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Mechanistic studies of Gemcitabine-loaded nanoplatforms in resistant pancreatic cancer cells
Get PDFBackground: Pancreatic cancer remains the deadliest of all cancers, with a mortality rate of 91%. Gemcitabine is considered the gold chemotherapeutic standard, but only marginally improves life-span due to its chemical instability and low cell penetrance. A new paradigm to improve Gemcitabine’s therapeutic index is to administer it in nanoparticles, which favour its delivery to cells when under 500 nm in diameter. Although promising, this approach still suffers from major limitations, as the choice of nanovector used as well as its effects on Gemcitabine intracellular trafficking inside pancreatic cancer cells remain unknown. A proper elucidation of these mechanisms would allow for the elaboration of better strategies to engineer more potent Gemcitabine nanotherapeutics against pancreatic cancer. Methods: Gemcitabine was encapsulated in two types of commonly used nanovectors, namely poly(lactic-co-glycolic acid) (PLGA) and cholesterol-based liposomes, and their physico-chemical parameters assessed in vitro. Their mechanisms of action in human pancreatic cells were compared with those of the free drug, and with each others, using cytotoxity, apoptosis and ultrastructural analyses. Results: Physico-chemical analyses of both drugs showed high loading efficiencies and sizes of less than 200 nm, as assessed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), with a drug release profile of at least one week. These profiles translated to significant cytotoxicity and apoptosis, as well as distinct intracellular trafficking mechanisms, which were most pronounced in the case of PLGem showing significant mitochondrial, cytosolic and endoplasmic reticulum stresses. Conclusions: Our study demonstrates how the choice of nanovector affects the mechanisms of drug action and is a crucial determinant of Gemcitabine intracellular trafficking and potency in pancreatic cancer settings.Canadian Institutes of Health Research (Fellowship)Breast Cancer Research Program (U.S.) (BCRP Era of Hope Scholar Award)Mary Kay Foundation (Mary Kay Ash Charitable Foundation Grant)Charles A. King Trust (Postdoctoral Research Fellowship Program
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Modulation of endothelial cell survival by the angiopoietin-1Tie-2 receptor pathway
No full textThe mechanisms by which Angiopoietin-1 (Ang-1) modulates the survival of human endothelial cells were investigated. Ang-1 inhibited both TNFalpha-induced and serum deprivation-evoked apoptosis, an effect which was associated with attenuation of caspase activation, inhibition of Smac release from the mitochondria, up-regulation of Survivin-1 expression (IAPs member) and a significant activation of the pro-survival PI-3 kinase/AKT pathway. In addition, Ang-1 activated, in a time-dependent fashion, both the anti-apoptotic ERK1/2 and pro-apoptotic p38 MAP kinases. Ang-1-evoked ERK1/2 activation was mediated in part through the PI-3 kinase pathway, whereas both, the PI-3 kinase and ERK1/2 attenuated p38 MAP kinase activation.We conclude that Ang-1 promotes endothelial cell survival through several pathways including the PI-3 kinase/AKT and ERK1/2 pathways, up-regulation of Survivin-1 as well as inhibition of Smac release and caspase activity. The preferential activation of these anti-apoptotic effects, as opposed to the activation of pro-apoptotic p38 MAP kinase, results in a net survival response
Signaling and biological roles of the angiopoietinstie-2 receptor pathways
No full textAngiopoietin (Ang)-1, -2 and -4 are ligands for the endothelial cell (EC)-selective Tie-2 receptors. Ang-1, and to a lesser degree Ang-4, promote EC survival, migration and angiogenesis, whereas Ang-2 was initially described as a Tie-2 antagonist but might also exert context-dependent roles. Angiopoietin expression was recently shown to be upregulated in breast cancer. Breast cancer progression to the more aggressive phenotype is characterized by the loss of estrogen receptor alpha (ERalpha) and the upregulation of angiogenic cytokines. The underlying mechanisms by which angiopoietins modulate EC apoptosis and their regulation during breast cancer progression remain unknown and were investigated.Ang-1 simultaneously activated antiapoptotic (P13K/AKT and ERK1/2) and proapoptotic (p38 MAPKs and SAPK/JNK) pathways in serum deprived ECs. Ang-1-mediated ERK1/2 activation was partly mediated downstream of the PI3K pathway, whereas both the PI3K and ERK1/2 pathways attenuated p38 MAPKs activation. The net effect of Ang-1 was to inhibit EC apoptosis through the preferential activation of the antiapoptotic pathways. Ang-1 also induced the production of reactive oxygen species (ROS) second messengers derived from a NADPH oxidase complex in ECs. These ROS inhibited Ang-1-induced ERK1/2 phosphorylation while promoting activation of the promigratory kinase PAK1. Ang-2 also inhibited serum deprivation-induced apoptosis in ECs through the selective activation of the P13K/AKT and ERK1/2 pathways over the p38 MAPKs pathways. However, Ang-2 treatment did not evoque significant SAPK/JNK and PAK1 activation like Ang-1.In breast cancer cell lines and mice xenografts, Ang-1 levels were inversely correlated with that of ERalpha but positively correlated with the expressions of the angiogenic markers, VEGF and CD31. Ang-1, Ang-2 and Ang-4 levels were also inhibited by estrogen in ERalpha-expressing cells.We conclude that Ang-1 and Ang-2 promote EC survival through the preferential activation of antiapoptotic (PI-3 kinase/AKT, ERK1/2) over proapoptotic (p38 MAPK, SAPK/JNK for Ang-1) pathways. However, only Ang-1 promoted EC migration through PAK1 activation downstream of ROS second messenger, indicating that ROS act as molecular switches to shift EC responses from survival to migration. During breast cancer progression, Ang-1 levels increased in the more aggressive ERalpha negative cancers, whereas in ERalpha positive cancers, Ang-1, Ang-2 and Ang-4 levels were inhibited by estrogen
Variations on the Author
Get PDF“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
Get PDFWe 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
Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy
Get PDFThe MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD,L-lactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.Department of Defense Breast Cancer Research Program Era of Hope Award (W81XWH-07–1-0482)Mary Kay Ash Charitable Trus
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe 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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