Robert V. Cooney

Predicting total, abdominal, visceral and hepatic adiposity with circulating biomarkers in Caucasian and Japanese American women.

Background Characterization of abdominal and intra-abdominal fat requires imaging, and thus is not feasible in large epidemiologic studies. Objective 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. Methods 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. Results Total body fat was well predicted by anthropometry alone (R2u200a=u200a0.85), 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]; R2u200a=u200a0.69), or by combining these 5 biomarkers with anthropometry (R2u200a=u200a0.91). Abdominal adiposity (DXA trunk-to-periphery fat ratio) was better predicted by combining the two types of predictors (R2u200a=u200a0.58) than by anthropometry alone (R2u200a=u200a0.53) 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; R2u200a=u200a0.35). Similarly, visceral fat was slightly better predicted by combining the predictors (R2u200a=u200a0.68) than by anthropometry alone (R2u200a=u200a0.65) or the 5 best biomarker predictors alone (leptin, C-reactive protein [CRP], LAR, lycopene, vitamin D3; R2u200a=u200a0.58). Percent liver fat was predicted better by the 5 best biomarker predictors (insulin, sex hormone binding globulin [SHBG], LAR, alpha-tocopherol, PAI1; R2u200a=u200a0.42) or by combining the predictors (R2u200a=u200a0.44) than by anthropometry alone (R2u200a=u200a0.29). Conclusion 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.

Non-Hodgkin Lymphoma and circulating markers of inflammation and adiposity in a nested case-control study: The Multiethnic Cohort

Background: Because 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 prediagnostic inflammatory markers and adipokines with NHL risk. Methods: 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). ORs and 95% confidence intervals (CI) for tertiles of analytes were estimated by conditional logistic regression. Results: 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, whereas 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 less than 1 year after phlebotomy attenuated all associations. Conclusions: IL-10 was the only cytokine and leptin the only adipokine associated with NHL, but due to the short follow-up time, preclinical effects cannot be excluded. Impact: 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. Cancer Epidemiol Biomarkers Prev; 22(3); 337–47. ©2012 AACR.

Elevated plasma γ-tocopherol and decreased α-tocopherol in men are associated with inflammatory markers and decreased plasma 25-OH vitamin D

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-hydroxy (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.

Low Plasma Coenzyme Q10 Levels and Breast Cancer Risk in Chinese Women

Background: 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. Methods: We prospectively examined the association of plasma CoQ10 with breast cancer risk in a nested case-control study of Chinese women within the Shanghai Womens Health Study (SWHS). Prediagnostic plasma samples were obtained from 340 cases and 653 age-matched controls and analyzed for total CoQ10. Results: A borderline significant inverse association for breast cancer incidence with plasma CoQ10 level was observed by a conditional logistic regression model adjusted for age and age at first live birth, which became significant after elimination of cases diagnosed within 1 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 α-tocopherol (r = 0.38; P < 0.0001) levels. Conclusions: 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. Impact: 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 suggest that the 2 studies may not be contradictory and indicate a possible nonlinear (U-shaped) association of CoQ10 with risk. Cancer Epidemiol Biomarkers Prev; 20(6); 1124–30. ©2011 AACR.

C-Reactive Protein, Lipid-soluble Micronutrients, and Survival in Colorectal Cancer Patients

Background: Identification of biomarkers associated with survival in patients with cancer is important for elucidating the underlying mechanisms of cancer progression and identifying possible interventions to reduce cancer morbidity and mortality. Methods: Using stored patient plasma samples from a multiethnic population-based case–control study of invasive colorectal cancer, we measured posttreatment 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). HRs were estimated by Cox proportional hazards regression with adjustment for stage, age at diagnosis, ethnicity, sex, smoking status, and month of blood draw. Results: A positive association with overall risk of death was observed for CRP [HR for highest vs. lowest quintile: 1.80; 95% confidence interval (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). HRs 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). Conclusions: These observations are consistent with a direct relationship between circulating CRP and overall survival among patients with colorectal cancer. Impact: These results, if reproduced, suggest that reduction of inflammation should be explored as a potential complementary treatment strategy. Cancer Epidemiol Biomarkers Prev; 22(7); 1278–88. ©2013 AACR.

Serum Coenzyme Q10, α-Tocopherol, γ-Tocopherol, and C-Reactive Protein Levels and Body Mass Index in Adolescent and Premenopausal Females

Objective: 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. Methods: 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 2 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. Results: 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. Conclusions: 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.

Effects of vitamin D3 and calcium supplementation on serum levels of tocopherols, retinol, and specific vitamin D metabolites

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 mo 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), whereas similar changes in γT (19% lower, 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 using larger, more homogeneous populations are warranted.

Food Components, Alternative Medicine, and Cancer: Progress and Promise

Cancer is the defining medical challenge of our times. An impressive body of evidence supports the notion that prevention can be a major component of cancer control. The prevention of cancer rests mainly on the development of biomarkers that identify subjects at risk for cancer and those who will benefit from a given intervention, and on the development of safe and effective agents. Compounds, like tamoxifen and raloxifene, already in clinical use for the prevention of breast cancer, underscore the viability of the approach. They also emphasize the need for additional agents against the various forms of cancer that claim so many lives. n nOf the several approaches followed by investigators in the quest for new chemopreventive agents, bioactive food components are emerging as most promising. The significant body of work on such agents to date made apparent the need to review the progress that has been made and to identify the challenges ahead. These considerations prompted us to organize a symposium focused on bioactive food components and alternative medicine. Its title was “Bioactive Food Components, Alternative Medicine and Cancer Chemoprevention: Recent Advances” and was held in October 2007 during the annual joint World Congress on Advances in Oncology and International Symposium on Molecular Medicine. Our symposium brought together in the Greek island of Crete leading experts in the field from many countries. This supplemental issue of Nutrition and Cancer includes twelve excellent papers presented at the symposium as well as a superb overview of both the meeting and the field by Gary Stoner. n nWe wish to thank Dr. Leonard Cohen, Editor-in-Chief of Nutrition and Cancer, for his enthusiastic support of this issue; the authors of the articles published here; Dr. Demetrios Spandidos, organizer of the World Congress on Advances in Oncology for hosting our symposium with exemplary hospitality; and the many participants, both presenters and discussants, who provided a high level of scientific exchange and made this a most exciting and useful event. n nOur symposium was supported in part by grant R13 CA132241, awarded by the National Cancer Institute (NCI) and National Center for Complimentary and Alternative Medicine (NCCAM), and grants from the University of Pittsburgh Cancer Institute, Ohio State University, and Oklahoma University Health Sciences Center. Their support, even more remarkable in a period of fiscal austerity, is greatly appreciated by organizers and participants alike. n nThe publication of the proceedings of the symposium, which makes accessible to the scientific community its key presentations, should contribute to the overall effort to conquer cancer through its prevention.

The paths of Andrew A. Benson: a radio-autobiography

Andrew A. Benson, one of the greatest biochemists of our time, is celebrated on his centennial by the authors with whom he interacted performing experiments or contemplating metabolic pathways in a wide range of biological kingdoms. He charted the chemical flow of energy in cells, tissues, organs, plants, animals, and ecosystems. Benson collaborated with hundreds of colleagues to examine the natural history of autotrophy, mixotrophy, and heterotrophy while elucidating metabolic pathways. We present here a biological perspective of his body of studies. Benson lived from September 24, 1917, to January 16, 2015. Out of over 1000 autoradiograms he produced in his life, he left a legacy of 50 labeled autoradiograms to the authors who tell the story of his life’s work that resulted in Benson’s Protocol (Nonomura et al., Photosynth Res 127:369–378, 2016) that has been applied, over the years, for the elucidation of major metabolic pathways by many scientists.

Changes in Whole Blood Gene Expression after Computed Tomography in Children: A Pilot Study

Computed tomography (CT) exposes patients to ionizing X-irradiation (IR) that can alter the expression of genes responsible for controlling complex regulatory pathways. We sought to determine trends in the expression of 24 documented radiation-responsive genes linked to cancer in vivo. A total of 17 children (0.25–6 years old) undergoing medically indicated CT examinations with radiation doses ranging from 92.46 to 525.55 mGy cm (equivalent to effective doses of 0.78–11.30 mSv) were enrolled. Blood was drawn immediately before and 1 hour after their CT exams and mixed with an RNA additive for stabilization of gene expression. RNA samples of 14 of the 17 children were analyzed on a gene expression microarray. Absolute changes in gene expression were subtle, averaging less than 10%, but trends in expression changes of several genes were observed. ERP29, an endoplasmic reticulum chaperone, thought to be involved in the folding of secretory proteins, showed significant change in expression (8% decrease, P = 0.002) in the expected direction consistent with previous literature. PCNA expression increased linearly with CT dose (mGy cm) (P = 0.001). TP53 and FLT3LG expression increased linearly with effective dose (mSv) (P = 0.02 and P = 0.02). Previous IR exposure was associated with decreased GADD45A (P = 0.001) and FLT3LG (P = 0.03) and increased MDM2 expression (P = 0.02). We observed in this pilot study modest gene expression changes in the 24 IR-responsive candidate genes studied. Our results showed trends in gene expression changes, and they need to be confirmed in future studies with larger sample sizes to help develop risk assessments and preventive modalities for young patients undergoing CT.