Tumour suppression mediated through DPC4, p53 and APC

Mutations in the tumour suppressor genes SMAD4 (or DPC4, deleted in pancreatic cancer locus 4), APC (adenomatous polyposis coli) and p53 have been implicated in pancreatic cancer in humans. This thesis firstly documents the in vivo effects of mutations in these genes singly and in combination through spontaneous and carcinogen- induced murine models of pancreatic tumourigenesis. Second, it examines the in vitro effects of TGF -ß signalling, of which SMAD4 is the central mediator, on murine primary cultured pancreatic acinar cells. Previously p53 ApcM "i+ mice have been shown to develop pancreatic tumours. To examine the effect of Smad4 heterozygous mutation on the development of these tumours, Smad4 +i mutation was introduced into p534- and p531- ApcM "v+ mice. No pancreatic phenotype was found in p534- Smad4 +i - animals. p53 4-ApcM1 Smad4 +i animals did not exhibit promotion of tumourigenesis in any tissues compared to the p53í- ApcM"+ mice. Immunohistochemical studies revealed loss of SMAD4 protein within the majority of the lesions arising in p53 - ApcM "i+Smad4 + / animals. Furthermore, microdissection and mutational analysis revealed LOH for Apc and Smad4. Treatment of wild -type (WT) Smad4 +i, ApcM "l+ or ApcM "i+Smade- mice with NNitroso- N- Methyl Urea (NMU) resulted in abnormal foci in pancreatic acinar cells, characterised by (3- catenin stabilisation. Previously these foci have been shown to be the precursors of pancreatic neoplasia. Only NMU- treated ApcM "i+Smad4 + / mice exhibited a significant increase in abnormal pancreas, which was found to be due to an increased number of abnormal foci rather than increased focus size. A range of foci sizes were analysed, but only smaller abnormal foci were characterised by morphological nuclear atypia. These studies suggest functional co- operation between TGF -(3 and Wnt signalling pathways in the suppression of pancreatic tumourigenesis in the mouse. In order to investigate TGF -ß signalling in WT murine primary pancreatic acinar cells TGF -3 was given to these cells under different conditions. Two main conclusions were drawn from these experiments. First that TGF -13 in conjunction with EGF could accentuate acinar cell attachment and motility in the presence of serum. This effect was not associated with changes in cell proliferation. Others working on primary culture of rat hepatocytes have also reported synergy between EGF and TGF -13 resulting in increased motility suggesting this interaction may be common among different cell types. Second, in serum free conditions, TGF -13 caused reduced BrdU incorporation and increased apoptosis. Immunofluorescent studies, analysed by confocal microscopy, revealed that these cellular behaviours were associated with changes in the cyclin dependent kinase inhibitor, p27, but not p21. Whether these effects are mediated by SMAD4 remains unconfirmed as immunoblotting revealed SMAD4 to be present in the nucleus of these cells in the absence and presence of TGF -ß. This investigation into the effect of TGF -ß on primary pancreatic acinar cells reflects the multi -functional nature of TGF -13 signalling, highlighting interaction between TGF -13 and EGF signalling pathways and suggesting a mechanism of TGF -ß- induced growth suppression via p27 in these cells. These studies provide insight into the combined effects of mutation in p53, Apc and Smad4 in the development of pancreatic cancer and suggest possible cellular mechanisms through which Smad4 mutation and disrupted TGF -ß signalling could promote pancreatic cancer in humans

Democratic governance through intermediary bodies: a case study of third sector interfaces in Scotland

This research focuses on third sector interfaces (TSIs) as a site through which to examine the relationship between the third sector and the state in Scotland. The TSI model was instituted by the Scottish Government in 2011 in each of Scotland’s 32 local authorities with a remit to build sector capacity, support volunteerism, encourage social enterprise, and represent the sector in community planning. Through its participation in state-initiated local governance networks, like Community Planning Partnerships, the sector has a prominence that was unthinkable just twenty years ago. This research study explores the impact of a TSI’s participation in state-initiated local governance networks, focusing on the TSI’s independence from the state and its representation of the sector. Using a qualitative interpretivist approach, 44 semi-structured interviews were conducted (13 with national stakeholders, 19 with local stakeholders, and 12 with TSI staff) and 16 local governance meetings observed. A large urban TSI was selected for the case study. Four key themes emerged from an iterative thematic analysis. One, that local governance sits within a space, literal and figurative, where representative and participatory democracy meet. Through its participation, the TSI is brought closer to the state implicating it in statutory decision making. Two, the TSI model is an example of a “civil servant construct” channelling the sector’s participation in local governance networks through structures that mirror state priorities, compromising the independence of the TSI and complicating its representation role. Three, the TSI’s closeness to the state creates distrust within the third sector which in turn weakens its legitimacy in representing the sector. Four, local governance spaces embody a culture of “managed talk” compromising the TSI’s ability to be activist and shaping its participation through a state logic. The study suggests that there is an impact on both the TSI’s independence from the state and the ways in which it represents the third sector. The current state approach to engaging the third sector risks “manufacturing civil society” (Brandsen, et al., 2014) where the sector becomes a reflection of the state rather than an expression of civil society. Recommendations from the study include the need for democratic governance spaces to be shaped collaboratively by the state and civil society, the state to reconsider its instrumental approach to the third sector, the third sector to assert its independence, and intermediary bodies to act as facilitators rather than representatives

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Contemporaneous Monitoring of the Whole Dynamic Earth System from Space, Part I: System Simulation Study Using GEO and Molniya Orbits

Despite the wealth of data produced by previous and current Earth Observation platforms feeding climate models, weather forecasts, disaster monitoring services and countless other applications, the public still lacks the ability to access a live, true colour, global view of our planet, and nudge them towards a realisation of its fragility. The ideas behind commercialization of Earth photography from space has long been dominated by the analytical value of the imagery. What specific knowledge and actionable intelligence can be garnered from these evermore frequent revisits of the planet’s surface? How can I find a market for this analysis? However, what is rarely considered is what is the educational value of the imagery? As students and children become more aware of our several decades of advance in viewing our current planetary state, we should find mechanisms which serve their curiosity, helping to satisfy our children’s simple quest to explore and learn more about what they are seeing. The following study describes the reasons why current GEO and LEO observation platforms are inadequate to provide truly global RGB coverage on an update time-scale of 5-min and proposes an alternative, low-cost, GEO + Molniya 3U CubeSat constellation to perform such an application

Treatment of paediatric burns with a nanocrystalline silver dressing compared with standard wound care in a burns unit: A cost analysis

Burns are a leading cause of non-natural death in South African infants and children. Conventional care of partial-thickness burns often requires painful, time consuming and costly twice-daily dressing changes to clean the wound and apply antimicrobial topical agents. A new topical nanocrystalline silver-coated (NS) dressing (Acticoat; Smith & Nephew) has been developed and is the first-line treatment of choice in many burn centres. However, because of its cost the Department of Health has been reluctant to introduce it as a standard of care. We retrospectively studied 4 randomly selected paediatric burn patients, calculating the cost associated with the use of NS dressings and comparing this with the projected costs of three previously standard burn wound treatment regimens. NS dressings were changed every 3 days based on their sustained and slow release of silver ions over 72 hours. Using NS clearly saved costs compared with the three other regimens. The demonstrated cost savings resulted primarily from the decreased number of dressings, and the presumed shorter hospital stay

Happiness as stable extraversion : internal consistency reliability and construct validity of the Oxford Happiness Questionnaire among undergraduate students

The Oxford Happiness Questionnaire (OHQ) was developed by Hills and Argyle (2002) to provide a more accessible equivalent measure of the Oxford Happiness Inventory (OHI). The aim of the present study was to examine the internal consistency reliability, and construct validity of this new instrument alongside the Eysenckian dimensional model of personality. The Oxford Happiness Questionnaire was completed by a sample of 131 undergraduate students together with the abbreviated form of the Revised Eysenck Personality Questionnaire. The data demonstrated good internal consistency reliability (alpha = .92) and good construct validity in terms of positive association with extraversion (r = .38 p < .001) and negative association with neuroticism (r = −.57 p < .001). The kind of happiness measured by the OHQ is clearly associated with stable extraversion

How to Undertake a Clinically Relevant Systematic Review in a Rapidly Evolving Field: Magnetic Resonance Angiography

Objectives: The aim was to determine which generations of the evolving technology of magnetic resonance angiography (MRA) are currently of clinical relevance in two clinical applications. Our purpose was to plan a systematic review that would be valuable both to purchasers driven by cost-effectiveness and to practicing clinicians. Methods: Information was gathered from a search of major bibliographic databases, from a short questionnaire sent to 500 U.K. vascular radiologists and vascular surgeons, and from local clinical The authors thank A. Jackson and all those who completed a questionnaire. This work was carried out with the financial support of the Secretary of State for Health under the NHS Health Technology Assessment Programme, project 97/13/04. The views and opinions expressed do not necessarily reflect those of the Secretary of State for Health. In part, this work was undertaken by the Leeds Teaching Hospitals NHS Trust, which received funding from the NHS Executive. The views expressed in this publication are those of the authors and not necessarily those of the NHS Executive.experts. We asked which of the MRA techniques were currently used and, assuming availability, what would be their technique of choice. Results: There were 206 published articles that satisfied preliminary inclusion criteria: 69 discussed 2D time of flight (TOF); 47, 3D TOF; and 38, contrast-enhanced techniques. There were 162 questionnaires returned (60 radiologists, 102 surgeons). Of the total respondents, 77/162 (48%) used MRA in the assessment of carotid artery stenosis; 47/77 (61%) used 2D TOF; 32/77 (42%), 3D TOF; and 26/77 (34%), contrast-enhanced techniques. Thirty-five of 162 (22%) respondents used MRA in the assessment of peripheral vascular disease (PVD); 15/35 (43%) used 2D TOF, 4/35 (11%) used 3D TOF, and 22/35 (63%) used contrast-enhanced techniques. For those wishing to use MRA, contrast-enhanced techniques were the method of choice. Conclusions: The TOF methods that represent earlier generations of the technology remain clinically relevant, and will therefore be included in our systematic review. To ensure complete and relevant coverage in reviews of other evolving technologies, it would be advisable to obtain data for guidance in a similar way

Use of magnetic resonance angiography to select candidates with recently symptomatic carotid stenosis for surgery: systematic review

Objective To determine if sufficient evidence exists to support the use of magnetic resonance angiography as a means of selecting patients with recently symptomatic high grade carotid stenosis for surgery. Design Systematic review of published research on the diagnostic performance of magnetic resonance angiography, 1990-9. Main outcome measures Performance characteristics of diagnostic test. Results 126 potentially relevant articles were identified, but many articles failed to examine die performance of magnetic resonance angiography as a diagnostic test at the surgical decision thresholds used in major clinical trials on endarterectomy. 26 articles were included in a meta-analysis that showed a maximal joint sensitivity and specificity of 99% (95% confidence interval 98% to 100%) for identifying 70-99% stenosis and 90% (81% to 99%) for identifying 50-99% stenosis. Only four articles evaluated contrast enhanced magnetic resonance angiography. Conclusions Magnetic resonance angiography is accurate for selecting patients for carotid endarterectomy at the surgical decision thresholds established in the major endarterectomy trials, but the evidence is not very robust because of the heterogeneity of the studies included. Research is to determine the diagnostic performance of the most recent developments in magnetic resonance angiography, including contrast enhanced techniques, as well as to assess the impact of magnetic resonance angiography on surgical decision making and outcomes

Participation and representation : strengthening the third sector voice in local governance

The report outlines the context of the work of STRiVE, a third sector interface (TSI) in East Lothian as it sought to strengthen the participation of third sector organisations in local governance. It reviews the process that was deployed, the challenges that were faced and the outcomes of this deliberative exercise. The process resulted in a fundamental shift in how the third sector is represented in East Lothian; rather than the third sector voice being mediated by STRiVE, third sector organisations now participate directly in the process of selecting delegates and in being delegates in local governance processes. The report has seven key insights: The current system of third sector representation struggles to be effective and democratic. Local third sector organisations are keen to develop and engage in models to strengthen participation and representation. Democratisation can be initiated from the top. Bringing third sector organisations into local governance requires negotiation. The commitment to subsidiarity in CPPs is a qualified one. There is still a long way to go for the third sector to be considered a full community planning partner. There is strong democratic potential in the TSI being a facilitator and an enabler, rather than a representative. The STRiVE experience highlights the potential for third sector interface organisations to play a facilitating and enabling role, rather than a traditional representative one. The researchers conclude that a TSI that works more democratically can help to enable better representation of the diversity of third sector voices. This, in turn, increases its legitimacy and scope for influence. It is harder for other local actors and institutions to disregard a TSI that demonstrates strong democratic credentials. Stronger third sector representation can, in turn, help to improve local governance and outcomes for the communities it serves

Disabled people and COVID-19: four urgent messages for the government

Tom Shakespeare (LSHTM), Nicholas Watson, Richard Brunner, Jane Cullingworth (University of Glasgow), Shaffa Hameed (LSHTM), Charlotte Pearson (University of Glasgow), Nathaniel Scherer and Veronika Reichenberger (LSHTM) report on in-depth qualitative interviews conducted with 69 disabled people in England and Scotland, and with 28 key informants from infrastructure organisations in the voluntary and statutory sectors, about the impact of COVID-19, and measures taken to control it. They discuss the dislocations it has caused in everyday life; the failures of social care; the use of new technologies; and participants’ views on leadership and communication