Objectives
The classical multidrug resistance (MDR) gene MDR1 (ABCB1) encodes for the drug efflux pump P‐glycoprotein (P‐gp). P‐gp expression is an adverse prognostic factor for treatment outcome in ...acute myeloid leukemia (AML) and is more frequently observed in older patients. Single‐nucleotide polymorphisms of the ABCB1 gene, C1236T, G2677T, and C3435T, have been associated with altered drug metabolism and treatment outcome. We prospectively determined these single‐nucleotide polymorphisms in AML blasts in a cohort of patients aged 60 years or older with AML and evaluated their relevance with regard to P‐gp function and expression, ABCB1 messenger ribonucleic acid (mRNA) expression, and clinical outcome.
Methods
We have analyzed purified bone marrow‐derived leukemic blasts, obtained at diagnosis, in 150 patients who were treated within a multicenter, randomized, phase 3 trial of elderly patients with AML. The significance of the allelic ABCB1 variants of C1236T, G2677T, and C3435T was evaluated with respect to P‐gp expression and function in leukemic blasts and ABCB1 mRNA expression levels, and these values were correlated with treatment outcome.
Results
P‐gp function and expression in leukemic blasts and ABCB1 mRNA levels in patients with AML did not vary significantly among any of the allelic variants of ABCB1. None of these allelic variations predicted a difference in complete response rate and survival endpoints.
Conclusions
In AML patients aged 60 years or older, allelic ABCB1 variations of C1236T, G2677T, or C3435T are not associated with altered P‐gp function or with MDR1 expression at the transcriptional or translational level in leukemic blasts, and they do not significantly affect clinical prognosis.
Clinical Pharmacology & Therapeutics (2006) 80, 427–439; doi: 10.1016/j.clpt.2006.07.005
The configuration of almost all silicon microstrip sensors instrumenting the tracker detectors of the current experiments in LHC is with readout from implanted p-strips on n-type silicon bulk (from ...300 to
400
μ
m
thick). The performance of these sensors will change with the irradiation and the time after irradiation (annealing). The effect of the annealing on the performance of the tracking devices has been a source of concern for the experiments due to the rise of the full depletion voltage with time. The experiments have anticipated to suppress annealing effects by keeping the sensors at low temperature also outside operation time. In fact, a scenario that allows a certain amount of annealing could be advantageous for running the silicon sensors towards the end of the experiment lifetime when the readout signal starts to be sensitively degraded. A new set of measurements of the full depletion voltage and charge collection as a function of annealing time with miniature silicon microstrip sensors is presented here and discussed in view of possible annealing scenarios.
The expression of P-glycoprotein (P-gp), encoded by theMDR1 gene, is an independent adverse prognostic factor for response and survival in de novo acute myeloid leukemia (AML). Little is known about ...MDR1 expression during the development of disease. The present study investigated whether MDR1 gene– related clonal selection occurs in the development from diagnosis to relapsed AML, using a genetic polymorphism of the MDR1 gene at position 2677. Expression and function of P-gp were studied using monoclonal antibodies MRK16 and UIC2 and the Rhodamine 123 retention assay with or without PSC 833. No difference was found in the levels of P-gp function and expression between diagnosis and relapse in purified paired blast samples from 30 patients with AML. Thirteen patients were homozygous for the genetic polymorphism ofMDR1 (n = 7 for guanine, n = 6 for thymidine), whereas 17 patients were heterozygous (GT). In the heterozygous patients, no selective loss of one allele was observed at relapse. Homozygosity for the MDR1 gene (GG or TT) was associated with shorter relapse-free intervals (P = .002) and poor survival rates (P = .02), compared with heterozygous patients. No difference was found in P-gp expression or function in patients with AML with either of the allelic variants of the MDR1 gene. It was concluded that P-gp function or expression is not upregulated at relapse/refractory disease and expression of one of the allelic variants is not associated with altered P-gp expression or function in AML, consistent with the fact that MDR1 gene–related clonal selection does not occur when AML evolves to recurrent disease.
Antineutrophil cytoplasmic autoantibodies (ANCA) have been described in sera of patients with several forms of systemic vasculitis, including Wegener's granulomatosis and microscopic polyarteritis. ...The two main targets of ANCA in vasculitis are proteinase 3 (PR3) and myeloperoxidase (MPO). ANCA are capable of activating neutrophils primed by tumor necrosis factor-α (TNF-α) in vitro, which may be relevant for the induction of the vascular inflammation observed in vivo. Recently, it has been suggested that engagement of Fcγ receptor IIa (FcγRlla) on the neutrophils is involved in the activation by ANCA. In the present study, we show that activation of the neutrophil respiratory burst by anti-PR3 and anti-MPO is strongly enhanced after TNF priming and lost on removal of the Fc parts of the antibodies. Similar results were obtained when the neutrophils were activated with antibodies against known membrane antigens without major changes in the expression of the target antigens. The TNF-induced enhancement of the neutrophil activation was not observed when adherence of the cells was prevented by continuous stirring of the suspension or by the addition of CD18 antibodies before TNF exposure. Hence, our results indicate that engagement of both FcγRlla and β2 integrins is instrumental in neutrophil activation induced by ANCA.
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