1,720,985 research outputs found
Abstract 4041: SUV39H2 inhibition enhances sensitivity of breast cancer cells to doxorubicin through downregulation of γ-H2AX production
No full textAbstract
Accumulating evidence has demonstrated the biological importance of protein methyltransferases in human tumorigenesis, and several small molecular inhibitors targeting these enzymes have been developed. Moreover, inhibiting pathways involved in DNA repair has been shown to enhance the cytotoxicity of DNA-damaging agents. Herein, we report the development of a potent SUV39H2 inhibitor (OTS193320) that decreases global histone H3 lysine 9 tri-methylation (H3K9me3) levels in cancer cells and attenuates cancer cell proliferation, and suppresses the tumor growth in mouse xenograft models. SUV39H2 (Suppressor of variegation 3-9 homolog 2), is a protein methyltransferase known to methylate histone H3 at lysine 9 (H3K9), and recently reported to methylate histone H2AX at lysine 134, which enhances the accumulation of phosphorylated H2AX (γ-H2AX) and regulates the DNA repair pathway in human cancer. SUV39H2 is highly expressed in many cancer types, including lung and breast cancers, while its expression levels are restricted to testis in normal adult tissues. Exposure of OTS193320 to two triple negative breast cancer cell lines attenuated H3K9me3 levels in a dose-dependent manner and triggered apoptotic cell death. Combination of OTS193320 and doxorubicin (DOX) resulted in reduction of γ-H2AX levels compared to single agent DOX, as visualized on western blot and immunocytochemical analysis. Furthermore, combination therapy attenuated the levels of p53-binding protein 1, which is reported to co-localize with γ-H2AX foci, compared to single agent DOX. Cell viability assays demonstrated a significant growth suppressive effect when OTS193320 was combined with DOX, compared to single agent treatment of either drug, suggesting chemosensitization to DOX. Importantly, in a mouse xenograft model of A549 lung cancer cells, we observed a tumor growth inhibition of 60.8% at day 14 with 25mg/kg intravenous administration of the inhibitor, without significant body weight loss or toxicity. Immunohistochemical staining of tumors treated with the inhibitor demonstrated a significantly lower number of Ki-67 positive cells and attenuated distribution patterns of H3K9me3 compared to the control tumors. Collectively, our results demonstrate that SUV39H2 inhibition may be a promising approach to develop a novel class of anti-cancer treatment.
Citation Format: Theodore Vougiouklakis, Vassiliki Saloura, Yo Matsuo, Yusuke Nakamura. SUV39H2 inhibition enhances sensitivity of breast cancer cells to doxorubicin through downregulation of γ-H2AX production [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 4041. doi:10.1158/1538-7445.AM2017-4041</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
Abstract 342: WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer
No full textAbstract
While multiple post-translational modifications have been reported to regulate the function of epidermal growth factor receptor (EGFR), the effect of protein methylation on its function has not been well characterized. In this study, we show that WHSC1L1 mono-methylates lysine 721 in the tyrosine kinase domain of EGFR, and that this methylation leads to enhanced activation of its downstream ERK cascade without EGF stimulation. We also show that EGFR K721 mono-methylation not only affects the function of cytoplasmic EGFR, but also that of nuclear EGFR. WHSC1L1-mediated methylation of EGFR in the nucleus enhanced its interaction with PCNA in squamous cell carcinoma of the head and neck (SCCHN) cells and resulted in enhanced DNA synthesis and cell cycle progression. Overall, our study demonstrates the multifaceted oncogenic function of the protein lysine methyltransferase WHSC1L1 in SCCHN, which is mediated through direct non-histone methylation of the EGFR protein with effects both in its cytoplasmic and nuclear functions.
Citation Format: Vassiliki Saloura, Theodore Vougiouklakis, Makda Zewde, Xiaolan Deng, Kazuma Kiyotani, Jae-Hyun Park, Yo Matsuo, Mark Lingen, Naoshi Dohmae, Takehiro Suzuki, Ryuji Hamamoto, Yusuke Nakamura. WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer [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 342. doi:10.1158/1538-7445.AM2017-342</jats:p
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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