MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

Creating a FACETS digital toolkit to promote quality of life of people with multiple sclerosis through Participatory Design

In this paper, we report on the first stages of creating a stand-alone digital toolkit focusing on the homework elements of FACETS (Fatigue: Applying Cognitive behavioural and Energy effectiveness Techniques to lifeStyle). FACETS is an evidence-based face-to-face fatigue management group programme for people with multiple sclerosis. This paper details the participatory design process from requirements elicitation to initial prototyping and how offline activities linked to each session have been mapped in the digitised solution (mobile app)

Oesophageal adenocarcinoma is associated with a deregulation in the MYC/MAX/MAD network

Oesophageal adenocarcinoma, which arises from an acquired columnar lesion, Barrett's metaplasia, is rising in incidence more rapidly than any other cancer in the Western world. Elevated expression of c-MYC has been demonstrated in oesophageal adenocarcinoma; however, the expression of other members of the MYC/MAX/MAD network has not been addressed. The aims of this work were to characterise the expression of c-MYC, MAX and the MAD family in adenocarcinoma development and assess the effects of overexpression on cellular behaviour. mRNA expression in samples of Barrett's metaplasia and oesophageal adenocarcinoma were examined by qRT–PCR. Semi-quantitative immunohistochemistry and western blotting were used to examine cellular localisation and protein levels. Cellular proliferation and mRNA expression were determined in SEG1 cells overexpressing c-MYCER or MAD1 using a bromodeoxyuridine assay and qRT–PCR, respectively. Consistent with previous work expression of c-MYC was deregulated in oesophageal adenocarcinoma. Paradoxically, increased expression of putative c-MYC antagonists MAD1 and MXI1 was observed in tumour specimens. Overexpression of c-MYC and MAD proteins in SEG1 cells resulted in differential expression of MYC/MAX/MAD network members and reciprocal changes in proliferation. In conclusion, the expression patterns of c-MYC, MAX and the MAD family were shown to be deregulated in the oesophageal cancer model

Estimating the number of children exposed to parental psychiatric disorders through a national health survey

<p>Abstract</p> <p>Objective</p> <p>Children whose parents have psychiatric disorders experience an increased risk of developing psychiatric disorders, and have higher rates of developmental problems and mortality. Assessing the size of this population is important for planning of preventive strategies which target these children.</p> <p>Methods</p> <p>National survey data (CCHS 1.2) was used to estimate the number of children exposed to parental psychiatric disorders. Disorders were diagnosed using the World Psychiatric Health Composite International Diagnostic Interview (WMH-CIDI) (12 month prevalence). Data on the number of children below 12 years of age in the home, and the relationship of the respondents with the children, was used to estimate exposure. Parent-child relations were identified, as was single parenthood. Using a design-based analysis, the number of children exposed to parental psychiatric disorders was calculated.</p> <p>Results</p> <p>Almost 570,000 children under 12 live in households where the survey respondent met criteria for one or more mood, anxiety or substance use disorders in the previous 12 months, corresponding to 12.1% of Canadian children under the age of 12. Almost 3/4 of these children have parents that report receiving no mental health care in the 12 months preceding the survey. For 17% of all Canadian children under age 12, the individual experiencing a psychiatric disorder is the only parent in the household.</p> <p>Conclusion</p> <p>The high number of children exposed causes major concern and has important implications. Although these children will not necessarily experience adversities, they possess an elevated risk of accidents, mortality, and of developing psychiatric disorders. We expect these estimates will promote further research and stimulate discussion at both health policy and planning tables.</p

Engaging community pharmacists in the primary prevention of cardiovascular disease: protocol for the Pharmacist Assessment of Adherence, Risk and Treatment in Cardiovascular Disease (PAART CVD) pilot study

Background: Cardiovascular disease (CVD) is the leading cause of death globally. Community pharmacist intervention studies have demonstrated clinical effectiveness for improving several leading individual CVD risk factors. Primary prevention strategies increasingly emphasise the need for consideration of overall cardiovascular risk and concurrent management of multiple risk factors. It is therefore important to demonstrate the feasibility of multiple risk factor management by community pharmacists to ensure continued currency of their role.Methods/Design: This study will be a longitudinal pre- and post-test pilot study with a single cohort of up to 100 patients in ten pharmacies. Patients aged 50-74 years with no history of heart disease or diabetes, and taking antihypertensive or lipid-lowering medicines, will be approached for participation. Assessment of cardiovascular risk, medicines use and health behaviours will be undertaken by a research assistant at baseline and following the intervention (6 months). Validated interview scales will be used where available. Baseline data will be used by accredited medicines management pharmacists to generate a report for the treating community pharmacist. This report will highlight individual patients&rsquo; overall CVD risk and individual risk factors, as well as identifying modifiablehealth behaviours for risk improvement and suggesting treatment and behavioural goals. The treating community pharmacist will use this information to finalise and implement a treatment plan in conjunction with the patient and their doctor. Community pharmacists will facilitate patient improvements in lifestyle, medicines adherence, and medicines management over the course of five counselling sessions with monthly intervals. The primary outcome will be the change to average overall cardiovascular risk, assessed using the Framingham risk equation.Discussion: This study will assess the feasibility of implementing holistic primary CVD prevention programs into community pharmacy, one of the most accessible health services in most developed countries.<br /

The influence of the built environment in enacting a household model of residential aged care for people living with a mental health condition: A qualitative post-occupancy evaluation

This study undertakes a spatial analysis of an Australian aged care setting to explore the role of the built environment in the delivery of a household model of aged care (where residents receive person-centred support in specially-designed, small, homelike environments). Four focus groups with 16 staff were conducted to explore the impact of the built environment in a new residential aged care setting for people living with mental illness. Drawing on Actor-Network Theory and Proxemics, we mapped how the built environment supports improved behaviours and care practices in four key areas: food preparation and dining, sleep and personal self-care, site layout and relationship

Lymphocyte migration across high endothelium is associated with increases in alpha 4 beta 1 integrin (VLA-4) affinity

The constitutive recirculation of lymphocytes between the widely distributed organs of the immune system is essential for host defence. We have developed an in vitro model of lymphocyte migration from the blood into lymph nodes which employs primary cultures of high endothelial cells (HEC). HEC-adherent lymphocytes adopt one of two distinct morphologies which correlates with their position in the endothelial layer; type I cells are bound to the surface of HEC and type II cells are underneath the endothelial layer. In a previous study we reported that the numbers of type I and type II cells are independently regulated, however the relationship between these two lymphocyte populations was not determined. In this study we have carried out detailed kinetic, phenotypic and functional analyses of type I and type II lymphocytes and determined their relationship. Using allotype marked lymphocytes from the PVG.RT7a and PVG.RT7b rat strains in a pulse-chase analysis, type I and type II lymphocytes were found to represent the same population of lymphocytes at different stages of interaction with the endothelial layer, rather than representing two independent lymphocyte populations. Migration was an irreversible event and the efficiency of migration (i.e. transition from type I to type II) was related to the concentration of lymphocytes plated on to the HEC layer. Following transmigration lymphocytes showed an increased ability to migrate across HEC layers and to bind to immobilised CS1 peptide. The increased binding to CS1 peptide was transient and fell to control levels over a 3 hour time period. The expression of alpha 4 integrin subunit on lymphocytes was unchanged following migration which suggests that the affinity of the CS1 receptor, alpha 4 beta 1, is upregulated by interaction with HEC. Together these results suggest that transendothelial migration is regulated by increases in the affinity of alpha 4 beta 1 integrin on lymphocytes following contact with HEC

Lessons from the syphilis outbreak in homosexual men in east London

Objectives: To describe the epidemiology, presentation, and diagnosis of early syphilis in 103 homosexual men in east London. Methods: A retrospective study using data from KC60 returns, the Health Protection Agency (HPA) enhanced surveillance forms and case notes. Results: 40 cases of primary (PS), 40 of secondary (SS) and 23 of early latent syphilis were identified, 33% co-infected with HIV. 41% had concurrent sexually transmitted infections (STIs). Pain featured in 35% of PS and itch in 13% of rashes. Dark ground microscopy (DGM), performed in 44 of the symptomatic cases, was positive in 37 (84%) allowing early management. Initial syphilis serology was negative in 15/40 (37%) cases of PS. 51% and 49% opted for parenteral and oral treatment, respectively. In 53/103 (51%) cases oral sex was the only risk factor. 86% of infections were UK acquired. Only 4% of contacts were seen. Conclusion: This outbreak, reflecting the resurgence of syphilis across the United Kingdom, highlights several important points. Painful chancres and itchy rash are common presentations. DGM is a highly sensitive diagnostic tool. Initial negative serological screening tests are common in PS and sero-surveillance for 3 months is recommended. The high prevalence of concomitant STIs indicates ongoing unprotected sexual intercourse. Oral sex is a significant risk factor and is a distinctly "unsafe" practice. Conventional partner notification is ineffective. Other methods of screening of the at-risk homosexual population are warranted. Continued education is required to reduce STI acquisition in homosexual men