Therapeutic potentials of umbilical cord-derived mesenchymal stromal cells for ischemic-type biliary lesions following liver transplantation.

BACKGROUND AIMS: Ischemic-type biliary lesions are severe, graft-threatening complications after orthotopic liver transplantation, and a novel and efficient therapeutic strategy is urgently needed. Due to the immunosuppressive and regenerative properties, mesenchymal stromal cells (MSCs) could be an interesting candidate. METHODS: We initiated safety and efficacy of human umbilical cord-derived MSC (UC-MSC) transfusions for patients with ischemic-type biliary lesions after liver transplantation. From January 2013 to June 2014, 12 ischemic-type biliary lesions patients were recruited as the MSCs group in this phase I, prospective, single-center clinical study. Patients in this group received six doses of UC-MSCs (about 1.0 × 106 MSCs per kilogram body weight through peripheral intravenous infusion). The traditional therapeutic protocol was applied during October 2003 to December 2012 in 70 ischemic-type biliary lesions patients who were treated as the control group. Liver function tests, the need for interventional therapies and graft survival rate were chosen to evaluate the therapeutic efficacy of MSC treatment. Adverse events were closely monitored up to 2 years after MSC transfusions. RESULTS: No significant MSC-related adverse events were observed during the trial. Compared with baseline, the levels of total bilirubin, γ-glutamyl transferase and alkaline phosphatase were decreased after UC-MSC treatment at week 20 and week 48. Interventional therapies were performed in 64.3% (45/70) of patients in the control group and 33.3% (4/12) of patients in the MSCs groups. MSC therapy significantly decreased the need for interventional therapies (P = 0.046). The 1- and 2-year graft survival rates were higher in the MSCs group (100% and 83.3%, respectively) than in the control group (72.9% and 68.6%, respectively). CONCLUSIONS: The UC-MSC transfusions are clinically safe and short-term favorable, which may become a novel treatment for patients with ischemic-type biliary lesions after liver transplantation.

Downregulation of miR-33a-5p in Hepatocellular Carcinoma: A Possible Mechanism for Chemotherapy Resistance.

BACKGROUND Multi-drug resistance is one of the major problems limiting the efficacy of cisplatin (CDDP) in treatment of hepatocellular carcinoma (HCC), and abnormal microRNA (miRNA) expression in drug-resistant cell lines plays an important role in liver cancer chemotherapy resistance. MATERIAL AND METHODS We established stable Hep3B and 97L HCC cell strains resistant to CDDP, both in vitro and in vivo. A combination of microRNA microarray and RT-qPCR experiments were used to screen differentially expressed miRNAs in HCC cell strains. A CCK-8 assay was carried out to detect and calculate the survival rates and relative inhibitory rates. Oligonucleotide transfection was used to confirm the regulatory function of the miRNA in HCC drug resistance. RESULTS The IC50 of Hep3B/CDDP(v), 97L/CDDP(v), Hep3B/CDDP(s), and 97L/CDDP(s) were significantly higher than that of their parental cells. Moreover, the doubling time of drug-resistant cells increased compared with their parent cells. MiRCURYTM LNA Array (v 16.0) high-throughput tests of resistant cell models and their parent cells showed that there were 5 downregulated microRNAs in the 4 drug-resistant cell lines, and we chose hsa-miR-33a-5p as our target for further study. Oligonucleotide transfection showed that miR-33a-5p overexpression increased the cisplatin sensitivity of Hep3B/CDDP(v) and 97L/CDDP(v) drug-resistant cells and reduced their resistance. Additionally, inhibition of miR-33a-5p expression reduced cisplatin sensitivity in Hep3B and 97L and increased their drug resistance. CONCLUSIONS This study confirmed that the most downregulated microRNA, miR-33a-5p, can mediate the cisplatin resistance of HCC cells, providing a new and feasible direction for research into combatting liver cancer chemotherapy resistance.

The protective effects of CHIR99021 against oxidative injury in LO2 cells.

Hepatic ischemia-reperfusion injury is one of the most important factors for the prognosis of liver transplantation and hepatic surgery. It was reported that glycogen synthase kinase-3 (GSK-3) regulated injury response during ischemia-reperfusion. In this study, we investigated the protective effects of the GSK-3 inhibitor CHIR99021 against hepatic ischemia-reperfusion injury. A H2O2-induced oxidative injury model using LO2 cells was established. LO2 cells were divided into four groups, including blank control group, CHIR99021 control group treated with CHIR99021 alone, H2O2-injury group treated with H2O2 and protection group treated with H2O2 plus CHIR99021. Cell viability, cell apoptosis or necrosis was determined. Meanwhile, mitochondrial membrane potential, lipid peroxidation, cellular ROS levels, SOD activity, and serum contents of ALS and AST were measured. Protein and mRNA expressions were also detected. The results showed that a cell oxidative injury model was established by treating LO2 cells with 200 µmol/L H2O2 for 6 h. Cells exposed to H2O2 resulted in a significant decrease of cell viability and increase of cell apoptosis, which was accompanied by increasing ROS levels, disruption of mitochondrial membrane potential, excessive lipid peroxidation, reduction of SOD activity, and increased levels of ALT and AST. Treatment with CHIR99021 significantly protected LO2 cells against H2O2-induce oxidative injury by inhibiting the changes of above oxidative injury related indicators. Moreover, CHIR99021 treatment significantly reversed H2O2-induced decrease in p-GSK-3ßSer9 , Bcl-2, Bcl-xl, survivin and ß-catenin expression, whereas it significantly attenuated H2O2-induced increase in caspase-3, cleaved caspase-3 and p-JNK protein expression. In conclusion, CHIR99021 protected LO2 cells against H2O2-induced oxidative injury through reducing GSK-3ß activity and apoptosis, with underlying mechanisms involved in stabilizing mitochondrial membrane potential, attenuating cellular ROS generation, suppressing mitochondria-mediated apoptotic pathway, and activation of GSK-3ß/ß-catenin signaling pathway.

miR-630 overexpression in hepatocellular carcinoma tissues is positively correlated with alpha-fetoprotein.

BACKGROUND: MicroRNA-630 (miR-630) has been shown to be involved in various human malignancies. However, its role in hepatocellular carcinoma (HCC) remains unknown. MATERIAL AND METHODS: TaqMan qRT-PCR assay was performed to detect the expression of miR-630 in 42 pairs of HCC tissues and corresponding noncancerous hepatocellular tissues, and its correlations with clinicopathologic features and serum alpha-fetoprotein (AFP) level of patients were analyzed. RESULTS: The present study found that miR-630 expression was significantly increased in HCC tissues and cells compared with their normal counterparts. miR-630 expression level did not significantly chang at stage I but was markedly increased at advanced TNM stage (stage II~III). In addition, the increased expression of miR-630 in tissues of HCC appeared in patients who exhibited elevated serum levels of AFP (>25 ng/ml), but not in those with normal AFP levels (≤25 ng/ml). The miR-630 expression in carcinoma tissues revealed a positive correlation with the levels of serum alpha-fetoprotein (AFP; R2=0.768). CONCLUSIONS: These results suggest that miR-630 is associated with tumor progression of hepatocellular carcinoma and may be a potential prognosis indicator.

Yes-associated protein expression is a predictive marker for recurrence of hepatocellular carcinoma after liver transplantation.

PURPOSE: To explore the expression of Yes-associated protein (YAP) in hepatocellular carcinoma (HCC) patients, and assess its prognostic value to recurrence of HCC after liver transplantation (LT). METHODS: Collected data of 105 consecutive patients undergoing LT for HCC were analyzed retrospectively. The immunohistochemistry was used to detect the expression of YAP, Mst1, Lats1/2, pYAP, pLats1/2 and pMst1/2 in tumor tissues. Contingency table and χ(2)-test were used to investigate the correlation between expression of YAP, Mst1, Lats1/2 and clinical characteristics. Univariate survival analysis and Multivariate Cox regression analysis were also performed to analyze the correlation of clinical and pathological factors with tumor recurrence after LT. The Kaplan-Meier method and log-rank test were used to analyze HCC-specific disease-free survival (DFS) rate. RESULTS: Forty patients fulfilled Milan criteria with 1-, 2-, 3- and 5-years DFS of 86.7, 84.6, 84, 84%, respectively. The positive rates of YAP, Lats1/2, Mst1 in HCC were 51.4, 45.7, 64.8%, respectively. YAP expression in HCC tumors was significantly associated with tumor size (p = 0.041), venous infiltration (p = 0.002), AJCC tumor stage (p = 0.027). Lats1/2 expression was significantly associated with tumor size (p = 0.001) and AJCC tumor stage (p = 0.019). Mst1 expression was also significantly associated with tumor size (p = 0.042). HCC-specific DFS was significantly longer for patients with YAP negative expression compared with patients with YAP positive expression (1-, 2-, 3- and 5-years DFS of 71.7, 65.3, 65.3, 65.3 vs. 42.5, 36.6, 32.5, 30.4%, respectively, log-rank = 12.89, p < 0.001). Multivariate Cox regression analysis indicated that YAP expression (HR = 2.011, p = 0.020) in HCC was an independent prognostic factor for HCC-specific DFS after liver transplantation. CONCLUSIONS: YAP is an independent prognostic marker for tumor recurrence for HCC patients after liver transplantation.

Long-term results of liver transplantation for over 60 years old patients with hepatitis B virus-related end-stage liver disease.

BACKGROUND: Hepatitis B virus (HBV)-related end-stage liver disease is the leading indication for liver transplantation in China, but long-term results of liver transplantation in patients aged over 60 years are not clear. The present study was to reveal the natural history of liver recipients with hepatitis B older than 60 years. METHODS: The recipients who had received liver transplantation between December 2003 and December 2005 were divided into two groups: those equal or older than 60 years (older group, n=60) and those younger than 60 years (younger group, n=305). Risk factors for poor long-term outcome in patients aged over 60 years were also analyzed. RESULTS: Except for age and preexisting chronic disease (P<0.05), no significant differences were observed in perioperative characteristics between the two groups. There was also no significant difference in HBV and hepatocellular carcinoma recurrence (P>0.05). The actuarial 1-, 3-, 5- and 8-year survival rates were 81.6%, 71.6%, 66.7% and 63.3% respectively for the older group vs 84.9%, 77.7%, 70.8% and 65.6% for the younger group (P>0.05). Multivariate analyses showed that pre-liver transplant renal insufficiency was a risk factor for poor outcome in the older group (odds ratio=3.615, P=0.014). CONCLUSIONS: Liver transplantation is safe and feasible for patients with HBV-related end-stage liver disease aged over 60 years. Older patients with renal insufficiency should undergo transplantation earlier than younger patients.

RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway.

Background and Aims: Hepatic ischemia-reperfusion injury (HIRI) is a prevalent complication of liver transplantation, partial hepatectomy, and severe infection, necessitating the development of more effective clinical strategies. Receptor activity-modifying protein 1 (RAMP1), a member of the G protein-coupled receptor adapter family, has been implicated in numerous physiological and pathological processes. The study aimed to investigate the pathogenesis of RAMP1 in HIRI. Methods: We established a 70% liver ischemia-reperfusion model in RAMP1 knockout (KO) and wild-type mice. Liver and blood samples were collected after 0, 6, and 24 h of hypoxia/reperfusion. Liver histological and serological analyses were performed to evaluate liver damage. We also conducted in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function. Results: Liver injury was exacerbated in RAMP1-KO mice compared with the sham group, as evidenced by increased cell death and elevated serum transaminase and inflammation levels. HIRI was promoted in RAMP1-KO mice via the induction of hepatocyte apoptosis and inhibition of proliferation. The absence of RAMP1 led to increased activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and yes-associated protein (YAP) phosphorylation, ultimately promoting apoptosis. SCH772984, an ERK/MAPK phosphorylation inhibitor, and PY-60, a YAP phosphorylation inhibitor, reduced apoptosis in in-vitro and in-vivo experiments. Conclusions: Our findings suggest that RAMP1 protects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction, highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention.

Retraction Notice to: LINC01234/MicroRNA-31-5p/MAGEA3 Axis Mediates the Proliferation and Chemoresistance of Hepatocellular Carcinoma Cells.

[This retracts the article DOI: 10.1016/j.omtn.2019.10.035.].

Development of a Risk Classifier to Predict Tumor Recurrence and Lenvatinib Benefits in Hepatocellular Carcinoma After Liver Transplantation.

BACKGROUND: Current selection tools were not precise enough to predict recurrence of hepatocellular carcinoma (HCC) and benefit of adjuvant lenvatinib for patients who received liver transplant (LT) for HCC. Thus, we aim at developing a risk classifier to predict recurrence of HCC and benefit of adjuvant Lenvatinib for those who underwent LT for HCC. METHODS: Cox regression model was applied to selected predictors and created the final model in a training cohort of 287 patients who underwent LT for HCC, which was tested in an internal validation cohort of 72 patients by using C-statistic and net classification index (NRI) compared with the following HCC selection criteria: the Milan criteria, the Up-to-7 criteria, and the University of California, San Francisco criteria. RESULTS: We built a Risk Classifier of South China Cohort (RCOSC) based on 4 variables: the maximum diameter plus number of viable tumors, alpha-fetoprotein, microvascular invasion, and highest alanine aminotransferase in 7 days after LT. In validation analyses, our RCOSC showed good predictive performance (C-statistic, 0.866; 95% confidence interval [CI], 0.833-0.899) and had better prognostic value than Milan criteria (NRI, 0.406; P < .001), University of California, San Francisco (NRI, 0.497; P < .001), and Up-to-7 (NRI, 0.527; P < .001). By applying the RCOSC, we were able to accurately categorize patients into high-risk and low-risk groups. Further survival analysis revealed that the patients in the high-risk group might have a better therapeutic response to preventive regimen of lenvatinib after LT for HCC (hazard ratio, 0.38; 95% CI, 0.161-0.871, P = .018). CONCLUSIONS: Our RCOSC presented favorable predictive performance for HCC recurrence. It might be capable of sifting out patients who benefit from adjuvant therapy after LT for HCC, providing a reliable tool for precise clinical decision-making of patients with HCC with LT.

Tenofovir versus entecavir on decreasing risk of HBV-related hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND: Recent studies have proved that tenofovir disoproxil fumarate (TDF) is associated with a lower risk of hepatocellular carcinoma (HCC) occurrence in chronic hepatitis B (CHB) patients and HCC recurrence in patients who underwent hepatectomy when compared to ETV. However, it is unclear whether TDF and ETV treatment, which are both recommended as first-line antiviral agents to prevent the hepatitis B (HBV) recurrence after liver transplantation (LT), are associated with equivalent prognosis. We aim to compare risk of HCC recurrence and survival of patients recieving TDF or ETV after LT for HBV-related HCC. METHOD: We performed a retrospective study including 316 patients who received treatment with ETV or TDF after LT for HBV-related HCC from 2015 January to 2021 Augest. The Recurrence-free survival (RFS) and overall survival (OS) of TDF and ETV groups were analyzed and compared by propensity score-matched (PSM), multivariable Cox regression analysis, competing risk analysis, sensitivity analyses and subgroup analyses. RESULT: Compared with ETV, TDF therapy was associated with significantly higher RFS rates in the entire cohort (P < 0.01), PSM cohort (P < 0.01) and beyond-Milan cohort (P < 0.01). By multivariable analysis, TDF group was associated with significantly lower rates of HCC recurrence (HR, 0.33; 95%CI, 0.14-0.75; P < 0.01). In subgroup analyses, the similar results were observed in patients with following tumor characteristics: Maximum diameter plus number of viable tumor ≥ 5, with MIV or MAT, AFP at LT ≥ 20 ng/ml, and well or moderate tumor grade. CONCLUSION: Tenofovir decrease risk of HBV-Related Hepatocellular Carcinoma recurrence after liver transplantation compared to Entecavir.

Thermal ablation as an alternative to liver transplantation for hepatocellular carcinoma with clinically significant portal hypertension: propensity score matching study.

Purpose: The objectives were to investigate the safety and efficacy of thermal ablation as an alternative to liver transplantation for hepatocellular carcinoma patients with clinically significant portal hypertension (CSPH). Materials and Methods: From July 2016 to September 2019, hepatocellular carcinoma patients with CSPH treated by liver transplantation (N=37) or thermal ablation (N=114) were enrolled. Cumulative intrahepatic recurrence, overall survival and major complications were compared by propensity score matching. Results: In the two matched groups, the 1-, 2-, and 3-year intrahepatic recurrence rates for the ablation group (22.3%, 50.0%, and 50.0%, respectively) were significantly higher than those for the transplantation group (4.5%, 4.5%, and 4.5%, respectively) (P=0.016). The 1-, 2-, and 3-year overall survival rates were comparable between the two groups [96.1%, 88.7%, and 88.7%, respectively (ablation group) vs. 84.6%, 76.2%, and 76.2%, respectively (transplantation group)] (P=0.07). The major complication rate for the ablation group [4.8% (3/62)] was significantly lower than that for the transplantation group [36.0% (9/25)] (P<0.001). Conclusions: Thermal ablation is a safe and effective alternative for hepatocellular carcinoma patients with CSPH.

Health-related quality of life after liver transplantation: the experience from a single Chinese center.

BACKGROUND: Few studies have been performed to assess health-related quality of life (HRQOL) in liver transplantation (LT) patients in the mainland of China. This study aimed to investigate the HRQOL of post-LT patients in a single center. METHODS: HRQOL was evaluated by the SF-36 (Chinese version) questionnaire in 60 patients (LT group) who had received LT for benign end-stage liver disease (BELD). Fifty-five patients with BELD (BELD group) and 50 healthy volunteers from the general population (GP group) were also evaluated, and the results were compared among the three groups. RESULTS: There was a significant difference among the three groups in terms of the scores of eight domains in the SF-36 (P<0.01). Patients in the BELD group had lower scores in each domain of the SF-36 in comparison with those in the GP group (P<0.025). The LT group had mental health scores equivalent to those of the BELD group (P>0.025), but higher scores for the remaining seven domains (P<0.025). Compared with the GP group, the LT group scored equivalently for role physical, body pain, vitality, social function and role emotion (P>0.025), but had lower scores for the remaining three domains (P<0.025). Lower family income was found to be associated with reduced physical function and mental health scores (P<0.05). Better education was associated with increased mental health scores (P<0.05). CONCLUSIONS: LT patients generally have a good HRQOL although some respects of their HRQOL remains to be improved. Lower family income and poor education are important factors relating to the poor HRQOL of LT patients.

[Reproduction after liver transplantation: a report of 13 cases from a single Chinese center].

OBJECTIVE: To explore the recipient's reproduction after liver transplantation (LT) and assess the outcomes of their offspring. METHODS: We retrospectively analyzed the reproduction status of 13 post-LT patients among 336 post-LT recipients during a follow-up period. Physical and intellectual status of their offspring were evaluated by developmental index and Denever developmental screening test. RESULTS: A total of 16 children were mothered or fathered by 13 LT patients. Two female patients mothered a boy and a girl. Ten male patients fathered 6 male and 8 female children while another male fathered a child at 28 gestational weeks. Eleven patients fathered the first gestation 21 mon (medium) since LT, and fathered 15 pregnancies. Twelve of 14 deliveries had a mean gestation age of (38.2 ± 1.8) weeks, with a mean birth weight of (3.1 ± 0.5) kg. Among 12 newborns, 3 were premature and 2 of a low birth weight. Two female patients delivered 2 babies with a gestation age of 37.3 and 40.4 weeks, a birth weight of 2.7 and 3.4 kg, and anoxia neonatorum in one case. No deformity was found. Thirteen of 16 children had almost normal developmental indices and ten had almost normal Denever developmental screening. CONCLUSION: Post-LT patients of reproductive age are able to reproduce offspring. The short-term development of their offspring is relatively normal.

Association of phenotypic transformation of circulating tumor cells and early recurrence in patients with hepatocellular carcinoma following liver transplantation.

BACKGROUND: CTCs play a critical role in the diagnosis and prognosis of liver cancer. However, there are few studies on whether different types of CTCs can predict the prognosis in patients with HCC following LT. METHODS: Retrospective data including CTCs detected by the CanPatrolTM platform combined with RNA-ISH were collected and analyzed on 56 patients from December 2016 to December 2019 at the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. RESULTS: During the study period, fifty-six patients (51 males, 5 females) were included with an mean age of 52 ± 9 years. The 1-, 2- and 3-year recurrence rates of postoperative interstitial CTC-positive and CTC-negative groups were 21.7% vs 10.8%, 37.5% vs 10.8% and 55.5% vs 10.8%, confirming a statistically significant difference between the 2 groups (p = 0.044). The 1-, 2- and 3-year recurrence rates of the increasing interstitial CTCs group were 25.2%, 36.9% and 66.9%, while 12.6%, 24.4% and 24.4% in the decreasing and unchanged group, indicating a significant difference (p = 0.038). CONCLUSION: CanPatrolTM platform presents a superior analytical sensitivity, and may be used as a dynamic monitoring tool for CTCs. And interstitial CTCs which are more aggressive and metastatic caused by EMT can be regarded as a predictor of post-transplant tumor recurrence after LT for HCC.

[Anxiety and depression for liver transplant recipients and their impact factors].

OBJECTIVE: To investigate the status of anxiety and depression for liver transplant (LT) recipients and explore their impact factors. METHODS: During the period of January 2005 to December 2008, the symptoms of anxiety and depression for 53 post-LT recipients (LT group) and 48 patients with benign end-stage liver disease (BELD group) were assessed by the self-rating anxiety scale (SAS) and the self-rating depression scale (SDS). And they were compared with that of domestic norm (Norm group). The impact factors of anxiety and depression for LT recipients were analyzed by stepwise logistic regression. RESULTS: The anxiety scores of LT, BELD and Norm groups were (42 ± 9), (47 ± 11) and (30 ± 10) and the depression scores of three groups (48 ± 11), (52 ± 11) and (33 ± 9) respectively. The anxiety score was different significantly among three groups (P < 0.01). It was higher in the LT and BELD groups than that in the Norm Group (P < 0.01) while it was lower in the LT group than that in the BELD group (P < 0.05). The depression scores were different significantly among three groups (P < 0.01). It was higher in the LT and BELD groups than that in the Norm Group. And it was lower in the LT group than that in the BELD group (P < 0.05). The impact factor of anxiety for LT recipients was patient age and that of depression per capita monthly family income. CONCLUSION: The level of anxiety and depression of post-LT recipients is higher than that of domestic norm. The main impact factor for post-LT anxiety is patient age and that of depression per capita monthly family income.

[Preoperative neutrophil-lymphocyte ratio as a prognostic predictor after liver transplantation for hepatocellular carcinoma].

OBJECTIVE: To analyze the negative impact of preoperative neutrophil-lymphocyte ratio (NLR) on the tumor recurrence of hepatocellular carcinoma (HCC) after orthotopic liver transplantation. METHODS: The clinical data of HBV (hepatitis B virus)-associated HCC patients undergoing liver transplantation were retrospectively analyzed. Their clinical and pathological risk factors for tumor-free survival were evaluated by univariate analysis. The analysis of Cox multiple regression was performed to determine the parameters of predicting the HCC recurrence. NLR ≥ 2.5 was considered to be elevated. RESULTS: A total of 76 patients were identified. Among them, 37 had an elevated NLR. The 1, 3 and 5-year tumor-free survival rates were 69.2%, 52.7% and 50.9% respectively. The disease-free survival for patients with high NLR was significantly worse than that for those with normal NLR (1, 3, and 5 year survivals at 56.3%, 37.6% and 37.6% vs 81.1%, 66.9% and 63.3% respectively; P = 0.011). Univariate analysis of factors revealed that tumor size > 5 cm, tumor number > 3, vascular invasion, serum α-fetoprotein level ≥ 400 µg/L and NLR ≥ 2.5 were preoperative predictors of disease-free survival. Cox regression analysis showed that the presence of vascular invasion, tumor number > 3 and NLR ≥ 2.5 were independent prognostic factors of worse disease-free survival. CONCLUSION: An elevated NLR significantly increases the risk for tumor recurrence in HCC patients undergoing liver transplantation.

[Clinical analysis between "early" versus "late" liver retransplantation].

OBJECTIVE: To compare early and late orthotopic liver retransplantation (re-OLT) for patients with poor graft function after primary transplantation at our center and sum up our clinical experience in re-OLT. METHODS: The clinical data of 36 re-OLTs from January 2004 to July 2009 were analyzed retrospectively, consisting of the first group with 17 cases of early re-OLT and the second group with 19 cases of late re-OLT. The average ages were (45 ± 13) years and (48 ± 10) years, and the time intervals were (49 ± 54) days and (514 ± 342) days in early re-OLT group and late re-OLT group, respectively. RESULTS: Biliary tract complications were the main indications for early re-OLT and late re-OLT. Other common indications were vascular complications in early re-OLT and recurrence of primary diseases in late re-OLT. No significant differences were found between the groups with regard to the volume of bleeding during operation, cold ischemia time, operative duration and perioperative mortality except the MELD score. Outcome was fatal for 8 patients in early re-OLT and 10 patients in late re-OLT. Three deaths were due to severe sepsis-related disease, 3 deaths due to multiple organ failure in early re-OLT and 4 deaths due to severe sepsis-related disease, 3 deaths due to recurrence of HCC in late re-OLT. One and 2-year actuarial survival rates after re-OLT were 52.9% and 41.2%, respectively, for patients in early re-OLT, and 63.2% and 52.6%, respectively, for patients in late re-OLT. No significant differences were found regarding survival rates between the two groups (P > 0.05). CONCLUSIONS: The similar clinical results can be achieved in early and late re-OLT. Proper indications and optimal operation timing, experienced surgical procedures and effective perioperative anti-infection strategy contribute to the improvement of the overall survival rate of the patients after re-OLT.

TSC1/2 mutations-a unique type of mutation suitable for liver transplantation of Hepatocellular carcinoma.

BACKGROUND: This study aimed to investigate the relationship between the prognosis of patients with hepatocellular carcinoma (HCC) after liver transplantation and mammalian target of rapamycin (mTOR) pathway-related genes-TSC1/2. METHODS: We retrospectively analyzed the clinical data of 46 patients who underwent liver transplantation for HCC and performed next generation sequencing to analyze the relationship between the efficacy of sirolimus after liver transplantation for HCC and mutations in mTOR pathway-related genes, especially tuberous sclerosis complex (TSC) mutations. RESULTS: The average age of 46 patients with liver transplantation for HCC was 51±21 years. After surgery, 35 patients received an anti-rejection/anti-tumor regimen that included sirolimus, and 11 patients did not receive sirolimus. There was no significant difference in survival rate between the two groups (P=0.761). The gene sequencing results showed mTOR-related pathway mutations in 10 patients, of whom five (10.9%) had TSC1/2 mutations. Of the 35 patients using sirolimus, those with mTOR-related mutations had significantly better survival rates than patients without mTOR-related mutations (P=0.016). CONCLUSIONS: According to genetic sequencing results, a personalized treatment plan for specific genetic mutations should be selected in patients undergoing liver transplantation for HCC. Patients with mTOR-related gene mutations, especially TSC mutations, can gain significant benefits from the use of mTOR inhibitors such as sirolimus.

Circular RNA circ-102,166 acts as a sponge of miR-182 and miR-184 to suppress hepatocellular carcinoma proliferation and invasion.

PURPOSE: Multiple circular RNAs (circRNAs) have been reported to be dysregulated in hepatocellular carcinoma (HCC). However, their functions and modes of action are still largely unclear. Identifying key circRNAs and revealing their potential functions and molecular mechanisms is considered important for improving the diagnosis and treatment of HCC. METHODS: Dysregulated circRNAs in HCC were identified through integration of three human HCC circRNAs microarray datasets (GSE94508, GSE97332 and GSE 78520), followed by qRT-PCR validation in primary HCC tissues and cell lines. circRNA characteristics were verified through Sanger sequencing, RNase R treatment, northern blotting and intracellular localization analyses. In addition, circRNA functions in HCC development were assessed using CCK8, colony formation, EDU incorporation, flow cytometry, transwell and scratch wound healing assays in vitro and tumor xenograft assays in vivo. Next, underlying molecular mechanisms in HCC were assessed using dual-luciferase reporter, RNA pull-down, RNA immunoprecipitation and western blotting assays. RESULTS: We found that a novel circular RNA, circ-102,166, was down-regulated in HCC and that its expression level was significantly associated with multiple clinicopathologic characteristics, as well as the clinical prognosis of HCC patients. In vitro and in vivo experiments revealed that circ-102,166 overexpression significantly inhibited the proliferation, invasion, migration and tumorigenicity of HCC cells. Furthermore, we found that circ-102,166 can bind to miR-182 and miR-184 to regulate the expression of several of their downstream targets (FOXO3a, MTSS1, SOX7, p-RB and c-MYC). CONCLUSION: Our data revealed a tumor-suppressing role of circ-102,166 in HCC. Down-regulation of circ-102,166 enhanced the proliferation and invasion of HCC cells by releasing the oncomiRs miR-182 and miR-184.

A novel MSC-based immune induction strategy for ABO-incompatible liver transplantation: a phase I/II randomized, open-label, controlled trial.

BACKGROUND: ABO-incompatible liver transplantation (ABO-i LT) has become a rescue therapeutic option for patients with severe hepatic failure. Although the use of rituximab greatly reduces the morbidity of antibody-mediated rejection (AMR), severe adverse effects, such as infection and biliary complications, still seriously threaten the survival of transplant recipients. The aim of this study was to evaluate the safety and feasibility of using mesenchymal stem cells (MSCs) to replace rituximab in ABO-i LT. METHODS: Twenty-two patients with severe hepatic failure undergoing ABO-i LT were enrolled and randomly divided into two groups: the MSC group and the rituximab group. The safety of the application of MSCs and the incidence of allograft rejection, including antibody-mediated rejection (AMR) and acute cellular rejection (ACR), were evaluated in both groups at the 2-year follow-up period as primary endpoints. Recipients and graft survival and other postoperative complications were compared as secondary endpoints. RESULTS: No severe MSC-related adverse events were observed during the trial. MSC treatment yielded comparable, if not better, results than rituximab at decreasing the incidence of acute rejection (9.1% vs 27.3%). Inspiringly, compared to those in the rituximab group, the rates of biliary complications (0% vs 45.5%) and infection (9.1% vs 81.8%) were significantly decreased in the MSC group. In addition, there were no significant differences in 2-year graft and recipient survival between the two groups (81.8% vs 72.7%). CONCLUSIONS: Our data show that MSC transfusion is comparable to rituximab treatment for AMR prophylaxis following ABO-i LT. Additionally, the results indicate that MSCs are more beneficial to the prevention of infection and biliary complications and may be introduced as a novel immunosuppressive approach for ABO-i LT. TRIAL REGISTRATION: Trial registration: chictr.org.cn , ChiCTR2000037732. Registered 31 August 2020- Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=57074 .