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51.
Lara S. Kallander David G. Washburn Tram H. Hoang James S. Frazee Patrick Stoy Latisha Johnson Qing Lu Marlys Hammond Linda S. Barton Jaclyn R. Patterson Leonard M. Azzarano Rakesh Nagilla Kevin P. Madauss Shawn P. Williams Eugene L. Stewart Chaya Duraiswami Eugene T. Grygielko Xiaoping Xu Nicholas J. Laping Jeffrey D. Bray Scott K. Thompson 《Bioorganic & medicinal chemistry letters》2010,20(1):371-374
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein. 相似文献
52.
Rogier AM Quax Jan W Koper Pascal HP de Jong Ramona van Heerebeek Angelique E Weel Anne M Huisman Derkjen van Zeben Frank H de Jong Steven WJ Lamberts Johanna MW Hazes Richard A Feelders 《Arthritis research & therapy》2012,14(4):R195
Introduction
Genetic and disease-related factors give rise to a wide spectrum of glucocorticoid (GC) sensitivity in rheumatoid arthritis (RA). In clinical practice, GC treatment is not adapted to these differences in GC sensitivity. In vitro assessment of GC sensitivity before the start of therapy could allow more individualized GC therapy. The aim of the study was to investigate the association between in vitro and in vivo GC sensitivity in RA.Methods
Thirty-eight early and 37 established RA patients were prospectively studied. In vitro GC sensitivity was assessed with dexamethasone-induced effects on interleukin-2 (IL-2) and glucocorticoid-induced leucine zipper (GILZ) messenger RNA expression in peripheral blood mononuclear cells (PBMCs). A whole-cell dexamethasone-binding assay was used to measure number and affinity (1/KD) of glucocorticoid receptors (GRs).In vivo GC sensitivity was determined by measuring the disease activity score (DAS) and health assessment questionnaire disability index (HAQ-DI) score before and after 2 weeks of standardized GC treatment.Results
GR number was positively correlated with improvement in DAS. IL-2-EC50 and GILZ-EC50 values both had weak near-significant correlations with clinical improvement in DAS in intramuscularly treated patients only. HAQ responders had lower GILZ-EC50 values and higher GR number and KD.Conclusions
Baseline cellular in vitro glucocorticoid sensitivity is modestly associated with in vivo improvement in DAS and HAQ-DI score after GC bridging therapy in RA. Further studies are needed to evaluate whether in vitro GC sensitivity may support the development of tailor-made GC therapy in RA. 相似文献53.
Diahann TSL Jansen Hanane el Bannoudi Ramon Arens Kim LL Habets Marjolijn Hameetman Tom WJ Huizinga Jeroen N. Stoop René EM Toes 《Arthritis research & therapy》2015,17(1)
IntroductionAbatacept is a fusion protein of human cytotoxic T-lymphocyte–associated protein (CTLA)-4 and the Fc portion of human immunoglobulin G1 (IgG1). It is believed to be effective in the treatment of rheumatoid arthritis by inhibiting costimulation of T cells via blocking CD28–B7 interactions as CTLA-4 binds to both B7.1 (CD80) and B7.2 (CD86). However, the interaction of CD28 with B7 molecules is crucial for activation of naive cells, whereas it is unclear whether the action of already activated CD4+ T cells, which are readily present in established disease, also depends on this interaction. The aim of this study was to determine whether the mode of action of abatacept depends solely on its ability to halt T cell activation in established disease.MethodsArthritis was induced in thymectomized male DBA/1 mice by immunisation with bovine collagen type II. The mice were subsequently depleted for CD4+ T cells. Abatacept or control treatment was started when 80 % of the mice showed signs of arthritis. Arthritis severity was monitored by clinical scoring of the paws, and anti-collagen antibody levels over time were determined by enzyme-linked immunosorbent assay.ResultsTreatment with abatacept in the absence of CD4+ T cells resulted in lower disease activity. This was associated with decreasing levels of collagen-specific IgG1 and IgG2a antibodies, whereas the antibody levels in control or CD4+ T cell–depleted mice increased over time.ConclusionsThese results show that abatacept decreased disease activity in the absence of CD4+ T cells, indicating that the mode of action of abatacept in established arthritis does not depend entirely on its effects on CD4+ T cell activation. 相似文献
54.
James W. Pennebaker Cindy K. Chung Joey Frazee Gary M. Lavergne David I. Beaver 《PloS one》2014,9(12)
The smallest and most commonly used words in English are pronouns, articles, and other function words. Almost invisible to the reader or writer, function words can reveal ways people think and approach topics. A computerized text analysis of over 50,000 college admissions essays from more than 25,000 entering students found a coherent dimension of language use based on eight standard function word categories. The dimension, which reflected the degree students used categorical versus dynamic language, was analyzed to track college grades over students'' four years of college. Higher grades were associated with greater article and preposition use, indicating categorical language (i.e., references to complexly organized objects and concepts). Lower grades were associated with greater use of auxiliary verbs, pronouns, adverbs, conjunctions, and negations, indicating more dynamic language (i.e., personal narratives). The links between the categorical-dynamic index (CDI) and academic performance hint at the cognitive styles rewarded by higher education institutions. 相似文献
55.
De Rooy DP Willemze A Mertens B Huizinga TW Van der Helm-van Mil AH 《Arthritis research & therapy》2011,13(5):R180
Introduction
Studies investigating genetic risk factors for susceptibility to rheumatoid arthritis (RA) studied anti-citrullinated peptide antibody (CCP)-positive RA more frequently than anti-CCP-negative RA. One of the reasons for this is the perception that anti-CCP-negative RA may include patients that fulfilled criteria for RA but belong to a wide range of diagnoses. We aimed to evaluate the validity of this notion and explored whether clinical subphenotypes can be discerned within anti-CCP-negative RA. 相似文献56.
Audrey Leprince Mark WJ van Passel Vitor AP Martins dos Santos 《Current opinion in biotechnology》2012,23(5):651-658
Highlights? Top-down and bottom-up approaches to genome streamlining. ? Computational support for constructing and refactoring streamlined genomes. ? From genome engineering to metabolic reprogramming. ? Perspectives in applied genome engineering. 相似文献
57.
YK Onno Teng Gillian Wheater Vanessa E Hogan Philip Stocks EW Nivine Levarht Tom WJ Huizinga Rene EM Toes Jacob M van Laar 《Arthritis research & therapy》2012,14(2):R57
Introduction
B-cell depletion has become a common treatment strategy in anti-TNF-refractory rheumatoid arthritis (RA). Although the exact mechanism of how B-cell depletion leads to clinical amelioration in RA remains to be elucidated, repetitive treatment with B-cell-depleting agents leading to long-term B-cell depletion has been reported to be beneficial. The latter has led to the hypothesis that the beneficial effects of B-cell depletion might act through their influence on pathogenic autoreactive plasma cells.Methods
In this study, we investigated the effects of a fixed retreatment regimen with anti-CD20 mAbs on the humoral (auto)immune system in a cohort of therapy-refractory RA patients.Results
Fixed retreatment led to long-term B-cell depletion in peripheral blood, bone marrow and, to a lesser extent, synovium. Also, pathologic autoantibody secretion (that is, anticitrullinated peptide antibodies (ACPAs)) was more profoundly affected by long-term depletion than by physiological protective antibody secretion (that is, against measles, mumps and rubella). This was further illustrated by a significantly shorter estimated life span of ACPA-IgG secretion compared to total IgG secretion as well as protective antibody secretion.Conclusion
By studying plasma cell function during an extensive 2-year period of B-cell depletion, autoantibody secretion was significantly shorter-lived than physiologically protective antibody secretion. This suggests that the longevity of autoreactive plasma cells is different from protective long-lived plasma cells and might indicate a therapeutic window for therapies that target plasma cells. 相似文献58.
Leon GJ Tertoolen Christophe Blanchetot Guoqiang Jiang John Overvoorde Theodorus WJ Gadella Jr Tony Hunter Jeroen den Hertog 《BMC cell biology》2001,2(1):8-14
Background
Dimerization is an important regulatory mechanism of single membrane-spanning receptors. For instance, activation of receptor protein-tyrosine kinases (RPTKs) involves dimerization. Structural, functional and biochemical studies suggested that the enzymatic counterparts of RPTKs, the receptor protein-tyrosine phosphatases (RPTPs), are inhibited by dimerization, but whether RPTPs actually dimerize in living cells remained to be determined. 相似文献59.
Thomas WJ Huizinga 《Arthritis research & therapy》2001,3(4):241-1
This is a brief review of the third volume of the series edited by AN Theofilopoulos, "Current Directions in Autoimmunity". This hard-cover volume comprises 282 pages, 46 figures and 14 tables. The book has a cover price of 196 Swiss Francs, or 255 Deutschmarks, or 170.50 US dollars. 相似文献
60.
Hanna W van Steenbergen Luis Rodríguez-Rodríguez Ewa Berglin Alexandra Zhernakova Rachel Knevel Jose Ivorra-Cortés Tom WJ Huizinga Benjamin Fernández-Gutiérrez Peter K Gregersen Solbritt Rantap??-Dahlqvist Annette HM van der Helm-van Mil 《Arthritis research & therapy》2015,17(1)
IntroductionThe severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.MethodsIn total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.ResultsNo associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10−7); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10−8. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.ConclusionVariants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.