Can we accurately report PTEN status in advanced colorectal cancer?

BACKGROUND: Loss of phosphatase and tensin homologue (PTEN) function evaluated by loss of PTEN protein expression on immunohistochemistry (IHC) has been reported as both prognostic in metastatic colorectal cancer and predictive of response to anti-EGFR monoclonal antibodies although results remain uncertain. Difficulties in the methodological assessment of PTEN are likely to be a major contributor to recent conflicting results. METHODS: We assessed loss of PTEN function in 51 colorectal cancer specimens using Taqman® copy number variation (CNV) and IHC. Two blinded pathologists performed independent IHC assessment on each specimen and inter-observer variability of IHC assessment and concordance of IHC versus Taqman® CNV was assessed. RESULTS: Concordance between pathologists (PTEN loss vs no loss) on IHC assessment was 37/51 (73%). In specimens with concordant IHC assessment, concordance between IHC and Taqman® copy number in PTEN loss assessment was 25/37 (68%). CONCLUSION: Assessment PTEN loss in colorectal cancer is limited by the inter-observer variability of IHC, and discordance of CNV with loss of protein expression. An understanding of the genetic mechanisms of PTEN loss and implementation of improved and standardized methodologies of PTEN assessment are required to clarify the role of PTEN as a biomarker in colorectal cancer

Characterisation of GLUT4 trafficking in HeLa cells: comparable kinetics and orthologous trafficking mechanisms to 3T3-L1 adipocytes

Insulin-stimulated glucose transport is a characteristic property of adipocytes and muscle cells and involves the regulated delivery of glucose transporter (GLUT4)-containing vesicles from intracellular stores to the cell surface. Fusion of these vesicles results in increased numbers of GLUT4 molecules at the cell surface. In an attempt to overcome some of the limitations associated with both primary and cultured adipocytes, we expressed an epitope- and GFP-tagged version of GLUT4 (HA–GLUT4–GFP) in HeLa cells. Here we report the characterisation of this system compared to 3T3-L1 adipocytes. We show that insulin promotes translocation of HA–GLUT4–GFP to the surface of both cell types with similar kinetics using orthologous trafficking machinery. While the magnitude of the insulin-stimulated translocation of GLUT4 is smaller than mouse 3T3-L1 adipocytes, HeLa cells offer a useful, experimentally tractable, human model system. Here, we exemplify their utility through a small-scale siRNA screen to identify GOSR1 and YKT6 as potential novel regulators of GLUT4 trafficking in human cells

‘You just have to work with what you’ve got’ Practitioner research with precarious migrant families

This is an accepted manuscript of an article published by Taylor and Francis in Practice on 09/10/2017, available online: https://doi.org/10.1080/09503153.2017.1385756 The accepted version of the publication may differ from the final published version.Undocumented migrant families experience high levels of food poverty, exclusion from mainstream benefits, and sometimes from social work services. This is an under-researched area for social work in the UK, and there is no statutory guidance for social workers on supporting undocumented migrants. Practitioner research is one way of ‘visibilising’ their experiences. Six migrant families accessing a voluntary sector stay and play project were interviewed using a practitioner research model of semi-structured interviews on the themes of food, access to services and children. The research found that families responded to their situation with a seemingly contradictory strategy of resignation and resilience. The implications for practitioners working with this user group are considered, and suggestions for support services for this group of families are offered

Parental psychopathology, adult attachment and risk of 12-month suicidal behaviours

Background: The mechanisms by which parental psychopathology and vulnerability to suicide is transmitted to offspring is not well understood. parental psychopathology and behaviour may impact upon the normal emotional and psychological adjustment of their offspring in various ways. Research shows attachment insecurities may also be a key factor in the facilitation of suicidal behaviours. Objective: To examine adult attachment insecurities as a potential mediating pathway between parental psychopathology and 12- month suicidality. Method: The study utilized data from the National co-morbidity Survey- Replication (NCS-R, N=5692). Parental psychopathology was assessed using items from the Familial History of Psychiatric Disorders section of the NSC-R in conjunction with items designed to capture dimensions of attachment and suicidal behaviours. Results: Resultant analyses demonstrated specificity effects in that, parental psychopathology was associated with specific suicidal components through specific dimensions of attachment. Discussion: The results align with literature linking parental psychopathology to both attachment insecurities and risk of suicide. Crucially, this study bridges these research areas by presenting attachment insecurity as possible risk indicator and intervening factor between parental mental health and behaviour and specific indicators of suicide

Genomic Evolution Shapes Prostate Cancer Disease Type

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression

UK-SCAPE flux tower network: monitoring terrestrial greenhouse gas, water and energy balance

To predict, assess and mitigate the impacts of anthropogenic climate change, it is essential to (i) understand the drivers and dynamics of terrestrial carbon sequestration, greenhouse gas (GHG) emission and energy balance at site scale; and (ii) to deploy standardised observation networks to quantify flux variability in space and time. Under UK-SCAPE, CEH continuously monitors long-term GHG, water and energy balance across a network of eddy covariance (EC) sites using harmonised protocols, data processing and quality assurance

Genomic evolution shapes prostate cancer disease type

H.R.F. was supported by a Cancer Research UK Programme Grant to Simon Tavaré (C14303/A17197), as, partially, was A.G.L. A.G.L. acknowledges the support of the University of St Andrews. A.G.L. and J.H.R.F. also acknowledge the support of the Cambridge Cancer Research Fund.The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Aalternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.Peer reviewe

Methane emissions from soils: synthesis and analysis of a large UK data set

Nearly 5000 chamber measurements of CH4 flux were collated from 21 sites across the UK, covering a range of soil and vegetation types, to derive a parsimonious model that explains as much of the variability as possible, with the least input requirements. Mean fluxes ranged from -0.3 to 27.4 nmol CH4 m−2 s−1, with small emissions or low rates of net uptake in mineral soils (site means of -0.3 to 0.7 nmol m−2 s−1) and much larger emissions from organic soils (site means of -0.3 to 27.4 nmol m−2 s−1). Less than half of the observed variability in instantaneous fluxes could be explained by independent variables measured. The reasons for this include measurement error, stochastic processes and, probably most importantly, poor correspondence between the independent variables measured and the actual variables influencing the processes underlying methane production, transport and oxidation. When temporal variation was accounted for, and the fluxes averaged at larger spatial scales, simple models explained up to ~75% of the variance in CH4 fluxes. Soil carbon, peat depth, soil moisture and pH together provided the best sub-set of explanatory variables. However, where plant species composition data were available, this provided the highest explanatory power. Linear and non-linear models generally fitted the data equally well, with the exception that soil moisture required a power transformation. To estimate the impact of changes in peatland water table on CH4 emissions in the UK, an emission factor of +0.4 g CH4 m−2 y−1 per cm increase in water table height was derived from the data

Observing America: what mass-observation reveals about British views of the USA

Since its foundation in 1937, the social research organisation Mass-Observation has systematically documented the opinions of a British public experiencing profound societal change. This includes the most extensive data available on grassroots attitudes towards the USA, from the outbreak of the Second World War to the final phase of the Cold War. Most of the scholarship on Anglo-American relations focuses on the political and diplomatic elites of Britain and the USA. The extent to which their interaction reflected and reinforced public opinion is seldom considered. This article uses the Mass-Observation archive to situate elite interaction within the broader context of public opinion. In so doing, it assesses the extent to which British political leaders have in their dealings with the USA represented the views of the electorate they serve