RESUMO
Serine protease granzyme B plays important roles in infections, autoimmunity, transplant rejection, and antitumor immunity. A triple-mutated granzyme B variant that encodes three amino substitutions (Q48R, P88A, and Y245H) has been reported to have altered biological functions. In the polymorphism rs8192917 (2364A>G), the A and G alleles represent wild type QPY and RAH mutant variants, respectively. In this study, we analyzed the impact of granzyme B polymorphisms on transplant outcomes in recipients undergoing unrelated HLA-fully matched T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The granzyme B genotypes were retrospectively analyzed in a cohort of 613 pairs of recipients with hematological malignancies and their unrelated donors. In patients with myeloid malignancies consisting of acute myeloid leukemia and myelodysplastic syndrome, the donor G/G or A/G genotype was associated with improved overall survival (OS; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41-0.89; Pâ=â0.01) as well as transplant related mortality (TRM; adjusted HR, 0.48; 95% CI, 0.27-0.86, Pâ=â0.01). The recipient G/G or A/G genotype was associated with a better OS (adjusted HR, 0.68; 95% CI, 0.47-0.99; Pâ=â0.05) and a trend toward a reduced TRM (adjusted HR, 0.61; 95% CI, 0.35-1.06; Pâ=â0.08). Granzyme B polymorphism did not have any effect on the transplant outcomes in patients with lymphoid malignancies consisting of acute lymphoid leukemia and malignant lymphoma. These data suggest that there is an association between the granzyme B genotype and better clinical outcomes in patients with myeloid malignancies after unrelated BMT.
Assuntos
Transplante de Medula Óssea/mortalidade , Granzimas/genética , Antígenos HLA/imunologia , Transtornos Mieloproliferativos/terapia , Polimorfismo Genético , Adolescente , Adulto , Idoso , Transplante de Medula Óssea/imunologia , Criança , Pré-Escolar , Variação Genética , Genótipo , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Lactente , Pessoa de Meia-Idade , Mortalidade , Transtornos Mieloproliferativos/mortalidade , Prognóstico , Doadores de Tecidos , Transplante Homólogo/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
Two new boldine derivatives: the 3-thiocarbamateboldine (3) and the 2,9-O,O-diacetyl-3-thiocarbamateboldine (4) have been synthesized and their cytotoxicity evaluated.