1,721,001 research outputs found
New dimension of ciprofloxacin hybrids: Synthesis, characterization and anticancer evaluation of newly C3-modified ciprofloxacin derivatives
Get PDFThe strategic application of drug repurposing and repositioning in the design of hybrid molecules represents a promising alternative in contemporary drug discovery. Recent studies have highlighted the anticancer activity of ciprofloxacin derivatives, attributing this effect primary to their capacity to inhibit DNA topoisomerase II. In silico ADME profiling of C3-modyfied ciprofloxacin analogues, have further identified their role as potential P-glycoprotein inhibitors. Building upon these findings, we proposed the synthesis of a series of ciprofloxacin-peptidomimetic hybrid compounds to explore the synergistic antitumor activity arising from the combined fluoroquinolone and peptidomimetic pharmacophores. To achieve this goal, a novel chemoselective synthetic protocol was developed, employing the Passerini multicomponent reaction, which revealed an unexpected yet versatile role of acetic acid as a reaction medium but not as a substrate. The cytotoxic effects and the potential to overcome multidrug resistance were evaluated using various cancer cell lines. In parallel, molecular docking simulations with the multidrug resistant transporter P-glycoprotein provided mechanistic insights into the mode of action of these hybrids. Importantly, the studied compounds demonstrated reduced cytotoxicity towards erythrocytes and non-cancerous cells derived from vascular, hepatic, and connective tissues compared to cancer cells. Overall, our findings indicate that these ciprofloxacin-peptidomimetic hybrids exhibit significantly enhanced cytotoxic and chemosensitizing activity against cancer cells while maintaining a favorable toxic profile in normal cells. This novel class of hybrid molecules represents a promising source of lead compounds for the development of anticancer agents with improved therapeutic efficiency and safety
A novel combinatory treatment against a CDDP-resistant non-small cell lung cancer based on a Ruthenium(II)-cyclopentadienyl compound
Get PDFThe therapeutic approach to many solid tumors, including non-small cell lung cancer (NSCLC), is mainly based on the use of platinum-containing anticancer agents and is often characterized by acquired or intrinsic resistance to the drug. Therefore, the search for safer and more effective drugs is still an open challenge. Two organometallic ruthenium(II)-cyclopentadienyl compounds [Ru(eta(5)-C5H4CHO)(Me(2)bipy)(PPh3)]+ (RT150) and [Ru(eta(5)-C5H4CH2OH)(Me(2)bipy)(PPh3)][CF3SO3] (RT151) were tested against a panel of cisplatinresistant NSCLC cell lines and xenografts. They were more effective than cisplatin in inducing oxidative stress and DNA damage, affecting the cell cycle and causing apoptosis. Importantly, they were found to be inhibitors of drug efflux transporters. Due to this property, the compounds significantly increased the retention and cytotoxicity of cisplatin within NSCLC cells. Notably, they did not display high toxicity in vitro against nontransformed cells (red blood cells, fibroblasts, bronchial epithelial cells, cardiomyocytes, and endothelial cells). Both compounds induced vasorelaxation and reduced endothelial cell migration, suggesting potential antiangiogenic properties. RT151 confirmed its efficacy against NSCLC xenografts resistant to cisplatin. Either alone or combined with low doses of cisplatin, RT151 showed a good biodistribution profile in the liver, kidney, spleen, lung, and tumor. Hematochemical analysis and post-mortem organ pathology confirmed the safety of the compound in vivo, also when combined with cisplatin. To sum up, we have confirmed the effectiveness of a novel class of drugs against cisplatin-resistant NSCLC. Additionally, the compounds have a good biocompatibility and safety profile
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Stock Market Asymmetries: A Copula Diffusion
Get PDFThe paper proposes a model for the dynamics of stock prices that incorporates increased asset co-movements during extreme market downturns in a continuous-time setting. The model is based on the construction of a multivariate diffusion with a pre-specified stationary density with tail dependence. I estimate the model with Markov Chain Monte Carlo using a sequential inference procedure that proves to be well-suited for the problem. The model is able to reproduce stylized features of the dependence structure and the dynamic behaviour of asset returns
The Evolving Beta-Liquidity Relationship of Hedge Funds
No full textUsing an optimal changepoint approach, we find a structural change in the relation between hedge funds’ stock market exposure and aggregate stock market liquidity that takes place in the period 2000 to 2002. Before the structural break, market betas have no relation to liquidity and only a few style categories of hedge funds show increased market presence when liquidity is low. After the break, the relationship is inverted, pointing towards an increased liquidity timing ability of hedge funds, as users of liquidity. We relate our findings to best execution rules and decimalization in the US stock market that were introduced in that period and impacted aggregate liquidity conditions. Furthermore, the returns to a momentum strategy display a similar structural break and momentum-loading funds constitute a sizeable proportion of hedge funds that manifest a distinct beta-liquidity evolution with a structural break in that period
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