Noncanonical regulation of HOIL-1 on cancer stemness and sorafenib resistance identifies pixantrone as a novel therapeutic agent for HCC.

BACKGROUND AND AIMS: Cancer stem cells (CSCs) contribute to therapy resistance in HCC. Linear ubiquitin chain assembly complex (LUBAC) has been reported to accelerate the progression of cancers, yet its role in the sorafenib response of HCC is poorly defined. Herein, we investigated the impact of LUBAC on sorafenib resistance and the CSC properties of HCC, and explored the potential targeted drugs. APPROACH AND RESULTS: We found that HOIL-1, but not the other components of LUBAC, played a contributing role in LUBAC-mediated HCC sorafenib resistance, independent of its ubiquitin ligase activity. Both in vitro and in vivo assays revealed that the upregulated HOIL-1 expression enhanced the CSC properties of HCC. Mechanistically, HOIL-1 promoted sorafenib resistance and the CSC properties of HCC through Notch1 signaling. Mass spectrometry, co-immunoprecipitation, western blot, and immunofluorescence were used to determine that the A64/Q65 residues of HOIL-1 bound with the K78 residue of Numb, resulting in impaired Numb-mediated Notch1 lysosomal degradation. Notably, pixantrone was screened out by Autodock Vina, which was validated to disrupt HOIL-1/Numb interaction to inhibit Notch1 signaling and CSC properties by targeting the Q65 residue of HOIL-1. Moreover, pixantrone exerted synergistic effects with sorafenib for the treatment of HCC in different HCC mouse models. CONCLUSIONS: HOIL-1 is critical in promoting sorafenib resistance and CSC properties of HCC through Notch1 signaling. Pixantrone targeting HOIL-1 restrains the sorafenib resistance and provides a potential therapeutic intervention for HCC.

Statin use and risk of gallstone disease: A meta-analysis.

AIM: There is emerging evidence from animal and human studies that current statins can decrease the formation of gallbladder cholesterol gallstones and subsequently decrease the risk of gallstone disease, but consistent results have not been reported. We performed a meta-analysis to provide an overview of the relevant studies. METHODS: Relevant studies published between January 1980 and February 2014 were identified by searching Medline, Embase and the Cochrane Library. Studies were selected using a priori defined criteria. The strength of the relationship between statin use and risk of gallstone disease was assessed by adjusted odds ratio (OR). RESULTS: A total of 622 868 participants from six studies (four case-control studies, one cohort study and one cross-sectional study) were identified in this meta-analysis. The studies provided adjusted overall OR estimates for current statin use versus non-use, leading to a pooled OR of 0.86 (95% confidence interval [CI], 0.77-0.97; P < 0.001). The overall OR of population-based case-control studies and cholecystectomy due to gallstone disease were 0.83 (95% CI, 0.73-0.95; P = 0.0131) and 0.78 (95% CI, 0.74-0.82; P = 0.615), respectively. CONCLUSION: There is evidence that current statin use lowers the risk of gallstone disease compared with non-use, especially for cholecystectomy due to gallstone disease. Low statin use (1-4 prescriptions) did not decrease the risk of gallstone disease, but moderate and high statin use significantly decreased the risk. Further multicenter and better controlled studies are needed to confirm these findings.

Ultrasound ablation of intravascular plaque for treating atherosclerosis obliterans of bilateral iliofemoral arteries: report of one case.

OBJECTIVE: A patient with atherosclerosis obliterans of bilateral iliofemoral arteries was successfully treated by ultrasound ablation of intravascular plaque, who had an uneventful postoperative recovery.

Meta-analysis of alcohol consumption and risk of extrahepatic bile system cancer.

AIM: Alcohol consumption increases the risk of liver cancer. However, there is still controversy regarding alcohol consumption and the risk of extrahepatic bile system cancer (EBSC). We performed a meta-analysis to provide an overview of the relevant studies and gain more robust estimates of the relationship between alcohol consumption and risk of EBSC. METHODS: Relevant studies published between January 1966 and October 2010 were identified by searching Medline, Embase and the Cochrane Library. Studies were selected using a priori defined criteria. The strength of the relationship between alcohol consumption and risk of EBSC was assessed by adjusted odds ratio (OR). RESULTS: A total of 113 767 participants from 10 studies (nine case-control studies and one cohort study) were identified in this meta-analysis. The studies provided adjusted overall OR estimates for drinkers versus non-/low drinkers, leading to a pooled adjusted OR of 0.82 (95% confidence interval [CI] = 0.72-0.94, P for heterogeneity = 0.194, I(2) = 27.2%). The overall adjusted OR of hospital-based studies and population-based studies were 0.80 (95% CI = 0.65-0.99, P = 0.260) and 0.79 (95% CI = 0.64-0.98, P = 0.119), respectively. For the heavy drinkers, the adjusted OR significance increased to 1.58 (95% CI = 0.97-2.57, P for heterogeneity = 0.055, I(2) = 65.4%), but it had no statistical significance. CONCLUSION: There is evidence that moderate alcohol consumption lowers the risk of EBSC compared with non-/low alcohol consumption, but not heavy alcohol consumption. Further multicenter and better controlled studies are required to confirm these findings.

[Adult-to-adult living-related donor liver transplantation: report of 2 cases].

OBJECTIVE: To investigate the feasibility and safety of adult-to-adult living-related donor liver transplantation using a right lobe graft. METHODS: The clinical data of 2 cases of living-related donor liver transplantation performed between July, 2010 and November, 2010 were analyzed. RESULTS: Liver transplantation was performed using a right lobe graft including the middle hepatic vein in one case and a right lobe graft without the middle hepatic vein in the other. The ratio of graft volume to standard liver volume was 46.2% and 47.3% in the two cases, with GR/WR of 0.83 and 0.80, and donor residue liver of 42.1% and 39.5%, respectively. The donor operation lasted for 6.5 h and 5 h in the two cases with blood loss of about 200-250 ml without blood transfusion. The donors recovered uneventfully without any surgical complications, whose liver function was normal 7 days after the operation, and were discharged 14 days and 16 days after the surgery, respectively. The recipient operation lasted for 8 h and 7 h with blood loss of about 800-1000 ml. The right hepatic vein, hepatic artery, portal vein and bile duct reconstruction were performed by end-to-end anastomoses in the 2 recipients. Bile duct anastomosis stricture occurred in the first recipient 2 months after transplantation and was treated with percutaneous transhepatic cholangiography and drainage. The second recipient recovered smoothly without any complications. The recipients have so far survived 9 months and 5 months, respectively. CONCLUSION: Adult-to-adult living-related donor liver transplantation is a safe and effective option for treatment of end-stage liver diseases in the context of cadaveric liver graft shortage.

[Therapeutic efficacy of Nexavar on liver cancer and its relation to the expression of Ki-67 and CD34].

OBJECTIVE: To study the therapeutic effects of Nexavar on liver cancer and its relation to the expressions of Ki-67 and CD34. METHODS: Twenty-eight patients with liver cancer were treated with Nexavar. The therapeutic efficacy of Nexavar on liver cancer was observed. Liver cancer tissues were examined for the expressions of Ki-67 and CD34 by immunohistochemistry. Microvessel density (MVD) was calculated according to the expression of CD34. RESULTS: Of 28 patients, none achieved a complete response (CR), 12 had a partial response (PR), 7 had stable disease (SD), and 9 progressive disease (PD). The efficacy of Nexavar was associated significantly with Ki-67 expression. The mean MVD count was 346.03-/+146.98 in PR patients, and 89.14-/+45.66 in PD patients. There was a significant difference in MVD between PR and PD patients. CONCLUSION: There is a better efficacy of Nexavar in treatment of liver cancer in the patients who had Ki-67-positive expression and high MVD count.

[Clinical research of donor liver procurement and preparation in liver transplantation].

OBJECTIVE: To summarize the experience of donor liver procurement and preparation in liver transplantation. METHODS: One hundred and twenty-six cases of donor liver and kidney procurement and 105 cases of donor liver preparation from August, 2004 to December, 2006 were analyzed. The 105 donor liver grafts were all used for orthotopic liver transplantation. RESULTS: The warm ischemia time of the graft ranged from 1 to 8.5 min with a mean of 4 min. The time of graft procurement ranged from 19 to 28 min (mean 22.5 min). Donor liver preparation lasted for 38 to 102 min in the 105 cases, with a mean of 51 min. The cold ischemia time of the donor liver was 5.5 to 13 h (mean 8 h). Anatomical variations were identified in 8 of the donor liver grafts. CONCLUSIONS: Cold perfusion of the donor liver and repair of the hepatic artery are important procedures in donor liver procurement and preparation. Hemorrhage due to the donor graft should be prevented and the procedures should be performed in close cooperation with the recipient operation.

[Effect of immunonanoparticles loaded with adriamycin on multidrug-resistant liver cancer in nude mice].

OBJECTIVE: To observe the effect of the immunonanoparticles loaded with adriamycin in reversing multidrug resistance (MDR) in liver cancer in a nude mouse model and explore the possible mechanisms. METHODS: The cytotoxicity of adriamycin, adriamycin-loaded nanoparticles, and adriamycin-loaded immunonanoparticles was assessed in a nude mouse model bearing implant tumors of adriamycin-resistant hepatoma cell line SMMC-7721/ADM. The concentration of adriamycin in the tumor tissue was determined. RESULTS: Adriamycin-loaded immunonanoparticles showed significantly stronger cytotoxicity against the implant tumors of SMMC-7721/ADM than adriamycin-loaded nanoparticles and adriamycin. Administration of adriamycin-loaded immunonanoparticles resulted in significantly higher drug concentrations in the tumor tissue than adriamycin-loaded nanoparticles and adriamycin. CONCLUSION: Adriamycin-loaded immunonanoparticles may reverse the MDR of liver cancers in vivo probably resulting from the close binding of the particles with the tumor cells to produce a high local concentration of adriamycin in the tumors.

[Preparation of the anti-HLJ1 monoclonal antibodies and establishment of method for detection of the antigen].

Monoclonal antibodies (McAbs) against human liver DnaJ-like protein (HLJ1) was produced by using lymphocyte-hybridoma technique and then one method for the detection of HLJ1 antigen was established. Two hybridoma cell lines which stably secreted monoclonal antibodies against HLJ1 were generated and named for A4C7 and C4C8. Subtypes of the two McAbs were both IgG1, and the antibodies showed high titer and good specificity. Using the prepared monoclonal antibody, human embryonic liver tissues were examined by immunohistochemistry. The results indicated that HLJ1 located in the cytoplasm of the human embryonic liver cell. A double antibodies sandwich ELISA was established by using C4C8 and HRP labeled A4C7. This assay had good specificity, and the lowest detection limit was 7.5 ng/mL and the linear range was 7.5-750 ng/mL. In conclusion, an immunohistochemistry method and a sensitive sandwich ELISA were established for the detection of HLJ1 protein.

[Analysis of factors for bacterial infection following liver transplantation].

OBJECTIVE: To investigate the association of surgical skills, anhepatic time and preoperative hepatic function grading with bacteria infection after the liver transplantation and identify the common bacterial flora involved for effective prevention and treatment of the posttransplant bacterial infection. METHODS;The clinical records of 31 cases of liver transplantation from August 2004 to August 2005 were reviewed and the collected data were analyzed statistically. RESULTS; Among the 31 cases, posttransplant bacterial infection occurred in 16 cases accounting for a total incidence of 51.61%, with the incidence of multi-system (or multi-organ) infection of 22.58%. The earlier cases had longer average surgery time and anhepatic period than the later cases, with also higher incidence of infection. Among the 19 patients with hepatic function class A before surgery, 7 acquired bacterial infection involving one system or organ, 2 had infections compromising multiple system or organ. In the 8 patients of hepatic function class B before surgery, 2 had single-system or -organ infection and 1 multi-system or -organ infection. Four out of the 5 patients with hepatic function class C before surgery acquired posttransplant bacterial infections, all involving multiple systems or organs. Pseudomonas aeruginosa was the most common bacteria responsible for the infections in these cases. CONCLUSION: Improvement of surgical skills can obviously reduce the incidence of bacterial infection after liver transplantation. No evidences suggest the correlation between the incidence of infections (including severe ones) and hepatic function class A or B before the operation, whereas patients with preoperative hepatic function class C seems to be at higher risk for infection involving multiple systems or organs. The anhepatic time does not significantly impact on the incidence or severity of the posttransplant infections, and Pseudomonas aeruginosa is the most common bacteria causing the infections.