Adolescent mental health difficulties and educational attainment: findings from the UK household longitudinal study.

OBJECTIVE: This study examines whether there is an independent association between mental difficulties in adolescence and educational attainment at age 16. DESIGN: Longitudinal study. SETTING: Nationally representative data from the UK Household Longitudinal Study (UKHLS) were linked to the National Pupil Database for England. PARTICIPANTS: Respondents (N=1100) to the UKHLS between 2009 and 2012 were linked to the National Pupil Database to investigate longitudinal associations between mental difficulties at ages 11-14 and educational attainment at age 16 (General Certificate of Secondary Education (GCSE)). PRIMARY OUTCOME MEASURE: Not gaining five or more GCSE qualifications at age 16, including English and maths at grade A*-C. RESULTS: An atypical total mental health difficulty score measured using the Strengths and Difficulties Questionnaire at ages 11-14 predicted low levels of educational attainment at age 16 (OR: 3.11 (95% CI: (2.11 to 4.57)). Controlling for prior attainment and family sociodemographic factors, happiness with school (/work) and parental health, school engagement and relationship with the child partially attenuated the association, which was significant in the fully adjusted model (2.05, 95% CI (1.15 to 3.68)). The association was maintained in the fully adjusted model for males only (OR: 2.77 (95% CI (1.24 to 6.16)) but not for females. Hyperactivity disorder strongly predicted lower attainment for males (OR: 2.17 (95% CI: (1.11 to 4.23)) and females (OR: 2.85 (95% CI (1.30 to 6.23)). CONCLUSION: Mental difficulties at ages 11-14 were independently linked to educational success at age 16, highlighting an important pathway through which health in adolescence can determine young people's life chances.

Does the neighborhood food environment contribute to ethnic inequalities in fast-food intake? findings from the ORiEL study.

The neighborhood food environment may contribute to ethnic inequalities in diet. Using data from 1389 participants in the Olympic Regeneration in East London (UK) study we assessed whether ethnic inequalities in neighborhood availability of fast-food restaurants mediated and/or modified ethnic inequalities in fast-food intake in 13-15 year-old adolescents. We compared the proportion of high fast-food consumers across "White UK", "Black", and "South Asian" ethnic categories. We used Poisson regression with robust standard errors to assess direct and indirect effects (mediation analysis) and risk ratios of high fast-food intake by ethnic category and fast-food restaurant availability level (effect measure modification analysis). There were ethnic inequalities in high fast-food intake, with risk ratios in adolescents of Black and South Asian background of 1.53 (95% CI: 1.25, 1.87) and 1.71 (95% CI: 1.41, 2.07) respectively compared to White UK participants. We found no evidence of a mediating effect by fast-food restaurant availability, but found some evidence of effect measure modification: ethnic inequalities in fast-food intake were largest in neighborhoods lacking fast-food restaurants, and narrowed as availability increased. Future research should explore why ethnic minorities are more likely to be high fast-food consumers than the majority ethnic group, especially when fast-food restaurant availability is lowest.

Associations between home and school neighbourhood food environments and adolescents' fast-food and sugar-sweetened beverage intakes: findings from the Olympic Regeneration in East London (ORiEL) Study.

OBJECTIVE: To examine associations between availability of fast-food restaurants and convenience stores in the home and school neighbourhoods, considered separately and together, and adolescents' fast-food and sugar-sweetened beverage (SSB) intakes. DESIGN: Cross-sectional observational study. SETTING: East London, UK. SUBJECTS: Adolescents (n 3089; aged 13-15 years) from the Olympic Regeneration in East London (ORiEL) Study self-reported their weekly frequency of fast-food and SSB consumption. We used food business addresses collected from local authority registers to derive absolute (counts) and relative (proportions) exposure measures to fast-food restaurants and convenience stores within 800 m from home, school, and home and school combined. Associations between absolute and relative measures of the food environment and fast-food and SSB intakes were assessed using Poisson regression models with robust standard errors. RESULTS: Absolute exposure to fast-food restaurants or convenience stores in the home, school, or combined home and school neighbourhoods was not associated with any of the outcomes. High SSB intake was associated with relative exposure to convenience stores in the residential neighbourhood (risk ratio=1·45; 95 % CI 1·08, 1·96) and in the home and school neighbourhoods combined (risk ratio=1·69; 95 % CI 1·11, 2·57). CONCLUSIONS: We found no evidence of an association between absolute exposure to fast-food restaurants and convenience stores around home and school and adolescents' fast-food and SSB intakes. Relative exposure, which measures the local diversity of the neighbourhood food environment, was positively associated with SSB intake. Relative measures of the food environment may better capture the environmental risks for poor diet than absolute measures.

A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers.

Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in FGFR1-amplified SQCLC cell lines and patient-derived xenografts.Experimental Design: On the basis of these data, we performed a phase I study of AZD4547 in patients with previously treated stage IV FGFR1-amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses.Results: Fifteen FGFR1-amplified patients were treated. The most common related adverse events (AE) were gastrointestinal and dermatologic. Grade ≥3-related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). Two of 15 patients (13.3%) were progression-free at 12 weeks, and the median overall survival was 4.9 months. Molecular tests, including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry, showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in 8p11 amplicon.Conclusions: AZD4547 was tolerable at a dosage of 80 mg oral twice a day, with modest antitumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational covariates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease. Clin Cancer Res; 23(18); 5366-73. ©2017 AACR.

The Local Food Environment and Fruit and Vegetable Intake: A Geographically Weighted Regression Approach in the ORiEL Study.

Studies that explore associations between the local food environment and diet routinely use global regression models, which assume that relationships are invariant across space, yet such stationarity assumptions have been little tested. We used global and geographically weighted regression models to explore associations between the residential food environment and fruit and vegetable intake. Analyses were performed in 4 boroughs of London, United Kingdom, using data collected between April 2012 and July 2012 from 969 adults in the Olympic Regeneration in East London Study. Exposures were assessed both as absolute densities of healthy and unhealthy outlets, taken separately, and as a relative measure (proportion of total outlets classified as healthy). Overall, local models performed better than global models (lower Akaike information criterion). Locally estimated coefficients varied across space, regardless of the type of exposure measure, although changes of sign were observed only when absolute measures were used. Despite findings from global models showing significant associations between the relative measure and fruit and vegetable intake (ß = 0.022; P < 0.01) only, geographically weighted regression models using absolute measures outperformed models using relative measures. This study suggests that greater attention should be given to nonstationary relationships between the food environment and diet. It further challenges the idea that a single measure of exposure, whether relative or absolute, can reflect the many ways the food environment may shape health behaviors.

Longitudinal Associations Between Cyberbullying Involvement and Adolescent Mental Health.

PURPOSE: Cyberbullying differs from face-to-face bullying and may negatively influence adolescent mental health, but there is a lack of definitive research on this topic. This study examines longitudinal associations between cyberbullying involvement and adolescent mental health. METHODS: Participants were 2,480 teenagers taking part in the Olympic Regeneration in East London study. We collected information from participants when they were 12-13 years old and again 1 year later to examine links between involvement in cyberbullying and future symptoms of depression and social anxiety, and mental well-being. RESULTS: At baseline, 14% reported being cybervictims, 8% reported being cyberbullies, and 20% reported being cyberbully-victims in the previous year. Compared to uninvolved adolescents, cybervictims and cyberbully-victims were significantly more likely to report symptoms of depression (cybervictims: odds ratio [OR] = 1.44, 95% confidence interval [CI] [1.00, 2.06]; cyberbully-victims: OR = 1.54, 95% CI [1.13, 2.09]) and social anxiety (cybervictims: OR = 1.52, 95% CI [1.11, 2.07]; cyberbully-victims: OR = 1.44, 95% CI [1.10, 1.89]) but not below average well-being (cybervictims: relative risk ratio = 1.28, 95% CI [.86, 1.91]; cyberbully-victims: relative risk ratio = 1.38, 95% CI [.95, 1.99]) at 1 year follow-up, after adjustment for confounding factors including baseline mental health. CONCLUSIONS: This study emphasizes the high prevalence of cyberbullying and the potential of cybervictimization as a risk factor for future depressive symptoms, social anxiety symptoms, and below average well-being among adolescents. Future research should identify protective factors and possible interventions to reduce adolescent cyberbullying.

ATM protein is deficient in over 40% of lung adenocarcinomas.

Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year.

High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.

UNLABELLED: FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy. SIGNIFICANCE: Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients. Cancer Discov; 6(8); 838-51. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.

Characterization of FGFR1 Locus in sqNSCLC Reveals a Broad and Heterogeneous Amplicon.

FGFR1 amplification occurs in ~20% of sqNSCLC and trials with FGFR inhibitors have selected FGFR1 amplified patients by FISH. Lung cancer cell lines were profiled for sensitivity to AZD4547, a potent, selective inhibitor of FGFRs 1-3. Sensitivity to FGFR inhibition was associated with but not wholly predicted by increased FGFR1 gene copy number. Additional biomarker assays evaluating expression of FGFRs and correlation between amplification and expression in clinical tissues are therefore warranted. We validated nanoString for mRNA expression analysis of 194 genes, including FGFRs, from clinical tumour tissue. In a panel of sqNSCLC tumours 14.4% (13/90) were FGFR1 amplified by FISH. Although mean FGFR1 expression was significantly higher in amplified samples, there was significant overlap in the range of expression levels between the amplified and non-amplified cohorts with several non-amplified samples expressing FGFR1 to levels equivalent to amplified samples. Statistical analysis revealed increased expression of FGFR1 neighboring genes on the 8p12 amplicon (BAG4, LSM1 and WHSC1L1) in FGFR1 amplified tumours, suggesting a broad rather than focal amplicon and raises the potential for codependencies. High resolution aCGH analysis of pre-clinical and clinical samples supported the presence of a broad and heterogeneous amplicon around the FGFR1 locus. In conclusion, the range of FGFR1 expression levels in both FGFR1 amplified and non-amplified NSCLC tissues, together with the breadth and intra-patient heterogeneity of the 8p amplicon highlights the need for gene expression analysis of clinical samples to inform the understanding of determinants of response to FGFR inhibitors. In this respect the nanoString platform provides an attractive option for RNA analysis of FFPE clinical samples.

Leptin, BMI, and a Metabolic Gene Expression Signature Associated with Clinical Outcome to VEGF Inhibition in Colorectal Cancer.

VEGF (vascular endothelial growth factor) signaling inhibitors are widely used in different cancer types; however, patient selection remains a challenge. Analyses of samples from a phase III clinical trial in metastatic colorectal cancer testing chemotherapy versus chemotherapy with the small molecule VEGF receptors inhibitor cediranib identified circulating leptin levels, BMI, and a tumor metabolic and angiogenic gene expression signature associated with improved clinical outcome in patients treated with cediranib. Patients with a glycolytic and hypoxic/angiogenic profile were associated with increased benefit from cediranib, whereas patients with a high lipogenic, oxidative phosphorylation and serine biosynthesis signature did not gain benefit. These findings translated to pre-clinical tumor xenograft models where the same metabolic gene expression profiles were associated with in vivo sensitivity to cediranib as monotherapy. These findings suggest a link between patient physiology, tumor biology, and response to antiangiogenics, which may guide patient selection for VEGF therapy in the future.

Ethnic differences in cognitive development in the first 7†years: does maternal generational status matter?

BACKGROUND: Differences in cognitive development have been observed across a variety of ethnic minority groups but relatively little is known about the persistence of these developmental inequalities over time or generations. METHODS: A repeat cross-sectional analysis assessed cognitive ability scores of children aged 3, 5 and 7 years from the longitudinal UK Millennium Cohort Study (white UK born n=7630; Indian n=248; Pakistani n=328; Bangladeshi n=87; black Caribbean n=172; and black African n=136). Linear regression estimated ethnic differences in age normed scores at each time point. Multivariable logistic regression estimated within-group generational differences in test scores at each age adjusting stepwise for sociodemographic factors, maternal health behaviours, indicators of the home learning environment and parenting styles. RESULTS: The majority of ethnic minority groups scored lower than the white UK born reference group at 3 years with these differences narrowing incrementally at ages 5 and 7 years. However, the black Caribbean group scored significantly lower than the white UK born reference group throughout early childhood. At 3 years, Pakistani, black Caribbean and black African children with UK born mothers had significantly higher test scores than those with foreign born mothers after baseline adjustment for maternal age and child gender. Controlling for social, behavioural and parenting factors attenuated this generational advantage. By 7 years there were no significant generational differences in baseline models. CONCLUSIONS: Ethnic differences in cognitive development diminish throughout childhood for the majority of groups. Cumulative exposure to the UK environment may be associated with higher cognitive development scores.

Complexity of FGFR signalling in metastatic urothelial cancer.

BACKGROUND: Urothelial cancers (UC) are the fourth most common tumours worldwide after prostate (or breast), lung and colorectal cancer. Despite recent improvements in their management, UC remain an aggressive disease associated with a poor outcome. Following disease progression on first-line platinum-based chemotherapy, very few effective treatment options are available and none of them have shown significant improvement in overall survival. Alterations of the fibroblast growth factor receptor (FGFR) pathway including amplification, mutations and overexpression are common in UC. Pre-clinical data suggest that the presence of such dysregulations may confer sensitivity to FGFR inhibitors. MATERIALS AND METHODS: We present here the case of a patient with a metastatic UC of the renal pelvis with lymph node metastases treated with the selective FGFR inhibitor AZD4547. RESULTS: To date, the patient has been on a study drug for 32 months with acceptable tolerance and maintained radiological partial response as per RECIST 1.1 criteria. Exploratory biomarker analysis showed FGFR3, FGFR1, FGF-ligand and fibroblast growth factor receptor substrate 2 (FRS2) expression in the patient's tumour, together with the presence of a germ-line mutation in the FGFR3 extracellular binding domain. This is not a known hotspot mutation, and the functional significance remains unclear. CONCLUSIONS: The FGFR inhibitor AZD4547 exhibits antitumour activity in a metastatic urothelial cancer displaying FGFR1, FGFR3, FGF-ligand and FRS2 expression. This lends support to the further exploration of FGFR inhibitors in urothelial cancer. Further studies are required to determinate the most effective way to select those patients most likely to respond.

The influence of social support on ethnic differences in well-being and depression in adolescents: findings from the prospective Olympic Regeneration in East London (ORiEL) study.

PURPOSE: This study examines the extent to which in adolescent positive mental well-being and depressive symptoms vary across ethnic groups, and prospectively examines whether social support is protective against low/poor well-being and depression. METHODS: A longitudinal survey of 2426 adolescents from the Olympic Regeneration in East London study measured well-being and depressive symptoms at baseline at ages 11-12 and at follow-up two years later at ages 13-14. Social support was assessed at ages 11-12 years by the Multidimensional Scale of Perceived Social Support, by the level of parental support for school, by the frequency of family activities and by friendship choices. Ethnic differences in well-being and depression in Bangladeshi (N = 337) and Black African (N = 249) adolescents compared to their White UK counterparts (N = 380) were estimated adjusted stepwise for socio-demographic factors and domains of social support. RESULTS: Black African and Bangladeshi adolescents scored significantly higher for well-being than their White UK counterparts. There were no significant ethnic differences in the prevalence of depressive symptoms. Lower levels of social support were prospectively associated with lower well-being and higher rates of depression in all ethnic groups. Adjustment for multiple domains of social support did not account for ethnic differences in well-being. CONCLUSION: Bangladeshi and Black African adolescents in East London may have a positive mental health advantage over their White UK counterparts though social support did not fully explain this difference. Further investigation of the reasons for lower well-being in the White UK group is needed.

Individual socio-demographic factors and perceptions of the environment as determinants of inequalities in adolescent physical and psychological health: the Olympic Regeneration in East London (ORiEL) study.

BACKGROUND: Populations living in urban areas experience greater health inequalities as well as higher absolute burdens of illness. It is well-established that a range of social and environmental factors determine these differences. Less is known about the relative importance of these factors in determining adolescent health within a super diverse urban context. METHODS: A cross-sectional sample of 3,105 adolescent participants aged 11 to 12 were recruited from 25 schools in the London boroughs of Newham, Tower Hamlets, Hackney and Barking & Dagenham. Participants completed a pseudo-anonymised paper-based questionnaire incorporating: the Warwick-Edinburgh Mental Well-being Scale used for assessing positive mental well-being, the Short Moods and Feelings Questionnaire based on the DSM III-R criteria for assessment of depressive symptoms, the Youth-Physical Activity Questionnaire and a self-assessment of general health and longstanding illness. Prevalence estimates and unadjusted linear models estimate the extent to which positive well-being scores and time spent in physical/sedentary activity vary by socio-demographic and environmental indicators. Logistic regression estimated the unadjusted odds of having fair/(very)poor general health, a long standing illness, or depressive symptoms. Fully adjusted mixed effects models accounted for clustering within schools and for all socio-demographic and environmental indicators. RESULTS: Compared to boys, girls had significantly lower mental well-being and higher rates of depressive symptoms, reported fewer hours physically active and more hours sedentary, and had poorer general health after full adjustment. Positive mental well-being was significantly and positively associated with family affluence but the overall relationship between mental health and socioeconomic factors was weak. Mental health advantage increased as positive perceptions of the neighbourhood safety, aesthetics, walkability and services increased. Prevalence of poor health varied by ethnic group, particularly for depressive symptoms, general health and longstanding illness suggesting differences in the distribution of the determinants of health across ethnic groups. CONCLUSIONS: During adolescence perceptions of the urban physical environment, along with the social and economic characteristics of their household, are important factors in explaining patterns of health inequality.

Mechanisms that influence tumour response to VEGF-pathway inhibitors.

There has been significant investment in developing novel therapies to target solid tumour vasculature. Different technical approaches have been utilized with the aim of inhibiting tumour angiogenesis or compromising the function or stability of pre-existing tumour blood vessels. The vascular endothelial growth factor (VEGF) signalling axis remains the most widely studied, with biological and small-molecule therapeutics now registered for clinical use. However, despite these successes, the activity of these agents is not as widespread as was first postulated. The present review discusses the clinical successes of the VEGF inhibitors, the factors that may limit their utility, and the potential opportunities to maximize benefit from treatment with these agents in the future.

A matrix approach to guide IHC-based tissue biomarker development in oncology drug discovery.

Immunohistochemistry (IHC) is a core platform for the analysis of tissue samples, and there is an increasing demand for reliable and quantitative IHC-based tissue biomarkers in oncology clinical research and development (R&D) environments. Biomarker assay and drug development proceed in parallel. Furthermore, biomarker assay requirements change with each phase of drug development. We have therefore developed a matrix tool to enable researchers to evaluate whether a particular IHC biomarker assay is fit for purpose. Experience gained from the development of 130 IHC biomarkers, supporting a large number of oncology drug projects, was used to formulate a practical approach to IHC assay development. The resultant matrix grid and accompanying work flow incorporates 16 core decision points that link antibody and assay specificity and sensitivity, and assay performance in preclinical and clinical samples, with stages of drug development. The matrix provides a means to ensure that relevant information on an IHC assay in development is recorded and communicated consistently and that minimum assay validation requirements are met.

Tumor stromal architecture can define the intrinsic tumor response to VEGF-targeted therapy.

PURPOSE: The aim of the study was to investigate the vascular and stromal architecture of preclinical tumor models and patient tumor specimens from malignancies with known clinical outcomes to VEGFi treatment, to gain insight into potential determinants of intrinsic sensitivity and resistance. EXPERIMENTAL DESIGN: The tumor stroma architecture of preclinical and clinical tumor samples were analyzed by staining for CD31 and α-smooth muscle actin (α-SMA). Tumor models representative of each phenotype were then tested for sensitivity to the VEGFR2-blocking antibody DC101. RESULTS: Human tumor types with high response rates to VEGF inhibitors (e.g., renal cell carcinoma) have vessels distributed amongst the tumor cells (a "tumor vessel" phenotype, TV). In contrast, those malignancies where single-agent responses are lower, such as non-small cell lung cancer (NSCLC), display a complex morphology involving the encapsulation of tumor cells within stroma that also supports the majority of vessels (a "stromal vessel" phenotype). Only 1 of 31 tumor xenograft models displayed the stromal vessel phenotype. Tumor vessel models were sensitive to VEGFR2-blocking antibody DC101, whereas the stromal vessel models were exclusively refractory. The tumor vessel phenotype was also associated with a better Response Evaluation Criteria in Solid Tumors (RECIST) response to bevacizumab + chemotherapy in metastatic colorectal cancer (CRC). CONCLUSION: The tumor stromal architecture can differentiate between human tumor types that respond to a VEGF signaling inhibitor as single-agent therapy. In addition to reconciling the clinical experience with these agents versus their broad activity in preclinical models, these findings may help to select solid tumor types with intrinsic sensitivity to a VEGFi or other vascular-directed therapies.

RNA-Seq Differentiates Tumour and Host mRNA Expression Changes Induced by Treatment of Human Tumour Xenografts with the VEGFR Tyrosine Kinase Inhibitor Cediranib.

Pre-clinical models of tumour biology often rely on propagating human tumour cells in a mouse. In order to gain insight into the alignment of these models to human disease segments or investigate the effects of different therapeutics, approaches such as PCR or array based expression profiling are often employed despite suffering from biased transcript coverage, and a requirement for specialist experimental protocols to separate tumour and host signals. Here, we describe a computational strategy to profile transcript expression in both the tumour and host compartments of pre-clinical xenograft models from the same RNA sample using RNA-Seq. Key to this strategy is a species-specific mapping approach that removes the need for manipulation of the RNA population, customised sequencing protocols, or prior knowledge of the species component ratio. The method demonstrates comparable performance to species-specific RT-qPCR and a standard microarray platform, and allowed us to quantify gene expression changes in both the tumour and host tissue following treatment with cediranib, a potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, including the reduction of multiple murine transcripts associated with endothelium or vessels, and an increase in genes associated with the inflammatory response in response to cediranib. In the human compartment, we observed a robust induction of hypoxia genes and a reduction in cell cycle associated transcripts. In conclusion, the study establishes that RNA-Seq can be applied to pre-clinical models to gain deeper understanding of model characteristics and compound mechanism of action, and to identify both tumour and host biomarkers.

The Olympic Regeneration in East London (ORiEL) study: protocol for a prospective controlled quasi-experiment to evaluate the impact of urban regeneration on young people and their families.

INTRODUCTION: Recent systematic reviews suggest that there is a dearth of evidence on the effectiveness of large-scale urban regeneration programmes in improving health and well-being and alleviating health inequalities. The development of the Olympic Park in Stratford for the London 2012 Olympic and Paralympic Games provides the opportunity to take advantage of a natural experiment to examine the impact of large-scale urban regeneration on the health and well-being of young people and their families. DESIGN AND METHODS: A prospective school-based survey of adolescents (11-12 years) with parent data collected through face-to-face interviews at home. Adolescents will be recruited from six randomly selected schools in an area receiving large-scale urban regeneration (London Borough of Newham) and compared with adolescents in 18 schools in three comparison areas with no equivalent regeneration (London Boroughs of Tower Hamlets, Hackney and Barking & Dagenham). Baseline data will be completed prior to the start of the London Olympics (July 2012) with follow-up at 6 and 18 months postintervention. Primary outcomes are: pre-post change in adolescent and parent mental health and well-being, physical activity and parental employment status. Secondary outcomes include: pre-post change in social cohesion, smoking, alcohol use, diet and body mass index. The study will account for individual and environmental contextual effects in evaluating changes to identified outcomes. A nested longitudinal qualitative study will explore families' experiences of regeneration in order to unpack the process by which regeneration impacts on health and well-being. ETHICS AND DISSEMINATION: The study has approval from Queen Mary University of London Ethics Committee (QMREC2011/40), the Association of Directors of Children's Services (RGE110927) and the London Boroughs Research Governance Framework (CERGF113). Fieldworkers have had advanced Criminal Records Bureau clearance. Findings will be disseminated through peer-reviewed publications, national and international conferences, through participating schools and the study website (http://www.orielproject.co.uk).