Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 292
Filtrar
1.
Sci Total Environ ; 692: 1005-1021, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31539933

RESUMO

Temporal and spatial atmospheric deposition trends of elements to the boreal forest surrounding bitumen production operations in the Athabasca Oil Sands Region (AOSR), Alberta, Canada were investigated as part of a long-term lichen bioindicator study. The study focused on eight elements (sulfur, nitrogen, aluminum, calcium, iron, nickel, strontium, vanadium) that were previously identified as tracers for the major oil sand production sources. Samples of the in situ epiphytic lichen Hypogymnia physodes were collected in 2002, 2004, 2008, 2011, 2014, and 2017 within a ~150 km radius from the center of surface oil sand production operations in the AOSR. Site-specific time series analysis conducted at eight jack pine upland sites that were repeatedly sampled generally showed significant trends of increasing lichen concentrations for fugitive dust linked elements, particularly at near-field (<25 km from a major oil sands production operation) sample locations. Multiple regional scale geostatistical models were developed and evaluated to characterize broad-scale changes in atmospheric deposition based on changes in H. physodes elemental concentrations between 2008 and 2014. Empirical Bayesian kriging and cokriging lichen element concentrations with oil sands mining, bitumen upgrading, coke materials handling, and limestone quarry/crushing influence variables produced spatial interpolation estimates with the lowest validation errors. Gridded zonal mean lichen element concentrations were calculated for the two comprehensive sampling years (2008, 2014) and evaluated for spatial and temporal change. Lichen sulfur concentrations significantly increased in every grid cell within the domain with the largest increases (44-88%) in the central valley in close proximity to the major surface oil sand production operations, while a minor nitrogen concentration decrease (-20%) in a single grid cell was observed. The areal extent of fugitive dust element deposition generally increased with significantly higher deposition to lichens restricted to the outer grids of the enhanced deposition field, reflecting new and expanding surface mining activity.

2.
Int J Cancer ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209889

RESUMO

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

3.
Epigenetics ; 14(11): 1065-1073, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31232174

RESUMO

Smoking accounts for approximately 52% of bladder cancer incidence among postmenopausal women, but the underlying mechanism is poorly understood. Our study investigates whether changes in DNA methylation, as measured in blood, mediate the impact of smoking on bladder cancer risk among postmenopausal women. We conducted analyses among 206 cases and 251 controls that were current or never smokers at baseline from a previous case-control study of bladder cancer and genome-wide DNA methylation nested within the Women's Health Initiative. Separate mediation analyses were conducted for three CpG sites demonstrating robust associations with smoking in prior methylome-wide association studies: cg05575921 (AhRR), cg03636183 (F2RL3), and cg19859270 (GPR15). We estimated causal effects using the regression-based, four-way decomposition approach, which addresses the interaction between smoking and each CpG site. The overall proportion of the excess relative risk mediated by cg05575921 was 92% (p-value = 0.004) and by cg19859270 was 79% (p-value = 0.02). The largest component of the excess relative risk of bladder cancer due to 30 pack-years of smoking history in current smokers was the mediated interaction for both cg05575921 (72%, p = 0.02) and cg19859270 (72%, p-value = 0.04), where the mediated interaction is the effect of smoking on bladder cancer that both acts through differential methylation and depends on smoking history. There was little evidence that smoking was mediated through cg03636183. Our results suggest that differential methylation of cg05575921 and cg19859270 mediate the effects of smoking on bladder cancer, potentially revealing downstream effects of smoking relevant for carcinogenesis.

4.
Eur J Clin Nutr ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209273

RESUMO

BACKGROUND: Inconsistent associations between milk and other dairy product consumption and bladder cancer (BC) have been reported. We aimed to investigate possible associations with BC risk for total and individual dairy products by bringing together the world's data on this topic. METHODS: Thirteen cohort studies, included in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study, provided data for 3590 BC cases and 593,637 non-cases. Associations between milk and other dairy product consumption and BC risk were investigated using Cox proportional hazard regression analyses stratified by study center and adjusted for potential confounders. RESULTS: Overall, total 'other' dairy product consumption was not associated with BC risk (HR comparing highest with lowest tertile: 0.97 (95% CI: 0.87-1.07; ptrend = 0.52) and likewise no association was observed for either liquid milk, processed milk, cream, cheese or icecream. However, an inverse association was observed between yoghurt consumption and BC risk when comparing those in the moderate (25-85 g/day) and high categories (>85 g/day) with non-consumers, with multivariate HR of 0.85 (95% CI: 0.75-0.96) and 0.88 (95% CI: 0.78-0.98), respectively. CONCLUSIONS: We found no evidence of association between either total or individual dairy products and BC risk, but suggestive evidence that consumption of yoghurt may be associated with a decreased risk.

5.
Int J Cancer ; 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31037736

RESUMO

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

6.
Eat Disord ; 27(2): 137-151, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31084430

RESUMO

The nature and presentation of eating pathology in ethnically diverse men are not well defined. This study examined associations among ethnicity, body image, and eating pathology in nonclinical college men (N = 343). Analysis of variance analyses indicated that markers of eating, weight, and shape concerns differed by ethnicity: Asian and Hispanic/Latino men reported more pathological levels than European and African American men. Hierarchical multiple regression analyses indicated that ethnicity moderated the relationship between drive for muscularity and body checking, which was strongest for Asian men. Results increase awareness of how ethnicity interacts with body image and eating pathology, which underscores the need for individualized, culturally sensitive treatment for ethnically diverse men.

7.
J Natl Cancer Inst ; 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127946

RESUMO

BACKGROUND: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. METHODS: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random effects meta-analysis produced summary estimates. All statistical tests were two-sided. RESULTS: Over a period of 38,369,156 person-years of follow-up, 1,391 gallbladder, 758 intrahepatic bile duct, 1,208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (e.g., current versus never smokers hazard ratio [HR] = 1.69, 95% confidence interval [CI] = 1.34 to 2.13 and 2.22, 95%CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all P-trend<0.01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (e.g., >40 cigarettes/day versus never smokers HR = 2.15, 95%CI: 1.15 to 4.00; P-trend=0.001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming ≥5 versus 0 drinks/day (HR = 2.35, 95%CI = 1.46 to 3.78; P-trend=0.04). There was evidence of statistical heterogeneity between several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. CONCLUSIONS: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

8.
Phys Rev E ; 99(2-1): 022904, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30934372

RESUMO

Percolation theory can be used to study the flow-related properties of various porous systems. In particular, recently developed membranes from silica nanoparticles with surface grafted polymer brushes represent a quintessential hard-sphere soft-shell system for which fluid-flow behavior can be illuminated via a percolation framework. However, a critical parameter in membrane design involves the maximum pass-through size of particles. While percolation theory considers path connectedness of a system, little explicit consideration is given to the size of the paths that traverse the space. This paper employs a hard-sphere soft-shell percolation model to investigate maximum particle pass-through size of membranes. A pixelated (as opposed to continuous) representation of the geometry is created, and combined with readily available homology software to analyze percolation behavior. The model is validated against previously published results. For a given sphere volume fraction, the maximum diameter of a percolating path is determined by applying iterative dilations to the spheres until the percolation threshold is reached. A simple approximate relationship between maximum particle size and sphere volume fraction is derived for application to membrane design. Experimental particle cutoff size results for the polymer modified silica nanoparticle membranes were used as a partial verification of the model created in this paper. The presence of a distribution of sphere sizes (naturally created by the manufacturing process) is found to have negligible effect, compared to results for a single sphere size.

9.
Sci Total Environ ; 654: 1241-1257, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30841398

RESUMO

The sources and spatial distribution of polycyclic aromatic hydrocarbons (PAHs) atmospheric deposition in the boreal forests surrounding bitumen production operations in the Athabasca Oil Sands Region (AOSR), Alberta, Canada were investigated as part of a 2014 passive in-situ bioindicator source apportionment study. Epiphytic lichen species Hypogymnia physodes samples (n = 127) were collected within a 150 km radius of the main surface oil sand production operations and analyzed for total sulfur, total nitrogen, forty-three elements, twenty-two PAHs, ten groups of C1-C2-alkyl PAHs and dibenzothiophenes (polycyclic aromatic compounds; PACs), five C1- and C2-alkyldibenzothiophenes, and retene. The ΣPAH + PAC in H. physodes ranged from 54 to 2778 ng g-1 with a median concentration of 317 ng g-1. Source apportionment modeling found an eight-factor solution that explained 99% of the measured ΣPAH + PAC lichen concentrations from four anthropogenic oil sands production sources (Petroleum Coke, Haul Road Dust, Stack Emissions, Raw Oil Sand), two local/regional sources (Biomass Combustion, Mobile Source), and two lichen biogeochemical factors. Petroleum Coke and Raw Oil Sand dust were identified as the major contributing sources of ΣPAH + PAC in the AOSR. These two sources accounted for 63% (43.2 µg g-1) of ΣPAH + PAC deposition to the entire study domain. Of this overall 43.2 µg g-1 contribution, approximately 90% (39.9 µg g-1) ΣPAH + PAC was deposited within 25 km of the closest oil sand production facility. Regional sources (Biomass Combustion and Mobile Sources) accounted for 19% of ΣPAH + PAC deposition to the entire study domain, of which 46% was deposited near-field to oil sand production operations. Source identification was improved over a prior lichen-based study in the AOSR through incorporation of PAH and PAC analytes in addition to inorganic analytes.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental , Líquens/química , Campos de Petróleo e Gás , Hidrocarbonetos Policíclicos Aromáticos/análise , Alberta
10.
Artigo em Inglês | MEDLINE | ID: mdl-30715497

RESUMO

Background: International guidelines recommend monitoring weight as an indicator of therapeutic response in childhood tuberculosis (TB) disease. This recommendation is based on observations in adults. In the current study, we evaluated the association between weight change and treatment outcome, the accuracy of using weight change to predict regimen efficacy, and whether successfully treated children achieve catch-up weight gain. Methods: We enrolled children treated for drug-susceptible TB disease (group 1) and multidrug-resistant TB disease (group 2) in Peru. We calculated the change in weight-for-age z score (ΔWAZ) between baseline and the end of treatment months 2-5 for group 1, and between baseline and months 2-8 for group 2. We used logistic regression and generalized estimating equation models to evaluate the relationship between ΔWAZ and outcome. We plotted receiver operating characteristic curves to determine the accuracy of ΔWAZ for predicting treatment failure or death. Results: Groups 1 and 2 included 100 and 94 children, respectively. In logistic regression, lower ΔWAZ in months 3-5 and month 7 was associated with treatment failure or death in groups 1 and 2, respectively. In generalized estimating equation models, children in both groups who experienced treatment failure or death had lower ΔWAZ than successfully treated children. The ΔWAZ predicted treatment failure or death with 60%-90% sensitivity and 60%-86% specificity in months 2-5 for group 1 and months 7-8 for group 2. All successfully treated children-except group 2 participants with unknown microbiologic confirmation status-achieved catch-up weight gain. Conclusions: Weight change early in therapy can predict the outcome of childhood TB treatment.

11.
Sci Total Environ ; 666: 540-558, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30802668

RESUMO

A comprehensive filter-based particulate matter polycyclic aromatic hydrocarbon (PAH) source apportionment study was conducted at the Wood Buffalo Environmental Association Bertha Ganter-Fort McKay (BGFM) community monitoring station from 2014 to 2015 to quantify ambient concentrations and identify major sources. The BGFM station is located in close proximity to several surface oil sands production facilities and was previously found to be impacted by their air emissions. 24-hour integrated PM2.5 and PM10-2.5 samples were collected on a 1-in-3-day schedule yielding 108 complete organic/inorganic filter sets for source apportionment modeling. During the study period PM2.5 averaged 8.6 ±â€¯11.8 µg m-3 (mean ±â€¯standard deviation), and PM10-2.5 averaged 8.5 ±â€¯9.5 µg m-3. Wind regression analysis indicated that the oil sands production facilities were significant sources of PM2.5 mass and black carbon (BC), and that wildland fires were a significant source of the highest PM2.5 (>10 µg m-3) and BC events. A six-factor positive matrix factorization (PMF) model solution explained 95% of the measured PM2.5 and 78% of the measured ΣPAH. Five sources significantly contributed to PM2.5 including: Biomass Combustion (3.57 µg m-3; 40%); Fugitive Dust (1.86 µg m-3; 28%); Upgrader Stack Emissions (1.44 µg m-3; 21%); Petrogenic PAH (1.20 µg m-3; 18%); and Transported Aerosol (0.43 µg m-3 and 6%). However, the analysis indicated that only the pyrogenic PAH source factor significantly contributed (78%) to the measured ΣPAH. A five-factor PMF model dominated by fugitive dust sources explained 98% of PM10-2.5 mass and 86% of the ΣPAH. The predominant sources of PM10-2.5 mass were (i) Haul Road Dust (4.82 µg m-3; 53%), (ii) Mixed Fugitive Dust (2.89 µg m-3; 32%), (iii) Fugitive Oil Sand (0.88 µg m-3; 10%), Mobile Sources (0.23 µg m-3; 2%), and Organic Aerosol (0.06 µg m-3; 1%). Only the Organic Aerosol source significantly contributed (86%) to the measured ΣPAH.

12.
Eur J Nutr ; 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30737562

RESUMO

PURPOSE: The role of diet in bladder carcinogenesis has yet to be established. To date most studies have investigated dietary components individually, rather than as dietary patterns, which may provide stronger evidence for any influence of diet on bladder carcinogenesis. The Mediterranean diet has been associated with many health benefits, but few studies have investigated its association with bladder cancer risk. METHODS: We investigated the potential association between the Mediterranean diet score (MDS) and risk of developing bladder cancer by pooling 13 prospective cohort studies included in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study and applying a Cox regression analysis. RESULTS: Dietary data from 646,222 study participants, including 3639 incident bladder cancer cases, were analysed. We observed an inverse association between Mediterranean diet and bladder cancer risk (HRhigh 0.85 [95% CI 0.77, 0.93]). When stratifying the results on non-muscle-invasive or muscle-invasive disease or sex the association remained similar and the HR estimate was consistently below 1.00 both for medium and high adherence to the Mediterranean diet. A consistent association was observed when disregarding fat or alcohol intake. CONCLUSION: We found evidence that adherence to the Mediterranean diet was associated with reduced risk of developing bladder cancer, suggesting a positive effect of the diet as a whole and not just one component.

13.
ACS Appl Mater Interfaces ; 11(3): 3407-3416, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30589251

RESUMO

We report the preparation and characterization of charged nanoporous membranes by self-assembly of "hairy" silica nanoparticles (HNPs) functionalized with polyelectrolyte copolymer brushes. We show that HNP membranes possess high water flux, have well-defined pore sizes, and rejection up to 80% of charged species in solution. The properties of these membranes can be tuned by controlling the length and composition of polymer brushes and the electrolyte concentration in solution. We demonstrate that membrane pore sizes undergo changes of up to 40% in response to changes in the ionic strength of the salt solution. Using MD computer simulations of a coarse-grained model, we link these tunable properties to the conformations of polymer chains in the spaces between randomly packed HNPs. As polymer length increases, the polymers fill the interparticle gaps, and the pore size decreases markedly. On the basis of their straightforward fabrication and tunable properties, HNP membranes may find applications in size- and charge-selective separations, water desalination, and responsive devices.

14.
Int J Cancer ; 145(1): 58-69, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561796

RESUMO

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.

15.
J Natl Cancer Inst ; 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541042

RESUMO

Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

16.
PLoS One ; 13(10): e0206519, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30379922

RESUMO

BACKGROUND: High levels of serum leptin and low levels of serum adiponectin are strongly correlated with obesity, a well-established risk factor for colorectal cancer (CRC). Growing evidence suggests that dysregulation of leptin and adiponectin levels may play an etiological role in colorectal carcinogenesis. We evaluated 20 candidate variants in 4 genes previously shown to alter serum leptin and adiponectin levels for associations with obesity (BMI>30 kg/m2) and CRC risk. METHODS: We analyzed 6,246 CRC cases and 7,714 population-based controls from 11 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations of each variant with obesity or CRC were evaluated using multivariate logistic regression models stratified by sex and adjusted for age, a study variable, and the first three principal components of genetic ancestry. Gene-specific False Discovery Rate (FDR)-adjusted p-values <0.05 denoted statistical significance. RESULTS: Two variants in the leptin gene showed statistically significant associations with CRC among women: LEP rs2167270 (OR = 1.13, 95% CI: 1.06-1.21) and LEP rs4731426 (OR = 1.09, 95% CI: 1.02-1.17). These associations remained significant after adjustment for obesity, suggesting that leptin SNPs may influence CRC risk independent of obesity. We observed statistically significant interactions of the leptin variants with hormone replacement therapy (HRT) for CRC risk; these variant associations were strengthened when analyses were restricted to post-menopausal women with low estrogen exposure, as estimated by 'never use' of HRT and/or non-obese BMI. No variants were associated with CRC among men. CONCLUSIONS: Leptin gene variants may exhibit sex-specific associations with CRC risk. Endogenous and exogenous estrogen exposure may modify the association between these variants, leptin levels, and CRC risk.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30476588

RESUMO

BACKGROUND & AIMS: Red and processed meat intake is associated with colorectal cancer (CRC) incidence, but it is not clear if intake is associated with patient survival after diagnosis METHODS: We pooled data from 7627 patients with stage I-IV CRC from 10 studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of intake of red and processed meat before diagnosis with overall and CRC-specific survival. RESULTS: Among 7627 patients with CRC, 2338 died, including 1576 from CRC, over a median follow-up time of 5.1 years. In multivariable-adjusted analyses, higher intake of red or processed meat was not associated with overall survival of patients with stage I-III CRC: Q4 vs Q1 red meat hazard ratio [HR], 1.08 (95% CI, 0.93-1.26) and Q4 vs Q1 processed meat HR, 1.10 (95% CI, 0.93-1.32) or with CRC-specific survival: Q4 vs Q1 red meat HR, 1.09 (95% CI, 0.89-1.33) and Q4 vs Q1 processed meat HR, 1.11 (95% CI, 0.87-1.42). Results were similar for patients with stage IV CRC. However, patients with stage I-III CRC who reported an intake of processed meat above the study-specific medians had a higher risk of death from any cause (HR, 1.12; 95% CI, 1.01-1.25) than patients who reported eating at or less than the median. CONCLUSION: In this large consortium of CRC patient cohorts, intake of red and processed meat before a diagnosis of CRC was not associated with shorter survival time after diagnosis, although a possible weak adverse association cannot be excluded. Studies that evaluate dietary data from several time points before and after cancer diagnosis are required to confirm these findings.

18.
Am J Epidemiol ; 187(12): 2672-2680, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30188971

RESUMO

Diagnosing pleiotropy is critical for assessing the validity of Mendelian randomization (MR) analyses. The popular MR-Egger method evaluates whether there is evidence of bias-generating pleiotropy among a set of candidate genetic instrumental variables. In this article, we propose a statistical method-global and individual tests for direct effects (GLIDE)-for systematically evaluating pleiotropy among the set of genetic variants (e.g., single nucleotide polymorphisms (SNPs)) used for MR. As a global test, simulation experiments suggest that GLIDE is nearly uniformly more powerful than the MR-Egger method. As a sensitivity analysis, GLIDE is capable of detecting outliers in individual variant-level pleiotropy, in order to obtain a refined set of genetic instrumental variables. We used GLIDE to analyze both body mass index and height for associations with colorectal cancer risk in data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry (multiple studies). Among the body mass index-associated SNPs and the height-associated SNPs, several individual variants showed evidence of pleiotropy. Removal of these potentially pleiotropic SNPs resulted in attenuation of respective estimates of the causal effects. In summary, the proposed GLIDE method is useful for sensitivity analyses and improves the validity of MR.

19.
J Neurosci ; 38(40): 8707-8722, 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30201775

RESUMO

Microcirculatory damage is a common complication for those with vascular risk factors, such as diabetes. To resolve vascular insults, the brain's immune cells (microglia) must rapidly envelop the site of injury. Currently, it is unknown whether Type 1 diabetes, a condition associated with chronic immune system dysfunction, alters microglial responses to damage and what mechanisms are responsible. Using in vivo two-photon microscopy in adult male mice, we show that microglial envelopment of laser-induced cerebral microbleeds is diminished in a hyperglycemic mouse model of Type 1 diabetes, which could not be fully rescued with chronic insulin treatment. Microglia were important for vessel repair because reduced microglial accumulation in diabetic mice or near-complete depletion in healthy controls was associated with greater secondary leakage of the damaged vessel. Broadly suppressing inflammation with dexamethasone in diabetic mice but not healthy controls, significantly enhanced microglial responses to microbleeds and attenuated secondary vessel leakage. These enhancements were associated with changes in IFN-γ signaling because dexamethasone suppressed abnormally high levels of IFN-γ protein levels in brain and blood serum of diabetic mice. Further, blocking IFN-γ in diabetic mice with neutralizing antibodies restored normal microglial chemotaxic responses and purinoceptor P2ry12 gene expression, as well as mitigated secondary leakage. These results suggest that abnormal IFN-γ signaling disrupts microglial function in the diabetic brain, and that immunotherapies targeting IFN-γ can stimulate microglial repair of damaged vessels.SIGNIFICANCE STATEMENT Although Type 1 diabetes is an established risk factor for vascular complications, such as microbleeds, and is known to hinder wound healing in the body, no study has examined how diabetes impacts the brain's innate immune reparative response (involving cells called microglia) to vascular injury. Here we show that microglial responses to brain microbleeds were diminished in diabetic animals, which also exacerbated secondary leakage from damaged vessels. These impairments were related to abnormally high levels of the proinflammatory cytokine IFN-γ because reducing IFN-γ with immunosuppressant drugs or blocking antibodies helped restore normal microglial responses and repair of damaged vessels. These data highlight the use of IFN-γ modulating therapeutics to enhance vascular repair in at-risk populations.

20.
Psychoneuroendocrinology ; 98: 30-38, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30092497

RESUMO

Low estradiol is associated with impaired extinction of conditioned physiological fear responses (e.g. skin conductance) in females. As fear extinction is the laboratory basis of exposure therapy for anxiety disorders, it has been speculated that estradiol may be related to the effectiveness of treatment for anxiety. The present study extended past research by examining whether estradiol is related to physiological and subjective fear responses during the impromptu speech task, where participants perform a surprise speech to camera. This task elicits psychosocial fear, and thus has relevance for social anxiety disorder (SAD). We used a quasi-experimental design with two groups of women: 39 naturally cycling women, and 19 women taking hormonal contraceptives. Based on the measured serum levels, naturally cycling women were further divided into women with higher- vs. lower estradiol levels. Compared to those with higher estradiol, women with lower estradiol, and those using hormonal contraceptives (chronically suppressed estradiol) displayed higher speech-elicited skin conductance yet reported no differences in subjective anxiety or affect. Conversely, irrespective of estradiol status, compared to those with low self-reported social anxiety, participants with higher social anxiety exhibited greater subjective anxiety and affect, yet no differences in skin conductance. These results demonstrate that the relationship between estradiol and physiological fear responses extends to psychosocial tasks. However, the dissociations between physiological and subjective measures highlight the need to consider the relevance of different response outputs so that the potential impact of estradiol on the treatment of anxiety disorders can be better understood.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA