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61.
Identifying the genetic variation underlying quantitative trait loci remains problematic. Consequently, our molecular understanding of genetically complex, quantitative traits is limited. To address this issue directly, we mapped three quantitative trait loci that control yeast sporulation efficiency to single-nucleotide resolution in a noncoding regulatory region (RME1) and to two missense mutations (TAO3 and MKT1). For each quantitative trait locus, the responsible polymorphism is rare among a diverse set of 13 yeast strains, suggestive of genetic heterogeneity in the control of yeast sporulation. Additionally, under optimal conditions, we reconstituted approximately 92% of the sporulation efficiency difference between the two genetically distinct parents by engineering three nucleotide changes in the appropriate yeast genome. Our results provide the highest resolution to date of the molecular basis of a quantitative trait, showing that the interaction of a few genetic variants can have a profound phenotypic effect. 相似文献
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W. Davis 《Cellular and molecular life sciences : CMLS》1959,15(8):294-297
Zusammenfassung Die Chemotherapie von bösartigen Gechwülsten und Leukämien wurde am VII. Internationalen Krebskongress in London sowohl vom Gesichtspunkt der Klinik wie von demjenigen der experimentellen Forschung aus behandelt.Nahezu alle in diesem Zusammenhang erwähnten Pharmaka gehören entweder zur Gruppe der Alkylierungsmittel oder aber zu derjenigen der Stoffwechselantagonisten.Das klinische Interesse galt vor allem der Verbesserung von therapeutischen Anwendungsweisen bereits anerkannter Heilmittel, deren Brauchbarkeit zur Unterstützung der Chirurgie, sowie der Prüfung neuartiger Substanzen mit möglicher Hemmungswirkung auf Tumoren.Die Beiträge auf dem experimentellen Gebiet umfassten biochemische Studien über den Wirkungsmechanismus von Krebspharmaka und über den biologischen Einbau von Stoffwechselantagonisten. Einige Vorträge behandelten die Frage, welche Bedeutung den Enzymen in der Chemotherapie des Krebses zukomme.
The Abstracts of the VIIth International Cancer Congress were published under the auspices of the International Union against Cancer in London, July 1958. The full reports of the Congress will be published in a special edition of the ACTA of the International Union against Cancer. 相似文献
The Abstracts of the VIIth International Cancer Congress were published under the auspices of the International Union against Cancer in London, July 1958. The full reports of the Congress will be published in a special edition of the ACTA of the International Union against Cancer. 相似文献
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Effect of lithium on the uptake of noradrenaline by synaptosomes 总被引:4,自引:0,他引:4
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R Straussman T Morikawa K Shee M Barzily-Rokni ZR Qian J Du A Davis MM Mongare J Gould DT Frederick ZA Cooper PB Chapman DB Solit A Ribas RS Lo KT Flaherty S Ogino JA Wargo TR Golub 《Nature》2012,487(7408):500-504
Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance. 相似文献