1,720,977 research outputs found
Synthesis and Biological Evaluation of a Novel Dual-Targeting Small Molecule Drug Conjugate Modulating the Crosstalk between α5β1 Integrin and MDM2 in Glioblastoma
Full text linkNegative crosstalk between alpha 5 beta 1 integrin and the p53-MDM2 regulatory axis contributes to glioblastoma progression and therapeutic resistance. To explore the potential of dual inhibition of these two biological targets, the dual targeting small molecule drug conjugate (SMDC) (1) was designed by coupling the MDM2 inhibitor SAR405838 to a selective alpha 5 beta 1 integrin ligand cyclo(phg-isoDGR-k) (7) through a stable chemical linker. The resulting conjugate retained antiproliferative activity in U87-MG glioblastoma cells and induced p53 reactivation with minimal MDM2 induction. Cell cycle distribution analysis revealed a redistribution of cells from the G0/G1 phase to the G2/M phase exclusively upon treatment with conjugate 1, suggesting that a different mechanism of action is engaged. These findings support the potential of this dual-targeting approach through a dual-targeting SMDC as a promising therapeutic strategy against high-grade glioma overexpressing the alpha 5 beta 1 integrin receptor
Kinetic analysis and molecular modeling of the inhibition mechanism of roneparstat (SST0001) on human heparanase
No full textHeparanase is a β-d-glucuronidase which cleaves heparan sulfate chains in the extracellular matrix and on cellular membranes. A dysregulated heparanase activity is intimately associated with cell invasion, tumor metastasis and angiogenesis, making heparanase an attractive target for the development of anticancer therapies. SST0001 (roneparstat; Sigma-Tau Research Switzerland S.A.) is a non-anticoagulant 100% N-acetylated and glycol-split heparin acting as a potent heparanase inhibitor, currently in phase I in advanced multiple myeloma. Herein, the kinetics of heparanase inhibition by roneparstat is reported. The analysis of dose-inhibition curves confirmed the high potency of roneparstat (IC50 ≈ 3 nM) and showed, at higher concentrations, a Hill coefficient consistent with the engagement of two molecules of inhibitor. A homology model of human heparanase GS3 construct was built and used for docking experiments with inhibitor fragments. The model has high structural similarity with the recently reported crystal structure of human heparanase. Different interaction schemes are proposed, which support the hypothesis of a complex binding mechanism involving the recruitment of one or multiple roneparstat chains, depending on its concentration. In particular, docking solutions were obtained in which (i) a single roneparstat molecule interacts with both heparin-binding domains (HBDs) of heparanase or (ii) two fragments of roneparstat interact with either HBD-1 or HBD-2, consistent with the possibility of different inhibitor:enzyme binding stoichiometries. This study provides unique insights into the mode of action of roneparstat as well as clues of its interaction with heparanase at a molecular level, which could be exploited to design novel potential inhibitor molecules
Design, Synthesis and Preliminary In‐Vitro Activity of 6‐Hydroxyalkyl β‐Carboline Derivatives for the Development of Drug Conjugates Targeting MDM2
Full text linkThe mouse-double-minute-2 (MDM2) protein, the main downregulator of the tumor suppressor p53 protein, represents a promising target for the development of novel anticancer therapies. However, the lack of selectivity and poor effectiveness in tumors bearing mutated-p53 impaired the approval of several MDM2 inhibitors for the market. In this context, the possibility of generating drug-conjugates within a MDM2 inhibitor is a growing research area aimed to overcome these drawbacks. Considering the promising MDM2 inhibition by the β-carboline-based 1, in this work we explored the introduction of a new functionalization on it for a future conjugation while preserving its anticancer properties. Based on preliminary docking studies, we synthesized derivatives 2 a–d having linear hydroxyalkyl chains with different lengths at the 6-position of the β-carboline core, which effectively preserved the submicromolar IC50 on wild-type-p53-U87MG glioblastoma cell line observed with 1. Candidates 2 a, d showed the functionalization was tolerated with respect of bioactivity also on mutated-p53-U138MG glioblastoma cell line, and their hydroxyl groups proved to be easily accessible when coupled to 4-pentynoic-N,N’-dimethylethylenediamine affording derivatives 10 a, d with high yields. In summary, our results led to generating novel 6-hydroxyalkyl-β-carboline compounds displaying a suitable hydroxyl-site useful to improve the efficacy and/or the tumor specificity of 1 through conjugation strategies
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
- …
