1,720,970 research outputs found
Role of miR-34a in HTLV-1-infected T-cells
Full text linkHuman T-cell leukaemia virus type 1 (HTLV-1) is the etiological agent of an aggressive neoplasm of CD4+ T-cells termed adult T-cell leukaemia/lymphoma (ATLL) and a neurodegenerative disease termed tropical spastic paraparesis/HTLV-associated myelopathy (TSP/HAM). To better understand the pathways controlling HTLV-1 infection, persistence and transformation, our laboratory is investigating the interplay between the virus and the cellular microRNA (miRNA) network.
This study was focused on miR-34a, which is known as a tumor suppressor in other contexts, but is highly expressed in HTLV-1 infected cell lines, newly infected PBMCs and ATLL samples.
Further studies of HTLV-1-infected cell lines C91PL and MT-2 treated with the NF-κB inhibitor Bay 11-7082 indicated that the NF-κB pathway contributes to sustain miR-34a expression in this cellular context.
Identification of the primary miR-34a precursor (pri-miRNA) produced in C91PL cells through the 5’RACE technique revealed that the main pri-miR-34a species present in this cell line corresponded to a two-exon transcript previously identified in cells of different lineage. The presence of an NF-κB binding site near the transcription start site of the primiR-34a provided further evidence that miR-34a expression is driven by this pathway in HTLV-1-infected cells.
Treatment of C91PL and MT-2 cells with the MDM2 inhibitor Nutlin-3a resulted in stabilization of p53, a further increase in the levels of miR-34a and downregulation of several of its targets, including SIRT1, a deacetylase whose substrates include p53, the inhibitor of apoptosis protein (IAP) BIRC5, which codes for Survivin, and the transcription factor E2F3, which is involved in controlling cell cycle. Interestingly, although Nutlin-3a induced G1 arrest in both cell lines, MT-2 cells entered late apoptosis,
while C91PL cells showed signs of senescence.
The last part of this project was aimed at investigating the effects of Nutlin-3a on viral gene expression and directly assessing the impact of miR-34a in C91PL cells by electroporating a miR-34a mimic.
We observed that Nultin-3a treatment of C91PL cells increased levels of the majority of the alternatively spliced HTLV-1 transcripts. Although the introduction of the miR-34a mimic
into C91PL cells resulted in a reduction in the expression of key targets of the miRNA, it did not induce cell cycle arrest, death, senescence, or alterations in viral gene expression, suggesting that other factors come into play in the response to Nutlin-3a
treatment
2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies
Full text linkThe oncometabolite 2-hydroxyglutarate (2-HG) plays a key role in differentiation blockade and metabolic reprogramming of cancer cells. Approximatively 20–30% of acute myeloid leukemia (AML) cases carry mutations in the isocitrate dehydrogenase (IDH) enzymes, leading to a reduction in the Krebs cycle intermediate α-ketoglutarate (α-KG) to 2-HG. Relapse and chemoresistance of AML blasts following initial good response to standard therapy account for the very poor outcome of this pathology, which represents a great challenge for hematologists. The decrease of 2-HG levels through pharmacological inhibition of mutated IDH enzymes induces the differentiation of AML blasts and sensitizes leukemic cells to several anticancer drugs. In this review, we provide an overview of the main genetic mutations in AML, with a focus on IDH mutants and the role of 2-HG in AML pathogenesis. Moreover, we discuss the impact of high levels of 2-HG on the response of AML cells to antileukemic therapies and recent evidence for highly efficient combinations of mutant IDH inhibitors with other drugs for the management of relapsed/refractory (R/R) AML
MiR-150 in HTLV-1 infection and T-cell transformation
Full text linkHuman T-cell leukemia virus-1 (HTLV-1) is a retrovirus that persistently infects CD4+ T-cells, and is the causative agent of adult T-cell leukemia/lymphoma (ATLL), tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) and several inflammatory diseases. T-cell transformation by HTLV-1 is driven by multiple interactions between viral regulatory proteins and host cell pathways that govern cell proliferation and survival. Studies performed over the last decade have revealed alterations in the expression of many microRNAs in HTLV-1-infected cells and ATLL cells, and have identified several microRNA targets with roles in the viral life cycle and host cell turnover. This review centers on miR-150-5p, a microRNA whose expression is temporally regulated during lymphocyte development and altered in several hematological malignancies. The levels of miR-150-5p are reduced in many HTLV-1-transformed- and ATLL-derived cell lines. Experiments in these cell lines showed that downregulation of miR-150-5p results in activation of the transcription factor STAT1, which is a direct target of the miRNA. However, data on miR-150-5p levels in freshly isolated ATLL samples are suggestive of its upregulation compared to controls. These apparently puzzling findings highlight the need for more in-depth studies of the role of miR-150-5p in HTLV-1 infection and pathogenesis based on knowledge of miR-150-5p-target mRNA interactions and mechanisms regulating its function in normal leukocytes and hematologic neoplasms
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
STR profiling of HTLV-1-infected cell lines
No full textMany investigations of the replication and pathogenesis of human T-cell leukemia virus type 1 (HTLV-1) employ chronically infected cell lines, cell lines stabilized from primary adult T-cell leukemia cells, and noninfected T-cell lines. The validity of data obtained from such studies depends on the unambiguous identification of each cell line, which can be performed by short-tandem-repeat (STR) profiling (DNA fingerprinting). While kit-based profiling represents the standard method for cell line authentication, not all labs have ready access to the required capillary electrophoresis equipment, and the costs of such tests can become substantial, especially if the cell lines are to be tested frequently. We analyzed DNA from a panel of HTLV-1-infected cell lines and noninfected T-cell lines using a commercial STR kit and then analyzed the same DNA for individual STR markers followed by nondenaturing polyacrylamide gel electrophoresis. This simplified method should facilitate routine confirmation of cell line identity in diverse laboratory settings
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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