Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma:A single-arm, multicenter, prospective study

Mammalian target of rapamycin(m TOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant(LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival(RFS) in hepatocellular carcinoma(HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specifc for the frst 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefts for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data.

hMex-3A is associated with poor prognosis and contributes to the progression of hepatocellular carcinoma

Background:HMex-3A,an RNA-binding protein,was found to be associated with tumorigenesis.However,the roles of h Mex-3A in hepatocellular carcinoma(HCC)progression remained unclear.Methods:The different expression of h Mex-3A between HCC tissues and non-tumor tissues was evaluated using The Cancer Genome Atlas database.Thereafter,the h Mex-3A expression was evaluated in HCC tissues using Western blotting and q RT-PCR.Immunohistochemistry was performed to investigate the association between h Mex-3 A level and clinicopathological features including prognosis in HCC patients.In addition,we used si-h Mex-3A to knockdown h Mex-3A in HCC cells to test Cell Counting Kit-8,colony formation,cell migration and invasion.Results:The h Mex-3A expression was significantly elevated in HCC tissues.Analysis of the clinicopathological parameters suggested that h Mex-3A expression was significantly associated with pathological grade(P=0.019)and TNM stage(P=0.001)in HCC.Moreover,univariate and multivariate Coxregression analyses revealed that high h Mex-3A expression(HR=1.491,95%CI:1.107–2.007;P=0.009)was an independent risk factor for overall survival in HCC patients.Finally,we confirmed that si-h Mex-3A could significantly inhibit HCC cell proliferation,migration,and invasion in vitro.Conclusions:HMex-3A may contribute to the progression of HCC and might be used as a novel therapeutic target and prognostic marker in HCC.

Protective Effects of Salubrinal on Liver Injury in Rat Models of Brain Death

Background： Previous studies have indicated that endoplasmic reticulum stress participates in and mediates liver injury and apoptosis in brain-dead （BD） rats. In this study, we observed the effect ofsalubrinal （Sal, Sigma, USA） on liver cells in BD rats and explored its relevant mechanisms. Methods： Thirty Sprague-Dawley rats were equally randomized into three groups： BD group, Sal group, and DMSO group. The BD models were established by increasing intracranial pressure in a modified, slow, and intermittent way. In the drug groups, Sal was administered I h before the induction of BD. After modeling was completed, the blood and liver samples were harvested. CHOP and Caspase-12 mRNA expression was detected using quantitative polymerase chain reaction. PKR-like ER kinase （PERK）, P-eukaryotic translation initiation factor 2a （elF2a）, elF2a, CHOP and caspase-12 expression was detected using western blotting （WB）. CHOP and caspase-12 distribution and expression in liver tissues were determined using immunohistochemistry （IHC）. Alanine aminotransferase and aspartate aminotransferase level were detected using an automatic biochemical analyzer. Hepatic cell apoptosis was detected using TUNEL. The results were analyzed using Quantity-one v4.62 software （Bio-Rad, USA）. Results： CHOP and caspase-12 expression and PERK, elF2a, and P-elF2a protein expression showed no significant difference between BD group and DMSO group. Compared with BD group, Sal group had a significantly higher P-elF2C level and a lower P-PERK level 2 h and 6 h alter BD （P 〈 0.05）. However, eIF2a expression showed no significant difference （P 〉 0.05）. After the Sal treatment, CHOP and caspase- 12 mRNA expression significantly decreased 4 hatter BD （P 〈 0.05）. WB and IHC indicated that CHOP and caspase- 12 expression also significantly decreased after Sal treatment. Sal was associated with improved liver function and decreased hepatic cell apoptosis. Conclusions： Sal can significantly reduce apoptosis in hepatic cells of BD rats. This protective effect may be achieved via the PERK-elF2a signaling pathway.