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Michael J. Monument Kirsten M. Johnson Elizabeth McIlvaine Lisa Abegglen W. Scott Watkins Lynn B. Jorde Richard B. Womer Natalie Beeler Laura Monovich Elizabeth R. Lawlor Julia A. Bridge Joshua D. Schiffman Mark D. Krailo R. Lor Randall Stephen L. Lessnick 《PloS one》2014,9(8)
Background
The genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood. EWS/FLI and related EWS/ETS chimeras upregulate numerous gene targets via promoter-based GGAA-microsatellite response elements. These microsatellites are highly polymorphic in humans, and preliminary evidence suggests EWS/FLI-mediated gene expression is highly dependent on the number of GGAA motifs within the microsatellite.Objectives
Here we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the NR0B1 promoter (a critical EWS/FLI target) in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes.Results
A complex, bimodal pattern of EWS/FLI-mediated gene expression was observed across a wide range of GGAA motifs, with maximal expression observed in constructs containing 20–26 GGAA motifs. Relative to white European and African controls, the NR0B1 GGAA-microsatellite in tumor cells demonstrated a strong bias for haplotypes containing 21–25 GGAA motifs suggesting a relationship between microsatellite function and disease susceptibility. This selection bias was not a product of microsatellite instability in tumor samples, nor was there a correlation between NR0B1 GGAA-microsatellite polymorphisms and survival outcomes.Conclusions
These data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma. 相似文献2.
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Naoki Kubo Hidehiro Toh Kenjiro Shirane Takayuki Shirakawa Hisato Kobayashi Tetsuya Sato Hidetoshi Sone Yasuyuki Sato Shin-ichi Tomizawa Yoshinori Tsurusaki Hiroki Shibata Hirotomo Saitsu Yutaka Suzuki Naomichi Matsumoto Mikita Suyama Tomohiro Kono Kazuyuki Ohbo Hiroyuki Sasaki 《BMC genomics》2015,16(1)
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Julia Sieber Capucine Daridon Sarah J Fleischer Vanessa Fleischer Falk Hiepe Tobias Alexander Guido Heine Gerd R Burmester Simon Fillatreau Thomas D?rner 《Arthritis research & therapy》2014,16(6)
Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with a break in self-tolerance reflected by a production of antinuclear autoantibodies. Since autoantibody production can be activated via nucleic acid Toll-like receptor 9 (TLR9), the respective pathway has been implicated in the development of SLE and pathogenic B cell responses. However, the response of B cells from SLE patients to TLR9 stimulation remains incompletely characterized.Methods
In the current study, the response of B cells from SLE patients and healthy donors upon TLR9 stimulation was analyzed in terms of proliferation and cytokine production and correlated with the lupus disease activity and anti-dsDNA titers.Results
B cells from SLE patients showed a reduced response to TLR9 agonist compared to B cells from healthy donors in terms of proliferation and activation. B cells from SLE patients with higher disease activity produced less interleukin (IL)-6, IL-10, vascular endothelial growth factor, and IL-1ra than B cells from healthy donors. Further analyses revealed an inverse correlation of cytokines produced by TLR9-stimulated B cells with lupus disease activity and anti-dsDNA titer, respectively.Conclusion
The capacity of B cells from lupus patients to produce cytokines upon TLR9 engagement becomes less efficient with increasing disease activity, suggesting that they either enter an exhausted state or become tolerant to TLR stimulation for cytokine production when disease worsens.Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0477-1) contains supplementary material, which is available to authorized users. 相似文献15.
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