1,720,964 research outputs found
Design of histone methyltransferase and deacetylase modulators: applications in cancer and non-cancer diseases
Full text linkIn our two previous studies, we reported the discovery and the optimization of novel 1,4-dihydropyridine-based sirtuin ligands. Starting from SIRT1-activating 1,4-DHPs, bearing benzyl group at N1, we identified carbonyl group at N1 to be responsible for an increased SIRT3 activation (MC2791 (1a) and MC2789 (1u)). However, the moderate potencies of 1a and 1u prompted us to screen for more potent derivatives. We generated new series of compounds by varying their “top” or “bottom” with other substituents at C1 or C4 position of the DHP scaffold, respectively. Hence, we reported the discovery and characterization of potent and specific activators for Sirt3 and/or Sirt5. The 1,4-DHP-based activators bind to the sirtuin catalytic core independent of bound substrates and increase the enzyme’s turnover. The compounds are selective for Sirt3 or Sirt5 and show cellular activity. Overall, our results provided a scaffold for potent and specific sirtuins activation and an activation model for Sirt3 and Sirt5 as a basis for functional studies and further drug development. Additionally, HBV-infected cells treated with our potent and selective Sirt3 activator 1a, demonstrated that 1a regulates the antiviral activity of cccDNA in HepAD38 cells. The treatment of HBV-infected cells with 1a through SIRT3 stimulation led to histone H3 and/or H4 hypoacetylation and reduction in the transcription from a viral cccDNA template, accompanied by a reduction in HBV replication. Together these results indicate that the Sirt3 activator 1a can modulate the acetylation status of cccDNA-bound H3/H4 histones, thus providing a novel therapeutic approach for the treatment of chronic HBV infection.Very recently, the trend to shift towards epi-polypharmacology drugs has been taken into account in order to acquire a superior therapeutic effect and eventually reduce drug-related doses and toxicity, as well. Based on these evidence, we design and synthesize novel dual HDAC/EZH2 inhibitors to achieve higher anticancer effect by regulating sinergically the expression of a huge number of tumor suppressor genes. For our purpose, we chose the HDAC pharmacophoric model due to its wide structural variety and feasibility to accommodate on the surface binding cap a high degree of different chemical entities. In our first investigation, we combined the well-known vorinostat HDACi moiety to the already optimised pyrazole and pyrrole EZH2i scaffolds MC3629 and MC3707, respectively. The first preliminary screening of our two hybrid compounds MC4134 and MC4128 showed that only the pyrrole derivative MC4128 was able to simultaneously inhibit EZH2 and HDAC, also exhibiting an interesting isoform selectivity for HDAC6. Prompted by these findings, we decided to develop a series of dual inhibitors of EZH2 and HDAC (8a-g and 6a-g), combining the well-known HDACi moieties to the already optimised EZH2i scaffold MC3707. Therefore, according to the HDACi pharmacophoric model, we have chosen different types of spacer: the aliphatic one (Vorinostat), the benzoic one (Entinostat) and the cinnamic one (Panobinostat and Belinostat). As zinc binding group we used, in turn, a hydroxamic acid or an ortho-amino anilide. Overall, compounds 8a-g and 6a-g have been confirmed to be dual inhibitors of EZH2 and HDACs in vitro, showing an interesting selectivity profile towards HDAC isoforms. In preliminary assays in U-937 AML cells, 8c (MC4128) decreased cell viability and induced apoptosis, with increased levels of acetyl-histone H3 and acetyl-α–tubulin. Importantly, we expect that our novel HDAC/EZH2 dual inhibitors can display a potent and synergic anti-cancer activity in vivo, thus becoming an attractive therapeutic approach to fight cancer.Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative mitochondrial disorder caused by an unstable GAA trinucleotide (TTC) repeat expansion in the first intron of the frataxin gene (FXN). In FRDA patients, the expanded GAA·TTC repeats lead to partial transcriptional silencing resulting in expression of structurally and functionally normal frataxin, but at lower levels compared to the normal. FRDA can be considered as an epigenetic disease due to the identification of several associated epigenetic marks, including 1) increased levels of methylated histones (H3K9me2, H3K9me3, H4K20me3) in regions flanking the GAA repeats, 2) increased DNA methylation at specific CpG sites upstream of the GAA repeats and, 3) reduced acetylation of several H3 and H4 lysine residues. Due to the importance of H4K20me to genomic integrity, very recently A-196 has been discovered as the first-in-class chemical probe of Suv4-20H1 and Suv4-20H2, with an IC50= 25 nM and IC50=144 nM, respectively. Despite the in vitro potency of A-196, confirmed by biochemical and cellular assays, preliminary in vitro metabolic studies in human liver microsomes (HLM) have shown some metabolic liability and potentially low solubility, with a Clint (μL/min/mg protein) =191 and a t1/2 (min)=7.28. Prompted by these findings, a lead chemical optimisation has been carried out with the aim to ameliorate chemical and physical properties of A-196. Preliminary biological results of our final compounds (1a-m and 2c) in HEK293 cell model of FRDA showed that only compound 1b (RM02) demonstrated similar effects (or slight better) than the reference compound A-196, with a luciferase fold reactivation of 1.20. The other compounds, unfortunately, showed no increase in frataxin expression beyond that one induced by the vehicle DMSO. Preliminary data for the evaluation of the cytotoxicity (adenylate kinase scores) showed that our compounds are probable non-toxic to the cells
Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy
Full text linkImmune checkpoint factors, such as programmed cell death protein-1/2 (PD-1, PD-2) or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) receptors, are targets for monoclonal antibodies (MAbs) developed for cancer immunotherapy. Indeed, modulating immune inhibitory pathways has been considered an important breakthrough in cancer treatment. Although immune checkpoint blockade therapy used to treat malignant diseases has provided promising results, both solid and haematological malignancies develop mechanisms that enable themselves to evade the host immune system. To overcome some major limitations and ensure safety in patients, recent strategies have shown that combining epigenetic modulators, such as inhibitors of histone deacetylases (HDACi) or DNA methyltransferases (DNMTi), with immunotherapeutics can be useful. Preclinical data generated using mouse models strongly support the feasibility and effectiveness of the proposed approaches. Indeed, co-treatment with pan- or class I-selective HDACi or DNMTi improved beneficial outcomes in both in vitro and in vivo studies. Based on the evidence of a pivotal role for HDACi and DNMTi in modulating various components belonging to the immune system, recent clinical trials have shown that both HDACi and DNMTi strongly augmented response to anti-PD-1 immunotherapy in different tumour types. This review describes the current strategies to increase immunotherapy responses, the effects of HDACi and DNMTi on immune modulation, and the advantages of combinatorial therapy over single-drug treatment
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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