Expression of Hippo signaling pathway and Aurora kinase genes in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from clonal expansion of hematopoietic stem cells positive for the Philadelphia chromosome. The CML pathogenesis is associated with expression of the BCR-ABL1 oncogene, which encodes the Bcr-Abl protein with tyrosine kinase activity, promoting the leukemic cell exacerbated myeloproliferation and resistance to apoptosis. CML patients are usually treated with tyrosine kinase inhibitors (TKI), but some of them acquire resistance or are refractory to TKI. Thus, it is still relevant to elucidate the CML pathogenesis and seek new therapeutic targets, such as the Hippo signaling pathway and cell cycle regulatory genes from the Aurora kinase family. The present study quantified the expression level of genes encoding components of the Hippo signaling pathway (LATS1, LATS2, YAP, and TAZ), AURKA and AURKB in CML patients at different stages of the disease, who were resistant or sensitive to imatinib mesylate therapy, and in healthy individuals. The expression levels of the target genes were correlated with the CML Sokal's prognostic score. The most striking results were the LATS2 and AURKA overexpression in CML patients, the overexpression of TAZ and AURKB in CML patients at advanced phases and TAZ in CML IM-resistant. The development of drugs and/or identification of tumor markers for the Hippo signaling pathway and the Aurora kinase family, either alone or in combination, can optimize CML treatment by enhancing the susceptibility of leukemic cells to apoptosis and leading to a better disease prognosis.

CR-LAAO antileukemic effect against Bcr-Abl(+) cells is mediated by apoptosis and hydrogen peroxide.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Bcr-Abl tyrosine kinase protein, which confers resistance to apoptosis in leukemic cells. Tyrosine kinase inhibitors (TKIs) are effectively used to treat CML; however, CML patients in the advanced (CML-AP) and chronic (CML-CP) phases of the disease are usually resistant to TKI therapy. Thus, it is necessary to seek for novel agents to treat CML, such as the enzyme l-amino acid oxidase from Calloselasma rhodostoma (CR-LAAO) snake venom. We examined the antitumor effect of CR-LAAO in Bcr-Abl(+) cell lines and peripheral blood mononuclear cells (PBMC) from healthy subjects and CML patients. CR-LAAO was more cytotoxic towards Bcr-Abl(+) cell lines than towards healthy subjects' PBMC. The H2O2 produced during the enzymatic action of CR-LAAO mediated its cytotoxic effect. The CR-LAAO induced apoptosis in Bcr-Abl(+) cells, as detected by caspases 3, 8, and 9 activation, loss of mitochondrial membrane potential, and DNA damage. CR-LAAO elicited apoptosis in PBMC from CML-CP patients without TKI treatment more strongly than in PBMC from healthy subjects and TKI-treated CML-CP and CML-AP patients. The antitumor effect of CR-LAAO against Bcr-Abl(+) cells makes this toxin a promising candidate to CML therapy.

Análise dos custos de medicamentos no tratamento das dislipidemias em Ribeirão Preto, SP, Brasil / Analysis of dyslipidemia treatment drug costs in Ribeirão Preto, São Paulo State, Brasil

Fundamentos: As dislipidemias representam importante fator de risco para o desenvolvimento de doençascardiovasculares, comprovado por meio de grandes estudos observacionais.Objetivo: Analisar os custos de utilização de atorvastatina, sinvastatina, bezafibrato e ciprofibrato por indivíduospertencentes ao Programa de Medicamentos Excepcionais do Ministério da Saúde, distribuídos pelo Hospital das Clínicas de Ribeirão Preto, SP, Brasil, em 2007. Métodos: Estudo observacional, descritivo e de carátertransversal. Casuística composta por 332 (31,11%) indivíduos sorteados aleatoriamente dentre 1067 pacientes, de ambos os sexos, encaminhados pelo Sistema Único de Saúde (SUS) e consultórios particulares. Os indivíduos foram entrevistados e seus prontuáriosmédicos analisados. Resultados: Dos 312 pacientes entrevistados, 157 (51%) eram do sexo masculino. A faixa etária variou de 15-63 anos (62,0±12,23 anos). Fizeram uso de estatinas 227 (73,22%) pacientes; 54 (17,42%) de fibratos e 31 (10%)pacientes formavam o grupo-controle. O tratamento do grupo atorvastatina apresentou o maior custo (R$994,69paciente/ano), já no grupo da sinvastatina (R$337,61 paciente/ano) houve maiores gastos com exameslaboratoriais e complementares. No grupo dos fibratos, a categoria de medicamentos foi a que gerou maiorgasto em ambos os grupos. Os pacientes do grupo ciprofibrato apresentaram mais necessidade de exameslaboratoriais e complementares em relação ao grupo bezafibrato.Conclusões: O tratamento com atorvastatina foi o mais oneroso, entretanto, os pacientes apresentaram menor ocorrência de eventos e procedimentos cardiovasculares, além do menor custo com exames laboratoriais.