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941.
Patrice Dubreuil Sébastien Letard Marco Ciufolini Laurent Gros Martine Humbert Nathalie Castéran Laurence Borge Bérengère Hajem Anne Lermet Wolfgang Sippl Edwige Voisset Michel Arock Christian Auclair Phillip S. Leventhal Colin D. Mansfield Alain Moussy Olivier Hermine 《PloS one》2009,4(9)
Background
The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT.Methodology/Principal Findings
In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC50) of 200±40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC50 of 150±80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant.Conclusions
Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity. 相似文献942.
943.
贵州兴义中三叠世 Nothosaurus一新种 总被引:8,自引:4,他引:8
记述了贵州兴义法郎组竹竿坡段幻龙一新种———Nothosaurusyoungisp .nov .。新种以眶后弓窄 ,上颌骨和眶后骨在轭骨之后相连 ,外翼骨形成明显的腹向凸缘 ,下颌具清晰的冠状突 ,和夹板骨前端进入下颌缝合部等特征区别于幻龙的其他种。支序分析的结果表明N .youngi的原始性仅次于N .juvenilis。新种N .youngi具有Nothosaurus中的一些原始特征 ,短的下颌缝合部 ,短的上颌齿列和窄的眶后弓 ,新种在法郎组竹杆坡段的发现支持含化石地层为中三叠世拉丁期的结论。 相似文献
944.
Tabary O Corvol H Boncoeur E Chadelat K Fitting C Cavaillon JM Clément A Jacquot J 《American journal of physiology. Lung cellular and molecular physiology》2006,290(3):L588-L596
Persistent presence of PMN in airways is the hallmark of CF. Our aim was to assess PMN adherence, percentage of apoptotic airway PMN (aPMN), and IL-6 and IL-8 production when aPMN are in contact with airway epithelial cells. Before coculture, freshly isolated CF aPMN have greater spontaneous and TNF-alpha-induced apoptosis compared with blood PMN from the same CF patients and from aPMN of non-CF patients. We then examined cocultures of PMN isolated from CF and non-CF airways with bronchial epithelial cells bearing mutated cftr compared with cftr-corrected bronchial epithelial cells. After 18-h coculture, the number of CF aPMN adhered on cftr-deficient bronchial epithelial cells was 2.3-fold higher compared with the coculture of non-CF aPMN adhered on cftr-corrected bronchial epithelial cells. The percentage of CF apoptotic aPMN (9.5 +/- 0.2%) adhered on cftr-deficient bronchial epithelial cells was similar to the percentage of non-CF apoptotic aPMN adhered on cftr-corrected bronchial epithelial cells (10.3 +/- 0.7%). IL-6 and IL-8 levels were enhanced 6.5- and 2.9-fold, respectively, in coculture of CF aPMN adhered on cftr-deficient bronchial epithelial cells compared with coculture of non-CF aPMN adhered on cftr-corrected bronchial epithelial cells. Moreover, blocking surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on cftr-deficient bronchial epithelial cells with specific MAbs inhibited the adherence of CF aPMN by 64, 51, and 50%, respectively. Our data suggest that in CF patients a high number of nonapoptotic PMN adhered on airway epithelium associated with elevated IL-6 and IL-8 levels may contribute to sustained and exaggerated inflammatory response in CF airways. 相似文献
945.
946.
Destaing O Planus E Bouvard D Oddou C Badowski C Bossy V Raducanu A Fourcade B Albiges-Rizo C Block MR 《Molecular biology of the cell》2010,21(23):4108-4119
Invadosomes are adhesion structures involved in tissue invasion that are characterized by an intense actin polymerization–depolymerization associated with β1 and β3 integrins and coupled to extracellular matrix (ECM) degradation activity. We induced the formation of invadosomes by expressing the constitutive active form of Src, SrcYF, in different cell types. Use of ECM surfaces micropatterned at the subcellular scale clearly showed that in mesenchymal cells, integrin signaling controls invadosome activity. Using β1−/− or β3−/− cells, it seemed that β1A but not β3 integrins are essential for initiation of invadosome formation. Protein kinase C activity was shown to regulate autoassembly of invadosomes into a ring-like metastructure (rosette), probably by phosphorylation of Ser785 on the β1A tail. Moreover, our study clearly showed that β1A links actin dynamics and ECM degradation in invadosomes. Finally, a new strategy based on fusion of the photosensitizer KillerRed to the β1A cytoplasmic domain allowed specific and immediate loss of function of β1A, resulting in disorganization and disassembly of invadosomes and formation of focal adhesions. 相似文献
947.
Riparian habitats are particularly prone to invasion of non-indigenous plant species and several species have been shown to
rapidly expand their range along river networks, possibly mediated by the occurrence of frequent long-distance seed dispersal
events. However, there is still relatively little empirical evidence for long-distance seed dispersal along river networks
and most studies to date are inconclusive with regards to the direction (upstream vs. downstream) of seed movement. Using
assignment analyses based on dominant AFLP markers, we provide empirical evidence that downstream long-distance seed dispersal
has facilitated range expansion of the exotic plant Sisymbrium austriacum along the Meuse River. Of 242 sampled individuals, 13 (5.4%) were allocated to a population other than the one from which
it was sampled. Of these, nine (3.7%) individuals were assigned to a known population within the area, the furthest being
more than 20 km away from the population from which it was sampled. All putative source populations were located upstream,
thus providing strong evidence for downstream migration of propagules. These results support the general view that river systems
may serve as efficient transport vectors of plant species and thus may play an important role in increasing the spatial spread
and range expansion of exotic plant species. 相似文献
948.
949.
TCP Transcription Factors Predate the Emergence of Land Plants 总被引:4,自引:0,他引:4
950.
Cyclosporin A (CsA) generates superoxide in smooth muscle cells. Our earlier studies have demonstrated that the increase in the vasopressin type 1 receptor induced in vascular smooth muscle cells in the presence of CsA is probably due to superoxide (Krauskopf et al., J Biol Chem 278, 41685-41690, 2003). This increase in vasopressin receptor is likely at the base of increased vascular responsiveness to vasoconstrictor hormones and hypertension induced by CsA. Here, we demonstrate that CsA produces superoxide. In addition, our data show that superoxide generation does not originate from the major cellular superoxide generating systems NAD(P)H oxidase or xanthine oxidase. Our results suggest that the side effects of CsA could be diminished with the help of SOD mimetic drugs. 相似文献