1,721,122 research outputs found
Heterogeneity of Kaposi's sarcoma-associated herpesvirus (HHV-8)-positive effusions
No full text[No abstract available
Retinoic acid and arsenic trioxide sensitize acute promyelocytic leukemia cells to ER stress.
No full textPromyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15:17). This translocation results
in the expression of the chimeric protein PML-RARα that arrests the differentiation program driven by RARα,
blocking the leukemic blasts at the promyelocytic stage. Pharmacological doses of Retinoic Acid (RA) are able to
resume granulocytic differentiation and partially degrade PML-RARα. The association of RA with chemotherapy or
with arsenic trioxide (ATO), which efficiently targets PML-RARα for degradation, results in high cure rates. Despite
showing a considerably improved safety profile RA and ATO are not completely devoid of toxicity. We show here
that granulocytic differentiation of human APL cells, driven by RA, generates mild ER stress, sufficient to render
them very sensitive to small quantities of ER stress inducing drugs, like Tunicamycin (Tm). Indeed, RA-induced
differentiation of human APL cell lines and primary blasts dramatically increases their sensitivity to Tm, at doses
that are not toxic in the absence of RA. Importantly the combination of RA and Tm results not toxic on human
bone marrow progenitors cells derived from healthy donors. We also show that the PERK pathway, triggered by ER
stress, plays a major protective role and, by using a specific PERK inhibitor, we potentiated the toxic effect of the
combination of RA and Tm. Moreover we found that small amounts of pharmacologically induced ER stress are also
able to strongly increase ATO toxicity even in the absence of RA: the combination of ATO with Tm efficiently induces
apoptosis in RA-sensitive and RA-resistant APL cell lines, at doses ineffective in the absence of ER stress. Eventually,
we demonstrate that insurgency of oxidative stress, tightly linked with the UPR, is at the basis of the toxicity induced
by Tm in combination with RA and/or ATO. In conclusion, our findings identify the ER stress-related pathways as
potential targets in the search for novel therapeutic strategies in AML
Retinoic acid-induced differentiation sensitizes myeloid progenitors cells to ER stress
Full text linkThe clonal expansion of hematopoietic myeloid precursors blocked at different stages of differentiation characterizes the acute myeloid leukemia (AML) phenotype. A subtype of AML, acute promyelocytic leukemia (APL), characterized by the chimeric protein PML-RARα is considered a paradigm of differentiation therapy. In this leukemia subtype the all-trans-retinoic acid (RA)-based treatments are able to induce PML-RARα degradation and leukemic blast terminal differentiation [1-2]. Granulocytic differentiation of APL cells driven by RA triggers a physiological Unfolded Protein Response (UPR), a series of pathways emanating from the ER in case of ER stress, which ensues when higher protein folding activity is required as during differentiation. We show here that, although mild, the ER stress induced by RA is sufficient to render human APL cell lines and primary blasts very sensitive to low doses of Tunicamycin (Tm), an ER stress inducing drug, at doses that are not toxic in the absence of RA. Importantly only human progenitors cells derived from APL patients resulted sensitive to the combined treatment with RA and Tm whereas those obtained from healthy donors were not affected. We also show that the UPR pathway downstream of PERK plays a major protective role against ER stress in differentiating cells and, by using a specific PERK inhibitor, we potentiated the toxic effect of the combination of RA and Tm. In conclusion, our findings identify the ER stress-related pathways as potential targets in the search for novel therapeutic strategies in AML
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
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