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排序方式: 共有208条查询结果,搜索用时 656 毫秒
1.
Tom Rossenbacker MD Sheila J. Carroll MD Huajun Liu MD Cuno Kuipri Thomy J.L. de Ravel FCP Koen Devriendt MD PhD Peter Carmeliet MD PhD Robert S. Kass PhD Hein Heidbüchel MD PhD 《Heart rhythm》2004,1(5):611-615
OBJECTIVES: The purpose of this study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation. BACKGROUND: Brugada syndrome and isolated cardiac conduction defect have been linked to SCN5A mutations. METHODS: Eleven members of a western European family underwent electrophysiologic investigations and mutation analysis of the SCN5A gene. Wild-type and mutant SCN5A channels were expressed in HEK293 cells, and whole cell currents were studied using patch clamp procedures. RESULTS: A novel mutation, R376H, in the first pore segment of SCN5A variably causes Brugada syndrome and/or conduction disease in a single family. Biophysical analysis demonstrated a significant current reduction for the mutant, a pathophysiologic profile consistent with Brugada syndrome and isolated cardiac conduction defect. Among 11 family members, 9 were carriers of the mutation. The proband's initial presentation was a saddleback Brugada ECG, atrial flutter, and diffuse conduction disturbances. He had no inducible ventricular arrhythmias but experienced sudden cardiac death. His brother was affected by atrial flutter and had a clear conduction disorder, but he did not display baseline or evocable ECG signs of Brugada syndrome. He received an implantable cardioverter-defibrillator that delivered one appropriate shock after 1 year of follow-up. The phenotype in the family members was highly variable and ranged from noninducible and inducible asymptomatic carriers of the mutations to isolated conduction disease and to symptomatic Brugada syndrome. CONCLUSIONS: We describe the functional characterization of a novel SCN5A pore mutation, R376H, with variable clinical expression in the same family. Differentiating between electrophysiologic entities (Brugada syndrome-isolated cardiac conduction defect) is more challenging. Recognition of factors modifying the clinical presentation may be important for clinical decision making. 相似文献
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Nieborowska-Skorska M Kopinski PK Ray R Hoser G Ngaba D Flis S Cramer K Reddy MM Koptyra M Penserga T Glodkowska-Mrowka E Bolton E Holyoake TL Eaves CJ Cerny-Reiterer S Valent P Hochhaus A Hughes TP van der Kuip H Sattler M Wiktor-Jedrzejczak W Richardson C Dorrance A Stoklosa T Williams DA Skorski T 《Blood》2012,119(18):4253-4263
Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML. 相似文献
4.
A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies the mutation pattern for PD166326, an alternative Abl kinase inhibitor 总被引:2,自引:5,他引:2
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von Bubnoff N Veach DR van der Kuip H Aulitzky WE Sänger J Seipel P Bornmann WG Peschel C Clarkson B Duyster J 《Blood》2005,105(4):1652-1659
In Philadelphia-positive (Ph(+)) leukemia, point mutations within the Bcr-Abl kinase domain emerged as a major mechanism of resistance to imatinib mesylate. We established a cell-based screening strategy for detection of clinically relevant point mutations using Bcr-Abl-transformed Ba/F3 cells. We identified 32 different single-point mutations within the kinase domain of Bcr-Abl. The pattern and frequency of mutations in this cell culture-based screen resembled the pattern and frequency observed in resistant patients. We then applied this screen to an alternative Abl kinase inhibitor. Using PD166326, the frequency of resistant colonies emerging at 5 to 10 times the median growth inhibition (IC50) of PD166326 was significantly lower than with imatinib. In addition, PD166326 produced a distinct pattern of Bcr-Abl mutations. The majority of mutations that came up with both imatinib and PD166326 could effectively be suppressed by increasing the dose of PD166326 to 50 to 500 nM. In contrast, only a few mutations could be suppressed by increasing the imatinib dose to 5 to 10 microM. However, 3 mutations affecting F317 displayed complete resistance to PD166326, but could be effectively inhibited by standard concentrations of imatinib. Thus, this robust and simple screening system provides a rational basis for combinatorial and sequential treatment strategies in targeted cancer therapy. 相似文献
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Engelbert RH Uiterwaal CS Gulmans VA Pruijs HE Helders PJ 《European journal of pediatrics》2000,159(8):615-620
This study was performed to achieve more detailed information regarding the age and sequence in the development of motor
milestones in the different types of osteogenesis imperfecta (OI). The parents of 98 patients with a diagnosis of OI were
sent a questionnaire regarding the age at which patients achieved motor milestones. All patients were attending the outpatient
clinic for children with OI at the Wilhelmina Children's Hospital. The motor milestones were classified into static motor
milestones and dynamic motor milestones and all data were checked with health care records. The age of development of motor
milestones was compared to reference values of the healthy population. The severity of the disease was classified according
to Sillence based on clinical, genetic and radiological data. The age of intramedullary rodding of the first nail in the lower
and upper extremity and the localisation was noted. A total of 76 parents responded to the 98 questionnaires (78%). In OI
type I, a delay exists in achieving motor milestones, comparable to the 95th percentile of the normal population. In type
III, the development of all motor milestones was significantly delayed compared to types I and IV with a discrepancy between
static and dynamic milestones. In OI type IV, a retardation in motor development developed after the milestone `sitting without
support' was achieved. Motor development in types I and IV was not influenced by intramedullary rodding of the lower extremities,
since rodding was rarely performed before the milestone `unsupported standing' was achieved. In type III, the influence of
intramedullary rodding on the age of achieving motor milestones remains questionable.
Conclusion The severity of osteogenesis imperfecta has a large influence on the age and sequence in the development of motor milestones.
No influence of intramedullary rodding of the lower extremities on motor development was found in osteogenesis imperfecta
types I and IV, whereas the influence in type III remains questionable.
Received: 11 November 1999 and in revised form: 9 February 2000 and 24 February 2000 Accepted: 24 February 2000 相似文献
7.
c-erbB2 and topoisomerase IIalpha protein expression independently predict poor survival in primary human breast cancer: a retrospective study 总被引:1,自引:0,他引:1
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Fritz P Cabrera CM Dippon J Gerteis A Simon W Aulitzky WE van der Kuip H 《Breast cancer research : BCR》2005,7(3):R374-R384
Introduction
c-erbB2 (also known as HER-2/neu) and topoisomerase IIα are frequently overexpressed in breast cancer. The aim of the study was to analyze retrospectively whether the expression of c-erbB2 and topoisomerase IIα protein influences the long-term outcome of patients with primary breast cancer.Methods
In this study c-erbB2 and topoisomerase IIα protein were evaluated by immunohistochemistry in formalin-fixed paraffin-embedded tissue from 225 samples of primary breast cancer, obtained between 1986 and 1998. The prognostic value of these markers was analyzed.Results
Of 225 primary breast tumor samples, 78 (34.7%) showed overexpression of either c-erbB2 (9.8%) or topoisomerase IIα protein (24.9%), whereas in 21 tumors (9.3%) both proteins were found to be overexpressed. Patients lacking both c-erbB2 and topoisomerase IIα overexpression had the best long-term survival. Overexpression of either c-erbB2 or topoisomerase IIα was associated with shortened survival, whereas patients overexpressing both c-erbB2 and topoisomerase IIα showed the worst disease outcome (P < 0.0001). Treatment with anthracyclines was not capable of reversing the negative prognostic impact of topoisomerase IIα or c-erbB2 overexpression.Conclusion
The results of this exploratory study suggest that protein expression of c-erbB2 and topoisomerase IIα in primary breast cancer tissues are independent prognostic factors and are not exclusively predictive factors for anthracycline response in patients with primary breast cancer. 相似文献8.
Noordzij M Uiterwaal CS Arends LR Kok FJ Grobbee DE Geleijnse JM 《Journal of hypertension》2005,23(5):921-928
PURPOSE: Coffee is a widely consumed beverage and small health effects of substances in coffee may have large public health consequences. It has been suggested that caffeine in coffee increases the risk of hypertension. We performed a meta-analysis of randomized controlled trials of coffee or caffeine and blood pressure (BP). DATA IDENTIFICATION: BP trials of coffee or caffeine published between January 1966 and January 2003 were identified through literature databases and manual search. STUDY SELECTION: A total of 16 studies with a randomized, controlled design and at least 7 days of intervention was selected, comprising 25 strata and 1010 subjects. DATA EXTRACTION: Two persons independently obtained data on sample size, type and duration of intervention, changes in BP and heart rate (HR), and subjects' characteristics for each trial. Meta-analysis was performed using a random-effects model. RESULTS: A significant rise of 2.04 mmHg [95% confidence interval (CI), 1.10-2.99] in systolic BP and 0.73 mmHg (95% CI, 0.14-1.31) in diastolic BP was found after pooling of coffee and caffeine trials. When coffee trials (n = 18, median intake: 725 ml/day) and caffeine trials (n = 7, median dose: 410 mg/day) were analysed separately, BP elevations appeared to be larger for caffeine [systolic: 4.16 mmHg (2.13-6.20); diastolic: 2.41 mmHg (0.98-3.84)] than for coffee [systolic: 1.22 mmHg (0.52-1.92) and diastolic: 0.49 mmHg (-0.06-1.04)]. Effects on HR were negligible. CONCLUSIONS: Regular caffeine intake increases BP. When ingested through coffee, however, the blood pressure effect of caffeine is small. 相似文献
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