1,720,956 research outputs found
RUOLO DI NOTCH3 NELLA MODULAZIONE DELL’ESPRESSIONE DI CXCR4 NEI TIMOCITI IMMATURI
No full text• RIASSUNTO
I recettori Notch (N1, N2 e N3) regolano la scelta differenziativa T (Artavanis-Tsakonas et al., 1999). L'attivazione costitutiva del signaling di Notch è una delle maggiori cause dell’insorgenza della leucemia linfoblastica acuta (T-ALL) nel topo e negli esseri umani.
La funzione di Notch3 come oncogene nella T-ALL è stata dimostrata da un modello murino creato nel nostro laboratorio, caratterizzato dall’espressione costitutiva della forma attiva di Notch3 (N3-IC) nei timociti immaturi (N3-IC Tg) (Bellavia et al., 2000). Nei topi N3-IC Tg è stata osservata una deregolazione della proliferazione e della maturazione nella fase di transizione da preT a T, oltre all'attivazione costitutiva del preTCR (Bellavia et al., 2002).
Il differenziamento delle cellule T dipende da molti segnali forniti dallo stroma, il quale produce citochine, chemochine e ligandi e sostiene i processi maturativi timocitari all'interno del micro-ambiente timico (Sun et al., 2010). In particolare è noto che il recettore di chemochine CXCR4 è espresso sulla superficie dei timociti dallo stadio DN1 (doppi negativi 1) a quello DP (doppi positivi), con un picco di espressione nelle transizioni DN2-DN3 e DN-DP, mentre è completamente assente nei SP (singolo positivi) (Plotkin et al., 2003). Ѐ altresì dimostrato che il signaling cooperativo fra il preTCR, CXCR4 e Notch3 è richiesto nella selezione β per consentire il differenziamento dei timociti T dallo stadio DN a quello DP (Janas et al., 2010). Infatti il fattore derivato dalle cellule stromali SDF-1 (CXCL12) ed il suo recettore CXCR4 promuovono la sopravvivenza dei timociti DN e regolano la migrazione durante la transizione da DN a DP (Plotkin et al., 2003). Inoltre è stato suggerito un ruolo dell'asse CXCR4/SDF-1 nello sviluppo e nella progressione della T-ALL (Scupoli et al., 2008).
Scopo della Tesi di Dottorato è stato lo studio del cross-talk molecolare della via di segnalazione, innescata dall’over-espressione di Notch3 sulla pathway della chemochina CXCR4, come possibile meccanismo deregolatore dei programmi differenziativi intratimici in un modello murino di T-ALL.
Esperimenti al FACS hanno dimostrato una diminuzione nella percentuale di cellule DN CXCR4 positive nel topo N3-IC Tg rispetto al wt, non attribuibile ad alcuna riduzione nel numero totale di timociti DN. Al contrario è stato osservato un incremento dell’espressione di CXCR4 nelle cellule DP. Esperimenti di migrazione ex vivo dei timociti, in risposta al ligando fisiologico, CXCL12, dimostrano una alterata migrazione dei timociti dei topi N3-IC Tg rispetto al wt. Inoltre sono stati eseguiti esperimenti di cell sorting focalizzati all’analisi molecolare della sottopopolazione timocitaria delle DN. I dati sembrano suggerire che l’over-espressione di Notch3 possa compromettere eventi iniziali nella maturazione delle cellule pre-T, riducendo anche l’espressione di EpCAM, una molecola di adesione omotipica coinvolta nell’interazione linfo/stromale del timo. Supponiamo che questi eventi possano essere coinvolti nello sviluppo della T-ALL
CXCR4 deregulated expression in Notch3-induced T cell leukemia
No full textBackground: Constitutive activation of Notch signaling is one of the major
causes of acute T cell lymphoblastic-leukemia (T-ALL). The oncogenic
function of Notch3 in T-ALL was demonstrated by a murine model in our
laboratory, characterized by enforced expression of the Notch3 active
form (N3-IC) in immature thymocytes (N3-ICtg). Deregulated proliferation
and maturation at the preT/T transition phase and constitutive activation of
preTCR were observed in N3-ICtg mice. Cooperative signaling among the
preTCR, CXC chemokine receptor (CXCR) 4 and Notch are required for
double-negative (DN) to double-positive (DP) T cell differentiation (β-
selection). CXCR4 and its ligand (SDF-1) promote DN thymocytes
survival, regulate the migration during the DN/DP transition and have
been recently suggested to play a role in the pathogenesis of T-ALL.
Methods: Freshly isolated thymocytes were analysed by FACS and RTPCR
was performed in sorted DN T cells.
Results: FACS experiments demonstrated a decrease of CXCR4+ cells
in DN-gated thymocytes of N3-ICtg mice with respect to wt, not
attributable to any reduction of DN cell numbers in N3-ICtg mice.Furthermore, reduced CXCR4 gene transcription was observed in
selected DN thymocytes of N3-ICtg with respect to wt mice. Notch3 may
disrupt early events in preT-cell progressive maturation accompanied by
altered migration through the thymus, as further supported by reduced
EpCAM expression, a homotypic adhesion molecule. In contrast, CXCR4
expression per cell was increased in DP-gated cells of N3-ICtg.
Conclusions: We hypothesize that Notch3 may deregulate positioning
and degrees of immature thymocytes in early steps of T-ALL
development
Intrathymic Notch3 and CXCR4 combinatorial interplay facilitates T-cell leukemia propagation.
Get PDFNotch hyperactivation dominates T-cell acute lymphoblastic leukemia development, but the mechanisms underlying "pre-leukemic-cells" dissemination are still unclear. Here we describe how deregulated Notch3 signaling enhances CXCR4 cell-surface expression and migratory ability of CD4+CD8+ thymocytes, possibly contributing to “pre-leukemic” cell propagation, early in disease progression. In transgenic mice overexpressing the constitutively active Notch3 intracellular domain, we detect the progressive increase in circulating blood and bone marrow of CD4+CD8+-cells, characterized by high and combined surface expression of Notch3 and CXCR4. We report for the first time that transplantation of such CD4+CD8+-cells, reveals their competence in infiltrating spleen and bone marrow of immunocompromised recipient mice. We also show that CXCR4 surface expression is central to the migratory ability of CD4+CD8+-cells and that such an expression is regulated by Notch3 through -arrestin in human leukemia cells.
De novo, we propose that hyperactive Notch3 signaling by boosting CXCR4-dependent migration promotes anomalous egression of CD4+CD8+-cells from the thymus in early leukemia stages. In fact, in vivo CXCR4 antagonism prevents bone marrow colonization by such CD4+CD8+ cells in young Notch3 transgenic mice.
Therefore, our data suggest that combined therapies precociously counteracting intrathymic Notch3/CXCR4 crosstalk, may prevent dissemination of “pre-leukemic” CD4+CD8+-cells, by a “thymus-autonomous” mechanism
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
- …
