1,720,957 research outputs found
Exploiting bivalent COX-2 inhibitors/TP antagonists for the control of cancer progression: effects on breast cancer and endothelial cells
No full textThe isoenzyme 2 of cyclooxygenase (COX-2) is upregulated in breast cancer and other malignancies, making it a significant therapeutic target. Several critical steps in tumorigenesis and tumor progression, such as cell proliferation, apoptosis evasion, immune escape, angiogenesis stimulation and increased invasiveness, have been associated with COX-2 overexpression. In particular, both in vitro and in vivo studies support a role for COX-2-derived prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) in promoting tumor progression and aggressiveness, through their effects on cancer cells or cells of the tumor microenvironment, such as endothelial cells. The beneficial effects of COX-2 inhibition with NSAIDs and coxibs in cancer treatment has emerged in colorectal cancer and other malignancies. However, the cardiovascular and gastrointestinal safety concerns as related to prolonged use of traditional NSAIDs and coxibs limit their clinical application in this setting.
This thesis project was aimed at evaluating the anticancer activity of two new bifunctional COX-2 inhibitors/TP receptor antagonists, ETO29 and SWE96. These compounds are characterized by a high potency of COX-2 inhibition and TP receptor antagonism, respectively. The use of dual compounds in the context of cancer might therefore maintain the beneficial effects of COX-2 inhibition while reducing the cardiovascular hazard thanks to TP receptor antagonism. Using several in vitro models, we investigated the effect of these compounds on different aspects of breast cancer progression, considering two different target cell types within the TME, such as breast cancer and endothelial cells.
Our results suggest the possible efficacy of these dual compounds in impairing breast cancer progression by acting on different prostanoid-related pathways. Indeed, we showed that, by inhibiting COX-2-dependent PGE2 production, ETO29 treatment reduced AA-induced MMP9 activation and invasion of MDA-MB-231 cells, a highly metastatic and COX-2-overexpressing breast cancer cell line. Moreover, SWE96, a highly potent TP receptor antagonist among our compounds, blocked cancer cell migration and activation of Src-FAK axis induced by the stable TP receptor agonist U46619. Of note, we provided the first evidence that TP receptor activation triggers this pathway in MDA-MB-231 cells. This is relevant since these kinases are strongly involved in cancer cell motility, proliferation and evasion of apoptosis, and are both targets of anticancer drugs and/or molecules under development.
In addition, we showed that these dual compounds, specifically SWE96, also act on endothelial cells by blocking different steps of the angiogenic process driven by TP receptor activation. Indeed, we observed that the thromboxane/TP receptor pathway in endothelial cells regulates cell cytoskeletal rearrangements and permeability through activation of the Rho/ROCK pathway. Noteworthy, our results also show for the first time the ability of TP receptor agonists to promote Src-FAK activation and endothelial cell migration. All these effects were inhibited by SWE96.
Therefore, blocking TP receptor activation in cancer and endothelial cells of the TME could contribute to preserve the physiological blood vessel permeability, thereby impairing tumor-promoted angiogenesis and contrasting cancer cell dissemination.
In conclusion, this thesis disclosed the potential efficacy of novel dual COX inhibitors/TP receptor antagonists in impairing breast cancer progression by acting on different cells of the TME, namely breast cancer and endothelial cells. Our results lay the foundation to further investigating the efficacy of these compounds in blocking cancer-associated angiogenesis and metastatization in in vivo studies
Gender differences and pharmacological regulation of angiogenesis induced by synovial fluids in inflammatory arthritis
Full text linkSeveral mediators including cytokines, growth factors and metalloproteinases (MMP) modulate pathological angiogenesis associated with inflammatory arthritis. The biological factors underlying sex disparities in the incidence and severity of rheumatic musculoskeletal diseases are only partially understood. We hypothesized that synovial fluids (SFs) from rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients would impact on endothelial biology in a sexually dimorphic fashion. Immune cell counts and levels of pro-angiogenic cytokines found in SFs from RA and PsA patients (n = 17) were higher than in osteoarthritis patients (n = 6). Synovial VEGF concentration was significantly higher in male than in female RA patients. Zymography revealed that SFs comprised solely MMP-9 and MMP-2, with significantly higher MMP-9 levels in male than female RA patients. Using in vitro approaches that mimic the major steps of the angiogenic process, SFs from RA and PsA patients induced endothelial migration and formation of capillary-like structures compared to control. Notably, endothelial cells from female donors displayed enhanced angiogenic response to SFs with respect to males. Treatment with the established anti-angiogenic agent digitoxin prevented activation of focal adhesion kinase and SF-induced in vitro angiogenesis. Thus, despite higher synovial VEGF and MMP-9 levels in male patients, the responsiveness of vascular endothelium to SF priming was higher in females, suggesting that gender differences in angiogenic responses were mainly related to the endothelial genotype. These findings may have implications for pathogenesis and targeted therapies of inflammatory arthritis
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
A novel sodium caseinate lipid-based auto-emulsifying delivery system to increase resveratrol intestinal permeation: characterization and in vitro assessment
Full text linkIn recent years, nutraceuticals have emerged as a promising strategy for maintaining health and represent a high-growth market in Italy and across Europe. However, the lack of strict regulations regarding formulation requirements and proof of efficacy raises serious concerns about their poor bioavailability and, consequently, their uncertain health benefits. An emblematic example is t-resveratrol (RES), a cardioprotective stilbene polyphenol that undergoes extensive metabolism in the intestine and liver, resulting in a bioavailability of less than 1%. This manuscript describes a novel technological matrix developed with the primary goal of improving RES oral bioavailability. This technology can be classified as a lipid-based autoemulsifying drug delivery system (LIBADDS), in which RES is thoroughly solubilized in a hot liquid phase composed of lipids and surfactants, and the mixture is further adsorbed onto a powder composed of polysaccharides and sodium caseinate (NaC), along with inert excipients, and then compressed. In this study, NaC was used for the first time to trigger pancreatin-mediated hydrolysis of an enteric-coated tablet, allowing micellar delivery of RES to the small intestine. The RES-containing tablets were characterized via differential scanning calorimetry (DSC) and X-ray diffraction (PXRD). The digested formulation, with simulated gastric and enteric fluids, was dimensionally assessed via dynamic light scattering (DLS). Finally, calculations of the bioaccessible fraction, dissolution tests, and in vitro permeability experiments using Caco-2 cell monolayers were carried out to preliminarily define the overall efficiency and applicability of this new technology in improving RES intestinal permeability
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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