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1.  Phytanic acid and the risk of non-Hodgkin lymphoma 
Carcinogenesis  2012;34(1):170-175.
Greater consumption of red meat, processed meat and dairy products has been associated with an increased risk of non-Hodgkin lymphoma (NHL) in several previous reports. Phytanic acid, a saturated fatty acid obtained primarily through the consumption of ruminant meat and dairy products, may offer a potential underlying mechanism for these associations. In a population-based case–control study of 336 cases and 460 controls conducted in Nebraska during 1999–2002, we examined whether phytanic acid-containing foods or total phytanic acid intake, estimated from a food frequency questionnaire and the published phytanic acid values of 151 food items, were associated with increased NHL risk. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals for overall NHL and the common NHL histologic subtypes. In multivariable models, higher intakes of density-adjusted beef [ORT3 vs. T1 = 1.5 (1.1–2.2); Ptrend = 0.02], total dairy products [OR = 1.5 (1.1–2.2); Ptrend = 0.02) and milk [OR = 1.6 (1.1–2.3); Ptrend = 0.01] were associated with an increased risk of NHL. Intake of total phytanic acid was positively associated with NHL risk [OR = 1.5 (1.0–2.1); Ptrend = 0.04]. In analyses stratified by NHL subtype, greater consumption of beef was associated with an increased risk of diffuse large B-cell lymphoma, and greater consumption of milk was associated with an increased risk of follicular lymphoma (FL). Total phytanic acid intake was associated with an increased risk of FL and small lymphocytic lymphoma/chronic lymphocytic leukemia. Our results provide support that total phytanic acid and phytanic acid-containing foods may increase NHL risk.
doi:10.1093/carcin/bgs315
PMCID: PMC3534193  PMID: 23042099
2.  Inverse Association Between Glutathione Peroxidase Activity and Both Selenium Binding Protein 1 Levels and Gleason Score in Human Prostate Tissue 
The Prostate  2011;72(9):1006-1012.
Background
Data from human epidemiological studies, cultured mammalian cells, and animal models have supported a potentially beneficial role of selenium (Se) in prostate cancer prevention. In addition, Se-containing proteins including members of the glutathione peroxidase (GPx) family and Selenium Binding Protein 1 (SBP1) have been linked to either cancer risk or development. For example, SBP1 levels are typically reduced in tumors compared to non-cancerous tissue, with the degree of reduction associated with increasingly poor clinical outcome.
Methods
In order to investigate inter-relationships between blood and tissue Se levels and GPx activity, tissue SBP1 levels, and disease aggressiveness using the Gleason Score, we measured these selenium status biomarkers in fasting serum and histologically normal prostate tissues obtained from 24 men undergoing radical prostatectomy for the treatment of localized prostate cancer.
Results
GPx enzyme activity was inversely correlated with SBP1 levels in prostate tissue as determined by densitometry of western blots obtained using anti-SBP1 antibodies (partial Spearman correlation coefficients and corresponding p-values overall and in African-Americans = −0.42 (0.08) and −0.53 (0.10), respectively), which is consistent with previous observations in cultured cells and mice. Of particular interest was the positive correlation between tissue GPx activity and Gleason Score, with this relationship achieving statistical significance among African Americans (r=0.67, p=0.02).
Conclusion
. These studies support the continued investigation of the role of Se and selenoproteins in prostate cancer prevention, development and prognosis.
doi:10.1002/pros.21506
PMCID: PMC3288333  PMID: 22072582
Selenium; GPx; SBP1; prostate; Gleason score
3.  Intakes of Fruit, Vegetables, and Specific Botanical Groups in Relation to Lung Cancer Risk in the NIH-AARP Diet and Health Study 
American Journal of Epidemiology  2008;168(9):1024-1034.
Increased fruit and vegetable consumption may protect against lung cancer, although epidemiologic findings are inconclusive. The authors prospectively examined associations between lung cancer risk and intakes of fruit, vegetables, and botanical subgroups in 472,081 participants aged 50–71 years in the National Institutes of Health (NIH)-AARP Diet and Health Study. Diet was assessed at baseline (1995–1996) with a 124-item dietary questionnaire. A total of 6,035 incident lung cancer cases were identified between 1995 and 2003. Total fruit and vegetable intake was unrelated to lung cancer risk in both men and women. Higher consumption of several botanical subgroups, however, was significantly inversely associated with risk, but only in men. For example, the relative risks of lung cancer among men in the highest versus lowest quintiles of intake of rosaceae, convolvulaceae, and umbelliferae were 0.82 (95% confidence interval (CI): 0.73, 0.91), 0.86 (95% CI: 0.75, 0.96), and 0.86 (95% CI: 0.78, 0.96), respectively; corresponding relative risks in women were 0.97 (95% CI: 0.85, 1.12), 0.95 (95% CI: 0.83, 1.09), and 0.92 (95% CI: 0.80, 1.06). These results provide support for a protective role of specific botanical subgroups of fruits and vegetables in lung cancer prevention in men, although the findings could also be due to residual confounding by smoking or chance.
doi:10.1093/aje/kwn212
PMCID: PMC2631557  PMID: 18791192
cohort studies; fruit; lung neoplasms; vegetables
4.  Effects of β-carotene supplementation on molecular markers of lung carcinogenesis in male smokers 
Two primary prevention trials unexpectedly demonstrated adverse effects of supplemental β-carotene on lung cancer incidence in cigarette smokers. To elucidate the molecular mechanisms that might underlie these effects, we studied the immunohistochemical expression of cytochrome P450 (CYP) 1A1, 1A2, and 2E1, retinoic acid receptor-β (RAR-β), activated protein-1 (AP-1) elements, cyclin D1, and Ki67 in lung tumors and, when available, adjacent normal tissues obtained from incident cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Archival lung tissue was available from 52 men randomized to receive 20 mg of β-carotene per day and 30 men randomized to the placebo arm, all of whom were diagnosed with incident non-small cell lung carcinoma during the course of the trial and subsequently underwent radical pulmonary resection. In normal appearing bronchial epithelium, positive staining for cyclin D1 was observed in 23% of cases in the β-carotene group and 0% of cases in the placebo group (based on only 3 of 13 versus 0 of 11 cases staining positively, however; p=0.04), with no differences in expression noted in lung tumor tissue (p=0.48). There were no statistically significant differences in Ki67 expression in normal or cancerous lung tissue between intervention groups, although a small increase in staining was noted among cases in the β-carotene versus placebo group (88% versus 71% of cases stained positive, respectively; p=0.13). Contrary to expectation, β-carotene supplementation had no apparent effect on RAR-β expression. These findings suggest that male smokers supplemented with β-carotene may have had an increased risk of lung cancer due to aberrant cell growth, although our results are based on a relatively small number of cases and require confirmation in other completed trials of β-carotene supplementation.
doi:10.1158/1940-6207.CAPR-09-0107
PMCID: PMC3496925  PMID: 20484175
β-carotene; immunohistochemistry; lung cancer; smoking; supplementation
5.  Associations between functional polymorphisms in antioxidant defense genes and urinary oxidative stress biomarkers in healthy, premenopausal women 
Genes & Nutrition  2011;7(2):191-195.
Functional polymorphisms in endogenous antioxidant defense genes including manganese superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX-1) have been linked with risk of cancer at multiple sites. Although it is presumed that these germline variants impact disease risk by altering the host’s ability to detoxify mutagenic reactive oxygen species, very few studies have directly examined this hypothesis. Concentrations of 8-isoprostane F2α (8-iso-PGF2α) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxoxdG)—sensitive indicators of lipid peroxidation and DNA oxidation, respectively—were measured in 24-h urine samples obtained from 93 healthy, premenopausal women participating in a dietary intervention trial. In addition, DNA was extracted from blood for genotyping of MnSOD Val16Ala, CAT-262 C > T, and GPX1 Pro198Leu genotypes by Taqman assay. Although geometric mean concentrations of 8-iso-PGF2α and 8-oxoxdG varied across several study characteristics including race, education level, body mass index, and serum antioxidant levels, there was little evidence that these biomarkers differed across any of the examined genotypes. In summary, functional polymorphisms in endogenous antioxidant defense genes do not appear to be strongly associated with systemic oxidative stress levels in young, healthy women.
doi:10.1007/s12263-011-0257-3
PMCID: PMC3316746  PMID: 22068340
Antioxidant; Biomarker; Oxidative stress; Polymorphism; Women
6.  Genome-wide association study identifies common variants associated with circulating vitamin E levels 
Human Molecular Genetics  2011;20(19):3876-3883.
In genome-wide association studies (GWAS) of common genetic variants associated with circulating alpha- and gamma-tocopherol concentrations in two adult cohorts comprising 5006 men of European descent, we observed three loci associated with alpha-tocopherol levels, two novel single-nucleotide polymorphisms (SNPs), rs2108622 on 19pter-p13.11 (P= 1.7 × 10−8) and rs11057830 on 12q24.31 (P= 2.0 × 10−8) and confirmed a previously reported locus marked by rs964184 on 11q23.3 (P= 2.7 × 10−10). The three SNPs have been reported to be associated with lipid metabolism and/or regulation. We replicated these findings in a combined meta-analysis with two independent samples, P= 7.8 × 10−12 (rs964184 on 11q23.3 near BUD13, ZNF259 and APOA1/C3/A4/A5), P= 1.4 × 10−10 (rs2108622 on 19pter-p13.11 near CYP4F2) and P= 8.2 × 10−9 (rs11057830 on 12q24.31 near SCARB1). Combined, these SNPs explain 1.7% of the residual variance in log alpha-tocopherol levels. In one of the two male GWAS cohorts (n= 992), no SNPs were significantly associated with gamma-tocopherol concentrations after including data from the replication sample for 71 independent SNPs with P< 1 × 10−4 identified.
doi:10.1093/hmg/ddr296
PMCID: PMC3168288  PMID: 21729881
7.  No association between fruit, vegetables, antioxidant nutrients and risk of renal cell carcinoma 
Previous epidemiologic studies that have examined the relationship between renal cell carcinoma (RCC) risk and intakes of plant foods and antioxidant nutrients have yielded inconsistent results. We therefore examined the associations between intakes of fruit, vegetables, carotenoids, flavonoids, vitamin E, and vitamin C and RCC risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. At baseline, 27,062 male Finnish smokers aged 50–69 years completed a 276-item dietary questionnaire that included questions on frequency of consumption and portion size. During up to 19 years of follow-up, 255 men developed RCC. Cox proportional hazards models were utilized to estimate relative risks (RR) and 95% confidence intervals (CI). Despite a large range in intake, no association was observed between fruit, vegetables, or antioxidant nutrients and RCC risk. For example, multivariate RRs and 95% CIs for the highest versus the lowest quartile of intake were 0.79 (0.55–1.14), 1.23 (0.85–1.79), 1.09 (0.74–1.60), 0.83 (0.57–1.21), 1.09 (0.73–1.64), and 0.99 (0.67–1.46) for fruit, vegetables, total carotenoids, total flavonoids, total vitamin E, and vitamin C, respectively (all p-values for trend > 0.05). Our results indicate that diet may not play a large role in the etiology of RCC in male smokers, although further examination of these associations in nonsmokers, women, and diverse racial populations is warranted.
doi:10.1002/ijc.24829
PMCID: PMC2811212  PMID: 19685494
antioxidants; cohort study; diet; fruit; renal cell cancer; vegetables
8.  Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Prostate Cancer 
Background
The mitogenic and growth-stimulatory effects of insulin-like growth factors appear to play a role in prostate carcinogenesis, yet any direct association of circulating insulin levels and risk of prostate cancer remains unclear.
Methods
We investigated the relationship of the level of serum insulin, glucose, and surrogate indices of insulin resistance (ie, the molar ratio of insulin to glucose and the homeostasis model assessment of insulin resistance [HOMA-IR]) to the development of prostate cancer in a case–cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of Finnish men. We studied 100 case subjects with incident prostate cancer and 400 noncase subjects without prostate cancer from the larger cohort. Fasting serum was collected 5–12 years before diagnosis. We determined insulin concentrations with a double-antibody immunochemiluminometric assay and glucose concentrations with a hexokinase assay. Multivariable logistic regression models estimated relative risks as odds ratios (ORs), and all statistical tests were two-sided.
Results
Insulin concentrations in fasting serum that was collected on average 9.2 years before diagnosis among case subjects were 8% higher than among noncase subjects, and the molar ratio of insulin to glucose and HOMA-IR were 10% and 6% higher, respectively, but these differences were not statistically significant. Among subjects in the second through fourth insulin quartiles, compared with those in the first quartile, increased insulin levels were associated with statistically significantly increased risks of prostate cancer (OR = 1.50, 95% confidence interval [CI] = 0.75 to 3.03; OR = 1.75, 95% CI = 0.86 to 3.56; and OR = 2.55, 95% CI = 1.18 to 5.51; for the second through fourth insulin quartiles, respectively; Ptrend = .02). A similar pattern was observed with the HOMA-IR (OR = 2.10, 95% CI = 1.03 to 4.26; Ptrend = .02) for the highest vs lowest quartiles. Risk varied inconsistently with glucose concentration (Ptrend = .38). A stronger association between insulin level and prostate cancer risk was observed among leaner men and among men who were less physically active at work. Crude prostate cancer incidence was 154 prostate cancers per 100 000 person-years in the lowest quartile of fasting serum insulin vs 394 prostate cancers per 100 000 person-years in the highest quartile.
Conclusion
Elevated fasting levels of serum insulin (but not glucose) within the normal range appear to be associated with a higher risk of prostate cancer.
doi:10.1093/jnci/djp260
PMCID: PMC2744728  PMID: 19700655
9.  Vitamin E intake and Risk of Esophageal and Gastric Cancers in the NIH-AARP Diet and Health Study 
We investigated the association of dietary α-tocopherol, γ-tocopherol, and supplemental vitamin E intake with the risk of esophageal squamous cell carcinoma (ESCC; n = 158), esophageal adenocarcinoma (EAC; n = 382), gastric cardia adenocarcinoma (GCA; n = 320), and gastric noncardia adenocarcinoma (GNCA; n = 327) in the NIH-AARP Diet and Health Study, a cohort of approximately 500,000 people. Data on dietary and supplemental vitamin E intake were collected using a validated questionnaire at baseline and were analyzed using Cox regression models. Intakes were analyzed as continuous variables and as quartiles.
For dietary α-tocopherol, we found some evidence of association with decreased ESCC and increased EAC risk in the continuous analyses, with adjusted hazard ratios (HR) and 95% confidence intervals (CI) of 0.90 (0.81 – 0.99) and 1.05 (1.00 – 1.11), respectively, per 1.17 mg (half the interquartile range) increased intake. However, in quartile analyses, the p-value for trend was non-significant for both of these cancers. There was no association between dietary α-tocopherol and GCA or GNCA. We observed no statistically significant associations with γ-tocopherol. For supplemental vitamin E, the results were mainly null, except for a significantly lower risk of GNCA with higher doses of supplemental vitamin E. An increase of 71 mg/day (half the interquartile range) in supplemental vitamin E had an HR (95% CI) of 0.92 (0.85–1.00) and the p-value for trend in the quartile analyses was 0.015.
doi:10.1002/ijc.24342
PMCID: PMC2686122  PMID: 19326432
10.  Genetic variation in sodium-dependent ascorbic acid transporters and risk of gastric cancer in Poland 
Higher ascorbic acid consumption is associated with a reduced risk of gastric cancer in numerous epidemiologic studies. We investigated whether single nucleotide polymorphisms (SNPs) in SLC23A1 and SLC23A2 — genes that encode key ascorbic acid transport proteins — affect gastric cancer risk in 279 incident cases and 414 age- and gender-matched controls drawn from a population-based case-control study in Poland. Compared to subjects who were homozygous for the common G allele of the SLC23A2 SNP rs12479919, carriers of the AA genotype had a 41% lower risk of gastric cancer [odds ratio (OR) = 0.59, 95% confidence interval (CI): 0.36-0.95; p trend = 0.06]. A haplotype that contained the common allele of the rs6139591, rs2681116, and rs14147458 SNPs in SLC23A2 was also significantly inversely associated with gastric malignancy. No other polymorphisms in either gene were related to risk, and there was no effect modification by ascorbic acid intake. These findings suggest that genetic variation in SLC23A2 impacts gastric cancer risk, although confirmation in other studies is required.
doi:10.1016/j.ejca.2009.01.027
PMCID: PMC2747493  PMID: 19243932
ascorbic acid; gastric cancer; single nucleotide polymorphism; susceptibility
11.  Association of variants in two vitamin E transport genes with circulating vitamin E concentrations and prostate cancer risk 
Cancer research  2009;69(4):1429-1438.
Significant reductions in prostate cancer incidence and mortality were observed in men randomized to receive 50 mg supplemental vitamin E (α-tocopherol) per day in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We hypothesized that variation in key vitamin E transport genes might directly affect prostate cancer risk or modify the effects of vitamin E supplementation. Associations between prostate cancer risk and 13 polymorphisms in two genes – TTPA and SEC14L2 – were examined in 982 incident prostate cancer cases and 851 controls drawn from the ATBC Study. There was no association between the genetic variants and prostate cancer risk. Significant interactions were observed, however, between two variants in SEC14L2 (IVS11+931A>G and IVS11−896A>T) and the trial α-tocopherol supplement such that vitamin E supplementation reduced prostate cancer risk among men who were homozygous for either common allele [odds ratios (OR) and 95% confidence intervals (CI) = 0.52 (0.30−0.90) and 0.64 (0.46−0.88), respectively] and nonsignificantly increased risk among those who carried one or two copies of either variant allele [ORs = 1.27 (0.90−1.79) and 1.21 (0.96−1.52), respectively] (both p for interaction < 0.05). Genotype-phenotype analyses revealed significant but modest differences in baseline circulating concentrations of α-tocopherol and serum responses to the vitamin E supplementation for several polymorphisms. This study demonstrates that genetic variation in TTPA and SEC14L2 is associated with serum α-tocopherol but does not have a direct impact on prostate cancer. Our results do, however, suggest that polymorphisms in SEC14L2 may modify the effect of vitamin supplementation regimens on prostate cancer risk.
doi:10.1158/0008-5472.CAN-08-2343
PMCID: PMC2644342  PMID: 19190344
genetic variants; prostate cancer; SNP; vitamin E
12.  Intakes of fruit, vegetables, and specific botanical groups in relation to lung cancer risk in the NIH-AARP Diet and Health Study 
American journal of epidemiology  2008;168(9):1024-1034.
Increased fruit and vegetable consumption may protect against lung cancer, although epidemiologic findings are inconclusive. The authors prospectively examined associations between lung cancer risk and intakes of fruit, vegetables, and botanical subgroups in 472,081 participants aged 50-71 years in the National Institutes of Health (NIH)-AARP Diet and Health Study. Diet was assessed at baseline with a 124-item dietary questionnaire. A total of 6,035 incident lung cancer cases were identified between 1995 and 2003. Total fruit and vegetable intake was unrelated to lung cancer risk in both men and women. Higher consumption of several botanical subgroups, however, was significantly inversely associated with risk, but only in men. For example, the relative risks (RR) and 95% confidence intervals (CI) for lung cancer among men in the highest versus lowest quintiles of intake of rosaceae, convolvulaceae, and umbelliferae were 0.82 (0.73, 0.91), 0.86 (0.78, 0.96), and 0.86 (0.78, 0.96), respectively; corresponding RRs in women were 0.97 (0,85, 1.12), 0.95 (0.83, 1.09), and 0.92 (0.80, 1.06). These results provide support for a protective role of specific botanical subgroups of fruit and vegetables in lung cancer prevention in men, although these findings could also be due to residual confounding by smoking or chance.
doi:10.1093/aje/kwn212
PMCID: PMC2631557  PMID: 18791192
cohort studies; fruit; lung neoplasms; vegetables
13.  Education and Risk of Cancer in a Large Cohort of Men and Women in the United States 
PLoS ONE  2008;3(11):e3639.
Background
Education inequalities in cancer incidence have long been noted. It is not clear, however, whether such inequalities persist in the United States, especially for less common malignancies and after adjustment for individual risk factors.
Methodology/Principal Findings
Within the NIH–AARP Diet and Health Study, we examined the association between education and the risk of developing cancers in a prospective cohort of 498 455 participants who were 50–71 year old and without cancer at enrollment in 1995/96. During a maximum 8.2 years of follow–up we identified 40 443 cancers in men and 18 367 in women. In age-adjusted models, the least educated men (
Conclusions/Significance
We found a higher risk of malignant disease, particularly smoking– related cancers, among those in the lowest educational attainment category. Only some of the educational gradient is attributable to smoking. The persistence of substantial education inequalities in cancer incidence poses a challenge for etiologic research and public health policy.
doi:10.1371/journal.pone.0003639
PMCID: PMC2572908  PMID: 18982064

Results 1-13 (13)