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.

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.

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.

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.

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.

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.

Expression of stromal genes associated with the angiogenic response are not differentiated between human tumour xenografts with divergent vascular morphologies.

Human tumour xenografts have commonly been used to explore the mechanisms of tumour angiogenesis and the interaction of tumour cells with their microenvironment, as well as predict potential utility of anti-angiogenic inhibitors across different tumour types. To investigate how well human tumour xenografts can be used to differentiate the effects of stromal targeting agents we performed a comparative assessment of the murine angiogenic response across a panel of pre-clinical tumour xenografts. By analysing a panel of 22 tumour xenografts with a range of vascular morphologies, micro-vessel densities and levels of fibroblast and inflammatory infiltrate, we have examined the relationship between angiogenic stroma and human tumour models. These models were studied using a combination of immunohistochemistry and species specific mRNA profiling to differentiate the tumour and stromal transcript mRNA profiles. Principal Component Analysis (PCA) and regression analysis was used to investigate the transcriptional relationships between the individual models and the correlation with the stromal architecture. We found the human tumour cell expressed factors to be independent of the murine host responses such as microvessel density, and fibroblast or macrophage cellular infiltrate. Moreover mRNA profiling of the mouse stroma suggested that the host response to the different tumours was relatively uniform despite differences in stromal structures within the tumour. Supporting this, models with different stromal compositions responded similarly to cediranib, a small molecule inhibitor of VEGF signalling. The data indicate that although the angiogenic response to the tumour results in reproducible stromal architectures, these responses are not differentiated at the level of gene expression.

The effects of acculturation on obesity rates in ethnic minorities in England: evidence from the Health Survey for England.

OBJECTIVES: To investigate the extent of generational differences in adult health-related lifestyles and socio-economic circumstances, and explore whether these differences might explain changing patterns of obesity in ethnic minorities in England. METHODS: Seven ethnic minority groups were selected from the ethnically boosted 1999 and 2004 Health Survey for England (Indian n = 1580; Pakistani n = 1858; Bangladeshi n = 1549; Black Caribbean n = 1472; Black African n = 587; Chinese n = 1559; and Irish n = 889). Age and sex adjusted odds of being obese in the second generation when compared with the first were estimated before and after adjusting for generational differences in health-related behaviours (snacking, eating cakes and fried foods, low levels of physical exercise, any drinking, current smoker, etc.) and socio-economic factors (social class, equivalized income and highest qualification). RESULTS: Indian [OR: 1.76 (1.14-2.71)] and Chinese [OR: 3.65 (1.37-9.78)] groups were more likely to be obese in the second generation than the first after adjusting for age and sex, with no significant differences observed in all other groups. However, the risk of obesity in all groups converged between generations to the risk observed in the White reference group, with exception to the Black Caribbean group. Adjusting independently for the mixed patterns of acculturative changes and the uniform upward social mobility in all groups increased the risk of obesity in the second generation. CONCLUSIONS: Obesity converged to the risk in the majority population following acculturation. Future research needs to consider generation and trans-cultural identities as a fundamental variable in determining the causes of ethnic health inequalities.

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.

Ion and liquid dependent dielectric failure in electrowetting systems.

Electrowetting devices often utilize aqueous solutions with ionic surfactants and inorganic salts to modify the electrowetting response. It has been observed in low-voltage electrowetting devices (thin dielectric, <12 V) that a frequent onset of dielectric failure (electrolysis) occurs with use of ionic solutes such as potassium chloride (KCl) or sodium dodecyl sulfate. More detailed current-voltage investigations reveal less dielectric failure for the larger size ions. Specifically, improved resistance to failure is seen for surfactant ions carrying a long alkane chain. Therefore, a catanionic surfactant (in which both ions are amphiphilic) was custom synthesized, and elimination of dielectric failure was observed in both negative and positive voltage. Because water is a small molecule that easily penetrates dielectrics, further experiments were performed to show that dielectric failure can also be eliminated by use of larger size polar molecules such as propylene glycol. In addition to these results, important parameters such as conductivity and interfacial tensions are reported.

Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in Apc(Min/+) mice.

Both the epidermal growth factor (EGF) and the vascular endothelial growth factor (VEGF) pathways are associated with intestinal cancer, and therapeutic approaches targeting either EGF receptor (EGFR) or VEGF receptor (VEGFR) signaling have recently been approved for patients with advanced colorectal cancer. The Apc(Min/+) mouse is a well-characterized in vivo model of intestinal tumorigenesis, and animals with this genetic mutation develop macroscopically detectable adenomas from approximately 6 weeks of age. Previous work in the Apc(Min/+) mouse has shown that therapeutic approaches targeting either VEGFR or EGFR signaling affect predominantly the size or number of adenomas, respectively. In this study, we have assessed the effect of inhibiting both these key pathways simultaneously using ZD6474 (Vandetanib, ZACTIMA), a selective inhibitor of VEGFR and EGFR tyrosine kinases. To assess the effects of ZD6474 on early- and later-stage disease, treatment was initiated in 6- and 10-week-old Apc(Min/+) mice for 28 days. ZD6474 markedly reduced both the number and the size of polyps when administered at either an early or a later stage of polyp development. This reduction in both adenoma number and size resulted in a total reduction in tumor burden in the small intestine of nearly 75% in both studies (P < 0.01). The current data build on the concept that EGFR-dependent tumor cell proliferation and VEGF/VEGFR2-dependent angiogenesis and survival are distinct key mechanisms in polyp development. Pharmacologic inhibition of both signaling pathways has significant antitumor effects at both early and late stages of polyp development. Therefore, targeting both VEGFR- and EGFR-dependent signaling may be a beneficial strategy in early intestinal cancer.

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.

Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor AZD2171 in Calu-6 human lung tumor xenografts.

The vascular endothelial growth factor-A (VEGF-A) signaling pathway, a key stimulant of solid tumor vascularization, is primarily dependent on the activation of the endothelial cell surface receptor VEGF receptor-2 (VEGFR-2). AZD2171 is an oral, highly potent small-molecule inhibitor of VEGFR tyrosine kinase activity that inhibits angiogenesis and the growth of human tumor xenografts in vivo. Here, we show pharmacodynamic changes in VEGFR-2 phosphorylation induced by AZD2171. In mouse lung tissue, a single dose of AZD2171 at 6 mg/kg inhibited VEGF-A-stimulated VEGFR-2 phosphorylation by 87% at 2 h with significant inhibition (>or=60%) maintained to 24 h. To examine inhibition of VEGFR-2 phosphorylation in tumor vasculature by immunohistochemistry, a comprehensive assessment of antibodies to various phosphorylation sites on the receptor was undertaken. Antibodies to the phosphotyrosine epitopes pY1175/1173 and pY1214/1212 were found suitable for this application. Calu-6 human lung tumor xenografts, from mice receiving AZD2171 or vehicle treatment (p.o., once daily), were examined by immunohistochemistry. A significant reduction in tumor vessel staining of phosphorylated VEGFR-2 (pVEGFR-2) was evident within 28 h of AZD2171 treatment (6 mg/kg). This effect preceded a significant reduction in tumor microvessel density, which was detectable following 52 h of AZD2171 treatment. These data show that AZD2171 is a potent inhibitor of VEGFR-2 activation in vivo and suggest that AZD2171 delivers therapeutic benefit in Calu-6 tumors by targeting vessels dependent on VEGFR-2 signaling for survival. In addition, this work highlights the utility of measuring either pY1175/1173 or pY1214/1212 on VEGFR-2 as a pharmacodynamic marker of VEGFR-2 activation.

AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer.

Inhibition of vascular endothelial growth factor-A (VEGF) signaling is a promising therapeutic approach that aims to stabilize the progression of solid malignancies by abrogating tumor-induced angiogenesis. This may be accomplished by inhibiting the kinase activity of VEGF receptor-2 (KDR), which has a key role in mediating VEGF-induced responses. The novel indole-ether quinazoline AZD2171 is a highly potent (IC50 < 1 nmol/L) ATP-competitive inhibitor of recombinant KDR tyrosine kinase in vitro. Concordant with this activity, in human umbilical vein endothelial cells, AZD2171 inhibited VEGF-stimulated proliferation and KDR phosphorylation with IC50 values of 0.4 and 0.5 nmol/L, respectively. In a fibroblast/endothelial cell coculture model of vessel sprouting, AZD2171 also reduced vessel area, length, and branching at subnanomolar concentrations. Once-daily oral administration of AZD2171 ablated experimental (VEGF-induced) angiogenesis in vivo and inhibited endochondral ossification in bone or corpora luteal development in ovary; physiologic processes that are highly dependent upon neovascularization. The growth of established human tumor xenografts (colon, lung, prostate, breast, and ovary) in athymic mice was inhibited dose-dependently by AZD2171, with chronic administration of 1.5 mg per kg per day producing statistically significant inhibition in all models. A histologic analysis of Calu-6 lung tumors treated with AZD2171 revealed a reduction in microvessel density within 52 hours that became progressively greater with the duration of treatment. These changes are indicative of vascular regression within tumors. Collectively, the data obtained with AZD2171 are consistent with potent inhibition of VEGF signaling, angiogenesis, neovascular survival, and tumor growth. AZD2171 is being developed clinically as a once-daily oral therapy for the treatment of cancer.

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.

Agile wide-angle beam steering with electrowetting microprisms.

A novel basis for beam steering with electrowetting microprisms (EMPs) is reported. EMPs utilize electrowetting modulation of liquid contact angle in order to mimic the refractive behavior for various classical prism geometries. Continuous beam steering through an angle of 14 degrees (+/-7 degrees ) has been demonstrated with a liquid index of n=1.359. Experimental results are well-matched to theoretical behavior up to the point of electrowetting contact-angle saturation. Projections show that use of higher index liquids (n~1.6) will result in steering through ~30 degrees (+/-15 degrees ). Fundamental factors defining achievable deflection range, and issues for Ladar use, are reviewed. This approach is capable of good switching speed (~ms), polarization independent operation, modulation of beam field-of-view (lensing), and high steering efficiency that is independent of deflection angle.

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.

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.

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.