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51.
Ventura A Kirsch DG McLaughlin ME Tuveson DA Grimm J Lintault L Newman J Reczek EE Weissleder R Jacks T 《Nature》2007,445(7128):661-665
Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes. Mouse models of human cancers have recently demonstrated that continuous expression of a dominantly acting oncogene (for example, Hras, Kras and Myc) is often required for tumour maintenance; this phenotype is referred to as oncogene addiction. This concept has received clinical validation by the development of active anticancer drugs that specifically inhibit the function of oncoproteins such as BCR-ABL, c-KIT and EGFR. Identifying additional gene mutations that are required for tumour maintenance may therefore yield clinically useful targets for new cancer therapies. Although loss of p53 function is a common feature of human cancers, it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance. To explore this issue, we developed a Cre-loxP-based strategy to temporally control tumour suppressor gene expression in vivo. Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues. The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas. These results support efforts to treat human cancers by way of pharmacological reactivation of p53. 相似文献
52.
Mullen AR Wheaton WW Jin ES Chen PH Sullivan LB Cheng T Yang Y Linehan WM Chandel NS DeBerardinis RJ 《Nature》2012,481(7381):385-388
Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells. In normally functioning tumour cell mitochondria, oxidative metabolism of glucose- and glutamine-derived carbon produces citrate and acetyl-coenzyme A for lipid synthesis, which is required for tumorigenesis. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function, and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP(+)/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetyl-coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism. 相似文献
53.
Ralph A. A. Khan 《Cellular and molecular life sciences : CMLS》1978,34(12):1598-1600
Summary The influences of dilution, storage and pH on the distribution of 99m-technetium methylene diphosphonate (99m-Tc-MDP) in bone and various soft tissues have been investigated in the rat. The results show a marked departure from normality when large dilution factors and very acidic or basic preparations are used. 相似文献
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55.
Imaging in the era of molecular oncology 总被引:1,自引:0,他引:1
New technologies for imaging molecules, particularly optical technologies, are increasingly being used to understand the complexity, diversity and in vivo behaviour of cancers. 'Omic' approaches are providing comprehensive 'snapshots' of biological indicators, or biomarkers, of cancer, but imaging can take this information a step further, showing the activity of these markers in vivo and how their location changes over time. Advances in experimental and clinical imaging are likely to improve how cancer is understood at a systems level and, ultimately, should enable doctors not only to locate tumours but also to assess the activity of the biological processes within these tumours and to provide 'on the spot' treatment. 相似文献
56.
Electrons in atoms possess both spin and orbital degrees of freedom. In non-relativistic quantum mechanics, these are independent, resulting in large degeneracies in atomic spectra. However, relativistic effects couple the spin and orbital motion, leading to the well-known fine structure in their spectra. The electronic states in defect-free carbon nanotubes are widely believed to be four-fold degenerate, owing to independent spin and orbital symmetries, and also to possess electron-hole symmetry. Here we report measurements demonstrating that in clean nanotubes the spin and orbital motion of electrons are coupled, thereby breaking all of these symmetries. This spin-orbit coupling is directly observed as a splitting of the four-fold degeneracy of a single electron in ultra-clean quantum dots. The coupling favours parallel alignment of the orbital and spin magnetic moments for electrons and antiparallel alignment for holes. Our measurements are consistent with recent theories that predict the existence of spin-orbit coupling in curved graphene and describe it as a spin-dependent topological phase in nanotubes. Our findings have important implications for spin-based applications in carbon-based systems, entailing new design principles for the realization of quantum bits (qubits) in nanotubes and providing a mechanism for all-electrical control of spins in nanotubes. 相似文献
57.
Ralph A.DeFronzo 《科学通报(英文版)》2021,(15):1497-1498
Thiazolidinediones(TZDs)are potent insulin sensitizers[1,2],effectively lower the glycosylated hemoglobin A1c HbA1c[1,3]and exert cardiovascular(CV)protective e... 相似文献
58.
59.
Kaminsky R Ducray P Jung M Clover R Rufener L Bouvier J Weber SS Wenger A Wieland-Berghausen S Goebel T Gauvry N Pautrat F Skripsky T Froelich O Komoin-Oka C Westlund B Sluder A Mäser P 《Nature》2008,452(7184):176-180
Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics. 相似文献
60.