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1.  C-Reactive Protein, Lipid-soluble Micronutrients, and Survival in Colorectal Cancer Patients 
Identification of biomarkers associated with survival in cancer patients is important for elucidating the underlying mechanisms of cancer progression and identifying possible interventions to reduce cancer morbidity and mortality.
Using stored patient plasma samples from a multiethnic population-based case-control study of invasive colorectal cancer, we measured post-treatment blood levels of C-reactive protein (CRP) and lipid-soluble micronutrients. Patients (n=368) were followed after phlebotomy (mean of 8 years), during which time 47% died (25% colorectal cancer-specific). Hazard ratios (HR) were estimated by Cox proportional hazards regression with adjustment for stage, age at diagnosis, ethnicity, sex, smoking status, and month of blood draw.
A positive association with overall risk of death was observed for CRP (HR for highest vs. lowest quintile: 1.80; 95% CI: 1.07-3.04; Ptrend=0.01) whereas, inverse associations were generally observed for retinol and carotenoids (HRs for overall risk of death for the highest quintile ranging from 0.5-0.8); these associations were significant for retinol (Ptrend=0.0002), α-carotene (Ptrend=0.02), and total carotenoids (Ptrend=0.02) and were generally consistent across subgroups (sex, ethnicity, cancer anatomical subtype, and stage). Hazard ratios for retinol and carotenoids were attenuated somewhat after adjustment for CRP. Similar trends for CRP were observed for colorectal cancer-specific deaths (HR for highest vs. lowest tertile: 2.06; 95% CI: 1.18-3.61; Ptrend=0.01) as for deaths from all other causes (Pheterogeneity=0.78).
These observations are consistent with a direct relationship between circulating CRP and overall survival among colorectal cancer patients.
These results, if reproduced, suggest that reduction of inflammation should be explored as a potential complementary treatment strategy.
PMCID: PMC3834261  PMID: 23677577
Survival; colorectal cancer; carotenoids; coenzyme Q10; C-reactive protein
2.  Prediagnostic serum tocopherol levels and the risk of Non-Hodgkin Lymphoma: The Multiethnic Cohort 
Compromised immunity and chronic inflammation are thought to contribute to the development of non-Hodgkin lymphoma (NHL). Because tocopherols protect cells through antioxidant mechanisms, they may play a role in NHL etiology.
This nested case-control study within the Multiethnic Cohort examined the association of prediagnostic serum tocopherols levels measured in 271 NHL cases and 538 matched controls by high pressure liquid chromatography/photodiode-array detection with NHL risk. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CI).
We observed U-shaped associations with NHL for total and α-tocopherols (Ptrend<0.01 for polynomial terms [3 df]). The ORs (95% CI) for total tocopherols, which consisted primarily of α-tocopherol, were 0.41 (0.25–0.68), 0.52 (0.32–0.85), 0.39 (0.23–0.65), and 0.78 (0.47–1.29) for the 2nd-5th quintiles as compared to the 1st. The risk estimates were similar for α-tocopherol but non-significant for β- and γ-tocopherol combined and for δ-tocopherol. Adjustment for serum lipids strengthened the non-linear associations for total and α-tocopherols. Serum total tocopherol levels were higher for vitamin E supplement users at cohort entry than non-users (21.32±9.04 vs 17.72±7.43 μg/mL; P <0.0001), but supplement use was not associated with NHL risk. No heterogeneity in risk estimates was detected by sex, ethnicity, vitamin E supplement use, or NHL subtype.
Circulating tocopherols, at levels likely reflecting adequate dietary intakes, may be protective against NHL, whereas higher intakes from supplementation may not be beneficial.
The association between serum tocopherol levels and NHL risk provides possible new insights into the etiology of NHL.
PMCID: PMC3819232  PMID: 24045922
non-Hodgkin lymphoma; tocopherols; ethnicity; prospective cohort; nested case-control study
3.  Effects of vitamin D3 and calcium supplementation on serum levels of tocopherols, retinol, and specific vitamin D metabolites 
Nutrition and cancer  2011;64(1):57-64.
γ-Tocopherol (γT) protects against DNA-damaging effects of nitrogen oxides, yet its physiologic regulation in vivo is unknown. Observational studies indicate inverse associations of 25[OH]-vitamin D with γT and leptin. To determine whether vitamin D3 supplementation alters levels of lipid-soluble micronutrients, serum samples (N=85 subjects) from a randomized, double-blind, placebo-controlled clinical trial of vitamin D3 (800 IU) and calcium (2 g) alone and in combination were analyzed for lipid micronutrients and specific vitamin D metabolites at baseline and after 6-months of supplementation. Serum 25[OH]-vitaminD3 levels increased 55% (P < 0.0001) and 48% (P = 0.0005), whereas 25[OH]-vitaminD2 levels were lower by 48% (P = 0.26) and 21% (P = 0.36) in the vitamin D3 and vitamin D3 plus calcium groups, respectively. At baseline, γT levels were inversely associated with 25[OH]D (r = −0.31, P = 0.004). With vitamin D3 plus calcium treatment, serum α-tocopherol decreased 14% (P = 0.04), while similar changes in γT (19% decrease, P = 0.14) were observed. No significant effects were observed for D3 supplementation on leptin or retinol levels. These results are consistent with the hypothesis that vitamin D3 +/− calcium affects serum tocopherol and 25[OH]D2 levels, however, studies utilizing larger populations are warranted.
PMCID: PMC3731208  PMID: 22149065
4.  Serum coenzyme Q10, α-tocopherol, γ-tocopherol, and C-reactive protein levels and body mass index in adolescent and premenopausal females 
Lipid-soluble antioxidants are associated with a lower incidence for many chronic diseases of aging, possibly by preventing damage from chronic inflammation. In the current study, we compared serum levels of coenzyme Q10 (CoQ10), α-tocopherol, γ-tocopherol, and C-reactive protein (CRP) between adolescent girls and premenopausal women to assess changes from childhood to midlife.
Baseline serum CoQ10, α-tocopherol, γ-tocopherol, and CRP levels were measured in 207 girls (13-19 years) and 183 premenopausal women (34-47 years) using standard methods and the two age groups were compared by t-test. The influence of age, body mass index (BMI) and race/ethnicity and interaction effects on serum values were assessed using analysis of covariance. Pearson correlation coefficients were used to assess associations between pairs of lipid micronutrients.
Overall, adolescent girls had significantly lower mean serum CoQ10, α-tocopherol, γ-tocopherol, and CRP levels relative to premenopausal women (CoQ10: 376 vs. 544 ng/mL, P<0.0001; α-tocopherol: 6.9 vs. 13.5 μg/mL, P<0.0001; γ-tocopherol: 1.3 vs. 1.7 μg/mL, P<0.0001; CRP: 1.29 vs. 2.13 mg/L, P<0.0001). The differences in CoQ10 and tocopherols remained significant after adjustment for BMI and race/ethnicity. CoQ10 was significantly and positively correlated to α- and γ-tocopherol, and BMI was positively associated with CRP and γ-tocopherol in both groups.
Lower serum CoQ10, α-tocopherol, γ-tocopherol, and CRP levels in adolescent girls compared to women suggests that adolescents may have a reduced need for antioxidants possibly due to their lower BMI and inflammatory status as indicated by CRP.
PMCID: PMC4069220  PMID: 24809382
Adolescent girls; premenopausal women; coenzyme Q10; tocopherols; C-reactive protein; Body mass index
5.  Low plasma coenzyme Q10 levels and breast cancer risk in Chinese women 
Low circulating levels of Coenzyme Q10 (CoQ10) have been associated with increased cancer incidence and poor prognosis for a number of cancer types, while a recent prospective study observed a positive association for CoQ10 with breast cancer risk.
We prospectively examined the association of plasma CoQ10 with breast cancer risk in a nested case-control study of Chinese women within the Shanghai Women's Health Study (SWHS). Pre-diagnostic plasma samples were obtained from 340 cases and 653 age-matched controls and analyzed for total CoQ10.
A borderline significant inverse association for breast cancer incidence with plasma CoQ10 level was observed using a conditional logistic regression model adjusted for age and age at first live birth, which became significant after elimination of cases diagnosed within one year of blood draw (ptrend = 0.03). This association was independent of menopausal status. Plasma CoQ10 levels were also observed to be significantly associated with circulating γ-tocopherol (r = 0.50; p < 0.0001) and with α-tocopherol (r =0.38; p < 0.0001) levels.
Circulating levels of CoQ10 were generally low in this population and the observed association with breast cancer risk may be limited to those women with exceptionally low values.
This study reports an inverse relationship between circulating CoQ10 and breast cancer risk, while the only other prospective study of CoQ10 and breast cancer to date found a positive association. Lower levels of CoQ10 in the SWHS population suggests that the two studies may not be contradictory and indicates a possible non-linear (U-shaped) association of CoQ10 with risk.
PMCID: PMC3545677  PMID: 21467235
6.  Coenzyme Q10 in human blood: Native levels and determinants of oxidation during processing and storage 
Free radical biology & medicine  2010;48(12):1610-1617.
Coenzyme Q10 (Q10) is present in the circulation mainly in its reduced form (ubiquinol-10; UL10), but oxidizes quickly ex vivo to ubiquinone-10 (UN10). Therefore, native UL10:UN10 ratios, used as markers of redox status and disease risk, are difficult to measure. We established an RP-(U)HPLC method with coulometric detection to measure natively circulating UL10 and UN10 concentrations by adding a ubiquinol/ubiquinone mixture as an internal standard immediately after plasma preparation. This allowed adjustment for unavoidable artificial UL10 oxidation as well as for total losses (or gains) of analytes during sample storage, processing, and analysis because the internal standards exactly paralleled the chemical behavior of Q10. This technique applied to blood (n = 13) revealed Q10 levels of 680–3300 nM with a mean UL10:UN10 ratio of 95:5, which was inversely associated with total Q10 (r=−0.69; p=0.004). The oxidation of UL10 to UN10 was equimolar, increased by O2, and decreased by lower temperatures or various degassing methods. Although UL10 was stable in blood or when pure in organic solvents at 22 °C, its oxidation was catalyzed dose dependently by α-tocopherol and butylated hydroxytoluene, particularly when present in combination. Key structural features for the catalytic pro-oxidant properties of phenolic antioxidants included two substituents vicinal to the phenolic hydroxyl group.
PMCID: PMC3983242  PMID: 20226852
Coenzyme Q10; Redox status; HPLC; Ubiquinol; Ubiquinone; Internal standard; Native blood levels; Free radicals
7.  Prediagnostic Leptin, Adiponectin, C-reactive Protein and the Risk of Postmenopausal Breast Cancer 
Obesity has been associated with an increased risk of postmenopausal breast cancer. Adipokines and systemic inflammation have been hypothesized to underlie this association. In a case-control study nested within the Multiethnic Cohort, conditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for postmenopausal breast cancer associated with prediagnostic levels of serum leptin, adiponectin, the leptin:adiponectin ratio, and C-reactive protein (CRP). The 706 cases and 706 controls were matched on ethnicity, location (Hawaii or Los Angeles), birth year, date and time of blood draw, hours fasting prior to blood draw, and hormone replacement therapy use at blood draw. Higher circulating levels of leptin (OR Q4 vs. Q1=1.94 [1.37-2.75]; Ptrend = < 0.001), the leptin:adiponectin ratio (OR=1.91 [1.36-2.68]; Ptrend = 0.005), and CRP (OR=1.41 [1.01-1.96]; Ptrend = 0.014) were associated with an increased risk of postmenopausal breast cancer. The positive associations for these markers remained after adjustment for body mass index (BMI). No associations were detected for adiponectin. These data suggest that adipokines and systemic inflammation may be associated with the risk of postmenopausal breast cancer independently of BMI. Further prospective studies examining the role of adipokines and inflammatory processes in the etiology of postmenopausal breast cancer are warranted.
PMCID: PMC3595121  PMID: 23466816
breast cancer; leptin; adiponectin; C-reactive protein; multiethnic population; obesity; nested case-control study; adipokines
8.  Non-Hodgkin Lymphoma and circulating markers of inflammation and adiposity in a nested case-control study: The Multiethnic Cohort 
Since immune dysfunction is thought to underlie the development of Non-Hodgkin Lymphoma (NHL), obesity and chronic inflammation may be involved in its etiology. We examined the association of pre-diagnostic inflammatory markers and adipokines with NHL risk.
We conducted a nested case-control analysis (272 cases and 541 matched controls) within the Multiethnic Cohort. Luminex technology was used to measure a 10-plex panel of cytokines, ELISA assays for adipokines, and an autoanalyzer for C-reactive protein (CRP). Odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles of analytes were estimated by conditional logistic regression.
After a median time of 2.7 years from phlebotomy to diagnosis, interleukin (IL)-10 was significantly related to NHL risk (ORT3 vs T1=3.07; 95%CI: 2.02–4.66; ptrend <0.001). TNF-α and IL-8 showed borderline elevated risks, while IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, and CRP were not associated with NHL. Leptin but not adiponectin was related to NHL risk (ORT3 vs T1=0.48, 95%CI: 0.30–0.76; ptrend<0.001). Adjustment for body mass index did not substantially affect the risk estimates. Stratification by subtype indicated significant associations with IL-10 and leptin for follicular but not for diffuse large B-cell lymphoma. Excluding cases diagnosed <1 year after phlebotomy attenuated all associations.
IL-10 was the only cytokine and leptin the only adipokine associated with NHL, but, due to the short follow-up time, pre-clinical effects cannot be excluded.
Although markers of inflammation and adiposity may provide new insights into the etiology of NHL, they need to be assessed many years before clinical diagnosis.
PMCID: PMC3596426  PMID: 23300021
Non-Hodgkin Lymphoma; inflammatory markers; adiponectin; leptin; nested case-control study; prospective cohort; ethnicity
9.  Plasma 25-hydroxyvitamin D3 is associated with decreased risk of postmenopausal breast cancer in whites: a nested case–control study in the multiethnic cohort study 
BMC Cancer  2014;14:29.
Higher sunlight exposure is correlated with lower incidence of breast cancer in ecological studies, but findings from prospective studies regarding the association of circulating levels of vitamin D with the risk of breast cancer have been null. The objective of this study was to examine the relation between plasma levels of vitamin D and the risk of postmenopausal breast cancer.
We conducted a nested case–control study within the Multiethnic Cohort Study of five race/ethnic groups (white, African-American, Native Hawaiian, Japanese, and Latino) from Hawaii and Los Angeles between 2001 and 2006. Pre-diagnostic plasma levels of 25-hydroxyvitamin D2 [25(OH)D2], 25-hydroxyvitamin D3 [25(OH)D3] and 25(OH)D (sum of 25(OH)D2 and 25(OH)D3) were examined among 707 postmenopausal breast cancer cases and matched controls.
Using conditional logistic regression models, 20 ng/mL increases of plasma 25(OH)D3 (odds ratio (OR) 0.28; 95% confidence interval (CI) 0.14-0.56) and 25(OH)D (OR 0.43; 95% CI 0.23-0.80) were inversely associated with breast cancer risk among white women, but not among women in other race/ethnic groups. Using two-segmented, piecewise-linear logistic regression models, the change-points of the ORs, either for 25(OH)D3 or for 25(OH)D, were detected as 20 ng/mL among whites.
Circulating 25(OH)D3 and 25(OH)D were associated with a reduced risk of postmenopausal breast cancer among whites, but not in other ethnic groups, who reside in low latitude regions.
PMCID: PMC3897897  PMID: 24438060
Breast cancer; 25-Hydroxyvitamin D3; 25-Hydroxyvitamin D2; Ethnic groups; Nested case–control study
10.  Soy Foods and Urinary Isoprostanes: Results from a Randomized Study in Premenopausal Women 
Food & function  2012;3(5):517-521.
In addition to their antiestrogenic effects, soy isoflavones may protect against cancer through alternate biologic actions including antioxidant properties. This randomized, crossover study explored the relation between dietary isoflavone intake through common soy foods and oxidative stress quantified by urinary isoprostane levels. Eighty-two women aged 39.2±6.1 years were randomized to a high soy diet of 2 soy food servings per day and a low soy diet of <3 servings per week for 6 months each, separated by a 1 month washout period. Urine samples were collected at baseline and at the end of each dietary period. Urinary isoprostane levels were measured using enzyme-linked immunosorbent assays (ELISA) and adjusted for creatinine levels. Mixed models using log-transformed values were applied to evaluate the effect of the high soy diet. Unadjusted isoprostane excretion levels were lower during the high than the low soy diet, but this effect was not statistically significant (p=0.81). After adjustment for urinary creatinine, isoprostane excretion was slightly higher during the high soy diet (p=0.02), an observation that was confirmed in a regression analysis between urinary isoflavones and isoprostanes during the high soy diet. The original association remained significant when restricted to adherent participants; however, this effect disappeared after exclusion of three extreme values. In agreement with several previous reports, these findings do not support the hypothesis that soy exerts antioxidant effects as measured by urinary isoprostane excretions, but additional markers of oxidative stress need to be investigated in future studies.
PMCID: PMC3559002  PMID: 22331037
soy foods; isoflavones; oxidative stress; isoprostane; randomized crossover trial
11.  Predicting Total, Abdominal, Visceral and Hepatic Adiposity with Circulating Biomarkers in Caucasian and Japanese American Women 
PLoS ONE  2012;7(8):e43502.
Characterization of abdominal and intra-abdominal fat requires imaging, and thus is not feasible in large epidemiologic studies.
We investigated whether biomarkers may complement anthropometry (body mass index [BMI], waist circumference [WC], and waist-hip ratio [WHR]) in predicting the size of the body fat compartments by analyzing blood biomarkers, including adipocytokines, insulin resistance markers, sex steroid hormones, lipids, liver enzymes and gastro-neuropeptides.
Fasting levels of 58 blood markers were analyzed in 60 healthy, Caucasian or Japanese American postmenopausal women who underwent anthropometric measurements, dual energy X-ray absorptiometry (DXA), and abdominal magnetic resonance imaging. Total, abdominal, visceral and hepatic adiposity were predicted based on anthropometry and the biomarkers using Random Forest models.
Total body fat was well predicted by anthropometry alone (R2 = 0.85), by the 5 best predictors from the biomarker model alone (leptin, leptin-adiponectin ratio [LAR], free estradiol, plasminogen activator inhibitor-1 [PAI1], alanine transaminase [ALT]; R2 = 0.69), or by combining these 5 biomarkers with anthropometry (R2 = 0.91). Abdominal adiposity (DXA trunk-to-periphery fat ratio) was better predicted by combining the two types of predictors (R2 = 0.58) than by anthropometry alone (R2 = 0.53) or the 5 best biomarkers alone (25(OH)-vitamin D3, insulin-like growth factor binding protein-1 [IGFBP1], uric acid, soluble leptin receptor [sLEPR], Coenzyme Q10; R2 = 0.35). Similarly, visceral fat was slightly better predicted by combining the predictors (R2 = 0.68) than by anthropometry alone (R2 = 0.65) or the 5 best biomarker predictors alone (leptin, C-reactive protein [CRP], LAR, lycopene, vitamin D3; R2 = 0.58). Percent liver fat was predicted better by the 5 best biomarker predictors (insulin, sex hormone binding globulin [SHBG], LAR, alpha-tocopherol, PAI1; R2 = 0.42) or by combining the predictors (R2 = 0.44) than by anthropometry alone (R2 = 0.29).
The predictive ability of anthropometry for body fat distribution may be enhanced by measuring a small number of biomarkers. Studies to replicate these data in men and other ethnic groups are warranted.
PMCID: PMC3422255  PMID: 22912885
12.  UH Cancer Center Hotline 
PMCID: PMC3313776  PMID: 22454814
13.  Plasma Coenzyme Q10 levels and Postmenopausal Breast Cancer Risk: The Multiethnic Cohort Study 
Coenzyme Q10 (CoQ10) is a component of the mitochondrial electron transport chain and is considered an important cellular antioxidant. Decreased circulating CoQ10 levels have been reported in women with breast cancer, but evidence is limited. We examined the association of plasma CoQ10 levels with postmenopausal breast cancer risk using prospectively collected blood samples.
Pre-diagnostic plasma levels of total CoQ10 were measured among 160 incident postmenopausal breast cancer cases and 289 controls in the Multiethnic Cohort Study. Cases and controls were individually-matched on age, sex, ethnicity, study location (Hawaii or California), hormone replacement therapy use, date/time of specimen collection and hours of fasting. Logistic regression was used to compute odds ratios and 95% confidence intervals.
Plasma CoQ10 levels were positively associated with breast cancer risk, overall (P = 0.04). The association was stronger after women diagnosed within one year of blood draw were excluded to eliminate possible preclinical cases (odds ratio for the highest versus the lowest tertile, 2.26; 95% confidence interval, 1.22-4.19; P for trend, 0.01).
Higher CoQ10 levels in postmenopausal women may be associated with increased breast cancer risk.
A potential role for CoQ10 in the development and progression of breast cancer has been postulated, but epidemiological evidence is lacking. Findings from this prospective cohort study add to the limited literature, indicating the potential positive association of circulating CoQ10 with postmenopausal breast cancer risk.
PMCID: PMC3013233  PMID: 20668119
Coenzyme Q10 postmenopausal breast cancer
14.  Serum 25-hydroxyvitamin D levels and mammographic density among premenopausal women in a multiethnic population 
While some evidence suggests a protective role of vitamin D against breast cancer, epidemiologic findings are inconsistent. The current study investigated the relation of serum 25-hydroxyvitamin D (25(OH)D) levels with mammographic density. Baseline serum samples from 182 premenopausal women including 67 Caucasians and 74 Asians from a nutritional trial were analyzed for 25(OH)D. Mammographic density was assessed using a computer assisted method. Serum 25(OH)D was not associated with mammographic density after adjustment for confounders (body mass index (BMI), age at mammogram, Asian ethnicity, age at first birth, parity and age at menarche). 25(OH)D levels were significantly lower in Asians than in Caucasians, but no significant ethnic differences in mammographic density were observed after adjusting for BMI. Although the current results indicate serum 25(OH)D levels were not associated with mammographic density among premenopausal women, a possible protective effect of vitamin D against breast cancer may be mediated through other pathways.
PMCID: PMC2900248  PMID: 20216557
Vitamin D; 25-Hydroxyvitamin D; mammographic density; breast cancer
15.  Associations between obesity and serum lipid soluble micronutrients among premenopausal women 
Elucidating potential pathways that micronutrients may reduce/promote chronic disease may contribute to our understanding of the underlying etiology of disease and their utility as markers of risk. In the current study, we examined associations of serum lipid soluble micronutrients with body mass index (BMI). We hypothesized that obesity may differentially influence serum micronutrient levels, thereby affecting risk for chronic disease incidence and mortality. Baseline serum samples from 180 premenopausal women from a nutritional trial were analyzed for leptin, C-reactive protein (CRP), 25-hydroxyvitamin D (25(OH)D), carotenoids, and tocopherols. Participants were stratified into normal weight (18.5-24.9), overweight (25-29.9), and obese (≥ 30) subgroups by BMI (kg/m12). Differences in serum biomarkers among BMI subgroups were adjusted for Asian ethnicity and smoking status. As expected, obese individuals had significantly higher serum levels of leptin and CRP (P's < 0.05) compared to normal weight women. γ-Tocopherol levels were significantly higher in obese individuals (P < 0.05), while α-tocopherol levels did not differ among BMI subgroups. Serum levels of 25(OH)D and carotenoids (except lycopene) were significantly lower in obese than in normal weight women (P's < 0.05). The associations between BMI and carotenoids were independent of dietary intake. The obesity-associated reduction for total pro-vitamin A carotenoids (45%) was approximately 3-fold greater than that observed for non pro-vitamin A carotenoids (16%). Our results indicate potential influences of obesity on serum levels of lipid soluble micronutrients and suggest that metabolism of pro-vitamin A carotenoids may contribute to the differences observed.
PMCID: PMC2884001  PMID: 20534324
Obesity; BMI; lipid soluble micronutrients; CRP; premenopausal women
16.  Plasma 25-hydroxyvitamin D and prostate cancer risk: the Multiethnic Cohort 
The purpose of this study was to examine the relationship of plasma 25-hydroxyvitamin D (25(OH)D) concentrations to prostate cancer within a large multiethnic cohort in Hawaii and California using a nested case-control design. The study included 329 incident prostate cancer cases of African American, Native Hawaiian, Japanese, Latino, and White ancestry, and 656 controls matched on age, race/ethnicity, date/time of blood collection, and fasting status. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). No association with prostate cancer risk was found in an analysis based on quartiles of 25(OH)D. When clinically defined cutpoints were used, there was no increased risk for the lowest 25(OH)D concentration (OR for <20 vs. 30–<50 ng/ml = 1.10, 95% CI = 0.68-1.78), while there was a suggestive increased risk for higher concentrations (OR for ≥50 ng/ml = 1.52, 95% CI = 0.92-2.51). The findings from this prospective study of men in the Multiethnic Cohort do not support the hypothesis that vitamin D lowers the risk of prostate cancer. Further follow-up is warranted to determine whether the findings are consistent across ethnic groups.
PMCID: PMC2834847  PMID: 20064705
25-hydroxyvitamin D; multiethnic cohort; nested case-control study; plasma; prostate neoplasms
17.  Leptin, Adiponectin, and Obesity among Caucasian and Asian Women 
Mediators of Inflammation  2011;2011:253580.
Ethnic differences in adipose tissue distribution may contribute to different chronic disease risks across ethnic groups, and adipokines may mediate the risk. In a cross-sectional study, we examined ethnic differences in adipokines and inflammatory markers as related to body mass index (BMI) among 183 premenopausal women with Caucasian and Asian ancestry. General linear models were used to estimate adjusted mean levels of leptin, adiponectin, interleukin-6, and C-reactive protein (CRP). Asian women had significantly lower serum levels of leptin, adiponectin, and CRP than Caucasian participants (P ≤ .01) across all levels of BMI. Among overweight and obese women, Asians showed a stronger association of CRP with leptin (β = 1.34 versus β = 0.64) and with adiponectin (β = −0.95 versus β = −0.75) than Caucasians. Compared to Caucasians of similar BMI, Asians may experience a higher chronic disease risk due to lower levels of adiponectin despite their lower levels of leptin.
PMCID: PMC3038565  PMID: 21331287
18.  The relation of leptin and adiponectin with breast density among premenopausal women 
The adipocytokine leptin may increase breast cancer risk, while adiponectin may be protective. We examined the association of the two circulating markers with mammographic density, a strong predictor of breast cancer risk.
For 183 premenopausal participants of a nutritional trial, mammograms performed at baseline, year 1, and year 2 were assessed for densities using a computer-assisted method. Serum samples obtained at the same time were analyzed for leptin and adiponectin by ELISA. We applied mixed models to incorporate the repeated measurements while adjusting for confounders including body mass index (BMI).
At baseline, the mean age of the subjects was 42.6 ± 2.9 years; 40% were of Asian ancestry. Leptin was lower and adiponectin higher in normal weight than overweight women. Neither marker was related to absolute breast density. The significant inverse association of leptin with percent density disappeared when BMI was added to the model. After stratification by weight, percent density decreased with higher leptin levels in normal weight women, whereas it increased among overweight subjects. After adjustment for BMI, the positive association between percent density and adiponectin was greatly reduced and no longer significant.
These results do not support a strong association of leptin or adiponectin with breast cancer risk as assessed by mammographic density. On the other hand, the findings suggest the possibility that the inverse association of BMI with breast cancer risk in premenopausal women is mediated by adipocytokines.
PMCID: PMC2903451  PMID: 19927000
Mammographic density; breast cancer risk; adiposity; leptin; adiponectin; ethnicity
19.  Association of selenium, tocopherols, carotenoids, retinol, and 15-isoprostane F2t in serum or urine with prostate cancer risk: the multiethnic cohort 
Cancer causes & control : CCC  2009;20(7):1161-1171.
We examine the association of antioxidants and 15-isoprostane F2t with risk of prostate cancer.
We conducted a nested case–control study of serum antioxidant biomarkers (selenium, tocopherols, carotenoids, and retinol) and a urinary oxidation biomarker (15-isoprostane F2t) with risk of prostate cancer within the Multiethnic Cohort. Demographic, dietary, and other exposure information was collected by self-administered questionnaire in 1993–1996. We compared prediagnostic biomarker levels from 467 prostate cancer cases and 936 cancer free controls that were matched on several variables. Multivariate conditional logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
We observed that there was no overall association of serum concentrations of antioxidants and urinary concentrations of 15-isoprostane F2t with risk of prostate cancer or risk of advanced prostate cancer. However, we did observe an inverse association for serum selenium only among African-American men (p trend = 0.02); men in the third tertile of selenium concentrations had a 41% lower risk (95% CI: 0.38–0.93) of prostate cancer when compared to men in the first tertile.
Overall, our study found no association of serum antioxidants or 15-isoprostane F2t with the risk of prostate cancer. The observed inverse association of selenium with prostate cancer in African-Americans needs to be validated in other studies.
PMCID: PMC2725220  PMID: 19212706
Prostate cancer; Risk; Ethnicity; Cohort; Serum antioxidants
20.  Elevated plasma γ-tocopherol and decreased α-tocopherol in men are associated with inflammatory markers and decreased plasma 25-OH vitamin D 
Nutrition and cancer  2008;60(Suppl 1):21-29.
Chronic inflammation is a risk factor for many diseases of aging. Endogenous oxidants are thought to mediate the effects of inflammation and γ-Tocopherol (γ-Toc) may mitigate damage from nitrogen-based oxidants, however, no physiological requirement for γ-Toc has been established. Regulation of tocopherols and their functional significance are poorly defined, thereby limiting their application in prevention. Using stored plasma samples from 657 male control subjects in a previous study of prostate cancer we have analyzed associations of the tocopherols, inflammation markers, and 25-OH vitamin D. Plasma α-Toc and γ-Toc were inversely correlated, whereas δ-Toc and α-Toc levels were positively correlated, suggesting a unique regulatory mechanism. γ-Toc levels were positively and α-Toc negatively associated with plasma C-reactive protein (CRP) and urinary isoprostane F2t, which are markers of inflammation and oxidation. Ethnic variability in tocopherols was observed, however, this may be explained by differences in plasma 25-OH vitamin D, as γ-Toc levels varied inversely and α-Toc positively with 25-OH vitamin D. In these data all-cause mortality appeared to be positively associated with CRP and inversely with 25-OH vitamin D. We hypothesize that plasma levels of tocopherols may serve as markers of systemic inflammation, complicating epidemiologic assessment of their role in cancer etiology.
PMCID: PMC2896320  PMID: 19003577
21.  Association of plasma micronutrient levels and urinary isoprostane with risk of lung cancer: The Multiethnic Cohort Study 
While smoking is the primary risk factor for lung cancer, there is evidence to suggest that fruit and vegetable intake are important co-factors. The present case-control study, nested within the Multiethnic Cohort Study, examined the associations of biomarkers of fruit and vegetable intake (individual plasma micronutrient levels), serum selenium and a urinary biomarker for total lipid peroxidation with lung cancer risk. 207 incident cases were matched to 414 controls on age, sex, ethnicity, study location (Hawaii or California), smoking status, date/time of collection and hours of fasting. We measured prediagnositic circulating levels of individual tocopherols and carotenoids, retinol, and serum selenium, and urinary 15-isoprostane F2t. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). For men, strong reductions in risk were seen with increasing tertiles of each plasma carotenoid, with the ORs for the third tertile, compared to the first tertile, ranging from 0.24 to 0.45 (p for trends: 0.002-0.04). No associations were found among women for carotenoids or among either sex for tocopherols, selenium and retinol. A doubling in risk was seen for men in the second and third tertiles, compared to the first tertile of urinary 15-isoprostane F2t (OR=2.31, 95% CI: 1.02-5.25 and OR=2.16, 95% CI: 0.98-4.78). This study supports the previously observed association between circulating carotenoids and lung cancer risk in men, and adds to the limited literature regarding urinary 15-isoprostane F2t as a marker of cancer risk. Future research examining the possible relationship between isoprostanes and lung cancer is warranted.
PMCID: PMC2755047  PMID: 19531680
antioxidant; biomarkers; tocopherol; carotenoid; selenium; retinol; isoprostane; lipid peroxidation; lung cancer
22.  Plasma carotenoids, retinol, and tocopherols and postmenopausal breast cancer risk in the Multiethnic Cohort Study: a nested case-control study 
Assessments by the handful of prospective studies of the association of serum antioxidants and breast cancer risk have yielded inconsistent results. This multiethnic nested case-control study sought to examine the association of plasma carotenoids, retinol, and tocopherols with postmenopausal breast cancer risk.
From the biospecimen subcohort of the Multiethnic Cohort Study, 286 incident postmenopausal breast cancer cases were matched to 535 controls on age, sex, ethnicity, study location (Hawaii or California), smoking status, date/time of collection and hours of fasting. We measured prediagnostic circulating levels of individual carotenoids, retinol, and tocopherols. Conditional logistic regression was used to compute odds ratios and 95% confidence intervals.
Women with breast cancer tended to have lower levels of plasma carotenoids and tocopherols than matched controls, but the differences were not large or statistically significant and the trends were not monotonic. No association was seen with retinol. A sensitivity analysis excluding cases diagnosed within 1 year after blood draw did not alter the findings.
The lack of significant associations in this multiethnic population is consistent with previously observed results from less racially-diverse cohorts and serves as further evidence against a causal link between plasma micronutrient concentrations and postmenopausal breast cancer risk.
PMCID: PMC2750110  PMID: 19619335
23.  Inflammatory markers in a 2-year soy intervention among premenopausal women 
Epidemiologic evidence supports a role of soy foods in breast cancer etiology. Because chronic inflammation appears to be a critical component in carcinogenesis, we examined the potential anti-inflammatory effects of soy foods.
The original 2-year dietary intervention randomized 220 premenopausal women of whom 183 women (90 in the intervention group and 93 in the control group) were included in the current investigation; 40% were of Asian ancestry. The intervention group consumed two daily soy servings containing 50 mg of isoflavones (aglycone equivalents), whereas the controls maintained their regular diet. Five serum samples obtained at month 0, 3, 6, 12, and 24 were analyzed for interleukin (IL)-6, C-reactive protein (CRP), leptin, and adiponectin by ELISA. For statistical analysis, mixed models were applied to incorporate the repeated measurements.
The levels of all analytes were lower in Asian than Caucasian women. Overweight women had significantly higher levels of CRP, IL-6, and leptin and lower levels of adiponectin than normal weight women. We did not observe a significant effect of soy foods on the four markers, but leptin increased in the control and not in the intervention group (p = 0.20 for group-time effect); this difference was significant for Asian (p = 0.01) and obese women (p = 0.005).
During this 2-year intervention, soy foods did not modify serum levels of CRP, IL-6, leptin, and adiponectin in premenopausal women although leptin levels remained stable among women in the intervention group who were obese or of Asian ancestry. Further studies with diverse markers of inflammation are necessary to clarify the specific effect of soy on immune responses.
PMCID: PMC2674030  PMID: 19348684
24.  Bioavailability and antioxidant effects of orange juice components in humans 
Seven healthy females and six males consumed daily 256 mg vitamin C, 229 mg hesperidin (main flavonoid occurring as glycoside), 6 mg carotenoids (mainly luteins and cryptoxanthins), and 0.16 mg folate by incorporation of daily 236 mL of not-from-concentrate orange juice (OJ) into their habitual diet. At the end of three weeks mean vitamin C, folate, carotenoid, and flavanone plasma concentrations increased significantly relative to baseline by 59% (p<0.001), 46% (p=0.018), and 22% (p<0.001), and 8 fold (p=0.045), respectively. Flavanones were excreted in urine 9 fold more at the end of the intervention (p=0.01) but returned to baseline two days after study completion. After the 3-week intervention plasma concentrations of vitamins A and E did not change. 8-Hydroxy deoxyguanosine (8OHdG) in white blood cells declined by 16% (p=0.38; n=11), and in individuals with high baseline concentrations by 29% (p=0.36; n=7), respectively. LDL-/HDL-cholesterol ratio decreased but cholesterol (HDL, LDL, total) and thiobarbituric acid reactive substance plasma concentrations did not change significantly. We conclude from this pilot study that OJ is an excellent food source to enhance circulating concentrations of valuable hydrophilic as well as lipophilic phytochemicals.
PMCID: PMC2533031  PMID: 15969493
orange juice; antioxidants; vitamins; flavonoids; folate; carotenoids
25.  Enhancement of intracellular γ-tocopherol levels in cytokine-stimulated C3H 10T1/2 fibroblasts: relation to NO synthesis, isoprostane formation, and tocopherol oxidation 
Stimulation of C3H 10T1/2 murine fibroblasts with interferon-γ(IFN) and bacterial lipopolysaccharide (LPS) generates reactive oxygen and nitrogen species leading to DNA damage, lipid oxidation, and tocopherol oxidation. The tocopherols possess unique chemical and biological properties that suggest they have important roles related to intracellular defense against radical-mediated damage.
Despite increased levels of reactive oxidants and decreased media tocopherol, cellular levels of γ-tocopherol, but not α-tocopherol, were observed to increase significantly when cells were treated with IFN/LPS. Inhibition of nitric oxide (NO) synthesis by a specific inhibitor of inducible NO synthase (iNOS) increased both intracellular α-tocopherol and γ-tocopherol concentrations, but did not significantly alter the reduction in media tocopherol levels caused by IFN/LPS treatment. Both exposure to exogenous NO and cellular synthesis of NO in cell culture increased media levels of 8-epi-prostaglandin F2α, a marker of oxidative lipid damage, whereas inhibition of endogenous NO synthesis reduced media 8-epi-prostaglandin F2α formation to control levels.
Elevated intracellular levels of γ-tocopherol in response to the cellular inflammatory state may indicate that it serves a unique role in minimizing cellular damage resulting from endogenous NO synthesis. Results of the current study suggest that NO is an important mediator of damage within the cell, as well as in the oxidation of both α- and γ-tocopherols. The paradoxical increase in cellular tocopherol associated with the induction of NO synthesis may indicate either enhanced cellular transport/decreased export for tocopherols or recruitment of free tocopherol from tocopherol storage molecules.
PMCID: PMC1931582  PMID: 17608946

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