1,721,024 research outputs found
Abstract 4910: Eribulin rapidly impairs TGF-β signaling
No full textAbstract
Microtubule targeting agents (MTAs) continue to be valuable in treating breast cancer. While decades of research have shown that these drugs cause mitotic arrest in cells by suppressing the dynamic instability of microtubules, recent evidence demonstrates that the ability of MTAs to disrupt the microtubule-dependent transport of key signaling components in interphase cells likely contributes to their anticancer actions. Cell signaling messages are relayed by proteins that organize or scaffold signaling hubs. These signaling nodes facilitate the complex organization and coordination of multiple signaling partners. NEDD9 is a member of the CAS scaffold family and it has been shown to coordinate TGF-β signaling, a driver of oncogenesis and epithelial-to-mesenchymal transition (EMT). Ligand-mediated stimulation of TGF-β receptors leads to the activation of downstream canonical and non-canonical signaling pathways. These pathways collectively induce the expression of Snail and Slug, key transcriptional-repressors that promote EMT. We tested the hypothesis that a short-term treatment of breast cancer cells with eribulin or 3 other clinically relevant MTAs would differentially disrupt interphase microtubules and alter TGF-β-dependent signaling. BT-549 cells were treated for 2 h with concentrations of MTAs that are clinically relevant and cause maximum disruption of the interphase microtubule network; 100 nM was used for the destabilizers, eribulin and vinorelbine and 1 µM was used for the stabilizers, paclitaxel and ixabepilone. The results showed that eribulin and vinorelbine significantly inhibited TGF-β- induced expression of Snail and Slug. The microtubule stabilizers had no effect on Snail and Slug expression following TGF-β stimulation. Further studies evaluated whether NEDD9 contributes to the downregulation of Snail and Slug. Co-immunoprecipitation and knockdown studies suggest that eribulin impairs the ability of NEDD9 to scaffold TGF-β signaling partners, thus inhibiting downstream transcriptional signaling. Consistent with the ability of eribulin to reverse EMT in experimental models within 7 days, this study begins to shed light on the mechanisms underlying its action. Funding for this work was provided by Eisai Inc.
Citation Format: Roma Kaul, April L. Risinger, Susan L. Mooberry. Eribulin rapidly impairs TGF-β signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4910. doi:10.1158/1538-7445.AM2017-4910</jats:p
Beyond mitotic arrest: the diverse effects of microtubule-targeting drugs on tumor vasculature
No full textFor decades microtubule-targeting agents (MTAs) have been a cornerstone of cancer treatment regimens and continue to be heavily employed as backbone chemotherapy in combination with new targeted agents. These drugs include both microtubule stabilizers (e.g. taxanes, ixabepilone) as well as destabilizers (e.g., vinca alkaloids, eribulin). MTAs are commonly referred to as antimitotic drugs based on the rationale that their anticancer efficacy is thought to be primarily due to the cell cycle arrest and subsequent apoptosis of rapidly dividing cancer cells downstream of microtubule disruption. However, accumulating evidence suggests that pharmacological microtubule disruption can also exert profound effects on the tumor microenvironment (TME), particularly through their influence on tumor vasculature and immune infiltration. While several MTAs with distinct binding sites and allosteric effects on microtubule structure are approved for the treatment of various cancers, little is known regarding how these drugs might differentially impact the TME. The recent study by He et al (2025) begins to shed light on these issues by demonstrating that structurally and functionally diverse MTAs can elicit markedly distinct effects on tumor vasculature through a process of pericyte phenotypic switching. These findings support the growing body of literature demonstrating that the antitumor efficacy of MTAs extends beyond their shared antimitotic effects and suggests these drugs could be used in a more rational and targeted manner, particularly as backbone chemotherapy in combination with immunotherapies and other targeted agents
Abstract 5115: Establishing an experimental paradigm to study the interphase effects of microtubule targeting agents
No full textAbstract
Microtubule targeting agents (MTAs) are highly effective anticancer drugs. While these drugs were traditionally classified as antimitotics, compelling evidence suggests that the ability of MTAs to interrupt microtubule-dependent trafficking and signaling in interphase cells contributes to their anticancer efficacies. Previous studies of the interphase effects of MTAs on oncogenic signaling pathways have led to an important reevaluation of their mechanisms of anticancer actions. These effects have been primarily reported in cells that have been treated with MTAs for extended periods of time. However, MTAs rapidly alter microtubule dynamics which results, within a few hours, in global changes to gene expression and cellular signaling. We propose that evaluating the effects of MTAs on oncogenic pathways at times and concentrations that are associated with early microtubule disruption will allow analysis of the initiating events that link the direct action of MTAs on microtubule structure and dynamics to effects on interphase signaling that contribute to anticancer efficacy. The concentrations and treatment times that were optimal for the study of clinically used MTAs on cellular trafficking and signaling events were first determined. Our experimental paradigm of a 2 h treatment of breast cancer cells with clinically relevant concentrations of MTAs eliminated contributions due to mitotic accumulation and changes in gene expression associated with longer treatments.
While all MTAs disrupt microtubule dynamics, the differences among MTAs in their rapid downstream effects on cellular signaling have not been systematically evaluated. A goal of this project was to identify differences in the effects of diverse MTAs on interphase signaling pathways that may underlie their differential efficacy in patient populations. This short term treatment paradigm led to the identification of profound differences among MTAs in their ability to disrupt Src-dependent E-cadherin re-localization, canonical and non-canonical TGF-β signaling, and β-catenin localization. These findings demonstrate the ability of diverse MTAs to rapidly impact interphase oncogenic signaling and trafficking pathways. This experimental design sets forth a method to evaluate the initial effects of diverse MTAs to gain critical insight into their differential abilities to inhibit key oncogenic signaling pathways. These types of studies might, in the future, help facilitate the rational selection of specific MTAs for patients depending on tumor characteristics. Funding for this work was provided by Eisai Inc.
Citation Format: April L. Risinger, Nicholas F. Dybdal-Hargreaves, Roma Kaul, Allison D. Clark, Susan L. Mooberry. Establishing an experimental paradigm to study the interphase effects of microtubule targeting agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5115. doi:10.1158/1538-7445.AM2017-5115</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
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
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