1,721,388 research outputs found
Arginase, Nitric Oxide Synthase, and Novel Inhibitors of L-arginine Metabolism in Immune Modulation
No full textIn higher organisms, the control of amino acid metabolism has been identified as an evolutionarily preserved strategy for limiting the expansion of actively proliferating cells, including antigen-activated T lymphocytes, and tumor cells have surreptitiously adopted it to avoid or restrain attack by the immune system. Tumor growth is often associated with an altered metabolism of the amino acid L-arginine (L-Arg) by the enzymes nitric oxide synthase (NOS) and arginase (ARG). In tumor-recruited myeloid cells or in cancerous cells the consequence of their activities causes L-Arg deprivation or release of NO, which have been shown to have profound effects directly on tumor outgrowth as well as on the regulation of antitumor T-cell-mediated immune responses. Experimental findings indicate that when either one of the two enzymes is active, the net effect on T lymphocytes can be attributed to cell cycle arrest whereas the concomitant activation of both enzymes within the same environment can lead to T-cell death by apoptosis. Moreover, an increasing amount of evidence reveals an intricate system of circuits controlling either pathway or their crosstalk in cancer and in immune cells. This highlights the broad range of cellular processes that might be affected by ARG and NOS activity. In general, immune regulation by L-Arg metabolism is not antigen specific but requires that T cells are activated through their clonotypic T-cell receptor in order to be susceptible to these inhibitory circuits. In this chapter, the main processes of tumor immunity influenced by L-Arg metabolism will be discussed, along with the description of novel compounds that can deactivate these metabolic pathways in tumor-bearing hosts and thus help to restore immune reactivity against cancer
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No full textAbstract
Elizabeth M. Jaffee, MD; Isaiah J. Fidler, DVM, PhD; and Joseph R. Bertino, MD, are featured.</jats:p
Abstract 4623: Transcriptional analysis of the functional differences between M1 and M2 macrophages to identify new targets for myeloid cell modulation in pancreatic tumors
No full textAbstract
Macrophages exhibit dynamic plasticity in their function in response to the accumulating genetic alterations that occur during tumorigenesis, resulting in the establishment of an immune tolerized tumor microenvironment. However, depending on their environmental cues, they can switch between two functional phenotypes: pro-inflammatory/anti-tumorigenic (M1) or anti-inflammatory/pro-tumorigenic (M2). The importance of these two macrophage subsets is well-recognized; however, identifying and distinguishing M1 from M2 macrophages in patient tumors still remains a challenge. Prior studies have utilized transcriptome profiling of artificially skewed M1 and M2 macrophages from healthy donors to identify individual genes or gene clusters unique to each macrophage subset. However, these studies are limited to surface marker expression and gene expression profiles alone to distinguish subsets and lack functional validation of M1 and M2 macrophages. Surface marker and gene expression profiling of human M1 and M2 macrophages provide an incomplete characterization, as functionality is an important feature distinguishing these macrophage subsets. To improve the characterization of M1 and M2 macrophages, we performed a thorough three-step validation of artificially skewed M1 and M2 macrophages from healthy donor monocytes using surface marker expression, gene expression profiling, and multi-analyte ELISA analyses. Using our validation assays, we tested previously published protocols for their efficacy in generating M1 and M2 macrophages. While M1 macrophages using these protocols generated as expected M1 characteristics, M2 macrophages lacked hallmark functional features, particularly IL-10 secretion. This necessitated the generation of an optimized protocol to skew M1 and M2 macrophages that exhibited distinctive surface marker expression, gene expression profiles, and cytokine and chemokine production for their respective subset. We then performed RNA-sequencing to interrogate the transcriptional landscape of functional M1 and M2 macrophages and have found 1,472 transcripts that have at least a two-fold change in differential expression between M1 and M2 macrophages across 4 different donors. These results represent the most in-depth characterization of human M1 and M2 macrophages and provide insights into better biomarkers and targets for novel immunotherapy approaches.
Citation Format: Kimberline R. Yang, Todd D. Armstrong, Elizabeth M. Jaffee. Transcriptional analysis of the functional differences between M1 and M2 macrophages to identify new targets for myeloid cell modulation in pancreatic tumors [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 4623. doi:10.1158/1538-7445.AM2017-4623</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
Abstract 480: Novel miRNA regulation in an early progression model of PDA
No full textAbstract
The success of immunotherapy is dependent on infiltration and function of T cells within the tumor microenvironment. However, for many cancers, inflammatory and stromal cells provide formidable barriers to T cell access. Emerging data suggests that the cellular barriers to T cell access and function are regulated by both genetic and epigenetic factors. Identification of these regulators should provide new targets for enhancing immunotherapy.
The overall goal of this research is to construct a comprehensive profile of miRNA expression within the inflammatory and stromal cells that develop in the earliest pre-malignant pancreatic intraepithelial neoplasias (PanINs) in the KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) mouse model, a spontaneous model of pancreatic ductal adenocarcinomas (PDA) tumorigenesis. Specifially, we aim to investigate the functional roles of key differentially expressed miRNAs in propagating the tumor microenvironment via modulating the signaling between transformed ductal epithelial cells and the recruited cancer associated fibroblasts (CAFs) that comprise the majority of the desmoplastic stroma that characterizes PDA. Although numerous studies have described molecular alterations that are involved in pancreatic cancer development and progression, little is known about the miRNA regulatory profile and the associated inflammatory changes within the tumor microenvironment in the earliest PanIN lesions.
We conducted miRNA microarray analysis to determine the levels of 750 unique miRNAs in the pancreata of KPC mice ranging from 4 to 12 weeks of age (pre-PanIN1 to PDA). miRNA was isolated from normal pancreatic ducts, PanIN grades 1 through 3, and PDA via laser capture microdissection. miRNA expression was quantified by Taqman miRNA OpenArrays and confirmed by qPCR analysis. Out of the 750 rodent miRNAs, 4 miRNAs (miR-21, miR-16, miR-19b, and miR-224) were significantly upregulated throughout PDA development. miR-21 and miR-224 are of particular interest for their regulation of targets in cancer promoting inflammatory pathways and epithelial-mesenchymal transition (EMT).
To investigate the roles that miR-21 and miR-224 play in the developing microenvironment, primary KPC pancreatic ductal epithelial and fibroblast cell lines were established via fluorescence activated cell sorting (FACS) in order to perform in vitro miRNA knock-in and knock-out studies. Additionally, miRNA fluorescence in situ hybridization (miR-FISH) was performed to examine the spatial expression of miR-21 throughout progression of the early microenvironment. miR-21 is expressed at low levels in wildtype pancreata, but is highly expressed particularly in ductal epithelial cells of late stage KPC pancreata. Additional studies are underway to determine the functional role of this miRNA in PDA development and progression.
Citation Format: Nina J. Chu, Todd D. Armstrong, Elizabeth M. Jaffee. Novel miRNA regulation in an early progression model of PDA [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 480. doi:10.1158/1538-7445.AM2017-480</jats:p
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
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