Brandon H. Hidaka

Depression as a disease of modernity: Explanations for increasing prevalence

There has been much speculation about modern environments causing an epidemic of depression. This review aims to (1) determine whether depression rates have increased and (2) review evidence for possible explanations. While available data indicate rising prevalence and an increased lifetime risk for younger cohorts, strong conclusions cannot be drawn due to conflicting results and methodological flaws. There are numerous potential explanations for changing rates of depression. Cross-cultural studies can be useful for identifying likely culprits. General and specific characteristics of modernization correlate with higher risk. A positive correlation between a countrys GDP per capita, as a quantitative measure of modernization, and lifetime risk of a mood disorder trended toward significance (p=0.06). Mental and physical well-being are intimately related. The growing burden of chronic diseases, which arise from an evolutionary mismatch between past human environments and modern-day living, may be central to rising rates of depression. Declining social capital and greater inequality and loneliness are candidate mediators of a depressiogenic social milieu. Modern populations are increasingly overfed, malnourished, sedentary, sunlight-deficient, sleep-deprived, and socially-isolated. These changes in lifestyle each contribute to poor physical health and affect the incidence and treatment of depression. The review ends with a call for future research and policy interventions to address this public health crisis.

Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Postmenopausal Women.

Associational studies suggest higher intakes/blood levels of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) are associated with reduced breast cancer risk. We performed a pilot study of high-dose EPA + DHA in postmenopausal women to assess feasibility before initiating a phase IIB prevention trial. Postmenopausal women with cytologic evidence of hyperplasia in their baseline random periareolar fine needle aspiration (RPFNA) took 1,860 mg EPA +1500 mg DHA ethyl esters daily for 6 months. Blood and breast tissue were sampled at baseline and study conclusion for exploratory biomarker assessment, with P values uncorrected for multiple comparisons. Feasibility was predefined as 50% uptake, 80% completion, and 70% compliance. Trial uptake by 35 study entrants from 54 eligible women was 65%, with 97% completion and 97% compliance. Favorable modulation was suggested for serum adiponectin (P = 0.0027), TNFα (P = 0.016), HOMA 2B measure of pancreatic β cell function (P = 0.0048), and bioavailable estradiol (P = 0.039). Benign breast tissue Ki-67 (P = 0.036), macrophage chemoattractant protein-1 (P = 0.033), cytomorphology index score (P = 0.014), and percent mammographic density (P = 0.036) were decreased with favorable effects in a proteomics array for several proteins associated with mitogen signaling and cell-cycle arrest; but no obvious overall effect on proteins downstream of mTOR. Although favorable risk biomarker modulation will need to be confirmed in a placebo-controlled trial, we have demonstrated feasibility for development of high-dose EPA and DHA ethyl esters for primary prevention of breast cancer. Cancer Prev Res; 8(10); 922–31. ©2015 AACR. See related article, p. 912.

Omega-3 and Omega-6 Fatty Acids in Blood and Breast Tissue of High-Risk Women and Association with Atypical Cytomorphology

The ratio of omega-3 to omega-6 fatty acids, especially the long-chain eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) to arachidonic acid (AA) ratio, is inversely associated with breast cancer risk. We measured the association between cytologic atypia, a biomarker for short-term risk of breast cancer development, and omega-3 and omega-6 fatty acid intake and levels in blood and breast tissue. Blood and benign breast tissue, sampled by random periareolar fine-needle aspiration (RPFNA), was obtained from 70 women at elevated risk for breast cancer. Self-reported dietary intake was assessed by the NCIs Food Frequency Questionnaire. The fatty acid composition of five lipid compartments, red blood cell, plasma and breast phospholipids, and plasma and breast triaclyglycerides (TAG), was analyzed by gas chromatography as weight percent. Median daily intakes of EPA+DHA and total omega-3 fatty acids were 80 mg and 1.1 g, respectively. The median total omega-3:6 intake ratio was 1:10. Compared with women without atypia, those with cytologic atypia had lower total omega-3 fatty acids in red blood cell and plasma phospholipids and lower omega-3:6 ratios in plasma TAGs and breast TAGs (P < 0.05). The EPA+DHA:AA ratio in plasma TAGs was also lower among women with atypia. This is the first report of associations between tissue levels of omega-3 and omega-6 fatty acids and a reversible tissue biomarker of breast cancer risk. RPFNA cytomorphology could serve as a surrogate endpoint for breast cancer prevention trials of omega-3 fatty acid supplementation. Cancer Prev Res; 8(5); 359–64. ©2015 AACR.

Omega-3-acid ethyl esters block the protumorigenic effects of obesity in mouse models of postmenopausal basal-like and claudin-low breast cancer

Obesity induces chronic inflammation and is an established risk and progression factor for triple-negative breast cancers, including basal-like (BL) and claudin-low (CL) subtypes. We tested the effects of dietary supplementation with ethyl esters of the marine-derived anti-inflammatory omega-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA+DHA; Lovaza) on growth of murine BL and CL mammary tumors. Female ovariectomized C57BL/6 mice were fed a control diet or a diet-induced obesity (DIO) diet with or without EPA+DHA (0.025%, resulting in blood levels of EPA and DHA comparable with women taking Lovaza 4 g/d) for 6 weeks. All mice were then orthotopically injected with Wnt-1 cells (a BL tumor cell suspension derived from MMTV-Wnt-1 transgenic mouse mammary tumors) or M-Wnt cells (a CL tumor cell line cloned from the Wnt-1 tumor cell suspension). Mice were killed when tumors were 1 cm in diameter. EPA+DHA supplementation did not significantly affect Wnt-1 or M-Wnt mammary tumor growth in normoweight control mice. However, EPA+DHA supplementation in DIO mice reduced growth of Wnt-1 and M-Wnt tumors; reduced leptin:adiponectin ratio and proinflammatory eicosanoids in the serum; improved insulin sensitivity; and decreased tumoral expression of COX-2 and phospho-p65. Thus, EPA+DHA supplementation in mouse models of postmenopausal BL and CL breast cancer offsets many of the protumorigenic effects of obesity. These preclinical findings, in combination with results from parallel biomarker studies in women, suggest that EPA+DHA supplementation may reduce the burden of BL and CL breast cancer in obese women. Cancer Prev Res; 8(9); 796–806. ©2015 AACR.

The status of evolutionary medicine education in North American medical schools

BackgroundMedical and public health scientists are using evolution to devise new strategies to solve major health problems. But based on a 2003 survey, medical curricula may not adequately prepare physicians to evaluate and extend these advances. This study assessed the change in coverage of evolution in North American medical schools since 2003 and identified opportunities for enriching medical education.MethodsIn 2013, curriculum deans for all North American medical schools were invited to rate curricular coverage and perceived importance of 12 core principles, the extent of anticipated controversy from adding evolution, and the usefulness of 13 teaching resources. Differences between schools were assessed by Pearson’s chi-square test, Student’s t-test, and Spearman’s correlation. Open-ended questions sought insight into perceived barriers and benefits.ResultsDespite repeated follow-up, 60 schools (39%) responded to the survey. There was no evidence of sample bias. The three evolutionary principles rated most important were antibiotic resistance, environmental mismatch, and somatic selection in cancer. While importance and coverage of principles were correlated (r = 0.76, P < 0.01), coverage (at least moderate) lagged behind importance (at least moderate) by an average of 21% (SD = 6%). Compared to 2003, a range of evolutionary principles were covered by 4 to 74% more schools. Nearly half (48%) of responders anticipated igniting controversy at their medical school if they added evolution to their curriculum. The teaching resources ranked most useful were model test questions and answers, case studies, and model curricula for existing courses/rotations. Limited resources (faculty expertise) were cited as the major barrier to adding more evolution, but benefits included a deeper understanding and improved patient care.ConclusionNorth American medical schools have increased the evolution content in their curricula over the past decade. However, coverage is not commensurate with importance. At a few medical schools, anticipated controversy impedes teaching more evolution. Efforts to improve evolution education in medical schools should be directed toward boosting faculty expertise and crafting resources that can be easily integrated into existing curricula.

X chromosome inactivation in women with alcoholism.

BACKGROUND All female mammals with 2 X chromosomes balance gene expression with males having only 1 X by inactivating one of their X chromosomes (X chromosome inactivation [XCI]). Analysis of XCI in females offers the opportunity to investigate both X-linked genetic factors and early embryonic development that may contribute to alcoholism. Increases in the prevalence of skewing of XCI in women with alcoholism could implicate biological risk factors. METHODS The pattern of XCI was examined in DNA isolated in blood from 44 adult women meeting DSM-IV criteria for an alcohol use disorder and 45 control women with no known history of alcohol abuse or dependence. XCI status was determined by analyzing digested and undigested polymerase chain reaction (PCR) products of the polymorphic androgen receptor (AR) gene located on the X chromosome. Subjects were categorized into 3 groups based upon the degree of XCI skewness: random (50:50 to 64:36%), moderately skewed (65:35 to 80:20%), and highly skewed (>80:20%). RESULTS XCI status from informative women with alcoholism was found to be random in 59% (n = 26), moderately skewed in 27% (n = 12), or highly skewed in 14% (n = 6). Control subjects showed 60, 29, and 11%, respectively. The distribution of skewed XCI observed among women with alcoholism did not differ statistically from that of control subjects (χ(2) test = 0.14, 2 df, p = 0.93). CONCLUSIONS Our data did not support an increase in XCI skewness among women with alcoholism or implicate early developmental events associated with embryonic cell loss or unequal (nonrandom) expression of X-linked gene(s) or defects in alcoholism among women.

Dietary Associations with a Breast Cancer Risk Biomarker Depend on Menopause Status.

ABSTRACT We investigated how timing influences the role of diet in breast cancer risk with a cross-sectional study of pre-malignant change in breast tissue. Women with an elevated risk of developing breast cancer (33 premenopausal and 32 postmenopausal) completed the National Cancer Institutes food frequency questionnaire and underwent random periareolar fine-needle aspiration for evaluation of cytologic atypia, an established risk biomarker. Fatty acid composition of breast adipose was measured in 32 (49%) subjects. We found that premenopausal and postmenopausal women had similar diets, but the associations between atypia and intake of total n-3 polyunsaturated fatty acids (PUFA) and soy differed by menopause status (both P interaction < 0.001). Total n-3 PUFA intake was inversely associated with atypia among premenopausal women (P < 0.0001), but not among postmenopausal women (P = 0.91); associations were similar for soy (P = 0.0003 and P = 0.48, respectively). This pattern of dietary interaction with menopause was mirrored in tissue fatty acids (P interaction < 0.05), wherein 1) higher levels of linolelaidic acid (an industrially-produced trans fat) and 2) lower levels of docosahexaenoic acid (the predominant long-chain n-3 PUFA) in breast adipose were associated with atypia in premenopausal (both P < 0.05) but not postmenopausal women (both P > 0.37). Dietary associations with breast cancer risk are stronger prior to menopause.

Is estrogen receptor negative breast cancer risk associated with a fast life history strategy

Risk factors for breast cancer are often confusing and contradictory. Discrepancies are likely due to different subtypes having divergent risk factors. An important distinction between breast cancer subtypes is hormone-receptor status. Compared to women diagnosed with estrogen receptor positive (ER+) breast cancer, those with estrogen receptor negative (ER−) tumors are usually diagnosed at a younger age and have a higher mortality [1]. Few studies have attempted to explain ‘why’ breast cancer subtypes have different risk factors.

Intrauterine DHA exposure and child body composition at 5 y: exploratory analysis of a randomized controlled trial of prenatal DHA supplementation

Background Observational studies find associations between maternal docosahexaenoic acid (DHA) and greater fat-free mass and lower percentage of body fat, but randomized trials of prenatal DHA supplementation have not found significant intent-to-treat effects on childhood body composition. Objective This study sought to explore associations between intrauterine DHA exposure and body composition and size at 5 y in the offspring of women who participated in a randomized trial of prenatal DHA supplementation (corn and soybean oil placebo or 600 mg/d). Design At 5 y, body composition was measured by air displacement plethysmography in 154 offspring of women who had participated in the Kansas University DHA Outcomes Study and who had red blood cell (RBC) phospholipid (PL) fatty acids assessed at enrollment and delivery. We used linear regression models to analyze the relation among 3 indicators of intrauterine DHA exposure-1) intent-to-treat (placebo or DHA), 2) maternal RBC PL DHA status at delivery, and 3) change in maternal DHA (delivery minus enrollment)-and 6 outcomes of interest: 5-y fat mass, fat-free mass, percentage of body fat, height, weight, and body mass index z score. Results Change in maternal RBC PL DHA correlated with higher fat-free mass (r = 0.21, P = 0.0088); the association was unchanged after adjustment for maternal, perinatal, and childhood dietary factors. Intent-to-treat and DHA status at delivery showed positive trends with fat-free mass that were not statistically significant. There was no evidence relating intrauterine DHA exposure to any other body composition measure. Conclusions Change in maternal DHA status during pregnancy was related to higher offspring 5-y fat-free mass. The other 2 indicators of intrauterine exposure to DHA suggested a trend for higher offspring 5-y fat-free mass. Our findings agree with an earlier observational study from the United Kingdom. This trial was registered at clinicaltrials.gov as NCT00266825.

Abstract 158: Modulation of breast tissue biomarkers by high dose omega-3 fatty acid supplementation in women at high risk for development of breast cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background. Previously, we had observed that women at high risk for development of breast cancer were more likely to exhibit cytologic hyperplasia with atypia in specimens acquired by random periareolar fine needle aspiration (RPFNA) if they had low intake and/or low plasma, red blood cell, or breast tissue levels of omega-3 relative to omega-6 fatty acids. We evaluated the effect of high dose omega-3 supplementation on breast tissue markers in two parallel pilot studies, one of pre-menopausal and one of post-menopausal women. Methods. 36 pre-menopausal and 35 post-menopausal women at high risk for breast cancer had breast tissue harvested by RPFNA before and after a 6-month intervention with 4 g daily of omega-3-acid ehyl esters [1.86 g eicosapentaenoic acid (EPA), 1.5 g docosahexaenoic acid (DHA)]. Premenopausal women were aspirated in the follicular phase of the menstrual cycle. Specimens were evaluated for tissue risk biomarkers including cytomorphology, proliferation (Ki-67). Fatty acid composition was determined in plasma, red blood cells, and breast RPFNA specimens. Additional blood and frozen breast tissue was reserved for assessment of hormones, adipokines, cytokines and gene expression. Results. To date, only two of the 71 subjects have discontinued the study early, while 50 subjects have completed study and are evaluable for modulation of tissue biomarkers. Grade 2 or greater gastrointestinal side effects have been reported by only seven subjects. Favorable modulation was observed for cytologic evidence of atypia (70% to 44%; p=0.012), Masood score (medians of 15 to 14; p=0.001), number of epithelial cells recovered (p=0.002), and Ki-67 expression (p=0.059 if all subjects are included even if they did not exhibit Ki-67 staining at baseline, medians of 1.7% to 0.8%; or p=0.001 for 27 women with baseline Ki-67 >1.5%, medians of 3.2% to 1.4%). Modulation was more prevalent (and was statistically significant for all variables) in pre-menopausal women than in post-menopausal women. Fatty acid assessment, adipokine and cytokine assays are batched to minimize variability and all results are not yet available. Preliminary results indicate that the ratio of omega-3:omega-6 fatty acids increased in erythrocytes and plasma by two-fold after 6 months of the high dose omega-3 fatty acid intervention. Conclusion. High dose supplementation with omega-3 fatty acids is well-tolerated in healthy women at high risk for development of breast cancer and was associated with favorable modulation of the tissue risk biomarkers of cytologic atypia and proliferation. This strategy will be explored further as a promising intervention that may reduce risk for development of breast cancer. Supported in part by funding from the Breast Cancer Research Foundation and the Kansas Bioscience Authority. Study agent was provided by GlaxoSmithKline. Citation Format: Carol J. Fabian, Bruce F. Kimler, Carola M. Zalles, Trina Metheny, Jessica A. Box, Jennifer L. Nydegger, Teresa A. Phillips, Brandon H. Hidaka, Susan E. Carlson. Modulation of breast tissue biomarkers by high dose omega-3 fatty acid supplementation in women at high risk for development of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 158. doi:10.1158/1538-7445.AM2013-158