1,721,035 research outputs found
Current advances in the development of anticancer drugs targeting tyrosine kinases of the Src family
No full textProtein kinases, either membrane-embedded receptorial or cytosolic non-receptorial ones, are important transducers of cell proliferation signals. In almost all tumor cells, the activity of some kinases is deregulated, either because of the presence of cancer-specific aberrant forms, or as a consequence of alterations in regulatory pathways, at the transcriptional or post-transcriptional level, which increase the activity of protein kinases with respect to normal cells. The study of the non-receptor tyrosine kinase Src plays a pivotal role in the field of the mol. genetics of cancer. The Src family of kinases (SFKs) comprises nine members, Src, Fyn, Yes, which are expressed in most tissues, and Blk, Yrk, Fgr, Hck, Lck and Lyn, which are more selectively expressed in particular tissues. To date, cellular (c-) Src has been implicated in the development of human cancer. Like oncogenic v-Src, activated mutants of c-Src can transform cells in culture and induce tumors in chickens. In addn., Src protein expression and/or activity is elevated in epithelial cancers, or cell lines derived from these, and there is often an assocn. with advancement of disease or with malignancy. During the past decade, examples of tyrosine kinases inhibitors have been reported. Many of these compds. were highly active in vitro, but only a few demonstrated in vivo activity. These approaches led to the characterization of the PP1/PP2 derivs. as very strong and selective inhibitors of the c-Src family of kinases. Unfortunately, attempts to improve the biol. profile of the latter compds. have so far met little success. Following these studies, some other inhibitors, possessing different chem. structures and interesting c-Src inhibitory activity, have been recently reported. Some of these mols. showed potent inhibition of tumor cell proliferation, which was due to the interference with the signalling pathway at the level of Src tyrosine kinase, providing proof-of-principle for the targeting of Src in anticancer chemotherapy
N-(thiazol-2-yl)-2-thiophene carboxamide derivatives as Abl inhibitors identified by a pharmacophore-based database screening of commercially available compounds
No full textSuggestions derived from a previous ligand-based ligand design approach and docking calculations aimed at finding compound with affinity toward Abl and molecular scaffolds previously untested as Abl inhibitors, led to the identification of commercially available N-(thiazol-2-yl)-2-thiophene carboxamide derivatives with affinity in a cell-free assay up to low nanomolar concentrations, significantly enhanced with respect to that of their parent compounds previously reported. In particular, among compounds of the Asinex database, molecular docking simulations guided the choice of high-affinity ligands, predicting their binding mode and their interaction pattern with the Abl catalytic binding site. Moreover, affinity of the new compounds was also rationalized in terms of their interactions with the enzyme
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
Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms
No full textThe tyrosine kinase Src and its close homolog Abl, both play important roles in chronic myelogenous leukemia (CML) progression and Imatinib resistance. No clin. approved inhibitors of the drug-resistant AblT315I exist to date. Here, we present a thorough kinetic anal. of two potent dual Src-Abl inhibitors towards wild type Src and Abl, and the AblT315I mutant. Our results show that the most potent compd. BO1 (I) shows only a modest loss of potency (fourfold) towards the AblT315I mutant in vitro and was an ATP-competitive inhibitor of wild type Abl but it acted as a non-competitive inhibitor in the case of AblT315I
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
Novel Indolyl Aryl Sulfones (IAAs) Highly Active in Vitro Against HIV-1 WT and Variants Carrying NNRTI Resistance Mutations.
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