1,722,417 research outputs found
L’evoluzione morfotettonica plio-quaternaria del sistema Golfo di Salerno-Piana del Sele-Monti Picentini (Appennino Meridionale)
No full textDescrizione bibliografica: C. Gesualdo, Madrigali a cinque voci. Libro secondo, V. Baldini, Ferrara 1594
No full textDescrizione bibliografica dell'edizione del secondo libro dei Madrigali a cinque voci di C. Gesualdo, stampata a Ferrara, da V. Baldini nel 159
PLEIOTROPIC EFFECTS OF PERIFOSINE ON GLIOBLASTOMA CELLS SURVIVAL: ALTERED MEMBRANE LIPID METABOLISM AND CELL SIGNALING
Full text linkGlioblastoma multiforme (GBM) is the most frequent and aggressive malignant tumor of the central nervous system in adults. Despite decades of experimentation to improve the outcome of patients with GBM, this type of neoplasm remains one of the most lethal human cancers.Therefore, the need to test different and new agents for efficacy and safety is urgent. Perifosine (PF) is a synthetic lipid analogue belonging to a relatively new class of structurally related antitumor agents: the alkylphospholipids (APLs). PF exhibits potent antineoplastic activity against a multitude of cancer cell lines and different tumor models and is currently being tested in phase II clinical trial against major human tumors. However, the effect of PF against gliomas is poorly investigated. PF can induce apoptosis and/or cell growth arrest in tumor cells, but the details of its molecular mechanism is still to be elucidated. To date, the Ser/Thr kinase Akt, which is a key regulator of multiple survival pathways, is considered as the most important molecular target of PF.
However, PF can induce also Akt-independent effects and the contribution of Akt inhibition to the clinical activity of PF remains to be assessed. As other ALPs, PF may alter the structure and function of cell membranes directly by inducing a biophysical disturbance of cell membranes where it accumulates and/or indirectly by interfering with the metabolism and transport of membrane lipids. In particular, alterations in the properties of lipid rafts, ordered membrane lipid domains enriched in cholesterol and sphingolipids (SLs), could affect numerous signaling pathways crucial to cell survival and proliferation that are dependent on these structures.
On these premises, the purpose of this study was to investigate the sensitivity of GBM cells to PF treatment and to provide a contribution to the understanding of its molecular mechanism by focusing on the ability of PF to target membrane lipid metabolism and content, and, as a consequence, membrane-related signaling pathways crucial in the regulation of cell demise.
At first, we evaluated the effect of PF on cell survival in several human GBM cell lines. We demonstrated that in these cell lines PF inhibits cell viability in a dose-dependent manner and that its cytotoxic effects are not solely due to Akt inhibition. Furthermore, we found that in glioma cells PF maintains ERK in its phosphorylated/active state in a sustained manner over time. Treatment with the MAPK inhibitor PD98059 potentiates PF toxicity, and strongly reduces PF-induced LC3B-II increase. This could thus represent a molecular mechanism for self-defense from PF, at least in part due to the induction of protective autophagy. Moreover, in cells exposed to PF we found a time-dependent increase in the number of giant and multinucleated cells with an irregular shape, these morphological changes resembling those described for mitotic catastrophe, suggesting that this could be the mechanism of PF-induced cells death, while apoptosis was undetectable.
Accumulating literature indicates that in several tumor cell lines PF inhibits the rate limiting step of phosphatidylcholine (PC) synthesis, which is catalyzed by CTP:phosphocholine cytidylyltransferase, and this was associated to cell death with still unclear mechanisms. Furthermore, PC is the donor of phosphocholine in the reaction catalyzed by the enzyme sphingomyelin synthase (SMS), so the inhibition of the PC biosynthesis may also affect the sphingomyelin (SM) biosynthesis from ceramide (Cer). We found that also in GBM cells PF affects PC biosynthesis. In addition, in our model PF inhibits SM biosynthesis by affecting SMS activity, and the reduced PC seems not to represent a limiting factor for SM synthesis. The decreased utilization of Cer for SM biosynthesis results in a modest increase of Cer, which can accumulate at the endoplasmic reticulum (ER). Therefore, both the increased Cer levels, both the inhibition of PC synthesis in the ER could trigger ER stress ultimately leading to cell death. However, it is known from literature that in our GBM cells model PF fails to provoke ER stress, suggesting that other aspects of membrane lipid homeostasis, such as that involved in membrane functionality, are most probably involved in PF-induced cell death. Indeed, PC is the most abundant phospholipid in eukaryotic cellular membranes, essential for new membrane formation. On the other hand, SM together with glycosphingolipids (GSLs) represent the major SLs of the plasma membrane, displaying an asymmetric or polarized distribution, and play important roles in the regulation of membrane fluidity and sub-domain structures involved in cell signaling.
We demonstrated that PF affected the endogenous levels of phospholipids (PLs), inducing a decrease in the total PLs/protein ratio accompanied by a change in the PLs pattern. PF-treated cells were poorer in PC, SM, and phosphatidylserine (PS), and richer in phosphatidylethanolamine (PE). In addition, PF induces an about 60% increase of endogenous gangliosides content compared to untreated cells.
The dramatic changes in PLs and SLs endogenous content induced by PF could significantly affect membrane composition and functionality, which in turn can be involved in the biological response of cells to PF treatment. Indeed, we found that the inhibition of SM synthesis mimicked and potentiate PF cytotoxic effects; in addition the inhibition of gangliosides biosynthesis reverses cytotoxic action of PF thus suggesting that increase of gangliosides content is essential for its cytotoxic action.
In conclusion, PF treatment in GBM cells results in a complex network of effects where the alteration of the metabolism and content of membrane-lipid components (and maybe their related secondary messengers), seems to play a key role in determining cell death.
This study indicates that PF is decisive in its target to fight GBM cells, this representing a critical push to study new aspects in its cellular mechanisms, implying PF as anti-GBM agent
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
IL BORDO MERIDIONALE DI M.TE MARZANO E LA VALLE DEL F. BIANCO: GEOLOGIA E GEOMORFOLOGIA.
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