Dioxin Toxicity In Vivo Results from an Increase in the Dioxin-Independent Transcriptional Activity of the Aryl Hydrocarbon Receptor

The Aryl hydrocarbon receptor (Ahr) is the nuclear receptor mediating the toxicity of dioxins -widespread and persistent pollutants whose toxic effects include tumor promotion, teratogenesis, wasting syndrome and chloracne. Elimination of Ahr in mice eliminates dioxin toxicity but also produces adverse effects, some seemingly unrelated to dioxin. Thus the relationship between the toxic and dioxin-independent functions of Ahr is not clear, which hampers understanding and treatment of dioxin toxicity. Here we develop a Drosophila model to show that dioxin actually increases the in vivo dioxin-independent activity of Ahr. This hyperactivation resembles the effects caused by an increase in the amount of its dimerisation partner Ahr nuclear translocator (Arnt) and entails an increased transcriptional potency of Ahr, in addition to the previously described effect on nuclear translocation. Thus the two apparently different functions of Ahr, dioxin-mediated and dioxin-independent, are in fact two different levels (hyperactivated and basal, respectively) of a single function

Comparative analysis and visualization of multiple collinear genomes

Abstract Background Genome browsers are a common tool used by biologists to visualize genomic features including genes, polymorphisms, and many others. However, existing genome browsers and visualization tools are not well-suited to perform meaningful comparative analysis among a large number of genomes. With the increasing quantity and availability of genomic data, there is an increased burden to provide useful visualization and analysis tools for comparison of multiple collinear genomes such as the large panels of model organisms which are the basis for much of the current genetic research. Results We have developed a novel web-based tool for visualizing and analyzing multiple collinear genomes. Our tool illustrates genome-sequence similarity through a mosaic of intervals representing local phylogeny, subspecific origin, and haplotype identity. Comparative analysis is facilitated through reordering and clustering of tracks, which can vary throughout the genome. In addition, we provide local phylogenetic trees as an alternate visualization to assess local variations. Conclusions Unlike previous genome browsers and viewers, ours allows for simultaneous and comparative analysis. Our browser provides intuitive selection and interactive navigation about features of interest. Dynamic visualizations adjust to scale and data content making analysis at variable resolutions and of multiple data sets more informative. We demonstrate our genome browser for an extensive set of genomic data sets composed of almost 200 distinct mouse laboratory strains

Trends in Antarctic Ice Sheet Elevation and Mass

Fluctuations in Antarctic Ice Sheet elevation and mass occur over a variety of time scales, owing to changes in snowfall and ice flow. Here we disentangle these signals by combining 25 years of satellite radar altimeter observations and a regional climate model. From these measurements, patterns of change that are strongly associated with glaciological events emerge. While the majority of the ice sheet has remained stable, 24% of West Antarctica is now in a state of dynamical imbalance. Thinning of the Pine Island and Thwaites glacier basins reaches 122 m in places, and their rates of ice loss are now five times greater than at the start of our survey. By partitioning elevation changes into areas of snow and ice variability, we estimate that East and West Antarctica have contributed −1.1 ± 0.4 and +5.7 ± 0.8 mm to global sea level between 1992 and 201

Study protocol to investigate the effect of a lifestyle intervention on body weight, psychological health status and risk factors associated with disease recurrence in women recovering from breast cancer treatment

Background Breast cancer survivors often encounter physiological and psychological problems related to their diagnosis and treatment that can influence long-term prognosis. The aim of this research is to investigate the effects of a lifestyle intervention on body weight and psychological well-being in women recovering from breast cancer treatment, and to determine the relationship between changes in these variables and biomarkers associated with disease recurrence and survival. Methods/design Following ethical approval, a total of 100 patients will be randomly assigned to a lifestyle intervention (incorporating dietary energy restriction in conjunction with aerobic exercise training) or normal care control group. Patients randomised to the dietary and exercise intervention will be given individualised healthy eating dietary advice and written information and attend moderate intensity aerobic exercise sessions on three to five days per week for a period of 24 weeks. The aim of this strategy is to induce a steady weight loss of up to 0.5 Kg each week. In addition, the overall quality of the diet will be examined with a view to (i) reducing the dietary intake of fat to ~25% of the total calories, (ii) eating at least 5 portions of fruit and vegetables a day, (iii) increasing the intake of fibre and reducing refined carbohydrates, and (iv) taking moderate amounts of alcohol. Outcome measures will include body weight and body composition, psychological health status (stress and depression), cardiorespiratory fitness and quality of life. In addition, biomarkers associated with disease recurrence, including stress hormones, estrogen status, inflammatory markers and indices of innate and adaptive immune function will be monitored. Discussion This research will provide valuable information on the effectiveness of a practical, easily implemented lifestyle intervention for evoking positive effects on body weight and psychological well-being, two important factors that can influence long-term prognosis in breast cancer survivors. However, the added value of the study is that it will also evaluate the effects of the lifestyle intervention on a range of biomarkers associated with disease recurrence and survival. Considered together, the results should improve our understanding of the potential role that lifestyle-modifiable factors could play in saving or prolonging lives

Elevated tumour interleukin-1β is associated with systemic inflammation: a marker of reduced survival in gastro-oesophageal cancer

Systemic inflammation is associated with adverse prognosis cancer but its aetiology remains unclear. We investigated the expression of proinflammatory cytokines within normal mucosa from healthy controls and tumour tissue in cancer patients and related these levels with markers of systemic inflammation and with the presence of a tumour inflammatory infiltrate. Tissue was collected from 56 patients with gastro-oesophageal cancer and from 12 healthy controls. Tissue cytokine mRNA concentrations were measured by real-time PCR and tissue protein concentrations by cytometric bead array. The degree of chronic inflammatory cell infiltrate was recorded. Serum cytokine and acute phase protein concentrations (including C-reactive protein (CRP)) were measured by enzyme-linked immunosorbent assay. Proinflammatory cytokines were significantly overexpressed (interleukin (IL)-1β, IL-6, IL-8 and tumour necrosis factor-α) both at mRNA and protein levels in the cancer specimens compared with mucosa from controls. Interleukin-1β was expressed in greatest (10–100-fold) concentration and protein levels correlated significantly with systemic inflammation (CRP) (P=0.05, r=0.31). A chronic inflammatory infiltrate was observed in 75% of the cancer specimens and was associated with systemic inflammation (CRP: P=0.01). However, the presence of chronic inflammation per se was not associated with altered cytokine expression within the tumour. Both a chronic inflammatory infiltrate and systemic inflammation (CRP) were associated with reduced survival (P=0.05 and P=0.03, respectively). Tumour chronic inflammatory infiltrate and tumour tissue IL-1β overexpression are potential independent factors influencing systemic inflammation in oesophagogastric cancer patients

Multilevel latent class casemix modelling: a novel approach to accommodate patient casemix

<p>Abstract</p> <p>Background</p> <p>Using routinely collected patient data we explore the utility of multilevel latent class (MLLC) models to adjust for patient casemix and rank Trust performance. We contrast this with ranks derived from Trust standardised mortality ratios (SMRs).</p> <p>Methods</p> <p>Patients with colorectal cancer diagnosed between 1998 and 2004 and resident in Northern and Yorkshire regions were identified from the cancer registry database (n = 24,640). Patient age, sex, stage-at-diagnosis (Dukes), and Trust of diagnosis/treatment were extracted. Socioeconomic background was derived using the Townsend Index. Outcome was survival at 3 years after diagnosis. MLLC-modelled and SMR-generated Trust ranks were compared.</p> <p>Results</p> <p>Patients were assigned to two classes of similar size: one with reasonable prognosis (63.0% died within 3 years), and one with better prognosis (39.3% died within 3 years). In patient class one, all patients diagnosed at stage B or C died within 3 years; in patient class two, all patients diagnosed at stage A, B or C survived. Trusts were assigned two classes with 51.3% and 53.2% of patients respectively dying within 3 years. Differences in the ranked Trust performance between the MLLC model and SMRs were all within estimated 95% CIs.</p> <p>Conclusions</p> <p>A novel approach to casemix adjustment is illustrated, ranking Trust performance whilst facilitating the evaluation of factors associated with the patient journey (e.g. treatments) and factors associated with the processes of healthcare delivery (e.g. delays). Further research can demonstrate the value of modelling patient pathways and evaluating healthcare processes across provider institutions.</p

Enhancing the immunogenicity of tumour lysate-loaded dendritic cell vaccines by conjugation to virus-like particles

BACKGROUND: Tumour cell lysates are an excellent source of many defined and undefined tumour antigens and have been used clinically in immunotherapeutic regimes but with limited success. METHODS: We conjugated Mel888 melanoma lysates to rabbit haemorrhagic disease virus virus-like particles (VLP), which can act as vehicles to deliver multiple tumour epitopes to dendritic cells (DC) to effectively activate antitumour responses. RESULTS: Virus-like particles did not stimulate the phenotypic maturation of DC although, the conjugation of lysates to VLP (VLP-lysate) did overcome lysate-induced suppression of DC activation. Lysate-conjugated VLP enhanced delivery of antigenic proteins to DC, while the co-delivery of VLP-lysates with OK432 resulted in cross-priming of naïve T cells, with expansion of a MART1(+) population of CD8(+) T cells and generation of a specific cytotoxic response against Mel888 tumour cell targets. The responses generated with VLP-lysate and OK432 were superior to those stimulated by unconjugated lysate with OK432. CONCLUSION: Collectively, these results show that the combination of VLP-lysate with OK432 delivered to DC overcomes the suppressive effects of lysates, and enables priming of naïve T cells with superior ability to specifically kill their target tumour cells

Development and validation of a questionnaire to measure moral distress in community pharmacists

The Author(s) 2016. . This article is published with open access at Springerlink.com This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Jayne L. Astbury, and Cathal T. Gallagher, 'Development and validation of a questionnaire to measure moral distress in community pharmacists', International Journal of Clinical Pharmacy (2017) Vol 39(1): 156-164, first published online on 22 December 2016, the version of record is available on line via doi: 10.1007/s11096-016-0413-3 Funding for this work was provided by Pharmacy Research UK (PRUK).Background Pharmacists work within a highly-regulated occupational sphere, and are bound by strict legal frameworks and codes of professional conduct. This regulatory environment creates the potential for moral distress to occur due to the limitations it places on acting in congruence with moral judgements. Very little research regarding this phenomenon has been undertaken in pharmacy: thus, prominent research gaps have arisen for the development of a robust tool to measure and quantify moral distress experienced in the profession. Objective The aim of this study was to develop an instrument to measure moral distress in community pharmacists. Setting Community pharmacies in the United Kingdom. Method This study adopted a three-phase exploratory sequential mixed-method design. Three semi-structured focus groups were then conducted to allow pharmacists to identify and explore scenarios that cause moral distress. Each of the identified scenarios were developed into a statement, which was paired with twin seven-point Likert scales to measure the frequency and intensity of the distress, respectively. Content validity, reliability, and construct validity were all tested, and the questionnaire was refined. Main outcome measure The successful development of the valid instrument for use in the United Kingdom. Results This research has led to the development of a valid and reliable instrument to measure moral distress in community pharmacists in the UK. The questionnaire has already been distributed to a large sample of community pharmacists. Conclusion Results from this distribution will be used to inform the formulation of coping strategies for dealing with moral distress.Peer reviewedFinal Published versio

A novel widespread cryptic species and phylogeographic patterns within several giant clam species (Cardiidae: Tridacna) from the Indo-Pacific Ocean

Giant clams (genus Tridacna) are iconic coral reef animals of the Indian and Pacific Oceans, easily recognizable by their massive shells and vibrantly colored mantle tissue. Most Tridacna species are listed by CITES and the IUCN Redlist, as their populations have been extensively harvested and depleted in many regions. Here, we survey Tridacna crocea and Tridacna maxima from the eastern Indian and western Pacific Oceans for mitochondrial (COI and 16S) and nuclear (ITS) sequence variation and consolidate these data with previous published results using phylogenetic analyses. We find deep intraspecific differentiation within both T. crocea and T. maxima. In T. crocea we describe a previously undocumented phylogeographic division to the east of Cenderawasih Bay (northwest New Guinea), whereas for T. maxima the previously described, distinctive lineage of Cenderawasih Bay can be seen to also typify western Pacific populations. Furthermore, we find an undescribed, monophyletic group that is evolutionarily distinct from named Tridacna species at both mitochondrial and nuclear loci. This cryptic taxon is geographically widespread with a range extent that minimally includes much of the central Indo-Pacific region. Our results reinforce the emerging paradigm that cryptic species are common among marine invertebrates, even for conspicuous and culturally significant taxa. Additionally, our results add to identified locations of genetic differentiation across the central Indo-Pacific and highlight how phylogeographic patterns may differ even between closely related and co-distributed species