1,720,969 research outputs found
Abstract 5429: The Warburg Effect: protons suck
No full textAbstract
Aerobic glycolysis (the Warburg Effect) is a hallmark of cancer and is associated with local invasion and metastasis. This metabolic phenotype results in acidification of the microenvironment in solid tumors, which is responsible for many of the known sequelae. For example, systemic buffer therapy directly and specifically increases extracellular tumor pH and reduces spontaneous and experimental metastasis in vivo. Further, extracellular acidosis can be a potent inhibitor of anti-tumor immunity. Removal of glycolytically-derived acids requires the activity of proton transporting mechanisms, such as NHE, V-ATPase and CA-IX. While it is commonly believed that these transporters are responding to the demands imposed by increased glycolytic flux, an alternative hypothesis states that glycolytic flux is increased to satisfy the demand driven by these transporters. Hence, expression of transporters that drive extracellular acidosis would induce a more glycolytic phenotype. To test this, we have transfected lowly glycolytic and non-metastatic MCF-7 breast adenocarcinoma cells with two different proton transporters.
In the first model, we used the yeast plasma membrane proton ATPase 1 (PMA1); a Type 1 P-type ATPase. PMA1 was stably over-expressed in MCF7 cell line and over-expression of PMA1 transformed the cells into a more aggressive phenotype with increased glucose consumption, lactate production, and proton production. Phenotypically, the transfected clones had elevated rates of migration and invasion in vitro and increased metastasis in vivo. This experimental evidence supports the hypothesis that proton export alone could drive the Warburg phenotype. Hence, in this system, glucose is metabolized to replenish either the ATP expended or the exported hydrogen-ions.
In the second model we used CA-IX; an exofacial carbonic anhydrase that is highly expressed in invasive cancers and materially participates in acidifying the microenvironment. CA-IX is upregulated in multiple cancer types with minimal expression in normal tissue, and is therefore an attractive and biologically relevant therapeutic target. In vitro, we have observed
that many cells expressing a glycolytic phenotype have elevated CA-IX expression, leading us to postulate that these phenotypes are coupled. To test this, we stably overexpressed CA-IX in MCF7 cells and again this resulted in a stable, glycolytic phenotype with increased glucose consumption, lactate production, and proton production observed using assay kits and live cell metabolic phenotyping with the Seahorse Extracellular Flux Analyzer. Through this study we have shown that acidosis leads to a more aggressive behavior and that CA-IX expression alone can induce a glycolytic phenotype. Hence, we hypothesise this is due to the enzymatic activity of CA-IX “sucking in” glucose to replenish intracellular H+ that are exported by this mechanism.
Citation Format: Shonagh Russell, Liping Xu, Rober J. Gillies. The Warburg Effect: protons suck [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 5429. doi:10.1158/1538-7445.AM2017-5429</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
Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma
No full textCancer-induced bone pain (CIBP) is common in patients with bone metastases (BM), significantly impairing quality of life. The current treatments for CIBP are limited since they are often ineffective. Local acidosis derived from glycolytic carcinoma and tumor-induced osteolysis is only barely explored cause of pain. We found that breast carcinoma cells that prefer bone as a metastatic site have very high extracellular proton efflux and expression of pumps/ion transporters associated with acid-base balance (MCT4, CA9, and V-ATPase). Further, the impairment of intratumoral acidification via V-ATPase targeting in xenografts with BM significantly reduced CIBP, as measured by incapacitance test. We hypothesize that in addition to the direct acid-induced stimulation of nociceptors in the bone, a novel mechanism mediated by the acid-induced and tumor-associated mesenchymal stroma might ultimately lead to nociceptor sensitization and hyperalgesia. Consistent with this, short-term exposure of cancer-associated fibroblasts, mesenchymal stem cells, and osteoblasts to pH 6.8 promotes the expression of inflammatory and nociceptive mediators (NGF, BDNF, IL6, IL8, IL1b and CCL5). This is also consistent with a significant correlation between breakthrough pain, measured by pain questionnaire, and combined high serum levels of BDNF and IL6 in patients with BM, and also by immunofluorescence staining showing IL8 expression that was more in mesenchymal stromal cells rather than in tumors cells, and close to LAMP-2 positive acidifying carcinoma cells in BM tissue sections.In summary, intratumoral acidification in BM might promote CIBP also by activating the tumor-associated stroma, offering a new target for palliative treatments in advanced cancer
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