www.clinicaltrials.gov (NCT 01287585).

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, resulting not only in liver dysfunction, glucose and lipid metabolism disorder, but also in neuropsychiatric damage. In the present study, a NAFLD rat model was established via feeding of a high-fat diet, and behaviour was observed via the open field test (OFT), the sucrose preference test (SPT), the elevated plus maze (EPM), the forced swimming test (FST) and the Morris water maze (MWM). The plasma concentrations of alanine aminotransferase (ALT), glucose, free fatty acid (FFA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were detected using chemiluminescence technique. The plasma levels of nesfatin-1, leptin and insulin were measured via enzyme-linked immunosorbent assay, and the protein expressions of p-glycogen synthase kinase-3β (GSK-3β), GSK-3β, p-β-catenin, β-catenin, cyclinD and copine 6 in the hippocampus and prefrontal cortex (PFC) were detected using western blotting. After 4 consecutive weeks of feeding with a high-fat diet, the rats showed obesity; increased plasma concentrations of ALT, glucose, FFA, TC, TG, HDL-C and LDL-C; decreased plasma levels of leptin and insulin; and inflammation and mild hepatocyte steatosis in the liver. Although there was no significant difference between groups with regard to performance in the OFT, EPM or FST, the NAFLD rats showed a decreased sucrose preference index in the SPT and impaired learning and memory in the MWM task. Moreover, the present study provides the first evidence of an increased plasma nesfatin-1 concentration in NAFLD rats, which was significantly correlated with plasma lipid concentrations and behavioural performance. Furthermore, copine 6 and p-β-catenin protein expression decreased and p-GSK-3β increased in the hippocampus and PFC of NAFLD rats. These results suggest that consuming of a high-fat diet for 4 consecutive weeks could successfully induce a NAFLD rat model. More importantly, these results provide the first evidence that impaired learning and memory in NAFLD rats was, at least partly, associated with increased plasma nesfatin-1 concentration and decreased copine 6 expression in the hippocampus and PFC.

Background: Combination of checkpoint inhibitors (CPIs) with anti-angiogenic agents are emerging as potential novel treatment options of hepatocellular carcinoma (HCC).Here we assessed the efficacy and safety of C+A in patients (pts) with advanced HCC.Methods: This phase II study was conducted at 25 study sites in China. Pts with advanced HCC, treatment-naive or failure to sorafenib or donafenib were enrolled. Pts received intravenous C 200 mg every 2 weeks plus A 250 mg qd. The primary endpoint was objective response assessed by independent central review per RECIST v1.1.Results: From Mar 2018 to Jan 2019, 70 pts in first-line setting and 120 pts in secondline setting were enrolled and received treatment of C+A. 168 (88%) of 190 pts were with HBV infection. As of Jan, 2020, median follow-up was 16.7 months and 14.0 months in the first-line and second-line treatment cohort, respectively. The objective response rate (ORR) assessed by independent central review per RECIST v1.1 was 34% and 23%; ORR assessed by independent central review per mRECIST was 46% and 25%; the 12-month overall survival (OS) rate was 75% and 68%, respectively. As of Apr 2020, the 18-month OS rate was 58% in the first-line cohort (table). Overall, 147 (77%) pts had grade 3 treatment-related AEs, with the most common being hypertension (34%), and increased g-GT (12%). Twenty-three (12%) pts discontinued the treatment of either drug due to a treatment-related AE.Conclusions: C+A provided high ORR, durable response with a manageable safety profile in advanced HCC pts. Notably, the remarkable survival benefit might suggest C+A is a promising strategy in advanced HCC pts.Clinical trial identification: NCT03463876.

No abstract

Metabolic syndrome is a cluster of conditions that occur together, increasing the risk of heart disease, stroke and type 2 diabetes. These conditions include obesity, hyperglycemia, hypertension, hyperlipidemia. Leptin and leptin receptor mutant mice, ob/ob and db/db, are two classic metabolic syndrome animal model. However, the transient hyperglycemia of ob/ob and severe hyperglycemia induced premature death of db/db limit the application of these two models. To fill the gap, GemPharmatech developed a metabolic disorder model based on the mutation of Alms1 gene in mice (B6-Alms1-del mice). B6-Alms1-del mice gradually developed obesity from 8 weeks old with chow diet, accompanied by hyperglycemia, glucose and insulin intolerance, dyslipidemia and impaired liver function. Moreover, B6-Alms1-del mice developed severe non alcoholic fatty liver spontaneously as early as 21 weeks old and no premature death was observed around 5~8 months of ages. As B6-Alms1-del mice copied major features of metabolic syndrome, we further tested whether B6-Alms1-del mice could response to the positive drug semaglutide, an agonist of GLP-1R. 16 weeks old B6-Alms1-del mice were treated with vehicle and semaglutide for 5 weeks, respectively. Our results indicate that semaglutide lead to benefit on metabolic syndrome, including body weight control, improvement in hyperglycemia, hyperlipidemia, liver injury and hepatic steatosis. In conclusion, we have established a metabolic syndrome animal model that develop clinically relevant metabolic phenotypes and overcome the limitation of ob/ob and db/db. Furthermore, B6-Alms1-del mice responds to the approval anti-obesity drug semaglutide, which provide a useful model to assess the efficacy of novel metabolic syndrome therapies. Disclosure Z.Chen: None. M.Gao: None. X.Zhao: None. Z.Li: None. J.Zhao: None. C.Ju: None. X.Gao: None.