Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Poly(vinyl acetate)–clay hybrids prepared via emulsion polymerization, assisted by a nonionic surfactant

Hybrid materials containing poly(vinyl acetate) and montmorillonite (MMT) were prepared using an one-batch emulsion polymerization recipe, assisted by a nonionic surfactant. To explain the results of our experiments, a thorough investigation of the specific interactions between the compounds was done, in the wet as well as the dried state of the end-products. In dispersion, polymer–surfactant interactions were found to be driven by hydrophobic coupling into superficial (mixt) admicelles. Another important finding is that the amount of clay used in the recipes and its relative concentration with respect to the other reaction partners influences drastically the morphological units in the end-products. For low [MMT], well-defined, spherical particles are formed. At the other extreme, for high [MMT], production of polymeric, water-swollen aggregates is favored. A small amount of reformed MMT tactoids was detected in all casted hybrid films, indicating that most of the inorganic is dispersed in the organic phase

Core Concepts for Future Cataloguers

The Linked Open Bibliographic Data project at UCL is developing an Open Educational Resource to enable the teaching and learning of BIBFRAME, the new RDF-based framework designed to take over from MARC. A new bibliographic dataset based on BIBFRAME, which will be linked with other online datasets, has been created for that purpose. The learning resource, which will be publicly available under an open licence on completion, will allow learners to access, explore, query and update the dataset through an intuitive interface built on top of the SPARQL query language. This masterclass shares experience in converting MARC records to BIBFRAME using the Library of Congress’s conversion tools [http://bibframe.org/tools/]. More fundamentally, it provides examples of how our model for Cataloguing is changing from linking record:record to field:field. Using publication data from library academics, we’ll look at what’s new in BIBFRAME and why this matters. Finally, we’ll discuss the extent to which those responsible for inputting data may (or may not) need to get to grips with the new data structure and ways that the enthusiastic can keep up

In silico evaluation of ultrafiltration and nanofiltration membrane cascades for continuous fractionation of protein hydrolysate from tuna processing byproduct

The present work proposes the design of cascades that integrate ultrafiltration (UF) and nanofiltration (NF) membranes to separate the different protein fractions from the protein hydrolysate obtained after hydrolysis of tuna byproducts. Experimental data (permeate flux and rejection of protein fractions under different applied pressures) previously obtained and published by this research group were fitted to empirical models, which were the basis for a process simulation model. High recovery rates (0.9) in the UF stages implied high process yields by reduced desired fraction losses, while similar recovery rates in the NF stages were required for high product purity. However, the applied pressures were not so influential over the performance of the system. Optimization problems were solved to identify the optimal design and operation conditions to maximize the product purity or the process yield. Maximal purity of the preferred 1-4 kDa fraction (49.3% from 19.0% in feed stream) obtained by the configuration with 3 UF stages and another 3 NF stages implied 2 and 5 bar pressures applied in the UF and NF stages, respectively, while 0.9 was the optimal recovery rate value for all the stages. These maximal purity conditions resulted in 62.6% process yield, defined as the percentage of the 1-4 kDa fraction in the feed stream recovered in the product stream. In addition, multiobjective optimization of the process was also carried out to obtain the Pareto graphs that represent the counterbalance between maximal yields and purities

Work in Progress: the Linked Open Bibliographic Data Project

Reports on the first stage of a project to create an Open Educational Resource for the teaching of new cataloguing format BIBFRAME. Collaborative creation of knowledge with students is a key aspect of the project, and this is discussed in the context of UCL's Connected Curriculum

Histone deacetylase inhibition results in a common metabolic profile associated with HT29 differentiation

Cell differentiation is an orderly process that begins with modifications in gene expression. This process is regulated by the acetylation state of histones. Removal of the acetyl groups of histones by specific enzymes (histone deacetylases, HDAC) usually downregulates expression of genes that can cause cells to differentiate, and pharmacological inhibitors of these enzymes have been shown to induce differentiation in several colon cancer cell lines. Butyrate at high (mM) concentration is both a precursor for acetyl-CoA and a known HDAC inhibitor that induces cell differentiation in colon cells. The dual role of butyrate raises the question whether its effects on HT29 cell differentiation are due to butyrate metabolism or to its HDAC inhibitor activity. To distinguish between these two possibilities, we used a tracer-based metabolomics approach to compare the metabolic changes induced by two different types of HDAC inhibitors (butyrate and the non-metabolic agent trichostatin A) and those induced by other acetyl-CoA precursors that do not inhibit HDAC (caprylic and capric acids). [1,2-13C2]-d-glucose was used as a tracer and its redistribution among metabolic intermediates was measured to estimate the contribution of glycolysis, the pentose phosphate pathway and the Krebs cycle to the metabolic profile of HT29 cells under the different treatments. The results demonstrate that both HDAC inhibitors (trichostatin A and butyrate) induce a common metabolic profile that is associated with histone deacetylase inhibition and differentiation of HT29 cells whereas the metabolic effects of acetyl-CoA precursors are different from those of butyrate. The experimental findings support the concept of crosstalk between metabolic and cell signalling events, and provide an experimental approach for the rational design of new combined therapies that exploit the potential synergism between metabolic adaptation and cell differentiation processes through modification of HDAC activity

Fine Mapping of Posttranslational Modifications of the Linker Histone H1 from Drosophila melanogaster

The linker histone H1 binds to the DNA in between adjacent nucleosomes and contributes to chromatin organization and transcriptional control. It is known that H1 carries diverse posttranslational modifications (PTMs), including phosphorylation, lysine methylation and ADP-ribosylation. Their biological functions, however, remain largely unclear. This is in part due to the fact that most of the studies have been performed in organisms that have several H1 variants, which complicates the analyses. We have chosen Drosophila melanogaster, a model organism, which has a single H1 variant, to approach the study of the role of H1 PTMs during embryonic development. Mass spectrometry mapping of the entire sequence of the protein showed phosphorylation only in the ten N-terminal amino acids, mostly at S10. For the first time, changes in the PTMs of a linker H1 during the development of a multicellular organism are reported. The abundance of H1 monophosphorylated at S10 decreases as the embryos age, which suggests that this PTM is related to cell cycle progression and/or cell differentiation. Additionally, we have found a polymorphism in the protein sequence that can be mistaken with lysine methylation if the analysis is not rigorous