1,720,987 research outputs found
Exploring drug molecular effects in cancer disease models
No full textHepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. As usually HCC diagnosis occurs in the advanced stage of the disease, available treatments such as resection, liver transplant, or local ablation are poorly if not at all effective. Also systemic chemotherapy has limited effectiveness. The only drug that can prolong patient survival is Sorafenib; unfortunately, however, the extent of increased survival is very modest being of few months. Together the above considerations clearly indicate that the development of novel therapeutic approaches for HCC are urgently necessary.
The demethylation agent 5-Azacytidine (5-AZA) is considered to be of great potential therapeutic value. This is due to the emerging knowledge of the important role of epigenetic modulation in HCC development and to the fact that the use of demethylation agents gave encouraging results in cultured human HCC derived cells.
Working with different cellular models of HCC (JHH6, HUH7, IHH) we got evidence of the potent anti-proliferative (cell counting, MTT, flow-cytometry, immuno-fluorescence) and anti-migratory (scratch assay, trans-well test, microscopic live observation of migration) effects of 5-AZA. Functional molecular analysis revealed that, upon 5-AZA treatment, a strong up-regulation of miRNA 139-5p occurs. This in turn causes the down regulation of the Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), a known target of miRNA 139-5p. ROCK2 inhibition then results in the reduced stabilization of the gelatinase MMP2, paralleled by the reduction of MMP2 activity (as evaluated by zymography). In addition, ROCK2 down regulation leads to the decrease in the expression of other targets including Cyclin D1, E2F1 and Pin-1, all proliferative genes. Thus, the potent anti-migratory and anti-proliferative effects of 5-AZA may occur via the inhibition of pathways miRNA139-5p/ROCK2/MMP2 and miRNA139-5p/ROCK2/CyclinD1/E2F1/Pin-1 pathway, respectively.
Finally, we have observed in a preliminary experiment in SCID xenograft mouse model of HCC that the intra-tumour injection of 5-AZA administered in two consecutive rounds, can significantly reduce tumour growth prolonging animal survival.
The effectiveness of 5-AZA against HCC we observed can significantly contribute to bring 5-AZA closer to the clinical use for HCC
Zebrafish as an Experimental Model for Human Disease
Full text linkBelonging to the family of Cyprinidae, the zebrafish is a small freshwater fish present in the rivers of Bangladesh, Northern India and Southern Nepal [...]
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
TRAIL treatment prevents renal morphological changes and TGF-β-induced mesenchymal transition associated with diabetic nephropathy
No full textBackground: TNF-related apoptosis-inducing ligand (TRAIL) has attracted attention not only as an anti-cancer agent, but also as a potential treatment for diabetes. Animal studies have shown that TRAIL delivery ameliorated glucose control in type 1 and type 2 diabetes. It is currently unknown whether TRAIL positive effects are maintained in more severe forms of type 2 diabetes, and whether they include renoprotection. Our study aimed at evaluating TRAIL effects in a severe form of type 2 diabetes with nephropathy.Materials and methods: A total of 20 db/db mice were treated with saline or TRAIL twice per week for 12 weeks. In parallel, renal tubular epithelial cells were cultured with TGF-beta 1 in the presence and absence of TRAIL, with and without silencing TRAIL-specific receptor (DR5) and leptin receptor.Results: TRAIL did not improve glucose control, but it significantly reduced circulating interleukin (IL)-6 and resistin. In the kidney, TRAIL treatment significantly ameliorated glomerular and tubular morphology with an improvement in kidney function, but no effect on proteinuria. Our in vitro studies on TGF-beta 1-treated cells, showed that by binding to DR5, TRAIL rescued normal tubular cell morphology, increasing E-cadherin and reducing alpha-smooth muscle actin (SMA) expression, with no effects on cell viability. Interestingly, both in vivo and in vitro, TRAIL reduced the accumulation of the autophagy substrate p62.Conclusions: Our data confirm TRAIL protective effects against organ damage and shed light on to promising anti-fibrotic actions, which are independent of glucose control. TRAIL anti-fibrotic actions might be due to the rescue of autophagy in diabetes
TRAIL/DR5 pathway promotes AKT phosphorylation, skeletal muscle differentiation, and glucose uptake
Full text linkTNF-related apoptosis-inducing ligand (TRAIL) is a protein that induces apoptosis in cancer cells but not in normal ones, where its effects remain to be fully understood. Previous studies have shown that in high-fat diet (HFD)-fed mice, TRAIL treatment reduced body weight gain, insulin resistance, and inflammation. TRAIL was also able to increase skeletal muscle free fatty acid oxidation. The aim of the present work was to evaluate TRAIL actions on skeletal muscle. Our in vitro data on C2C12 cells showed that TRAIL treatment significantly increased myogenin and MyHC and other hallmarks of myogenic differentiation, which were reduced by Dr5 (TRAIL receptor) silencing. In addition, TRAIL treatment significantly increased AKT phosphorylation, which was reduced by Dr5 silencing, as well as glucose uptake (alone and in combination with insulin). Our in vivo data showed that TRAIL increased myofiber size in HFD-fed mice as well as in db/db mice. This was associated with increased myogenin and PCG1α expression. In conclusion, TRAIL/DR5 pathway promotes AKT phosphorylation, skeletal muscle differentiation, and glucose uptake. These data shed light onto a pathway that might hold therapeutic potential not only for the metabolic disturbances but also for the muscle mass loss that are associated with diabete
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
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