Search

Hepatocellular carcinoma (HCC) recurrence after liver transplantation remains a significant clinical problem. Ischemia-reperfusion injury (IRI) occurred inevitably at the early phase after liver transplantation (LT) spawns a significant risk of HCC recurrence. However, their linkage and IRI-derived risk factors for HCC recurrence remain exclusive. Understanding the mechanism of post-transplantation hepatic injury could provide new strategies to prevent the later event of HCC recurrence. We demonstrated that glutathione S-transferase A2 (GSTA2) expression was significantly associated with early phase hepatic and systemic injury and ROS level after liver transplantation. Early phase circulating GSTA2 (EPCGSTA2) protein was a significant predictor of HCC recurrence and survival. Heterogeneous single nucleotide polymorphism at G335C of GSTA2 was significantly associated with poor survival of HCC recipients. Enhancement of GSTA2 could protect HCC cells against H2O2-induced cell death by compensating for the elevated ROS stress. We also demonstrated that GSTA2 played crucial roles in regulating the ROS-associated JNK and AKT signaling pathways and ROS metabolism in HCCs in responding to a dynamic ROS environment. Functionally, endogenous or exogenous upregulation of GSTA2 could promote HCC growth and invasion through activating the epithelial–mesenchymal-transition process. Targeted inhibition of GSTA2 could suppress HCC growth and metastasis. In conclusion, GSTA2 could be a novel prognostic and therapeutic target to combat HCC recurrence after liver transplantation.

Tumor recurrence is the major obstacle for pushing the envelope of liver transplantation for hepatocellular carcinoma (HCC) patients. The inflammatory cascades activated by acute liver graft injury promote tumor recurrence. We aimed to explore the role and mechanism of myeloid-derived suppressor cell (MDSC) mobilization induced by liver graft injury on tumor recurrence. By analyzing 331 HCC patients who received liver transplantation, the patients with graft weight ratio (GWR, the weight of liver graft divided by the estimated standard liver weight of recipient) CXCL10/TLR4 levels were significantly increased in patients with GWR CXCL10−/− and TLR4−/− mice of hepatic ischemia/reperfusion injury plus major hepatectomy (IRH) model, monocytic MDSCs, instead of granulocytic MDSCs, were significantly decreased. Importantly, CXCL10 deficiency reduced the accumulation of TLR4+ monocytic MDSCs, and CXCL10 increased MDSC mobilization in the presence of TLR4. Moreover, MMP14 was identified as the key molecule bridging CXCL10/TLR4 signaling and MDSC mobilization. Knockout or inhibition of CXCL10/TLR4 signaling significantly reduced the tumor growth with decreased monocytic MDSCs and MMP14 in the mouse tumor recurrent model. Our data indicated that monocytic MDSCs were mobilized and recruited to liver graft during acute phase injury, and to promote HCC recurrence after transplantation. Targeting MDSC mobilization via CXCL10/TLR4/MMP14 signaling may represent the therapeutic potential in decreasing post-transplant liver tumor recurrence.

Objectives Apolipoprotein A-1 (ApoA-1) is involved in regulating both lipid and energy metabolism, which may play important roles in liver regeneration, especially for the liver with steatosis. We here intended to investigate the role of ApoA-1 in regeneration of small-for-size fatty liver graft and to explore the underlying mechanism. Methods The association of ApoA-1 expression with liver regeneration was studied in rat liver transplantation models using small-for-size normal graft or small-for-size fatty graft. The direct role of ApoA-1 in liver regeneration was studied in mouse hepatectomy model in vivo and hepatocytes in vitro. Results Compared to small-for-size normal graft, decreased expression of ApoA-1 associated with delayed regeneration were detected in small-for-size fatty liver graft after transplantation. In functional study, the expression of ApoA-1 was decreased in hepatocytes with steatosis and was inversely associated with the concentration of oleic acid. The ApoA-1 administration effectively attenuated hepatocytes steatosis and accelerated hepatocytes proliferation. In mouse model, ApoA-1 treatment promoted liver regeneration at day 2 after major hepatectomy. In addition, the treatment of ApoA-1 increased the expressions of PGC-1α and its target genes Tfam, Ucp2 and SDHB. Conclusions ApoA-1 may accelerate regeneration of small-for-size fatty liver graft at day 2 after transplantation through regulating mitochondrial function. ApoA-1 may be the potential new therapy of promoting liver regeneration.

BackgroundAn inevitable hepatic injury at the early phase after liver transplantation vitally affects the late phase hepatocellular carcinoma (HCC) recurrence. However, their linkage and underlying risk factors of HCC recurrence are unclear. This study aimed to clarify the clinical impact and functional roles of glutathione S-transferase A2 (GSTA2) in affecting HCC recurrence after liver transplantation.MethodsExpression significance and prognostic value of hepatic and circulating GSTA2 in HCC recipients were examined. The polymorphism of GSTA2 transcript was analysed by Sanger sequencing. The functions and molecular mechanisms of GSTA2 in the proliferation and metastasis of HCC were characterized by molecular, cellular and animal experiments. ResultsThe GSTA2 expression was significantly correlated with the early phase hepatic and systemic injury and reactive oxygen species (ROS) level after liver transplantation. Importantly, the level of the early phase circulating GSTA2 protein was a significant predictor of HCC recurrence and survival of HCC recipients. Heterogeneous single nucleotide polymorphism at G335C of GSTA2 was significantly associated with poor survival of HCC recipients. The GSTA2 expression was positively correlated with the aggressiveness of HCCs. Overexpression of GSTA2, by endogenous or exogenous approaches, could enhance the proliferation and invasion of HCCs through activating epithelial-mesenchymal-transition promoting proteins. Targeted inhibition of GSTA2 remarkably suppressed the proliferation and metastasis of HCCs. Increased level of GSTA2 could compensate the H2O2-induced ROS stress and therefore protect the HCC cells from damage. Alteration of GSTA2 expression in HCC cells could influence the activation of ROS-associated JNK and AKT signaling pathways and the expression of ROS-associated genes in responding to the H2O2 condition. ConclusionsOur research discovered GSTA2 to be the significant risk factor of HCC recurrence via providing a favorable ROS environment for HCC to survival and progress. This study presents a novel functional biomarker for combating HCC recurrence after liver transplantation.

Chang Xian Li,1 Xin Xiang Yang,2 Hong Wei Wang,1 Xiang Cheng Li,1 Kevin Tak-Pan Ng,2 Chung Mau Lo,2 Kwan Man2 1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Nanjing, Jiangsu Province, People’s Republic of China; 2Department of Surgery, The University of Hong Kong, Hong Kong, People’s Republic of ChinaCorrespondence: Kwan ManDepartment of Surgery, The University of Hong Kong, L9-55, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong, People’s Republic of ChinaTel +852 39179646Fax +852 39179634Email kwanman@hku.hkBackground: In this study, we aimed to study the effect of FTY720 treatment in reducing circulating Tregs level and then suppressing liver tumor metastasis after hepatectomy and I/R injury in animal models. Furthermore, we also investigated the synergistic anti-tumor effect of FTY720 combined with rapamycin on hepatocellular carcinoma.Methods: The effect of FTY720 on suppressing Tregs mobilization and tumor metastasis after hepatectomy was investigated in an orthotopic liver tumor rat model with hepatectomy and hepatic ischemia/reperfusion (I/R) injury. The synergistic anti-tumor effect of FTY720 combined with rapamycin was further explored both in in vitro functional study and in orthotopic liver tumor mouse model.Results: In rat model, hepatic I/R promoted tumor metastasis and increased circulating Tregs after hepatectomy. The treatment of FTY720 reduced liver tumor metastasis and the number of circulating Tregs. Furthermore, FTY720 enhanced the anti-tumor capacity of rapamycin by inhibiting tumor cell proliferation and migration in vitro and reducing tumor growth in vivo through suppressing hepatic stellate cell activation and tumor angiogenesis.Conclusion: FTY720 suppressed liver tumor growth and metastasis by reducing the population of circulating Tregs and enhancing the anti-tumor effect of rapamycin. It was suggested that FTY720 single or combined with rapamycin might provide novel insight for suppressing tumor growth and metastasis for HCC patients.Keywords: FTY720, rapamycin, regulatory T cells, hepatic ischemia/reperfusion, tumor recurrence

// Chang Xian Li 1, 3 , Chung Mau Lo 1, 2, 3 , Qizhou Lian 4 , Kevin Tak-Pan Ng 1, 3 , Xiao Bing Liu 1, 3 , Yuen Yuen Ma 1, 3 , Xiang Qi 1, 3 , Oscar Wai Ho Yeung 1, 3 , Vinay Tergaonkar 5 , Xin Xiang Yang 1 , Hui Liu 1, 3 , Jiang Liu 1, 3 , Yan Shao 1, 3 , Kwan Man 1, 2, 3 1 Department of Surgery, The University of Hong Kong, Hong Kong, China 2 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China 3 Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China 4 Department of Medicine, The University of Hong Kong, Hong Kong, China 5 Institute of Molecular and Cellular Biology, Biopolis, Singapore Correspondence to: Kwan Man, e-mail: kwanman@hku.hk Keywords: liver transplantation, hepatic ischemia reperfusion injury, neutrophils migration, inflammatory response, nuclear factor-κB Received: February 22, 2016 Accepted: March 22, 2016 Published: March 30, 2016 ABSTRACT Repressor and activator protein (Rap1) directly regulates nuclear factor-κB (NF-κB) dependent signaling, which contributes to hepatic IRI. We here intended to investigate the effect of Rap1 in hepatic ischemia reperfusion injury (IRI) and to explore the underlying mechanisms. The association of Rap1 expression with hepatic inflammatory response were investigated in both human and rat liver transplantation. The effect of Rap1 in hepatic IRI was studied in Rap1 knockout mice IRI model in vivo and primary cells in vitro . Our results showed that over expression of Rap1 was associated with severe liver graft inflammatory response, especially in living donor liver transplantation. The results were also validated in rat liver transplantation model. In mice hepatic IRI model, the knockout of Rap1 reduced hepatic damage and hepatic inflammatory response. In primary cells, the knockout of Rap1 suppressed neutrophils migration activity and adhesion in response to liver sinusoidal endothelial cells through down-regulating neutrophils F-Actin expression and CXCL2/CXCR2 pathway. In addition, the knockout of Rap1 also decreased production of pro-inflammatory cytokines/chemokines in primary neutrophils and neutrophils-induced hepatocyte damage. In conclusion, Rap1 may induce hepatic IRI through promoting neutrophils inflammatory response. Rap1 may be the potential therapeutic target of attenuating hepatic IRI.

Objective: To explore the effects of integrated traditional Chinese and western Medicine on the vision recovery and serum trace elements in patients with herpes simplex keratitis.Methods: A total of 86 cases of HSK patients admitted in Baogang Hospital of Inner Mongolia from January 2015 to October 2016 were selected and divided randomly into the observation group (n = 43) and the control group (n = 43) according to the random number table. The control group was treated with ganciclovir eye drops and chondroitin sulfate eye drops, and the observation group was treated with Qinggan Mingmu Decoction on the basis of the control group. The 2 groups were treated for 4 weeks continuously. The clinical efficacy was compared between two groups. The vision recovery, serum trace elements and tear immune factor levels were also compared between two groups before and after treatment.Results: After treatment, the effective rate of treatment in the observation group was significantly higher than that in the control group (p < .05); in the observation group of patients, visual analogue scale (VAS) score and visual acuity after treatment were obviously higher than those before treatment, and also remarkably higher than those in the control group of patients (p < .05); after treatment, the levels of Fe, Ca and Cu ions in the observation group were significantly lower than those in the control group and before treatment (p < .05); after treatment, the level of zinc ions in the serum in the observation group was significantly higher than that before treatment and in the control group (p < .05); after treatment, the levels of tear IgA, IgG and C3 in the observation group were prominently higher than those before treatment and in the control group (p < .05).Conclusions: In the treatment of HSK, integrated traditional Chinese and western medicine can promote effectively the vision recovery, regulate the level of trace elements in the serum and enhance the level of tear immune factors, with the clinical efficacy better than the treatment of western medicine alone.

Background and Aims: Down-regulation of GPx3 accelerated hepatic senescence, which further caused overwhelming inflammation and severe liver graft injury. MSCs derived from human induced pluripotent stem cells (hiPSC-MSCs) have been developed as more efficient delivery vehicle with the property of injury tropism. Here, we aimed to explore the suppressive role of GPx3 in hepatic IR injury using novel delivery system of hiPSC-MSCs. Methods: The mice IR injury model with partial hepatectomy was established. The engineered hiPSC-MSCs delivering GPx3 was constructed. All the mice were segregated into three groups. hiPSC-MSC-GPx3, hiPSC-MSC-pCDH (vector control) or PBS were injected via portal vein after reperfusion. Liver injury was evaluated by histological and serological test. Hepatic apoptosis was detected by Tunel staining and remnant liver regeneration was assessed by Ki67 staining. The role of hepatic senescence in liver graft injury was evaluated in rat orthotopic liver transplantation model. The suppressive effect of GPx3 on hepatic senescence was examined in mice IR injury model and confirmed in vitro. Hepatic senescence was detected by SA-β-Gal and P16/ink4a staining. Results: GPx3 can be successfully delivered by hiPSC-MSCs into liver tissues. Histological examination showed that hiPSC-MSC-GPx3 treatment significantly ameliorated hepatic IR injury post-operation. Significantly lower LDH (891.43±98.45 mU/mL, P, published_or_final_version

Background & AimsLiver graft injury and tumor recurrence are the major challenges of liver transplantation for the patients with hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of liver graft injury mobilizing regulatory T cells (Tregs), which lead to late phase tumor recurrence after liver transplantation.MethodsThe correlation among tumor recurrence, liver graft injury and Tregs mobilization were studied in 257 liver transplant recipients with HCC and orthotopic rat liver transplantation models. The direct roles of CXCL10/CXCR3 signaling on Tregs mobilization and tumor recurrence were investigated in CXCL10−/− and CXCR3−/− mice models with hepatic IR injury.ResultsClinically, patients received the graft with graft weight ratio (GWR)

This paper studies a class of O(N) approximate QR-based least squares (A-QR-LS) algorithm recently proposed by Liu in 1995. It is shown that the A-QR-LS algorithm is equivalent to a normalized LMS algorithm with time-varying stepsizes and element-wise normalization of the input signal vector. It reduces to the QR-LMS algorithm proposed by Liu et al. in 1998, when all the normalization constants are chosen as the Euclidean norm of the input signal vector. An improved transform-domain approximate QR-LS (TA-QR-LS) algorithm, where the input signal vector is first approximately decorrelated by some unitary transformations before the normalization, is proposed to improve its convergence for highly correlated signals. The mean weight vectors of the algorithms are shown to converge to the optimal Wiener solution if the weighting factor w of the algorithm is chosen between 0 and 1. New Givens rotations-based algorithms for the A-QR-LS, TA-QR-LS, and the QR-LMS algorithms are proposed to reduce their arithmetic complexities. This reduces the arithmetic complexity by a factor of 2, and allows square root-free versions of the algorithms be developed. The performances of the various algorithms are evaluated through computer simulation of a system identification problem and an acoustic echo canceller.