1,720,972 research outputs found
Leukemic cell/microenvironment interactions in Chronic Lymphocytic Leukemia: role of JAK/STAT axis in the survival of neoplastic clone
Full text linkChronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of mature clonal CD19+/CD5+/CD23+ B lymphocytes in peripheral blood, bone marrow, and lymphoid tissues. Despite their in vivo prolonged lifespan due to intrinsic defects, CLL leukemic cells rapidly undergo spontaneous apoptosis in vitro, highlighting the need of extrinsic signals delivered by the microenvironment.
Several molecules, including those released by mesenchymal stromal cells (MSCs), signal through JAK (Janus kinases)-STAT (signal transducers and activators of transcription) pathways. During the PhD course, we particularly focused on JAK2/STAT3 axis since IL-6, one of the most abundant cytokines released in the CLL microenvironment, is the key ligand of the receptor triggering this pathway. The deregulation of JAK2/STAT3 axis may lead to aberrant activation of STAT3 and, as a result, to tumor development in hematopoietic cells.
By western blotting, flow cytometry analysis, subcellular fractionation, and confocal microscopy, we analyzed 76 CLL patients and 23 healthy donors to investigate STAT3 involvement in CLL cell survival.
We demonstrated that STAT3 expression was higher in malignant B cells (MFI: CLL cells 1.28±0.13 vs normals 0.61±0.09, Student’s t test, p<0.001) and the protein is significantly phosphorylated at Tyr705 compared with the normal counterpart (B lymphocytes from healthy donors) (MFI: CLL cells 211.3±35.85 vs normals 46.50±6.12, Student’s t test, p<0.05), thus showing its constitutive activation in CLL.
Afterwards, we pointed out that the in vitro incubation of leukemic B cells with AG490 and Stattic, specific inhibitors of JAK2 and STAT3, respectively, induce a dose-dependent apoptosis of CLL B cells (e.g. Cell viability, 24h: CLL cells alone 62.90±4.24% vs CLL cells + AG490 50M 38.30±7.22%, Student’s t test, p<0.01; CLL cells alone 60.96±3.91% vs CLL cells + Stattic 10M 31.78±4.31%, Student’s t test, p<0.0001). Both AG490 and Stattic were able to bypass the microenvironmental protection when neoplastic B cells were co-cultured with MSCs (e.g. Cell viability, 48h: CLL cells 66.80±6.28% vs CLL cells + AG490 100M 22.50±7.50%, Student’s t test, p<0.01; CLL cells 57.51±4.95% vs CLL cells + Stattic 10M 26.25±5.45%, Student’s t test, p<0.001).
In addition to JAK2/STAT3 inhibition, we showed that AG490 treatment on CLL cells can mediate other effects: i) it activates SHP-1, decreasing its phosphorylation at Ser591; ii) it inactivates protein Lyn, reducing the phosphorylation in its active site at Tyr396. Lyn, a Tyr-kinase, and SHP-1, a Tyr-phosphatase, are both involved in the prolonged lifespan of neoplastic CLL cells.
In conclusion, the ability of AG490 and Stattic to induce apoptosis in leukemic B cells, bypassing the pro-survival stimuli provided by the tumor microenvironment, represents a starting point for the development of new therapeutic strategies in CLL, providing at the same time new insights on the cross-talk between JAK/STAT and BCR/Lyn axes in CLL cells
Targeting Brutons Tyrosine Kinase in Chronic Lymphocytic Leukemia at the Crossroad between Intrinsic and Extrinsic Pro-survival Signals
Full text linkChemo immunotherapies for chronic lymphocytic leukemia (CLL) showed a positive impact on clinical outcome, but many patients relapsed or become refractory to the available treatments. The main goal of the researchers in CLL is the identification of specific targets in order to develop new therapeutic strategies to cure the disease. The B cell receptor-signalling pathway is necessary for survival of malignant B cells and its related molecules recently become new targets for therapy. Moreover, leukemic microenvironment delivers survival signals to neoplastic cells also overcoming the apoptotic effect induced by traditional drugs. In this context, the investigation of Bruton’s tyrosine kinase (Btk) is useful in: i) dissecting CLL pathogenesis; ii) finding new therapeutic approaches striking simultaneously intrinsic as well as extrinsic pro-survival signals in CLL. This paper will review these main topics
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
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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