Breast cancer incidence and mortality by metabolic syndrome and obesity: The Women's Health Initiative.

BACKGROUND: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials. METHODS: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status. RESULTS: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m2; p < .001). CONCLUSIONS: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies.

Effect of minocycline on changes in affective behaviors, cognitive function, and inflammation in breast cancer survivors undergoing chemotherapy: a pilot randomized controlled trial.

PURPOSE: Minocycline suppresses chemotherapy-induced neuroinflammation in preclinical models, but its effects in cancer survivors are unknown. This study evaluated the longitudinal effects of minocycline on affective behaviors, cognitive functions, and inflammation in women with breast cancer (BC) undergoing chemotherapy. METHODS: This is a pilot, double-blind, randomized controlled trial of oral minocycline (100 mg BID) versus placebo for chemotherapy-induced affective disorders in women initiating chemotherapy for stage I-III BC. Participants received minocycline or placebo up to one week before chemotherapy, continuing through cycle 4 (C4). Epidemiologic Studies Depression Scale (CES-D) and State-Trait Anxiety Inventory (STAI) were assessed at baseline, each cycle of chemotherapy (C1-C4), 2-3-week post-chemotherapy (end of chemotherapy), and 6-month post-chemotherapy (6 M) as the primary outcomes. Sub-group analysis of CES-D and STAI based on the severity of symptoms was also performed. Changes in self-reported cognition and serum inflammatory markers were also evaluated. RESULTS: Fifty-seven women enrolled and 55 completed the study. Except for Interleukin-8 (p ≤ 0.03), changes in inflammatory markers, cognitive function, CES-D, and STAI were not significantly different between groups from baseline to any cycle or post-chemotherapy time point (all p > 0.05), adjusting for baseline scores. Increases in serum Interleukin-8 from baseline to C4 and 6 M were ameliorated by minocycline (p < 0.05). The sub-group symptomatic for depression (CES-D > = 16 at baseline) treated with minocycline had a greater reduction in CES-D score compared to placebo from baseline to 6 M (p = 0.01). CONCLUSION: Despite attenuation of IL-8, minocycline did not alter self-reported affective symptoms or cognition in this cohort of BC survivors undergoing chemotherapy. The effect of minocycline on BC survivors symptomatic for depression before chemotherapy warrants further investigation.

Dietary EPA and DHA enrichment of a high fat diet during doxorubicin-based chemotherapy attenuated neuroinflammatory gene expression in the brain of C57bl/6 ovariectomized mice.

Chemotherapy agents in breast cancer are associated with chemotherapy-related cognitive impairments (CRCI). Mechanisms are not fully clear, but alterations of glucose and lipid metabolism, neuroinflammation and neurodegeneration may contribute to CRCI. The aim of this study was to investigate the combined effects of a high fat (HF) diet combined with doxorubicin-based chemotherapy on glucose and lipid metabolism, neuroinflammation, and neurodegeneration in mice. Additionally, we examined the therapeutic potential of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to attenuate these effects. Female C57Bl/6 mice (n = 42) were fed HF, HFn-3 (2 % kcals as EPA + DHA) or Low Fat (LF) diets for seven weeks, with and without chemotherapy. In this study, two chemotherapy injections led to weight and body fat loss associated with a decrease in insulin resistance measured by HOMA-IR. HOMA-IR was significantly greater in HF versus LF groups; but HOMA-IR in HFn-3 group did not significantly differ from either HF or LF groups. Chemotherapy resulted in higher brain concentrations of the inflammatory chemokine KC/GRO. Compared to LF diet plus chemotherapy, HF diet plus chemotherapy upregulated multiple genes involved in neuroinflammation and neurodegeneration pathways. HFn-3 diet plus chemotherapy attenuated gene expression by downregulating multiple genes involved in neuroinflammation and blood brain barrier regulation, including Mapkapk2, Aqp4, and s100b, and upregulating Kcnb1 and Atxn3, genes involved in reduction of oxidative stress and anxiety, respectively. Overall, a HF diet combined with chemotherapy is associated with neuroinflammatory and neurodegenerative gene expression changes in this mouse model; dietary enrichment of EPA and DHA attenuated these effects. Further studies are needed to understand how diet impacts behavioral outcomes of CRCI.

Mental health in society's margins: poor n-3 PUFA intake and psychological well-being of homeless youth.

Dietary intake of long-chain n-3 PUFA (n-3 PUFA), particularly EPA and DHA, has been associated with psychological well-being, but little is known about the n-3 PUFA intake of homeless youth. The current study determined the association between depression and anxiety symptoms and n-3 PUFA intake and erythrocytes status in homeless youth. Totally, 114 homeless youth aged 18-24 years were recruited from a drop-in centre. n-3 PUFA dietary intake was assessed using an FFQ, and erythrocytes status was determined by gas chromatography (GC). Linear regression models were used to determine the relationship between psychological well-being and n-3 PUFA intake and status. The mean intakes of EPA and DHA for all participants (0·06 ± 0·13 g/d and 0·11 ± 0·24 g/d) were well below recommended levels, and mean erythrocytes EPA + DHA (n-3 index) in the cohort (2·42 %) was lower than reported for healthy, housed adolescents and those with clinical depression. There was no association of n-3 PUFA intake and erythrocytes status with either depression or anxiety. However, the relationships of depression with dietary EPA (P = 0·017) and DHA (P = 0·008), as well as erythrocytes DHA (P = 0·007) and n 3-index (P = 0·009), were significantly moderated by sex even after adjusting for confounders. Specifically, among females, as the intake and status of these n-3 PUFA decreased, depression increased. Our findings show poor dietary intake and low erythrocytes status of n-3 PUFA among homeless youth, which is associated with depressive symptoms among females.

A remote Whole Food Dietary Intervention to Reduce Fatigue and Improve Diet Quality in Lymphoma Survivors: Results of a Feasibility Pilot Study.

Long-term, persistent cancer-related fatigue (CRF) is the most common side effect reported by lymphoma survivors. CRF reduces quality of life, and treatments are limited. This pilot study aimed to determine feasibility of recruiting and retaining diffuse large B-cell lymphoma (DLBCL) survivors in a 12-week remote Fatigue Reduction Diet (FRD) intervention and evaluate preliminary efficacy of the intervention. Participants met remotely with a registered dietitian nutritionist for eight individual sessions. FRD goals included consuming specific fruits, vegetables, whole grains, and omega-3 fatty acid rich foods. Acceptability was assessed by session attendance, FRD goal attainment, and exit surveys. Self-reported dietary intake and fatigue were measured using the Healthy Eating Index-2015 and PROMIS Fatigue Short Form, respectively, at baseline and post-intervention. Ten DLBCL survivors enrolled; nine attended all sessions and completed the intervention. Weekly adherence to targeted food intake goals improved significantly throughout the study (all p < 0.05), with participants meeting goals over 4 day per week by week 11. Mean[SD] diet quality improved significantly from baseline (65.9[6.3]) to post-intervention (82.2[5.0], p < 0.001). Mean[SD] fatigue reduced significantly from baseline (50.41[9.18]) to post-intervention (45.79[6.97], p < 0.05). The 12-week remote FRD intervention was feasible, acceptable, and holds promise to improve diet quality and fatigue in DLBCL survivors.

Sugars measured enzymatically in a fasting overnight urine sample are not sensitive biomarkers of dietary added sugar intake in postmenopausal women.

BACKGROUND: Restricting dietary sugar is a leading recommendation, but limited biomarkers assessing intake exist. Although 24-h urinary sucrose (U-Suc) and urinary fructose (U-Fruc) excretion has been used with mixed success, collection is burdensome. AIM: This study aimed to test the sensitivity of an enzymatic assay of U-Suc and U-Fruc to detect changing added sugar intake using low-burden overnight urine samples in 30 postmenopausal women. METHODS: Women consumed usual dietary intake during day 1 and usual intake plus a sugar sweetened beverage during day 2. Weighed, photographed food records assessed intake. Enzymatic assay measured U-Suc and U-Fruc from fasting overnight samples; liquid chromatography mass spectrometry (LC-MS) validated U-Suc findings. RESULTS: Dietary added sugars increased significantly during day 2 (p < 0.001), but urinary sugars were not significantly increased. Enzymatic assay detected urinary sugars in 75% (U-Suc) and 35% (U-Fruc) of samples. Dietary sucrose was not associated with U-Suc, however dietary fructose was significantly associated with U-Fruc [ß = 0.031; p < 0.05] among women with detectable urinary sugars. Participants with detectable U-Fruc consumed more energy from added sugars [12.6% kcal day 1; 21.5% kcal day 2] than participants with undetectable U-Fruc [9.3% kcal day 1; 17.4% kcal day 2], p < 0.05. Using LC-MS, U-Suc predicted sucrose and added sugar intake [ß = 0.017, ß = 0.013 respectively; both p < 0.05]. CONCLUSIONS: Urinary sugars measured enzymatically from overnight urine samples were not sensitive biomarkers of changing added sugar intake in postmenopausal women. However, urinary fructose measured by enzymatic assay or LC-MS may differentiate low versus high added sugar consumers.

Psychoneurological symptom cluster in breast cancer: the role of inflammation and diet.

Patients with breast cancer experience treatment-related symptoms which are unlike side effects associated with therapy such as surgery, chemotherapy or radiation. These symptoms are collectively referred to as symptoms cluster and include concurrent physical and/or psychosocial symptoms. Psychoneurological symptom cluster has been used to describe fatigue, mood changes, cognitive and sleep disturbances and pain seen in patients diagnosed with cancer. The etiology of psychoneurological symptom cluster is unclear; however, inflammation has been shown to play a role. High quality diets defined as diets rich in fruits, vegetables, whole grains and polyunsaturated fatty acids and low in added sugar have been shown to decrease inflammation in patients. This article reviews the role of inflammation and high quality diet on the prevalence of psychoneurological symptoms clusters.

Randomized placebo-controlled pilot trial of omega 3 fatty acids for prevention of aromatase inhibitor-induced musculoskeletal pain.

PURPOSE: Aromatase inhibitor (AI)-induced joint symptoms negatively impact drug adherence and quality of life in breast cancer survivors. Mechanisms underlying symptoms may include inflammation. It is hypothesized that n - 3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties and may reduce symptoms. METHODS: We conducted a randomized, double-blind, placebo-controlled study comparing 4.3 g/day n - 3 PUFA supplements vs placebo for 24 weeks in postmenopausal breast cancer patients starting adjuvant AIs. Primary endpoints were adherence and tolerability; secondary outcomes included inflammatory cytokines and symptoms assessed by the Brief Pain Inventory short form (BPI-SF) and Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) at 0, 12, and 24 weeks. RESULTS: Forty-four women were randomized, of which 35 completed the study. Adherence was ≥ 88% based on these 35 patients with pill counts as well as change in red blood cell (RBC) n - 3 PUFAs. Common toxicities included grade 1 flatulence (55% of both groups) and belching (45% of n - 3 group). Mean pain severity scores (BPI-SF) did not change significantly by time or treatment arm. Quality of life, based on FACT-ES scores, significantly decreased within placebo (p = 0.04), but not the n - 3 group (p = 0.58), with a trend toward between-group differences (p = 0.06) at 12 weeks, but no significant differences at 24 weeks. RBC n - 3 levels were strongly positively correlated with FACT-ES at 12 weeks, but attenuated at 24 weeks. CONCLUSION: High-dose n - 3 PUFA supplementation is feasible and well tolerated when administered with AIs. Additional studies are needed to evaluate efficacy in prevention of joint symptoms.

Clearing the fog: a review of the effects of dietary omega-3 fatty acids and added sugars on chemotherapy-induced cognitive deficits.

Cancer treatments such as chemotherapy have been an important part of extending survival in women diagnosed with breast cancer. However, chemotherapy can cause potentially toxic side effects in the brain that impair memory, verbal fluency, and processing speed in up to 30% of women treated. Women report that post-chemotherapy cognitive deficits negatively impact quality of life and may last up to ten years after treatment. Mechanisms underlying these cognitive impairments are not fully understood, but emerging evidence suggests that chemotherapy induces structural changes in the brain, produces neuroinflammation, and reduces adult hippocampal neurogenesis. Dietary approaches that modify inflammation and neurogenesis are promising strategies for reducing chemotherapy-induced cognitive deficits in breast cancer survivors. In this review, we describe the cognitive and neuronal side effects associated with commonly used chemotherapy treatments for breast cancer, and we focus on the often opposing actions of omega-3 fatty acids and added sugars on cognitive function, neuroinflammation, and adult hippocampal neurogenesis. Omega-3 fatty acids administered concurrently with doxorubicin chemotherapy have been shown to prevent depressive-like behaviors and reduce neuroinflammation, oxidative stress, and neural apoptosis in rodent models. In contrast, diets high in added sugars may interact with n-3 FAs to diminish their anti-inflammatory activity or act independently to increase neuroinflammation, reduce adult hippocampal neurogenesis, and promote cognitive deficits. We propose that a diet rich in long-chain, marine-derived omega-3 fatty acids and low in added sugars may be an ideal pattern for preventing or alleviating neuroinflammation and oxidative stress, thereby protecting neurons from the toxic effects of chemotherapy. Research testing this hypothesis could lead to the identification of modifiable dietary choices to reduce the long-term impact of chemotherapy on the cognitive functions that are important to quality of life in breast cancer survivors.

Low sucrose diets protect long-term memory and EPA & DHA enriched diets alter insulin resistance in a mouse model of chemotherapy.

Chemotherapy-related cognitive impairment (CRCI) and affective symptoms negatively impact quality of life in breast cancer survivors. The aim of this study was to determine the efficacy of high eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) and low sucrose diets to alleviate these symptoms in a mouse model of chemotherapy. Potential mechanisms involving insulin resistance were explored. We hypothesized that diets enriched in EPA+DHA and low amounts of sucrose would protect against the impact of chemotherapy on measures of CRCI. Female C57Bl/6 mice were randomized to 1 of 4 diets (2% kcal eicosapentaenoic acid + docosahexaenoic acid [EPA+DHA]/high or low sucrose, low omega-3/high or low sucrose) for 6 weeks and treated with two injections of doxorubicin-based chemotherapy or vehicle during week 2 and 4. Behavioral tests were performed 7 days after second injection. Chemotherapy increased serum insulin and decreased body weight, locomotion and exploratory behavior (all p < .05). Low sucrose consumption resulted in better long-term memory regardless of chemotherapy or vehicle injection (p < .05). 2% EPA+DHA consumption lessened insulin resistance (p < .05); however, controlling for body weight attenuated this effect (p = .08). There were no significant differences by diet or injection on liver lipid content; however, liver lipid content was positively correlated with insulin resistance scores (p < .05). Low sucrose diets may protect long-term memory during chemotherapy. The effect of EPA+DHA on insulin resistance and affective side effects during chemotherapy requires further investigation.

A systematic review of omega-3 fatty acids and osteoporosis.

Some epidemiological evidence suggests that diets high in omega 3 fatty acids (n-3 FAs) may be beneficial for skeletal health. The aim of this systematic review was to determine if randomized controlled trials (RCTs) support a positive effect of n-3 FAs on osteoporosis. A systematic search was performed in PubMed and EMBASE databases. We included RCTs with skeletal outcomes conducted in adults or children (> = 1 year old) using n-3 FA fortified foods, diets or supplements alone or in combination with other vitamins/minerals, versus placebo. Primary outcomes were incident fracture at any site and bone mineral density (BMD) in g/cm2. Secondary outcomes included bone formation or resorption markers and bone turnover regulators. A total of 10 RCTs met inclusion criteria. Effect sizes with 95 % confidence intervals were estimated to compare studies across various treatments and outcome measures. No pooled analysis was completed due to heterogeneity of studies and small sample sizes. No RCTs included fracture as an outcome. Four studies reported significant favorable effects of n-3 FA on BMD or bone turnover markers. Of these, three delivered n-3 FA in combination with high calcium foods or supplements. Five studies reported no differences in outcomes between n-3 FA intervention and control groups; one study included insufficient data for effect size estimation. Strong conclusions regarding n-3 FAs and bone disease are limited due to the small number and modest sample sizes of RCTs, however, it appears that any potential benefit of n-3 FA on skeletal health may be enhanced by concurrent administration of calcium.

Potential Cardioprotective Effects and Lipid Mediator Differences in Long-Chain Omega-3 Polyunsaturated Fatty Acid Supplemented Mice Given Chemotherapy.

Many commonly used chemotherapies induce mitochondrial dysfunction in cardiac muscle, which leads to cardiotoxicity and heart failure later in life. Dietary long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) have demonstrated cardioprotective function in non-chemotherapy models of heart failure, potentially through the formation of LC n-3 PUFA-derived bioactive lipid metabolites. However, it is unknown whether dietary supplementation with LC n-3 PUFA can protect against chemotherapy-induced cardiotoxicity. To test this, 36 female ovariectomized C57BL/6J mice were randomized in a two-by-two factorial design to either a low (0 g/kg EPA + DHA) or high (12.2 g/kg EPA + DHA) LC n-3 PUFA diet, and received either two vehicle or two chemotherapy (9 mg/kg anthracycline + 90 mg/kg cyclophosphamide) tail vein injections separated by two weeks. Body weight and food intake were measured as well as heart gene expression and fatty acid composition. Heart mitochondria were isolated using differential centrifugation. Mitochondrial isolate oxylipin and N-acylethanolamide levels were measured by mass spectrometry after alkaline hydrolysis. LC n-3 PUFA supplementation attenuated some chemotherapy-induced differences (Myh7, Col3a1) in heart gene expression, and significantly altered various lipid species in cardiac mitochondrial preparations including several epoxy fatty acids [17(18)-EpETE] and N-acylethanolamines (arachidonoylethanolamine, AEA), suggesting a possible functional link between heart lipids and cardiotoxicity.

Adherence to a MIND-Like Dietary Pattern, Long-Term Exposure to Fine Particulate Matter Air Pollution, and MRI-Based Measures of Brain Volume: The Women's Health Initiative Memory Study-MRI.

BACKGROUND: Previous studies suggest that certain dietary patterns and constituents may be beneficial to brain health. Airborne exposures to fine particulate matter [particulate matter with aerodynamic diameter ≤2.5µm (PM2.5)] are neurotoxic, but the combined effects of dietary patterns and PM2.5 have not been investigated. OBJECTIVES: We examined whether previously reported association between PM2.5 exposure and lower white matter volume (WMV) differed between women whose usual diet during the last 3 months before baseline was more or less consistent with a Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND)-like diet, a dietary pattern that may slow neurodegenerative changes. METHODS: This study included 1,302 U.S. women who were 65-79 y old and free of dementia in the period 1996-1998 (baseline). In the period 2005-2006, structural brain magnetic resonance imaging (MRI) scans were performed to estimate normal-appearing brain volumes (excluding areas with evidence of small vessel ischemic disease). Baseline MIND diet scores were derived from a food frequency questionnaire. Three-year average PM2.5 exposure prior to MRI was estimated using geocoded participant addresses and a spatiotemporal model. RESULTS: Average total and temporal lobe WMVs were 0.74 cm3 [95% confidence interval (CI): 0.001, 1.48) and 0.19 cm3 (95% CI: 0.002, 0.37) higher, respectively, with each 0.5-point increase in the MIND score and were 4.16 cm3 (95% CI: -6.99, -1.33) and 1.46 cm3 (95% CI: -2.16, -0.76) lower, respectively, with each interquartile range (IQR) (IQR=3.22 µg/m3) increase in PM2.5. The inverse association between PM2.5 per IQR and WMV was stronger (p-interaction<0.001) among women with MIND scores below the median (for total WMV, -12.47 cm3; 95% CI: -17.17, -7.78), but absent in women with scores above the median (0.16 cm3; 95% CI: -3.41, 3.72), with similar patterns for WMV in the frontal, parietal, and temporal lobes. For total cerebral and hippocampus brain volumes or WMV in the corpus callosum, the associations with PM2.5 were not significantly different for women with high MIND scores and women with low MIND scores. DISCUSSION: In this cohort of U.S. women, PM2.5 exposure was associated with lower MRI-based WMV, an indication of brain aging, only among women whose usual diet was less consistent with the MIND-like dietary pattern at baseline. https://doi.org/10.1289/EHP8036.

Knowledge, Attitudes, and Practices Regarding Dietary Sodium in College Students.

OBJECTIVE: Test a dietary sodium survey in a US adult population of college students using a survey previously validated in a non-US adult population. METHODS: Cross-sectional study of a convenience sample of college students from a Midwest (n = 168) and Pacific Island (n = 152) university. Main outcome measures were knowledge, attitudes, and practices regarding dietary sodium (38 items). Sum scores and percentages for constructs were calculated. A score <75% was considered unfavorable; t test or ANOVA were used to examine group differences. RESULTS: Midwest students were primarily non-Hispanic White individuals (81%) and 65% female. Pacific Island students were predominantly Asian (51%) and 66% female. Mean ± SD construct scores (percentage) for knowledge, attitudes, and practices were 58.69 ± 10.62, 63.96 ± 16.18, 66.00 ± 12.34 (Midwest) and 57.54 ± 10.93, 64.84 ± 14.96, 64.94 ± 13.18 (Pacific Island), respectively; there were no significant differences between schools or race. CONCLUSIONS AND IMPLICATIONS: College students scored low in knowledge, attitudes, and practices regarding sodium. Results from this formative study may inform assessment strategies in future dietary sodium interventions.

Associations of Erythrocyte Polyunsaturated Fatty Acids with Inflammation and Quality of Life in Post-Menopausal Women with Obesity Completing a Pilot Dietary Intervention.

Study objectives were to determine if erythrocyte omega-3 polyunsaturated fatty acids (n-3 PUFAs) increased in women participating in a dietary intervention that reduced inflammation and body weight and examine PUFA associations with markers of inflammation and quality of life (QOL). An experimental pre-post test, single group design was used. Fifteen post-menopausal women with obesity were enrolled in a 12-week pilot intervention focusing on lowering added sugars and increasing fiber and fish rich in n-3 PUFAs. Measurements included fasting blood samples, anthropometric, lifestyle and dietary data collected at baseline, end of intervention (Week 12) and follow-up (Week 24). Primary outcomes were change in erythrocyte PUFAs and associations between erythrocyte PUFAs, QOL (Short Form 12), and inflammatory markers (interleukin-6, tumor necrosis factor-α-receptor 2, and high sensitivity C-reactive protein (CRP)). Fourteen women completed all intervention visits. Mean erythrocyte docosahexaenoic acid and arachidonic acid (AA) increased at Week 12 and Week 24 (p < 0.001 for both), while eicosapentaenoic acid increased at Week 24 (p < 0.01). After adjustment for percent weight change, week 12 QOL related to physical function was significantly associated with erythrocyte linoleic acid (p < 0.05) and trended toward significant association with EPA (p = 0.051); week 24 CRP was directly associated with erythrocyte AA (p < 0.05). Erythrocyte n-3 PUFAs were not associated with inflammation.

The Effects of Doxorubicin-based Chemotherapy and Omega-3 Supplementation on Mouse Brain Lipids.

Chemotherapy-induced cognitive impairment affects ~30% of breast cancer survivors, but the effects on how chemotherapy impacts brain lipids, and how omega-3 polyunsaturated fatty acid supplementation may confer protection, is unknown. Ovariectomized mice were randomized to two rounds of injections of doxorubicin + cyclophosphamide or vehicle after consuming a diet supplemented with 2% or 0% EPA+DHA, and sacrificed 4, 7, and 14 days after the last injection (study 1, n = 120) or sacrificed 10 days after the last injection (study 2, n = 40). Study 1 whole brain samples were extracted and analyzed by UHPLC-MS/MS to quantify specialized pro-resolving mediators (SPMs). Lipidomics analyses were performed on hippocampal extracts from study 2 to determine changes in the brain lipidome. Study 1 results: only resolvin D1 was present in all samples, but no differences in concentration were observed (P > 0.05). Study 2 results: chemotherapy was positively correlated with omega-9 fatty acids, and EPA+DHA supplementation helped to maintain levels of plasmalogens. No statistically significant chemotherapy*diet effect was observed. Results demonstrate a limited role of SPMs in the brain post-chemotherapy, but a significant alteration of hippocampal lipids previously associated with other models of cognitive impairment (i.e., Alzheimer's and Parkinson's disease).

Improving Diet Quality Is Associated with Decreased Inflammation: Findings from a Pilot Intervention in Postmenopausal Women with Obesity.

BACKGROUND: Chronic inflammation is associated with obesity, morbidity, and mortality in postmenopausal women. OBJECTIVE: The objective of this pilot study was to determine preliminary feasibility and efficacy of a dietary intervention to improve diet quality and lower inflammation. DESIGN: The study had a single-arm, pre- and posttest design. PARTICIPANTS/SETTING: Fourteen postmenopausal women (body mass index >30 [calculated as kg/m2]) from the greater Columbus, OH, area participated between August 2015 and April 2016. INTERVENTION: This was a 12-week individualized dietary intervention targeting lower consumption of added sugars and increased fiber and fatty fish. MAIN OUTCOME MEASURES: Primary outcomes of this analysis were serum tumor necrosis factor α receptor-2 (TNFαR-2), interleukin-6 (IL-6), and high sensitivity C-reactive protein (hsCRP); other outcomes included intake of targeted food components and Healthy Eating Index-2010 (HEI-2010) scores calculated from food frequency questionnaires at baseline, end of intervention (week 12 [WK12]), and 24-week (WK24) follow-up. STATISTICAL ANALYSES PERFORMED: Repeated measures analysis of variance and partial Pearson correlations, respectively, were used to assess changes in outcomes and associations between dietary variables and inflammatory markers, controlling for percent weight change. RESULTS: Mean levels of TNFαR-2 decreased pre- to postintervention (P<0.01) and remained reduced at WK24 (P<0.001). Mean intake of added sugars and n-3-rich fish improved from baseline to WK12 and remained better at WK24 (all P<0.001); mean fiber intake did not change significantly (P=0.66; baseline to WK24). Mean HEI-2010 score increased (P<0.001; baseline to WK12). Change in HEI-2010 score inversely correlated with change in TNFαR-2 (P<0.05; baseline to WK24). Change in added sugars directly correlated with change in TNFαR-2 (P<0.05; baseline to WK24), but inversely correlated with change in hsCRP (P<0.05; baseline to WK12, and WK12 to WK24). All participants lost weight by WK12 (P<0.001). CONCLUSIONS: These pilot intervention findings suggest that improving diet quality is associated with decreases in TNFαR-2.

Diet Quality, Inflammation, and Quality of Life in Breast Cancer Survivors: A Cross-Sectional Analysis of Pilot Study Data.

BACKGROUND: Modifiable lifestyle factors, such as diet quality, could reduce inflammation and improve quality of life (QOL) in breast cancer survivors, but data are inconclusive. OBJECTIVE: To determine whether diet quality, as measured by Healthy Eating Index-2010 (HEI-2010) score, is associated with inflammation, health status, or functional outcomes affecting QOL in survivors of early-stage breast cancer. DESIGN: This is a cross-sectional, secondary analysis of baseline data collected from breast cancer survivors after completion of primary therapy and before random assignment to a pilot nutritional intervention aimed at reducing side effects of aromatase inhibitor treatment. PARTICIPANTS/SETTING: Participants were 44 postmenopausal women with stage I to III endocrine receptor-positive breast cancer receiving outpatient care at a midwestern cancer center between November 2011 and October 2013. MAIN OUTCOME MEASURES: Primary outcomes were serum proinflammatory cytokines (interleukin-6 [IL-6], IL-17, and tumor necrosis factor-α receptor 2 [TNFR-2]). Secondary outcomes included QOL measured by the Stanford Health and Disability Questionnaire and the Functional Assessment of Cancer Therapy-Breast with Endocrine Subscale. STATISTICAL ANALYSES PERFORMED: Pearson correlation coefficients (r) and linear regression models were used to evaluate the relationship of dietary variables with inflammatory cytokines and QOL measures. RESULTS: A higher overall HEI-2010 score (healthier diet) was associated with lower IL-6 (r=-0.46; P=0.002) and TNFR-2 (r=-0.41; P=0.006); however, associations were attenuated by body mass index (BMI) (IL=6 [r=-0.26; P=0.10]; TNFR-2 [r=-0.30; P=0.06]). In women with prior chemotherapy, a higher HEI-2010 score was strongly associated with lower IL-6 (r=-0.67; P=0.009) and TNFR-2 (r=-0.59; P=0.03) after BMI adjustment. There were no significant correlations between HEI-2010 score and QOL measures after adjustment for BMI. CONCLUSIONS: These data suggest the need for more rigorous investigation into the relationship of diet quality, BMI, and inflammation in breast cancer survivors.

Low Sucrose, Omega-3 Enriched Diet Has Region-Specific Effects on Neuroinflammation and Synaptic Function Markers in a Mouse Model of Doxorubicin-Based Chemotherapy.

Chemotherapeutic agents such as doxorubicin may negatively affect long-term brain functioning in cancer survivors; neuroinflammation may play a causal role. Dietary approaches that reduce inflammation, such as lowering sucrose and increasing eicosapentaenoic acid plus docosahexaenoic acid (EPA + DHA), may attenuate chemotherapy-induced neuroinflammation and synaptic damage, thereby improving quality of life. Ovariectomized, C57BL/6 mice were assigned to a chemotherapy (9 mg/kg doxorubicin + 90 mg/kg cyclophosphamide) or vehicle two-injection regimen, with injections two and four weeks after starting diets. In Study 1, mice received low sucrose diets with EPA + DHA or No EPA + DHA for four to six weeks; tissues were collected four, seven, or 14 days after the second injection. Compared to vehicle, chemotherapy increased pro-inflammatory cytokine IL-1ß at day seven in the cortex and hippocampus, and reduced gene expression of synaptic marker Shank 3 at all timepoints in cortex, while EPA + DHA increased expression of Shank 3. In Study 2, high or low sucrose/EPA + DHA or No EPA + DHA diets were fed for five weeks; tissues were collected ten days after the second injection. Among chemotherapy-treated mice, brain DHA was higher with low sucrose feeding. Furthermore, low sucrose increased gene expression of Shank 1, while EPA + DHA increased expression of Shank 3 and reduced protein concentrations of pro-inflammatory markers IL-5, IL-6 and KC/GRO in the cortex, but not the hippocampus. Low sucrose, EPA + DHA diets may attenuate neuroinflammation and synaptic damage induced by doxorubicin-based chemotherapy in specific brain regions.

TNF Receptors Predict Hip Fracture Risk in the WHI Study and Fatty Acid Intake Does Not Modify This Association.

CONTEXT: Chronic inflammation may increase the risk of fracture, and omega-3 polyunsaturated fatty acids (PUFAs) may reduce fracture risk via down-regulation of inflammatory cytokine gene expression and other mechanisms. OBJECTIVE: We investigated associations between baseline samples of inflammatory markers, TNFα soluble receptors 1 and 2 (TNFα-sR1 and -sR2), and incident hip fracture. These associations were then tested for effect modification by dietary PUFA intake estimated by a baseline food frequency questionnaire. DESIGN AND SETTING: A nested case-control study was conducted among participants of the Women's Health Initiative Observational Study (ages, 50-79 y). Multivariable conditional logistic regression models were constructed to account for the paired design. PARTICIPANTS: This study sampled 400 pairs of hip fracture cases and controls without incident hip fracture, matched on age, year of enrollment, and menopausal hormone use. MAIN OUTCOME MEASURES: Odds ratio of hip fracture by quartile of TNF soluble receptors. RESULTS: The odds ratio of hip fracture comparing the highest to lowest quartiles was 2.24 (95% confidence interval, 1.05-4.79; P for linear trend, .048) for TNFα-sR1 and 2.83 (95% confidence interval, 1.34-5.99; P for linear trend, .011) for TNFα-sR2, adjusted for FRAX hip fracture score, nutritional variables, and selected factors impacting inflammation; there was a gradient of risk by increasing quartile in TNFα-sR1. PUFA intake did not modify these associations. CONCLUSIONS: Women with the highest levels of TNFα-sR1 and TNFα-sR2 had a greater than 2-fold increased hip fracture risk, independent of other fracture risk factors. These associations did not differ by high vs low PUFA intake.