RESUMEN
In vitro CD40-stimulated chronic lymphocytic leukemia (CLL) cells are resistant to cytotoxic drugs. In sharp contrast, we here show that CD40 stimulation sensitizes CLL cells to rituximab-mediated cell death. This increased sensitivity is specific for anti-CD20 treatment. Rituximab-mediated death in CD40-stimulated CLL cells shows rapid kinetics (within hours), and is caspase and p53 independent, but depends on extracellular Ca(2+) and reactive oxygen species (ROS) production. By increasing basal ROS production, CD40 stimulation sensitizes CLL cells to rituximab-mediated death. Our findings provide a rationale for combination treatment of CLL with cytotoxic drugs and anti-CD20 monoclonal antibodies.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/farmacología , Antígenos CD40/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Antineoplásicos , Calcio , Muerte Celular/efectos de los fármacos , Humanos , Cinética , Especies Reactivas de Oxígeno/metabolismo , Rituximab , Células Tumorales CultivadasRESUMEN
We have developed a multilayer mirror for extreme ultraviolet (EUV) radiation that has low reflectance for IR radiation at 10.6 mum wavelength. The mirror is based on a multilayer coating comprising alternating layers of diamondlike carbon and silicon, for which we demonstrate an EUV reflectance of up to 49.7%. We have made a functional prototype in which the multilayer coating is included as part of an antireflection coating for IR radiation, resulting in reflectance values of 42.5% and 4.4% for EUV and IR, respectively. The mirror can replace a standard Mo/Si mirror in an EUV lithography tool to form an efficient solution for the suppression of unwanted CO(2) laser radiation.
RESUMEN
Seliciclib (R-roscovitine) is a cyclin-dependent kinase inhibitor in clinical development. It triggers apoptosis by inhibiting de novo transcription of the short-lived Mcl-1 protein, but it is unknown how this leads to Bax/Bak activation that is required for most forms of cell death. Here, we studied the effects of seliciclib in B-cell chronic lymphocytic leukemia (B-CLL), a malignancy with aberrant expression of apoptosis regulators. Although seliciclib-induced Mcl-1 degradation within 4 h, Bax/Bak activation occurred between 16 and 20 h. During this period, no transcriptional changes in apoptosis-related genes occurred. In untreated cells, prosurvival Mcl-1 was engaged by the proapoptotic proteins Noxa and Bim. Upon drug treatment, Bim was quickly released. The contribution of Noxa and Bim as a specific mediator of seliciclib-induced apoptosis was demonstrated via RNAi. Significantly, 16 h after seliciclib treatment, there was accumulation of Bcl-2, Bim and Bax in the 'mitochondria-rich' insoluble fraction of the cell. This suggests that after Mcl-1 degradation, the remaining apoptosis neutralizing capacity of Bcl-2 is gradually overwhelmed, until Bax forms large multimeric pores in the mitochondria. These data demonstrate in primary leukemic cells hierarchical binding and crosstalk among Bcl-2 members, and suggest that their functional interdependence can be exploited therapeutically.
Asunto(s)
Apoptosis , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteínas de Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Purinas/farmacología , Anciano , Anciano de 80 o más Años , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Línea Celular Tumoral , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Interferencia de ARN , Roscovitina , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
UNLABELLED: We evaluated the complement system in 29 children (mean age: 4.5 years) who survived fulminant meningococcal septic shock. No terminal complement deficiencies were found. One patient, who experienced the most dramatic disease course, had a decreased haemolytic activity in the haemolysis-in-gel test for the alternative pathway. The properdin concentration in serum of this patient was < 0.1 microgram/ml (n = 17.1-27.7 micrograms/ml). Coagulation studies revealed a heterozygeous type I protein C deficiency as well. He was the only patient with a Neisseria meningitidis group Y infection. CONCLUSION: Fulminant meningococcal disease due to uncommon serogroups should lead to screening of the alternative pathway of complement activation.