1,721,272 research outputs found
Role of "B-cell activating factor" (BAFF) and B-cells in lung and skin fibrosis in systemic sclerosis
No full textLa sclérodermie systémique (ScS) est une maladie autoimmune rare qui se caractérise par une fibrose cutanée et parfois pulmonaire. Nous avons tout d’abord évalué le rôle de BAFF, une cytokine impliquée dans le développement des lymphocytes B (LB), dans la fibrose pulmonaire induite par la bléomycine chez la souris. Nous avons démontré que BAFF était augmenté en réponse à la bléomycine et que les souris BAFF-/- ou traitées par le BAFF-R-Ig sont protégées de la fibrose pulmonaire. Ensuite, nous avons évalué si les LB et BAFF pouvaient moduler la production de collagène par des fibroblastes de peau isolés de patients atteints de ScS. Nous avons démontré que les LB augmentent la production de collagène et de cytokines impliquées dans la fibrose cutanée et l’ajout de BAFF augmente cet effet des LB sur les fibroblastes. Enfin, nous avons étudié la régulation de l’expression de BAFF par les microARNs. Nos résultats montrent que les miR-30a*, d* et e* ciblent directement l’ARNm de BAFF.Systemic sclerosis (SSc) is a rare autoimmune disease characterized by skin fibrosis and occasionally pulmonary fibrosis. We first assessed the role of BAFF, a cytokine involved in B cell maturation, in bleomycin-induced pulmonary fibrosis in mice. We showed that BAFF was increased in response to bleomycin and that BAFF-/- mice or BAFF-R-Igtreated mice are protected from pulmonary fibrosis. Then, we assessed whether B cells and BAFF could regulate collagen production by skin fibroblasts isolated from SSc patients. We demonstrated that B cells increase collagen production and cytokines involved in skin fibrosis. The addition of BAFF increases the effect of B cells on fibroblasts. Lastly, we studied the regulation of BAFF expression by microRNAs. Our results show that miR-30a*, d* and e* directly target the BAFF mRNA
Identification of new therapeutic targets in primary Sjögren's syndrome (pSS)
No full textL’objectif de cette thèse était d’identifier de nouvelles cibles thérapeutiques dans le syndrome de Sjögren primitif (SJp). Par nos 3 approches variées mais complémentaires, nous avons été en mesure de confirmer l’intérêt de cibler BAFF, une molécule cruciale pour la survie et l’activation des LB, combiné à une déplétion B. Cette efficacité passe, au moins en partie, par l’accumulation de Trég. Notre étude de repositionnement thérapeutique, basée sur une analyse transcriptomique, a permis de confirmer l’intérêt de cibles les interférons dans le SJp. Elle a également identifié de potentielles nouvelles cibles thérapeutiques, les HDAC et les PI3K. Enfin, notre recherche de nouveaux acteurs potentiellement impliqués dans la physiopathologie du SJp nous a mené vers les innate lymphoid cells (ILC). A l’instar des Trég, cette population cellulaire rare et longtemps méconnue pourrait jouer un rôle pathogène important. Nos résultats suggèrent que les ILC3 pourraient être à l’origine de la mise en place des infiltrats lymphocytaires au sein des glandes salivaires. Ainsi, ce travail complète notre connaissance de la physiopathologie du SJp et ouvre de nouvelles perspectives thérapeutiques.The aim of this thesis was to identify new therapeutic targets in primary Sjögren's syndrome (pSS). Using our 3 varied but complementary approaches, we were able to confirm the value of targeting BAFF, a molecule that is crucial for the survival and activation of B cells, combined with B depletion. Our drug repurposing study, based on transcriptomic analysis, confirmed the value of targeting interferons in pSS. It also identified potential new therapeutic targets, HDACs and PI3Ks. Finally, our search for new actors potentially involved in the pathophysiology of pSS led us to innate lymphoid cells (ILCs). Like Tregs, this rare and long-ignored cell population could play an important pathogenic role. Our results suggest that ILC3 may be responsible for the development of lymphocytic infiltrates in the salivary glands. This work adds to our knowledge of the pathophysiology of pSS and opens up new therapeutic prospects
Body mass does not impact the clinical response to intravenous abatacept in patients with rheumatoid arthritis. Analysis from the “pan-European registry collaboration for abatacept (PANABA)
No full textSome evidences suggest that obesity impairs the effectiveness of TNF inhibitors. We examined the impact of body mass index (BMI) on the clinical effectiveness of abatacept in rheumatoid arthritis (RA) patients. This is a pooled analysis of 10 prospective cohorts of RA patients. All patients with available BMI were included in this study. The primary endpoint was drug retention of abatacept in the different BMI categories. Multivariable Cox regression was used to estimate hazard ratios (HRs) for drug discontinuation. A secondary endpoint was EULAR/LUNDEX response rates at 6/12 months. Of the 2015 RA patients initiating therapy with IV abatacept, 380 (18.9%) were classified as obese. Obese patients had more functional disability, and were less often RF positive. The median abatacept retention time was 1.91 years for obese RA patients compared to 2.12 years for non-obese patients (p = 0.15). The risk of abatacept discontinuation was not significantly different for overweight (HR 1.03 (95% CI 0.89–1.19)), or for obese (HR 1.08 (95% CI 0.89–1.30)) compared to normal-weight patients. Rheumatoid factor positivity reduced the risk of abatacept discontinuation (HR 0.83 (95% CI 0.72–0.95)), while previous biologic therapy was positively associated with drug interruption (HRs increasing from 1.68 to 2.16 with the line of treatments). Obese and non-obese patients attained similar rates of EULAR/LUNDEX clinical response at 6/12 months. Drug retention and clinical response rates to abatacept do not seem to be decreased by obesity in RA patients
High reactive oxygen species in fibrotic and non-fibrotic skin of Patients with diffuse cutaneous systemic sclerosis
No full textpeer reviewedSystemic Sclerosis (SSc) is a chronic multisystemic connective tissue disease characterized by progressive fibrosis affecting skin and internal organs. Despite serious efforts to unveil the pathogenic mechanisms of SSc, they are still unclear. High levels of Reactive Oxygen Species (ROS) in affected patients have been shown, and ROS are suggested to play a role in fibrosis pathogenesis. In this study we evaluate ROS levels in non-fibrotic and fibrotic skin of patients with SSc and we compare them with those obtained from healthy controls.
Patients and Methods
We enrolled 9 SSc patients fulfilling the EULAR/ACR classification criteria and 7 healthy controls. Patients included were 4 men and 5 women with mean age of 46 ±10 yrs. Controls were matched by sex and age. All patients were affected by diffuse cutaneous form of SSc and the ANA pattern anti-Scl70. Mean disease duration was 7.5±5 yrs. Skin involvement was evaluated by modified Rodnan Skin Score (mRSS). Skin samples (4 mm punch biopsy) were taken from fibrotic skin and non-fibrotic skin of patients and from healthy controls as well. To detect ROS, specimens were analyzed immediately after sampling by electron paramagnetic resonance spectroscopy. Blood samples have been drawn from all patients and controls to assess oxidative stress biomarkers.
Results
ROS levels (expressed as median and range, unit of measurement was nmol/l/min/mg of dry weight) were 24.7 (10.9– 47.0) in fibrotic skin, 18.7 (7.3–34.0) in non-fibrotic skin and 7.7 (3.5–13.6) in healthy controls skin. ROS levels in Fibrotic and Non-fibrotic skin of SSc patients were significantly higher than in Healthy Controls (p=0.002 and p=0.009, respectively). ROS levels in fibrotic skin were raised in comparison to non-fibrotic skin, when samples related to each patient were compared (p=0.01). ROS levels in fibrotic skin were correlated with forced vital capacity (r= -0.75, p=0.02) and erythrocyte sedimentation rate (r=0.70, p=0.04). All other clinical and lab parameters showed no significant correlation. When compared to controls, blood from SSc patients showed lower ascorbate (vitamin C) levels (8 [3.8-9.8] vs. 10.5 [9-19.1] mg/L, p=0.004) and higher lipid peroxides (873.5 [342-1973] vs. 422 [105-576] μmol/L, p=0.004).
Conclusion
Our results indicate the presence of high oxidative stress both in non-fibrotic skin and fibrotic skin of SSc patients, but with higher tendency in the latter. Raised ROS levels in non-fibrotic skin of SSc patients might be a hint of early involvement in skin fibrogenesis. However, a longitudinal prospective study is necessary for such proof
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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