Randomized trial of weight loss in primary breast cancer: Impact on body composition, circulating biomarkers and tumor characteristics.

Obesity adversely impacts overall and cancer-specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two-arm, single-blinded, randomized controlled weight-loss trial was undertaken presurgery among 32 overweight/obese, Stage 0-II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper-body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68-0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery ∼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline-to-follow-up changes in weight (-3.62 vs. -0.52 kg), %body fat (-1.3 vs. 0%), moderate-to-vigorous physical activity (+224 vs. +115 min/week), caloric density (-0.3 vs. 0 kcal/g), serum leptin (-12.3 vs. -4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle-apoptosis related genes (CC-ARG; all p-values <0.05). Cytolytic CD56dim NK cell expression was positively associated with weight loss; CC-ARG increased with physical activity. Increased tumor (nuclear) TNFα and IL-1ß, CX3CL1 and CXCL1 gene expression was observed in the WLI. Tumor Ki67 did not differ between arms. Feasibility benchmarks included 80% accrual, 100% retention, no adverse effects and excellent adherence. Short-term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to presurgical caloric restriction, but possible benefits of physical activity.

Adult weight gain accelerates the onset of breast cancer.

PURPOSE: Weight gain in adulthood is a risk factor for breast cancer; however, the impact on age of onset is unknown. The objective of this study was to investigate whether weight gain from early- to mid-adulthood influenced the timing of breast cancer onset. METHODS: Increase in body mass index (BMI) from lowest adult BMI to BMI at diagnosis and age at which these events occurred were calculated from breast cancer survivors enrolled in a weight loss trial (n = 660). Quartiles (Q) of the average increase in BMI were determined and associations between weight gain and age at disease onset were analyzed using analysis of covariance and spline regression models. RESULTS: A significant linear trend was observed across the quartiles of BMI change for earlier age at diagnosis [Q1 52.3 (± 0.73), Q2 51.9 (± 0.70), Q3 49.6 (± 0.66), Q4 47.3 (± 0.67), p < 0.0001] after adjusting for potential confounders. In analyses that stratified by tumor subtype and menopausal status, significant linear trends continued to be observed for earlier age at diagnosis across quartiles of BMI for ER ± , PR ± , HER2 + , as well as pre- and postmenopausal status (p-values < 0.001). CONCLUSIONS: Women who gain excess weight during adulthood are not only at risk for breast cancer, but also may experience earlier onset of disease and reduced cancer-free years.

Presurgical weight loss affects tumour traits and circulating biomarkers in men with prostate cancer.

BACKGROUND: Obesity is associated with aggressive prostate cancer. To explore whether weight loss favourably affects tumour biology and other outcomes, we undertook a presurgical trial among overweight and obese men with prostate cancer. METHODS: This single-blinded, two-arm randomised controlled trial explored outcomes of a presurgical weight loss intervention (WLI) that promoted ∼1 kg per week loss via caloric restriction and increased physical activity (PA). Forty overweight/obese men with clinically confirmed prostate cancer were randomised to the WLI presurgery or to a control arm; changes in weight, body composition, quality-of-life, circulating biomarkers, gene expression, and immunohistochemical markers in tumour and benign prostatic tissue were evaluated. RESULTS: The study period averaged 50 days. Mean (s.d.) change scores for the WLI vs control arms were as follows: weight: -4.7 (3.1) kg vs -2.2 (4.4) kg (P=0.0508); caloric intake: -500 (636) vs -159 (600) kcal per day (P=0.0034); PA: +0.9 (3.1) vs +1.7 (4.6) MET-hours per day (NS); vitality: +5.3 (7.l4) vs -1.8 (8.1) (P=0.0491); testosterone: +55.1 (86.0) vs -48.3 (203.7) ng dl-1 (P=0.0418); sex hormone-binding globulin: +14.0 (14.6) vs +1.8 (7.6) nmol l-1 (P=0.0023); and leptin: -2.16 (2.6) vs -0.03 (3.75) (P=0.0355). Follow-up Ki67 was significantly higher in WLI vs control arms; median (interquartile range): 5.0 (2.5,10.0) vs 0.0 (0.0,2.5) (P=0.0061) and several genes were upregulated, for example, CTSL, GSK3B, MED12, and LAMC2. CONCLUSIONS: Intentional weight loss shows mixed effects on circulating biomarkers, tumour gene expression, and proliferative markers. More study is needed before recommending weight loss, in particular rapid weight loss, among men with prostate cancer.

Feasibility outcomes of a presurgical randomized controlled trial exploring the impact of caloric restriction and increased physical activity versus a wait-list control on tumor characteristics and circulating biomarkers in men electing prostatectomy for prostate cancer.

BACKGROUND: Obesity is associated with tumor aggressiveness and disease-specific mortality for more than 15 defined malignancies, including prostate cancer. Preclinical studies suggest that weight loss from caloric restriction and increased physical activity may suppress hormonal, energy-sensing, and inflammatory factors that drive neoplastic progression; however, exact mechanisms are yet to be determined, and experiments in humans are limited. METHODS: We conducted a randomized controlled trial among 40 overweight or obese, newly-diagnosed prostate cancer patients who elected prostatectomy to explore feasibility of a presurgical weight loss intervention that promoted a weight loss of roughly one kg. week(-1) via caloric restriction and physical activity, as well as to assess effects on tumor biology and circulating biomarkers. Measures of feasibility (accrual, retention, adherence, and safety) were primary endpoints. Exploratory aims were directed at the intervention's effect on tumor proliferation (Ki-67) and other tumor markers (activated caspase-3, insulin and androgen receptors, VEGF, TNFß, NFκB, and 4E-BP1), circulating biomarkers (PSA, insulin, glucose, VEGF, TNFß, leptin, SHBG, and testosterone), lymphocytic gene expression of corresponding factors and cellular bioenergetics in neutrophils, and effects on the gut microbiome. Consenting patients were randomized in a 1:1 ratio to either: 1) weight loss via a healthful, guidelines-based diet and exercise regimen; or 2) a wait-list control. While biological testing is currently ongoing, this paper details our methods and feasibility outcomes. RESULTS: The accrual target was met after screening 101 cases (enrollment rate: 39.6%). Other outcomes included a retention rate of 85%, excellent adherence (95%), and no serious reported adverse events. No significant differences by age, race, or weight status were noted between enrollees vs. non-enrollees. The most common reasons for non-participation were "too busy" (30%), medical exclusions (21%), and "distance" (16%). CONCLUSIONS: Presurgical trials offer a means to study the impact of diet and exercise interventions directly on tumor tissue, and other host factors that are feasible and safe, though modifications are needed to conduct trials within an abbreviated period of time and via distance medicine-based approaches. Pre-surgical trials are critical to elucidate the impact of lifestyle interventions on specific mechanisms that mediate carcinogenesis and which can be used subsequently as therapeutic targets. TRIAL REGISTRATION: NCT01886677.

Reduced mitogenicity of sera following weight loss in premenopausal women.

We investigated whether serum from normal weight women is less mitogenic and more apoptotic than sera from the same women in the overweight state. Sera from premenopausal women, age (mean ± SEE) 34.6 ± 0.53 years, who were randomized to caloric restriction (CR) (n = 13), CR + aerobic exercise (AE) (n = 14), or CR + resistance training (RT) (n = 20) were used to culture endometrial cancer cells. Phases of the cell cycle were determined, and proliferating cell nuclear antigen (PCNA) positivity was used to assess proliferation and apoptosis was assessed by determining cleaved caspase-3 and poly-ADP-ribose polymerase (PARP). Analyses showed that overall, cells grown in sera from the weight-reduced state had significantly more cells in G0/G1 and significantly fewer cells in the S and G2/M phases of the cell cycle than cells grown in sera from the overweight state. PCNA staining confirmed that cells grown in sera from the weight-reduced state had fewer proliferating cells. Cleaved caspase-3 and PARP were not different in cells grown in sera from the weight-reduced state compared to the overweight state. We conclude that weight loss with or without exercise could lower the risk for cancer through changes in serum that result in reduced cellular mitogenicity.

IgA Vasculitis with Nephritis in Adults: Histological and Clinical Assessment.

Patients with IgA vasculitis (IgAV), an immune complex-mediated disease, may exhibit kidney involvement-IgAV with nephritis (IgAVN). The kidney-biopsy histopathologic features of IgAVN are similar to those of IgA nephropathy, but little is known about histopathologic disease severity based on the interval between purpura onset and diagnostic kidney biopsy. We assessed kidney histopathology and clinical and laboratory data in a cohort of adult patients with IgAVN (n = 110). The cases were grouped based on the interval between the onset of purpura and kidney biopsy: Group 1 (G1, <1 month, n = 14), Group 2 (G2, 1-6 months, n = 58), and Group 3 (G3, >6 months, n = 38). Glomerular leukocytes were more common in G1 than in the other groups (p = 0.0008). The proportion of neutrophils among peripheral-blood leukocytes was the highest in the patients biopsied within a month after onset of purpura (G1: 71 ± 8%). In the patients with an interval >6 months, the neutrophil proportion was lower, 60%. Moreover, the glomerular mesangial proliferation score correlated with the serum total IgA concentration (p = 0.0056). In conclusion, IgAVN patients biopsied <1 month from purpura onset showed an elevated percentage of blood neutrophils and glomerular leukocytes, consistent with an acute-onset inflammatory reaction. In all IgAVN patients, the mesangial proliferation score correlated with the serum IgA level.

Mandatory fortification with folic acid in the United States is associated with increased expression of DNA methyltransferase-1 in the cervix.

OBJECTIVE: The objective of this study was to evaluate whether mandatory fortification of grain products with folic acid in the United States is associated with changes in DNA methyltransferase-1 (Dnmt-1) expression in cells involved in cervical carcinogenesis. METHODS: Archived specimens of cervical intraepithelial neoplasia (CIN) diagnosed before (1990-1992) and after (2000-2002) mandatory folic acid fortification were used to examine the expression of Dnmt-1 in specific lesions involved in cervical carcinogenesis by immunohistochemistry. The total number of lesions examined was 101 in the prefortification period and 96 in the postfortification period. Immunohistochemical staining for Dnmt-1, its assessment, and data entry were blinded with regard to the fortification status. RESULTS: Age- and race-adjusted mean percentage of cells positive for Dnmt-1 or the Dnmt-1 score was significantly higher in all lesion types (i.e., normal cervical epithelium, reactive cervical epithelium, metaplastic cervical epithelium, CIN, or carcinoma in situ) detected in the postfortification period compared with the prefortification period (P < 0.05, all comparisons). The degree of Dnmt-1 was significantly higher (P < 0.0001) in CIN > or = 2 lesions compared with CIN < or = 1 lesions, regardless of the fortification group. CONCLUSION: These results suggest that mandatory fortification with folic acid in the United States seems to have resulted in a change in the degree of expression of Dnmt-1 in cells involved in cervical carcinogenesis. Because the approach we have taken to demonstrate these differences have limitations inherent to a study of this nature and this is the first study to report a folate fortification associated change in Dnmt-1, validating these results in other study populations and/or with other techniques of assessing Dnmt-1 will increase the scientific credibility of these findings.

Dietary Changes Impact the Gut Microbe Composition in Overweight and Obese Men with Prostate Cancer Undergoing Radical Prostatectomy.

BACKGROUND: Diet and obesity influence prostate cancer risk and progression-effects that may be mediated through the gut microbiome. OBJECTIVE: Our aim was to explore relationships among diet, gut microbes, and Gleason sum in overweight and obese prostate cancer patients enrolled in a presurgical weight-loss trial. DESIGN: Randomized controlled trial (NCT01886677) secondary analysis. PARTICIPANTS/SETTING: In 2013-2014, 40 prostate cancer patients in the southeastern United States were randomized and allocated equally to weight-loss and wait-list control arms while they awaited prostatectomy; stool samples were collected on a subset of 22 patients. INTERVENTION: Registered dietitian nutritionists and exercise physiologists provided semi-weekly in-person and telephone-based guidance on calorie-restricted diets and exercise to promote an approximate weight loss of 0.91 kg/wk. MAIN OUTCOME MEASURES: Baseline and follow-up 24-hour dietary recalls were conducted and analyzed (using the Automated Self-Administered 24-hour dietary recall system; National Cancer Institute, Bethesda, MD) for macronutrients, micronutrients, and food groups. Microbiome analysis targeting the V4 region of the 16S ribosomal RNA gene was performed on fecal samples. Biopsy Gleason sum data were accessed from diagnostic pathology reports. STATISTICAL ANALYSES PERFORMED: Associations between dietary factors and operational taxonomic units were determined by ß-diversity analysis. Wilcoxon signed rank, and Mann-Whitney U testing assessed within- and between-arm differences. Associations between Gleason sum and operational taxonomic units, and diet and operational taxonomic units, were analyzed using Spearman correlations. RESULTS: At baseline, Proteobacteria (median 0.06, interquartile range 0.01 to 0.16) were abundant, with four orders positively associated with Gleason sum. Gleason sum was associated with Clostridium (ρ=.579; P=0.005) and Blautia (ρ=-0.425, P=0.049). Increased red meat consumption from baseline was associated with Prevotella (ρ=-.497; P=0.018) and Blautia (ρ=.422; P=0.039). Men who increased poultry intake had decreased Clostridiales abundance (P=0.009). CONCLUSIONS: This hypothesis-generating study provides a starting point for investigating the relationships between the fecal microbiome, diet, and prostate cancer. Adequately powered studies are required to further explore and validate these findings.

Protective association of MTHFR polymorphism on cervical intraepithelial neoplasia is modified by riboflavin status.

OBJECTIVES: We previously reported that women polymorphic for the methylenetetrahydrofolate reductase (MTHFR) gene were less likely to have cervical intraepithelial neoplasia (CIN) 2 or 3 (odds ratio [OR] 0.40, 95% confidence interval [CI] 0.21-0.78, P = 0.007). In the present study, we tested whether this protective association is modified by circulating riboflavin status in the same study population. METHODS: Riboflavin status was assessed by the erythrocyte glutathione reductase assay and expressed in terms of an erythrocyte glutathione reductase activity coefficient. The status of MTHFR polymorphism, riboflavin, and circulating concentrations of folate, vitamins B12, A, E, and C, and total carotene were ascertained in 170 White and 265 African-American women positive for the cervical presence of high-risk human papilloma virus. Presence/absence of CIN 2 or 3 was determined histologically, and associations with risk factors were examined using multiple logistic regression. Eighty women with CIN 2 or 3 lesions were compared with 355 women without cervical lesions. Based on the median erythrocyte glutathione reductase activity coefficient of 1.4, women were grouped into low (>1.4) and high (< or =1.4) riboflavin status. RESULTS: Women with MTHFR polymorphism and low riboflavin status were significantly less likely to have CIN 2 or 3 than was the referent group of women without the polymorphism and high riboflavin status (OR 0.35, 95% CI 0.13-0.92, P = 0.034). MTHFR polymorphism was not associated with CIN 2 or 3 in women with high riboflavin status (OR 0.51, 95% CI 0.22-1.19, P = 0.119), nor were any of the associations influenced by folate levels. CONCLUSION: A further inactivation of polymorphic MTHFR by low riboflavin status and a resulting shift in the folate metabolic pathway toward DNA synthesis may explain these observations. The practical implications of this complex gene-nutrient-disease interaction will require further investigation.

Exploring effects of presurgical weight loss among women with stage 0-II breast cancer: protocol for a randomised controlled feasibility trial.

INTRODUCTION: Obesity is a known risk factor for postmenopausal breast cancer and is associated with poorer prognosis for premenopausal and postmenopausal patients; however, the aetiological mechanisms are unknown. Preclinical studies support weight loss via caloric restriction and increased physical activity as a possible cancer control strategy, though few clinical studies have been conducted. We undertook a feasibility trial among women recently diagnosed with stage 0-II breast cancer hypothesising that presurgical weight loss would be feasible, safe and result in favourable changes in tumour markers and circulating biomarkers. METHODS AND ANALYSIS: A two-arm randomised controlled trial among 40 overweight or obese women, newly diagnosed with stage 0-II breast cancer and scheduled for surgery was planned. The attention control arm received upper body progressive resistance training and diet counselling to correct deficiencies in nutrient intake; the experimental arm received the same plus counselling on caloric restriction and aerobic exercise to achieve a weight loss of 0.68-0.919 kg/week. In addition to achieving feasibility benchmarks (accruing and retaining at least 80% of participants, and observing no serious adverse effects attributable to the intervention), we will explore the potential impact of an acute state of negative energy balance on tumour proliferation rates (Ki-67), as well as other tumour markers, serum biomarkers, gene expression, microbiome profiles and other clinical outcomes (eg, quality of life). Outcomes for the 2 study arms are compared using mixed models repeated-measures analyses. ETHICS AND DISSEMINATION: Ethics approval was received from the University of Alabama at Birmingham Institutional Review Board (Protocol number F130325009). Study findings will be disseminated through peer-reviewed publications. Given that this is one of the first studies to investigate the impact of negative energy balance directly on tumour biology in humans, larger trials will be pursued if results are favourable. TRIAL REGISTRATION NUMBER: NCT02224807; Pre-results.

Peptide-based, two-fluorophore, ratiometric probe for quantifying mobile zinc in biological solutions.

Small-molecule fluorescent sensors are versatile agents for detecting mobile zinc in biology. Capitalizing on the abundance of validated mobile zinc probes, we devised a strategy for repurposing existing intensity-based sensors for quantitative applications. Using solid-phase peptide synthesis, we conjugated a zinc-sensitive Zinpyr-1 derivative and a zinc-insensitive 7-hydroxycoumarin derivative onto opposite ends of a rigid P9K peptide scaffold to create HcZ9, a ratiometric fluorescent probe for mobile zinc. A plate reader-based assay using HcZ9 was developed, the accuracy of which is comparable to that of atomic absorption spectroscopy. We investigated zinc accumulation in prostatic cells and zinc levels in human seminal fluid. When normal and tumorigenic cells are bathed in zinc-enriched media, cellular mobile zinc is buffered and changes slightly, but total zinc levels increase significantly. Quantification of mobile and total zinc levels in human seminal plasma revealed that the two are positively correlated with a Pearson's coefficient of 0.73.

The association between adiposity and breast cancer recurrence and survival: A review of the recent literature.

Breast Cancer (BC) is the most common and second deadliest malignancy among American women. Many factors contribute to BC prognosis but a key modifiable lifestyle factor is body weight. In this review, we update the reader on the association between adiposity and poor BC outcomes. We summarize the findings from studies that show obesity to be a risk factor for BC recurrence and reduced survival, including research that shows that treatment with aromatase inhibitors in hormone-receptor positive BC survivors who are obese may not be as effective as in normal weight women. In addition, we summarize the findings from studies that show that obesity-induced changes in glucose metabolism, type-2 diabetes and metabolic syndrome contribute to negative outcomes in BC survivors. Given the evidence, there is a critical need to determine whether weight loss can improve outcomes in BC survivors.

Obesity is associated with higher 4E-BP1 expression in endometrial cancer.

PURPOSE: Obesity is associated with risk and prognosis of endometrial cancer (EC), and the mammalian target of rapamycin complex 1 (mTORC1) pathway may play an instrumental role. We sought to explore the associations between cellular proliferation, Akt, and 4E binding protein-1 (4E-BP1) (a downstream target of mTORC1), in obese and nonobese women with and without EC. METHODS: Archival tissue-specimens from endometrial biopsies were grouped into two broad categories based on the observed disease behavior and similarities in tissue staining patterns: benign/hyperplasia (without cytologic atypia) (n=18) versus atypia (complex hyperplasia with cytologic atypia)/carcinoma (n=25). The characteristics of the study population, including height and weight to determine body mass index (BMI: kg/m2), were abstracted from medical records. Immunohistochemistry was used to assess the phosphorylated (p)Akt, p4E-BP1, and antigen Ki67. RESULTS: Cytoplasmic and nuclear pAkt were significantly associated with cytoplasmic p4E-BP1 (ρ=+0.48, ρ=+0.50) (P<0.05) and nuclear p4E-BP1 (ρ=+0.40, ρ=+0.44) (P<0.05); cytoplasmic and nuclear p4E-BP1 were significantly associated with Ki67 (ρ=+0.46, ρ=+0.59) (P<0.05). Compared with the benign/hyperplasia group, the women with atypia/carcinoma had significantly higher cytoplasmic and nuclear p4E-BP1 and Ki67. This staining pattern was similar in obese women; however, in nonobese women, neither cytoplasmic nor nuclear p4E-BP1staining differed between benign/hyperplasia versus atypia/carcinoma. CONCLUSION: The activation of 4E-BP1 was higher in the obese women with EC. Adiposity may be a key factor to consider in future studies investigating the role of 4E-BP1 as a biomarker and therapeutic target in EC.

Weight gain prior to entry into a weight-loss intervention study among overweight and obese breast cancer survivors.

PURPOSE: Changes in cancer therapy, in addition to changes in obesity prevalence, suggest the need for a current assessment of weight gain patterns following breast cancer diagnosis. The aim of this study was to evaluate factors associated with weight gain among breast cancer survivors prior to enrolling into a behavioral weight loss intervention. METHODS: Anthropometric measures and data on weight-related factors were collected at baseline on 665 breast cancer survivors. Postdiagnosis weight gain was determined between entry into the trial and previous diagnosis up to 5 years. Multivariate logistic regression analyses were used to evaluate the association between weight gain and influencing factors. RESULTS: The mean weight gain was 4.5 % body weight (standard deviation = 10.6); 44 % of women experienced ≥5 % body weight gain. The risk of weight gain was inversely associated with age (adjusted odds ratio (ORadj) = 0.97, 95 % confidence interval (95 % CI) 0.95-0.99), Hispanic ethnicity (ORadj = 0.30, 95 % CI 0.13-0.68), and overweight (ORadj = 0.11, 95 % CI 0.05-0.23) or obese (ORadj = 0.03, 95 % CI 0.02-0.07) status at diagnosis and positively associated with time elapsed since diagnosis (ORadj = 1.19/year, 95 % CI 1.04-1.36). Women prescribed aromatase inhibitors were 46 % less likely to gain weight compared to women prescribed selective estrogen-receptor modulators (ORadj = 0.54, 95 % CI 0.31-0.93). The risk of weight gain was positively associated with smoking at diagnosis (ORadj = 2.69, 95 % CI 1.12-6.49) although this was attributable to women who subsequently quit smoking. CONCLUSIONS: Postdiagnosis weight gain is common and complex and influenced by age, ethnicity, weight, smoking status, time elapsed since diagnosis, and endocrine-modulating therapy. IMPLICATIONS FOR CANCER SURVIVORS: Weight gain continues to be a concern following a diagnosis of breast cancer. Factors influencing this weight gain include age, ethnicity, weight, smoking status, time elapsed since diagnosis, and endocrine-modulating therapy. Effective weight management strategies are needed for this population of women.

Current evidence linking polyunsaturated Fatty acids with cancer risk and progression.

There is increasing evidence that polyunsaturated fatty acids (PUFAs) play a role in cancer risk and progression. The n-3 family of PUFAs includes alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) while the n-6 family includes linolenic acid (LA) and arachidonic acid (AA). EPA and DHA are precursors for anti-inflammatory lipid mediators while AA is a precursor for pro-inflammatory lipid mediators. Collectively, PUFAs play crucial roles in maintaining cellular homeostasis, and perturbations in dietary intake or PUFA metabolism could result in cellular dysfunction and contribute to cancer risk and progression. Epidemiologic studies provide an inconsistent picture of the associations between dietary PUFAs and cancer. This discrepancy may reflect the difficulties in collecting accurate dietary data; however, it also may reflect genetic variation in PUFA metabolism which has been shown to modify physiological levels of PUFAs and cancer risk. Also, host-specific mutations as a result of cellular transformation could modify metabolism of PUFAs in the target-tissue. Clinical trials have shown that supplementation with PUFAs or foods high in PUFAs can affect markers of inflammation, immune function, tumor biology, and prognosis. Pre-clinical investigations have begun to elucidate how PUFAs may mediate cell proliferation, apoptosis and angiogenesis, and the signaling pathways involved in these processes. The purpose of this review is to summarize the current evidence linking PUFAs and their metabolites with cancer and the molecular mechanisms that underlie this association. Identifying the molecular mechanism(s) through which PUFAs affect cancer risk and progression will provide an opportunity to pursue focused dietary interventions that could translate into the development of personalized diets for cancer control.

Racial differences in adiponectin and leptin in healthy premenopausal women.

The aim of this article is to longitudinally investigate racial differences in serum adiponectin and leptin in European-American (EA) and African-American (AA) women in the overweight and weight-reduced states. Sixty-two EA and 58 AA premenopausal women were weight reduced from body mass index (BMI) 27-30 kg/m(2) to BMI ≤ 24. Fasting serum adiponectin and leptin were determined; body composition and intra-abdominal adipose tissue (IAAT) were measured with dual-energy X-ray absorptiometry and computed tomography, respectively. In repeated-measure MANOVA, there was a significant race effect for IAAT and total fat mass; compared to AA women, EA women had higher IAAT and total fat mass (p < 0.0001 and p = 0.027, respectively). In the mixed-model for adiponectin that adjusted for IAAT, limb fat, and total fat, race was significantly associated with adiponectin (p = 0.046). AA women had significantly lower adjusted adiponectin compared to EA women at baseline [7.67 (6.85, 8.60) vs. 9.32 (8.34, 10.4) µg/ml, p < 0.05] and following weight loss [9.75 (8.70, 10.9) vs. 11.8 (10.6, 13.2) µg/ml, p < 0.05]. In a mixed-model for leptin that adjusted for insulin, estradiol, and fat mass, race was significantly associated with leptin (p < 0.0001). AA women had significantly higher adjusted leptin compared to EA women at baseline [24.7 (22.3, 27.4) vs. 19.9 (18.1, 21.8) ng/dl, p < 0.05] and following weight loss [11.7 (10.2, 13.3) vs. 8.48 (7.50, 9.57) ng/dl, p < 0.05]. Despite having a more favorable body fat distribution, AA women had lower adjusted adiponectin and higher leptin. Differences in body composition and fat distribution do not appear to be significant factors in explaining lower adiponectin and higher leptin in AA women.

Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer.

Enterolactone and enterodiol, mammalian lignans derived from dietary sources such as flaxseed, sesame seeds, kale, broccoli, and apricots, may impede tumor proliferation by inhibiting activation of nuclear factor kappa B (NFκB) and vascular endothelial growth factor (VEGF). We examined the associations between urinary enterolactone and enterodiol with prostatic tumor expression of NFκB, VEGF, and Ki67 among 147 patients with prostate cancer who participated in a presurgical trial of flaxseed supplementation (30 g/day) for ~30 days. Urinary enterolignans and tissue biomarkers were determined by high-performance liquid chromatography and immunohistochemistry, respectively. After supplementation, we observed significant correlations between intakes of plant lignan and urinary concentrations of total enterolignans (ρ=0.677, P<.0001), enterolactone (ρ=0.676, P<.0001), and enterodiol (ρ=0.628, P<.0001). Importantly, we observed that total urinary enterolignans and enterolactone were significantly and inversely correlated with Ki67 in the tumor tissue (ρ=-0.217, P=.011, and ρ=-0.230, P=.007, respectively), and a near-significant inverse association was observed for enterodiol (ρ=-0.159, P=.064). An inverse association was observed between enterolactone and VEGF (ρ=-0.143, P=.141), although this did not reach statistical significance. We did not observe an association between enterolignans and NFκB. In conclusion, flaxseed-derived enterolignans may hinder cancer cell proliferation via VEGF-associated pathways.

Intra-abdominal adipose tissue is independently associated with sex-hormone binding globulin in premenopausal women.

Lower serum concentrations of sex-hormone binding globulin (SHBG) are associated with increased risk for several obesity-related diseases in women including hormone-sensitive cancers, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Previous investigations have reported that body composition, specifically central obesity, and/or higher insulin concentrations are key factors associated with lower SHBG in overweight and obese women; however, these studies were limited by their cross-sectional design. We hypothesized that intra-abdominal adipose tissue (IAAT), a fat depot linked with an abnormal metabolic profile, is inversely and independently associated with SHBG. Therefore, we determined the longitudinal associations among SHBG, insulin, and IAAT in 107 premenopausal women enrolled in a weight loss study. Overweight (BMI 27-30 kg/m(2)) women were weight reduced until BMI of ≤ 24 was achieved. Body composition and IAAT were measured at baseline and after weight loss with dual-energy X-ray absorptiometry and computed tomography, respectively. Serum concentrations of insulin and SHBG were determined. Paired t-test showed that insulin and IAAT decreased significantly and SHBG increased significantly following weight loss (P < 0.0001 for all). Simple correlations from baseline showed no association with insulin and SHBG (r = -0.142, P = 0.143) and a significant inverse association between IAAT and SHBG (r = -0.43, P < 0.0001). Repeated measures mixed-model showed that after adjusting for age and time (weight loss), IAAT was significantly inversely associated with SHBG (P = 0.0002) and there was no association with insulin and SHBG (P = 0.180). We conclude that SHBG concentrations are influenced by IAAT and not insulin in premenopausal women.