1,720,985 research outputs found
The FGF2-binding domain of thrombospondin-1: functional characterization and exploitation to design antiangiogenic compounds
No full textIncreased tumorigenicity and invasiveness of C6 rat glioma cells transfected with the human alpha-2,8 sialyltransferase cDNA
No full textGangliosides are thought to be involved in tumor cell proliferation, migration and invasiveness as so far demonstrated by the addition of exogenous gangliosides to the culture medium. To better understand the direct influence that alterations in ganglioside synthesis can exert on these functional aspects of cell biology, in the present study, we investigated the behaviour of C6 rat glioma cells after stable transfection with the human CMP-NeuAc:NeuAcalpha2-3Galbeta1-4GlcCer alpha2,8-sialyltransferase (SAT-II, EC 2.4.99.8) gene. The enzyme synthesizes ganglioside GD(3) by adding a sialic acid residue to ganglioside GM(3). Stable transfection of the constructs into C6 cells and expression of the human SAT-II gene were evaluated using PCR and RT-PCR amplification, respectively. Qualitative and quantitative analysis of the ganglioside profile was performed by conventional HP-TLC and identity of de novo synthesized species was assessed by TLC immunostaining. Results show that whereas C6 parental cells and C6 cells transfected with the empty expression vector synthesize, almost exclusively, ganglioside GM(3), de novo synthesis of GD(3) is clearly observed in clones expressing the alpha2,8-sialyltransferase. Subcutaneous grafting in athymic nude mice of cells expressing high levels of GD(3) induces tumors growing faster and more aggressively than controls. In in vitro assays, the same cells demonstrate increased proliferation rate, motility and invasiveness. Chemotaxis and chemoinvasion were assayed using the modified Boyden chamber. Data obtained suggest that endogenously neosynthesized GD(3) is able to modify proliferation rate, motility and invasion of C6 rat glioma cells, enhancing the features of malignancy of this tumor cell line
Vascular Disrupting Activity of Tubulin-Binding 1,5-Diaryl-1H-imidazoles
No full textHighly cytotoxic 1,5-diaryl-1H-imidazoles were studied to clarify the relationship between cytotoxicity and activity as vascular disrupting agents (VDA). All the compounds disorganized the tubulin cytoskeleton, affected endothelial cell morphology and capillary formation in vitro, and caused vessel shutdown and tumor necrosis in vivo, thus confirming their vascular disrupting properties. Nonetheless, the substitution patterns on the imidazole ring, responsible for greater interaction energy with tubulin and higher cytotoxicity, were not associated to greater vascular disrupting activity
New vicinal diaryl-substituted imidazole derivatives with vascular disrupting activity
No full textRecently, our research group turned its attention to the identification of structurally new vascular disrupting agents (VDAs) which are water soluble or may be easily converted into water soluble derivatives, possess vascular disrupting activity, and exhibit antitumor activity at non-toxic doses. In particular, we prepared 1,5- and 1,2-diaryl-1H-imidazoles of general formula 1 and 2, respectively, which can be considered as cis-locked analogues of combretastatin A-4 (CA-4), a natural tubulin-binding VDA.
We became interested in the imidazole core since the basicity of its N-3 atom might be exploited to prepare water soluble salts having improved physico-chemical properties. On the other hand, since the 3,4,5-trimethoxyphenyl substituted A ring of the CA-4 seems to be essential for the bioactivity of this natural product, we maintained this moiety in compounds 1 and 2 and evaluated the effect due to the replacement of the B-ring of CA-4 with a variety of aryl substituents.
Imidazoles 1 and 2 were prepared using the innovative synthetic protocols we recently developed. These protocols let us to prepare selectively compounds 1 and 2 starting from common and cheap precursors on a multigram scale.
We then evaluated the vascular disrupting activity of some selected imidazole derivatives in vitro on HUVECs, and in vivo on experimental tumors. In particular, we observed that imidazoles 1a–c caused profound changes in the morphology of endothelial cells (ECs) (IC50 = 6.5, 27.1 and 38.8 μM, respectively). Interestingly, in comparable experimental conditions, 1a - but not 1b and 1c - induced changes in the shape of ECs at concentrations that did not affect their proliferation. By immunohistochemistry we confirmed the ability of 1a to cause depolymerization of microtubules in ECs. We next analyzed the ability of the selected compounds to induce necrosis of experimental tumors in vivo, the hallmark of vascular disrupting activity. Following a single treatment, imidazoles 1a–c caused massive central necrosis of tumors.
They were also subjected to primary cytotoxicity screening against the NCI 60 tumor cell line panel. On the analogy of CA-4, imidazole 1a–c had a definite cytotoxic activity, displaying MG_MID LogGI50 values of -6.59, -7.40 and -7.14, respectively.
Docking experiments also showed that the trend of the calculated interaction energies of 1 and 2 with the colchicine binding site on tubulin, which is the main biological target for combretastatins, is similar to that of the in vitro LogGI50 values of these compounds.
In conclusion, the combretastatin-like imidazole derivatives 1 and 2 possess vascular disrupting activity and represent promising chemical entities for the design of novel VDAs
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
Adhesive and invasive properties of C6 rat glioma cells stably transfected with the human alpha2,8 sialyltransferase cDNA
No full textVariations 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
- …
