OBJECTIVETo explore the strategies which reduce the amount of xenoantigen Galalpha1,3Gal.

METHODSHuman alpha-galactosidase gene and alpha1,2-fucosyltransferase gene were transferred into cultured porcine vascular endothelial cells PEDSV.15 and human alpha-galactosidase transgenic mice were produced. The Galalpha1,3Gal on the cell surface and susceptibility of cells to human antibody-mediated lysis were analyzed.

RESULTSHuman alpha-galactosidase gene alone reduced 78% of Galalpha1,3Gal on PEDSV.15 cell surface while human alpha-galactosidase combined with alpha1,2-fucosyltransferase genes removed Galalpha1,3Gal completely. Decrease of Galalpha1,3Gal could reduce susceptibility of cells to human antibody-mediated lysis, especially during co-expression of alpha-galactosidase gene and alpha1,2-fucosyltransferase gene. RT-PCR indicated positive human alpha-galactosidase gene expression in all organs of positive human alpha-galactosidase transgenic F1 mice including heart, liver, kidney, lung, and spleen, the amount of Galalpha1,3Gal antigens on which was reduced largely. 58% of spleen cells from F1 mice were destroyed by complement-mediated lysis compared with 24% of those from normal mice.

CONCLUSIONSHuman alpha-galactosidase gene and alpha1,2-fucosyltransferase gene effectively reduce the expression of Galalpha1,3Gal antigens on endothelial cell surface and confers resistance to human serum-mediated cytolysis. The expression of human alpha-galactosidase in mice can also eliminate the Galalpha1,3Gal antigens in most tissues and decrease the susceptibility of spleen cells to human serum-mediated cytolysis.

Animals ; Antigens, Heterophile ; metabolism ; Cell Death ; Cells, Cultured ; Disaccharides ; metabolism ; Endothelial Cells ; metabolism ; Fucosyltransferases ; genetics ; metabolism ; Graft Rejection ; genetics ; Humans ; Mice ; Mice, Transgenic ; Spleen ; cytology ; Swine ; Transfection ; alpha-Galactosidase ; genetics ; metabolism

Objective: To investigte the efficacy of docetaxel combined with androgen deprivation therapy for the treatment of metastatic hormone-sensitive prostate cancer based on Chinese population. Methods: A total of 497 patients were enrolled from January 2004 to July 2018 in the Changhai Hospital. 459 patients received androgen deprivation therapy alone and 38 patients received androgen deprivation therapy combined with docetaxel. The mean age was (72.1±8.7)years. The median PSA level was 100.0 ng/ml, ranging 42.3-999.0 ng/ml. Patients of clinical T₂, T₃, T₄ stage were 213(42.9%), 160(32.2%), 124(24.9%), respectively. Patients of clinical N₀, N₁, N_x stage were 319(64.2%), 144(29.0%), 34(6.8%), respectively. Patients of clinical M₀, M_1a, M_1b, M_1c, M_x stage were 100(20.1%), 51(10.3%), 332(66.8%), 9(1.8%), 5(1.0%), respectively. Gleason scores of biopsy showed that 146(29.4%) patients was ≤7, 103(20.7%) was 8 and 248(49.9%)was ≥9. Propensity score matching was used to match the baseline between groups. Caliper value was set at 0.02. SPSS 22 software was used to achieve a 1∶1 match between the two groups. There were no statistical difference in the age(P=0.102), PSA(P=0.713), T stage(P=0.113), N stage(P=0.226), M stage(P=0.514), Gleason score(P=0.612), tumor loading(P=0.812)between the two groups. The castration resistance-free rate and cancer specific survival rate of the two groups were compared by log-rank and breslow-wilcoxon test. Furthermore, forest plots were used to display the analysis results of different subgroups such as age, PSA, clinical stage, Gleason score, tumor load, whether patients had received palliative resection, and the differences in castration resistance-free rate were compared between the subgroups with high tumor load. Results: The median follow-up time was 22.6 months in the androgen deprivation therapy group and 13.7 months in the combined therapy group. The number of patients with castration resistance in the two groups was 23 and 17, respectively. There were 3 and 6 deaths, respectively. There was no statistically significant difference in the overall progression time to castration resistance between the two groups (10.3 m vs. 16.5 m, P>0.05), and no statistically significant difference in the prostate cancer specific survival rate (21.9 m vs.14.8 m, P>0.05). When subgroup analysis was performed, it was found that patients in the high-metastasis-volume subgroup who received the combination therapy had a significantly longer castration resistance free lifetime (10.6 m vs. 7.2 m, P=0.044), but there was no significant difference in the low- metastasis-volume subgroup(10.5 m vs.12.6 m, P>0.05). Conclusion Docetaxel combined with androgen deprivation therapy can improve the castration resistance free rate in patients with high metastasis volume, but not in low metastasis volume group.