Copper modulates zinc metalloproteinase-dependent ectodomain shedding of key signaling and adhesion proteins and promotes the invasion of prostate cancer epithelial cells

A disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs) are zinc metalloproteinases (ZMPs) that catalyse the 'ectodomain shedding' of a range of cell surface proteins including signalling and adhesion molecules. These 'sheddases' are associated with the invasion and metastasis of a range of cancers. Increased serum and tumour tissue levels of copper are also observed in several cancers although little is known about how the metal might promote disease progression at the molecular level. In the current study, we investigated whether copper might regulate the ectodomain shedding of two key cell surface proteins implicated in the invasion and metastasis of prostate cancer, the Notch ligand Jagged1 and the adhesion molecule E-cadherin, and whether the metal was able to influence the invasion of the prostate cancer epithelial cell line PC3. Physiological copper concentrations stimulated the ZMP-mediated proteolysis of Jagged1 and E-cadherin in cell culture models whilst other divalent metals had no effect. Copper-mediated Jagged1 proteolysis was also observed following the pre-treatment of cells with cycloheximide and in a cell-free membrane system, indicating a post-translational mechanism of sheddase activation. Finally, the concentrations of copper that stimulated ZMP-mediated protein shedding also enhanced PC3 invasion; an effect which could be negated using a sheddase inhibitor or copper chelators. Collectively, these data implicate copper as an important factor in promoting prostate cancer cell invasion and indicate that the selective post-translational activation of ZMP-mediated protein shedding might play a role in this process.

Reducing youth suicide : systems modelling and simulation to guide targeted investments across the determinants

Background: Reducing suicidal behaviour (SB) is a critical public health issue globally. The complex interplay of social determinants, service system factors, population demographics, and behavioural dynamics makes it extraordinarily difficult for decision makers to determine the nature and balance of investments required to have the greatest impacts on SB. Real-world experimentation to establish the optimal targeting, timing, scale, frequency, and intensity of investments required across the determinants is unfeasible. Therefore, this study harnesses systems modelling and simulation to guide population-level decision making that represent best strategic allocation of limited resources. Methods: Using a participatory approach, and informed by a range of national, state, and local datasets, a system dynamics model was developed, tested, and validated for a regional population catchment. The model incorporated defined pathways from social determinants of mental health to psychological distress, mental health care, and SB. Intervention scenarios were investigated to forecast their impact on SB over a 20-year period. Results: A combination of social connectedness programs, technology-enabled coordinated care, post-attempt assertive aftercare, reductions in childhood adversity, and increasing youth employment projected the greatest impacts on SB, particularly in a youth population, reducing self-harm hospitalisations (suicide attempts) by 28.5% (95% interval 26.3–30.8%) and suicide deaths by 29.3% (95% interval 27.1–31.5%). Introducing additional interventions beyond the best performing suite of interventions produced only marginal improvement in population level impacts, highlighting that ‘more is not necessarily better.’ Conclusion: Results indicate that targeted investments in addressing the social determinants and in mental health services provides the best opportunity to reduce SB and suicide. Systems modelling and simulation offers a robust approach to leveraging best available research, data, and expert knowledge in a way that helps decision makers respond to the unique characteristics and drivers of SB in their catchments and more effectively focus limited health resources

Study of Flare Assessment in Systemic Lupus Erythematosus Based on Paper Patients

© 2017, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. Objective: To determine the level of agreement of disease flare severity (distinguishing severe, moderate, and mild flare and persistent disease activity) in a large paper-patient exercise involving 988 individual cases of systemic lupus erythematosus. Methods: A total of 988 individual lupus case histories were assessed by 3 individual physicians. Complete agreement about the degree of flare (or persistent disease activity) was obtained in 451 cases (46%), and these provided the reference standard for the second part of the study. This component used 3 flare activity instruments (the British Isles Lupus Assessment Group [BILAG] 2004, Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] flare index [SFI] and the revised SELENA flare index [rSFI]). The 451 patient case histories were distributed to 18 pairs of physicians, carefully randomized in a manner designed to ensure a fair case mix and equal distribution of flare according to severity. Results: The 3-physician assessment of flare matched the level of flare using the 3 indices, with 67% for BILAG 2004, 72% for SFI, and 70% for rSFI. The corresponding weighted kappa coefficients for each instrument were 0.82, 0.59, and 0.74, respectively. We undertook a detailed analysis of the discrepant cases and several factors emerged, including a tendency to score moderate flares as severe and persistent activity as flare, especially when the SFI and rSFI instruments were used. Overscoring was also driven by scoring treatment change as flare, even if there were no new or worsening clinical features. Conclusion: Given the complexity of assessing lupus flare, we were encouraged by the overall results reported. However, the problem of capturing lupus flare accurately is not completely solved

The effects of changes in the order of verbal labels and numerical values on children's scores on attitude and rating scales

Research with adults has shown that variations in verbal labels and numerical scale values on rating scales can affect the responses given. However, few studies have been conducted with children. The study aimed to examine potential differences in children’s responses to Likert-type rating scales according to their anchor points and scale direction, and to see whether or not such differences were stable over time. 130 British children, aged 9 to 11, completed six sets of Likert-type rating scales, presented in four different ways varying the position of positive labels and numerical values. The results showed, both initially and 8-12 weeks later, that presenting a positive label or a high score on the left of a scale led to significantly higher mean scores than did the other variations. These findings indicate that different arrangements of rating scales can produce different results which has clear implications for the administration of scales with children

Understanding Compliance Dynamics in Community Justice Settings

This article seeks to expand the existing literature on compliance in community justice settings by highlighting the importance of service user participation in efforts to achieve compliance. The article’s central argument is that although co-productive strategies can enhance service user participation, the degree to which co-production is achievable in penal supervision is perhaps uncertain, and has received insufficient theoretical or empirical attention. To address the gap in knowledge, the article draws on the data generated from a study of compliance in Wales, United Kingdom, and employs the Bourdieusian concepts of habitus, field, and capital to argue that the convergence of two key factors undermines the viability of co-productive strategies in penal settings. One factor is the service users’ habitus of powerlessness which may breed passivity rather than active participation. The second also relates to the power dynamics that characterize penal supervision contexts. Within these contexts, practitioners are statutorily empowered to implement and enforce the requirements of community orders. In the current target-focused policy climate in England and Wales, practitioners may prioritize measurable compliance over forms of compliance that stem from service user participation and engagement perhaps because these are not readily quantifiable

Variation of electric shielding on virtual Frisch-grid detectors

Because of the low mobility of holes, CdZnTe (CZT) detectors operate as electron-transport-only type devices whose particular geometrical parameters and contacts configurations are specially chosen to minimize the contribution of uncollected holes into the output signal amplitudes (induction effect). Several detector configurations have been proposed to address this problem. One of them employs a large geometrical aspect ratio, parallelepiped-shaped crystal with two planar contacts on the top and bottom surfaces (anode and cathode) and an additional shielding electrode placed on a crystal\u27s side to create the virtual Frisch-grid effect. We studied the effect of the shielding electrode length, as well as its location, on the responses of 6 x 6 x 15 mm(3) virtual Frisch-grid detectors. We found that the length of the shielding electrode placed next to the anode can be reduced to 5 mm with no adverse effects on the device performance. Meanwhile, this allows for charge loss correction by reading the cathode signal

A school-based social-marketing intervention to promote sexual health in English secondary schools: the Positive Choices pilot cluster RCT

Background: The UK still has the highest rate of teenage births in western Europe. Teenagers are also the age group most likely to experience unplanned pregnancy, with around half of conceptions in those aged < 18 years ending in abortion. After controlling for prior disadvantage, teenage parenthood is associated with adverse medical and social outcomes for mothers and children, and increases health inequalities. This study evaluates Positive Choices (a new intervention for secondary schools in England) and study methods to assess the value of a Phase III trial. Objectives: To optimise and feasibility-test Positive Choices and then conduct a pilot trial in the south of England assessing whether or not progression to Phase III would be justified in terms of prespecified criteria. Design: Intervention optimisation and feasibility testing; pilot randomised controlled trial. Setting: The south of England: optimisation and feasibility-testing in one secondary school; pilot cluster trial in six other secondary schools (four intervention, two control) varying by local deprivation and educational attainment. Participants: School students in year 8 at baseline, and school staff. Interventions: Schools were randomised (1 : 2) to control or intervention. The intervention comprised staff training, needs survey, school health promotion council, year 9 curriculum, student-led social marketing, parent information and review of school/local sexual health services. Main outcome measures: The prespecified criteria for progression to Phase III concerned intervention fidelity of delivery and acceptability; successful randomisation and school retention; survey response rates; and feasible linkage to routine administrative data on pregnancies. The primary health outcome of births was assessed using routine data on births and abortions, and various self-reported secondary sexual health outcomes. Data sources: The data sources were routine data on births and abortions, baseline and follow-up student surveys, interviews, audio-recordings, observations and logbooks. Results: The intervention was optimised and feasible in the first secondary school, meeting the fidelity targets other than those for curriculum delivery and criteria for progress to the pilot trial. In the pilot trial, randomisation and school retention were successful. Student response rates in the intervention group and control group were 868 (89.4%) and 298 (84.2%), respectively, at baseline, and 863 (89.0%) and 296 (82.0%), respectively, at follow-up. The target of achieving ≥ 70% fidelity of implementation of essential elements in three schools was achieved. Coverage of relationships and sex education topics was much higher in intervention schools than in control schools. The intervention was acceptable to 80% of students. Interviews with staff indicated strong acceptability. Data linkage was feasible, but there were no exact matches for births or abortions in our cohort. Measures performed well. Poor test–retest reliability on some sexual behaviour measures reflected that this was a cohort of developing adolescents. Qualitative research confirmed the appropriateness of the intervention and theory of change, but suggested some refinements. Limitations: The optimisation school underwent repeated changes in leadership, which undermined its participation. Moderator analyses were not conducted as these would be very underpowered. Conclusion: Our findings suggest that this intervention has met prespecified criteria for progression to a Phase III trial. Future work: Declining prevalence of teenage pregnancy suggests that the primary outcome in a full trial could be replaced by a more comprehensive measure of sexual health. Any future Phase III trial should have a longer lead-in from randomisation to intervention commencement

Novel Assays of Thrombogenic Pathogenicity in the Antiphospholipid Syndrome Based on the Detection of Molecular Oxidative Modification of the Major Autoantigen β2-Glycoprotein I

Objective. Beta-2-glycoprotein I (beta(2)GPI) constitutes the major autoantigen in the antiphospholipid syndrome (APS), a common acquired cause of arterial and venous thrombosis. We recently described the novel observation that beta(2)GPI may exist in healthy individuals in a free thiol (biochemically reduced) form. The present study was undertaken to quantify the levels of total, reduced, and posttranslationally modified oxidized beta(2)GPI in APS patients compared to various control groups.Methods. In a retrospective multicenter analysis, the proportion of beta(2)GPI with free thiols in serum from healthy volunteers was quantified. Assays for measurement of reduced as well as total circulating beta(2)GPI were developed and tested in the following groups: APS (with thrombosis) (n = 139), autoimmune disease with or without persistent antiphospholipid antibodies (aPL) but without APS (n = 188), vascular thrombosis without APS or aPL (n = 38), and healthy volunteers (n = 91).Results. Total beta(2)GPI was significantly elevated in patients with APS (median 216.2 mu g/ml [interquartile range 173.3-263.8]) as compared to healthy subjects (median 178.4 mu g/ml [interquartile range 149.4-227.5] [P < 0.0002]) or control patients with autoimmune disease or vascular thrombosis (both P < 0.0001). The proportion of total beta(2)GPI in an oxidized form (i.e., lacking free thiols) was significantly greater in the APS group than in each of the 3 control groups (all P < 0.0001).Conclusion. This large retrospective multicenter study shows that posttranslational modification of beta(2)GPI via thiol-exchange reactions is a highly specific phenomenon in the setting of APS thrombosis. Quantification of posttranslational modifications of beta(2)GPI in conjunction with standard laboratory tests for APS may offer the potential to more accurately predict the risk of occurrence of a thrombotic event in the setting of APS

Biofortified Maize Improves Selenium Status of Women and Children in a Rural Community in Malawi: Results of the Addressing Hidden Hunger With Agronomy Randomized Controlled Trial

Background: Selenium deficiency is widespread in the Malawi population. The selenium concentration in maize, the staple food crop of Malawi, can be increased by applying selenium-enriched fertilizers. It is unknown whether this strategy, called agronomic biofortification, is effective at alleviating selenium deficiency. Objectives: The aim of the Addressing Hidden Hunger with Agronomy (AHHA) trial was to determine whether consumption of maize flour, agronomically-biofortified with selenium, affected the serum selenium concentrations of women, and children in a rural community setting. Design: An individually-randomized, double-blind placebo-controlled trial wasconducted in rural Malawi. Participants were randomly allocated in a 1:1 ratio to receive either intervention maize flour biofortified with selenium through application of selenium fertilizer, or control maize flour not biofortified with selenium. Participant households received enough flour to meet the typical consumption of all household members (330 g capita−1 day−1) for a period of 8 weeks. Baseline and endline serum selenium concentration (the primary outcome) was measured by inductively coupled plasma mass spectrometry (ICP-MS). Results: One woman of reproductive age (WRA) and one school-aged child (SAC) from each of 180 households were recruited and households were randomized to each group. The baseline demographic and socioeconomic status of participants were well-balanced between arms. No serious adverse events were reported. In the intervention arm, mean (standard deviation) serum selenium concentration increased over the intervention period from 57.6 (17.0) μg L−1 (n = 88) to 107.9 (16.4) μg L−1 (n = 88) among WRA and from 46.4 (14.8) μg L−1 (n = 86) to 97.1 (16.0) μg L−1 (n = 88) among SAC. There was no evidence of change in serum selenium concentration in the control groups Conclusion: Consumption of maize flour biofortified through application of selenium-enriched fertilizer increased selenium status in this community providing strong proof of principle that agronomic biofortification could be an effective approach to address selenium deficiency in Malawi and similar settings. Clinical Trial Registration http://www.isrctn.com/ISRCTN85899451, identifier: ISRCTN85899451