1,721,030 research outputs found
K-Ras Binds Calmodulin-Related Centrin1 with Potential Implications for K-Ras Driven Cancer Cell Stemness
Get PDFpeer reviewedRecent data suggest that K-Ras4B (hereafter K-Ras) can drive cancer cell stemness via calmodulin (CaM)-dependent, non-canonical Wnt-signalling. Here we examined whether another Ca2+-binding protein, the CaM-related centrin1, binds to K-Ras and could mediate some K-Ras functions that were previously ascribed to CaM. While CaM and centrin1 appear to distinguish between peptides that were derived from their classical targets, they both bind to K-Ras in cells. Cellular BRET- and immunoprecipitation data suggest that CaM engages more with K-Ras than centrin1 and that the interaction with the C-terminal membrane anchor of K-Ras is sufficient for this. Surprisingly, binding of neither K-Ras nor its membrane anchor alone to CaM or centrin1 is sensitive to inhibition of prenylation. In support of an involvement of the G-domain of K-Ras in cellular complexes with these Ca2+-binding proteins, we find that oncogenic K-RasG12V displays increased engagement with both CaM and centrin1. This is abrogated by addition of the D38A effector-site mutation, suggesting that K-RasG12V is held together with CaM or centrin1 in complexes with effectors. When treated with CaM inhibitors, the BRET-interaction of K-RasG12V with centrin1 was also disrupted in the low micromolar range, comparable to that with CaM. While CaM predominates in regulating functional membrane anchorage of K-Ras, it has a very similar co-distribution with centrin1 on mitotic organelles. Given these results, a significant overlap of the CaM- and centrin1-dependent functions of K-Ras is suggested
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
Characterization of novel covalent and non-covalent drugs against K-Ras surrogate targets
Get PDFMutations in the KRAS gene are associated with approximately 15% of all human cancers. This makes it one of the most frequently mutated oncogenes known. Whilst recent breakthroughs in Ras drug discovery have led to the FDA approval of the first direct and covalent inhibitor of the KRAS-G12C mutant, the majority of KRAS driven cancers are not G12C mutated. Furthermore, recent studies have identified resistance mechanisms against the new inhibitors. Consequently, research into other direct and indirect Ras inhibition strategies, as well as synergistic drug combination efforts are being vigorously pursued.
In the first part of this thesis, I describe my contributions to the development and characterization of novel PDE6D inhibitors with activity against KRAS driven cancers. PDE6D is a trafficking chaperone of K-Ras that facilitates its dynamic localization to the plasma membrane. Although some progress had been made in identifying lead drug candidates against this protein, an Arl2 dependent PDE6D cargo ejection mechanism continues to hamper progress. We describe the development of Deltaflexin 1 and Deltaflexin 2, into which we engineered a ‘molecular spring’ to improve resilience to Arl2 ejection of PDE6D cargo. We show that these compounds selectively inhibit K-Ras membrane organization and exhibited K-Ras selective anti-proliferative effects against cancer cell lines from colon and breast tissues whilst blocking the 3D spheroid growth of lung and breast cancer cell lines.
In the second part, I describe my main project, the identification of a novel covalent inhibitor of calmodulin (CaM) with anti-cancer activity in K-Ras mutated cancers named Calmirasone1. A relevance of the K-Ras/ CaM interaction for the promotion of cancer cell stemness has been previously suggested. We previously showed that the natural product Ophiobolin A (OphA) blocked K-Ras membrane organization in a CaM dependent manner and cancer cell spheroid formation. However, because of the broad toxicity of OphA, its suitability as a tool compound to further study this K-Ras/CaM associated stemness properties is limited. We have therefore characterized a set of benzazulenones with distant chemical similarity to OphA in a battery of assays. We identified Calmirasone1 which exhibits improved CaM affinity and a significantly lower unspecific toxicity relative to OphA. Furthermore, Calmirasone1 selectively blocked K-Ras membrane organization and inhibited the 3D spheroid growth of K-Ras dependent cancer cell lines.
In the third part of this thesis, I assessed the synergistic potential of targeting CaM and protein phosphatase 2A (PP2A) in Ras-MAPK dependent cancer cell lines. PP2A is a tumor suppressor that catalyze the dephosphorylation of multiple targets in the cell. Using specific CaM inhibitors and PP2A agonists as well as the already clinically approved phenothiazines (PTZs), our results from this study suggests that synergistic targeting of CaM and PP2A improves anti-cancer effects and that PTZs combine CaM inhibitory and PP2A re-activating properties in their cancer killing activity.Targeting Ras trafficking chaperone
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
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
- …
