1,720,988 research outputs found
Investigation of the role of RGD-binding integrins and associated sig-nalling pathways in the development of BRAF inhibitor resistance and a new combination therapy approach for metastatic melanoma
No full textMetastatic melanoma is the most deadly type of skin cancers. It is the fifth most common cancer in UK. BRAF V600E mutation is observed in approximately 50% of melanomas and causes excessive stimulation of the MAPK signalling leading to proliferation, metastasis and invasion. In BRAF V600E positive mela-noma patients, BRAF is inhibited to prevent MAPK over activity. However, after a while, BRAF inhibition induces different mechanisms resulting in gaining re-sistance to the inhibitor. It is known that there is an increase in the expression of integrins during the development of BRAFi resistance.
To understand which RGD binding integrins and mechanisms are involved in BRAFi resistance in melanoma cells, in this study, BRAFV600E mutant vemu-rafenib resistant cell lines were generated and gene expression analysis (2-ΔΔCt) for 25 different target genes compared between parental and resistant cells in the presence and absence of the integrin ligand fibrinogen to determine alterations in active pathways and integrin levels linked to resistance.
It was found that increased integrin β3, integrin α5 and PAI-1 and p21 levels were associated with vemurafenib resistant BRAFV600E melanoma cells and the TGF-β pathway is the major regulator. Combination of cilengitide with vemurafenib, showed a highly synergistic effect and significantly blocked the in-vasive and colony initiating features and also decreased ITGB3, ITGA5, PAI-1, p21 levels of resistant cells.
Altogether these findings emphasize the potential druggable role of integ-rin β3, integrin α5, PAI-1, p21 and can be beneficial to overcome drug resistance or develop better approaches to block tumourigenic properties.The Ministry of National Education-Turke
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
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
Synthetic Methodology and Application of Enamine [2+2] Cyclisations for Cyclobutane Synthesis. Development of Integrin Antagonists as Anticancer Therapeutics Towards a Total Synthesis of Providencin
Get PDFCyclobutanes represent an underutilised structural feature in medicinal chemistry, partially due to difficulties in forming them in an easy and controlled manner. Herein is described their application to a drug discovery project and development of the enamine [2+2] cyclisation; a straightforward synthesis of functionalised cyclobutanes.
A library of 30 cyclobutane based integrin antagonists have been designed and synthesised to explore the SAR around the hit dual β3 integrin antagonist ICT9055. Several of which were shown to be highly potent antagonists inhibiting cancer cell adhesion, migration and invasion while remaining non-toxic. ICT9072 had comparable β3 activity to hit compound ICT9055 but also had activity against αvβ5 and therefore showed greater inhibition of migration of DLD-1 cells. This showed the ability to modify this scaffold for multi integrin antagonism and potential benefit of this.
Synthetic studies towards the marine natural product providencin has led to the development of a previously unknown intramolecular enamine [2+2] cyclisation which has been shown to proceed in a diastereoselective manner. This reaction has been applied to the synthesis of a highly functionalised enatiopure cyclobutene suitable for inclusion into the total synthesis. A model furyl cyclobutane has also been synthesised to exemplify the route from the enantiopure cyclobutene through to the furyl cyclobutane fragment of providencin.Yorkshire Cancer Researc
Synthesis, Physicochemical And Biopharmaceutical Characterisation Of Pro-Antibiotic Esters; Free Bases Of Ciprofloxacin
No full textPhysicochemical and biopharmaceutical properties of drugs play a crucial role in their performance in vivo, especially with respect to oral bioavailability. In the case of antibiotics, poor bioavailability can indirectly encourage antimicrobial resistance from pressure selection resulting from subtherapeutic dosing. This study was designed to synthesise esters of Ciprofloxacin, a model drug using alcohol co-formers (isopentanol, n-butanol and isobutanol) with a view to improving the physicochemical and biopharmaceutical properties of Ciprofloxacin. Three esters of ciprofloxacin were synthesised, i.e., isopentanoate (CIP), n-butanoate (CNB) and isobutanoate (CIB). The effect of esterification on the physicochemical and biopharmaceutical properties of Ciprofloxacin was investigated. Thus, the lipophilicity, solubility, permeability, metabolism and
antimicrobial efficacies were studied. The extent of uptake of these esters into E. Coli and S. aureus compared to Ciprofloxacin was also studied.
A significant increase in lipophilicity and permeability was noted in all esters, with the branch-chained esters (CIP and CIB) having higher lipophilicity than the straight-chain ester (CNB). Solubility also increased compared to the parent drug, and all esters were successfully bioconverted into the parent compound without loss of activity. Esterification of Ciprofloxacin with isopenatanol, n-butanol and isobutanol improved its physicochemical and biopharmaceutical properties.Schlumberger Faculty for the Future Foundatio
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
Evaluation of new succinimide-based small molecules as alphavbeta3 integrin antagonists: from design to preliminary biological testing
No full textIntegrins are a family of cell surface protein receptors consisting of two subunits, called α and β, involved in several biological processes, including regulation of signalling between cells and other cells or ECM.
Integrins are overexpressed in diseases, first of all cancer. Being able to bind several ligands which contain the endogenous peptidic motif, RGD, αvβ3 is the most important of the family, associated with angiogenesis and aggressiveness of the tumour. However, molecules designed as antagonists based on RGD have shown partial agonism. This limit may be overpassed by switching from RGD to isoDGR motif.
Here, some isoDGR analogues prodrugs have been designed and synthesised, by a multi-step route to obtain the different fragments (isoAsp, Gly and Arg) subsequently connected together [Fig. A.01].
The molecules have been tested in ex-vivo metabolism assay in liver, kidney and tumour tissues. Cytotoxicity has been tested for all compounds in M14 and DLD1 cell lines: no effect was observed in MTT assay. Migration inhibition has been evaluated by performing scratch assay on M14 and DLD1 cell lines.
Compound 4 has shown the best migration inhibition, with IC50 = 4.62 ± 1.70 μM at 12h and IC50 = 5.63 ± 1.77 μM at 24h. [Fig A.01]
The work made in this project can be used as preliminary evaluation for a deeper investigation in succinamides-based prodrugs as integrins
antagonists
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