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Kitahara C.M.,U.S. National Cancer Institute | Flint A.J.,Harvard University | Berrington de Gonzalez A.,U.S. National Cancer Institute | Bernstein L.,Beckman Research Institute | And 37 more authors.
PLoS Medicine | Year: 2014

Background:The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity.Methods and Findings:In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m2) compared with those classified as normal weight (BMI 18.5-24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976-2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report.Conclusions:Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight.Please see later in the article for the Editors' Summary.


Vinik A.I.,Strelitz Diabetes Center and Neuroendocrine Unit | Cincotta A.H.,VeroScience LLC | Scranton R.E.,VeroScience LLC | Bohannon N.,St Lukes Hospital | And 4 more authors.
Endocrine Practice | Year: 2012

Objective: To investigate the effect of Bromocriptine-QR on glycemic control in patients with type 2 diabetes whose glycemia is poorly controlled on one or two oral anti-diabetes agents. Methods: Five hundred fifteen Type 2 Diabetes Mellitus (T2DM) subjects (ages 18 to 80 and average body mass index [BMI] of 32.7) with baseline HbA1c ≥7.5 and on one or two oral anti-diabetes (OAD) medications (metformin, sulfonylurea, and/or thiazolidinediones) were randomized 2:1 to bromocriptine-QR (1.6 to 4.8 mg/day) or placebo for a 24 week treatment period. Study investigators were allowed to adjust, if necessary, subject anti-diabetes medications during the study to attempt to achieve glycemic control in case of glycemic deterioration. The impact of bromocriptine-QR treatment intervention on glycemic control was assessed in subjects on any one or two OADs (ALL treatment category) (N = 515), or on metformin with or without another OAD (Met/OAD treatment category) (N = 356), or on metformin plus a sulfonylurea (Met/SU treatment category) (N = 245) 1) by examining the between group difference in change from baseline a) concomitant OAD medication changes during the study, and b) HbA1c and 2) by determining the odds of reaching HbA1c of ≤7.0% on bromocriptine-QR versus placebo. Results: Significantly more patients (approximately 1.5 to 2-fold more; P<.05) intensified concomitant anti-diabetes medication therapy during the study in the placebo versus the bromocriptine-QR arm. In subjects that did not change the intensity of the baseline diabetes therapy (72%), and that were on any one or two OADs (ALL), or on metformin with or without another OAD (Met/OAD), or on metformin plus sulfonylurea (Met/SU), the HbA1c change for bromocriptine-QR versus placebo was -0.47 versus +0.22 (between group delta of -0.69, P<.0001), -0.55 versus +0.26 (between group delta of -0.81, P<.0001) and -0.63 versus +0.20 (between group delta of -0.83, P<.0001) respectively, after 24 weeks on therapy. The odds ratio of reaching HbA1c of ≤7.0% was 6.50, 12.03 and 11.45 (P<.0002) for these three groups, respectively. Conclusion: In T2DM subjects whose hyperglycemia is poorly controlled on one or two oral agents, bromocriptine-QR therapy for 24 weeks can provide significant added improvement in glycemic control relative to adding placebo. Copyright © 2012 AACE.


Wolpin B.M.,Dana-Farber Cancer Institute | Wolpin B.M.,Harvard University | Rizzato C.,German Cancer Research Center | Kraft P.,Harvard University | And 133 more authors.
Nature Genetics | Year: 2014

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10-12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10-10), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10-9) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10-8). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10-14). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10-7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies. © 2014 Nature America, Inc. All rights reserved.


Kitahara C.M.,U.S. National Cancer Institute | Linet M.S.,U.S. National Cancer Institute | Brenner A.V.,U.S. National Cancer Institute | Wang S.S.,Beckman Research Institute | And 28 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2014

Background: Brain glioma is a relatively rare and fatal malignancy in adulthood with fewknown risk factors. Some observational studies have reported inverse associations between diabetes and subsequent glioma risk, but possible mechanisms are unclear. Methods: Weconducted a pooled analysis of original data fromfive nested case-control studies and two case- control studies fromtheUnited States and China that included 962 glioma cases and 2,195 controls. Weexamined self-reported diabetes history in relation to glioma risk, as well as effect modification by seven glioma riskassociated single-nucleotide polymorphisms(SNP). We also examined the associations between 13 diabetes riskassociated SNPs, identified from genome-wide association studies, and glioma risk. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable-adjusted logistic regression models. Results: We observed a 42% reduced risk of glioma for individuals with a history of diabetes (OR = 0.58; 95% CI, 0.40-0.84). The association did not differ by sex, study design, or after restricting to glioblastoma, the most common histological subtype. We did not observe any significant per-allele trends among the 13 diabetesrelated SNPs examined in relation to glioma risk. Conclusion: These results support an inverse association between diabetes history and glioma risk. The role of genetic susceptibility to diabetes cannot be excluded, and should be pursued in future studies together with other factors that might be responsible for the diabetes-glioma association. Impact: These data suggest the need for studies that can evaluate, separately, the association between type 1 and type 2 diabetes and subsequent risk of adult glioma. Cancer Epidemiol Biomarkers Prev; 23(1); 47-54. © 2013 AACR.


Albanes D.,U.S. National Cancer Institute | Till C.,Fred Hutchinson Cancer Research Center | Klein E.A.,Cleveland Clinic | Goodman P.J.,Fred Hutchinson Cancer Research Center | And 10 more authors.
Cancer Prevention Research | Year: 2014

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed higher prostate cancer incidence in men supplemented with high-dose α-tocopherol. We, therefore, examined whether presupplementation plasma α-tocopherol or γ-tocopherol was associated with overall or high-grade prostate cancer. A stratified case-cohort sample that included 1,746 incident prostate cancer cases diagnosed through June 2009 and a subcohort of 3,211 men was derived from the SELECT trial of 35,533 men. Plasma was collected at entry from 2001 to 2004, and median follow-up was 5.5 years (range, 0-7.9 years). Incidence of prostate cancer as a function of plasma α-tocopherol, γ-tocopherol, and supplementation with α-tocopherol or selenomethionine was estimated by the hazard ratio (HR). Plasma γ-tocopherol was not associated with prostate cancer. Men with higher α-tocopherol concentrations seemed to have risk similar to that of men with lower concentrations [overall HR for fifth (Q5) vs. first quintile (Q1), 1.21; 95 % confidence interval (CI), 0.88-1.66; P-trend = 0.24; in the trial placebo arm, Q5 HR, 0.85; 95% CI, 0.44-1.62; P-trend = 0.66]. We found a strong positive plasma α-tocopherol association among men receiving the trial selenomethionine supplement [Q5 HR, 2.04; 95% CI, 1.29-3.22; P-trend = 0.005]. A positive plasma α-tocopherol-prostate cancer association also seemed limited to high-grade disease (Gleason grade, 7-10; overall Q5 HR, 1.59; 95% CI, 1.13-2.24; P-trend = 0.001; among men receiving selenomethionine, Q5 HR, 2.12; 95% CI, 1.32-3.40; P-trend = 0.0002). Our findings indicate that higher plasma α-tocopherol concentrations may interact with selenomethionine supplements to increase high-grade prostate cancer risk, suggesting a biologic interaction between α-tocopherol and selenium itself or selenomethionine. © 2014 American Association for Cancer Research.


Agler A.H.,Cornell University | Kurth T.,Brigham and Women's Hospital | Kurth T.,French Institute of Health and Medical Research | Kurth T.,University Pierre and Marie Curie | And 4 more authors.
Thorax | Year: 2011

Background: The oxidant/antioxidant balance in lung tissue is hypothesised to contribute to the risk of chronic obstructive pulmonary disease (COPD). Observational studies consistently report higher antioxidant status associated with lower COPD risk, but few randomised studies have been reported. Methods: A post hoc analysis of 38 597 women without chronic lung disease at baseline was conducted in the Women's Health Study (WHS) to test the effect of vitamin E on the risk of incident chronic lung disease. The WHS is a randomised double-blind placebo-controlled factorial trial of vitamin E (600 IU every other day) and aspirin (100 mg every other day) in female health professionals aged ≥45 years. Using Cox proportional hazards models, the effect of randomised vitamin E assignment on self-reported physician-diagnosed chronic lung disease was evaluated. Results: During 10 years of follow-up (376 710 person-years), 760 first occurrences of chronic lung disease were reported in the vitamin E arm compared with 846 in the placebo arm (HR 0.90; 95% CI 0.81 to 0.99; p=0.029). This 10% reduction in the risk of incident chronic lung disease was not modified by cigarette smoking, age, randomised aspirin assignment, multivitamin use or dietary vitamin E intake (minimum p for interaction=0.19). Current cigarette smoking was a strong predictor of chronic lung disease risk (HR 4.17; 95% CI 3.70 to 4.70; vs. never smokers). Conclusions: In this large randomised trial, assignment to 600 IU vitamin E led to a 10% reduction in the risk of chronic lung disease in women.


PubMed | University of California at Irvine, Research and Information Center, University of Houston, National Cancer Institute and 4 more.
Type: Journal Article | Journal: Cancer prevention research (Philadelphia, Pa.) | Year: 2014

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed higher prostate cancer incidence in men supplemented with high-dose -tocopherol. We, therefore, examined whether presupplementation plasma -tocopherol or -tocopherol was associated with overall or high-grade prostate cancer. A stratified case-cohort sample that included 1,746 incident prostate cancer cases diagnosed through June 2009 and a subcohort of 3,211 men was derived from the SELECT trial of 35,533 men. Plasma was collected at entry from 2001 to 2004, and median follow-up was 5.5 years (range, 0-7.9 years). Incidence of prostate cancer as a function of plasma -tocopherol, -tocopherol, and supplementation with -tocopherol or selenomethionine was estimated by the hazard ratio (HR). Plasma -tocopherol was not associated with prostate cancer. Men with higher -tocopherol concentrations seemed to have risk similar to that of men with lower concentrations [overall HR for fifth (Q5) vs. first quintile (Q1), 1.21; 95 % confidence interval (CI), 0.88-1.66; P-trend = 0.24; in the trial placebo arm, Q5 HR, 0.85; 95% CI, 0.44-1.62; P-trend = 0.66]. We found a strong positive plasma -tocopherol association among men receiving the trial selenomethionine supplement [Q5 HR, 2.04; 95% CI, 1.29-3.22; P-trend = 0.005]. A positive plasma -tocopherol-prostate cancer association also seemed limited to high-grade disease (Gleason grade, 7-10; overall Q5 HR, 1.59; 95% CI, 1.13-2.24; P-trend = 0.001; among men receiving selenomethionine, Q5 HR, 2.12; 95% CI, 1.32-3.40; P-trend = 0.0002). Our findings indicate that higher plasma -tocopherol concentrations may interact with selenomethionine supplements to increase high-grade prostate cancer risk, suggesting a biologic interaction between -tocopherol and selenium itself or selenomethionine.


Chuang C.,Chiba University | Woo T.-P.,National Taiwan University | Woo T.-P.,Research and Information Center | Liu F.-H.,National Taiwan University | And 4 more authors.
2016 Compound Semiconductor Week, CSW 2016 - Includes 28th International Conference on Indium Phosphide and Related Materials, IPRM and 43rd International Symposium on Compound Semiconductors, ISCS 2016 | Year: 2016

Chemical vapor deposition (CVD) graphene would find great applications in industrial graphene-based electronics recently. Most importantly, the one-dimensional constriction of CVD graphene due to its grain boundaries and merged domains revealing interesting interference effects, like Aharonov-Bohm effect. Such interesting interference transport behavior can be revealed by low-temperature scanning gate microscopy (LT-SGM) and be numerical simulated about the dynamic transport point of view by mean-field Gross-Pitaevskii equation. In order to realize graphene-based quantum transport device, our results suggested that the supplying additional thermal current could flood into the grain boundaries and merged domains in one-dimensional quantum confined CVD graphene so as to suppress the interference effect, a great discovery for graphene-based materials coherent electronic devices. © 2016 IEEE.


Gavin M.C.,Beth Israel Deaconess Medical Center | Newton-Cheh C.,The Broad Institute of MIT and Harvard | Newton-Cheh C.,Massachusetts General Hospital | Gaziano J.M.,Research and Information Center | And 5 more authors.
Heart Rhythm | Year: 2011

Background: Homozygosity for a common nonsynonymous single nucleotide polymorphism (Gln27Glu) in the β2-adrenergic receptor gene (ADRB2) has been inconsistently associated with sudden cardiac death (SCD) in individual studies of small sample size. Objective: The purpose of this study was to examine the association between the Gln27Glu polymorphism and SCD in a large combined sample of SCD cases. Methods: Nested case-control analysis was performed for individuals of Caucasian ancestry enrolled in six prospective cohort studies. Genotypes for the Gln27Glu variant were determined for 492 cases of SCD and 1,388 controls matched for age, sex, cohort, follow-up time, and history of cardiovascular disease (CVD) and at the time of the blood draw. Individual studies were combined with conditional logistic regression with fixed effects meta-analysis assuming a recessive model. Results: Homozygosity for the Gln27 allele conferred a nonsignificant elevation of the age-adjusted odds ratio (OR 1.22, 95% confidence interval [CI] 0.981.53, P = .08) for SCD, which became marginally significant after controlling for multiple cardiac risk factors (OR 1.30, 95% CI 1.011.67, P = .046). In secondary analyses using controls additionally matched for the development of nonfatal CVD after the blood draw, results were attenuated (OR 1.19, 95% CI 0.921.52, P = .19). When the results of the primary analysis were combined in meta-analysis with published reports, a significant association between ADRB2 genotype and SCD emerged (OR 1.35, 95% CI 1.151.60, P = .0003). Conclusion: These data from a large prospective case-control series, when combined with published studies, provide further evidence for an association between ADRB2 genotype and SCD. The mechanism is unknown but appears to be partly mediated by development of CVD. © 2011 Heart Rhythm Society.

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