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Η επίδραση του abatacept στη λειτουργία των ανθρώπινων δενδριτικών κυττάρων
No full textΗ πλήρης ενεργοποίηση και διαφοροποίηση των Τ-κυττάρων ρυθμίζεται
από μια λεπτή ισορροπία μεταξύ θετικών και αρνητικών σημάτων, τα οποία
παρέχονται από συν-διεγερτικά και συν-ανασταλτικά μόρια αντίστοιχα, σε
συνδυασμό με το σήμα που παρέχεται από τον υποδοχέα των Τ-κυττάρων (TCR). Το
σημαντικότερο ανασταλτικό μόριο στην επιφάνεια των Τ-κυττάρων είναι το CTLA-4,
ένα μόριο δομικά ομόλογο με το CD28, το οποίο συνδέεται με Β7 συνδέτες
(CD80/CD86) στην επιφάνεια των επαγγελματικών αντιγονοπαρουσιαστικών
κυττάρων για να τερματίσει τις Τ-κυτταρικές αποκρίσεις. Ποντίκια στα οποία λείπει
το CTLA-4 αναπτύσσουν μια ανεξέλεγκτη ανοσιακή αντίδραση και τελικά
υποκύπτουν σε μια σοβαρή λεμφουπερπλαστική νόσο από Τ- κύτταρα. Η ικανότητα
του CTLA-4 να μπλοκάρει την ενεργοποίηση των Τ-κυττάρων έχει αξιοποιηθεί
θεραπευτικά για την αντιμετώπιση της υπερβολικής ενεργοποίησης του
ανοσολογικού συστήματος στα αυτοάνοσα νοσήματα. Το abatacept είναι μιία
ανασυνδυασμένη πρωτεΐνη που αποτελείται από το εξωκυττάριο τμήμα του CTLA-4
ενωμένο με το Fc τμήμα της ανθρώπινης IgG (CTLA4-Ig) και κατασκευάστηκε ως
ένας διαλυτός ανταγωνιστής του CD28. Απ’ το Δεκέμβριο του 2005, το abatacept
είναι το πρώτο φάρμακο που στοχεύει εκλεκτικά τη συν-ενεργοποίηση των Τ-
κυττάρων, εγκεκριμένο για τη θεραπεία ασθενών με ρευματοειδή αρθρίτιδα.
Τα δενδριτικά κύτταρα αποτελούν μια ετερογενή ομάδα κυττάρων με
πολλαπλές υποομάδες, τα οποία μπορούν υπό διαφορετικές προϋποθέσεις να
προάγουν είτε ανοσία είτε ανοχή στην περιφέρεια. Παρά το ότι σαφή,
συγκεκριμένα χαρακτηριστικά των κυττάρων αυτών που προάγουν την ανοχή δεν
έχουν ταυτοποιηθεί, είναι γενικά παραδεκτό ότι ο μειωμένος βαθμος ωριμότητας, η
έκφραση ανασταλτικών μορίων επιφανείας και η παραγωγή «ενζύμων ανοχής»,
όπως το IDO, είναι σημαντικά χαρακτηριστικά για ένα φαινότυπο ανοχής.
Παρά το ότι ο ανταγωνισμός με το CD28 για τα μόρια CD80 και CD86
θεωρείται ο κύριος μηχανισμός δράσης του abatacept, ο ακριβής τρόπος δράσης
του χρήζει περαιτέρω διερεύνησης. Ο σκοπός της παρούσας μελέτης ήταν η
εκτίμηση της δυνατότητας του abatacept να δημιουργήσει ανθρώπινα δενδριτικά
κύτταρα με ικανότητες προαγωγής ανοχής τόσο σε υγιείς όσο και σε ασθενείς με
ΡΑ. Συγκεκριμένα, εξετάστηκε η ικανότητα δενδριτικών κυττάρων, επωασθέντων
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προηγουμένως με abatacept, να αναστέλλουν τον πολλαπλασιασμό αλλογενών Τ-
κυττάρων και δευτερευόντως εξετάστηκε ο μηχανισμός αυτής της αναστολής.
Σύμφωνα με τα αποτελέσματα μας, η χορήγηση abatacept δεν ήταν ικανή να
«δημιουργήσει» δενδριτικά κύτταρα με τη δυνατότητα κατόπιν να μπλοκάρουν τον
πολλαπλασιασμό αλλογενών Τ-κυττάρων σε μια μεικτή λεμφοκυτταρική αντίδραση.
Το abatacept δε φάνηκε να προκαλεί ούτε αύξηση της παραγωγής IDO στα
δενδριτικά κύτταρα αλλά ούτε και αλλαγές στην έκφραση μορίων επιφανείας των
δενδριτικών κυττάρων, όπως τα ICOS-L και PD-L1, τα οποία θα μπορούσαν δυνητικά
να προκαλέσουν ένα φαινότυπο ανοχής στα κύτταρα αυτά.T-cell activation and effector function is regulated by a delicate fine-tuning of
antagonistic positive and negative signals carried out by costimulatory and
coinhibitory molecules respectively, in conjunction to the signal provided by the Tcell
receptor. Probably the most important inhibitory molecule on the surface of Tcells
is CTLA-4, a molecule structurally homologous to CD28, which binds to B7
ligands (CD80/CD86) on the surface of professional antigen-presenting cells (APCs) to
terminate T- cell responses. CTLA-4 knockout mice develop an uncontrolled
deleterious immune response and eventually succumb to a serious T-cell
lymphoproliferative disorder. The ability of CTLA-4 to block the activation of T-cells
has been therapeutically exploited for the attenuation of excessive immune system
activation in autoimmune diseases. Abatacept is a recombinant protein consisting of
the extracellular domain of human CTLA-4 fused to the Fc portion of human IgG1
(CTLA4-Ig) and was developed as a soluble CD28 antagonist. Since December 2005,
abatacept is the first FDA approved T-cell costimulation modulator for the treatment
of patients with rheumatoid arthritis.
Dendritic cells constitute a heterogeneous group of cells with multiple
subsets that are able, under different circumstances, to induce either immunity or
tolerance in the periphery. While a unique tolerogenic “signature” for DCs has not
yet been established and is not restricted to one specific DC subset, it is generally
accepted that an immature state, high net expression of co-inhibitory molecules and
production of tolerogenic enzymes, such as indoleamine 2,3 deoxygenase (IDO), are
important, though not the sole, prerequisites for a tolerogenic DC phenotype.
Although competition with CD28 for binding to CD80 and CD86 is considered
to be the major mechanism by which abatacept blocks T-cell activation, its complete
mode of action still remains to be elucidated. The aim of the present study was to
investigate the ability of abatacept to influence the tolerogenic properties of human
DCs both in healthy subjects as well as in RA settings. Specifically, we examined
whether abatacept can induce DCs with a tolerogenic phenotype by assessing the
ability of abatacept-treated DCs to block the proliferation of responder T-cells and
attempted to delineate the mechanism of this inhibition.
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In our study, treatment of human DCs with abatacept was insufficient to halt
the proliferation of allogeneic T-cells in a mixed leukocyte reaction. Abatacept was
unable to induce either IDO upregulation inside DCs or changes in the expression of
potential tolerogenic surface markers of DCs, such as ICOS-L or PD-L1
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
2019 update of the EULAR recommendations for the management of systemic lupus erythematosus
Full text linkOur objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.</p
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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