Endoplasmic reticulum stress triggers delanzomib-induced apoptosis in HCC cells through the PERK/eIF2α/ATF4/CHOP pathway.

For limited clinical benefits and acquired resistance by sorafenib, new therapeutic strategies and molecular targets for the treatment of advanced hepatocellular carcinoma (HCC) are urgently needed. This study aimed to evaluate the potential antitumor effects of the second-generation proteasome inhibitor delanzomib on HCC. The results demonstrated that delanzomib displayed excellent antitumor activity on HCC cells with sensitivity or resistance to sorafenib in a time- and dose-response manner, by inducing G2/M cell cycle arrest and apoptosis in vitro. Cell cycle arrest was associated with the activation of p21/Cdc2/cyclin B1 pathway, and cell apoptosis was confirmed by PARP and caspase-3 cleavage. In addition, delanzomib induced endoplasmic reticulum stress (ERS) in HCC cells by activating the PERK and ERS-associated proteins including p-eIF2α, ATF4 and CHOP. Selective inhibition of eIF2α dephosphorylation by salubrinal could significantly reduce delanzomib-induced apoptosis in HCC cells. In vivo, delanzomib could also exhibit effective antitumor properties on patient-derived xenograft mouse model of HCC with relative low drug-associated cytotoxicity. Compared to control group, 3 and 10 mg/kg of delanzomib significantly reduced the tumor volume by 33.1% and 87.2% respectively after 3 weeks treatment, with no significant change on the body weight and the level of serum biochemical indexes including ALT, AST and BUN. In conclusion, delanzomib could exhibit good pre-clinical antitumor effects against HCC cells by inducing ERS and activating the PERK/eIF2α/ATF4/CHOP pathway, as potential drug candidate on treatment of advanced HCC patients.

[Detection of peripheral blood Th1/Th2 and Tc1/Tc2 subsets in patients with condyloma acuminatum and its significance].

OBJECTIVE: To investigate the role of T-helper (Th) and cytotoxic T (Tc) lymphocyte polarization in the pathogenesis of condyloma acuminatum (CA) and its correlation with recurrence. METHODS: Three-colour immunofluorescent flow cytometry was used to detect the proportion of CD3+ CD8- /IFN-gamma+ (Th1), CD3+ CD8- /IL-4+ (Th2), CD3+ CD8+/IFN-gamma+ (Tc1) and CD3+ CD8+ /IL-4+ (Tc2) cells in the peripheral blood of CA patients and health controls. RESULTS: Compared to health controls, CA patients showed a decreased number of Th1 (P < 0.01) and Tc1 cells (P < 0.05), as well as a decreased Th1/Th2 and Tc1/Tc2 ratio (P < 0.05). Furthermore, in 15 recurrent CA patients the ratio of Th1/Th2 was remarkably decreased (P < 0.01), while the ratio of Tc1/Tc2 had no significant change in comparison with health controls. CONCLUSION: The decrease of Th1 and Tc1 subsets results in relative Th2 and Tc2 predominance, and this tendency is more significant in recurrent CA patients. The Th1 to Th2 and Tc1 to Tc2 shifts in CA patients could be responsible for the fact that human papilloma virus (HPV) is hard to be eliminated.

[Life history characteristics of different genotype clones of Brachionus calyciflorus (Rotifera) population in Jinghu Lake].

By means of life table demographic approach, the life-table demographic parameters and the percentage of mictic females in the offspring of thirteen genetically different Brachionus calyciflorus clones were studied at 15 degrees C, 20 degrees C, 25 degrees C and 30 degrees C. The results showed that the responses of the generation time, average lifespan, life expectancy at hatching, intrinsic rate of population increase, net reproductive rate, and percentage of mictic females in the offspring of B. calyciflorus to increasing temperature differed with rotifer clones. Temperature, clone, and their interaction influenced the life-table demographic parameters and the percentage of mictic females in the offspring of B. calyciflorus significantly. The temporal heterogeneity of water temperature could be one of the reasons for the high genetic diversity in B. calyciflorus population in Jinghu Lake. Natural selection occurred in coexisting clones, and its function might be too weak or too time-limited to make the clonal exclusion occur. Genetic drift might play an important role in genotype frequency variation. The coexistence of different genotype clones of B. calyciflorus population is of significance for the existence of the population in water environment.