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91.
Simon J. Watson Pinky Langat Scott M. Reid Tommy Tsan-Yuk Lam Matthew Cotten Michael Kelly Kristien Van Reeth Yu Qiu Ga?lle Simon Emilie Bonin Emanuela Foni Chiara Chiapponi Lars Larsen Charlotte Hjulsager Iwona Markowska-Daniel Kinga Urbaniak Ralf Dürrwald Michael Schlegel Anita Huovilainen Irit Davidson ádám Dán Willie Loeffen Stephanie Edwards Michel Bublot Thais Vila Jaime Maldonado Laura Valls ESNIP Consortium Ian H. Brown Oliver G. Pybus Paul Kellam 《Journal of virology》2015,89(19):9920-9931
92.
Gillian Stynes Henrik Svedsater Jaro Wex Sally Lettis David Leather Emanuela Castelnuovo Michelle Detry Scott Berry 《Respiratory research》2015,16(1)
Background
Fluticasone furoate (FF)/vilanterol (VI) 100/25 mcg is a once-daily inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) treatment approved in the United States, Canada and Europe for the long-term maintenance therapy of COPD. We report data from mixed treatment comparisons (MTC) of once-daily FF/VI against established twice-daily ICS/LABA combination therapies on clinical efficacy outcomes.Methods
Data from 33 parallel-group randomised controlled trials (RCTs) of ICS/LABAs, of ≥8 weeks’ duration in patients ≥12 years of age with COPD, identified by systematic review, were analysed using covariate-adjusted Bayesian hierarchical models for three efficacy outcomes. Lung function, assessed by change from baseline in forced expiratory volume in one second (FEV1), was the outcome of primary interest (n = 28 studies). Secondary objectives were assessment of annual rate of moderate/severe exacerbations (n = 15) and patient-reported health status, measured by change from baseline in St George’s Respiratory Questionnaire (SGRQ) Total score (n = 20). Overall, 25 different treatments were included in the MTC; we report findings, including probabilities of non-inferiority, for comparisons of once-daily FF/VI 100/25 mcg with twice-daily fluticasone propionate (FP)/salmeterol (SAL) 500/50 mcg and budesonide (BUD)/formoterol (FORM) 400/12 mcg.Results
For FEV1, FF/VI 100/25 mcg demonstrated >99% probability of non-inferiority to FP/SAL 500/50 mcg and BUD/FORM 400/12 mcg using a 50 mL margin. For annual rate of moderate/severe exacerbations, FF/VI 100/25 mcg demonstrated 73% and 77% probability of non-inferiority to FP/SAL 500/50 mcg and BUD/FORM 400/12 mcg, respectively, using a 10% rate ratio margin. For SGRQ Total score, the corresponding probabilities of non-inferiority were 99% and 98%, respectively, on a 2-unit margin. Significant covariate effects were identified: increased age was associated with deterioration in FEV1 and reduced exacerbation frequency; shorter study duration was associated with reduced exacerbation frequency.Conclusions
FF/VI 100/25 mcg was comparable with corresponding doses of FP/SAL and BUD/FORM on lung function and health status outcomes. Non-inferiority on moderate/severe exacerbation rate was not demonstrated to the same degree of confidence, though observed rates were similar. Model limitations include a weak treatment network for the exacerbation analysis and variability across the included studies. Our data support previous RCT findings suggesting that the efficacy of FF/VI 100/25 mcg on lung function and health status in COPD is comparable with twice-daily ICS/LABAs.Electronic supplementary material
The online version of this article (doi:10.1186/s12931-015-0184-8) contains supplementary material, which is available to authorized users. 相似文献93.
Dubravka Vu?i?evi? Olivia Corradin Evgenia Ntini Peter C Scacheri Ulf Andersson ?rom 《Cell cycle (Georgetown, Tex.)》2015,14(2):253-260
Long non-coding RNAs (ncRNA) have recently been demonstrated to be expressed from a subset of enhancers and to be required for the distant regulation of gene expression. Several approaches to predict enhancers have been developed based on various chromatin marks and occupancy of enhancer-binding proteins. Despite the rapid advances in the field, no consensus how to define tissue specific enhancers yet exists. Here, we identify 2,695 long ncRNAs annotated by ENCODE (corresponding to 28% of all ENCODE annotated long ncRNAs) that overlap tissue-specific enhancers. We use a recently developed algorithm to predict tissue-specific enhancers, PreSTIGE, that is based on the H3K4me1 mark and tissue specific expression of mRNAs. The expression of the long ncRNAs overlapping enhancers is significantly higher when the enhancer is predicted as active in a specific cell line, suggesting a general interdependency of active enhancers and expression of long ncRNAs. This dependency is not identified using previous enhancer prediction algorithms that do not account for expression of their downstream targets. The predicted enhancers that overlap annotated long ncRNAs generally have a lower ratio of H3K4me1 to H3K4me3, suggesting that enhancers expressing long ncRNAs might be associated with specific epigenetic marks. In conclusion, we demonstrate the tissue-specific predictive power of PreSTIGE and provide evidence for thousands of long ncRNAs that are expressed from active tissue-specific enhancers, suggesting a particularly important functional relationship between long ncRNAs and enhancer activity in determining tissue-specific gene expression. 相似文献
94.
Screpanti E De Antoni A Alushin GM Petrovic A Melis T Nogales E Musacchio A 《Current biology : CB》2011,21(5):391-398
Kinetochores are proteinaceous scaffolds implicated in the formation of load-bearing attachments of chromosomes to microtubules during mitosis. Kinetochores contain distinct chromatin- and microtubule-binding interfaces, generally defined as the inner and outer kinetochore, respectively (reviewed in). The constitutive centromere-associated network (CCAN) and the Knl1-Mis12-Ndc80 complexes (KMN) network are the main multisubunit protein assemblies in the inner and outer kinetochore, respectively. The point of contact between the CCAN and the KMN network is unknown. Cenp-C is a conserved CCAN component whose central and C-terminal regions have been implicated in chromatin binding and dimerization. Here, we show that a conserved motif in the N-terminal region of Cenp-C binds directly and with high affinity to the Mis12 complex. Expression in HeLa cells of the isolated N-terminal motif of Cenp-C prevents outer kinetochore assembly, causing chromosome missegregation. The KMN network is also responsible for kinetochore recruitment of the components of the spindle assembly checkpoint, and we observe checkpoint impairment in cells expressing the Cenp-C N-terminal segment. Our studies unveil a crucial and likely universal link between the inner and outer kinetochore. 相似文献
95.
Balestrieri E Pizzimenti F Ferlazzo A Giofrè SV Iannazzo D Piperno A Romeo R Chiacchio MA Mastino A Macchi B 《Bioorganic & medicinal chemistry》2011,19(6):2084-2089
The effects of an extract from Citrus bergamia (BSext) and those of two products purified from the same extract, that is, nomilin and limonin, and reference compounds, towards HTLV-1 have been reported. Moreover, they were also compared with those obtained towards HIV-1. Results showed that the efficacy of both BSext and limonin in inhibiting HTLV-1 as well as HIV-1 expression in infected cells, as evaluated by comparable quantitative assays, was close to that of the effective, reference compounds, respectively. The protective effect of BSext and of the purified products was associated with the inhibition of both HTLV-1 and HIV-1 RT activities in conceptually similar, cell-free assays. The cytotoxicity of the assayed compounds of natural origin was substantially less pronounced than that of the reference compounds, thus showing a favourable selectivity index for the novel BSext product. 相似文献
96.
Monari E Casali C Cuoghi A Nesci J Bellei E Bergamini S Fantoni LI Natali P Morandi U Tomasi A 《Proteome science》2011,9(1):55-10
Background
Non Small Cell Lung Cancer (NSCLC) is the major cause of cancer related-death. Many patients receive diagnosis at advanced stage leading to a poor prognosis. At present, no satisfactory screening tests are available in clinical practice and the discovery and validation of new biomarkers is mandatory. Surface Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-ToF-MS) is a recent high-throughput technique used to detect new tumour markers. In this study we performed SELDI-ToF-MS analysis on serum samples treated with the ProteoMiner? kit, a combinatorial library of hexapeptide ligands coupled to beads, to reduce the wide dynamic range of protein concentration in the sample. Serum from 44 NSCLC patients and 19 healthy controls were analyzed with IMAC30-Cu and H50 ProteinChip Arrays.Results
Comparing SELDI-ToF-MS protein profiles of NSCLC patients and healthy controls, 28 protein peaks were found significantly different (p < 0.05), and were used as predictors to build decision classification trees. This statistical analysis selected 10 protein peaks in the low-mass range (2-24 kDa) and 6 in the high-mass range (40-80 kDa). The classification models for the low-mass range had a sensitivity and specificity of 70.45% (31/44) and 68.42% (13/19) for IMAC30-Cu, and 72.73% (32/44) and 73.68% (14/19) for H50 ProteinChip Arrays.Conclusions
These preliminary results suggest that SELDI-ToF-MS protein profiling of serum samples pretreated with ProteoMiner? can improve the discovery of protein peaks differentially expressed between NSCLC patients and healthy subjects, useful to build classification algorithms with high sensitivity and specificity. However, identification of the significantly different protein peaks needs further study in order to provide a better understanding of the biological nature of these potential biomarkers and their role in the underlying disease process. 相似文献97.
Najm FJ Zaremba A Caprariello AV Nayak S Freundt EC Scacheri PC Miller RH Tesar PJ 《Nature methods》2011,8(11):957-962
Myelin-related disorders such as multiple sclerosis and leukodystrophies, for which restoration of oligodendrocyte function would be an effective treatment, are poised to benefit greatly from stem cell biology. Progress in myelin repair has been constrained by difficulties in generating pure populations of oligodendrocyte progenitor cells (OPCs) in sufficient quantities. Pluripotent stem cells theoretically provide an unlimited source of OPCs, but current differentiation strategies are poorly reproducible and generate heterogenous populations of cells. Here we provide a platform for the directed differentiation of pluripotent mouse epiblast stem cells (EpiSCs) through defined developmental transitions into a pure population of highly expandable OPCs in 10 d. These OPCs robustly differentiate into myelinating oligodendrocytes in vitro and in vivo. Our results demonstrate that mouse pluripotent stem cells provide a pure population of myelinogenic oligodendrocytes and offer a tractable platform for defining the molecular regulation of oligodendrocyte development and drug screening. 相似文献
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