1,720,964 research outputs found
DNA damage response in adult stem cells
No full textThis review discusses the processes of DNA-damage-response and DNA-damage repair in stem and progenitor cells of several tissues. The long life-span of stem cells suggests that they may respond differently to DNA damage than their downstream progeny and, indeed, studies have begun to elucidate the unique stem cell response mechanisms to DNA damage. Because the DNA damage responses in stem cells and progenitor cells are distinctly different, stem and progenitor cells should be considered as two different entities from this point of view. Hematopoietic and mammary stem cells display a unique DNA-damage response, which involves active inhibition of apoptosis, entry into the cell-cycle, symmetric division, partial DNA repair and maintenance of self-renewal. Each of these biological events depends on the up-regulation of the cell-cycle inhibitor p21. Moreover, inhibition of apoptosis and symmetric stem cell division are the consequence of the down-regulation of the tumor suppressor p53, as a direct result of p21 up-regulation. A deeper understanding of these processes is required before these findings can be translated into human anti-aging and anti-cancer therapies. One needs to clarify and dissect the pathways that control p21 regulation in normal and cancer stem cells and define (a) how p21 blocks p53 functions in stem cells and (b) how p21 promotes DNA repair in stem cells. Is this effect dependent on p21s ability to inhibit p53? Such molecular knowledge may pave the way to methods for maintaining short-term tissue reconstitution while retaining long-term cellular and genomic integrity
Leukemia-associated fusion proteins : multiple mechanisms of action to drive cell transformation
No full textLeukemic cells are defined by two main biological features: arrest of differentiation at a specific stage compatible with continued proliferation, and enhanced resistance to stress. Recent work shows that the leukemia-associated fusion protein PML-RAR can mediate both biological effects targeting independent pathways, through a unifying mechanism. Differentiation block is achieved through transcriptional silencing of genes physiologically regulated by RAR, which are involved in hematopoietic differentiation. In contrast, enhanced resistance to stress is due to the capacity of the fusion protein to cause degradation of the tumor suppressor p53, thus explaining the puzzling observation that mutations of p53 are remarkably rare in acute myeloid leukemias (AMLs). Interestingly, this latter phenomenon depends on expression of wild-type PML, acting as a molecular bridge between p53 and the fusion protein. Strikingly, both effects require a unifying molecular mechanism: aberrant recruitment of histone deacetylases (HDACs). Therefore, the study of this form of leukemia appears also of interest for a better understanding of the action of HDAC inhibitors, potential antitumor drugs that are at the early stages of clinical studies
Mechanisms of selective anticancer action of histone deacetylase inhibitors
Full text linkHistone deacetylases (HDACs) regulate transcription and specific functions, such as tumor suppression by p53, and are frequently altered in cancer. Inhibitors of HDACs (HDACl) possess anti-tumor activity and are well tolerated, suggesting that they might develop into a specific strategy for cancer treatment. Indeed, HDACls have successfully entered clinical trials, but the molecular basis for their selective anti-tumor activities is not clear. Recent work on leukemias expressing the PML-RAR or AML1-ETO oncogenes, known to initiate leukemogenesis through deregulation of HDACs, shows that HDACls induce massive blast cell apoptosis. Interestingly, the pro-apoptotic activity of the drug is not due to the relief of oncogene-mediated inhibition of the p53 tumor-suppressor pathway but, instead, relies on the selective upregulation of the death receptors DR5 and Fas and their cognate ligands TRAIL and FasL. Significantly, normal myeloid progenitors are not sensitive to HDACl-induced apoptosis and oncogene expression is not sufficient to confer HDACl-sensitivity to normal cells, demonstrating that sensitivity to HDACl is a property of the fully transformed phenotype. In principle, our findings could thus apply to other cancers, where the contribution of HDACs to tumorigenesis is not yet defined. (copyright)2005 Landes Bioscience
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
The emerging role of p53 in stem cells
Full text linkAmong the hundreds of oncogenes and tumor suppressors that have been identified in the past 50 years, p53 is probably the best characterized; nevertheless, new functions are constantly being discovered. As a tumor suppressor, p53 regulates cellular responses to different stress stimuli by inducing reversible cell cycle arrest and DNA repair, or triggering senescence or apoptosis. Recent findings on the regulation of stem cell (SC) division and reprogramming suggest the intriguing possibility that p53 also carries out its tumor suppression function by regulating SC homeostasis. Specifically, p53 activation may counteract SC expansion by several emerging mechanisms including restriction of self-renewing divisions, inhibition of symmetric division and block of reprogramming of somatic/progenitor cells into SCs
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