Xiaoshun He

Upregulation of miR-23a approximately 27a approximately 24 decreases transforming growth factor-beta-induced tumor-suppressive activities in human hepatocellular carcinoma cells.

Transforming growth factor‐beta (TGF‐beta) plays a dual and complex role in human cancer. In this report, we observe a specific set of MicroRNAs (miRNAs) changed in response to TGF‐beta in human hepatocellular carcinoma (HCC) cells by miRNA microarray screening. A cluster of miRNA, miR‐23a∼27a∼24, is induced in an early stage by TGF‐beta in Huh‐7 cells. Knockdown of Smad4, Smad2 or Smad3 expression by RNA interference can attenuate the response of miR‐23a∼27a∼24 to TGF‐beta addition, indicating that this induction is dependent on Smad pathway. We also explore that miR‐23a∼27a∼24 can function as an antiapoptotic and proliferation‐promoting factor in liver cancer cells. In addition, expression of this miRNA cluster is found to be remarkably upregulated in HCC tissues versus normal liver tissues. These findings suggest a novel, alternative mechanism through which TGF‐beta could induce specific miRNA expression to escape from tumor‐suppressive response in HCC cells.

Sirolimus‐based immunosuppression in liver transplantation for hepatocellular carcinoma: A meta‐analysis

Sirolimus (SRL) is a novel immunosuppressant with antitumor properties. We performed a meta‐analysis to determine whether SRL can improve patient survival and decrease the risks of tumor recurrence in patients with a pretransplant diagnosis of hepatocellular carcinoma (HCC). We searched databases for controlled clinical trials assessing the survival and oncological benefits of SRL for liver transplant recipients with pretransplant HCC. Five studies with a total of 2950 participants were included in this study. In comparison with SRL‐free regimens, SRL‐based regimens improved overall survival at 1 [odds ratio (OR) = 4.53, 95% confidence interval (95% CI) = 2.31‐8.89], 3 (OR = 1.97, 95% CI = 1.29‐3.00), and 5 years (OR = 2.47, 95% CI = 1.72‐3.55). The pooled results showed that in comparison with SRL‐free regimens, SRL‐based regimens decreased tumor recurrence (OR = 0.42, 95% CI = 0.21‐0.83). No significant differences in the frequencies of episodes of major posttransplant complications were observed between the groups. In conclusion, SRL is generally safe and prolongs patient survival in liver transplant recipients with pretransplant HCC. Liver Transpl 18:62–69, 2012.

Can immune cell function assay identify patients at risk of infection or rejection? A meta-analysis.

Background. The Cylex ImmuKnow cell function assay (CICFA) is being considered as a possible tool for identification of infection and rejection in transplant recipients. However, the predictive capability of CICFA is still unclear. Methods. Herein, we performed a meta-analysis to assess the efficacy of CICFA in identifying risks of infection and rejection posttransplantation. After a careful review of eligible studies, sensitivity, specificity, and other measures of the accuracy of CICFA were pooled. Summary receiver operating characteristic curves were used to represent the overall test performance. Results. Nine studies met the inclusion criteria. The pooled estimates for CICFA in identification of infection risk were poor, with a sensitivity of 0.58 (95% confidence interval [CI]: 0.52–0.64), a specificity of 0.69 (95% CI: 0.66–0.70), a positive likelihood ratio of 2.37 (95% CI: 1.90–2.94), a negative likelihood ratio of 0.39 (95% CI: 0.16–0.70), and a diagnostic odds ratio of 7.41 (95% CI: 3.36–16.34). The pooled estimates for CICFA in identifying risk of rejection were also fairly poor with a sensitivity of 0.43 (95% CI: 0.34–0.52), a specificity of 0.75 (95% CI: 0.72–0.78), a positive likelihood ratio of 1.30 (95% CI: 0.74–2.28), a negative likelihood ratio of 0.96 (95% CI: 0.85–1.07), and a diagnostic odds ratio of 1.19 (95% CI: 0.65–2.20). Conclusion. The current evidence suggests that CICFA is not able to identify individuals at risk of infection or rejection. Additional studies are still needed to clarify the usefulness of this test for identifying risks of infection and rejection in transplant recipients.

Down-Regulation of microRNA-26a Promotes Mouse Hepatocyte Proliferation during Liver Regeneration

Background Inadequate liver regeneration (LR) is still an unsolved problem in major liver resection and small-for-size syndrome post-living donor liver transplantation. A number of microRNAs have been shown to play important roles in cell proliferation. Herein, we investigated the role of miR-26a as a pivotal regulator of hepatocyte proliferation in LR. Methodology/Principal Findings Adult male C57BL/6J mice, undergoing 70% partial hepatectomy (PH), were treated with Ad5-anti-miR-26a-LUC or Ad5-miR-26a-LUC or Ad5-LUC vector via portal vein. The animals were subjected to in vivo bioluminescence imaging. Serum and liver samples were collected to test liver function, calculate liver-to-body weight ratio (LBWR), document hepatocyte proliferation (Ki-67 staining), and investigate potential targeted gene expression of miR-26a by quantitative real-time PCR and Western blot. The miR-26a level declined during LR after 70% PH. Down-regulation of miR-26a by anti-miR-26a expression led to enhanced proliferation of hepatocytes, and both LBWR and hepatocyte proliferation (Ki-67+ cells %) showed an increased tendency, while liver damage, indicated by aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (T-Bil), was reduced. Furthermore, CCND2 and CCNE2, as possible targeted genes of miR-26a, were up-regulated. In addition, miR-26a over-expression showed converse results. Conclusions/Significance MiR-26a plays crucial role in regulating the proliferative phase of LR, probably by repressing expressions of cell cycle proteins CCND2 and CCNE2. The current study reveals a novel miRNA-mediated regulation pattern during the proliferative phase of LR.

Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: A meta-analysis†

Because of the severe organ shortage, living donor liver transplantation (LDLT) offers a timely alternative to deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC). However, the higher recurrence rate of HCC after LDLT and the indication criteria remain controversial. By conducting a quantitative meta‐analysis, we sought to compare the survival outcomes and recurrence rates with LDLT and DDLT for patients with HCC. Comparative studies of LDLT and DDLT for HCC, which were identified by a comprehensive literature search, were included in this study. The evaluated outcomes included patient survival, recurrence‐free survival (RFS), and recurrence rates at defined time points. Seven studies with a total of 1310 participants were included in this study. For LDLT and DDLT recipients, we found comparable patient survival rates [1 year, odds ratio (OR) = 1.03, 95% confidence interval (CI) = 0.62‐1.73; 3 years, OR = 1.07, 95% CI = 0.77‐1.48; and 5 years, OR = 0.64, 95% CI = 0.33‐1.24] and RFS rates (1 year, OR = 0.86, 95% CI = 0.54‐1.38; 3 years, OR = 1.04, 95% CI = 0.69‐1.58; and 5 years, OR = 1.11, 95% CI = 0.70‐1.77). Moreover, we found no significant differences in the 1‐, 3‐, or 5‐year recurrence rates between LDLT and DDLT recipients (1 year, OR = 1.55, 95% CI = 0.36‐6.58; 3 years, OR = 2.57, 95% CI = 0.53‐12.41; and 5 years, OR = 1.21, 95% CI = 0.44‐3.32). A subgroup analysis revealed similar outcomes for patients with HCC meeting the Milan criteria. These findings demonstrate that for HCC patients (especially those within the Milan criteria), LDLT represents an acceptable option that does not compromise patient survival or increase HCC recurrence in comparison with DDLT. Liver Transpl 18:1226–1236, 2012.

Machine Perfusion versus Cold Storage of Kidneys Derived from Donation after Cardiac Death: A Meta-Analysis

Background In response to the increased organ shortage, organs derived from donation after cardiac death (DCD) donors are becoming an acceptable option once again for clinical use in transplantation. However, transplant outcomes in cases where DCD organs are used are not as favorable as those from donation after brain death or living donors. Different methods of organ preservation are a key factor that may influence the outcomes of DCD kidney transplantation. Methods We compared the transplant outcomes in patients receiving DCD kidneys preserved by machine perfusion (MP) or by static cold storage (CS) preservation by conducting a meta-analysis. The MEDLINE, EMBASE and Cochrane Library databases were searched. All studies reporting outcomes for MP versus CS preserved DCD kidneys were further considered for inclusion in this meta-analysis. Odds ratios and 95% confidence intervals (CI) were calculated to compare the pooled data between groups that were transplanted with kidneys that were preserved by MP or CS. Results Four prospective, randomized, controlled trials, involving 175 MP and 176 CS preserved DCD kidney transplant recipients, were included. MP preserved DCD kidney transplant recipients had a decreased incidence of delayed graft function (DGF) with an odd ration of 0.56 (95% CI = 0.36–0.86, P = 0.008) compared to CS. However, no significant differences were seen between the two technologies in incidence of primary non-function, one year graft survival, or one year patient survival. Conclusions MP preservation of DCD kidneys is superior to CS in terms of reducing DGF rate post-transplant. However, primary non-function, one year graft survival, and one year patient survival were not affected by the use of MP or CS for preservation.

Liver transplantation versus liver resection in the treatment of hepatocellular carcinoma: a meta-analysis of observational studies.

Background A number of cohort studies have compared the outcomes of liver transplantation (LT) and liver resection (LR) in hepatocellular carcinoma (HCC) patients. However, the effects of LT versus LR remain unclear. We searched electronic databases and reference lists for relevant articles published before February 2013. Methods The primary endpoints were pooled using random-effects models to model potential heterogeneity, including overall survival (OS), disease-free survival, and recurrence rate. Results We found similar 1-year OS (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.81–1.43; P=0.61) yet significantly better 3-year OS (OR, 1.47; 95% CI, 1.18–1.84; P<0.001) and 5-year OS (OR, 1.77; 95% CI, 1.45–2.16; P<0.001) after LT compared with LR with relative risk differences of 9% (P<0.001) and 14% (P<0.001), respectively. The 1-, 3-, and 5-year difference-free survival were 13%, 29%, and 39% higher (P<0.001 in all) in LT recipients than LR patients. Additionally, recurrence rate was 30% less (P<0.001) in LT than LR. Furthermore, better 5-year difference-free survival (P<0.001) and recurrence rates (P<0.05) were yielded after LT when patients from the entire HCC population were included. Conclusions When including all the 62 previous studies comparing LT and resection, LT provides increased survival and lower recurrence rates than LR for HCC patients. These results of disease-free survival and recurrence rate are similar among early HCC patients with Child-Turcotte-Pugh class A cirrhosis. However, summary ORs and risk differences cannot be interpreted as causal effects of LT versus LR.

Pretransplantation soluble CD30 level as a predictor of acute rejection in kidney transplantation: a meta-analysis.

Background The question of whether high pretransplantation soluble CD30 (sCD30) level can be a predictor of kidney transplant acute rejection (AR) is under debate. Herein, we performed a meta-analysis on the predictive efficacy of sCD30 for AR in renal transplantation. Methods PubMed (1966–2012), EMBASE (1988–2012), and Web of Science (1986–2012) databases were searched for studies concerning the predictive efficacy of sCD30 for AR after kidney transplantation. After a careful review of eligible studies, sensitivity, specificity, and other measures of the accuracy of sCD30 were pooled. A summary receiver operating characteristic curve was used to represent the overall test performance. Results Twelve studies enrolling 2507 patients met the inclusion criteria. The pooled estimates for pretransplantation sCD30 in prediction of allograft rejection risk were poor, with a sensitivity of 0.70 (95% confidence interval (CI), 0.66–0.74), a specificity of 0.48 (95% CI, 0.46–0.50), a positive likelihood ratio of 1.35 (95% CI, 1.20–1.53), a negative likelihood ratio of 0.68 (95% CI, 0.55–0.84), and a diagnostic odds ratio of 2.07 (95% CI, 1.54–2.80). The area under curve of the summary receiver operating characteristic curve was 0.60, indicating poor overall accuracy of the serum sCD30 level in the prediction of patients at risk for AR. Conclusions The results of the meta-analysis show that the accuracy of pretransplantation sCD30 for predicting posttransplantation AR was poor. Prospective studies are needed to clarify the usefulness of this test for identifying risks of AR in transplant recipients.

Characterization of the middle hepatic artery and its relevance to living donor liver transplantation.

In comparison with the left and right hepatic arteries, there is a relative lack of information on the middle hepatic artery (MHA). In this study, data obtained by multidetector computed tomography from 145 patients were studied to evaluate anatomical variations of the MHA, a hilar artery that primarily supplies hepatic segment 4. An MHA was present in 103 (71%) of the subjects. In livers that had a replaced left hepatic artery, the MHA originated from the right hepatic artery; in livers that had a replaced right hepatic artery, it originated from the left hepatic artery. It always arose directly or indirectly from the common hepatic artery, from which the gastroduodenal artery also arose. We classified MHAs into 5 types according to the anatomical variations of the origin. This classification may have major relevance to modern surgical practice related to living donor liver transplantation (LDLT). The new classification of hepatic arterial anatomy may enhance the acquisition of further knowledge on arterial development, and its application may favorably influence the outcome of LDLT. Liver Transpl 16:736‐741, 2010.

Recombinant Adiponectin Ameliorates Liver Ischemia Reperfusion Injury via Activating the AMPK/eNOS Pathway

Background It is of importance to minimize ischemia reperfusion (I/R) injury during liver operations. Reducing the inflammatory reaction is an effective way to achieve this goal. Notably, adiponectin (APN) was found to have anti-inflammatory activity in heart and renal I/R injury. Herein, we investigated the role of APN in liver I/R injury. Methods Wistar rats were randomized to four groups: (1) sham group; (2) I/R control group; (3) I/R+APN group; and (4) I/R+APN+AMPK inhibitor group. Liver and blood samples were collected 6h and 24h after reperfusion. Liver function and histopathologic changes were assessed. Macrophage and neutrophil infiltration was detected by immunohistochemistry staining, while pro-inflammatory cytokines and chemokines released in the liver were measured using ELISA and RT-PCR, respectively. Apoptosis was analyzed by TUNEL staining and caspase-3 expression in the liver. Downstream molecules of APN were investigated by Western blotting. Results Circulatory APN was down-regulated during liver I/R. When exogenous APN treatment was administered during liver I/R, alanine transaminase (ALT) and aspartate aminotransferase (AST) were decreased, and less hepatocyte necrosis was observed. Less inflammatory cell infiltration and pro-inflammatory cytokines/chemokines release were also observed in the I/R+APN group when compared with the I/R control group. APN treatment also reduced hepatocyte apoptosis, evidenced by reduced TUNEL positive cells and less caspase-3 expression in the reperfused liver. Finally, the AMPK/eNOS pathway was found to be activated by APN, and administration of an AMPK inhibitor reversed the beneficial effects of APN. Conclusion APN can protect the liver from I/R injury by reducing the inflammatory response and hepatocyte apoptosis, a process that likely involves the AMPK/eNOS pathway. The current study provides a potential pharmacologic target for liver I/R injury.