Anbin Hu

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.

A tolerogenic semimature dendritic cells induce effector T-cell hyporesponsiveness by activation of antigen-specific CD4+CD25+ T regulatory cells that promotes skin allograft survival in mice.

Semimature dendritic cells (smDCs) can induce autoimmune tolerance by activation of host antigen-specific CD4(+)CD25(+) regulatory T (Treg) cells. We hypothesized that donor smDCs injected into recipients would induce effector T-cell hyporesponsiveness by activating CD4(+)CD25(+)Treg cells, and promote skin allograft survival. Myeloid smDCs were derived from C57BL/6J mice (donors) in vitro. BALB/c mice (recipients) were injected with smDCs to generate antigen-specific CD4(+)CD25(+)Treg cells in vivo. Allograft survival was prolonged when BALB/c recipients received either C57BL/6J smDCs prior to grafting or C57BL/6J smDC-derived CD4(+)CD25(+)Treg cells post-grafting, and skin flaps from these grafts showed the highest IL-10 production regardless of rapamycin treatments. Our findings confirm that smDCs constitute an independent subgroup of DCs that play a key role for inducing CD4(+)CD25(+)Treg cells to express high IL-10 levels, which induce hyporesponsiveness of effector T cells. Pre-treating recipients with donor smDCs may have potential for transplant tolerance induction.

Living donor vs. deceased donor liver transplantation for patients with hepatitis C virus-related diseases

BACKGROUND & AIMS Living donor liver transplantation (LDLT) provides a timely alternative to deceased donor liver transplantation (DDLT) for patients with hepatitis C virus-related (HCV-related) diseases in the circumstances of severe organ dearth. However, the patient and graft outcomes, and recurrence of HCV after LDLT remain controversial. Here we sought to compare the post-transplant outcomes after LDLT and DDLT. METHODS A systematic review and meta-analysis were performed. PubMed/MEDLINE, EMBASE, and the Cochrane database were searched for eligible literatures. The major end points were patient survival, graft survival, recurrence rate, and acute rejection. The pooled odds ratio (OR) was calculated using random-effects model to synthesize the results. Heterogeneity and publication bias were quantitatively evaluated. RESULTS Fourteen studies with a total of 2024 participants were included in this analysis. We found comparable patient survival between groups (1-year: OR, 0.78, 95% CI, 0.48-1.26, p=0.31; 2-year: OR, 0.71, 95% CI, 0.41-1.23, p=0.23; 3-year: OR, 0.79, 95% CI, 0.5-1.12, p=0.18; 4-year: OR, 0.92, 95% CI, 0.43-1.95, p=0.83; 5-year: OR, 1.06, 95% CI, 0.53-2.14, p=0.86, respectively). Although 1- and 3-year graft survivals were inferior in LDLT, 2-, 4- and 5-year graft survivals were similar. HCV recurrence rates and acute rejection rates were equivalent. CONCLUSIONS LDLT was equivalent to DDLT in terms of patient survival, long-term graft survival, HCV recurrence, and acute rejection rates, with potentially lower short-term patient and graft survival.

Donor-derived bone marrow transfusion produces mixed chimerism and promotes a Th2 shift in Th1/Th2 balance in rat heterotopic small bowel transplantation

BACKGROUND AND AIM In this study, we investigated immunomodulatory effects of donor-derived bone marrow transfusion in rat heterotopic small bowel transplantation. METHODS Rat heterotopic segmental small bowel transplantation models (male Brown Norway to female Lewis) were established. The recipients were randomly divided into control group (pute small bowel transplantation), tacrolimus group (small bowel transplantation plus oral tacrolimus) and small bowel transplantation plus oral tacrolimus and intraportal infusion of donor-derived bone marrow cells group. We investigated the survival time, graft pathologic injuries and rejection grade by haematoxylin-eosin staining, serum IL-2 and IL-10 detection by enzyme labelled immunosorbent assay after small bowel transplantation. The recipients mixed chimerism were observed by detecting sex-determining region of Y chromosome gene in blood, liver, spleen and intestine by using real-time polymerase chain reaction and fluorescence in situ hybridization. RESULTS Bone marrow cells group showed a superior survival than the other groups, accompanied by milder pathologic injuries and lower rejection grade, decreasing serum IL-2 and increasing serum IL-10. The recipient chimerism rate in blood, liver, spleen and intestine in bone marrow cells group was significantly higher than the other groups. CONCLUSION Transfusion of donor-derived bone marrow cells via portal vein induces mixed chimerism in rats after small bowel transplantation, which may promote a Th2 shift in Th1/Th2 balance and facilitate the induction of immune tolerance.

Enhanced generation of human induced pluripotent stem cells by ectopic expression of Connexin 45

Somatic cells can be successfully reprogrammed into pluripotent stem cells by the ectopic expression of defined transcriptional factors. However, improved efficiency and better understanding the molecular mechanism underlying reprogramming are still required. In the present study, a scrape loading/dye transfer assay showed that human induced pluripotent stem cells (hiPSCs) contained functional gap junctions partially contributed by Connexin 45 (CX45). We then found CX45 was expressed in human embryonic stem cells (hESCs) and human dermal fibroblasts (hDFs) derived hiPSCs. Then we showed that CX45 was dramatically upregulated during the reprogramming process. Most importantly, the ectopic expression of CX45 significantly enhanced the reprogramming efficiency together with the Yamanaka factors (OCT4, SOX2, KLF4, cMYC - OSKM), whereas knockdown of endogenous CX45 expression significantly blocked cellular reprogramming and reduced the efficiency. Our further study demonstrated that CX45 overexpression or knockdown modulated the cell proliferation rate which was associated with the reprogramming efficiency. In conclusion, our data highlighted the critical role of CX45 in reprogramming and may increase the cell division rate and result in an accelerated kinetics of iPSCs production.

Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma

BACKGROUND The immunosuppression of tumor-infiltrating lymphocytes (TILs) is associated with rapid progression of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). T cell Ig- and mucin-domain-containing molecule-3 (Tim-3) and programmed cell death 1 (PD-1) are important inhibitory molecules expressed on the surface of T cells, but their roles in the function of TILs in HBV-HCC are poorly understood. We aimed to study the roles of these two markers in HBV-HCC. METHODS Ninety patients with pathologically confirmed HBV-associated HCC were enrolled in our study. Blood samples, paired fresh tumor tissues and adjacent tissues were collected, and isolating peripheral blood mononuclear cells, TILs and adjacent-infiltrating lymphocytes were isolated from these samples. The patients were followed-up to allow survival analysis. RESULTS Tim-3 or/and PD-1 was up-regulated expressed on CD4+ and CD8+ TILs in HBV-HCC patients and a higher proportion of TILs expressed PD-1 alone. Tim-3+ and PD-1+ TILs greatly decreased secretion of IFN-? and TNF-a. Expression of Tim-3 and PD-1 on TILs negatively correlated with disease-free survival of HCC patients. Direct blockade of Tim-3 and PD-1 in vitro significantly enhanced TILs proliferation and secretion of IFN-? and TNF-a. CONCLUSION Expression of Tim-3 and/or PD-1 on TILs impairs their function and correlates negatively with disease-free survival in HBV-HCC. Direct blockade of Tim-3 and PD-1 restores anti-tumor effects of TILs, which suggests a potential target for novel immunotherapy in HBV-HCC.

Active immunization in patients transplanted for hepatitis B virus related liver diseases: A prospective study

Introduction Prophylactic administration of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues (NAs) is the standard treatment for controlling hepatitis B virus (HBV) recurrence after liver transplantation (LT). Since lifelong use of HBIG is expensive and inconvenient and the antibodies level in anti-hepatitis B surface (HBs) is not sustainable and stable, an alternative strategy is to produce anti-HBs antibodies by active immunization. Our present study aimed to prospectively investigate the efficacy and safety of procedural HBV vaccination in transplanted patients. Methods Recipients who had undergone LT for hepatitis B related liver diseases more than one year before, with no evidence of HBV recurrence or rejection and normal liver function were enrolled. All subjects received the hepatitis B vaccine (40 μg) by intramuscular injection at months 0, 1, 2, 6 and 12 after enrollment with continuous administration of NAs. The liver function and anti-HBs titers were measured before each vaccination and HBIG (400U) was administrated intramuscularly when anti-HBs titer was lower than 30 IU/L during the course. The results of routine blood tests, liver function, concentration of immunosuppressant, and HBV-DNA copies were monitored during the research. After completion of the vaccination procedure, recipients were regarded as responders if their anti-HBs greater than 30 IU/L were maintained for up to six months without using HBIG and vaccine. Results Twenty-seven patients were enrolled in this study and the average anti-HBs titer before vaccination was 19.86±14.80 IU/L. The average anti-HBs titer of the nine responders at the end of the follow-up was 57.14±22.75 IU/L, giving an overall response rate of 33.3% (9/27). There were no reports of reactivation of HBV, rejection, severe anaphylaxis or other adverse events. Responders and non-responders showed their significant difference in anti-HBs titers after the fourth vaccination (P<0.01). Moreover, the majority of non-responders (11/18, 63.64%) had high LY/EO rates (lymphocyte number/eosinophil number>15) while most responders (8/9, 88.89%) had low LY/EO rates at the beginning of vaccination (P = 0.019). Conclusions Active immunization is an effective, cost-saving, and safe method for the prevention of HBV reactivation in patients transplanted for hepatitis B virus related liver diseases. The LY/EO rate may be a valuable indicator in selecting potential recipients for vaccination.

Early thrombolytic failure in a patient with massive pulmonary embolism combined with multiple organ dysfunction syndrome: what next?:

Carbon monoxide (CO) poisoning, the most frequent type of poisoning, alters hemodynamics and creates tissue hypoxia that ultimately leads to thromboembolism. We herein describe a previously healthy 17-year-old male patient who developed acute CO poisoning while bathing in the same room as a gas heater. He was first treated with urokinase thrombolytic therapy at a local hospital, which proved ineffective. The patient was admitted to our hospital with unstable circulation and was diagnosed with massive pulmonary embolism combined with multiple organ dysfunction syndrome. His Acute Physiology and Chronic Health Evaluation II score was 22, and his Sequential Organ Failure Assessment score was 15. We faced a difficult decision regarding whether to perform surgical embolectomy or to repeat the thrombolysis. We opted to repeat the thrombolysis with successful results. Our experience may help clinicians manage similar cases in the future.

Outcome of the use of paediatric donor livers in adult recipients: A single Chinese centre experience

BACKGROUND Paediatric liver allografts sometimes are allocated to adult recipients when there are no suitable paediatric recipients on the waiting list. However, debate exits regarding the reported outcomes of liver transplants using such small grafts. METHODS Records from adult patients undergoing liver transplantation between February 2010 and January 2016 who received whole grafts from paediatric (≤ 13 years) donors or ideal deceased adult (18-35 years) donors were reviewed. Patient and graft survival, post-transplant liver function, and complications between the two groups were compared. RESULTS The baseline characteristics were comparable, except that the paediatric donor allografts had smaller size. The 3-month, 1-year, and 3-year rates of patient survival were 91.3%, 85.2%, and 85.2% in the paediatric donor group and 93.4%, 88.9%, and 85.0% in the adult donor group (P = 0.947), respectively. One patient receiving a paediatric allograft developed small-for-size liver syndrome post-transplantation. There was no difference in primary non-function, early allograft dysfunction, biliary complications, vascular complications, or infection between the two groups. CONCLUSION Our study indicates that using paediatric donor livers in well-selected adult recipients is a safe procedure, considering there was no suitable paediatric recipient. However, the risk of portal hyperperfusion should be considered in clinical cases such as size-mismatched transplants.

Does ischemia free liver procurement under normothermic perfusion benefit the outcome of liver transplantation

Background In contrast to conventional static cold preservation, normothermic machine perfusion (NMP) provides a beneficial alternative preservation of donor livers. However, the liver still suffered cold ischemic injury before attaching to the perfusion device. Material/Methods To prevent cold ischemic injury during procurement, we describe a novel procedure called ischemia-free liver procurement (IFLP) under NMP. Two liver grafts were procured from brain death donor under NMP and underwent 2-hour ex vivo NMP followed by 3 and 6 hours of static cold preservation. From procurement to post-transplantation course, evidence was collected to prove that IFLP is safe and benefits recipients. Results The post-transplantation course was uneventful, and the liver function tests and histological study revealed minimal hepatocyte and biliary epithelium injury during the preservation. Conclusions This preliminary experience demonstrates the clinical feasibility and safety of IFLP under NMP which offering opportunities to increase the number of donor livers and to improve the organ function.