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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.
93.
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94.
Paul K. Crellin Julian P. Vivian Judith Scoble Frances M. Chow Nicholas P. West Rajini Brammananth Nicholas I. Proellocks Adam Shahine Jerome Le Nours Matthew C. J. Wilce Warwick J. Britton Ross L. Coppel Jamie Rossjohn Travis Beddoe 《The Journal of biological chemistry》2010,285(39):30050-30060
The highly complex and unique mycobacterial cell wall is critical to the survival of Mycobacteria in host cells. However, the biosynthetic pathways responsible for its synthesis are, in general, incompletely characterized. Rv3802c from Mycobacterium tuberculosis is a partially characterized phospholipase/thioesterase encoded within a genetic cluster dedicated to the synthesis of core structures of the mycobacterial cell wall, including mycolic acids and arabinogalactan. Enzymatic assays performed with purified recombinant proteins Rv3802c and its close homologs from Mycobacterium smegmatis (MSMEG_6394) and Corynebacterium glutamicum (NCgl2775) show that they all have significant lipase activities that are inhibited by tetrahydrolipstatin, an anti-obesity drug that coincidently inhibits mycobacterial cell wall biosynthesis. The crystal structure of MSMEG_6394, solved to 2.9 Å resolution, revealed an α/β hydrolase fold and a catalytic triad typically present in esterases and lipases. Furthermore, we demonstrate direct evidence of gene essentiality in M. smegmatis and show the structural consequences of loss of MSMEG_6394 function on the cellular integrity of the organism. These findings, combined with the predicted essentiality of Rv3802c in M. tuberculosis, indicate that the Rv3802c family performs a fundamental and indispensable lipase-associated function in mycobacteria. 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.
S. J. Mayo R. Allkin W. Baker V. Blagoderov I. Brake B. Clark R. Govaerts C. Godfray A. Haigh R. Hand K. Harman M. Jackson N. Kilian D. W. Kirkup I. Kitching S. Knapp G. P. Lewis P. Malcolm E. von Raab-Straube D. M. Roberts M. Scoble D. A. Simpson C. Smith V. Smith S. Villalba L. Walley P. Wilkin 《Kew Bulletin》2008,63(1):1-16
98.
99.
Amino acid sequence versus morphological data and the interordinal relationships of mammals 总被引:2,自引:0,他引:2
To a large extent, the mutual affinities of the mammalian orders continue
to puzzle systematists, even though comparative anatomy and amino acid
sequencing offer a massive data base from which these relationships could
potentially be adduced. In the present paper the consistency index--the
number of character states less the number of characters in a data set,
divided by the total number of changes in the character states on a
cladogram--was used to examine the relative resolving powers of recently
published morphological and molecular- sequence data. Consistency indices
were calculated for previously published alpha crystallin A chain and
myoglobin amino acid-sequence cladograms and for four original amino
acid-sequence cladograms (alpha crystallin A, myoglobin, and alpha and beta
hemoglobin); these were found to be comparable to the consistency indices
of morphologically based cladograms. Qualitative comparisons between the
morphologically based and molecularly based trees were also made; only
moderate congruence between the two was observed. Moreover, there was a
general lack of congruence between the cladograms specified by each of the
four proteins. Amino acid-sequence and morphological data agreed on the
placement of edentates as an early eutherian offshoot and on the grouping
of hyracoids, proboscideans, and sirenians. Otherwise there was only
limited congruence: morphology strongly supported the grouping of
lagomorphs and rodents and the alliance of pholidotes and edentates, but
sequence analyses did not. The placement of tubulidentates differed widely
among proteins. Morphology indicated the close association of sirenians
with proboscideans; proteins suggested a pairing of sirenians with
hyracoids. Sequence data did not identify many (morphologically
well-diagnosed) orders as monophyletic (e.g., Lagomorpha).(ABSTRACT
TRUNCATED AT 250 WORDS)
相似文献
100.
I Prieto-Potín JA Roman-Blas MJ Martínez-Calatrava R Gómez R Largo Gabriel Herrero-Beaumont 《Arthritis research & therapy》2013,15(4):R81