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401.
The Earth acts as a gigantic heat engine driven by the decay of radiogenic isotopes and slow cooling, which gives rise to plate tectonics, volcanoes and mountain building. Another key product is the geomagnetic field, generated in the liquid iron core by a dynamo running on heat released by cooling and freezing (as the solid inner core grows), and on chemical convection (due to light elements expelled from the liquid on freezing). The power supplied to the geodynamo, measured by the heat flux across the core-mantle boundary (CMB), places constraints on Earth's evolution. Estimates of CMB heat flux depend on properties of iron mixtures under the extreme pressure and temperature conditions in the core, most critically on the thermal and electrical conductivities. These quantities remain poorly known because of inherent experimental and theoretical difficulties. Here we use density functional theory to compute these conductivities in liquid iron mixtures at core conditions from first principles--unlike previous estimates, which relied on extrapolations. The mixtures of iron, oxygen, sulphur and silicon are taken from earlier work and fit the seismologically determined core density and inner-core boundary density jump. We find both conductivities to be two to three times higher than estimates in current use. The changes are so large that core thermal histories and power requirements need to be reassessed. New estimates indicate that the adiabatic heat flux is 15 to 16 terawatts at the CMB, higher than present estimates of CMB heat flux based on mantle convection; the top of the core must be thermally stratified and any convection in the upper core must be driven by chemical convection against the adverse thermal buoyancy or lateral variations in CMB heat flow. Power for the geodynamo is greatly restricted, and future models of mantle evolution will need to incorporate a high CMB heat flux and explain the recent formation of the inner core. 相似文献
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D Southwood 《Nature》2012,488(7412):451-453
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Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer 总被引:1,自引:0,他引:1
Misale S Yaeger R Hobor S Scala E Janakiraman M Liska D Valtorta E Schiavo R Buscarino M Siravegna G Bencardino K Cercek A Chen CT Veronese S Zanon C Sartore-Bianchi A Gambacorta M Gallicchio M Vakiani E Boscaro V Medico E Weiser M Siena S Di Nicolantonio F Solit D Bardelli A 《Nature》2012,486(7404):532-536
A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. 相似文献
408.
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
409.
Stephens PJ Tarpey PS Davies H Van Loo P Greenman C Wedge DC Nik-Zainal S Martin S Varela I Bignell GR Yates LR Papaemmanuil E Beare D Butler A Cheverton A Gamble J Hinton J Jia M Jayakumar A Jones D Latimer C Lau KW McLaren S McBride DJ Menzies A Mudie L Raine K Rad R Chapman MS Teague J Easton D Langerød A;Oslo Breast Cancer Consortium 《Nature》2012,486(7403):400-404
All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease. 相似文献
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