1,721,304 research outputs found
Abstract IA14: Targeting Ras
No full textAbstract
We are exploring multiple ways of targeting Ras proteins and Ras-driven cancers. We have identified compounds that covalently bind to cysteine-185 on K-Ras 4B, and to the G-domain of K-Ras 4A and 4B. We are also screening for compounds that bind directly to K-Ras using a new technique referred to as Second Harmonic Generation and are developing compounds that promote phosphorylation of K-Ras4B on serine-181. In addition, we are attempting to solve novel structures of oncogenic Ras proteins on their own, or complexed with effectors, regulators and chaperones, in an attempt to identify new targeting opportunities. For example, we have solved the structure of fully processed K-Ras 4B bound to PDE-delta. This co-structure suggests several new approaches to targeting K-Ras processing.
In addition to targeting K-Ras directly, we are validating downstream dependencies that are specific for K-Ras cancers, including the cytokine LIF, which is expressed at high levels in K-Ras transformed cells and plays a major role in stem-like properties of K-Ras cancers. Suppressing LIF expression using shRNA, CRISPR or monoclonal antibodies has profound effects on K-Ras tumor initiation and maintenance, and suggests new therapeutic opportunities. We are also analyzing signaling pathways that differ between Ras mutants and between Ras isoforms. These results, and their opportunities for intervention, will be discussed.
Citation Format: Frank McCormick. Targeting Ras. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA14.</jats:p
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
Abstract IA17: New ways of targeting Ras
No full textAbstract
Activating K-Ras mutations occur frequently in many cancers, and account for about one million cancer deaths per year worldwide. Currently, no therapies exist that target K-Ras directly, and K-Ras cancers are very difficult to treat. Indeed, they are excluded from treatment with targeted agents such as tarceva and vemurafenib. The K-Ras protein is a member of a large family of related proteins, of which H-Ras and N-Ras are the closest relatives. Ablation of all three Ras genes is likely to be toxic, as these proteins are essential in most signaling transduction pathways. We therefore need to target the mutant oncoprotein itself, or target K-Ras, without affecting H-Ras or N-Ras. The striking similarity of these proteins makes this task challenging, together with the fact that the K-Ras gene expresses two splice variants, K-Ras 4A and K-Ras 4B, each of which can contribute to cancer. Nevertheless, differences do exist between these proteins, and ways in which these can be exploited will be discussed. One approach takes advantage of unique properties of K-Ras 4B, the other targets an amino acid that is shared between K-Ras isoforms, but is not present in H-Ras or N-Ras, or other members of the Ras family. K-Ras processing can be prevented by compounds that block the CAAX box cysteine. We have identified compounds that interact covalently with this cysteine and block prenylation by farnesyl transferase or geranylgeranyl transferase. These compounds reduce expression of K-Ras in cells and have specificity for K-Ras relative to H-Ras and N-Ras and represent another approach to targeting K-Ras specifically. We have also used new biophysical methods to target K-Ras, including second harmonic generation. This method detects small allosteric changes in proteins, and thus allows identification of small molecules that bind to K-Ras at novel allosteric sites. Drug resistance is likely to be a problem with Ras inhibitors, as it is for all types of cancer therapies. We have identified an approach to killing drug resistant cells that appears effective against a wide range of resistance mechanisms. This was achieved by targeting persister cells that survive targeted agents, but have unique properties that make them vulnerable to attack. The implications of this new strategy will be discussed.
Citation Format: Frank McCormick. New ways of targeting Ras [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA17.</jats:p
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
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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