Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells.

Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.

‘A system that works for the sea’? Exploring Stakeholder Engagement in Marine Spatial Planning

This paper aims to contribute to the current debate on Marine Spatial Planning (MSP) by exploring the issue of stakeholder engagement. MSP is an emergent policy field that is subject to an increasing body of research, yet the role, scope and nature of participatory engagement within the process remains a neglected topic. This paper briefly reviews the nature of the ‘marine problem’, to which MSP is seen to be the response and describes the emergence of MSP policy in the UK with specific emphasis on participatory aspects. Drawing on the experience of terrestrial planning it discusses the potential benefits of stakeholder engagement in MSP and highlights some of the key issues that need to be taken into account when shaping stakeholder input into the process. It then goes on to describe the findings from a series of interviews with key stakeholders in the Irish Sea Region, which suggest that we need to develop a more critical and deeper understanding of how various interests frame the ‘marine problem’, and how they see their role in shaping the form of the MSP process. This highlights the importance of encouraging stakeholder involvement in MSP, the need to develop a shared vision of a ‘sea interest’. Priorities are then set for research to support this important policy agenda.

Personnel radiation dose considerations in the use of an integrated PET–CT scanner for radiotherapy treatment planning of an integrated PET-CT scanner for radiotherapy treatment planning

The acquisition of radiotherapy planning scans on positron emission tomography (PET)-CT scanners requires the involvement of radiotherapy radiographers. This study assessed the radiation dose received by these radiographers during this process. Radiotherapy planning F- fluorodeoxyglucose (F-FDG) PET-CT scans were acquired for 28 non-small cell lung cancer patients. In order to minimise the radiation dose received, a two-stage process was used in which the most time-consuming part of the set-up was performed before the patient received their F-FDG injection. Throughout this process, the radiographers wore electronic personal dosemeters and recorded the doses received at different stages of the process. The mean total radiation dose received by a radiotherapy radiographer was 5.1±2.6 mSv per patient. The use of the two-stage process reduced the time spent in close proximity to the patient by approximately a factor of four. The two-stage process was effective in keeping radiation dose to a minimum. The use of a pre-injection set-up session reduces the radiation dose to the radiotherapy radiographers because of their involvement in PET-CT radiotherapy treatment planning scans by approximately a factor of three.

Innovative Approaches to Involving Service Users in Palliative Care Social Work Education

Service user involvement in social work education is now a firmly established concept in UnitedKingdom.As a result, it is common practice for service users to occupy central roles the education and training of social work students and staff in both qualifying and postqualifying programmes. This paper describes an initiative, undertaken inNorthern Ireland, which compares two methods of user involvement employed with undergraduate and postqualifying social work students. In both situations the students firstly observed discussedDVDexcerpts of narratives from people affected by cancer and secondly observed live facilitated interview with a 25-year-old male service user who shared his experiences being diagnosedwith cancer at a young age.Understanding the social work role in palliative care is crucial as all social workers, regardless of practice context, will have some degree involvement in helping individuals and families to address end-of-life care issues. paper compares the findings of evaluations from two student groups which may help inform social work educators about the effectiveness of different teaching methods used achieve meaningful and effective user involvement with seldom heard groups.

Nociception or pain in a decapod crustacean?

Nociception is the ability to perceive a noxious stimulus and react in a re flexive manner and occurs across a wide range of taxa. However, the ability to experience the associated aversive sensation and feeling, known as pain, is not widely accepted to occur in nonvertebrates. We examined the responses of a decapod crustacean, the prawn, Palaemon elegans, to different noxious stimuli applied to one antenna to assess reflex responses (nociception) and longer-term, specifically directed behavioural responses that might indicate pain. We also examined the effects of benzocaine, a local anaesthetic, on these responses. Noxious stimuli elicited an immediate reflex tail flick response, followed by two prolonged activities, grooming of the antenna and rubbing of the antenna against the side of the tank, with both activities directed specifically at the treated antenna. These responses were inhibited by benzocaine; however, benzocaine did not alter general swimming activity and thus the decline in grooming and rubbing is not due to general anaesthesia. Mechanical stimulation by pinching also resulted in prolonged rubbing, but this was not inhibited by benzocaine. These results indicate an awareness of the location of the noxious stimuli, and the prolonged complex responses indicate a central involvement in their organization. The inhibition by a local anaesthetic is similar to observations on vertebrates and is consistent with the idea that these crustaceans can experience pain.

ATM acts downstream of ATR in the DNA damage response signaling of bystander cells.

This study identifies ataxia-telangiectasia mutated (ATM) as a further component of the complex signaling network of radiation-induced DNA damage in nontargeted bystander cells downstream of ataxia-telangiectasia and Rad3-related (ATR) and provides a rationale for molecular targeted modulation of these effects. In directly irradiated cells, ATR, ATM, and DNA-dependent protein kinase (DNA-PK) deficiency resulted in reduced cell survival as predicted by the known important role of these proteins in sensing DNA damage. A decrease in clonogenic survival was also observed in ATR/ATM/DNA-PK–proficient, nonirradiated bystander cells, but this effect was completely abrogated in ATR and ATM but not DNA-PK–deficient bystander cells. ATM activation in bystander cells was found to be dependent on ATR function. Furthermore, the induction and colocalization of ATR, 53BP1, ATM-S1981P, p21, and BRCA1 foci in nontargeted cells was shown, suggesting their involvement in bystander DNA damage signaling and providing additional potential targets for its modulation. 53BP1 bystander foci were induced in an ATR-dependent manner predominantly in S-phase cells, similar to ?H2AX foci induction. In conclusion, these results provide a rationale for the differential modulation of targeted and nontargeted effects of radiation.

(Pro)Motion Pictures: Len Lye in the Thirties

This article examines Len Lye’s film-making in the 1930s within a broader visual arts context, seeking to clarify the nature and extent of his involvement in British documentary film culture at this time. In particular, it demonstrates how Lye's method of fusing 'live action', found footage, and animation techniques created the possibility of a radical documentary practice that could reconcile promotional advertising and commercial art with avant-garde abstraction and kinaesthetic experimentation. In particular, the article focusses on Lye's N. or N.W. (1937, 35mm, b&w, 10 mns), arguing that his work from this period should be regarded as central - and not marginal - to any serious reassessment of Britain's “Documentary Movement” of the inter-war era, and its relations to any history of the cinema and visual culture.

Association analysis of Notch pathway signalling genes in diabetic nephropathy

Several studies have provided compelling evidence implicating the Notch signalling pathway in diabetic nephropathy. Co-regulation of Notch signalling pathway genes with GREM1 has recently been demonstrated and several genes involved in the Notch pathway are differentially expressed in kidney biopsies from individuals with diabetic nephropathy. We assessed single-nucleotide polymorphisms (SNPs; n = 42) in four of these key genes (JAG1, HES1, NOTCH3 and ADAM10) for association with diabetic nephropathy using a case-control design.
Tag SNPs and potentially functional SNPs were genotyped using Sequenom or Taqman technologies in a total of 1371 individuals with type 1 diabetes (668 patients with nephropathy and 703 controls without nephropathy). Patients and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK (http://pngu.mgh.harvard.edu/similar to purcell/plink/) and haplotype frequencies in patients and controls were compared. Adjustment for multiple testing was performed by permutation testing.
In analyses stratified by centre, we identified six SNPs, rs8708 and rs11699674 (JAG1), rs10423702 and rs1548555 (NOTCH3), rs2054096 and rs8027998 (ADAM10) as being associated with diabetic nephropathy before, but not after, adjustment for multiple testing. Haplotype and subgroup analysis according to duration of diabetes also failed to find an association with diabetic nephropathy.
Our results suggest that common variants in JAG1, HES1, NOTCH3 and ADAM10 are not strongly associated with diabetic nephropathy in type 1 diabetes among white individuals. Our findings, however, cannot entirely exclude these genes from involvement in the pathogenesis of diabetic nephropathy.

'Rule of Law and Politics of Anti-Corruption Campaigns in a Post-Authoritarian State- The Nigerian Case'

This article evaluates the anti-corruption campaign instituted in Nigeria following on the post-authoritarian transition in the country, with specific focus on political corruption. The anti-corruption campaign is being prosecuted within a context where law is as critical a factor as politics. This article examines whether the judiciary, in view of its accountability deficit, can offer legitimacy to the campaign. How has its questionable credentials impacted on its involvement in the campaign to sanitise public life? What has been the impact of the judicial role on the rule of law? These are some of the important questions this article seeks to answer. The inquiry in this article demonstrates how the guardian institution of the rule of law faces an uphill task in the performance of that role in a post-authoritarian context.

MicroRNA regulation of core apoptosis pathways in cancer

Recent research has demonstrated that microRNAs (miRNAs) are key regulators of many cell processes often deregulated in cancer, including apoptosis. Indeed, it is becoming clear that many miRNAs are anti-apoptotic and mediate this effect by targeting pro-apoptotic mRNAs or positive regulators of pro-apoptotic mRNAs. Conversely, many pro-apoptotic miRNAs target anti-apoptotic mRNAs or their positive regulators. We have reviewed the current knowledge in this area including evidence of miRNA involvement in cancer drug resistance. (C) 2010 Elsevier Ltd. All rights reserved.

N-epsilon-(carboxymethyl)lysine content of foods commonly consumed in a Western style diet

The potential adverse effects on health of diet-derived advanced glycation end-products (AGEs) is of current interest, due to their proposed involvement in the disease progression of diabetic and uraemic conditions. However, accurate information about levels of AGEs in foods is lacking. The objective of this investigation was to determine the level of one particular AGE, N-epsilon-(carboxymethyl)lysine (CML), a marker of AGE formation, in a wide range of foods commonly consumed in a Western style diet. Individual foods (n = 257) were mixed, lyophilised, ground, reduced, fat-extracted, hydrolysed, and underwent solid-phase extraction. Extracts were analysed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Cereal (2.6 mg/100 g food) and fruit and vegetable (0.13 mg/100 g food) categories had the highest and lowest mean level of CML, respectively, when expressed in mg/100 g food. These data can be used for estimating potential consumer intakes, and provide information that can be used to educated consumers on how to reduce their CML intake. (C) 2011 Elsevier Ltd. All rights reserved.

A self-reported work sampling study in community pharmacy practice

Lack of time to implement pharmaceutical care has been cited as a barrier to the routine provision of this extended patient-care service. Using self-reported work sampling methodology, this study investigated how community pharmacists utilise their time. Pharmacists working in community pharmacies in the Greater Belfast area were found to spend approximately 49% of their time engaged in professional activities, 29% in semi-professional activities and 22% involved in non-professional activities. The activity to which pharmacists devoted the majority of their time was product assembly and labelling, this being a task which can be performed by trained technical staff. Only 9.5% of community pharmacists' time was devoted to counselling patients on their prescription medicines. Wide variation in the amount of time apportioned to each activity was observed between the participating community pharmacists (n=30). Staffing levels within the community pharmacy were found to significantly influence pharmacists' involvement in a number of activities, with pharmacists who worked in pharmacies employing multiple pharmacists devoting more time to the assembly and labelling of products and less time to administrative tasks, non-professional encounters and to miscellaneous professional activities. Pharmacists working in pharmacies with a high prescription turnover were found to devote significantly less time to counselling patients regarding OTC products and in responding to patient symptoms.

Evidence of bacteriophage-mediated horizontal transfer of bacterial 16S rRNA genes in the viral metagenome of the marine sponge Hymeniacidon perlevis

Marine sponges have never been directly examined with respect to the presence of viruses or their potential involvement in horizontal gene transfer. Here we demonstrate for the first time, the presence of viruses in the marine sponge Hymeniacidon perlevis. Moreover, bacterial 16s rDNA was detected in DNA isolated from these viruses, indicating that phage-derived transduction appears to occur in H. perlevis. Phylogenetic analysis revealed that bacterial 16s rDNA isolated from sponge-derived viral and total DNA differed significantly, indicating that not all species are equally involved in transduction.

Expanding DDR: The Transformative Role of Former Prisoners in Community-Based Reintegration in Northern Ireland

This article explores the process of Disarmament, Demobilization and Reintegration (DDR) in Northern Ireland. In particular, it examines the role and experiences of former combatants, who were incarcerated during the Troubles. It is shown that upon release from prison, many of these former combatants have played key roles in the development of community-based initiatives, which have not only facilitated the reintegration of former prisoners, but have also contributed to a broader process of post-conflict regeneration and social development. The author considers the notion of expanding the ‘R’ phase of DDR, and contends that additional attention needs to be paid to both to the specific needs of former combatants/former prisoners and to their involvement in the overall process of reintegration and peacebuilding.