Measuring a cell's response to stress: the p53 pathway

The characterization of complex cellular responses to diverse stimuli can be studied by the use of emerging chip-based technologies

Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer

SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials

Endovascular repair or open repair for ruptured abdominal aortic aneurysm: a Cochrane systematic review

OBJECTIVES: Emergency endovascular aneurysm repair (eEVAR) may improve outcomes for patients with ruptured abdominal aortic aneurysm (RAAA). The study aim was to compare the outcomes for eEVAR with conventional open surgical repair for the treatment of RAAA. SETTING: A systematic review of relevant publications was performed. Randomised controlled trials (RCTs) comparing eEVAR with open surgical repair for RAAA were included. PARTICIPANTS: 3 RCTs were included, with a total of 761 patients with RAAA. INTERVENTIONS: Meta-analysis was performed with fixed-effects models with ORs and 95% CIs for dichotomous data and mean differences with 95% CIs for continuous data. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was short-term mortality. Secondary outcome measures included aneurysm-specific and general complication rates, quality of life and economic analysis. RESULTS: Overall risk of bias was low. There was no difference between the 2 interventions on 30-day (or in-hospital) mortality, OR 0.91 (95% CI 0.67 to 1.22; p=0.52). 30-day complications included myocardial infarction, stroke, composite cardiac complications, renal complications, severe bowel ischaemia, spinal cord ischaemia, reoperation, amputation and respiratory failure. Reporting was incomplete, and no robust conclusion was drawn. For complication outcomes that did include at least 2 studies in the meta-analysis, there was no clear evidence to support a difference between eEVAR and open repair. Longer term outcomes and cost per patient were evaluated in only a single study, thus precluding definite conclusions. CONCLUSIONS: Outcomes between eEVAR and open repair, specifically 30-day mortality, are similar. However, further high-quality trials are required, as the paucity of data currently limits the conclusions

Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer

SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials

Arts on prescription for community‐dwelling older people with a range of health and wellness needs

Published evidence for the role of participatory art in supporting health and well‐being is growing. The Arts on Prescription model is one vehicle by which participatory art can be delivered. Much of the focus of Arts on Prescription has been on the provision of creative activities for people with mental health needs. This Arts on Prescription program, however, targeted community‐dwelling older people with a wide range of health and wellness needs. Older people were referred to the program by their healthcare practitioner. Professional artists led courses in visual arts, photography, dance and movement, drama, singing, or music. Classes were held weekly for 8–10 weeks, with six to eight participants per class, and culminated with a showing of work or a performance. Program evaluation involved pre‐ and postcourse questionnaires, and focus groups and individual interviews. Evaluation data on 127 participants aged 65 years and older were available for analysis. We found that Arts on Prescription had a positive impact on participants. Quantitative findings revealed a statistically significant improvement in the Warwick–Edinburgh Mental Well‐being Scale(WEMWBS) as well as a statistically significant increase in the level of self‐reported creativity and frequency of creative activities. Qualitative findings indicated that the program provided challenging artistic activities which created a sense of purpose and direction, enabled personal growth and achievement, and empowered participants, in a setting which fostered the development of meaningful relationships with others. This evaluation adds to the evidence base in support of Arts on Prescription by expanding the application of the model to older people with a diverse range of health and wellness needs

Cricket, migration and diasporic communities

Ever since different communities began processes of global migration, sport has been an integral feature in how we conceptualise and experience the notion of being part of a diaspora. Sport provides diasporic communities with a powerful means for creating transnational ties, but also shapes ideas of their ethnic and racial identities. In spite of this, theories of diaspora have been applied sparingly to sporting discourses. Due mainly to its central role in spreading dominant white racial narratives within the British Empire, and the various ways different ethnic groups have ‘played’ with the meanings and associations of the sport in the (post-)colonial period, cricket is an interesting focus for academic research. Despite W.G. Grace’s claim that cricket advances civilisation by promoting a common bond, binding together peoples of vastly different backgrounds, to this day cricket operates strict symbolic boundaries; defining those who do, and equally, do not belong. C.L.R. James’ now famous metaphor of looking ‘beyond the boundary’ captures the belief that, to fully understand the significance of cricket, and the sport’s roles in changing and shaping society, one must consider the wider social and political contexts within which the game is played. The collection of papers in this special issue does just that. Cricket acts as the point of departure in each, but the way in which ideas of power, representation and inequality are ‘played out’ is unique in each

Ultra-short pulses in linear and nonlinear media

We consider the evolution of ultra-short optical pulses in linear and nonlinear media. For the linear case, we first show that the initial-boundary value problem for Maxwell's equations in which a pulse is injected into a quiescent medium at the left endpoint can be approximated by a linear wave equation which can then be further reduced to the linear short-pulse equation. A rigorous proof is given that the solution of the short pulse equation stays close to the solutions of the original wave equation over the time scales expected from the multiple scales derivation of the short pulse equation. For the nonlinear case we compare the predictions of the traditional nonlinear Schr\"odinger equation (NLSE) approximation which those of the short pulse equation (SPE). We show that both equations can be derived from Maxwell's equations using the renormalization group method, thus bringing out the contrasting scales. The numerical comparison of both equations to Maxwell's equations shows clearly that as the pulse length shortens, the NLSE approximation becomes steadily less accurate while the short pulse equation provides a better and better approximation