Shanghai Johnson & Johnson Pharmaceutical Ltd.

Hepatocellular carcinoma (HCC) is the fifth most common type of cancers worldwide. However, current therapeutic approaches for this epidemic disease are limited, and its 5-year survival rate hasn't been improved in the past decades. Patient-derived xenograft (PDX) tumor models have become an excellent in vivo system for understanding of disease biology and drug discovery. In order to identify new therapeutic targets for HCC, whole-exome sequencing (WES) was performed on more than 60 HCC PDX models. Among them, four models exhibited protein-altering mutations in JAK1 (Janus Kinase 1) gene. To explore the transforming capability, these mutations were then introduced into HEK293FT and Ba/F3 cells. The results demonstrated that JAK1S703I mutation was able to activate JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway and drive cell proliferation in the absence of cytokine stimulation in vitro. Furthermore,the sensitivity to the treatment of a JAK1/2 inhibitor, ruxolitinib, was observed in JAK1S703I mutant PDX model, but not in other non-activating mutant or wild type models. Pharmacodynamic analysis showed that phosphorylation of STAT3 in the Ruxolitinib-treated tumor tissues was significantly suppressed. Collectively, our results suggested that JAK1S703I is an activating mutation for JAK-STAT signaling pathway in vitro and in vivo, and JAK-STAT pathway might represent a new therapeutic approach for HCC treatment. Monotherapy using a more potent and specific JAK1 inhibitor and combinatory therapy should be further explored in JAK1 mutant PDX models.

The gastric mucosa protection effect of three natural plant extracts, Hericium erinaceus (HE), Centella asiatica (CA) and Amomum villosum (AV), were evaluated using the indomethacin damage model. Compared with a single extract, a combination of HE/CA/AV, especially with the ratios of 80:10:10, 45:45:10 and 45:10:45, showed significant synergistic effects for protection of the gastric mucosa with gastric ulcer inhibition rates of 97.8 ± 0.7%, 86.5 ± 2.8% and 86.1 ± 3.6%, respectively. Microscopic appearances of the gastric mucosa were carried out to help confirm the results.

The objective of the present study was to develop a topical preparation with enhanced skin permeation, high safety and self-preserving ability. Microemulsion (ME) and cationic polymer based micro-emulgel (CPBM) were investigated for the transdermal delivery of diclofenac sodium (DS). Medium-chain triglyceride was selected as the oil phase of ME due to its good solubilization of DS and high safety. Orthogonal test was applied to optimize the formula of ME based on the cumulative skin permeation amount in vitro after preliminary formula test. Chitosan (CS) or polylysine was employed as the cationic polymer in the formula of CPBM. The transdermal delivery of DS was evaluated through in vitro skin permeation test. The results showed that the skin permeation rate of DS from the optimized CPBM (126.17 ± 15.82 μg/cm(2)/h) were 1.86-folds and 5.76-folds higher than that of DS commercial Emulgel and DS control hydrogel, respectively. MEs and the cationic polymer were found to have skin penetration co-enhancing effect when they were combined in the CPBM system. Furthermore, the CPBM showed a good growth inhibition of E. coli and S. aureus. The stability test revealed that the CPBM was stable at room temperature and 4 °C for a period of three months.