1,720,984 research outputs found
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) that results in the expression of the chimeric protein PML-RARα. The fusion of PML, a tumor suppressor that is the major component of the PML-nuclear bodies, with the Retinoic Acid Receptor-α arrests the differentiation program driven by RARα, blocking the leukemic blasts at the promyelocytic stage. Pharmacological doses of Retinoic Acid (RA) are able to remove the block, resume granulocytic differentiation and partially degrade PML-RARα leading to reformation of nuclear bodies. The association of RA with chemotherapy or with arsenic trioxide (ATO), the latter efficiently targeting PML-RARα for degradation, results in high cure rates of acute promyelocytic leukemia (APL). Despite showing a considerably improved safety profile, either RA or ATO are not devoid of toxicity, with the most important and potentially life-threatening one being the so-called retinoic acid differentiation syndrome. We show here that RA-induced differentiation of human APL cell lines and primary blasts dramatically increases their sensitivity to ER stress inducing drugs, like Tunicamycin (Tm), 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. Granulocytic differentiation of APL cells driven by RA triggers a physiological Unfolded Protein Response, 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. Although mild, the ER stress induced by RA is sufficient to render differentiating APL cells very sensitive to low doses of Tm. 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. Moreover we found that low amounts of pharmacologically induced ER stress are also able to strongly increase ATO toxicity even in the absence of RA. Indeed the combination of ATO with Tm efficiently induced 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 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
Chemo-physical properties of asbestos bodies in human lung tissues studied at the nano-scale by non-invasive, label free x-ray imaging and spectroscopic techniques
No full textIn the lungs, asbestos develops an Fe-rich coating (Asbestos Body, AB) that becomes the actual interface between the foreign fibers and the host organism. Conventional approaches to study ABs require an invasive sample preparation that can alter them. In this work, a novel combination of x-ray tomography and spectroscopy allowed studying unaltered lung tissue samples with chrysotile and crocidolite asbestos. The thickness and mass density maps of the ABs obtained by x-ray tomography were used to derive a truly quantitative elemental analysis from scanning x-ray fluorescence spectroscopy data. The average mass density of the ABs is compatible with that of highly loaded ferritin, or hemosiderin. The composition of all ABs analyzed was similar, with only minor differences in the relative elemental fractions. Silicon concentration decreased in the core-to-rim direction, indicating a possible partial dissolution of the inner fiber. The Fe content in the ABs was higher than that possibly contained in chrysotile and crocidolite. This finding opens two opposite scenarios, the first with Fe coming from the fiber bulk and concentrating on the surface as long as the fiber dissolves, the second where the Fe that takes part to the formation of the AB originates from the host organism Fe-pool
Structure of water in Zn2+ aqueous solutions from ambient conditions up to the gigapascal pressure range: A XANES and molecular dynamics study
No full textThe structural modifications induced on a 0.5 M Zn2+ aqueous solution by increasing the pressure to 6.4 GPa were investigated using a combination of X-ray absorption near edge structure (XANES) spectroscopy and molecular dynamics (MD) simulations. The Zn K-edge XANES experimental spectra show two different trends depending on the pressure and temperature conditions of the system. On the one hand, when the pressure is increased to 1.0 GPa while keeping the temperature at 300 K, the highly structured nature of Zn2+ second hydration shell is preserved. On the other hand, when the Zn2+ aqueous solution is simultaneously pressurized and heated to follow the melting curve above 1.0 GPa, the Zn2+ second shell loses its high degree of structuring and becomes much more disordered and unstructured. These results are confirmed by the analysis of MD simulations of Zn2+ aqueous solutions under high pressure. By combining distance and angular distribution functions it is possible to highlight the loss of water structuring in the Zn2+ second coordination shell that takes place upon pressurization and heating. A progressive crowding of the Zn2+ second shell is observed with increasing pressure; the water structure becomes remarkably different from that found at ambient conditions, and for pressure values higher than 1.0 GPa the tetrahedral arrangements of water molecules is highly distorted. Moreover, MD simulations of Zn2+ aqueous solutions performed at 1.0 GPa and at increasing temperature values have shown that the loss of water structuring in the Zn2+ second coordination shell observed by simultaneously pressurizing and heating is due to a combined effect of pressure and temperature, both producing an increase of the Zn2+ second-shell disorder. © 2017 American Chemical Society
Spatial coherence of light inside three-dimensional media
Full text linkLight in disordered materials generates rich interference patterns called speckle, whose properties are known only on the outside of a sample. Here, the authors provide direct measurements and understanding of speckle generated inside a material, retrieving fundamental information that remained inaccessible up to now
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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