A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study

Objective. To examine the association between pre-diagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk of colorectal cancer in European populations. Design Nested case-control study. Setting. The study was conducted within the EPIC study, a cohort of more than 520 000 participants from 10 western European countries. Participants: 1248 cases of incident colorectal cancer, which developed after enrolment into the cohort, were matched to 1248 controls. Main outcome measures. Circulating vitamin D concentration (25-hydroxy-vitamin-D, 25-(OH)D) was measured by enzyme immunoassay. Dietary and lifestyle data were obtained from questionnaires. Incidence rate ratios and 95% confidence intervals for the risk of colorectal cancer by 25-(OH)D concentration and levels of dietary calcium and vitamin D intake were estimated from multivariate conditional logistic regression models, with adjustment for potential dietary and other confounders. Results. 25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer (P for trend <0.001). Compared with a pre-defined mid-level concentration of 25-(OH)D (50.0-75.0 nmol/l), lower levels were associated with higher colorectal cancer risk (<25.0 nmol/l: incidence rate ratio 1.32 (95% confidence interval 0.87 to 2.01); 25.0-49.9 nmol/l: 1.28 (1.05 to 1.56), and higher concentrations associated with lower risk (75.0-99.9 nmol/l: 0.88 (0.68 to 1.13); ≥100.0 nmol/l: 0.77 (0.56 to 1.06)). In analyses by quintile of 25-(OH)D concentration, patients in the highest quintile had a 40% lower risk of colorectal cancer than did those in the lowest quintile (P<0.001). Subgroup analyses showed a strong association for colon but not rectal cancer (P for heterogeneity=0.048). Greater dietary intake of calcium was associated with a lower colorectal cancer risk. Dietary vitamin D was not associated with disease risk. Findings did not vary by sex and were not altered by corrections for season or month of blood donation. Conclusions The results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations. Further randomised trials are needed to assess whether increases in circulating 25-(OH)D concentration can effectively decrease the risk of colorectal cancer.

Comparison of application of the ACC/AHA guidelines, Adult Treatment Panel III guidelines, and European Society of Cardiology guidelines for cardiovascular disease prevention in a European cohort.

IMPORTANCE: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines introduced a prediction model and lowered the threshold for treatment with statins to a 7.5% 10-year hard atherosclerotic cardiovascular disease (ASCVD) risk. Implications of the new guideline's threshold and model have not been addressed in non-US populations or compared with previous guidelines. OBJECTIVE: To determine population-wide implications of the ACC/AHA, the Adult Treatment Panel III (ATP-III), and the European Society of Cardiology (ESC) guidelines using a cohort of Dutch individuals aged 55 years or older. DESIGN, SETTING, AND PARTICIPANTS: We included 4854 Rotterdam Study participants recruited in 1997-2001. We calculated 10-year risks for "hard" ASCVD events (including fatal and nonfatal coronary heart disease [CHD] and stroke) (ACC/AHA), hard CHD events (fatal and nonfatal myocardial infarction, CHD mortality) (ATP-III), and atherosclerotic CVD mortality (ESC). MAIN OUTCOMES AND MEASURES: Events were assessed until January 1, 2012. Per guideline, we calculated proportions of individuals for whom statins would be recommended and determined calibration and discrimination of risk models. RESULTS: The mean age was 65.5 (SD, 5.2) years. Statins would be recommended for 96.4% (95% CI, 95.4%-97.1%; n = 1825) of men and 65.8% (95% CI, 63.8%-67.7%; n = 1523) of women by the ACC/AHA, 52.0% (95% CI, 49.8%-54.3%; n = 985) of men and 35.5% (95% CI, 33.5%-37.5%; n = 821) of women by the ATP-III, and 66.1% (95% CI, 64.0%-68.3%; n = 1253) of men and 39.1% (95% CI, 37.1%-41.2%; n = 906) of women by ESC guidelines. With the ACC/AHA model, average predicted risk vs observed cumulative incidence of hard ASCVD events was 21.5% (95% CI, 20.9%-22.1%) vs 12.7% (95% CI, 11.1%-14.5%) for men (192 events) and 11.6% (95% CI, 11.2%-12.0%) vs 7.9% (95% CI, 6.7%-9.2%) for women (151 events). Similar overestimation occurred with the ATP-III model (98 events in men and 62 events in women) and ESC model (50 events in men and 37 events in women). The C statistic was 0.67 (95% CI, 0.63-0.71) in men and 0.68 (95% CI, 0.64-0.73) in women for hard ASCVD (ACC/AHA), 0.67 (95% CI, 0.62-0.72) in men and 0.69 (95% CI, 0.63-0.75) in women for hard CHD (ATP-III), and 0.76 (95% CI, 0.70-0.82) in men and 0.77 (95% CI, 0.71-0.83) in women for CVD mortality (ESC). CONCLUSIONS AND RELEVANCE: In this European population aged 55 years or older, proportions of individuals eligible for statins differed substantially among the guidelines. The ACC/AHA guideline would recommend statins for nearly all men and two-thirds of women, proportions exceeding those with the ATP-III or ESC guidelines. All 3 risk models provided poor calibration and moderate to good discrimination. Improving risk predictions and setting appropriate population-wide thresholds are necessary to facilitate better clinical decision making.

New insights into trypanosomatid U5 small nuclear ribonucleoproteins

Several protozoan parasites exist in the Trypanosomatidae family, including various agents of human diseases. Multiple lines of evidence suggest that important differences are present between the translational and mRNA processing (trans splicing) systems of trypanosomatids and other eukaryotes. In this context, certain small complexes of RNA and protein, which are named small nuclear ribonucleoproteins (U snRNPs), have an essential role in pre-mRNA processing, mainly during splicing. Even though they are well defined in mammals, snRNPs are still not well characterized in trypanosomatids. This study shows that a U5-15K protein is highly conserved among various trypanosomatid species. Tandem affinity pull-down assays revealed that this protein interacts with a novel U5-102K protein, which suggests the presence of a sub-complex that is potentially involved in the assembly of U4/U6-U5 tri-snRNPs. Functional analyses showed that U5-15K is essential for cell viability and is somehow involved with the trans and cis splicing machinery. Similar tandem affinity experiments with a trypanonosomatid U5-Cwc21 protein led to the purification of four U5 snRNP specific proteins and a Sm core, suggesting U5-Cwc-21 participation in the 35S U5 snRNP particle. Of these proteins, U5-200K was molecularly characterized. U5-200K has conserved domains, such as the DEAD/DEAH box helicase and Sec63 domains and displays a strong interaction with U5 snRNA.

Nutrient patterns and their food sources in an International Study Setting: report from the EPIC study.

BACKGROUND Compared to food patterns, nutrient patterns have been rarely used particularly at international level. We studied, in the context of a multi-center study with heterogeneous data, the methodological challenges regarding pattern analyses. METHODOLOGY/PRINCIPAL FINDINGS We identified nutrient patterns from food frequency questionnaires (FFQ) in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study and used 24-hour dietary recall (24-HDR) data to validate and describe the nutrient patterns and their related food sources. Associations between lifestyle factors and the nutrient patterns were also examined. Principal component analysis (PCA) was applied on 23 nutrients derived from country-specific FFQ combining data from all EPIC centers (N = 477,312). Harmonized 24-HDRs available for a representative sample of the EPIC populations (N = 34,436) provided accurate mean group estimates of nutrients and foods by quintiles of pattern scores, presented graphically. An overall PCA combining all data captured a good proportion of the variance explained in each EPIC center. Four nutrient patterns were identified explaining 67% of the total variance: Principle component (PC) 1 was characterized by a high contribution of nutrients from plant food sources and a low contribution of nutrients from animal food sources; PC2 by a high contribution of micro-nutrients and proteins; PC3 was characterized by polyunsaturated fatty acids and vitamin D; PC4 was characterized by calcium, proteins, riboflavin, and phosphorus. The nutrients with high loadings on a particular pattern as derived from country-specific FFQ also showed high deviations in their mean EPIC intakes by quintiles of pattern scores when estimated from 24-HDR. Center and energy intake explained most of the variability in pattern scores. CONCLUSION/SIGNIFICANCE The use of 24-HDR enabled internal validation and facilitated the interpretation of the nutrient patterns derived from FFQs in term of food sources. These outcomes open research opportunities and perspectives of using nutrient patterns in future studies particularly at international level.

Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries.

With advances in the effectiveness of treatment and disease management, the contribution of chronic comorbid diseases (comorbidities) found within the Charlson comorbidity index to mortality is likely to have changed since development of the index in 1984. The authors reevaluated the Charlson index and reassigned weights to each condition by identifying and following patients to observe mortality within 1 year after hospital discharge. They applied the updated index and weights to hospital discharge data from 6 countries and tested for their ability to predict in-hospital mortality. Compared with the original Charlson weights, weights generated from the Calgary, Alberta, Canada, data (2004) were 0 for 5 comorbidities, decreased for 3 comorbidities, increased for 4 comorbidities, and did not change for 5 comorbidities. The C statistics for discriminating in-hospital mortality between the new score generated from the 12 comorbidities and the Charlson score were 0.825 (new) and 0.808 (old), respectively, in Australian data (2008), 0.828 and 0.825 in Canadian data (2008), 0.878 and 0.882 in French data (2004), 0.727 and 0.723 in Japanese data (2008), 0.831 and 0.836 in New Zealand data (2008), and 0.869 and 0.876 in Swiss data (2008). The updated index of 12 comorbidities showed good-to-excellent discrimination in predicting in-hospital mortality in data from 6 countries and may be more appropriate for use with more recent administrative data.

Aortic valve dysfunction and aortic dilation in adults with coarctation of the aorta.

OBJECTIVES: To determine the prevalence of aortic valve dysfunction, aortic dilation, and aortic valve and ascending aortic intervention in adults with coarctation of the aorta (CoA). BACKGROUND: Aortic valve dysfunction and aortic dilation are rare among children and adolescents with CoA. With longer follow-up, adults may be more likely to have progressive disease. METHODS: We retrospectively reviewed all adults with CoA, repaired or unrepaired, seen at our center between 2004 and 2010. RESULTS: Two hundred sixteen adults (56.0% male) with CoA were identified. Median age at last evaluation was 28.3 (range 18.0 to 75.3) years. Bicuspid aortic valve (BAV) was present in 65.7%. At last follow-up, 3.2% had moderate or severe aortic stenosis, and 3.7% had moderate or severe aortic regurgitation. Dilation of the aortic root or ascending aorta was present in 28.0% and 41.6% of patients, respectively. Moderate or severe aortic root or ascending aortic dilation (z-score > 4) was present in 8.2% and 13.7%, respectively. Patients with BAV were more likely to have moderate or severe ascending aortic dilation compared with those without BAV (19.5% vs. 0%; P < 0.001). Age was associated with ascending aortic dilation (P = 0.04). At most recent follow-up, 5.6% had undergone aortic valve intervention, and 3.2% had aortic root or ascending aortic replacement. CONCLUSION: In adults with CoA, significant aortic valve dysfunction and interventions during early adulthood were uncommon. However, aortic dilation was prevalent, especially of the ascending aorta, in patients with BAV.

Automatic generation of active coordinates for quantum dynamics calculations: application to the dynamics of benzene photochemistry

A new practical method to generate a subspace of active coordinates for quantum dynamics calculations is presented. These reduced coordinates are obtained as the normal modes of an analytical quadratic representation of the energy difference between excited and ground states within the complete active space self-consistent field method. At the Franck-Condon point, the largest negative eigenvalues of this Hessian correspond to the photoactive modes: those that reduce the energy difference and lead to the conical intersection; eigenvalues close to 0 correspond to bath modes, while modes with large positive eigenvalues are photoinactive vibrations, which increase the energy difference. The efficacy of quantum dynamics run in the subspace of the photoactive modes is illustrated with the photochemistry of benzene, where theoretical simulations are designed to assist optimal control experiments

Report to Government Oversight Committee Regrading Soil and Water Conservation Districts Competition with Small Business, 2006

At the request of the Government Oversight Committee, the Ombudsman gathered information regarding competition by county Soil and Water Conservation Districts (SWCD) with small business through the sale of products and services. The goal of the Ombudsman’s review was to assist the Government Oversight Committee (Committee) in gaining an objective understanding of the issues so the Committee can ascertain whether there is a problem that requires legislation this legislative session. The Ombudsman focused on gathering specific information from four SWCD offices in central Iowa; Dallas, Greene, Guthrie and Jasper. These offices were specifically identified in documentation presented to the Government Oversight Committee by affected small business owners (contractors), Jon Judson of Diversity Farms and Dan Brouse of Iowa Restorations. However, with 100 SWCDs in Iowa,1 each with their own elected commissioners and each with different practices, priorities and fundraising activities, what the Ombudsman learned about these four counties may not be applicable to all the SWCDs in Iowa. The Ombudsman assigned the case to the Assistant Citizens’ Aide/Ombudsman for Small Business, Kristie Hirschman. For reference purposes in this report, actions taken by Ms. Hirschman will be ascribed to the Ombudsman.

Biodiversidade de moscas-das-frutas (Diptera, Tephritoidea) em matas nativas e pomares domésticos de dois municípios do Estado do Tocantins, Brasil

Este trabalho apresenta análise faunística comparativa das espécies de moscas-das-frutas capturadas em armadilhas McPhail (junho a dezembro de 2002) com proteína hidrolisada de milho a 5%. Foram comparadas a riqueza de espécies e a estrutura populacional entre ambientes de mata e pomar dos municípios de Palmas e Porto Nacional, TO. Foram capturados 1.748 indivíduos de espécies de três gêneros de Tephritidae: Tomoplagia Coquillett, 1910, Anastrepha Schiner, 1868 e Ceratitis MacLeay, 1829. De Lonchaeidae foram capturadas espécies de três gêneros: Lonchaea Fallén, 1820, Neosilba McAlpine, 1962 e Dasiops Rondani, 1856. Ceratitis capitata (Wiedemann, 1824). Dezenove espécies de Anastrepha foram coletadas, sendo a maioria dos indivíduos (69,1%) de A. obliqua (Macquart, 1835). Não houve diferença significativa (P < 0,05) do número médio de espécies coletadas entre municípios e entre ambientes, mas o número médio de indivíduos de Tephritidae do município de Palmas e do ambiente mata foram significativamente menores do que de Porto Nacional e pomar, respectivamente. Pelo índice de diversidade de Shannon (H'), utilizado para comparar a diversidade de moscas-das-frutas entre os ambientes dos dois municípios, verificou-se que apenas a diversidade do pomar de Palmas (H' = 1,96) foi maior do que a do pomar de Porto Nacional (H' = 0,81). Na determinação dos índices faunísticos, A. obliqua e A. distincta Greene, 1934 apresentaram-se geralmente como constantes, dominantes e muito abundantes.

Measuring ecological niche overlap from occurrence and spatial environmental data

1. Aim - Concerns over how global change will influence species distributions, in conjunction with increased emphasis on understanding niche dynamics in evolutionary and community contexts, highlight the growing need for robust methods to quantify niche differences between or within taxa. We propose a statistical framework to describe and compare environmental niches from occurrence and spatial environmental data.¦2. Location - Europe, North America, South America¦3. Methods - The framework applies kernel smoothers to densities of species occurrence in gridded environmental space to calculate metrics of niche overlap and test hypotheses regarding niche conservatism. We use this framework and simulated species with predefined distributions and amounts of niche overlap to evaluate several ordination and species distribution modeling techniques for quantifying niche overlap. We illustrate the approach with data on two well-studied invasive species.¦4. Results - We show that niche overlap can be accurately detected with the framework when variables driving the distributions are known. The method is robust to known and previously undocumented biases related to the dependence of species occurrences on the frequency of environmental conditions that occur across geographic space. The use of a kernel smoother makes the process of moving from geographical space to multivariate environmental space independent of both sampling effort and arbitrary choice of resolution in environmental space. However, the use of ordination and species distribution model techniques for selecting, combining and weighting variables on which niche overlap is calculated provide contrasting results.¦5. Main conclusions - The framework meets the increasing need for robust methods to quantify niche differences. It is appropriate to study niche differences between species, subspecies or intraspecific lineages that differ in their geographical distributions. Alternatively, it can be used to measure the degree to which the environmental niche of a species or intraspecific lineage has changed over time.

Fitness cost of resistance to Bacillus thuringiensis in velvetbean caterpillar Anticarsia gemmatalis Hübner (Lepidoptera, Noctuidae)

Selection pressure to obtain resistant genotypes can result in fitness cost. In this study, we report the effects of the selection pressure of a commercial formulation of Bacillus thuringiensis on biological aspects of a Dipel-resistant strain of velvetbean caterpillar, Anticarsia gemmatalis Hübner. Comparisons of Dipel-resistant and susceptible individuals revealed significant differences in pupal weight and larval development time. Both strains (Dipel-resistant and susceptible) were susceptible to Cry1Ac toxin expressed in foliar cotton tissues. Resistant and susceptible strains showed low survival rates of 22.5% and 51.2%, respectively, when fed with Greene diet containing Bt-cotton. Larvae bioassayed after three laboratory generations presented lower survival and less instar numbers than individuals maintained in the laboratory for more than 144 generations. Pupal weight was 9.4% lower and larval development time was 1.9 days longer in the resistant population than in the susceptible strain. Other parameters, such as duration of pupal stage, adult longevity, number of eggs per female, oviposition period, and egg fertility, remained unaffected.

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Fruit flies (Diptera, Tephritidae) and their parasitoids on cultivated and wild hosts in the Cerrado-Pantanal ecotone in Mato Grosso do Sul, Brazil

Fruit flies (Diptera, Tephritidae) and their parasitoids on cultivated and wild hosts in the Cerrado-Pantanal ecotone in Mato Grosso do Sul, Brazil. Information on frugivorous flies in cultivated or wild host plants and their parasitoids in the Cerrado-Pantanal ecotone in Aquidauana, Mato Grosso do Sul is presented and discussed. Fruit fly samples were collected weekly in specific fruit trees, and McPhail® traps were installed in the same trees for a period of two years. The fruit flies infested ripe and unripe fruits of Averrhoa carambola L., Schoepfia sp., Psidium guajava L. and Pouteria torta (Mart.) Radlk and mature fruits of Anacardium occidentale L. and Inga laurina (Sw.) Willd. Nineteen fruit fly species were obtained with the combination of sampling methods (collecting fruits and trapping), nine of them obtained with both methods, five found only in fruits and five only in traps. This is the first record of Anastrepha striata Schiner in a species of Sapotaceae, as well as for A. castanea Norrbom and A. daciformes Bezzi in Schoepfia sp. (Olacaceae), and for A. distincta Greene in fruits of P. guajava in the state of Mato Grosso do Sul. Fruit collections simultaneously associated with capture of fruit flies by McPhail traps in the same host plants are essential to understand the diversity of fruit flies and their relationship with hosts and parasitoids. Species of Braconidae and Pteromalidae were recovered, where Doryctobracon areolatus (Szépligeti) was the most abundant parasitoid in larvae of tephritids infesting both cultivated and wild host fruits.

Comparação dos métodos de pesquisa de parasitas intestinais utilizados nos laboratórios clínicos em Cabo Verde com o método de Ritchie modificado – O caso de Rincão

Os parasitas intestinais constituem um problema médico-sanitário de grande importância, tanto pela frequência que ocorrem como causarem muitas vezes, distúrbios orgânicos capazes de incapacitarem os indivíduos infectados, reduzindo a resistência do organismo, predispondo-o inclusive a outras infecções ( MARCONDES et al., 2003 ) . Devido a estas incapacitações e maleficência que estes podem causar ao homem, tornase necessário que seja feito um diagnóstico fidedigno, através de técnicas sensíveis e específicas, pois o diagnóstico laboratorial constitui um processo importante e essencial no mecanismo de controlo e combate aos parasitas intestinais. Várias técnicas são usadas na identificação destes microrganismos, entre os quais o exame direto ou a fresco e vários métodos de concentração, como o método de Willis, Faust e Cols,Ritchie modificado, técnicas de sedimentação como Hoffmam, Pons e Janer, método de Baermann, método de Graham ( fita adesiva ) , métodos de coloração com a hematoxilina férrica, coloração tricrómica, assim como o uso de técnicas moleculares e testes rápidos ( DOLDMAN, 2009 ) . Utilizado na pesquisa sobretudo de ovos de helmintos, o método de concentração de Willis fundamenta-se na propriedade que determinados ovos têm em flutuarem na superfície de uma solução saturada com cloreto de sódio e ficarem na superfície, aderindo assim a uma lamela colocada a superfície e observada ao microscópio ( NEVES, 2005) . O método de concentração difásico de Ritchie modificado constitui uma das técnicas mais utilizadas na pesquisa de quistos de protozoários e helmintos. Esta baseia-se na sedimentação por centrifugação e lavagem do material com éter, um solvente orgânico que forma uma fase apolar, retendo os artefactos vegetais e lípidos contida na amostra, durante a centrifugação da suspensão de fezes ( REY, 2001) . Para um melhor diagnóstico, é importante associar aos métodos de pesquisa de parasitas intestinais, métodos indirectos, como a avaliação da eosinofilia sanguínea, esteatoreia e a pesquisa de cristais de Charcot-Leyden nas fezes, ou seja, métodos auxiliares na pesquisa e identificação de parasitas intestinais ( ENGELKIRK et ENGELKIRK, 2008 ) . O estudo teve como objetivo avaliar a sensibilidade e especificidades das técnicas utilizadas no diagnóstico de parasitas intestinais, comparando com as técnicas utilizadas nos laboratórios públicos de análises clínicas em Cabo Verde com o método de Ritchie modificado.