RESUMO
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm derived from the balanced reciprocal translocation of chromosomes 9 and 22 t (9q34 and 22q11), which leads to the formation of the Philadelphia chromosome and fusion of the BCR-ABL genes. The first-line treatment for CML is imatinib, a tyrosine kinase inhibitor that acts on the BCR-ABL protein. However, even though it is a target-specific drug, about 25% of patients do not respond to this treatment. The resistance mechanisms involved in this process have been investigated and studies have shown that germinal alterations can influence this mechanism. The aim of this work was to investigate 32 polymorphisms in 24 genes of carcinogenic pathway to verify the influence of these genetic variants on the response to treatment with imatinib. Our results demonstrated that individuals with the recessive GG genotype for the rs2372536 variant in the ATIC gene are approximately three times more likely to experience treatment failure with imatinib (p = 0.045, HR = 2.726, 95% CI = 0.9986-7.441), as well as individuals with the TT genotype for the rs10821936 variant in the ARID5B gene, who also have a higher risk for treatment failure with imatinib over time (p = 0.02, HR = 0.4053, IC 95% = 0.1802-0.911). In conclusion, we show that variants in the ATIC and ARIDB5 gene, never screened in previous studies, could potentially influence the therapeutic response to imatinib in patients treated for CML.
Assuntos
Benzamidas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Hidroximetil e Formil Transferases , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Complexos Multienzimáticos , Nucleotídeo Desaminases , Piperazinas , Pirimidinas/uso terapêutico , Fatores de Transcrição/genética , Translocação GenéticaRESUMO
Rough mutants of Brucella abortus were generated by disruption of wbkC gene which encodes the formyltransferase enzyme involved in LPS biosynthesis. In bone marrow-derived macrophages the B. abortusDeltawbkC mutants were attenuated, could not reach a replicative niche and induced higher levels of IL-12 and TNF-alpha when compared to parental smooth strains. Additionally, mutants exhibited attenuation in vivo in C57BL/6 and interferon regulatory factor-1 knockout mice. DeltawbkC mutant strains induced lower protective immunity in C56BL/6 than smooth vaccine S19 but similar to rough vaccine RB51. Finally, we demonstrated that Brucella wbkC is critical for LPS biosynthesis and full bacterial virulence.
Assuntos
Vacina contra Brucelose/imunologia , Brucella abortus/enzimologia , Brucelose/imunologia , Hidroximetil e Formil Transferases/metabolismo , Macrófagos/imunologia , Animais , Células da Medula Óssea/imunologia , Brucella abortus/genética , Brucella abortus/imunologia , Brucella abortus/patogenicidade , Brucelose/microbiologia , Hidroximetil e Formil Transferases/genética , Interleucina-12/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fator de Necrose Tumoral alfa/imunologia , Vacinas Atenuadas/imunologia , VirulênciaRESUMO
The molecular nature of the glycine cleavage system was investigated in eight patients with typical (neonatal) and two patients with atypical (late onset) nonketotic hyperglycinemia (NKH). The overall activity of the glycine cleavage system was found to be decreased in all of the liver and brain tissue studied, but it was undetectable or extremely low in typical NKH, whereas there was some residual activity in atypical NKH. Six patients with typical NKH had a specific defect in the P protein, and one a defect in the T protein; the activity of the T protein was defective in one patient with atypical NKH.