Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis

FLIP is a potential anti-cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors. We report a novel interaction between FLIP and the DNA repair protein Ku70 that regulates FLIP protein stability by inhibiting its polyubiquitination. Furthermore, we found that the histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) enhances the acetylation of Ku70, thereby disrupting the FLIP/Ku70 complex and triggering FLIP polyubiquitination and degradation by the proteasome. Using in vitro and in vivo colorectal cancer models, we further demonstrated that SAHA-induced apoptosis is dependant on FLIP downregulation and caspase 8 activation. In addition, an HDAC6-speci?c inhibitor Tubacin recapitulated the effects of SAHA, suggesting that HDAC6 is a key regulator of Ku70 acetylation and FLIP protein stability. Thus, HDAC inhibitors with anti-HDAC6 activity act as ef?cient post-transcriptional suppressors of FLIP expression and may, therefore, effectively act as ‘FLIP inhibitors’ © 2012 Macmillan Publishers Limited.

Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials

Background: After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk.
Methods: We undertook a meta-analysis of individual patient data for 10?801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease.
Findings: Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7–17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6–6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2–17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8–5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (=20%), intermediate (10–19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1–12·5), 1·1% (–2·0 to 4·2), and 0·1% (–7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5–27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8–15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease.
Interpretation: After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.
Funding: Cancer Research UK, British Heart Foundation, and UK Medical Research Council.

Dense spectrum of resonances and particle capture in a near-black-hole metric

We show that a quantum scalar particle in the gravitational field of a massive body of radius R which slightly exceeds the Schwarzschild radius rs, possesses a dense spectrum of narrow resonances. Their lifetimes and density tend to infinity in the limit R?rs. We determine the cross section of the particle capture into these resonances and show that it is equal to the absorption cross section for a Schwarzschild black hole. Thus, a nonsingular static metric acquires black-hole properties before the actual formation of a black hole.

A Pupil Baseline Study in Northern Ireland: Reported Willingness to Challenge Sectarian Bullying in School

Topic Background: Peace education initiatives in schools are often based on social psychological theories assuming that social identity affects ingroup and outgroup attitudes and, in turn, behaviors relating to relevant outgroups. However, research evidence on the role of children's social identity has often failed to take account of different social identity dimensions or to conceptualise behavior in the context of children's understandings of the social world. While recent research relating to bullying and bystander behavior amongst children has addressed the latter point, this has rarely been considered in conjunction with a differentiated view of social identity. This paper is therefore distinctive as it will address the role of social identity dimensions with regards to reported behavior as captured in bystander scenarios relating to outgroup derogation. This is particularly important in the context of divided societies, where peace education initiatives are crucial in promoting positive community relations for the future and where such initiative may be hampered by communities' concerns about loss of identity. In the context of Northern Ireland, a divided society emerging from conflict, social identity, outgroup attitudes and behaviours have been key concepts addressed by peace educators
for many years.

Research questions: This paper therefore set out to investigate the relationship between social identity, measured as affiliation with the group and exploration of its meaning for the child, sectarian attitudes and pupils' reported willingness to challenge sectarian bullying in their school environment in Northern Ireland.
Research methods: The findings are based on the analysis of a baseline survey, which forms part of a randomised control trial of an intervention aimed at promoting community relations and reconciliation. The trial includes 35 primary and post-primary schools and about 800 pupils from 8-11 years old who completed an online questionnaire at the start of the programme. Main instruments for this study included adapted scales measuring identity affiliation and identity exploration, sectarian attitudes and scenarios capturing pupils' intentions in bystander situations relating to sectarian bullying.

Analytical framework: Results are analysed using regression analysis and additionally investigate gender and religious differences.

Research findings and/or contribution to knowledge: Results are discussed in the light of the role of social identity dimensions and their relationship to outgroup attitudes and willingness to challenge outgroup derogation. The paper concludes with potential implications for peace education initiatives in Northern Ireland and beyond.

Evidence from a Baseline Study of Teachers and Young People in Northern Ireland: Implications for Peace Education.

Peace education initiatives in schools are often based on social psychological theories assuming that social identity affects ingroup and outgroup attitudes and, in turn, behaviors relating to relevant outgroups. However, research evidence on the role of young people’s social identity has often failed to take account of different social identity dimensions or to conceptualise outgroup behavior in the context of young people’s understandings of the social world. While recent research relating to bullying and bystander behavior amongst young people has addressed the latter point, this has rarely been considered in conjunction with a differentiated view of social identity. This paper is therefore distinctive as it will address the role of social identity dimensions with regards to behavior as captured in bystander scenarios relating to intergroup discrimination. This is particularly important in the context of divided societies, where peace education initiatives are crucial in promoting positive community relations for the future and where such initiative may be hampered by communities’ concerns about loss of identity and hardened intergroup attitudes. Furthermore, previous research frequently highlighted teachers’ fears to tackle outgroup attitudes in the classroom, especially in contexts where pupils and the wider school community are seen as entrenched in community divisions (Hughes, Donnelly, Hewstone, Gallagher & Carlisle, 2010). However, there is no research investigating the relationship between pupils’ attitudes and teacher confidence to talk about such issues in the classroom, which is explored in this paper.

In the context of Northern Ireland, a divided society emerging from sectarian conflict, social identity, outgroup attitudes and outgroup behaviours have been key concepts addressed by peace educators for many years. Building on this work, this paper provides a detailed picture of young people’s strength of group identification and their willingness to explore ingroup perspectives, sectarian attitudes and their reported willingness to challenge sectarian bullying. Using data from a baseline survey, which forms part of a randomized control trial investigating the effect of an educational intervention aimed to promote reconciliation, the sample involved young people of different denominational backgrounds, attending separate school sectors. The baseline data will be used to compare with post intervention data. Therefore, the data and its findings would be of particular interest to educators and policy makers in other European countries who are working to develop peace education interventions in societies emerging from conflict. Additionally, this paper considers the results from a baseline teacher survey, collected before training and teaching of the intervention began. The teacher survey focused on confidence in tackling sectarian issues in the classroom, previous experience of teaching such issues and their hopes and concerns for the reconciliation intervention.

This paper therefore set out to investigate the relationship between dimensional concept of social identity, sectarian attitudes and pupils’ reported willingness to challenge sectarian bullying and to compare this with their teachers’ attitudes to teaching about sectarian issues in the classroom.



Method

The pupil sample included 35 primary and post-primary schools and about 800 pupils from 8-11 years old who completed an online questionnaire in December 2011 and January 2012. Main instruments for young people’s survey included an adapted version of the Multi-ethnic identity measure (Phinney, 1992) incorporating the dimensions identity affirmation and exploration, outgroup attitude scales, including an adaptation of the social distance measure (Bogardus, 1947), as well as a measure adapted from Palmer and Cameron (2011) involving scenarios to capture pupils’ intentions in bystander situations relating to intergroup discrimination. Results are analysed using regression analysis and take account of potential gender and religious differences. The teacher questionnaire was completed by the 35 primary and post-primary teachers who will deliver the intervention. Results are analysed in terms of how teachers’ responses compare with their pupil attitudes by considering their confidence in tackling sectarian issues in the classroom and how their previous experience and training relate to their hopes and concerns for the intervention.


Expected Outcomes

Results from the young people’s survey are discussed in the light of the role of social identity dimensions and their relationship to sectarian attitudes and reported bystander behaviour in sectarian school incidents. Furthermore, results related to pupils’ sectarian attitudes will be compared with teachers’ reported confidence in tackling sectarianism in the classroom. The teacher questionnaire also presents interesting findings in relation to teachers’ previous training and experience and how this may influence different perspectives on peace and reconciliation interventions and their expectations of what these could achieve. The paper concludes with potential implications for peace education initiatives and related teacher training in Northern Ireland and beyond. The implications will be of particular interest to policy makers, educators and those working in the area of peace education to design and implement interventions.


References

Bogardus, E. S. (1947) Measurement of Personal-Group Relations. Sociometry, 10: 4: 306–311. Hughes, J., Donnelly, C., Hewstone, M., Gallagher, T. & Carlisle, K. (2010) School partnerships and reconciliation: An evaluation of school collaboration in Northern Ireland. Belfast: Queen’s University Belfast. Available online: http://www.schoolsworkingtogether.com/documents/School%20collaboration%20in%20NI%202010.pdf. (accessed 27th Jan 2010) Palmer, S. & Cameron, L. (2011, May). What are the moderators and mediators of children’s bystander behaviour in the context of intergroup discrimination? Paper session presented at the UNA Global Biennial Conference 2011: Building Peaceable Communities: The Power of Early Childhood, Amsterdam, Holland. Phinney, J. S. (1992). The Multigroup Ethnic Identity Measure: A new scale for use with diverse groups. Journal of Adolescent Research, 7, 156–176.

Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly:a randomized comparative trial

Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly.

Efficacy of a powered wheelchair simulator for school aged children: A randomised controlled trial.

Purpose: To determine the efficacy of a custom made wheelchair simulation in training children to use a powered wheelchair (PWC). Design: Randomised controlled trial employing the 4C/ID-model of learning. Twenty-eight typically developing children (13M, 15F; mean age 6 years, SD 6 months) were assessed on their operation of a PWC using a functional evaluation rating scale. Participants were randomly assigned to intervention (8x 30minute training sessions using a joystick operated wheelchair simulation) or control conditions (no task), and were re-assessed on their PWC use following the intervention phase. Additional data from the simulation on completion times, errors and total scores were recorded for the intervention group. Results: Analysis of variance showed a main effect of time, with planned comparisons revealing a statistically significant change in PWC use for the intervention (p = 0.022) but not the control condition. Whilst the intervention group showed greater improvement than the controls this did not reach statistical significance. Multiple regression analyses showed that gender was predictive of pre-test (p = 0.005) functional ability. Implications: A simulated wheelchair task appears to be effective in helping children learn to operate a PWC. Greater attention should be given to female learners who underperformed when compared to their male counterparts. This low cost intervention could be easily employed at home to reduce PWC training times in children with motor disorders.

Pedometer-driven walking for chronic low back pain:A feasibility randomized controlled trial

OBJECTIVES: To evaluate the feasibility of an RCT of a pedometer-driven walking program and education/advice to remain active compared with education/advice only for treatment of chronic low back pain (CLBP). METHODS: Fifty-seven participants with CLBP recruited from primary care were randomly allocated to either: (1) education/advice (E, n=17) or (2) education/advice plus an 8-week pedometer-driven walking program (EWP, n=40). Step targets, actual daily step counts, and adverse events were recorded in a walking diary over the 8 weeks of intervention for the EWP group only. All other outcomes (eg, functional disability using the Oswestry Disability Questionnaire (ODQ), pain scores, physical activity (PA) measurement etc.) were recorded at baseline, week 9 (immediately post-intervention), and 6 months in both groups. RESULTS: The recruitment rate was 22% and the dropout rate was lower than anticipated (13% to 18% at 6 mo). Adherence with the EWP was high, 93% (n=37/40) walked for =6 weeks, and increased their steps/day [mean absolute increase in steps/d, 2776, 95% confidence interval (CI), 1996-3557] by 59% (95% CI, 40.73%-76.25%) from baseline. Mean percentage adherence with weekly step targets was 70% (95% CI, 62%-77%). Eight (20%) minor-related adverse events were observed in 13% (5/40) of the participants. The EWP group participants demonstrated an 8.2% point improvement [95% CI, -13 to -3.4] on the ODQ at 6 months compared with 1.6% points [95% CI, -9.3 to 6.1) for the E group (between group d=0.44). There was also a larger mean improvement in pain (d=0.4) and a larger increase in PA (d=0.59) at 6 months in EWP. DISCUSSION: This preliminary study demonstrated that a main RCT is feasible. EWP was safe and produced a real increase in walking; CLBP function and pain improved, and participants perceived a greater improvement in their PA levels. These improvements require confirmation in a fully powered RCT.

Early Medieval Ireland, AD 400-1100: The evidence from archaeological excavations

Overview and synthesis of early medieval Irish excavations between 1930 and the present.