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Over the past 50 years, increases in dietary n-6 PUFA, such as linoleic acid, have been hypothesised to cause or exacerbate chronic inflammatory diseases. The present study examines an individual's innate capacity to synthesise n-6 long-chain PUFA (LC-PUFA) with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes or the metabolic syndrome. Compared with European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7·9 (sd 2·1), AfAm 9·8 (sd 1·9) % of total fatty acids; P < 2·29 × 10− 9) and the AA:n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5·4 (sd 2·2), AfAm 6·9 (sd 2·2); P = 1·44 × 10− 5). In all, seven SNP mapping to the FADS locus revealed strong association with AA, EPA and dihomo-γ-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT 6·3 (sd 1·0); GG 8·5 (sd 2·1); P = 3·0 × 10− 5) and AA:DGLA ratios (TT 3·4 (sd 0·8), GG 6·5 (sd 2·3); P = 2·2 × 10− 7) but higher DGLA levels (TT 1·9 (sd 0·4), GG 1·4 (sd 0·4); P = 3·3 × 10− 7) compared with those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0·81) compared with EAm (0·46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are probably important differences in the capacity of different populations to synthesise LC-PUFA. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent.

Younger women being treated for breast cancer consistently show greater depression shortly after diagnosis than older women. In this longitudinal study, we examine whether these age differences persist over the first 26 months following diagnosis and identify factors related to change in depressive symptoms. A total of 653 women within 8 months of a first time breast cancer diagnosis completed questionnaires at baseline and three additional timepoints (6, 12, and 18 months after baseline) on contextual/patient characteristics, symptoms, and psychosocial variables. Chart reviews provided cancer and treatment-related data. The primary outcome was depressive symptomatology assessed by the Beck Depression Inventory. Among women younger than age 65, depressive symptoms were highest soon after diagnosis and significantly decreased over time. Depressive symptoms remained stable and low for women aged 65 and older. Age was no longer significantly related to depressive symptoms in multivariable analyses controlling for a wide range of covariates. The primary factors related to levels of and declines in depressive symptomatology were the ability to pay for basics; completing chemotherapy with doxorubicin; and decreases in pain, vasomotor symptoms, illness intrusiveness, and passive coping. Increased sense of meaning/peace and social support were related to decreased depression. Interventions to reduce symptoms and illness intrusiveness, improve a sense of meaning and peace, and increase social support, may help reduce depression and such interventions may be especially relevant for younger women.

Background Proper functional association between mural cells and endothelial cells (EC) causes EC of blood vessels to become quiescent. Mural cells on tumor vessels exhibit decreased attachment to EC, which allows vessels to be unstable and proliferative. The mechanisms by which tumors prevent proper association between mural cells and EC are not well understood. Since gap junctions (GJ) play an important role in cell-cell contact and communication, we investigated whether loss of GJ plays a role in tumor-induced mural cell dissociation. Methods Mural cell regulation of endothelial proliferation was assessed by direct co-culture assays of fluorescently labeled cells quantified by flow cytometry or plate reader. Gap junction function was assessed by parachute assay. Connexin 43 (Cx43) protein in mural cells exposed to conditioned media from cancer cells was assessed by Western and confocal microscopy; mRNA levels were assessed by quantitative real-time PCR. Expression vectors or siRNA were utilized to overexpress or knock down Cx43. Tumor growth and angiogenesis was assessed in mouse hosts deficient for Cx43. Results Using parachute dye transfer assay, we demonstrate that media conditioned by MDA-MB-231 breast cancer cells diminishes GJ communication between mural cells (vascular smooth muscle cells, vSMC) and EC. Both protein and mRNA of the GJ component Connexin 43 (Cx43) are downregulated in mural cells by tumor-conditioned media; media from non-tumorigenic MCF10A cells had no effect. Loss of GJ communication by Cx43 siRNA knockdown, treatment with blocking peptide, or exposure to tumor-conditioned media diminishes the ability of mural cells to inhibit EC proliferation in co-culture assays, while overexpression of Cx43 in vSMC restores GJ and endothelial inhibition. Breast tumor cells implanted into mice heterozygous for Cx43 show no changes in tumor growth, but exhibit significantly increased tumor vascularization determined by CD31 staining, along with decreased mural cell support detected by NG2 staining. Conclusions Our data indicate that i) functional Cx43 is required for mural cell-induced endothelial quiescence, and ii) downregulation of Cx43 GJ by tumors frees endothelium to respond to angiogenic cues. These data define a novel and important role for maintained Cx43 function in regulation of vessel quiescence, and suggest its loss may contribute to pathological tumor angiogenesis.

Younger women with breast cancer consistently show greater psychological distress than older women. This study examined a range of factors that might explain these age differences. A total of 653 women within 8 months of a first-time breast cancer diagnosis provided data on patient characteristics, symptoms, and psychosocial variables. Chart reviews provided cancer and treatment-related data. The primary outcome was depressive symptomatology assessed by the Beck Depression Inventory. A succession of models that built hierarchically upon each other was used to determine which variables could account for age group differences in depression. Model 1 contained age group only. Models 2–5 successively added patient characteristics, cancer-related variables, symptoms, and psychosocial variables. As expected, in the unadjusted analysis (Model 1) younger women were significantly more likely to report depressive symptomatology than older women ( p  < 0.0001). Age remained significantly related to depression until Model 4 which added bodily pain and vasomotor symptoms ( p  = 0.24; R 2  = 0.27). The addition of psychosocial variables in Model 5 also resulted in a model in which age was nonsignificant ( p  = 0.49; R 2  = 0.49). Secondary analyses showed that illness intrusiveness (the degree that illness intrudes on specific areas of life such as work, sex life, recreation, etc.) was the only variable which, considered individually with age, made the age group-depression association nonsignificant. Age differences in risk of depression following a breast cancer diagnosis can be explained by the impact of cancer and its treatment on specific areas of a woman’s life.

Breast cancers that over-express a lipoxygenase or cyclooxygenase are associated with poor survival possibly because they overproduce metabolites that alter the cancer's malignant behaviors. However, these metabolites and behaviors have not been identified. We here identify which metabolites among those that stimulate breast cancer cell proliferation in vitro are associated with rapidly proliferating breast cancer. We used selective ion monitoring-mass spectrometry to quantify in the cancer and normal breast tissue of 27 patients metabolites that stimulate (15-, 12-, 5-hydroxy-, and 5-oxo-eicosatetraenoate, 13-hydroxy-octadecaenoate [HODE]) or inhibit (prostaglandin [PG]E2 and D2) breast cancer cell proliferation. We then related their levels to each cancer's proliferation rate as defined by its Mib1 score. 13-HODE was the only metabolite strongly, significantly, and positively associated with Mib1 scores. It was similarly associated with aggressive grade and a key component of grade, mitosis, and also trended to be associated with lymph node metastasis. PGE2 and PGD2 trended to be negatively associated with these markers. No other metabolite in cancer and no metabolite in normal tissue had this profile of associations. Our data fit a model wherein the overproduction of 13-HODE by 15-lipoxygenase-1 shortens breast cancer survival by stimulating its cells to proliferate and possibly metastasize; no other oxygenase-metabolite pathway, including cyclooxygenase-PGE2/D2 pathways, uses this specific mechanism to shorten survival.

Women diagnosed with obesity and breast cancer have an increased risk of recurrence and death (Protani et al., Breast Cancer Res Treat 123:627–635, 1 ). Obesity is associated with the metabolic syndrome—a pathophysiologically distinct inflammatory process comprised of central obesity, insulin resistance, hypertension, and atherogenic dyslipidemia. The relationship of obesity as a risk factor for breast cancer is complex with a protective effect for younger women in contrast to a risk for older women (Kabat et al., Cancer Epidemiol Biomarkers Prev 18:2046–2053, 2 ; Ursin et al., Epidemiology 6:137–141, 3 ). The metabolic syndrome has been associated with the risk of cancer, and pro-inflammatory circulating factors may be associated with risk of more aggressive breast cancer (Capasso et al., Cancer Biol Ther 10:1240–1243, 4 ; Healy et al., Clin Oncol (R Coll Radiol) 22:281–288, 5 ; Laukkanen et al., Cancer Epidemiol Biomarkers Prev 13:1646–1650, 6 ). We conducted a retrospective review of 860 breast cancer patients to determine the relationship between estrogen receptor status and the metabolic syndrome. We collected the relevant metabolic diagnoses, medications, physical findings, and laboratory values and adapted the National Cholesterol Education Program criteria to define the metabolic syndrome retrospectively. No relationship was found between estrogen receptor status and the individual components of the metabolic syndrome. Based on findings in the medical records, 15% of the women with breast cancer had the metabolic syndrome, and 26% of the women were considered obese, 16% hyperglycemic, 54% hypertensive, and 30% dyslipidemic. The metabolic syndrome was associated with advanced age and African-American race ( P  < 0.001). When adjusted for age, race, and stage, the metabolic syndrome was marginally associated with estrogen receptor-positive tumors ( P  = 0.054). Our findings do not support the concern that the metabolic syndrome may contribute to more biologically aggressive breast cancer.

Despite evidence of a genetic role in stroke, the identification of common genetic risk factors for this devastating disorder remains problematic. We aimed to identify any common genetic variability exerting a moderate to large effect on risk of ischaemic stroke, and to generate publicly available genome-wide genotype data to facilitate others doing the same. We applied a genome-wide high-density single-nucleotide-polymorphism (SNP) genotyping approach to a cohort of samples with and without ischaemic stroke (n=278 and 275, respectively), and did an association analysis adjusted for known confounders in a final cohort of 249 cases and 268 controls. More than 400 000 unique SNPs were assayed. We produced more than 200 million genotypes in 553 unique participants. The raw genotypes of all the controls have been posted publicly in a previous study of Parkinson's disease. From this effort, results of genotype and allele association tests have been publicly posted for 88% of stroke patients who provided proper consent for public release. Preliminary analysis of these data did not reveal any single locus conferring a large effect on risk for ischaemic stroke. The data generated here comprise the first phase of a genome-wide association analysis in patients with stroke. Release of phase I results generated in these publicly available samples from each consenting individual makes this dataset a valuable resource for data-mining and augmentation.

ObjectiveTo identify specific ECG and clinical predictors that separate atherosclerotic sudden cardiac death (SCD) from incident coronary heart disease (CHD) (non-fatal events and non-sudden death) in the combined cohorts of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study.MethodsThis analysis included 18 497 participants (58% females, 24% black individuals, mean age 58 years) who were initially free of clinical CHD. A competing risk analysis was conducted to examine the prognostic significance of baseline clinical characteristics and an extensive electronic database of ECG measurements for prediction of 229 cases of SCD as a first event versus 2297 incident CHD cases (2122 non-fatal events and 175 non-sudden death) that occurred during a median follow-up time of 13 years in the Cardiovascular Health Study and 14 years in the Atherosclerosis Risk in Communities study.ResultsAfter adjusting for common CHD risk factors, a number of clinical characteristics and ECG measurements were independently predictive of SCD and CHD. However, the risk of SCD versus incident CHD was significantly different for race/ethnicity, hypertension, body mass index (BMI), heart rate, QTc, abnormally inverted T wave in any ECG lead group and level of ST elevation in V2. Black race/ethnicity (compared to non-black) was predictive of high SCD risk but less risk of incident CHD (p value for differences in the risk (HR) for SCD versus CHD <0.0001). Hypertension, increased heart rate, prolongation of QTc and abnormally inverted T wave were stronger predictors of high SCD risk compared to CHD (p value=0.0460, 0.0398, 0.0158 and 0.0265, respectively). BMI was not predictive of incident CHD but was predictive of high SCD risk in a quadratic fashion (p value=0.0220). On the other hand, elevated ST height as measured at the J point and that measured at 60 ms after the J point in V2 were not predictive of SCD but were predictive of high incident CHD risk (p value=0.0251 and 0.0155, respectively).ConclusionsSCD and CHD have many risk factors in common. Hypertension, race/ethnicity, BMI, heart rate, QTc, abnormally inverted T wave in any ECG lead group and level of ST elevation in V2 have the potential to separate between the risks of SCD and CHD. These results need to be validated in another cohort.

Background. Head and neck cancer (HNC) patients are at an increased risk for developing second primary tumors (SPTs). Diets rich in fruits and vegetables (FVs) may lower HNC risk. FV concentrates may offer a potential alternative to increasing FV intake. Methods. We conducted a randomized, double-blind, placebo-controlled trial to evaluate whether Juice PLUS+ (JP; a commercial product with multiple FV concentrates) has an effect on p27 and Ki-67, biomarkers associated with the risk of SPTs. During 2004-2008, we randomized 134 HNC patients to 12 weeks of JP (n = 72) or placebo (n = 62). Oral cavity mucosal biopsies and whole blood were obtained at baseline and after 12 weeks. All participants were given the opportunity to receive JP for 5 years following the end of the intervention period, and they were followed yearly for the development of SPTs. Results. After 12 weeks, patients on JP had significantly higher serum α-carotene (P = .009), β-carotene (P < .0001), and lutein (P = .003) but did not differ significantly in p27 (P = .23) or Ki-67 (P = .95). JP use following the initial 12-week trial was not significantly associated with SPT prevention. Conclusions. Despite increased serum micronutrient levels, our results do not suggest a clinical benefit of JP in HNC patients. Future studies should focus on longer intervention periods and/or modified supplement formulations with demonstrated chemopreventive properties.

Purpose: Rural US adults have increased risk of poor outcomes after cancer, including increased cancer mortality. Rural—urban differences in health behaviors have been identified in the general population and may contribute to cancer health disparities, but have not yet been examined among US survivors. We examined rural—urban differences in health behaviors among cancer survivors and associations with self-reported health and health-related unemployment. Methods: We identified rural (n = 1,642) and urban (n = 6,162) survivors from the cross-sectional National Health Interview Survey (2006–2010) and calculated the prevalence of smoking, physical activity, overweight/obesity, and alcohol consumption. Multivariable models were used to examine the associations of fair/poor health and health-related unemployment with health behaviors and rural—urban residence. Results: The prevalence of fair/poor health (rural 36.7 %, urban 26.6 %), health-related unemployment (rural 18.5 %, urban 10.6 %), smoking (rural 25.3 %, urban 15.8 %), and physical inactivity (rural 50.7 %, urban 38.7 %) was significantly higher in rural survivors (all p < .05); alcohol consumption was lower (rural 46.3 %, urban 58.6 %), and there were no significant differences in overweight/obesity (rural 65.4 %, urban 62.6 %). All health behaviors were significantly associated with fair/poor health and health-related unemployment in both univariate and multivariable models. After adjustment for behaviors, rural survivors remained more likely than urban survivors to report fair/poor health (OR = 1.21, 95 % CI 1.03–1.43) and health-related unemployment (OR = 1.49, 95 % CI 1.18–1.88). Conclusions: Rural survivors may need tailored, accessible health promotion interventions to address health-compromising behaviors and improve outcomes after cancer.