Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.     

数值学报（2003年第12卷）

本书是由英国剑桥大学出版、发行的不定期专题论文集，每年出版一卷，登载数值分析、计算方法及其应用等方面的高水平创造性研究论文或综述报告，论文作者多为当代相关领域的国际性学术带头人。     

The development of the Neurath principle: unearthing the Romantic link

Otto Neurath’s thoroughgoing anti-foundationalism is connected to the recognition that protocol sentences are not inviolable, that is they are fallible and their choice cannot be determined: ‘Poincaré, Duhem and others have adequately shown that even if we have agreed on the protocol statements, there is a not limited number of equally applicable, possible systems of hypotheses. We have extended this tenet of the uncertainty of systems of hypotheses to all statements, including protocol statements that are alterable in principle’ (Neurath, 1983, p. 105). Later historiography has called Neurath’s extension of Duhemian holism the Neurath principle. Based on a study of Neurath’s early works on the history of optics, the paper investigates a previously unnoticed influence on the development of this principle, Neurath’s reading of Goethe’s Theory of colours. The historical and polemical parts of Goethe’s tripartite book provided Neurath with ideal examples for the vertical extension of Duhem’s thesis to observation statements. Moreover, Goethe’s critique of the language of science and his views on the theory-ladenness of observation, as well as on the history of science show strong parallels to many of Neurath’s ideas. These demonstrate the existence of surprisingly direct textual links between Romantic views on science and the development of twentieth-century philosophy of science. Neurath’s usage of Goethe’s examples also indicates that the birth of the Neurath principle is more tightly connected to actual scientific practice than to theory-testing, and that by admitting the theory-ladenness of observation reports and fallibility of protocol statements Neurath does not throw empiricism overboard.