1,720,958 research outputs found
NOTCH1 inhibition regulates evolutionary conserved miRNAs in T-cell Acute Lymphoblastic Leukemia (T-ALL)
Full text linkT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor, resulting from the transformation of T-cell progenitors. Activating mutations in the NOTCH1 ligand-activated transcription factor oncogene are found in over 60% of T-ALL cases. Recently, several microRNAs have been shown to cooperate with NOTCH1 in the pathogenesis of T-ALL. However, little is currently known on the microRNAs that are regulated following NOTCH1 inhibition. Thus, in view of future therapies that may combine NOTCH1 inhibition with microRNA based therapy we pursued to study the microRNAs regulated following NOTCH1 inhibition and their functional role in T-ALL pathogenesis. We first generated a mouse model of NOTCH1-induced leukemia, that carries a NOTCH1 mutation recurrently found in human T-ALL patients (L1601P-PEST), and inhibited NOTCH1 signaling in vivo by treating diseased animals with a potent gamma secretase inhibitor (DBZ). These NOTCH1-induced T-ALL samples were subjected to miRNA profiling using a mouse array (8X60K release 19.0; Agilent) and, in parallel, gene expression analysis using SurePrint G3 Mouse Gene Expression v2 array (Agilent). The MYC and NOTCH signatures resulted strongly down-regulated following NOTCH1 inhibition by Gene Set Enriched Analysis (GSEA) demonstrating the efficacy of our experimental model. Among the NOTCH1 down-regulated miRNAs, we found the miR-17-92 cluster, previously reported to be highly expressed in T-ALL samples. Their regulation was also confirmed in another mouse model of NOTCH1-induced T-ALL and in human T-leukemia cells. Notably, we identified miR-34a-5p, miR-22a-3p and miR-199a-5p to be significantly up-regulated following NOTCH1-inhibition suggesting a putative role as tumor suppressors in NOTCH1-driven leukemia. Even if we can hypothesize that these miRNAS could play an important role in murine T-cell leukemia, they resulted not expressed in human T-ALL cells. Differently, miR-22a-3p resulted significantly up-regulated following NOTCH1 inhibition both in mouse and human T-ALL cells. Moreover, the overexpression of miR-22a-3p inhibited in vitro colony formation in T-ALL cell lines carrying constitutive NOTCH1 activation and significantly impaired tumor growth in vivo when overexpressed in human T-ALL cells, suggesting a tumor suppressor role for miR-22 in T-ALL downstream of NOTCH1. Meta-analysis from the human T-ALL dataset already published showed, amongst the significantly up-regulated gene sets, targets of the microRNAs belonging to the miR-17/92 cluster. These results are in accordance with our murine microRNA differential expression analysis, in which we found components of miR-17/92 cluster to be strongly down-regulated.
Moreover, using the same human dataset, we ran GSEA against the C3 sub collection of mir targets in the MSigDB v6.0, including additional gene sets with putative targets of miR-22. Amongst the downregulated gene sets, we identified 23 down-regulated genes that were consistently contributing to the negative enrichment of all the three selected gene sets of miR-22 targets. Amongst these genes, we found the Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Beta (PGC-1β), that is involved in mitochondrial metabolism. Notably, GSEA analysis, identified transcription factors significantly regulated upon treatment with DBZ in human T-ALL cells, finding that the PPARG_01 gene set, containing targets of the PPARG transcription factor, was significantly down-regulated in this context. PGC-1β resulted significantly down-regulated following NOTCH1 inhibition in vivo in human PDTALL xenografts and in one of three miR-22 overexpressing T-ALL cell lines at transcription level. On the other hand, the amount of PGC-1b protein was found to be very high and insensitive to NOTCH1 inhibition or miR-22 overexpression.
In conclusion, we found that miR-22-3p was down-regulated in T-ALL cells and its expression level could be restored following NOTCH1 inhibition. miR-22-3p over-expression affected in vivo tumor growth, possibly altering homing to supportive niches and so favouring disease progression, supporting its tumor suppressor role in NOTCH1-mutated T-ALL cells. Meta-analysis of NOTCH1 regulated genes in human T-ALL cell lines indicated PGC-1β as a putative miR-22 target gene, whose expression appeared significantly regulated only at the transcriptional level, while protein level was found unaltered.
Thus, we are still investigating on the role of NOTCH1/has-miR-22/PPARG axis because understanding the mechanism of action of miR-22-3p in T-ALL cells could be contribute to the successful treatment for T-ALL, opening possibilities of future therapeutic interventions that may combine NOTCH1 inhibition with microRNA based therapy
Calcineurin complex isolated from T-cell acute lymphoblastic leukemia (T-ALL) cells identifies new signaling pathways including mTOR/AKT/S6K whose inhibition synergize with Calcineurin inhibition to promote T-ALL cell death
No full textCalcineurin (Cn) is a calcium activated protein phosphatase involved in many aspects of normal T cell physiology, however the role of Cn and/or its downstream targets in leukemogenesis are still ill-defined. In order to identify putative downstream targets/effectors involved in the pro-oncogenic activity of Cn in T-cell acute lymphoblastic leukemia (T-ALL) we used tandem affinity chromatography, followed by mass spectrometry to purify novel Cn-interacting partners. We found the Cn-interacting proteins to be part of numerous cellular signaling pathways including eIF2 signaling and mTOR signaling. Coherently, modulation of Cn activity in T-ALL cells determined alterations in the phosphorylation status of key molecules implicated in protein translation such as eIF-2α and ribosomal protein S6. Joint targeting of PI3K-mTOR, eIF-2α and 14-3-3 signaling pathways with Cn unveiled novel synergistic pro-apoptotic drug combinations. Further analysis disclosed that the synergistic interaction between PI3K-mTOR and Cn inhibitors was prevalently due to AKT inhibition. Finally, we showed that the synergistic pro-apoptotic response determined by jointly targeting AKT and Cn pathways was linked to down-modulation of key anti-apoptotic proteins including Mcl-1, Claspin and XIAP. In conclusion, we identify AKT inhibition as a novel promising drug combination to potentiate the pro-apoptotic effects of Cn inhibitors
Crosstalk between Hedgehog pathway and the glucocorticoid receptor pathway as a basis for combination therapy in T-cell acute lymphoblastic leukemia
Full text linkAberrant signaling pathways in t-cell acute lymphoblastic leukemia
Full text linkAbstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long-term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therap
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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