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91.
Steven JM Jones Janessa Laskin Yvonne Y Li Obi L Griffith Jianghong An Mikhail Bilenky Yaron S Butterfield Timothee Cezard Eric Chuah Richard Corbett Anthony P Fejes Malachi Griffith John Yee Montgomery Martin Michael Mayo Nataliya Melnyk Ryan D Morin Trevor J Pugh Tesa Severson Sohrab P Shah Margaret Sutcliffe Angela Tam Jefferson Terry Nina Thiessen Thomas Thomson Richard Varhol Thomas Zeng Yongjun Zhao Richard A Moore David G Huntsman Inanc Birol Martin Hirst Robert A Holt Marco A Marra 《Genome biology》2010,11(8):1-12
Background
Adenocarcinomas of the tongue are rare and represent the minority (20 to 25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment.Results
In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. There were 1,078 genes that exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations, administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumors and 9 new somatic protein coding mutations. The observed mutations and amplifications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways.Conclusions
We conclude that complete genomic characterization of a rare tumor has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual. 相似文献92.
Ori Elkayam Refael Segal Daniele Bendayan Robert van Uitert Carla Onnekink Ger JM Pruijn 《Arthritis research & therapy》2010,12(1):R12
Introduction
Patients with tuberculosis (TB) frequently produce anti-citrullinated protein antibodies (ACPA). The objective of this study is to characterize the citrulline-dependence of the ACPA reactivity in sera of patients with mycobacterium infections. 相似文献93.
Esther Heikens Masja Leendertse Lucas M Wijnands Miranda van Luit-Asbroek Marc JM Bonten Tom van der Poll Rob JL Willems 《BMC microbiology》2009,9(1):19-7
Background
Enterococcus faecium has globally emerged as a cause of hospital-acquired infections with high colonization rates in hospitalized patients. The enterococcal surface protein Esp, identified as a potential virulence factor, is specifically linked to nosocomial clonal lineages that are genetically distinct from indigenous E. faecium strains. To investigate whether Esp facilitates bacterial adherence and intestinal colonization of E. faecium, we used human colorectal adenocarcinoma cells (Caco-2 cells) and an experimental colonization model in mice. 相似文献94.
95.
Firdaus AA Mohamed Hoesein Pieter Zanen Pim A de Jong Bram van Ginneken H Marike Boezen Harry JM Groen Mathijs Oudkerk Harry J de Koning Dirkje S Postma Jan-Willem J Lammers 《Respiratory research》2013,14(1):55
Background
Little is known about the factors associated with CT-quantified emphysema progression in heavy smokers. The objective of this study was to investigate the effect of length of smoking cessation and clinical / demographical factors on the rate of emphysema progression and FEV1-decline in male heavy smokers.Methods
3,670 male smokers with mean (SD) 40.8 (17.9) packyears underwent chest CT scans and pulmonary function tests at baseline and after 1 and 3 years follow-up. Smoking status (quitted ≥5, ≥1-<5, <1 years or current smoker) was noted. Rate of progression of emphysema and FEV1-decline after follow-up were assessed by analysis of variance adjusting for age, height, baseline pulmonary function and emphysema severity, packyears, years in study and respiratory symptoms. The quitted ≥5 group was used as reference.Results
Median (Q1-Q3) emphysema severity,<-950 HU, was 8.8 (5.1 – 14.1) and mean (SD) FEV1 was 3.4 (0.73) L or 98.5 (18.5) % of predicted. The group quitted ‘>5 years’ showed significantly lower rates of progression of emphysema compared to current smokers, 1.07% and 1.12% per year, respectively (p<0.001). Current smokers had a yearly FEV1-decline of 69 ml, while subjects quit smoking >5 years had a yearly decline of 57.5 ml (p<0.001).Conclusion
Quit smoking >5 years significantly slows the rate of emphysema progression and lung function decline.Trial registration
Registered at http://www.trialregister.nl with trial number ISRCTN63545820. 相似文献96.
97.
98.
We have shown previously that the β-adrenergic agonist isoproterenol (2μM) and the phosphodiesterase inhibitor isobutylmethylxanthine (1 mM) produce a much greater increase in cyclic AMP in human leukocytes that have been pretreated with colchicine (or with other agents that affect microtubule assembly) than in control leukocytes. The effects of colchicines were both time- and dose-dependant. These and other data suggested that the generation of cyclic AMP is normally restricted by an intact system of cytoplasmic microtubules. If so, then the same time and dose dependencies might apply to other colchicines-induced changes in leukocyte function. We have now assayed the distribution of concanavalin A (Con A)-receptor complexes on the leukocyte membrane, taking into account that leukocytes competent to assemble microtubules show a uniform distribution of surface- bound Con A whereas microtubule-deficient cells accumulate Con A in surface caps. We have found that the effect of colchicine on capping is also both time- and dose dependent, and that the dose-response relationships conform to those required to increase cyclic AMP levels. These findings provide further evidence that both colchicine-induced Con-A capping and colchicine- induced cyclic AMP generation depend upon the relaxation of constraints normally imposed by cytoplasmic microtubules upon the plasma membrane, which limit, respectively, lateral mobility of the lectin-receptor complexes, and expression of hormone-sensitive adenylate cyclase. Moreover, colchicine-induced Con-A cap formation is not affected even by very large changes in leukocyte cyclic AMP levels. Thus, elevated cyclic AMP levels do not appear to promote the dissolution of microtubules; rather, the dissolution of microtubules permits the generation of increased amounts of cyclic AMP. 相似文献
99.
Accurate prediction of protein secondary structure and solvent accessibility by consensus combiners of sequence and structure information 总被引:1,自引:0,他引:1
Gianluca Pollastri Alberto JM Martin Catherine Mooney Alessandro Vullo 《BMC bioinformatics》2007,8(1):201
Background
Structural properties of proteins such as secondary structure and solvent accessibility contribute to three-dimensional structure prediction, not only in the ab initio case but also when homology information to known structures is available. Structural properties are also routinely used in protein analysis even when homology is available, largely because homology modelling is lower throughput than, say, secondary structure prediction. Nonetheless, predictors of secondary structure and solvent accessibility are virtually always ab initio. 相似文献100.
Cross-adaptation and molecular modeling study of receptor mechanisms common to four taste stimuli in humans 总被引:2,自引:2,他引:0
Psychophysical cross-adaptation experiments were performed with two
carbohydrates, sucrose (SUC) and fructose (FRU), and two sweeteners,
acesulfame-K (MOD) and dulcin (DUL). Seven subjects were asked to match
concentrations that elicited the same intensity as a sucrose reference (30
g/l). Cross-adaptation levels were calculated as the ratio of isointense
concentrations measured for a given stimulus before and under adaptation.
On average, cross-adaptation between SUC and FRU is low and apparently
reciprocal. By contrast, cross-adaptation between SUC and MOD is clearly
non-reciprocal: SUC adapts MOD significantly (24%, P < 0.005), but MOD
fails to adapt SUC (2%, P < 0.79). Significant and reciprocal
cross-enhancement is observed between DUL and MOD (approximately -20%, P
< 0.03), and also between SUC and DUL (approximately -15%, P < 0.08).
In parallel, molecular modeling of the four tastants was performed in order
to look for the 12 common binding motifs that were isolated on 14 other
tastants in a previous study. SUC and FRU each display 10 out of the 12
binding motifs, whereas DUL and MOD only display four and five distinct
motifs respectively and do not have any motif in common. Experimental
cross-adaptation levels seem to correlate well with the number of motifs
that molecules have in common. FRU and SUC share a majority of binding
motifs and correlatively show mutual cross-adaptation. Four motifs of MOD
are found among the 10 motifs of SUC, which may explain why SUC
cross-adapts MOD but not vice versa. By contrast, DUL and MOD do not share
any motif and do not cross- adapt. The various molecular mechanisms that
may be responsible for cross-adaptation and/or cross-enhancement are
discussed in light of our results.
相似文献