RESUMO
The efficacy of azacitidine has been demonstrated in acute myeloid leukemia (AML) patients with 20-30% bone marrow (BM) blasts, but limited data is available on patients with ≥30% blasts. We analyzed 55 newly diagnosed AML patients, treated with azacitidine. The overall response rate was 42%. Median overall survival (OS) was 12.3 months. We confirmed poor-risk cytogenetics, therapy-related AML, performance score ≥2, and white blood cell count ≥15×10(9)/L as independent adverse predictors for OS. The BM blast percentage, however, had no impact on OS (P=0.55). In conclusion, administration of azacitidine is effective in AML patients with 20-30% and >30% BM blasts.
Assuntos
Azacitidina/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Azacitidina/administração & dosagem , Medula Óssea/patologia , Células da Medula Óssea/patologia , Contagem de Células , Ensaios de Uso Compassivo , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide/sangue , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Indução de Remissão , Estudos RetrospectivosRESUMO
Glial cell-line-derived neurotrophic factor (GDNF), neurturin and persephin are neurotrophic factors involved in neuroneal differentiation, development and maintenance. They act on different types of neuroneal cells and signal through a receptor complex composed of a specific ligand-binding subunit of the GDNF family receptor alpha (GFRalpha) family together with a common signaling partner, the cRET protein tyrosine kinase. We describe the molecular cloning, expression, chromosomal localization and functional characterization of enovin, a fourth GDNF family member almost identical to the recently described artemin. We show the occurence in most tissues of several differently spliced mRNA variants for enovin, of which only two are able to translate into functional enovin protein. Some tissues seem to express only nonfunctional transcripts. These observations may underlie a complex transcriptional regulation pattern. Enovin mRNA expression is detectable in all adult and fetal human tissues examined, but expression levels are highest in peripheral tissues including prostate, placenta, pancreas, heart and kidney. This tissue distribution pattern is in accordance with that of GFRalpha-3, which here is shown to be the preferred ligand-binding receptor for enovin (Kd = 3.1 nM). The human enovin gene is localized on chromosome 1, region p31.3-p32. In vitro, enovin stimulates neurite outgrowth and counteracts taxol-induced neurotoxicity in staurosporine-differentiated SH-SY5Y human neuroblastoma cells. The peripheral expression pattern of enovin and its receptor together with its effects on neuroneal cells suggest that enovin might be useful for the treatment of neurodegenerative diseases in general and peripheral neuropathies in particular.
Assuntos
Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Adulto , Processamento Alternativo , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Clonagem Molecular , Primers do DNA/genética , DNA Complementar/genética , Escherichia coli/genética , Feminino , Expressão Gênica , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial , Humanos , Hibridização in Situ Fluorescente , Masculino , Dados de Sequência Molecular , Fatores de Crescimento Neural/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Gravidez , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Distribuição TecidualRESUMO
Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. The gene coding for human prostate-specific membrane antigen, a marker of prostatic carcinomas, and its rat homologue glutamate carboxypeptidase II have recently been shown to possess such NAALADase activity. In contrast, a closely related member of this gene family, rat ileal 100-kDa protein, possesses a dipeptidyl peptidase IV activity. Here, we describe the cloning of human ileal 100-kDa protein, which we have called a NAALADase- "like" (NAALADase L) peptidase based on its sequence similarity to other members of this gene family, and its inability to hydrolyze NAAG in transient transfection experiments. Furthermore, we describe the cloning of a third novel member of this gene family, NAALADase II, which codes for a type II integral membrane protein and which we have localized to chromosome 11 by fluorescent in situ hybridization analysis. Transient transfection of NAALADase II cDNA confers both NAALADase and dipeptidyl peptidase IV activity to COS cells. Expression studies using reverse transcription-polymerase chain reaction and Northern blot hybridization show that NAALADase II is highly expressed in ovary and testis as well as within discrete brain areas.
