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Aim： To investigate the effects of a novel dithiocarbamate derivative TM208 on human breast cancer cells as well as the pharmacoki- netic characteristics of TM208 in human breast cancer xenograft mice. Methods： Human breast cancer MCF-7 and MDA-MB-231 cells were treated with TM208 or a positive control drug tamoxifen. Cell pro- liferation was examined using SRB and colony formation assays. Cell apoptosis was analyzed with Annexin V-FITC/PI staining assay. Protein expression was examined with Western blot, ELISA and immunohistochemical analyses. MCF-7 breast cancer xenograft nude mice were orally administered TM208 （50 or 150 mg.k$1〈1-1） or tamoxifen （50 mg.kgl〈t-~） for 18 d. On d 19, the tumors were collected for analyses. Blood samples were collected from the mice treated with the high dose of TM208, and plasma concentrations of TM208 were measured using LC-MS/MS. Results： Treatment of MCF-7 and MDA-MB-231 cells with TM208 dose-dependently inhibited the cell proliferation and colony formation in vitro （the IC~o values were 36.38＋3.77 and 18.13＋0.76 pmol/L, respectively）. TM208 （20-150pmol/L） dose-dependently induced apoptosis of both the breast cancer cells in vitro. In MCF-7 breast cancer xenograft nude mice, TM208 administration dose-depend- ently reduced the tumor growth, but did not result in the accumulation of TM208 or weight loss. TM208 dose-dependently inhibited the phosphorylation of EGFR and ERK1/2 in both the breast cancer cells in vitro as well as in the MCF-7 xenograft tumor. Conclusion： Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.

Background：The phosphorylation ofp70S6 kinase （p70S6K） represents an important target for sensitive detection on pharmacodynamic effects of sirolimus,but the methods of assessing p70S6K phosphorylation are still unclear.The aim of this study was to investigate p70S6K phosphorylation located down-stream of the mammalian target ofrapamycin （mTOR） pathway in peripheral blood mononuclear cells （PBMCs） of liver transplant patients through different methods.Methods：Seventy-five liver transplant recipients from Beijing Chaoyang Hospital of the Capital Medical University were analyzed in this study.Patients were divided into three groups,patient treated with sirolimus （n =22）,patient treated with tacrolimus （n =30）,patient treated with cyclosporine （n =23）.The p70S6K phosphorylation of PBMCs in patients and healthy control （HC,n =12） were analyzed by phospho-flow cytometry and Western blotting.A correlation analysis of data from phospho-flow cytometry and Western blotting was performed.Intra-assay variability of p70S6K phosphorylation in HC and different patients were measured.Results：Intra-assay variability ofp70S6K phosphorylation in phospho-flow cytometry was from 4.1% to 8.4% and in Western blotting was from 8.2% to 18%.The p70S6K phosphorylation in patients receiving a sirolimus （19.5 ± 7.7） was significantly lower than in HC （50.1 ± 11.3,P 〈 0.001）,tacrolimus （37.7 ± 15.7,P 〈 0.001） or cyclosporine treated patients （41.7 ± 11.7,P 〈 0.001）.The p70S6K phosphorylation in HC （50.1± 11.3） was significantly higher than in tacrolimus （37.7 ± 15.7,P 〈 0.01） or cyclosporine-treated patients （41.7 ± 11.7,P 〈 0.01）.There was correlation between data from phospho-flow cytometry and data from Westem blotting （r =0.88,P 〈 0.001）.Conclusions：The degree of mTOR inhibition by assessing p70S6K phosphorylation was established by phospho-flow cytometry and Westem blotting.Assessment of p70S6K phosphorylation may play an adjunct role to on pharmacodynamically guide and individualize sirolimus based on immunosuppression.