The prognostic and therapeutic value of EpHA2 in early colorectal cancer (CRC).

Background: EpHA2 is a 130 kD transmembrane glycoprotein belonging to ephrin receptor subfamily and involved in angiogenesis/tumour neovascularisation. High EpHA2 mRNA level has recently been implicated in cetuximab resistance. Previously, we found high EpHA2 levels in a panel of invasive colorectal cancer (CRC) cells, which was associated with high levels of stem-cell marker CD44. Our aim was to investigate the prognostic value of EpHA2 and subsequently correlate expression levels to known clinico-pathological variables in early stage CRC. Methods: Tissue samples from 509 CRC patients were analysed. EpHA2 expression was measured using IHC. Kaplan-Meier graphs were used. Univariate and multivariate analyses employed Cox Proportional Hazards Ratio (HR) method. A backward selection method (Akaike’s information criterion) was used to determine a refined multivariate model. Results: EpHA2 was highly expressed in CRC adenocarcinoma compared to matched normal colon tissue. In support of our preclinical invasive models, strong correlation was found between EpHA2 expression and CD44 and Lgr5 staining (p<0.001). In addition, high EpHA2 expression significantly correlated with vascular invasion (p=0.03).HR for OS for stage II/III patients with high EpHA2 expression was 1.69 (95%CI: 1.164-2.439; p=0.003). When stage II/III was broken down into individual stages, there was significant correlation between high EpHA2 expression and poor 5-years OS in stage II patients (HR: 2.18; 95%CI: 1.28-3.71; p=0.005).HR in the stage III group showed a trend to statistical significance (HR: 1.48; 95%CI=0.87-2.51; p=0.05). In both univariate and multivariate analyses of stage II patients, high EpHA2 expression was the only significant factor and was retained in the final multivariate model. Higher levels of EpHA2 were noted in our RAS and BRAF mutant CRC cells, and silencing EpHA2 resulted in significant decreases in migration/invasion in parental and invasive CRC sublines. Correlation between KRAS/NRAS/BRAFmutational status and EpHA2 expression in clinical samples is ongoing. Conclusions: Taken together, our study is the first to indicate that EpHA2 expression is a predictor of poor clinical outcome and a potential novel target in early stage CRC.

TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma

Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.

A novel method of microsatellite genotyping-by-sequencing using individual combinatorial barcoding

This study examines the potential of next-generation sequencing based ‘genotyping-by-sequencing’ (GBS) of microsatellite loci for rapid and cost-effective genotyping in large-scale population genetic studies. The recovery of individual genotypes from large sequence pools was achieved by PCR-incorporated combinatorial barcoding using universal primers. Three experimental conditions were employed to explore the possibility of using this approach with existing and novel multiplex marker panels and weighted amplicon mixture. The GBS approach was validated against microsatellite data generated by capillary electrophoresis. GBS allows access to the underlying nucleotide sequences that can reveal homoplasy, even in large datasets and facilitates cross laboratory transfer. GBS of microsatellites, using individual combinatorial barcoding, is potentially faster and cheaper than current microsatellite approaches and offers better and more data.

Validating the use of intrinsic markers in body feathers to identify inter‑individual differences in non‑breeding areas of northern fulmars

Many wildlife studies use chemical analyses to explore spatio-temporal variation in diet, migratory patterns and contaminant exposure. Intrinsic markers are particularly valuable for studying non-breeding marine predators, when direct methods of investigation are rarely feasible. However, any inferences regarding foraging ecology are dependent upon the time scale over which tissues such as feathers are formed. In this study, we validate the use of body feathers for studying non-breeding foraging patterns in a pelagic seabird, the northern fulmar. Analysis of carcasses of successfully breeding adult fulmars indicated that body feathers moulted between September and March, whereas analyses of carcasses and activity patterns suggested that wing feather and tail feather moult occurred during more restricted periods (September to October and September to January, respectively). By randomly sampling relevant body feathers, average values for individual birds were shown to be consistent. We also integrated chemical analyses of body feather with geolocation tracking data to demonstrate that analyses of δ13C and δ15N values successfully assigned 88 % of birds to one of two broad wintering regions used by breeding adult fulmars from a Scottish study colony. These data provide strong support for the use of body feathers as a tool for exploring non-breeding foraging patterns and diet in wide-ranging, pelagic seabirds.

Efficient Key Generation by Exploiting Randomness from Channel Responses of Individual OFDM Subcarriers

Key generation from the randomness of wireless channels is a promising technique to establish a secret cryptographic key securely between legitimate users. This paper proposes a new approach to extract keys efficiently from channel responses of individual orthogonal frequency-division multiplexing (OFDM) subcarriers. The efficiency is achieved by (i) fully exploiting randomness from time and frequency domains and (ii) improving the cross-correlation of the channel measurements. Through the theoretical modelling of the time and frequency autocorrelation relationship of the OFDM subcarrier's channel responses, we can obtain the optimal probing rate and use multiple uncorrelated subcarriers as random sources. We also study the effects of non-simultaneous measurements and noise on the cross-correlation of the channel measurements. We find the cross-correlation is mainly impacted by noise effects in a slow fading channel and use a low pass filter (LPF) to reduce the key disagreement rate and extend the system's working signal-to-noise ratio range. The system is evaluated in terms of randomness, key generation rate, and key disagreement rate, verifying that it is feasible to extract randomness from both time and frequency domains of the OFDM subcarrier's channel responses.

Verification of Key Generation from Individual OFDM Subcarrier's Channel Response

This paper presents a key generation system derived from the channel response of individual subcarrier in orthogonal frequency-division multiplexing (OFDM) systems. Practical aspects of the security were investigated by implementing our key generation scheme on a wireless open-access research platform (WARP), which enables us to obtain channel estimation of individual OFDM subcarriers, a feature not currently available in most commercial wireless interface cards. Channel response of individual OFDM subcarrier is usually a wide sense stationary random process, which allows us to find the optimal probing period and maximize the key generation rate. The implementation requires cross layer design as it involves interaction between physical and MAC layer. We have experimentally verified the feasibility and principles of key generation, and also evaluated the performance of our system in terms of randomness, key generation rate and key disagreement rate, which proves that OFDM subcarrier's channel responses are valid for key generation.

Quantification of the smoking-associated cancer risk with rate advancement periods: meta-analysis of individual participant data from cohorts of the CHANCES consortium

BACKGROUND: Smoking is the most important individual risk factor for many cancer sites but its association with breast and prostate cancer is not entirely clear. Rate advancement periods (RAPs) may enhance communication of smoking related risk to the general population. Thus, we estimated RAPs for the association of smoking exposure (smoking status, time since smoking cessation, smoking intensity, and duration) with total and site-specific (lung, breast, colorectal, prostate, gastric, head and neck, and pancreatic) cancer incidence and mortality.

METHODS: This is a meta-analysis of 19 population-based prospective cohort studies with individual participant data for 897,021 European and American adults. For each cohort we calculated hazard ratios (HRs) for the association of smoking exposure with cancer outcomes using Cox regression adjusted for a common set of the most important potential confounding variables. RAPs (in years) were calculated as the ratio of the logarithms of the HRs for a given smoking exposure variable and age. Meta-analyses were employed to summarize cohort-specific HRs and RAPs.

RESULTS: Overall, 140,205 subjects had a first incident cancer, and 53,164 died from cancer, during an average follow-up of 12 years. Current smoking advanced the overall risk of developing and dying from cancer by eight and ten years, respectively, compared with never smokers. The greatest advancements in cancer risk and mortality were seen for lung cancer and the least for breast cancer. Smoking cessation was statistically significantly associated with delays in the risk of cancer development and mortality compared with continued smoking.

CONCLUSIONS: This investigation shows that smoking, even among older adults, considerably advances, and cessation delays, the risk of developing and dying from cancer. These findings may be helpful in more effectively communicating the harmful effects of smoking and the beneficial effect of smoking cessation.

Fulminant hepatic failure: a Portuguese experience

BACKGROUND: Fulminant hepatic failure (FHF) is a rare condition. Several series have been reported either by individual centres or in multicentre studies but, to our knowledge, this is the first report from a Portuguese population and might be a good example of FHF cases in a SouthWestern European population. AIMS: To present the experience in FHF of a Portuguese Hepatogastroenterological Intensive Care Unit. MATERIALS AND METHODS: Retrospective study of 61 cases of FHF consecutively admitted between February 1992 and October 2006. Definition and classification of FHF were those suggested by Trey and Davidson (1970) and O'Grady et al. (1993), respectively. Criteria and contraindications for hepatic transplantation (HT) were those proposed by Bernuau et al. (1991) and Muñoz (1993), respectively. RESULTS: Fifty-seven per cent of patients were women and median age was 37 years (range: 8-73). Most common cause of FHF was indeterminate (26%) followed by viral (23%) and drug-induced (23%), with 51% of cases with a hyperacute evolution. Global HT rate was 54% with criteria for HT present in 87% of the patients resulting in an applicability rate of 62%. Overall survival was 69% and transplant-free survival was 15%; transplanted patients had survival rates of 70 and 68% at 6 and 12 months, respectively. CONCLUSIONS: Drug-induced and viral agents were responsible for almost half of FHF cases with a clear predominance of hyperacute presentation. The HT rate was 54% and the applicability rate was 62%. The overall 1 year survival of 69% might reflect the adequacy of the HT criteria used.

Níveis de actividade e participação das pessoas com afasia: desenvolvimento de instrumentos de avaliação portugueses

A International Classification of Functioning, Disability and Health (ICF) (WHO 2001) realça a necessidade dos profissionais de saúde considerarem, na intervenção que realizam com a pessoa, as possíveis consequências de uma doença em diferentes domínios, nomeadamente nas suas Funções e Estruturas do Corpo, nas suas Actividades diárias e na sua Participação em situações da vida real. Realça ainda a possível interferência dos Factores Contextuais neste processo. Em Portugal, os instrumentos existentes utilizados pelos terapeutas da fala (TFs) na sua prática clínica com pessoas com afasia (PCAs), não permitem avaliar estes domínios, o que poderá limitar uma intervenção mais alargada, que integre estas directivas. Pretendeu-se com este estudo efectuar a tradução e adaptação à língua portuguesa do Communication Disability Profile (CDP) (Swinburn and Byng 2006) e do Participation Objective Participation Subjective (POPS) (Brown, Dijkers et al. 2004), ambos desenvolvidos à luz da ICF, de modo a apetrechar os TFs do país, com instrumentos de avaliação que lhes permitam abordar os diferentes domínios referidos. Pretendeu-se ainda conhecer as reais necessidades de PCAs portuguesas, ou seja, efectuar um levantamento das consequências dos AVCs e da afasia na sua vida diária e verificar de que modo os instrumentos escolhidos permitem identificar com precisão estas necessidades. Foram envolvidos três grupos distintos de participantes, nomeadamente catorze PCAs, catorze familiares e amigos (F/A) e dez TFs, consultados em três fases distintas. Recorreu-se ao uso de diferentes métodos e instrumentos de recolha de dados, nomeadamente o brainstorming e o uso de entrevistas aprofundadas semiestruturadas, realizadas individualmente e em grupo. Construíram-se dois instrumentos de raiz (o TAPP e a GABF) que permitiram complementar os dados recolhidos junto das PCAs. A análise dos dados foi predominantemente qualitativa (Análise Temática). Da análise dos resultados obtidos nestas três fases, resultaram as primeiras versões portuguesas do CDP e do POPS. No que diz respeito às consequências dos AVCs e da afasia na vida diária das PCAs na componente das Funções e Estruturas do Corpo, os três grupos consideraram a categoria das Funções Mentais Especificas como sendo a mais perturbada. Relativamente à componente das Actividades/Participação, as consequências relatadas centram-se nas categorias das Interacções e Relacionamentos Pessoais, Vida Comunitária Social e Cívica e Áreas Principais da Vida. Quanto às Barreiras e Facilitadores, os TFs valorizam as Barreiras de Informação e as Barreiras Estruturais como as que mais interferem com a Participação social das PCAs, enquanto estas e os F/A valorizam os Factores Pessoais, as Barreiras Ambientais e as Barreiras Atitudinais. Os TFs realçam a importância de existirem “redes de suporte familiar” como Facilitadores. As PCAs e os F/A valorizam os Facilitadores Ambientais e os Facilitadores Atitudinais. No que diz respeito aos instrumentos em estudo, a maioria dos TFs assim como o grupo dos F/A considerou a apresentação visual do POPS e mais especificamente as escalas de notação usadas como sendo muito complexas, enquanto as PCAs envolvidas no estudo não fizeram qualquer referência ou crítica às mesmas. A maioria dos TFs considerou os itens do POPS como sendo relevantes para a população portuguesa com afasia. Contudo, metade destes mostrou preocupação com a ambiguidade de alguns dos seus itens e cerca de um terço considerou as instruções difíceis de compreender. As PCAs, assim como os F/A consideraram os itens do POPS, na sua generalidade, como sendo claros, relevantes e não ambíguos. A maioria dos TFs e dos F/A referem falta de clareza de algumas das imagens utilizadas no CDP. Contudo, o grupo das PCAs considera que estas são claras e facilitam a compreensão dos itens. Nenhum dos três grupos consultados fez referência ao tipo e tamanho de letra usada no CDP pelo que se considera ser adequada. A maior parte dos TFs não faz qualquer referência à falta de clareza dos itens do CDP, contudo metade considera alguns dos seus itens ambíguos e um terço questiona também a sua relevância. Os itens do CDP são considerados claros, relevantes e não ambíguos quer pelo grupo das PCAs quer pelo grupo dos F/A. Conclui-se que ambos os instrumentos vão, de uma forma geral, ao encontro das necessidades apresentadas pelas PCAs envolvidas no nosso estudo. Poderá afirmar-se também que estes mostraram ser ferramentas terapêuticas importantes para utilizar em Portugal. Contudo, ambos deixam a descoberto algumas áreas consideradas importantes pelos grupos envolvidos e pela literatura internacional, sugerindo-se a sua utilização simultânea de modo a poderem complementar-se, assim como o recurso a outras formas de avaliação disponíveis, no sentido de colmatar possíveis lacunas encontradas após a sua utilização. Sugere-se o desenvolvimento de investigações futuras que permitam o seu aperfeiçoamento.

Physical activity in deprived communities in London: examining individual and neighbourhood-level factors

Introduction: The objectives of this study were to examine relationships between neighbourhood-level and individual-level characteristics and physical activity in deprived London neighbourhoods. Methods: In 40 of the most deprived neighbourhoods in London (ranked in top 11% in London by Index of Multiple Deprivation) a cross-sectional survey (n = 4107 adults aged > = 16 years), neighbourhood audit tool, GIS measures and routine data measured neighbourhood and individual-level characteristics. The binary outcome was meeting the minimum recommended (CMO, UK) 5×30 mins moderate physical activity per week. Multilevel modelling was used to examine associations between physical activity and individual and neighbourhood-level characteristics. Results: Respondents living more than 300 m away from accessible greenspace had lower odds of achieving recommended physical activity levels than those who lived within 300 m; from 301–600 m (OR = 0.7; 95% CI 0.5–0.9) and from 601–900 m (OR = 0.6; 95% CI 0.4–0.8). There was substantial residual between-neighbourhood variance in physical activity (median odds ratio = 1.7). Other objectively measured neighbourhood-level characteristics were not associated with physical activity levels. Conclusions Distance to nearest greenspace is associated with meeting recommended physical activity levels in deprived London neighbourhoods. Despite residual variance in physical activity levels between neighbourhoods, we found little evidence for the influence of other measured neighbourhood-level characteristics.

Brain responses to audiovisual speech mismatch in infants are associated with individual differences in looking behaviour

Research on audiovisual speech integration has reported high levels of individual variability, especially among young infants. In the present study we tested the hypothesis that this variability results from individual differences in the maturation of audiovisual speech processing during infancy. A developmental shift in selective attention to audiovisual speech has been demonstrated between 6 and 9 months with an increase in the time spent looking to articulating mouths as compared to eyes (Lewkowicz & Hansen-Tift. (2012) Proc. Natl Acad. Sci. USA, 109, 1431–1436; Tomalski et al. (2012) Eur. J. Dev. Psychol., 1–14). In the present study we tested whether these changes in behavioural maturational level are associated with differences in brain responses to audiovisual speech across this age range. We measured high-density event-related potentials (ERPs) in response to videos of audiovisually matching and mismatched syllables /ba/ and /ga/, and subsequently examined visual scanning of the same stimuli with eye-tracking. There were no clear age-specific changes in ERPs, but the amplitude of audiovisual mismatch response (AVMMR) to the combination of visual /ba/ and auditory /ga/ was strongly negatively associated with looking time to the mouth in the same condition. These results have significant implications for our understanding of individual differences in neural signatures of audiovisual speech processing in infants, suggesting that they are not strictly related to chronological age but instead associated with the maturation of looking behaviour, and develop at individual rates in the second half of the first year of life.

Physical Activity in Deprived Communities in London: Examining Individual and Neighbourhood-Level Factors

Introduction The objectives of this study were to examine relationships between neighbourhood-level and individual-level characteristics and physical activity in deprived London neighbourhoods. Methods In 40 of the most deprived neighbourhoods in London (ranked in top 11% in London by Index of Multiple Deprivation) a cross-sectional survey (n = 4107 adults aged > = 16 years), neighbourhood audit tool, GIS measures and routine data measured neighbourhood and individual-level characteristics. The binary outcome was meeting the minimum recommended (CMO, UK) 5×30 mins moderate physical activity per week. Multilevel modelling was used to examine associations between physical activity and individual and neighbourhood-level characteristics. Results Respondents living more than 300 m away from accessible greenspace had lower odds of achieving recommended physical activity levels than those who lived within 300 m; from 301–600 m (OR = 0.7; 95% CI 0.5–0.9) and from 601–900 m (OR = 0.6; 95% CI 0.4–0.8). There was substantial residual between-neighbourhood variance in physical activity (median odds ratio = 1.7). Other objectively measured neighbourhood-level characteristics were not associated with physical activity levels. Conclusions Distance to nearest greenspace is associated with meeting recommended physical activity levels in deprived London neighbourhoods. Despite residual variance in physical activity levels between neighbourhoods, we found little evidence for the influence of other measured neighbourhood-level characteristics.

Compte rendu: Johann Wolfgang Unger (2013), The Discursive Construction of the Scots Language : Education, Politics and Everyday Life, Amsterdam, John Benjamins, coll. « Discourse Approaches to Politics, Society and Culture, 51 », 178 p. [ISBN : 978-9-027-20642-8]

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