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Smith CC Wang Q Chin CS Salerno S Damon LE Levis MJ Perl AE Travers KJ Wang S Hunt JP Zarrinkar PP Schadt EE Kasarskis A Kuriyan J Shah NP 《Nature》2012,485(7397):260-263
Effective targeted cancer therapeutic development depends upon distinguishing disease-associated 'driver' mutations, which have causative roles in malignancy pathogenesis, from 'passenger' mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis. Abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts. 相似文献
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Factor stimulating transcription by RNA polymerase 总被引:106,自引:0,他引:106
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The RNA polymerase mutation, alt-1, affects the sigma subunit and alters the in vitro selectivity of RNA polymerase to parallel the in vivo phenotype. We propose that the mutation changes the distribution of functionally distinct polymerase isomers. 相似文献
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Bacteriophage sigma factor for RNA polymerase 总被引:17,自引:0,他引:17
A A Travers 《Nature》1969,223(5211):1107-1110
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Homozygotes for Huntington's disease 总被引:5,自引:0,他引:5
N S Wexler A B Young R E Tanzi H Travers S Starosta-Rubinstein J B Penney S R Snodgrass I Shoulson F Gomez M A Ramos Arroyo 《Nature》1987,326(6109):194-197
Careful comparison of symptomatic individuals with normal controls has revealed the primary biochemical abnormality in many human genetic diseases, particularly recessive disorders. This strategy has proved less successful for most human disorders which are not recessive, and where a single copy of the aberrant gene has clinically significant effects even though the normal gene product is present. An alternative approach that eliminates the impediment of a normal protein in affected individuals is to study homozygotes for the mutant allele. For virtually all dominant human disorders in which homozygotes have been described, symptoms have been significantly more severe in the homozygote than in the heterozygote. Thus, these disorders do not conform to the classical definition of dominance which states that homozygotes and heterozygotes for a defect are phenotypically indistinguishable. Instead, they display incomplete dominance, indicating that the normal allele may play a role in ameliorating the disease process. The D4S10 locus, defined by the probe G8 and linked to the gene for Huntington's disease (HD), has permitted us to identify individuals with a high probability of being homozygous for this autosomal dominant neurodegenerative disorder. These homozygotes do not differ in clinical expression or course from typical HD heterozygotes. HD appears to be the first human disease of genetically documented homozygosity that displays complete phenotypic dominance. 相似文献
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Control of ribosomal RNA synthesis in vitro 总被引:21,自引:0,他引:21
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G Alonso J Gabrion F Travers N Van Thoa? I Assenmacher 《Comptes rendus des séances de l'Académie des sciences. Série D, Sciences naturelles》1979,288(19):1473-1478
Incubation of rat neural lobes with heavy meromyosin (HMM) after prolonged glycerination, induced characteristic arrowhead decoration of a number of microfilaments at different levels of the neurosecretory axons. In non terminal sections of axons the labelled microfilaments showed preferential relationships with microtubules in addition to occasional contacts with the axolemma and various axonal organelles. In axonal endings, they were mainly associated to microvesicles and appeared to be anchored on the axolemma facing the perivascular space at the level of membranous densifications. 相似文献