N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer

Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK1 R and CCK2R receptors are ideal molecular targets for novel smart chemo‒ therapeutics with a beneficial overall profile due to their anxiolytic and antidepressant properties. Lung cancers are fuelled by gastrin and therefore, selective gastrin (CCK2 R) antagonists are ideal experimental drug candidates. Objective: Synthesis and evaluation of novel CCK antagonists, most preferred CCK2 / gastrin selective for the treatment of lung cancers. Methods: A fast and efficient synthesis of hydroxy‒pyrrolones in 2 steps from renewable biomass was performed. After initial radiolabelled receptor binding studies with hot CCK8, subsequent in vitro evaluation with isolated duodenum preparations confirmed CCK antagonism. Cell based studies using the MTT assay provided a candidate for in vivo xenograft models with nude mice. Rational drug design was supported by molecular modelling experiments. Results: Potent and selective CCK antagonists were prepared as stable crystalline materials in high yields. Gastrin antagonists were in vitro active on isolated tissue preparations and inhibited breast, colon and lung cancer cell lines in vitro with IC50 to 45nM for the privileged hydroxyl‒pyrrolone lead structure in the MTT assay for human cancer cell lines. PNB‒101, a fluorinated 5‒hydroxy‒5‒aryl‒pyrrol‒2‒one, gave up to 80% inhibition of tumour growths by oral administration in athymic mice transplanted with the human lung cancer cell line H727. Conclusion: PNB‒101 is a potential chemotherapeutic agent for CCK‒gastrin related cancers and entered preclinical development

Relative Roles of Grey Squirrels, Supplementary Feeding, and Habitat in Shaping Urban Bird Assemblages

Non-native species are frequently considered to influence urban assemblages. The grey squirrel Sciurus carolinensis is one such species that is widespread in the UK and is starting to spread across Europe; it predates birds’ nests and can compete with birds for supplementary food. Using distance sampling across the urbanisation intensity gradient in Sheffield (UK) we test whether urban grey squirrels influence avian species richness and density through nest predation and competition for supplementary food sources. We also assess how urban bird assemblages respond to supplementary feeding. We find that grey squirrels slightly reduced the abundance of breeding bird species most sensitive to squirrel nest predation by reducing the beneficial impact of woodland cover. There was no evidence that grey squirrel presence altered relationships between supplementary feeding and avian assemblage structure. This may be because, somewhat surprisingly, supplementary feeding was not associated with the richness or density of wintering bird assemblages. These associations were positive during the summer, supporting advocacy to feed birds during the breeding season and not just winter, but explanatory capacity was limited. The amount of green space and its quality, assessed as canopy cover, had a stronger influence on avian species richness and population size than the presence of grey squirrels and supplementary feeding stations. Urban bird populations are thus more likely to benefit from investment in improving the availability of high quality habitats than controlling squirrel populations or increased investment in supplementary feeding

Pulling together: keeping track of pedagogy, design and evaluation through the development of scenarios: a case study

This case study describes the multipurpose use of scenarios in a large multinational research project (MOBIlearn) whose aims are to design and develop a pedagogically sound mobile learning environment. Maintaining effective communication and design focus in large consortia is a wellknown problem (see Carroll, 2000), and we describe the role of scenarios in addressing this. Scenarios were initially used to simply envision the future system in order to inform design, but as the project progressed, the role of the scenarios grew to encompass (i) relating system design and implementation to pedagogy by providing a common frame of reference for developers and pedagogic experts; (ii) through a process of refinement, defining the evaluation strategy for the user trials; and (iii) allowing us to keep the user at the heart of the development project. Thus, scenarios helped to resolve the difficulty identified by Taylor (2004) of how to bring together the relatively high level issues of pedagogic evaluation and the more technical user-centred system evaluation. The development of a first-aid training scenario is used as an illustrative example

Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Friedreich ataxia patient tissues exhibit increased 5-hydroxymethylcytosine modification and decreased CTCF binding at the FXN locus

© 2013 Al-Mahdawi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Friedreich ataxia (FRDA) is caused by a homozygous GAA repeat expansion mutation within intron 1 of the FXN gene, which induces epigenetic changes and FXN gene silencing. Bisulfite sequencing studies have identified 5-methylcytosine (5 mC) DNA methylation as one of the epigenetic changes that may be involved in this process. However, analysis of samples by bisulfite sequencing is a time-consuming procedure. In addition, it has recently been shown that 5-hydroxymethylcytosine (5 hmC) is also present in mammalian DNA, and bisulfite sequencing cannot distinguish between 5 hmC and 5 mC.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242193/EFACTS (CS), the Wellcome Trust [089757] (SA) and Ataxia UK (RMP) to MAP

Changes in visual function after intraocular pressure reduction using antiglaucoma medications

Purpose To evaluate the change in visual function after starting glaucoma treatment and correlate this to a decrease in intraocular pressure (IOP) in primary open-angle glaucoma patients.Methods A prospective, randomized clinical trial was carried out involving 54 glaucoma patients (54 eyes). After inclusion, patients randomly received timolol maleate 0.5%, brimonidine tartrate 0.2%, or travoprost 0.004% in one randomly selected eye. Patients underwent Goldmann applanation tonometry, visual acuity test, standard automated perimetry (SAP), visual quality perception test (visual analogue scale), and contrast sensitivity (CS) test, in a random order before and after the 4-week glaucoma treatment.Results There were statistically significant changes in IOP (mean change [standard deviation], 7.8 [3.6] mmHg, P 0.001), SAP mean deviation index (0.84 [2.45] dB, P = 0.02), visual quality perception (0.56 [1.93], P = 0.045), and CS at frequencies of 12 cycles/degree (0.10 [0.37], P = 0.03) and 18 cycles/degree (0.18 [0.42], P = 0.02) after the 4-week treatment when compared with baseline. No statistically significant differences were found between the treatment groups in visual function changes after treatment (P > 0.40). No significant correlations between IOP reduction and changes in visual function were found (P > 0.30).Conclusions Visual quality perception, visual field mean deviation index, and CS at higher frequencies improve after starting glaucoma therapy. However, no correlation was found between IOP reduction and changes in visual function, and no differences were found in visual function when the three medications studied were compared. Eye (2009) 23, 1081-1085; doi:10.1038/eye.2008.226; published online 1 August 2008Universidade Federal de São Paulo, Glaucoma Serv, Dept Ophthalmol, BR-01404001 São Paulo, BrazilUniversidade Federal de São Paulo, Glaucoma Serv, Dept Ophthalmol, BR-01404001 São Paulo, BrazilWeb of Scienc

A randomised feasibility study to investigate the impact of education and the addition of prompts on the sedentary behaviour of office workers

Abstract Background Office workers have been identified as being at risk of accumulating high amounts of sedentary time in prolonged events during work hours, which has been associated with increased risk of a number of long-term health conditions. There is some evidence that providing advice to stand at regular intervals during the working day, and using computer-based prompts, can reduce sedentary behaviour in office workers. However, evidence of effectiveness, feasibility and acceptability for these types of intervention is currently limited. Methods A 2-arm, parallel group, cluster-randomised feasibility trial to assess the acceptability of prompts to break up sedentary behaviour was conducted with office workers in a commercial bank (n = 21). Participants were assigned to an education only group (EG) or prompt and education group (PG). Both groups received education on reducing and breaking up sitting at work, and the PG also received hourly prompts, delivered by Microsoft Outlook over 10 weeks, reminding them to stand. Objective measurements of sedentary behaviour were made using activPAL monitors worn at three time points: baseline, in the last 2 weeks of the intervention period and 12 weeks after the intervention. Focus groups were conducted to explore the acceptability of the intervention and the motivations and barriers to changing sedentary behaviour. Results Randomly generated, customised prompts, delivered by Microsoft Outlook, with messages about breaking up sitting, proved to be a feasible and acceptable way of delivering prompts to office workers. Participants in both groups reduced their sitting, but changes were not maintained at follow-up. The education session seemed to increase outcome expectations of the benefits of changing sedentary behaviour and promote self-regulation of behaviour in some participants. However, low self-efficacy and a desire to conform to cultural norms were barriers to changing behaviour. Conclusions Prompts delivered by Microsoft Outlook were a feasible, low-cost way of prompting office workers to break up their sedentary behaviour, although further research is needed to determine whether this has an additional impact on sedentary behaviour, to education alone. The role of cultural norms, and promoting self-efficacy, should be considered in the design of future interventions. Trial registration This study was registered retrospectively as a clinical trial on ClinicalTrials.gov (ID no. NCT02609282 ) on 23 March 2015

A cross-national study on the antecedents of work–life balance from the fit and balance perspective

Drawing on the perceived work–family fit and balance perspective, this study investigates demands and resources as antecedents of work–life balance (WLB) across four countries (New Zealand, France, Italy and Spain), so as to provide empirical cross-national evidence. Using structural equation modelling analysis on a sample of 870 full time employees, we found that work demands, hours worked and family demands were negatively related to WLB, while job autonomy and supervisor support were positively related to WLB. We also found evidence that resources (job autonomy and supervisor support) moderated the relationships between demands and work–life balance, with high resources consistently buffering any detrimental influence of demands on WLB. Furthermore, our study identified additional predictors of WLB that were unique to some national contexts. For example, in France and Italy, overtime hours worked were negatively associated with WLB, while parental status was positively associated with WLB. Overall, the implications for theory and practice are discussed.Peer ReviewedPostprint (author's final draft

Mining multi-item drug adverse effect associations in spontaneous reporting systems

<p>Abstract</p> <p>Background</p> <p>Multi-item adverse drug event (ADE) associations are associations relating multiple drugs to possibly multiple adverse events. The current standard in pharmacovigilance is bivariate association analysis, where each single drug-adverse effect combination is studied separately. The importance and difficulty in the detection of multi-item ADE associations was noted in several prominent pharmacovigilance studies. In this paper we examine the application of a well established data mining method known as association rule mining, which we tailored to the above problem, and demonstrate its value. The method was applied to the FDAs spontaneous adverse event reporting system (AERS) with minimal restrictions and expectations on its output, an experiment that has not been previously done on the scale and generality proposed in this work.</p> <p>Results</p> <p>Based on a set of 162,744 reports of suspected ADEs reported to AERS and published in the year 2008, our method identified 1167 multi-item ADE associations. A taxonomy that characterizes the associations was developed based on a representative sample. A significant number (67% of the total) of potential multi-item ADE associations identified were characterized and clinically validated by a domain expert as previously recognized ADE associations. Several potentially novel ADEs were also identified. A smaller proportion (4%) of associations were characterized and validated as known drug-drug interactions.</p> <p>Conclusions</p> <p>Our findings demonstrate that multi-item ADEs are present and can be extracted from the FDA’s adverse effect reporting system using our methodology, suggesting that our method is a valid approach for the initial identification of multi-item ADEs. The study also revealed several limitations and challenges that can be attributed to both the method and quality of data.</p

Prevalence of pre- and postpartum depression in Jamaican women

BACKGROUND: Maternal depression during pregnancy has been studied less than depression in postpartum period. The aims of this study were to find out the prevalence of prepartum and postpartum depression and the risk factors associated in a cohort of Afro-Jamaican pregnant women in Jamaica. METHODS: The Zung self-rating depression scale instrument was administered to 73 healthy pregnant women at 28 weeks gestation and at 6 weeks postpartum for quantitative measurement of depression. Blood samples were collected at 8, 28, 35 weeks gestation and at day 1 and 6 weeks postpartum to study the thyroid status. RESULTS: Study demonstrated depression prevalence rates of 56% and 34% during prepartum and postpartum period, respectively. 94% women suffering depression in both periods were single. There were significant variations in both FT(3 )and TT(4 )concentrations which increased from week 8 to week 28 prepartum (p < 0.05) and then declined at the 35(th )week (p < 0.05 compared with week 28) and 1 day post delivery study (p < 0.05 compared with week 35). The mean values for TSH increased significantly from week 8 through week 35. The mean values at 1 day postpartum and 6 week postpartum were not significantly different from the 35 week values. For FT(3), TT(4 )and TSH there were no significant between group differences in concentrations. The major determinants of postpartum depression were moderate and severe prepartum depression and change in TT(4 )hormone concentrations. CONCLUSION: High prevalence of depression was found during pre- and postpartum periods. Single mothers, prepartum depression and changes in TT(4 )were factors found to be significantly associated with postpartum depression