Clinical progress and pharmacology of small molecule bromodomain inhibitors

Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. The excitement centred on the clinical potential of BET inhibition has stimulated intense interest in the broader family and the growing number of non-BET bromodomain chemical probes has facilitated phenotypic investigations, implicating these targets in a variety of disease pathways including cancer, inflammation, embryonic development and neurological disorders

Systematic grid-wise radon concentration measurements and first radon map in Cyprus

A systematic study of the indoor airborne radon concentration in the central part of the Nicosia district was conducted, using high-sensitivity active radon portable detectors of the type "RADIM3A". From a total of 108 measurements in 54 grids of 1 km^2 area each, the overall mean value is 20.6 \pm 13.2 Bq m^-3 (A.M.\pm S.D.). That is almost twice less than the corresponding average worldwide value. The radon concentration levels in drinking water were also measured in 24 sites of the residential district, using the high-sensitivity radon detector of the type "RADIM3W". The mean value obtained from these measurements is 243.8 \pm 224.8 mBq L^-1, which is relatively low compared to the corresponding internationally accepted level. The associated annual effective dose rates to each measurement were also calculated and compared to the corresponding worldwide values. From the geographical coordinates of the measuring sites and the corresponding radon concentration values, the digital radon map of the central part of the Nicosia district was constructed for the first time, by means of the ArcMap software package.Comment: 21 pages including 2 tables and 8 figure

Mid-term migration of a cementless, porous acetabular cup; A 5 year Radiostereometric Analysis

© 2017 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This author accepted manuscript is made available following 12 month embargo from date of publication (July 2017) in accordance with the publisher’s archiving policyPurpose The aim of the study was to determine the 5 year migratory and wear patterns, adverse events and clinical outcomes of a cementless, porous acetabular cup. Methods RSA imaging of a cohort of 11 patients was retrospective analysed at 5 years post Total Hip Arthroplasty (THA). Changes in pain, function and symptoms of the hip at 5 years post-THA were compared to preoperative and 2 year postoperative assessments on the Harris Hip Score (HHS) and Hip dysfunction and Osteoarthritis Outcome Score (HOOS). Results The majority of cup migration occurred up to 6 months and stabilised thereafter (6 months to 5 years, p = 0.091–0.866, Wilcoxon Signed Rank test). The direction of rotation around the 3 axes was evenly distributed among the cups between anterior-posterior rotation, internal-external rotation and increased-decreased inclination. The majority of the cups translated proximally, at an average migration of 0.36 mm (±95%CI 0.17) at 5-years post-THA. Following initial bedding in, up to 6 months, there was no detectable polyethylene wear between 6 months and 5 years. At 5 years postoperatively, a statistically significant difference was observed across all HOOS subscales in comparison to preoperative values, with higher means reported at 5 years (p < 0.001). The total mean HHS displayed a statistically significant improvement, increasing from ‘poor’ preoperatively to ‘good’ at 5 years post-THA. Conclusion Following initial migration between discharge and 6 months, the cementless porous acetabular cup demonstrated a tendency for stabilisation from 6 months up to 5 years post-THA, suggesting good mid-term fixation. Additionally, improvements in clinical outcome measures of pain, function and quality-of-life remained high following THA at 5 years post-surgery

Alkene anti-dihydroxylation with malonoyl peroxides

Malonoyl peroxide 1, prepared in a single step from the commercially available diacid, is an effective reagent for the anti-dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of acetic acid at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (35-92%) with up to 13:1 anti-selectivity. A mechanism consistent with experimental findings is proposed that accounts for the selectivity observed

The ATP-Binding Cassette Proteins of the Deep-Branching Protozoan Parasite Trichomonas vaginalis

The ATP binding cassette (ABC) proteins are a family of membrane transporters and regulatory proteins responsible for diverse and critical cellular process in all organisms. To date, there has been no attempt to investigate this class of proteins in the infectious parasite Trichomonas vaginalis. We have utilized a combination of bioinformatics, gene sequence analysis, gene expression and confocal microscopy to investigate the ABC proteins of T. vaginalis. We demonstrate that, uniquely among eukaryotes, T. vaginalis possesses no intact full-length ABC transporters and has undergone a dramatic expansion of some ABC protein sub-families. Furthermore, we provide preliminary evidence that T. vaginalis is able to read through in-frame stop codons to express ABC transporter components from gene pairs in a head-to-tail orientation. Finally, with confocal microscopy we demonstrate the expression and endoplasmic reticulum localization of a number of T. vaginalis ABC transporters

Bad news from Fallujah

This study uses the thematic analysis developed by the Glasgow University Media Group to explore how the US, UK and German national press covered the US/Coalition assault on the Iraqi city of Fallujah in November 2004. The study relies on quantitative and qualitative full text content analyses to assess 428 news, editorial and commentary items. The article suggests that, while government and military officials of the US/Coalition had argued the military ‘operation’ was necessary to secure Iraq and defeat an ‘insurgency’, organisations and actors from Iraqi society refer to the ‘operation’ as ‘collective punishment’ and a ‘massacre’ that targeted the Iraqi population. The article investigates how the press represented each of these perspectives. The findings suggest that the press overemphasised the US/Coalition perspective despite striking counter evidence. Critical aspects of coverage largely focused on tactical elements of the military dimension of the event. The article concludes that such findings are in accord with hegemonic models of media performance

The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition

Identification of genes differentially expressed in a resistant reaction to Mycosphaerella pinodes in pea using microarray technology

<p>Abstract</p> <p>Background</p> <p>Ascochyta blight, caused by <it>Mycosphaerella pinodes </it>is one of the most important pea pathogens. However, little is known about the genes and mechanisms of resistance acting against <it>M. pinodes </it>in pea. Resistance identified so far to this pathogen is incomplete, polygenic and scarce in pea, being most common in <it>Pisum </it>relatives. The identification of the genes underlying resistance would increase our knowledge about <it>M. pinodes-</it>pea interaction and would facilitate the introgression of resistance into pea varieties. In the present study differentially expressed genes in the resistant <it>P. sativum </it>ssp. <it>syriacum </it>accession P665 comparing to the susceptible pea cv. Messire after inoculation with <it>M. pinodes </it>have been identified using a <it>M. truncatula </it>microarray.</p> <p>Results</p> <p>Of the 16,470 sequences analysed, 346 were differentially regulated. Differentially regulated genes belonged to almost all functional categories and included genes involved in defense such as genes involved in cell wall reinforcement, phenylpropanoid and phytoalexins metabolism, pathogenesis- related (PR) proteins and detoxification processes. Genes associated with jasmonic acid (JA) and ethylene signal transduction pathways were induced suggesting that the response to <it>M. pinodes </it>in pea is regulated via JA and ET pathways. Expression levels of ten differentially regulated genes were validated in inoculated and control plants using qRT-PCR showing that the P665 accession shows constitutively an increased expression of the defense related genes as peroxidases, disease resistance response protein 39 (DRR230-b), glutathione S-transferase (GST) and 6a-hydroxymaackiain methyltransferase.</p> <p>Conclusions</p> <p>Through this study a global view of genes expressed during resistance to <it>M. pinodes </it>has been obtained, giving relevant information about the mechanisms and pathways conferring resistance to this important disease. In addition, the <it>M. truncatula </it>microarray represents an efficient tool to identify candidate genes controlling resistance to <it>M. pinodes </it>in pea.</p