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排序方式: 共有160条查询结果,搜索用时 62 毫秒
91.
The mTOR inhibitor everolimus (RAD001, Afinitor) is an orally active anticancer agent. Everolimus demonstrates growth-inhibitory activity against a broad range of tumor cell histotypes in vitro and has the capacity to retard tumor growth in preclinical tumor models in vivo through mechanisms directed against both the tumor cell and the solid tumor stroma components. These properties have rendered it to be a clinically active drug, with subsequent registration in renal cell carcinoma (Motzer et al. [2008]. Lancet 372, 449–456) as well as showing strong potential as a combination partner (André F et al. [2008]. J Clin Oncol 26. Abstract 1003). Although everolimus has a high specificity for its molecular target, the ubiquitous nature of mTOR and the multifactorial influence that mTOR signaling has on cell physiology have made studies difficult on the identification and validation of a biomarker set to predict and monitor drug sensitivity for clinical use. In this review, a summary of the preclinical and clinical data relevant to biomarker development for everolimus is presented, and the advantages and problems of current biomarkers are reviewed. In addition, alternative approaches to biomarker development are proposed on the basis of examples of a combination of markers and functional noninvasive imaging. In particular, we show how basal levels of pAKT and pS6 together could, in principle, be used to stratify patients for likely response to an mTOR inhibitor. 相似文献
92.
Dimitrios Daoussis Vasileios Panoulas Tracey Toms Holly John Ioannis Antonopoulos Peter Nightingale Karen MJ Douglas Rainer Klocke George D Kitas 《Arthritis research & therapy》2009,11(4):R116-8
Introduction
Recent evidence suggests that uric acid (UA), regardless of crystal deposition, may play a direct pathogenic role in renal disease. We have shown that UA is an independent predictor of hypertension and cardiovascular disease (CVD), and that CVD risk factors associate with renal dysfunction, in patients with rheumatoid arthritis (RA). In this study we investigated whether UA associates with renal dysfunction in patients with RA and whether such an association is independent or mediated through other comorbidities or risk factors for renal impairment. 相似文献93.
Juan M. Morales Paul R. Moorcroft Jason Matthiopoulos Jacqueline L. Frair John G. Kie Roger A. Powell Evelyn H. Merrill Daniel T. Haydon 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2010,365(1550):2289-2301
While the mechanistic links between animal movement and population dynamics are ecologically obvious, it is much less clear when knowledge of animal movement is a prerequisite for understanding and predicting population dynamics. GPS and other technologies enable detailed tracking of animal location concurrently with acquisition of landscape data and information on individual physiology. These tools can be used to refine our understanding of the mechanistic links between behaviour and individual condition through ‘spatially informed’ movement models where time allocation to different behaviours affects individual survival and reproduction. For some species, socially informed models that address the movements and average fitness of differently sized groups and how they are affected by fission–fusion processes at relevant temporal scales are required. Furthermore, as most animals revisit some places and avoid others based on their previous experiences, we foresee the incorporation of long-term memory and intention in movement models. The way animals move has important consequences for the degree of mixing that we expect to find both within a population and between individuals of different species. The mixing rate dictates the level of detail required by models to capture the influence of heterogeneity and the dynamics of intra- and interspecific interaction. 相似文献
94.
John G. Kie Jason Matthiopoulos John Fieberg Roger A. Powell Francesca Cagnacci Michael S. Mitchell Jean-Michel Gaillard Paul R. Moorcroft 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2010,365(1550):2221-2231
Recent advances in animal tracking and telemetry technology have allowed the collection of location data at an ever-increasing rate and accuracy, and these advances have been accompanied by the development of new methods of data analysis for portraying space use, home ranges and utilization distributions. New statistical approaches include data-intensive techniques such as kriging and nonlinear generalized regression models for habitat use. In addition, mechanistic home-range models, derived from models of animal movement behaviour, promise to offer new insights into how home ranges emerge as the result of specific patterns of movements by individuals in response to their environment. Traditional methods such as kernel density estimators are likely to remain popular because of their ease of use. Large datasets make it possible to apply these methods over relatively short periods of time such as weeks or months, and these estimates may be analysed using mixed effects models, offering another approach to studying temporal variation in space-use patterns. Although new technologies open new avenues in ecological research, our knowledge of why animals use space in the ways we observe will only advance by researchers using these new technologies and asking new and innovative questions about the empirical patterns they observe. 相似文献
95.
Arno Wegkamp Astrid E Mars Magda Faijes Douwe Molenaar Ric CH de Vos Sebastian MJ Klaus Andrew D Hanson Willem M de Vos Eddy J Smid 《Microbial cell factories》2010,9(1):100
Background
Using a functional genomics approach we addressed the impact of folate overproduction on metabolite formation and gene expression in Lactobacillus plantarum WCFS1. We focused specifically on the mechanism that reduces growth rates in folate-overproducing cells. 相似文献96.
97.
98.
Andrew Giovanni Joachim Roehr Shannon Dwyer Kent Neuenschwander Anthony Scotese Neil D. Moorcroft Larry Davis Zhongli Gao 《Bioorganic & medicinal chemistry letters》2013,23(5):1498-1501
A series of tetrahydroisoquinolines were designed, synthesized and evaluated as the first non-natural product type of compounds with dual D1 receptor (D1R) agonism and D2 receptor (D2R) antagonism properties for treatment of schizophrenia. The initial SAR of the series was explored. The lead in the series, 3g, exhibited high affinity and good potency. Compound 3g displayed 95% of D1R occupancy (10 mg/kg, sc) and 75% of D2R occupancy (10 mg/kg, sc) in the striatum of male CD-1 mice. The series exhibited unique pharmacology and merit as tool compounds for target validation and future optimizations. 相似文献
99.
I Prieto-Potín JA Roman-Blas MJ Martínez-Calatrava R Gómez R Largo Gabriel Herrero-Beaumont 《Arthritis research & therapy》2013,15(4):R81
Objective
The aim of this study was to determine whether hypercholesterolemia increases articular damage in a rabbit model of chronic arthritis.Methods
Hypercholesterolemia was induced in 18 rabbits by administrating a high-fat diet (HFD). Fifteen rabbits were fed normal chow as controls. Chronic antigen-induced arthritis (AIA) was induced in half of the HFD and control rabbits, previously immunized, by intra-articular injections of ovalbumin. After sacrifice, lipid and systemic inflammation markers were analyzed in blood serum. Synovium was analyzed by Krenn score, multinucleated cell counting, immunohistochemistry of RAM11 and CD31, and TNF-α and macrophage chemoattractant protein-1 (MCP-1) gene expression. Active bone resorption was assessed by protein expression of receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and quantification of cathepsin K, contact surface and the invasive area of pannus into bone.Results
Rabbits receiving the HFD showed higher total serum cholesterol, HDL, triglycerides and CRP levels than rabbits fed a normal diet. Synovitis score was increased in HFD, and particularly in AIA and AIA + HFD groups. AIA + HFD synovium was characterized by a massive infiltration of RAM11+ cells, higher presence of multinucleated foam cells and bigger vascularization than AIA. Cathepsin K+ osteoclasts and the contact surface of bone resorbing pannus were also increased in rabbits with AIA + HFD compared with AIA alone. Synovial TNF-α and MCP-1 gene expression was increased in AIA and HFD rabbits compared with healthy animals. RANKL protein expression in AIA and AIA + HFD groups was higher compared with either HFD or normal groups.Conclusions
This experimental model demonstrates that hypercholesterolemia increments joint tissue damage in chronic arthritis, with foam macrophages being key players in this process. 相似文献100.
Impacts of yeast metabolic network structure on enzyme evolution 总被引:1,自引:1,他引:0
A comment on D Vitkup, P Kharchenko and A Wagner: Influence of metabolic network structure and function on enzyme evolution. Genome Biol 2006, 7:R39. 相似文献