排序方式: 共有118条查询结果,搜索用时 31 毫秒
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Chen Z Cheng K Walton Z Wang Y Ebi H Shimamura T Liu Y Tupper T Ouyang J Li J Gao P Woo MS Xu C Yanagita M Altabef A Wang S Lee C Nakada Y Peña CG Sun Y Franchetti Y Yao C Saur A Cameron MD Nishino M Hayes DN Wilkerson MD Roberts PJ Lee CB Bardeesy N Butaney M Chirieac LR Costa DB Jackman D Sharpless NE Castrillon DH Demetri GD Jänne PA Pandolfi PP Cantley LC Kung AL Engelman JA Wong KK 《Nature》2012,483(7391):613-617
Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies. 相似文献
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Paolo Fornaro 《Journal of forecasting》2016,35(6):477-492
In this paper, I use a large set of macroeconomic and financial predictors to forecast US recession periods. I adopt Bayesian methodology with shrinkage in the parameters of the probit model for the binary time series tracking the state of the economy. The in‐sample and out‐of‐sample results show that utilizing a large cross‐section of indicators yields superior US recession forecasts in comparison to a number of parsimonious benchmark models. Moreover, the data‐rich probit model gives similar accuracy to the factor‐based model for the 1‐month‐ahead forecasts, while it provides superior performance for 1‐year‐ahead predictions. Finally, in a pseudo‐real‐time application for the Great Recession, I find that the large probit model with shrinkage is able to pick up the recession signals in a timely fashion and does well in comparison to the more parsimonious specification and to nonparametric alternatives. Copyright © 2016 John Wiley & Sons, Ltd. 相似文献
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Paolo Palmieri 《Studies in history and philosophy of science》2009,40(2):131-142
Evangelista Torricelli (1608-1647) is perhaps best known for being the most gifted of Galileo’s pupils, and for his works based on indivisibles, especially his stunning cubature of an infinite hyperboloid. Scattered among Torricelli’s writings, we find numerous traces of the philosophy of mathematics underlying his mathematical practice. Though virtually neglected by historians and philosophers alike, these traces reveal that Torricelli’s mathematical practice was informed by an original philosophy of mathematics. The latter was dashed with strains of Thomistic metaphysics and theology. Torricelli’s philosophy of mathematics emphasized mathematical constructs as human-made beings of reason, yet mathematical truths as divine decrees, which upon being discovered by the mathematician ‘appropriate eternity’. In this paper, I reconstruct Torricelli’s philosophy of mathematics—which I label radical mathematical Thomism—placing it in the context of Thomistic patterns of thought. 相似文献
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Paolo Palmieri 《Archive for History of Exact Sciences》2009,63(5):471-495
Bonaventura Cavalieri has been the subject of numerous scholarly publications. Recent students of Cavalieri have placed his
geometry of indivisibles in the context of early modern mathematics, emphasizing the role of new geometrical objects, such
as, for example, linear and plane indivisibles. In this paper, I will complement this recent trend by focusing on how Cavalieri
manipulates geometrical objects. In particular, I will investigate one fundamental activity, namely, superposition of geometrical objects. In Cavalieri’s practice, superposition is a means of both manipulating geometrical objects and drawing
inferences. Finally, I will suggest that an integrated approach, namely, one which strives to understand both objects and
activities, can illuminate the history of mathematics. 相似文献
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Colaluca IN Tosoni D Nuciforo P Senic-Matuglia F Galimberti V Viale G Pece S Di Fiore PP 《Nature》2008,451(7174):76-80
NUMB is a cell fate determinant, which, by asymmetrically partitioning at mitosis, controls cell fate choices by antagonising the activity of the plasma membrane receptor of the NOTCH family. NUMB is also an endocytic protein, and the NOTCH-NUMB counteraction has been linked to this function. There might be, however, additional functions of NUMB, as witnessed by its proposed role as a tumour suppressor in breast cancer. Here we describe a previously unknown function for human NUMB as a regulator of tumour protein p53 (also known as TP53). NUMB enters in a tricomplex with p53 and the E3 ubiquitin ligase HDM2 (also known as MDM2), thereby preventing ubiquitination and degradation of p53. This results in increased p53 protein levels and activity, and in regulation of p53-dependent phenotypes. In breast cancers there is frequent loss of NUMB expression. We show that, in primary breast tumour cells, this event causes decreased p53 levels and increased chemoresistance. In breast cancers, loss of NUMB expression causes increased activity of the receptor NOTCH. Thus, in these cancers, a single event-loss of NUMB expression-determines activation of an oncogene (NOTCH) and attenuation of the p53 tumour suppressor pathway. Biologically, this results in an aggressive tumour phenotype, as witnessed by findings that NUMB-defective breast tumours display poor prognosis. Our results uncover a previously unknown tumour suppressor circuitry. 相似文献
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Rainville S Thompson JK Myers EG Brown JM Dewey MS Kessler EG Deslattes RD Börner HG Jentschel M Mutti P Pritchard DE 《Nature》2005,438(7071):1096-1097
One of the most striking predictions of Einstein's special theory of relativity is also perhaps the best known formula in all of science: E=mc(2). If this equation were found to be even slightly incorrect, the impact would be enormous--given the degree to which special relativity is woven into the theoretical fabric of modern physics and into everyday applications such as global positioning systems. Here we test this mass-energy relationship directly by combining very accurate measurements of atomic-mass difference, Delta(m), and of gamma-ray wavelengths to determine E, the nuclear binding energy, for isotopes of silicon and sulphur. Einstein's relationship is separately confirmed in two tests, which yield a combined result of 1-Delta(mc2)/E=(-1.4+/-4.4)x10(-7), indicating that it holds to a level of at least 0.00004%. To our knowledge, this is the most precise direct test of the famous equation yet described. 相似文献
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Madhuri Kalathur Silvia Baiguera Paolo Macchiarini 《Cellular and molecular life sciences : CMLS》2010,67(24):4185-4196
There are a variety of airway diseases with different clinical settings, which may extend from a surgical approach to total
organ replacement. Tissue engineering involves modifying cells or tissues in order to repair, regenerate, or replace tissue
in the body and seems to be a promising approach for airway replacement. The successful implantation of stem-cell-based tissue-engineered
trachea in a young woman with end-stage post-tuberculosis left main bronchus collapse serves as a prototype for the airway
tissue-engineered-based approach. The trachea indeed could represent a perfect model system to investigate the translational
aspects of tissue engineering, largely due to its low-oxygen needs. This review highlights the anatomy of the airways, the
various disease conditions that cause damage to the airways, elaborates on the essential components of the tissue-engineering
approach, and discusses the success of the revolutionary trachea transplantation approach. 相似文献