Elucidating the interactions between the adhesive and transcriptioanl functions of beta-catenin in normal and cancerous cells

Wnt signalling is involved in a wide range of physiological and pathological processes. The presence of an extracellular Wnt stimulus induces cytoplasmic stabilisation and nuclear translocation of beta-catenin, a protein that also plays an essential role in cadherin-mediated adhesion. Two main hypotheses have been proposed concerning the balance between beta-catenin's adhesive and transcriptional functions: either beta-catenin's fate is determined by competition between its binding partners, or Wnt induces folding of beta-catenin into a conformation allocated preferentially to transcription. The experimental data supporting each hypotheses remain inconclusive. In this paper we present a new mathematical model of the Wnt pathway that incorporates beta-catenin's dual function. We use this model to carry out a series of in silico experiments and compare the behaviour of systems governed by each hypothesis. Our analytical results and model simulations provide further insight into the current understanding of Wnt signalling and, in particular, reveal differences in the response of the two modes of interaction between adhesion and signalling in certain in silico settings. We also exploit our model to investigate the impact of the mutations most commonly observed in human colorectal cancer. Simulations show that the amount of functional APC required to maintain a normal phenotype increases with increasing strength of the Wnt signal, a result which illustrates that the environment can substantially influence both tumour initiation and phenotype.

The Virtual International Stroke Trials Archive

Background and Purpose - Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. Methods - Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. Results - ”Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on 15 000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 6912 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials. Conclusions - This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning. (Stroke. 2007;38:1905-1910.)

Are we teaching our students what they need to know about ageing? Results from the National Survey of Undergraduate Teaching in Ageing and Geriatric Medicine

Introduction - Learning about ageing and the appropriate management of older patients is important for all doctors. This survey set out to evaluate what medical undergraduates in the UK are taught about ageing and geriatric medicine and how this teaching is delivered. Methods – An electronic questionnaire was developed and sent to the 28/31 UK medical schools which agreed to participate. Results – Full responses were received from 17 schools. 8/21 learning objectives were recorded as taught, and none were examined, across every school surveyed. Elder abuse and terminology and classification of health were taught in only 8/17 and 2/17 schools respectively. Pressure ulcers were taught about in 14/17 schools but taught formally in only 7 of these and examined in only 9. With regard to bio- and socio- gerontology, only 9/17 schools reported teaching in social ageing, 7/17 in cellular ageing and 9/17 in the physiology of ageing. Discussion – Even allowing for the suboptimal response rate, this study presents significant cause for concern with UK undergraduate education related to ageing. The failure to teach comprehensively on elder abuse and pressure sores, in particular, may be significantly to the detriment of older patients.