1,720,961 research outputs found
Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-κB activation
Full text linkThe role of mesenchymal stem cells (MSC) in osteosarcoma (OS), the most common primary tumor of bone, has not been extensively elucidated. We have recently shown that OS is characterized by interstitial acidosis, a microenvironmental condition that is similar to a wound setting, in which mesenchymal reactive cells are activated to release mitogenic and chemotactic factors. We therefore intended to test the hypothesis that, in OS, acid-activated MSC influence tumor cell behavior. Conditioned media or co-culture with normal MSC previously incubated with short-term acidosis (pH 6.8 for 10 hr, H+-MSC) enhanced OS clonogenicity and invasion. This effect was mediated by NF-κB pathway activation. In fact, deep-sequencing analysis, confirmed by Real-Time PCR and ELISA, demonstrated that H+-MSC differentially induced a tissue remodeling phenotype with increased expression of RelA, RelB and NF-κB1, and downstream, of CSF2/GM-CSF, CSF3/G-CSF and BMP2 colony-promoting factors, and of chemokines (CCL5, CXCL5 and CXCL1), and cytokines (IL6 and IL8), with an increased expression of CXCR4. An increased expression of IL6 and IL8 were found only in normal stromal cells, but not in OS cells, and this was confirmed in tumor-associated stromal cells isolated from OS tissue. Finally, H+-MSC conditioned medium differentially promoted OS stemness (sarcosphere number, stem-associated gene expression), and chemoresistance also via IL6 secretion. Our data support the hypothesis that the acidic OS microenvironment is a key factor for MSC activation, in turn promoting the secretion of paracrine factors that influence tumor behavior, a mechanism that holds the potential for future therapeutic interventions aimed to target OS
Evolutionary Mechanisms for Host Resistance to Tumor Growth and Subsequent Cancer Cell Counter-Adaptations
No full textCancer is well-recognized as an evolutionary system, as first proposed by Cairns and Nowell more than 60 years ago. In an evolutionary context, cancers growing in vivo typically consist of heterogeneous subpopulations of cells that interact with each other and with host cells through selection forces operating at many temporal and spatial scales. Moreover, the tumor environment comprises more than just cancer cells; it includes a rich cancer stroma and cancer-driving molecules such as cytokines and metabolites. The tumor’s environment comprises intratumoral heterogeneity that often leads to therapy resistance attributed to the essential roles of many genetic and nongenetic mechanisms. My dissertation investigated possible outcomes from complex eco-evolutionary interactions between cancer cells and their host organism. By exploring phenotypic, genetic, and epigenetic mechanisms and responses, I discovered that both immune and non-immune resistance strategies are evolutionarily possible. Thus, my findings from three related studies provide novel insights into the evolutionary “arms race” of tumor progression in immune-competent and immune-deficient mice.
In the first study involving interactions between the tumor and the host immune system, I identified the consequence of disturbing the equilibrium phase of the dynamic process that consists of immunosurveillance and tumor progression (i.e., cancer immunoediting). This phase is a characteristic of tumor dormancy that is achieved when a complex equilibrium occurs between the tumor cell and the immune system, and the tumor remains in stasis. My studies have shown that perturbation of this equilibrium by a stress stimulus, such as administration of volatile and intravenous anesthetics, enhances tumor growth in immune-competent mice but not in immune-deficient mice. This suggests that the immune system can be a key component in the oncological stress response for those pharmacologic agents for hosts that are not immune compromised.
In the second study, I identified different strategies that allow tumors to be resistant to one type of cancer by applying selective breeding over 10 generations to laboratory immune-competent and immune-deficient mice inoculated with subcutaneous tumors. My studies showed that both mice strains evolved greater cancer resistance and suppression mechanisms after 10 generations of selection, but the tumors of these mice responded differently. In the absence of an intact adaptive immune system, the immune-deficient mice evolved with changes in mesenchymal cells that limited resources and cancer cell growth. In contrast, the immune-competent mice evolved with improved immune-mediated killing of cancer cells through changes in immune cell frequency, phenotype, and function. Cancer cells deployed observable counter- responses to the hosts’ cancer suppression mechanisms. These counter-responses included increased proliferation in immune-competent mice and both less cell proliferation and higher necrosis in immune-deficient mice. My studies suggest that host species can rapidly evolve both immunologic and non-immunologic tumor defenses depending on the lineage. However, cancer cells maintain sufficient plasticity to deploy effective phenotypic and population-based counterstrategies quickly. For example, variation in tumor gene expression was largely explained by the differences between the hosts and the fact that the hosts responded differently to selection for resistance to the tumor.
In the third study, I examined how transcriptomic responses evolved in the hosts in response to selection for resistance as well as the transcriptomic response of the original cancer cell line. In immune-competent mice compared to immune-deficient mice, I found increased expression in genes enriched for developmental processes, cell migration and movement, and cell membrane composition. The gene with the highest fold expression increase was Semaphorin 3D (Sema3D). This gene is implicated in the development and formation of blood vessels during angiogenesis for the regulation of the epithelial to mesenchymal transition. In addition, genes related to integrin binding, cell adhesion molecular binding, and extracellular matrix (ECM) binding were differentially expressed in immune-deficient mice. Expression levels of extracellular matrix markers, such as collagen type VI (Col18a1), alpha, prolyl 3-hydroxylase 2 (p3h2), and collagen, type XII alpha (Col12a1), were decreased. My future plans include associating the genome-wide differentially expressed genes with methylation changes, as well as how examining how patterns of gene expression and methylation may change across the tumor and the host in response to selection for cancer resistance.
The data presented here demonstrates the importance of molecular-level mechanisms that can be effectively targeted for therapeutic benefits. Furthermore, the mice strains developed in these studies can be used to discover more mechanisms of tumor growth resistance and metastasis that may lead to significant advancements in clinical treatments for patients with cancer
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
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