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11.
Barlaam B Ballard P Bradbury RH Ducray R Germain H Hickinson DM Hudson K Kettle JG Klinowska T Magnien F Ogilvie DJ Olivier A Pearson SE Scott JS Suleman A Trigwell CB Vautier M Whittaker RD Wood R 《Bioorganic & medicinal chemistry letters》2008,18(2):674-678
Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration. 相似文献
12.
Carla GS Saad Ana CM Ribeiro Julio CB Moraes Liliam Takayama Celio R Goncalves Marcelo B Rodrigues Ricardo M de Oliveira Clovis A Silva Eloisa Bonfa Rosa MR Pereira 《Arthritis research & therapy》2012,14(5):R216
Introduction
Sclerostin levels have been reported to be low in ankylosing spondylitis (AS), but there is no data regarding the possible role of this Wnt inhibitor during anti-tumor necrosis factor (TNF) therapy. The present study longitudinally evaluated sclerostin levels, inflammatory markers and bone mineral density (BMD) in AS patients under anti-TNF therapy.Methods
Thirty active AS patients were assessed at baseline, 6 and 12 months after anti-TNF therapy regarding clinical parameters, inflammatory markers, BMD and baseline radiographic damage (mSASSS). Thirty age- and sex-matched healthy individuals comprised the control group. Patients'' sclerostin levels, sclerostin binding low-density lipoprotein receptor-related protein 6 (LRP6) and BMD were evaluated at the same time points and compared to controls.Results
At baseline, AS patients had lower sclerostin levels (60.5 ± 32.7 vs. 96.7 ± 52.9 pmol/L, P = 0.002) and comparable sclerostin binding to LRP6 (P = 0.387) than controls. Improvement of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Ankylosing Spondylitis quality of life (ASQoL) was observed at baseline vs. 6 vs. 12 months (P < 0.01). Concomitantly, a gradual increase in spine BMD (P < 0.001) and a positive correlation between baseline mSASSS and spine BMD was found (r = 0.468, P < 0.01). Inflammatory parameters reduction was observed comparing baseline vs. 6 vs. 12 months (P <0.01). Sclerostin levels progressively increased [baseline (60.5 ± 32.7) vs. 6 months (67.1 ± 31.9) vs. 12 months (72.7 ± 32.3) pmol/L, P <0.001]. At 12 months, the sclerostin levels remained significantly lower in patients compared to controls (72.7 ± 32.3 vs. 96.70 ± 52.85 pmol/L, P = 0.038). Moreover, sclerostin serum levels at 12 months were lower in the 10 patients with high C reactive protein (CRP) (≥ 5 mg/l) compared to the other 20 patients with normal CRP (P = 0.004). Of note, these 10 patients with persistent inflammation also had lower sclerostin serum levels at baseline compared to the other patients (P = 0.023). Univariate logistic regression analysis demonstrated that AS patients with lower sclerostin serum levels had an increased risk to have high CRP at 12 months (odds ratio = 7.43, 95% CI 1.23 to 45.01, P = 0.020) than those with higher sclerostin values.Conclusions
Persistent low sclerostin levels may underlie continuous inflammation in AS patients under anti-TNF therapy. 相似文献13.
Anne-Christine Bay-Jensen Nadine CB Tabassi Lene V Sondergaard Thomas L Andersen Frederik Dagnaes-Hansen Patrick Garnero Moustapha Kassem Jean-Marie Delaissé 《Arthritis research & therapy》2009,11(1):R9
Introduction
The urinary level of the type II collagen degradation marker CTX-II is increased in postmenopausal women and in ovariectomised rats, suggesting that oestrogen deprivation induces cartilage breakdown. Here we investigate whether this response to oestrogen is also true for other type II collagen turnover markers known to be affected in osteoarthritis, and whether it relates to its presence in specific areas of cartilage tissue. 相似文献14.
Ducray R Ballard P Barlaam BC Hickinson MD Kettle JG Ogilvie DJ Trigwell CB 《Bioorganic & medicinal chemistry letters》2008,18(3):959-962
Novel 4-anilino-1H-pyrazolo[3,4-d]pyrimidines have been synthesized and evaluated in vitro for erbB2 and EGFR kinase inhibition. A representative compound displaying oral bioavailability in rat and dog illustrates the potential of this series to provide orally active erbB2 inhibitors. 相似文献
15.
Background
State-of-the-art signal processing methods are known to detect information in single-trial event-related EEG data, a crucial aspect in development of real-time applications such as brain computer interfaces. This paper investigates one such novel approach, evaluating how individual classifier and feature subset tailoring affects classification of single-trial EEG finger movements. The discrete wavelet transform was used to extract signal features that were classified using linear regression and non-linear neural network models, which were trained and architecturally optimized with evolutionary algorithms. The input feature subsets were also allowed to evolve, thus performing feature selection in a wrapper fashion. Filter approaches were implemented as well by limiting the degree of optimization. 相似文献16.
Natália H Mendes Fernando AF Melo Adolfo CB Santos José RC Pandolfi Elisabete A Almeida Rosilene F Cardoso Henri Berghs Suzana David Faber K Johansen Lívia G Espanha Sergio RA Leite Clarice QF Leite 《BMC research notes》2011,4(1):269
Background
Tuberculosis is a major health problem in São Paulo, Brazil, which is the most populous and one of the most cosmopolitan cities in South America. To characterize the genetic diversity of Mycobacterium tuberculosis in the population of this city, the genotyping techniques of spoligotyping and MIRU were applied to 93 isolates collected in two consecutive years from 93 different tuberculosis patients residing in São Paulo city and attending the Clemente Ferreira Institute (the reference clinic for the treatment of tuberculosis).Findings
Spoligotyping generated 53 different spoligotype patterns. Fifty-one isolates (54.8%) were grouped into 13 spoligotyping clusters. Seventy- two strains (77.4%) showed spoligotypes described in the international databases (SpolDB4, SITVIT), and 21 (22.6%) showed unidentified patterns. The most frequent spoligotype families were Latin American Mediterranean (LAM) (26 isolates), followed by the T family (24 isolates) and Haarlem (H) (11 isolates), which together accounted for 65.4% of all the isolates. These three families represent the major genotypes found in Africa, Central America, South America and Europe. Six Spoligo-International-types (designated SITs by the database) comprised 51.8% (37/72) of all the identified spoligotypes (SIT53, SIT50, SIT42, SIT60, SIT17 and SIT1). Other SITs found in this study indicated the great genetic diversity of M. tuberculosis, reflecting the remarkable ethnic diversity of São Paulo city inhabitants. The MIRU technique was more discriminatory and did not identify any genetic clusters with 100% similarity among the 93 isolates. The allelic analysis showed that MIRU loci 26, 40, 23 and 10 were the most discriminatory. When MIRU and spoligotyping techniques were combined, all isolates grouped in the 13 spoligotyping clusters were separated.Conclusions
Our data indicated the genomic stability of over 50% of spoligotypes identified in São Paulo and the great genetic diversity of M. tuberculosis isolates in the remaining SITs, reflecting the large ethnic mix of the São Paulo city inhabitants. The results also indicated that in this city, M. tuberculosis isolates acquired drug resistance independently of genotype and that resistance was more dependent on the selective pressure of treatment failure and the environmental circumstances of patients.17.
Daniel CB Jeffery Naoko Kakusho Zhiying You Marlene Gharib Brandon Wyse Erin Drury Michael Weinreich Pierre Thibault Alain Verreault Hisao Masai Krassimir Yankulov 《Cell cycle (Georgetown, Tex.)》2015,14(1):74-85
Chromatin Assembly Factor I (CAF-I) plays a key role in the replication-coupled assembly
of nucleosomes. It is expected that its function is linked to the regulation of the cell
cycle, but little detail is available. Current models suggest that CAF-I is recruited to
replication forks and to chromatin via an interaction between its Cac1p subunit and the
replication sliding clamp, PCNA, and that this interaction is stimulated by the kinase
CDC7. Here we show that another kinase, CDC28,
phosphorylates Cac1p on serines 94 and 515 in early S phase and regulates its association
with chromatin, but not its association with PCNA. Mutations in the Cac1p-phosphorylation
sites of CDC28 but not of CDC7 substantially reduce the
in vivo phosphorylation of Cac1p. However, mutations in the putative
CDC7 target sites on Cac1p reduce its stability. The association of
CAF-I with chromatin is impaired in a cdc28–1 mutant and to a
lesser extent in a cdc7–1 mutant. In addition, mutations in the
Cac1p-phosphorylation sites by both CDC28 and CDC7
reduce gene silencing at the telomeres. We propose that this phosphorylation represents a
regulatory step in the recruitment of CAF-I to chromatin in early S phase that is distinct
from the association of CAF-I with PCNA. Hence, we implicate CDC28 in the
regulation of chromatin reassembly during DNA replication. These findings provide novel
mechanistic insights on the links between cell-cycle regulation, DNA replication and
chromatin reassembly. 相似文献
18.
Two contrasting approaches have been used to construct the overall tree of life from molecular data: one involves the analysis of single large datasets, while the other involves joining many independent smaller analyses into a supertree. A recent study uses the latter approach to produce the most complete phylogeny yet of flowering plant families. 相似文献
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