1,721,181 research outputs found
Predicting the future of signaling for 2018
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Science Signaling
Chief Scientific Editor Michael B. Yaffe looks forward to what this year has in store for signaling research.
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Abstract 52: Dynamic rewiring of apoptotic signaling networks by combined EGFR/FRGR inhibition enhances killing of head and neck squamous tumor by DNA damage
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We have previously shown that a subset of triple-negative breast cancers can be dramatically sensitized to killing by DNA-damaging chemotherapy by time-staggered inhibition of EGFR. This sensitization effect results from dynamic re-wiring of apoptotic signaling pathways to engage a caspase-8-dependent cell death mechanism (Figure 1). Here we explored whether combined EGFR and/or FGFR inhibition could enhance the killing of head and neck squamous cell cancers by DNA damaging treatments through a similar re-wiring mechanism.
The epidermal growth factor receptor (EGFR) and FGFR pathways are two of the most dysregulated molecular pathways in human head-and-neck squamous cell carcinoma (HNSCC). Despite overexpression in approximately 90% of HNSCC tumors, EGFR inhibitors alone have not exerted a major therapeutic impact on tumor response or patient survival. A recent study provides evidence that the insensitivity of the majority of HNSCC to EGFR inhibitors is mediated by dominant activity of alternative receptor tyrosine kinase (RTK) systems such as FGFR signaling (Clinical Cancer Research 2011).
We have found that time-staggered administration of either EGFR inhibitors, or FGFR inhibitors, can dramatically enhance the apoptotic response of HNSCCs to DNA damage from doxorubicin. Importantly, combined inhibition of both the EGFR and FGFR pathways was more effective than inhibition of either pathway alone, at inducing sensitization to cytotoxic chemotherapy through dynamic network re-rewiring. Enhanced cell death by dual EGFR/FGFR inhibition and subsequent genotoxic injury results from greater activation of Caspase-8 than that seen by either EGFR or FGFR inhibitors alone. This enhanced Caspase-8 acitivty, together with Caspase-9 activation, accounts for the majority of apoptotic death. Our data further suggest that Src family kinases are a critical downstream node of EGFR/FGFR activity since treatment of HNSCC cell lines with Src kinase inhibitors resulted in similar sensitization to doxorubicin treatment.
In summary, our data extend the utility of therapeutic dynamic rewiring for the targeting of tumors with redundant receptor signaling pathways as well as their critical downstream nodes.
Citation Format: Yogesh Dayma, Michael B. Yaffe. Dynamic rewiring of apoptotic signaling networks by combined EGFR/FRGR inhibition enhances killing of head and neck squamous tumor by DNA damage [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 52.</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 B32: Loss of MK2 in tumor stroma promotes aggressive tumor development in an advanced stage lung cancer model
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MAPKAP Kinase-2 (MK2) is a serine/threonine protein kinase that is activated by p38MAPK in response to a variety of stresses including DNA damage, osmotic shock, thermal injury, and inflammation/innate immune signaling downstream of TLR4 activation. MK2 controls the synthesis of many pro-inflammatory cytokines, modulates the actin cytoskeleton in stressed cells, and is responsible for maintaining both the G1/S and G2/M cell cycle checkpoints in p53-defective tumor cells after genotoxic damage. We recently created a “Cre-reversible" MK2 knock-out mouse model that allows the function of MK2 within either the tumor cells or within the tumor microenvironment to be studied independently. We found that MK2-deficient tumor cells in an MK2 wild-type stroma were dramatically sensitized to the anti-tumor effects of cisplatinum and doxorubicin (Morandell et al., Cell Reports, 2013). Here, we report that loss of MK2 in the tumor stroma with preservation of MK2 in tumor cells results in an aggressive tumor-promoting phenotype in an immuno-competent transplant K-RasG12D/p53-/- model of NSCLC. A similar tumor aggressive phenotype was observed in Tie2-Cre-driven endothelial and bone marrow-specific MK2-knockout mice compared to wild-type controls. Tumor-bearing mice with MK2-null stroma display increased total levels of MIP-1α, G-CSF, GM-CSF and IL-6 in the lung. Myeloperoxidase immunohistochemistry reveals enhanced tumor infiltration by neutrophils in these stromal MK2-deficient animals, consistent with the cytokine profile. In contrast with loss of MK2 in the stroma, direct activation of the p38MAPK/MK2 pathway in the tumor microenvironment by weekly intra-tracheal LPS exposure dramatically reduces tumor formation in an autochthonous K-RasG12D/p53-/- murine NSCLC model. Collectively, these results suggest that MK2 signaling in the endothelium and/or immune cells suppresses NSCLC tumor progression and modulates the inflammatory milieu in the tumor microenvironment.
Citation Format: Ganapathy Sriram, Lucia Suarez-Lopez, Michael B. Yaffe. Loss of MK2 in tumor stroma promotes aggressive tumor development in an advanced stage lung cancer model. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B32.</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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