RESUMO
MK-0457, an Aurora kinase and BCR-ABL inhibitor, was studied on a Phase I/II study in 77 patients with refractory hematologic malignancies. The average number of cycles per patient was 3 (range 1-21). Maximum tolerated doses for a 5-day short infusion and continuous infusion regimens were 40 mg/m(2)/h and 144 mg/m(2)/h, respectively. Drug-related adverse events (AEs) included transient mucositis and alopecia. Eight of 18 patients with BCR-ABL T315I-mutated chronic myelogenous leukemia (44%) had hematologic responses and one of three patients (33%) with Philadelphia chromosome-positive acute lymphoblastic leukemia obtained complete remission. MK-0457 has important activity in patients with leukemias expressing the highly resistant T315I BCR-ABL mutation.
Assuntos
Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação/genética , Piperazinas/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aurora Quinases , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Indução de Remissão , Adulto JovemRESUMO
The rate of nuclear muon capture by the proton has been measured using a new technique based on a time projection chamber operating in ultraclean, deuterium-depleted hydrogen gas, which is key to avoiding uncertainties from muonic molecule formation. The capture rate from the hyperfine singlet ground state of the microp atom was obtained from the difference between the micro(-) disappearance rate in hydrogen and the world average for the micro(+) decay rate, yielding Lambda(S)=725.0+/-17.4 s(-1), from which the induced pseudoscalar coupling of the nucleon, g(P)(q(2)=-0.88m(2)(micro))=7.3+/-1.1, is extracted.
Assuntos
Linfoma de Células B/patologia , Pinealoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Progressão da Doença , Evolução Fatal , Fadiga/etiologia , Feminino , Humanos , Dor Lombar/etiologia , Linfoma de Células B/tratamento farmacológico , Imageamento por Ressonância Magnética , Transtornos da Memória/etiologia , Pinealoma/tratamento farmacológicoRESUMO
P-selectin is a multidomain adhesion protein on the surface of activated platelets and endothelial cells that functions in the recruitment of leukocytes to the site of inflammation. The amino-terminal lectin and EGF domains constitute the ligand recognition unit. We have produced a synthetic 40-residue P-selectin EGF domain (P-sel:EGF) to examine the structure and function of this domain independent of P-selectin. The peptide was folded in vitro and exhibited the same disulfide bonding pattern as other EGF-like domains. P-sel:EGF did not inhibit P-selectin-mediated cellular adhesion assays, indicating that the lectin domain is also required. We undertook the study of the P-selectin EGF by 1H NMR to determine its structure independent of the lectin domain and to compare its structure to that of E-selectin determined crystallographically [Graves et al. (1994) Nature 367, 532]. Although the binding of P-selectin to its carbohydrate ligand is calcium dependent, and some EGF domains have calcium binding sites, addition of calcium had no effect on the NMR spectrum or on the pH-induced changes. Nearly complete resonance assignments were made from 2D 1H NMR spectra at pH 6.0. Two sections of antiparallel beta-sheet were identified on the basis of the pattern of long-range NOEs, 3JHN alpha coupling constants, and slowly exchanging amides. The solution structure of the peptide backbone was determined using distance geometry and simulated annealing calculations. The backbone RMSD to the geometric average for 19 final structures is 0.64 +/- 0.17 A. The resulting fold closely resembles that of other EGF-like peptides, including the E-selectin EGF domain (RMSD approximately 1.08 A). However, compared to the E-selectin EGF structure which also contains the lectin domain, some residues from 1-11 are less ordered, and novel contacts occur between the amino terminus and the core beta-sheet. Despite marked structural homology of the selectin polypeptide backbones, the selectin EGF surfaces show unique distributions of charged residues, a feature that likely correlates to the functional differences.
Assuntos
Fator de Crescimento Epidérmico/química , Selectina-P/química , Sequência de Aminoácidos , Cálcio/metabolismo , Adesão Celular/efeitos dos fármacos , Cristalografia por Raios X , Dissulfetos/química , Selectina E/química , Leucócitos/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Dados de Sequência Molecular , Selectina-P/metabolismo , Selectina-P/farmacologia , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Conformação Proteica , Dobramento de Proteína , Estrutura Secundária de Proteína , Termolisina/metabolismoRESUMO
The gamma-carboxyglutamic acid-rich domain of blood coagulation Factor IX is required for the binding of the protein to phospholipid membranes. To investigate the three-dimensional structure of this domain, a synthetic peptide corresponding to residues 1-47 of Factor IX was studied by 1H NMR spectroscopy. In the absence of metal ions, the proton chemical shift dispersion in the one-dimensional NMR spectrum indicated that the peptide contains regular structural elements. Upon the addition of Ca(II) or Mg(II), large chemical shift changes were observed in the amide proton and methyl proton regions of the spectrum, consistent with the conformational transitions that metal ions are known to induce in native Factor IX. The apopeptide was studied by two-dimensional NMR spectroscopy at 500 MHz to determine its solution structure. Protons were assigned using total correlation spectroscopy, nuclear Overhauser effect spectroscopy, and double quantum-filtered correlation spectroscopy experiments. Intensities of cross-peaks in the nuclear Overhauser effect spectrum were used to generate a set of interproton distance restraints. The structure of the apopeptide was then calculated using distance geometry methods. There are three structural elements in the apopeptide that are linked by a flexible polypeptide backbone. These elements include a short amino-terminal tetrapeptide loop (amino acids 6-9), the disulfide-containing hexapeptide loop (amino acids 18-23), and a carboxyl-terminal alpha helix (amino acids 37-46). Amide hydrogen exchange kinetics indicate that the majority of the peptide is solvent accessible, except in the carboxyl-terminal element. The structured regions in the apopeptide are insufficient to support phospholipid binding, indicating the importance of additional structural features in the Ca(II)-stabilized conformer.
Assuntos
Ácido 1-Carboxiglutâmico/metabolismo , Fator X/metabolismo , Sequência de Aminoácidos , Membrana Celular/metabolismo , Fator X/química , Cinética , Espectroscopia de Ressonância Magnética/métodos , Metais , Dados de Sequência Molecular , Conformação ProteicaRESUMO
The effect of heat shock on the expression of the nuclear protooncogenes c-fos, c-jun, and c-myc was studied in human lymphoid cells. Heat shock caused an increase in c-fos and c-jun mRNA levels and a decrease in c-myc mRNA levels in pre-B (Hyon) and T (DND-41) cell lines as well as in freshly isolated normal human thymocytes. The changes in the mRNA levels of these protooncogenes in Hyon cells were most pronounced at 42 and 43 degrees C; kinetic analysis demonstrated that the changes could be detected within 30 min of heat shock. Altered transcription of c-fos and c-myc genes was the primary effect of heat shock. Secondarily, heat shock of Hyon cells stabilized the c-myc mRNA level by increasing its half-life from 24 to 45 min. The overall effect of heat shock on c-myc mRNA level, however, was a marked inhibition of its transcription. These results demonstrate that the transcription of nuclear protooncogenes is regulated by heat shock indicating a role for nuclear protooncogenes in the stress response of lymphoid cells.