1,721,027 research outputs found
Abstract IA22: Myeloid derived suppressor cells as mediators of local immune suppression in head and neck cancer
No full textAbstract
Development of local immune suppression is a major barrier to effective antitumor immunotherapy. Within head and neck squamous cell carcinomas, infiltration of both immature myeloid cells (myeloid derived suppressor cells, or MDSCs) and regulatory T-cells (Tregs) contributes to local immunosuppression. Analysis of The Cancer Genome Atlas head and neck cancer subset reveals that patients with T-cell inflamed tumors also demonstrate robust MDSC and Treg gene expression profiles, indicating that both cell subsets may be limiting effective antitumor immunity in the setting of an otherwise activated immune response. The carcinogen-induced, syngeneic mouse oral cancer (MOC) model demonstrates robust MDSC infiltration and provides a model to study how modulation of MDSCs can alter anti-tumor immunity at baseline and in response to checkpoint inhibitor immunotherapy.
Time course analysis of immune cell infiltration into MOC tumors demonstrates an inverse relationship between granulocytic MDSC (gMDSC) and CD8 tumor-infiltrating T-cells (TIL). Antibody-mediated elimination of gMDSC from the MOC tumor microenvironment rescues antigen-specific T-cell responses lost with tumor progression. While CTLA4 mAb treatment alone controls growth of a subset of MOC tumors, combining gMDSC depletion with CTLA4 checkpoint blockade induces consistent CD8 TIL-dependent rejection of established MOC tumors, resulting in immunologic memory and rejection of subsequent MOC cell challenge. Within MOC tumors, MDSCs express the largest individual pool of PD-L1. Combination PD-L1 and CTLA4 checkpoint blockade adds no benefit over CTLA4 blockade alone, suggesting that the effects of gMDSC depletion are not simply due to the elimination of PD-L1 from the tumor microenvironment. CTLA4 mAb treatment appears to have multiple mechanisms including partial depletion of tumor-infiltrating Tregs and direct activation of CD8 TIL.
Given these results, we have studied multiple translational approaches to inhibit the function of MDSCs within the MOC tumor microenvironment with the goal of sensitizing tumors to checkpoint inhibition. Given that immune cells exhibit dependence on the γ/δ subunits for signaling through PI3K, we hypothesized that a PI3Kγ/δ-selective small molecule inhibitor (IPI-145) would functionally inhibit MDSCs. We demonstrated that low-dose IPI-145 reduced arginase-dependent MDSC suppression of TIL function and enhanced responses to PD-L1 blockade in MOC tumor-bearing mice. However, higher doses of IPI-145 reversed this enhancement of tumor control due to direct suppression of TIL function. As an alternative approach, we have evaluated the effect of blockade of sema4D, a semaphoring family protein involved in cell migration and potentially involved in the polarization of myeloid cells to an immunosuppressive phenotype. We demonstrated that sema4D mAb monotherapy reduced gMDSC tumor infiltration and T-cell suppressive capacity through multiple mechanisms. Similar to complete gMDSC depletion, sema4D plus CTLA4 mAb treatment induced immune-mediated rejection of established MOC tumors.
Blockade of immunosuppressive cell recruitment into tumor through interruption of chemokine signaling has been demonstrated in other solid tumor types. Historical and current evidence demonstrates that gMDSCs recruitment into head and neck tumors appears to be dependent on the CXCL1(tumor)/CXCR2(expressed on gMDSC) signaling axis. Experiments combining small molecule or mAb-based CXCR2 inhibitors with PD-L1 or CTLA4 checkpoint inhibition are underway in the MOC model.
Strong lines of evidence suggest that modulation of MDSCs within the tumor microenvironment can partially reverse local immunosuppression and improve responses to checkpoint inhibitor therapies. These and similar findings have widespread implications as local immunosuppression likely limits effective responses to immune-activating anticancer therapies across many tumor types.
Citation Format: Clint T. Allen. Myeloid derived suppressor cells as mediators of local immune suppression in head and neck cancer [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 IA22.</jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Full text linkWe 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
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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