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111.
Brahimi F Matheson SL Dudouit F McNamee JP Tari AM Jean-Claude BJ 《The Journal of pharmacology and experimental therapeutics》2002,303(1):238-246
The Combi-Targeting concept postulates that a molecule termed combi-molecule (C-molecule) with binary epidermal growth factor receptor (EGFR) targeting/DNA-damaging properties and with the ability to be hydrolyzed to another EGFR inhibitor should induce sustained antiproliferative activity in cells overexpressing EGFR. Because we postulate that the EGFR affinity of the C-molecule and that of its hydrolytic metabolites are critical parameters for sustained potency against EGFR-overexpressing cells, we synthesized BJ2000 (IC(50) = 0.1 microM, competitive binding at ATP site), a novel C-molecule that can decompose into a 6-amino-4-anilinoquinazoline FD105 (IC(50) = 0.2 microM). Studies using the EGFR-overexpressing A431 cells revealed that BJ2000 could damage DNA and block epidermal growth factor-stimulated EGFR autophosphorylation by a partially irreversible mechanism. Blockade of EGFR autophosphorylation subsequently induced inhibition of mitogen-activated protein kinase activation and c-fos gene expression. Enzyme-linked immunosorbent assay and growth factor-mediated stimulation of proliferation assays in the EGFR-expressing NIH3T3HER14 demonstrated the preferential EGFR-targeting properties of BJ2000, and more importantly suggest that blockade of EGFR phosphorylation by this drug translate into significant growth inhibitory effects. These properties culminated into irreversible antiproliferative effects as confirmed by a sulforhodamine B assay. Five days after a 2-h treatment, BJ2000 retained significant antiproliferative effect in A431 cells, whereas its reversible metabolite FD105 almost completely lost its activity. This result in toto lend support to the Combi-Targeting concept according to which a molecular conjugate kept small enough to interact with EGFR and designed to degrade into another inhibitor of the same target plus a DNA-damaging species may induce sustained growth inhibitory effect in EGFR-overexpressing cells. 相似文献
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Hélène Desqueyroux Jean-Claude Pujet Michel Prosper Yvon Le Moullec Isabelle Momas 《Archives of environmental & occupational health》2013,68(6):554-560
Few studies have been conducted on the effects of air pollution on patients with chronic obstructive pulmonary disease (COPD). During a 14-mo period, 39 Parisian adults with severe COPD were monitored by their physicians. Daily levels of 4 air pollutants were provided by an urban air-quality network. Exacerbation of COPD was associated only with ozone (O3) (odds ratio [OR] = 1.44 for a 10-μg/m3 increase in O3; 95% confidence interval [Cl] = 1.14, 1.82), with a lag of 2-3 days. The effect of O3 was greater in patients whose carbon dioxide pressure (PaCO2) was higher than 43 mm Hg (OR = 1.83; 95% Cl = 1.36, 2.47) vs. those with a lower PaCO2 (OR = 1.26; 95% Cl = 0.90, 1.77). The effect of O3 was unchanged, regardless of the maintenance medications used. The only air pollutant to which patients with severe COPD were particularly sensitive was O3. 相似文献
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Pierre-Antoine Chabriac Antonin Fabbri Jean-Claude Morel Jean-Paul Laurent Joachim Blanc-Gonnet 《Materials》2014,7(4):3002-3020
Rammed earth is a sustainable material with low embodied energy. However, its development as a building material requires a better evaluation of its moisture-thermal buffering abilities and its mechanical behavior. Both of these properties are known to strongly depend on the amount of water contained in wall pores and its evolution. Thus the aim of this paper is to present a procedure to measure this key parameter in rammed earth or cob walls by using two types of probes operating on the Time Domain Reflectometry (TDR) principle. A calibration procedure for the probes requiring solely four parameters is described. This calibration procedure is then used to monitor the hygrothermal behavior of a rammed earth wall (1.5 m × 1 m × 0.5 m), instrumented by six probes during its manufacture, and submitted to insulated, natural convection and forced convection conditions. These measurements underline the robustness of the calibration procedure over a large range of water content, even if the wall is submitted to quite important temperature variations. They also emphasize the importance of gravity on water content heterogeneity when the saturation is high, as well as the role of liquid-to-vapor phase change on the thermal behavior. 相似文献
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The neuromuscular fatigue induced by repeated scrums generates instability that can be limited by appropriate recovery 下载免费PDF全文
The aim of this study was to evaluate the influence of the fatigue on the machine scrum pushing sagittal forces during repeated scrums and to determine the origin of the knee extensor fatigue. Twelve elite U23 rugby union front row players performed six 6-s scrums every 30 s against a dynamic scrum machine with passive or active recovery. The peak, average, and the standard deviation of the force were measured. A neuromuscular testing procedure of the knee extensors was carried out before and immediately after the repeated scrum protocol including maximal voluntary force, evoked force, and voluntary activation. The average and peak forces did not decrease after six scrums with passive recovery. The standard deviation of the force increased by 70.2 ± 42.7% (P < 0.001). Maximal voluntary/evoked force and voluntary activation decreased (respectively 25.1 ± 7.0%, 14.6 ± 5.5%, and 24 ± 9.9%; P < 0.001). The standard deviation of the force did not increase with active recovery and was associated with lower decrease of maximal voluntary/evoked force and voluntary activation (respectively 12.8 ± 7.9%, 4.9 ± 6.5%, and 7.6 ± 4.1%; all P < 0.01). As a conclusion repeated scrummaging induced an increased machine scrum pushing instability associated with central and peripheral fatigue of the knee extensors. Active recovery seems to limit all these manifestations of fatigue. 相似文献
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