1,721,179 research outputs found
¿ALTERATIONS OF CHOLINE PHOSPHOLIPID METABOLISM IN OVARIAN CANCER: STUDY OF THE ACTIVITY AND EXPRESSION OF CHOLINE KINASE AS A PROGNOSTIC VALUE¿
Full text linkEpithelial ovarian cancer (EOC) is a highly lethal malignancy due to late diagnosis and early relapse associated with development of chemoresistance. So far, the origin of drug resistance is not completely understood and several mechanisms seem to be responsible for this process including the ability of cancer cells to modify/reprogram cellular metabolism. Aberrant choline metabolism, characterized by increased phosphocholine (PCho) levels sustained by enhanced choline kinase (ChoK) activity, is a new cancer metabolic hallmark that can be monitored by Magnetic Resonance Spectroscopy (MRS) and that reflects the interactions between oncogenic signaling and cellular metabolism. EOC possesses an altered MRS-choline profile, characterized by increased PCho content to which mainly contribute over-expression and activation of Choline kinase-alpha (ChoKα). The project aimed to investigate the biological and clinical relevance of increased ChoK expression and activity in EOC. We showed that transient CHKA silencing induced: a significant reduction in PCho accumulation as assessed by MRS analysis; an inhibition of in vitro cell growth; down modulation of genes related to inflammation and EOC aggressiveness; a significantly reduced cell motility and invasion and a significant increase of sensitivity to platinum, paclitaxel and doxorubicin even in a drug-resistant context. Since the dynamics of biological effects related to CHKA silencing could not possibly be detectable by transient RNAi, we stably downregulated ChoKα mRNA expression using a lentiviral vector, expressing GFP and specific CHKA shRNA, in two EOC cell lines, INTOV11 and SKOV3. In both transduced cell lines, we confirmed the data obtained with the transient downmodulation, as reduction of PCho content, inhibition of in vitro cell growth, reduction of invasive potential and migration capability. Furthermore, a significant decrease of in vivo tumor growth (sub-cutaneous injection) was evident in both sh-CHKA cellular models as compared to their controls. The global metabolic profiles of sh-CHKA and control EOC cell lines, performed with the Metabolon technology platform, revealed in both cellular models an alteration of glutathione metabolism, commonly characterized by a decrease of reduced glutathione (GSH) content in shCHKA cells as compaired to their controls. Interestingly, sh-CHKA showed an increased sensitivity to drug treatment (platinum and doxorubicin) suggesting that CHKA knocking down may change antioxidant cellular defense thus increasing drug sensitivity. Since the GSH intracellular levels are well known to interfere with treatment efficacy of several DNA damaging drugs, we have investigated whether the alteration of GSH/GSSG levels dependent upon CHKA silencing is the mechanism by which response/resistance to DNA-damaging drugs is affected. Artificial reduction of intracellular GSH in wild type EOC cells phenocopied CHKA silencing effects while restoration of GSH levels in CHKA silenced cells caused a recovery of the wt phenotype by rescuing drug resistance. The concurrent modulation of active ROS species following CHKA silencing demonstrates the direct involvement of oxidative stress pathway regulation by ChoKα expression. Finally, in order to investigate the putative role of CHKA in EOC pathogenesis we performed an in silico analysis on seven public data sets of gene expression profile, including 698 EOC patients and we found a progressive increase of CHKA expression along EOC grading. Interestingly the CHKB expression in the same samples showed an opposite trend. Given these premises, we propose that a metabolic approach to EOC treatment might have the potential to address some of the issues that contribute to the high EOC lethality and open the way for the validation of ChoKα as a new therapeutic target to be used alone or in combination with conventional drugs for EOC treatment
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
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