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91.
Nazarian R Shi H Wang Q Kong X Koya RC Lee H Chen Z Lee MK Attar N Sazegar H Chodon T Nelson SF McArthur G Sosman JA Ribas A Lo RS 《Nature》2010,468(7326):973-977
Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ~7% of human malignancies and ~60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies. 相似文献
92.
Evidence for lateral gene transfer between Archaea and bacteria from genome sequence of Thermotoga maritima. 总被引:27,自引:0,他引:27
K E Nelson R A Clayton S R Gill M L Gwinn R J Dodson D H Haft E K Hickey J D Peterson W C Nelson K A Ketchum L McDonald T R Utterback J A Malek K D Linher M M Garrett A M Stewart M D Cotton M S Pratt C A Phillips D Richardson J Heidelberg G G Sutton R D Fleischmann J A Eisen O White S L Salzberg H O Smith J C Venter C M Fraser 《Nature》1999,399(6734):323-329
The 1,860,725-base-pair genome of Thermotoga maritima MSB8 contains 1,877 predicted coding regions, 1,014 (54%) of which have functional assignments and 863 (46%) of which are of unknown function. Genome analysis reveals numerous pathways involved in degradation of sugars and plant polysaccharides, and 108 genes that have orthologues only in the genomes of other thermophilic Eubacteria and Archaea. Of the Eubacteria sequenced to date, T. maritima has the highest percentage (24%) of genes that are most similar to archaeal genes. Eighty-one archaeal-like genes are clustered in 15 regions of the T. maritima genome that range in size from 4 to 20 kilobases. Conservation of gene order between T. maritima and Archaea in many of the clustered regions suggests that lateral gene transfer may have occurred between thermophilic Eubacteria and Archaea. 相似文献
93.
D. S. Nelson S. Kossaŕd Prudence E. Cox 《Cellular and molecular life sciences : CMLS》1967,23(6):490-491
Résumé Des souris immunisés avec des globules rouges de mouton dans l'adjuvant de Freund produisent deux types de facteurs cytophiles pour macrophages. L'un s'attache aux macrophages trypsinisées et se trouve parmi les immunoglobulines. L'autre ne s'attache pas aux macrophages trypsinisées et se rencontre dans une fraction de sérum contenant de l'albumine et de la globuline-1.
Supported by grants from the Australian Research Grants Committee, the National Health and Medical Research Council of Australia and the Postgraduate Medical Foundation, University of Sydney. 相似文献
Supported by grants from the Australian Research Grants Committee, the National Health and Medical Research Council of Australia and the Postgraduate Medical Foundation, University of Sydney. 相似文献
94.
Wild howler monkeys (Alouatta palliata) get most of their calories from carbohydrates (65%) and fats (18%) of native tropical plants, but little is known about their intake of individual fatty acids. The fatty acid composition of several natural food sources of howler monkeys collected in Panama was determined by gas-liquid chromatography. The predominant fatty acids were palmitic (30%), linoleic (23%), linoleic (23%), -linolenic (16%) and oleic (15%). Fatty acids with less than 16, and more than 18, carbon chains were uncommon (0–7%). Although total saturated fatty acids were high in some specific food sources (22–54% of total fatty acids and 8 energy %), most of the calories from fat in the animals' diets are derived from mono-and polyunsaturated fatty acids (9.75 energy %) All food sources had significant amounts of the -3 fatty acid, -linolenic acid (2.9 energy %). In terms of human diets, the howler monkey's fat consumption would not be considered atherogenic. Unless these animals show a particular adverse susceptibility to dietary fat, it is unlikely that their fat intake is the primary cause of the low, but significant, incidence of atherosclerosis that develops in these animals in the wild state. 相似文献
95.
The evolutionary interaction between influenza A virus and the human immune system, manifest as 'antigenic drift' of the viral haemagglutinin, is one of the best described patterns in molecular evolution. However, little is known about the genome-scale evolutionary dynamics of this pathogen. Similarly, how genomic processes relate to global influenza epidemiology, in which the A/H3N2 and A/H1N1 subtypes co-circulate, is poorly understood. Here through an analysis of 1,302 complete viral genomes sampled from temperate populations in both hemispheres, we show that the genomic evolution of influenza A virus is characterized by a complex interplay between frequent reassortment and periodic selective sweeps. The A/H3N2 and A/H1N1 subtypes exhibit different evolutionary dynamics, with diverse lineages circulating in A/H1N1, indicative of weaker antigenic drift. These results suggest a sink-source model of viral ecology in which new lineages are seeded from a persistent influenza reservoir, which we hypothesize to be located in the tropics, to sink populations in temperate regions. 相似文献
96.
A long-standing issue in ecology is reconciling the apparent stability of many populations with robust predictions of large-amplitude population cycles from general theory on consumer-resource interactions. Even when consumers are decoupled from dynamic resources, large-amplitude cycles can theoretically emerge from delayed feedback processes found in many consumers. Here we show that resource-dependent mortality and a dynamic developmental delay in consumers produces a new type of small-amplitude cycle that coexists with large-amplitude fluctuations in coupled consumer-resource systems. A distinctive characteristic of the small-amplitude cycles is slow juvenile development for consumers, leading to a developmental delay that is longer than the cycle period. By contrast, the period exceeds the delay in large-amplitude cycles. These theoretical predictions may explain previous empirical results on coexisting attractors found in Daphnia-algal systems. To test this, we used bioassay experiments that measure the growth rates of individuals in populations exhibiting each type of cycle. The results were consistent with predictions. Together, the new theory and experiments establish that two very general features of consumers--a resource-dependent juvenile stage duration and resource-dependent mortality--combine to produce small-amplitude resource-consumer cycles. This phenomenon may contribute to the prevalence of small-amplitude fluctuations in many other consumer-resource populations. 相似文献
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The extracellular patch clamp technique developed by Neher et al. to record the responses of single channels in skeletal muscle has provided firm evidence for the two-state nature of the conductance event in nicotinic endplate channels. We report here the use of the extracellular patch technique to record single-channel responses from tissue-cultured chick skeletal muscle cells. The temperature dependence of channel conductance and gating kinetics shows no evidence of discontinuous behaviour between 17 and 37 degrees C. 相似文献