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1.  Total Energy Intake and Breast Cancer Risk in Sisters: the Breast Cancer Family Registry 
Energy restriction inhibits mammary tumor development in animal models. Epidemiologic studies in humans generally do not support an association between dietary energy intake and breast cancer risk, although some studies suggest a more complex interplay between measures of energy intake, physical activity and body size. We examined the association between total energy intake jointly with physical activity and body mass index (BMI) and the risk of breast cancer among 1,775 women diagnosed with breast cancer between 1995 and 2006 and 2,529 of their unaffected sisters enrolled in the Breast Cancer Family Registry (BCFR). We collected dietary data using the Hawaii-Los Angeles Multiethnic Cohort food frequency questionnaire. Using conditional logistic regression to estimate the odds ratios (OR) and 95% confidence intervals (CI) associated with total energy intake, we observed an overall 60% -70% increased risk of breast cancer among women in the highest quartile of total energy intake compared to those in the lowest quartile (Q4 vs. Q1: OR =1.6, 95% CI: 1.3-2.0; P trend < 0.0001); these associations were limited to pre-menopausal women or women with hormone receptor positive cancers. Although the associations were slightly stronger among women with a higher BMI or lower level of average lifetime physical activity, we observed a positive association between total energy intake and breast cancer risk across different strata of physical activity and, BMI. Our results suggest that within sisters, high energy intake may increase the risk of breast cancer risk independent from physical activity and body size. If replicated in prospective studies, these findings suggest that reductions in total energy intake may help modify breast cancer risk.
doi:10.1007/s10549-012-2342-8
PMCID: PMC4032289  PMID: 23225141
Breast cancer; energy balance; energy intake; physical activity; body mass index
2.  White blood cell global methylation and IL-6 promoter methylation in association with diet and lifestyle risk factors in a cancer-free population 
Epigenetics  2012;7(6):606-614.
Altered levels of global DNA methylation and gene silencing through methylation of promoter regions can impact cancer risk, but little is known about their environmental determinants. We examined the association between lifestyle factors and levels of global genomic methylation and IL-6 promoter methylation in white blood cell DNA of 165 cancer-free subjects, 18–78 years old, enrolled in the COMIR (Commuting Mode and Inflammatory Response) study, New York, 2009–2010. Besides self-administrated questionnaires on diet and physical activity, we measured weight and height, white blood cell (WBC) counts, plasma levels of high sensitivity C-reactive protein (hs-CRP), and genomic (LINE-1) and gene-specific methylation (IL-6) by pyrosequencing in peripheral blood WBC. Mean levels of LINE-1 and IL-6 promoter methylation were 78.2% and 57.1%, respectively. In multivariate linear regression models adjusting for age, gender, race/ethnicity, body mass index, diet, physical activity, WBC counts and CRP, only dietary folate intake from fortified foods was positively associated with LINE-1 methylation. Levels of IL-6 promoter methylation were not significantly correlated with age, gender, race/ethnicity, body mass index, physical activity or diet, including overall dietary patterns and individual food groups and nutrients. There were no apparent associations between levels of methylation and inflammation markers such as WBC counts and hs-CRP. Overall, among several lifestyle factors examined in association with DNA methylation, only dietary folate intake from fortification was associated with LINE-1 methylation. The long-term consequence of folate fortification on DNA methylation needs to be further evaluated in longitudinal settings.
doi:10.4161/epi.20236
PMCID: PMC3398989  PMID: 22531363
DNA Methylation; cancer; diet; lifestyle factors
3.  Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood 
Epigenetics  2011;6(5):623-629.
Reduced levels of global DNA methylation are associated with genomic instability and are independent predictors of cancer risk. Little is known about the environmental determinants of global DNA methylation in peripheral blood. We examined the association between demographic and lifestyle factors and levels of global leukocyte DNA methylation in 161 cancer-free subjects enrolled in the North Texas Healthy Heart Study aged 45–75 years in 2008. We used in-person interviews for demographics and lifestyle factors, a self-administrated Block food frequency questionnaire for diet, and bioelectrical impedance analysis and CT-scan for body composition. We measured genomic DNA methylation using bisulfite conversion of DNA and pyrosequencing for LINE-1. Body composition measures including body mass index, waist circumference, areas of subcutaneous fat and visceral fat, percent of fat mass and fat-free mass were not associated with global genomic DNA methylation after controlling the effect of age, gender and race/ethnicity. Instead, female gender was significantly associated with a reduced level of global methylation (β = −2.77, 95% CI: −4.33, −1.22). Compared to non-Hispanic whites, non-Hispanic blacks (β = −2.02, 95% CI: −3.55, −0.50) had significantly lower levels of global methylation. No association was found with age, cigarette smoking, alcohol drinking and dietary intake of nutrients in one-carbon metabolism. Global leukocyte DNA methylation differs by gender and race/ethnicity, suggesting these variables need to be taken into consideration in studies of global DNA methylation as an epigenetic marker for cancer.
doi:10.4161/epi.6.5.15335
PMCID: PMC3230547  PMID: 21739720
gender; race/ethnicity; DNA methylation
4.  Physical activity and global genomic DNA methylation in a cancer-free population 
Epigenetics  2011;6(3):293-299.
Changes in DNA methylation may represent an intermediate step between the environment and human diseases. Little is known on whether behavioral risk factors may modify gene expression through DNA methylation. To assess whether DNA methylation is associated with different levels of physical activity, we measured global genomic DNA methylation using bisulfite-converted DNA and real-time PCR (MethyLight) for LINE-1 in peripheral blood of 161 participants aged 45–75 years enrolled in the North Texas Healthy Heart Study and levels of physical activity using an accelerometer (Actigraph GT1M Monitor). We found that individuals with physical activity 26–30 min/day had a significantly higher level of global genomic DNA methylation compared to those with physical activity ≤10 min/day (β = 2.52, 95% CI: 0.70, 4.35). However, the association was attenuated and became statistically insignificant after multivariate adjustment (β = 1.24, 95% CI: −0.93, 3.40). There were some suggestions of a positive association between physical activity and global genomic DNA methylation in non-Hispanics (β = 1.50, 95% CI: −0.08, 3.08) that warrants further investigation.
doi:10.4161/epi.6.3.14378
PMCID: PMC3092677  PMID: 21178401
DNA methylation; physical activity; peripheral blood
5.  An international case-control study of adult diet and brain tumor risk: a histology-specific analysis by food group 
Annals of epidemiology  2009;19(3):10.1016/j.annepidem.2008.12.010.
PURPOSE
Existing studies of diet and adult brain tumors have been limited by small numbers in histology–specific subgroups. Dietary data from an international collaborative case-control study on adult brain tumors were used to evaluate associations between histology-specific risk and consumption of specific food groups.
METHODS
The study included 1,548 cases diagnosed between 1984 and 1991 and 2,486 controls from 8 study centers in 6 countries. Of the 1,548 cases, 1,185 were gliomas, 332 were meningiomas, and 31 were other tumor types. Dietary consumption was measured as average g/day.
RESULTS
We found inverse associations between some vegetable groups and glioma risk, the strongest for yellow-orange vegetables (odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.5–0.9 for the 4th vs. 1st quartile of consumption, p for trend < 0.001), and the association was limited to specific glioma subtypes. There was no association with cured meat. Non-cured meat was associated with a modest increase in glioma risk (OR = 1.3, CI = 1.0–1.7 for 4th quartile vs. 1st quartile, p for trend = 0.01). We also found positive associations between egg, grain, and citrus fruit consumption and glioma but not meningioma risk.
CONCLUSIONS
Our study suggests that selected dietary food groups may be associated with adult gliomas and its subtypes, but not meningiomas.
doi:10.1016/j.annepidem.2008.12.010
PMCID: PMC3832293  PMID: 19216998
brain tumors; glioma; meningioma; diet; N-nitroso compounds; vegetables
6.  Neuropathic Pain in Rats with a Partial Sciatic Nerve Ligation Is Alleviated by Intravenous Injection of Monoclonal Antibody to High Mobility Group Box-1 
PLoS ONE  2013;8(8):e73640.
High mobility group box-1 (HMGB1) is associated with the pathogenesis of inflammatory diseases. A previous study reported that intravenous injection of anti-HMGB1 monoclonal antibody significantly attenuated brain edema in a rat model of stroke, possibly by attenuating glial activation. Peripheral nerve injury leads to increased activity of glia in the spinal cord dorsal horn. Thus, it is possible that the anti-HMGB1 antibody could also be efficacious in attenuating peripheral nerve injury-induced pain. Following partial sciatic nerve ligation (PSNL), rats were treated with either anti-HMGB1 or control IgG. Intravenous treatment with anti-HMGB1 monoclonal antibody (2 mg/kg) significantly ameliorated PSNL-induced hind paw tactile hypersensitivity at 7, 14 and 21 days, but not 3 days, after ligation, whereas control IgG had no effect on tactile hypersensitivity. The expression of HMGB1 protein in the spinal dorsal horn was significantly increased 7, 14 and 21 days after PSNL; the efficacy of the anti-HMGB1 antibody is likely related to the presence of HMGB1 protein. Also, the injury-induced translocation of HMGB1 from the nucleus to the cytosol occurred mainly in dorsal horn neurons and not in astrocytes and microglia, indicating a neuronal source of HMGB1. Markers of astrocyte (glial fibrillary acidic protein (GFAP)), microglia (ionized calcium binding adaptor molecule 1 (Iba1)) and spinal neuron (cFos) activity were greatly increased in the ipsilateral dorsal horn side compared to the sham-operated side 21 days after PSNL. Anti-HMGB1 monoclonal antibody treatment significantly decreased the injury-induced expression of cFos and Iba1, but not GFAP. The results demonstrate that nerve injury evokes the synthesis and release of HMGB1 from spinal neurons, facilitating the activity of both microglia and neurons, which in turn leads to symptoms of neuropathic pain. Thus, the targeting of HMGB1 could be a useful therapeutic strategy in the treatment of chronic pain.
doi:10.1371/journal.pone.0073640
PMCID: PMC3749159  PMID: 23991202
7.  Soft drink intake and progression of radiographic knee osteoarthritis: data from the osteoarthritis initiative 
BMJ Open  2013;3(7):e002993.
Objectives
We examine the prospective association of soft drink consumption with radiographic progression of knee osteoarthritis (OA).
Design
Prospective cohort study.
Setting
This study used data from the osteoarthritis initiative (OAI).
Participants
In OAI, 2149 participants with radiographic knee OA and having dietary data at baseline were followed up to 12, 24, 36 and 48 months.
Measures
The soft drink consumption was assessed with a Block Brief Food Frequency Questionnaire completed at baseline. To evaluate knee OA progression, we used quantitative medial tibiofemoral joint space width (JSW) based on plain radiographs. The multivariate linear models for repeated measures were used to test the independent association between soft drink intake and the change in JSW over time, while adjusting for body mass index and other potential confounding factors.
Results
In stratified analyses by gender, we observed a significant dose–response relationship between baseline soft drink intake and adjusted mean change of JSW in men. With increasing levels of soft drink intake (none, ≤1, 2–4 and ≥5 times/week), the mean decreases of JSW were 0.31, 0.39, 0.34 and 0.60 mm, respectively. When we further stratified by obesity, a stronger dose–response relationship was found in non-obese men. In obese men, only the highest soft drink level (≥5 times/week) was associated with increased change in JSW compared with no use. In women, no significant association was observed.
Conclusions
Our results suggest that frequent consumption of soft drinks may be associated with increased OA progression in men. Replication of these novel findings in other studies demonstrating the reduction in soft drink consumption leads to delay in OA progression is needed.
doi:10.1136/bmjopen-2013-002993
PMCID: PMC3717463  PMID: 23872291
Rheumatology; Nutrition & Dietetics
8.  BIOLOGIC AND EPIGENETIC IMPACT OF COMMUTING TO WORK BY CAR OR USING PUBLIC TRANSPORTATION: A CASE-CONTROL STUDY 
Preventive medicine  2012;54(0):229-233.
Background and Aims
Commuting by public transportation (PT) entails more physical activity and energy expenditure than by cars, but its biologic consequences are unknown.
Methods
In 2009-2010, we randomly sampled New York adults, usually commuting either by car (n=79) or PT (n=101). Measures comprised diet and physical activity questionnaires, weight and height, white blood cell (WBC) count, C reactive protein, (CRP) gene-specific methylation (IL-6), and global genomic DNA methylation (LINE-1 methylation).
Results
Compared to the 101 PT commuters, the 79 car drivers were about 9 years older, 2 kg/m2 heavier, more often non-Hispanic whites, and ate more fruits and more meats. The 2005 guidelines for physical activity were met by more car drivers than PT users (78.5% vs. 65.0%). There were no differences in median levels of CRP (car vs. PT: 0.6 vs. 0.5 mg/dl), mean levels of WBC (car vs. PT: 6.7 vs. 6.5 cells/mm3), LINE-1 methylation (car vs. PT: 78.0% vs. 78.3%), and promoter methylation of IL-6 (car vs. PT: 56.1% vs. 58.0%).
Conclusions
PT users were younger and lighter than car drivers, but their commute mode did not translate into a lower inflammatory response or a higher DNA methylation, maybe because, overall, car drivers were more physically active.
doi:10.1016/j.ypmed.2012.01.019
PMCID: PMC3670595  PMID: 22313796
9.  Blood leukocyte DNA hypomethylation and gastric cancer risk in a high-risk Polish population 
Global hypomethylation has been shown to increase genome instability potentially leading to increased cancer risk. We determined whether global methylation in blood leukocyte DNA was associated with gastric cancer in a population-based study on 302 gastric cancer cases and 421 age- and sex-matched controls in Warsaw, Poland, between 1994 and 1996. Using PCR-pyrosequencing, we analyzed methylation levels of Alu and LINE-1, 2 CG-rich repetitive elements, to measure global methylation levels. Gastric cancer risk was highest among those with lowest level of methylation in either Alu (OR = 1.3, 95% CI = 0.9–1.9) or LINE-1 (OR = 1.4, 95% CI = 0.9–2.0) relative to those with the highest levels, although the trends were not statistically significant. For Alu, the association was stronger among those aged 70 or older (OR = 2.6, 95% CI = 1.3–5.5, p for interaction = 0.02). We did not observe meaningful differences in the associations by other risk factors and polymorphisms examined. For LINE-1, the association tended to be stronger among individuals with a family history of cancer (OR = 3.1, 95% CI = 1.4–7.0, p for interaction = 0.01), current alcohol drinkers (OR = 1.9, 95% CI = 1.0–3.6, p for interaction = 0.05), current smokers (OR = 2.3, 95% CI = 1.1–4.6, p for interaction = 0.02), those who rarely or never consumed fruit (OR = 3.1, 95% CI = 1.2–8.1, p for interaction = 0.03), CC carriers for the MTRR Ex5+123C>T polymorphism (OR = 2.3, 95% CI = 1.2–4.4, p for interaction = 0.01) and TT carriers for the MTRR Ex15+572T>C polymorphism (OR = 1.7, 95% CI = 1.0–2.8, p for interaction = 0.06). The association was not different by sex, Helicobacter pylori infection, intake of folate, vitamin B6 and total protein and the remaining polymorphisms examined. Our results indicate that interactions between blood leukocyte DNA hypomethylation and host characteristics may determine gastric cancer risk.
doi:10.1002/ijc.25190
PMCID: PMC3009461  PMID: 20099281
gastric cancer; methylation; global hypomethylation; gastric cancer risk
10.  Cigarette smoking, body mass index, gastro-esophageal reflux disease, and non-steroidal anti-inflammatory drug use and risk of subtypes of esophageal and gastric cancers by P53 overexpression 
Cancer causes & control : CCC  2008;20(3):361-368.
A number of risk factors for esophageal and gastric cancers have emerged, yet little is known whether risk factors map to molecular tumor markers such as overexpression of the tumor suppressor TP53. Using a US multicenter, population-based case-control study (170 cases of esophageal adenocarcinomas, 147 gastric cardia adenocarcinomas, 220 non-cardia gastric adenocarcinomas, and 112 esophageal squamous cell carcinomas), we examined whether the risk associated with cigarette smoking, body mass index (BMI), gastroesophageal reflux disease (GERD), and non-steroidal anti-inflammatory drug (NSAID) use varied by P53 overexpression. We defined P53 overexpression through immunohistochemistry of paraffin-embedded tumor tissues, using cutpoints based on percent of cells positive. Polytomous logistic regression was used to assess differences between each case group (defined by tumor subtype and P53 expression) and the control group by risk factors. The proportion of cases overexpressing P53 by tumor subtype was 72% for esophageal adenocarcinoma, 69% for gastric cardia adenocarcinoma, 52% for non-cardia gastric adenocarcinoma, and 67% for esophageal squamous cell carcinoma. For most tumor subtypes, we found little difference in risk factors by tumor P53 overexpression. For non-cardia gastric cancer however, an association with cigarette smoking was suggested for tumors that do not overexpress P53, while larger BMI was related with tumors that overexpress P53 verses no overexpression. Overall, this study did not find a clear relationship between P53 protein overexpression and known risk factors for subtypes of esophageal and gastric cancers. Further research with these tumors is needed to identify molecular markers associated with variations in the risk factor profiles.
doi:10.1007/s10552-008-9250-6
PMCID: PMC2726999  PMID: 18989634

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