day 1 after transplantation but returned to normal on day 2. The recipient's pancreas pathological sections did not exhibit any rejection changes on days 1 and 3 after transplantation but showed rejection damage on days 5 and 7. CONCLUSION: ICAM-1, Fas, and FasL were found to be sensitive biomarkers of acute pancreas allograft dysfunction after pancreaticoduodenal transplantation in pigs, and their monitoring could be used to evaluate the effectiveness of the immunosuppression therapy.

Interventional therapy combined with tyrosine kinase inhibitors with or without immune checkpoint inhibitors as initial treatment for hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis.

BACKGROUND: Interventional therapy, in conjunction with tyrosine kinase inhibitors (TKIs), has shown promising outcomes for treating hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). With the advent of immunotherapy, the combined use of immune checkpoint inhibitors (ICIs) has attracted great attention due to their potential effectiveness in advanced HCC. This study aims to compare the efficacy and safety of a triple therapy regimen (Interventional therapy, TKIs and ICIs, IT-TKI-ICI) with a dual therapy regimen (Interventional therapy and TKIs, IT-TKI) in the treatment of HCC and PVTT (HCC-PVTT). METHODS: A comprehensive search was carried out in PubMed, Web of Science, Embase, Scopus, and the Cochrane Library databases. Primary outcome measures were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included tumor response rate, adverse event incidence as well as downstaging surgery rate. Statistical analysis was conducted using Revman 5.4 software. RESULTS: The meta-analysis finally included 6 cohort studies. The triple therapy group demonstrated significantly prolonged OS and PFS compared to the dual therapy group. Meanwhile, the former exhibited significantly higher rates of objective response rate (ORR), disease control rate (DCR) and better downstaging effects with a higher salvage surgery rate without significantly increasing adverse events. CONCLUSION: In comparison to dual therapy, the triple therapy with interventional therapy, TKIs, and ICIs demonstrates superior efficacy and equivalent safety for HCC-PVTT.

Human islet amyloid polypeptide-induced ß-cell cytotoxicity is linked to formation of α-sheet structure.

Type 2 diabetes (T2D) results from insulin secretory dysfunction arising in part from the loss of pancreatic islet ß-cells. Several factors contribute to ß-cell loss, including islet amyloid formation, which is observed in over 90% of individuals with T2D. The amyloid is comprised of human islet amyloid polypeptide (hIAPP). Here we provide evidence that early in aggregation, hIAPP forms toxic oligomers prior to formation of amyloid fibrils. The toxic oligomers contain α-sheet secondary structure, a nonstandard secondary structure associated with toxic oligomers in other amyloid diseases. De novo, synthetic α-sheet compounds designed to be nontoxic and complementary to the α-sheet structure in the toxic oligomers inhibit hIAPP aggregation and neutralize oligomer-mediated cytotoxicity in cell-based assays. In vivo administration of an α-sheet design to mice for 4 weeks revealed no evidence of toxicity nor did it elicit an immune response. Furthermore, the α-sheet designs reduced endogenous islet amyloid formation and mitigation of amyloid-associated ß-cell loss in cultured islets isolated from an hIAPP transgenic mouse model of islet amyloidosis. Characterization of the involvement of α-sheet in early aggregation of hIAPP and oligomer toxicity contributes to elucidation of the molecular mechanisms underlying amyloid-associated ß-cell loss.

Glycogen synthase kinase 3 inhibitor attenuates endotoxin-induced liver injury.

BACKGROUND/AIMS: Endotoxin (lipopolysaccharide, LPS)-induced acute liver injury was attenuated by endotoxin tolerance (ET), which is characterized by phosphatidylinositol 3-kinase pathway/Akt signaling. Glycogen synthase kinase 3 (GSK-3) acts downstream of phosphatidylinositol 3-kinase pathway/Akt and GSK-3 inhibitor protects against organic injury. This study evaluates the hypothesis that ET attenuated LPS-induced liver injury through inhibiting GSK-3 functional activity and downstream signaling. METHODS: Sprague-Dawley rats with or without low-dose LPS pretreatment were challenged with or without large dose of LPS and subsequently received studies. Serum tumor necrosis factor-alpha, interleukin-10, alanine aminotransferase, lactate dehydrogenase, and total bilirubin levels were analyzed, morphology of liver tissue was performed, glycogen content, myeloperoxidase content, phagocytosis activity of Kupffer cells, and the expression and inhibitory phosphorylation as well as kinase activity of GSK-3 were examined. Survival after LPS administration was also determined. RESULTS: LPS induced significant increases of serum TNF-α, alanine aminotransferase, lactate dehydrogenase, and total bilirubin (P < 0.05), which were companied by obvious alterations in liver: the injury of liver tissue, the decrease of glycogen, the infiltration of neutrophils, and the enhancement of phagocytosis of Kupffer cells (P < 0.05). LPS pretreatment significantly attenuated these alterations, promoted the inhibitory phosphorylation of GSK-3 and inhibited its kinase activity, and improved the survival rate (P < 0.05). CONCLUSIONS: ET attenuated LPS-induced acute liver injury through inhibiting GSK-3 functional activity and its downstream signaling.

Radiofrequency-assisted versus clamp-crushing parenchyma transection in cirrhotic patients with hepatocellular carcinoma: a randomized clinical trial.

BACKGROUND: Surgical resection remains the optimal therapy for cirrhotic patients with hepatocellular carcinoma (HCC) that are not suitable for liver transplantation (LT). Recently, various innovative techniques for liver resection have been developed. AIM: The aim of the study was to compare radiofrequency-assisted parenchyma transection (RF-PT) with the traditional clamp-crushing (CC) technique to explore the preferred therapy in cirrhotic patients with HCC. METHODS: From January 2009 to December 2010, 75 cirrhotic patients with HCC who underwent hepatectomy were randomized to RF-PT (group 1, n = 38) or CC-PT (group 2, n = 37) groups. The primary endpoint was intraoperative blood loss. The secondary endpoints included hepatic transection time, total operating time, postoperative morbidity, mortality, length of intensive care unit and hospital stays, and liver function. RESULTS: The characteristics of the two patient groups were closely matched. The Pringle maneuver was not used in RF-PT patients. The blood loss of the RF-PT group, total or during transection, was significantly lower than that of the CC-PT group (385 vs. 545 ml, p = 0.001; 105 vs. 260 ml, p = 0.000, respectively). Compared with CC-PT patients, the morbidity of the RF-PT group was lower though not statistically significant (28.9 vs. 38.8 %, p = 0.197). One death occurred in the RF-PT group 12 days postoperative due to a large area cerebral embolism. CONCLUSION: RF-PT is a safe and feasible surgical resection method for patients with cirrhosis and concomitant HCC. In addition, RF-PT results in lower blood loss and lower morbidity than the CC technique during liver resection.

Designed α-sheet peptides disrupt uropathogenic E. coli biofilms rendering bacteria susceptible to antibiotics and immune cells.

Uropathogenic Escherichia coli account for the largest proportion of nosocomial infections in the United States. Nosocomial infections are a major source of increased costs and treatment complications. Many infections are biofilm associated, rendering antibiotic treatments ineffective or cause additional complications (e.g., microbiome depletion). This work presents a potentially complementary non-antibiotic strategy to fight nosocomial infections by inhibiting the formation of amyloid fibrils, a proteinaceous structural reinforcement known as curli in E. coli biofilms. Despite extensive characterization of the fibrils themselves and their associated secretion system, mechanistic details of curli assembly in vivo remain unclear. We hypothesized that, like other amyloid fibrils, curli polymerization involves a unique secondary structure termed "α-sheet". Biophysical studies herein confirmed the presence of α-sheet structure in prefibrillar species of CsgA, the major component of curli, as it aggregated. Binding of synthetic α-sheet peptides to the soluble α-sheet prefibrillar species inhibited CsgA aggregation in vitro and suppressed amyloid fibril formation in biofilms. Application of synthetic α-sheet peptides also enhanced antibiotic susceptibility and dispersed biofilm-resident bacteria for improved uptake by phagocytic cells. The ability of synthetic α-sheet peptides to reduce biofilm formation, improve antibiotic susceptibility, and enhance clearance by macrophages has broad implications for combating biofilm-associated infections.

Research trends and hotspots of neoadjuvant therapy in pancreatic cancer: a bibliometric analysis based on the Web of Science Core Collection.

Neoadjuvant therapy (NAT) for pancreatic cancer (PC) has achieved certain results. This article was aimed to analyze the trends in NAT in PC over the past 20 years using bibliometric analysis and visualization tools to guide researchers in exploring future research hotspots. Articles related to NAT for PC were retrieved from the Web of Science Core Collection for the period 2002-2021. The information was analyzed and visualized using VOSviewer, Citespace, Microsoft Excel and R software. The number of articles per year has continued to increase over the past 20 years. Of the 1,598 eligible articles, the highest number was from the United States (760), and an analysis of institutions indicated that the University of Texas System (150) had the highest number of articles. Matthew H. G. Katz had the highest number of citations and the highest H-index. "Pancreatic cancer" (981), "Resection" (623), "Cancer" (553), "Neoadjuvant therapy" (509) and "Survival" (484) were the top five ranked keywords. Combined with the keywords-cluster analysis and citation burst analysis, current research hotspots were the optimal NAT regimen, NAT response assessment, NAT for resectable PC and management of complications. NAT has received increasing attention in the field of PC over the past 20 years, but greater collaboration between countries and additional multicenter randomized clinical trials are needed. Overall, we have revealed current research hotspots and provided valuable information for the choice of future research directions.

Role of Kupffer cells in tolerance induction after liver transplantation.

Currently, liver transplantation has reached a level of maturity where it is considered an effective treatment for end-stage liver disease and can significantly prolong the survival time of patients. However, acute and chronic rejection remain major obstacles to its efficacy. Although long-term use of immunosuppressants can prevent rejection, it is associated with serious side effects and significant economic burden for patients. Therefore, the investigation of induced immune tolerance holds crucial theoretical significance and socio-economic value. In fact, the establishment of immune tolerance in liver transplantation is intricately linked to the unique innate immune system of the liver. Kupffer cells, as a crucial component of this system, play a pivotal role in maintaining the delicate balance between inflammatory response and immune tolerance following liver transplantation. The important roles of different functions of Kupffer cells, such as phagocytosis, cell polarization, antigen presentation and cell membrane proteins, in the establishment of immune tolerance after transplantation is comprehensively summarized in this paper. Providing theoretical basis for further study and clinical application of Kupffer cells in liver transplantation.

Clostridium perfringens Liver Abscess Disguised as Biliary Disease: A Report of Two Cases and a Review of the Literature.

Liver abscesses caused by Clostridium perfringens are rare but rapidly fatal. In only a few days, patients progress from liver abscess to sepsis, intravascular hemolysis, multiple organ failure, and even death. These abscesses often occur in patients after trauma or surgery or in those with immunodeficiency. Because patients only show non-specific symptoms such as fever and abdominal pain in the early stage, they can easily be misdiagnosed and miss the therapeutic window, resulting in a poor prognosis. The diagnosis of Clostridium perfringens liver abscess mainly depends on computed tomography (CT), needle aspiration, and/or blood culture. After diagnosis, treatments such as antibiotic therapy, surgical abscess drainage, blood transfusion as needed, and correction of metabolic disturbances must be immediately administered to prevent severe complications. Here, we present two cases of liver abscess due to Clostridium perfringens infection. Both patients initially presented only with fever, abdominal pain, and jaundice, symptoms that were easily confused with cholangitis caused by cholelithiasis. The patients then progressed rapidly and, despite receiving antimicrobial and multimodal sepsis treatment, both eventually died of multiple organ dysfunction syndrome. Clinicians should be on high alert for Clostridium perfringens liver abscesses disguised as biliary disease. Early diagnosis and treatment with the appropriate antibiotics and surgery are fundamental for the survival of the affected patients.

Comprehensive multimodal management of borderline resectable pancreatic cancer: Current status and progress.

Borderline resectable pancreatic cancer (BRPC) is a complex clinical entity with specific biological features. Criteria for resectability need to be assessed in combination with tumor anatomy and oncology. Neoadjuvant therapy (NAT) for BRPC patients is associated with additional survival benefits. Research is currently focused on exploring the optimal NAT regimen and more reliable ways of assessing response to NAT. More attention to management standards during NAT, including biliary drainage and nutritional support, is needed. Surgery remains the cornerstone of BRPC treatment and multidisciplinary teams can help to evaluate whether patients are suitable for surgery and provide individualized management during the perioperative period, including NAT responsiveness and the selection of surgical timing.

Association between gut microbiota and NAFLD/NASH: a bidirectional two-sample Mendelian randomization study.

Background: Recent studies have suggested a relationship between gut microbiota and non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). However, the nature and direction of this potential causal relationship are still unclear. This study used two-sample Mendelian randomization (MR) to clarify the potential causal links. Methods: Summary-level Genome-Wide Association Studies (GWAS) statistical data for gut microbiota and NAFLD/NASH were obtained from MiBioGen and FinnGen respectively. The MR analyses were performed mainly using the inverse-variance weighted (IVW) method, with sensitivity analyses conducted to verify the robustness. Additionally, reverse MR analyses were performed to examine any potential reverse causal associations. Results: Our analysis, primarily based on the IVW method, strongly supports the existence of causal relationships between four microbial taxa and NAFLD, and four taxa with NASH. Specifically, associations were observed between Enterobacteriales (P =0.04), Enterobacteriaceae (P =0.04), Lachnospiraceae UCG-004 (P =0.02), and Prevotella9 (P =0.04) and increased risk of NAFLD. Dorea (P =0.03) and Veillonella (P =0.04) could increase the risks of NASH while Oscillospira (P =0.04) and Ruminococcaceae UCG-013 (P=0.005) could decrease them. We also identified that NAFLD was found to potentially cause an increased abundance in Holdemania (P =0.007) and Ruminococcus2 (P =0.002). However, we found no evidence of reverse causation in the microbial taxa associations with NASH. Conclusion: This study identified several specific gut microbiota that are causally related to NAFLD and NASH. Observations herein may provide promising theoretical groundwork for potential prevention and treatment strategies for NAFLD and its progression to NASH in future.

Correlation between augmenter of liver regeneration and IFN-γ expression in graft after rat orthotopic liver transplantation.

BACKGROUND: Previous data suggested that augmenter of liver regeneration (ALR) has immunomodulation function by suppressing liver-resident NK cell activity and reducing IFN-γ expression in human liver diseases. The correlation between ALR and IFN-γ expression in graft after rat orthotopic liver transplantation remains uncertain. METHODS: A Lewis-to-BN (allograft group) and BN-to-BN (isograft group) rat liver transplantation model was used to investigate the ALR and IFN-γ expression in liver graft. Graft recipients were sacrificed at days 1, 3, 5, and 7 posttransplantation. The histopathologic changes of grafts were observed under light microscope and the intragraft expression of ALR and IFN-γ mRNA and protein was determined by real-time PCR and immunohistochemistry staining, respectively. Correlation between ALR and IFN-γ expression in graft was evaluated by Spearman rank correlation analysis. RESULTS: The light microscope inspection revealed severe acute rejection in the allograft group but not in the isograft group at day 7 after liver transplantation. The intragraft ALR showed slight protein expression at day 1 after liver transplantation in both groups and it was significantly increased at days 3, 5, and 7 (P < 0.05). There was no significant difference in ALR mRNA expression between the allograft group and isograft group at day 1 (1.09 ± 0.12 and 1.13 ± 0.10, respectively; P > 0.05, n = 3). The ALR mRNA level was slightly reduced at day 3 in both groups compared with that at day 1 (0.81 ± 0.11 and 0.59 ± 0.10, respectively, P > 0.05). However, it was markedly increased at day 5 (2.86 ± 0.37) and day 7 (3.19 ± 0.33) in the isograft group and was 1.57 ± 0.27 and 1.98 ± 0.13 in the allograft group at days 5 and 7, respectively. IFN-γ protein and mRNA expression in the allograft group was increased at day 1 posttransplantation and reached a peak at day 3, and then it had a slight tendency of decline at day 5 and day 7. And they in the isograft group were at a low level at all times. The levels of ALR mRNA showed a negative correlation with levels of IFN-γ mRNA in the allograft group (r = -0.86, P < 0.05, y = -0.241x + 0.586), whereas there is no correlation between ALR and IFN-γ mRNA expression in the isograft group. CONCLUSION: These data revealed an obviously negative correlation between ALR and IFN-γ levels intragraft, which indicated that ALR may participate in immunoregulation of acute rejection.

Hepatitis B virus infection increases the risk of cholangiocarcinoma: a meta-analysis and systematic review.

BACKGROUND AND AIM: A number of studies have shown that hepatitis virus infections may be associated with cholangiocarcinoma (CC). However, the relationship between hepatitis B virus (HBV) infection and CC, especially intrahepatic cholangiocarcinoma (ICC), is still controversial. METHODS: Relevant studies were identified by searching PUBMED, EMBASE and Web of Science Datebases up to September 2011. Pooled risk estimates were calculated using a random-effects model. Potential sources of heterogeneity were performed by subgroup analyses. A total of 18 papers were included in this meta-analysis. RESULTS: The pooled risk estimate of all studies showed a statistically significant increased risk of CC among individuals with HBV infection (rate ratio [RR]: 2.66; 95% confidence interval [CI]: 1.97, 3.60). Compared with those without HBV infection, persons with HBV infection had an increased risk of intra-CC (ICC) (RR: 3.42; 95% CI: 2.46, 43.74), extrahepatic CC (OR: 1.46; 95% CI: 0.98, 2.17), and CC (OR: 2.03; 95% CI: 1.15, 3.56). In a subgroup analysis of HBV infection and risk of ICC, the pooled risk estimate of studies in Asians (RR: 3.63; 95% CI: 2.56, 5.13) was higher than that in non-Asians (RR: 1.93; 95% CI: 0.78, 4.76). A Begg funnel plot and Egger test revealed no evidence for publication bias. CONCLUSIONS: This meta-analysis shows that HBV is associated with increased risk of CC, especially for ICC. Further investigation is needed to focus on the mechanism by which HBV may be involved in the pathogenesis of CC.

Impact of Surgery on Non-Functional Pancreatic Neuroendocrine Tumors ≤2†cm: Analyses With Propensity Score-Based Inverse Probability of Treatment Weighting.

Purpose: The impact of surgery on non-functional pancreatic neuroendocrine tumors (NF-PNETs) ≤2 cm is controversial. This study sought to demonstrate the impact of surgery on the prognosis of NF-PNETs ≤2 cm with different biological behaviors. Methods: Patients with NF-PNETs ≤2 cm from 2004 to 2015 in the Surveillance, Epidemiology, and End Results database were included in this study. An inverse probability of treatment weighting (IPTW) method was used to reduce the selection bias. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to evaluate the effect of surgery on the prognosis. Results: In the IPTW-adjusted Cox proportional hazards regression analysis, surgery improved the cancer-specific survival (CSS) in the overall cohort (hazard ratio [HR], 0.187; 95% confidence interval [CI], 0.102-0.343; p < 0.001), patients with poorly differentiated or undifferentiated tumor grades (HR, 0.238; 95% CI, 0.105-0.64; p < 0.001), patients with distant metastasis (HR, 0.102; 95% CI, 0.021-0.496; p = 0.005), and patients with local invasion (HR, 0.059; 95% CI, 0.005-0.683; p = 0.002). Surgery did not improve the CSS in patients with lymph node metastasis only (HR, 0.26; 95% CI, 0.0462-1.461; p = 0.126) or patients with well or moderate differentiation while without distant and lymph node metastasis (HR, 0.387; 95% CI, 0.146-1.028; p = 0.057). Conclusions: Among patients with NF-PNETs ≤2 cm, different biological behaviors correlate with different prognostic impacts of surgery. As long as distant metastasis does not occur and the grade is well-moderately differentiated, these patients will not benefit from surgery no matter whether lymph node metastasis occurs or not. However, when local invasion appears in this group of patients, surgery should be performed. Moreover, patients with a tumor grade of poorly differentiated or undifferentiated or those with distant metastases may benefit from surgery.

Kupffer cells depletion alters cytokine expression and delays liver regeneration after Radio-frequency-assisted Liver Partition with Portal Vein Ligation.

Radio-frequency-assisted Liver Partition with Portal Vein Ligation (RALPP) induces comparable hypertrophy of the liver remnant compared to Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) in humans. However, whether it is significantly improved compared to ALPPS is unclear, and the underlying mechanisms of liver regeneration after RALPP need to further investigate. The present study was to develop an animal model mimicking RALPP and explore mechanisms of liver regeneration. The mice in RALPP group received liver radiofrequency ablation and 90% portal vein ligation (PVL), followed by resection of the targeted liver within two days after the first surgery. The mice in ALPPS group underwent 90% PVL combined with parenchyma transection. Controls received liver radiofrequency ablation (RAF group) or PVL (PVL group) or small left lateral lobe (LLL group) resection alone. Liver regeneration was assessed by liver weight and proliferation-associated molecules. The role of Kupffer cells (KCs) in liver regeneration was investigated after RALPP. The results showed that RALPP induced comparable liver regeneration compared to ALPPS, but with less liver injury and mortality in mice. RALPP led to over-expression of TNF-α and IL-6 in the circulating plasma compared with PVL. KCs infiltrating in liver tissues was a characteristic of mice in the RALPP group. KCs depletion markedly depressed cytokine expression and delayed liver regeneration after RALPP. These results suggested that RALPP in mice induced accelerated liver regeneration similar to ALPPS, but safer than ALPPS. KCs depletion altered cytokine expression and delayed liver regeneration after RALPP.

SCARF1 promotes M2 polarization of Kupffer cells via calcium-dependent PI3K-AKT-STAT3 signalling to improve liver transplantation.

OBJECTIVES: This study aimed to investigate the protective effect of SCARF1 on acute rejection (AR), phagocytic clearance of Kupffer cells (KCs), M2 polarization and the exact mechanism underlying these processes. METHODS: AAV was transfected into the portal vein of rats, and AR and immune tolerance (IT) models of liver transplantation were established. Liver tissue and blood samples were collected. The level of SCARF1 was detected via WB and immunohistochemical staining. Pathological changes in liver tissue were detected using HE staining. Apoptotic cells were detected using TUNEL staining. KC polarization was assessed via immunohistochemical staining. Primary KCs were isolated and co-cultured with apoptotic T lymphocytes. Phagocytosis of apoptotic cells and polarization of KCs were both detected using immunofluorescence. Calcium concentration was determined using immunofluorescence and a fluorescence microplate reader. The levels of PI3K, p-AKT and P-STAT3 were assessed via WB and immunofluorescence. RESULTS: Compared to the IT group, the level of SCARF1 was significantly decreased in the AR group. Overexpression of SCARF1 in KCs improved AR and liver function markers. Enhanced phagocytosis mediated by SCARF1 is beneficial for improving the apoptotic clearance of AR and promoting M2 polarization of KCs. SCARF1-mediated enhancement of phagocytosis promotes increased calcium concentration in KCs, thus further activating the PI3K-AKT-STAT3 signalling pathway. CONCLUSIONS: SCARF1 promotes the M2 polarization of KCs by promoting phagocytosis through the calcium-dependent PI3K-AKT-STAT3 signalling pathway.

IL-4 Alleviates Ischaemia-Reperfusion Injury by Inducing Kupffer Cells M2 Polarization via STAT6-JMJD3 Pathway after Rat Liver Transplantation.

BACKGROUND: Liver ischaemia-reperfusion injury (IRI) remains a problem in liver transplantation. Interleukin-4 (IL-4) has been found to reduce liver IRI, but the exact mechanism remains unclear. METHODS: Donor livers were infused with recombinant IL-4 or normal saline during cold storage, and the hepatocellular apoptosis and the inflammatory response were detected. The effect of IL-4 treatment on Kupffer cells (KCs) polarization and expression of the STAT6-JMJD3 pathway was evaluated in vivo and in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. RESULTS: IL-4 treatment decreased sALT and sAST levels and alleviated hepatocellular apoptosis and inflammation at 6 h after liver transplantation. IL-4 treatment induced KCs alternatively activated (M2) polarization in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. in vivo and in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. CONCLUSIONS: IL-4 treatment-induced KCs M2 polarization was dependent on the STAT6-JMJD3 pathway and protected liver grafts from IRI after liver transplantation.