1,720,956 research outputs found
Abstract 1957: Molecular pathogenesis and drug synergism in a zebrafish model of high risk neuroblastoma
No full textAbstract
We have developed a transgenic zebrafish model that overexpresses MYCN and harbors loss-of-function mutations of the nf1 tumor suppressor. In this model, loss of nf1 leads to aberrant activation of RAS-MAPK signaling, promoting both increased tumor cell survival and rapid tumor cell proliferation. These neuroblastomas are very aggressive in that almost all of the fish develop neuroblastoma by 3 weeks of age. Three-week old juvenile fish are very small, making it feasible to test the effectiveness of many drugs and drug combinations in vivo for activity against the primary tumors. We demonstrate these advantages of the model by showing marked synergistic anti-tumor effects of a MEK inhibitor (trametinib) and a retinoid (isotretinoin) in vivo at several different dosage combinations by in vivo isobologram analysis. Thus, inhibition of RAS-MAPK signaling can significantly improve the treatment of this very aggressive form of neuroblastoma when it is combined with the inhibition of other key pathways. Because of the very high penetrance and rapid onset of neuroblastoma in our nf1-deficient, MYCN-transgenic zebrafish model, it is one of the only model systems in which extensive analysis of the synergistic activity of two or more drugs can be evaluated in primary tumors in vivo. This capability is especially valuable given that mutations causing RAS-MAPK pathway hyperactivation have been shown to arise frequently at the time of relapse of childhood neuroblastomas, indicating the need to eliminate these mutated tumor cells as a component of the primary treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Shuning He, Marc R. Mansour, Mark W. Zimmerman, Hillary M. Layden, A. Thomas Look. Molecular pathogenesis and drug synergism in a zebrafish model of high risk neuroblastoma [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 1957. doi:10.1158/1538-7445.AM2017-1957</jats:p
Abstract 801: A zebrafish model of <i>NF1</i>-mutant melanomas that lack activating mutations of <i>BRAF</i> or <i>NRAS</i>
No full textAbstract
Cutaneous melanoma is the most lethal type of skin cancer, with ~76,380 newly diagnosed melanoma and ~10,130 melanoma-associated deaths per year in the US. Thus, there is a need for improved understanding of the molecular pathogenesis and more effective targeted therapies for this devastating disease. The recent work of The Cancer Genome Atlas Network has defined melanoma as an RTK/RAS-driven solid tumor that can be classified into four genomic subtypes: BRAF-mutant, RAS-mutant, NF1-mutant, and triple-wild-type. This landmark study highlighted the important role of the previously understudied NF1 tumor suppressor in melanoma pathogenesis, especially for the 9% of melanoma patients who have acquired inactivating NF1-mutations, but lack hotspot mutations that activate BRAF or RAS. To date, animal models have not been developed for the NF1-mutant subtype of melanoma, which has significantly impaired the development of novel therapeutic strategies for this subtype. Here we report the first zebrafish model for NF1-mutant melanoma, which we generated by combining the loss of nf1 with loss of both pten and p53. The resultant compound mutant zebrafish develop aggressive melanomas from the age of 7 weeks and the tumor penetrance is 80% by the age of 18 weeks. We demonstrate further that these high-risk zebrafish melanomas were exclusive of hotspot mutations of braf and nras. Sustained inhibition of both MEK and PI3K suppressed tumor progression in vivo, whereas inhibition of MEK or PI3K alone was insufficient to suppress the growth of these tumors. Surprisingly, single agent therapy with rapamycin, an MTOR inhibitor, proved even better for short- and long-term suppression of tumor cell growth in nf1/pten-mutant melanomas. Thus our model appears ideal for the testing of drugs that will prove uniquely active for the significant subset of NF1-mutant, BRAF/NRAS-wildtype human melanomas.
Citation Format: Shuning He, Marc R. Mansour, Hillary M. Layden, Scott J. Rodig, E. Elizabeth Patton, A. Thomas Look. A zebrafish model of NF1-mutant melanomas that lack activating mutations of BRAF or NRAS [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 801. doi:10.1158/1538-7445.AM2017-801</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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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