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1.  Effects of physical activity on melatonin levels in previously sedentary men and women 
The inverse association between physical activity and cancer risk may be mediated by higher melatonin levels. However,few studies have examined the effect of increased physical activity on melatonin levels.
The parent study was a randomized controlled trial (RCT) which randomized 51 men and 49 women to a 12-month moderate-to-vigorous aerobic exercise intervention (‘exercisers’) and 51 men and 51 women to a stretching control (‘controls’). Participants were aged 40-75 years, and previously sedentary. Levels of the principal urinary metabolite of melatonin 6-sulphatoxymelatonin (aMT6s), corrected for creatinine levels, were measured in spot morning urine samples by immunoassay at baseline and 12-months. Changes in levels between exercisers and controls were compared using generalized estimating equations for linear regression.
We observed no statistically significant difference in the change in aMT6s levels from baseline to 12-months in exercisers compared with controls (change in aMT6s levels: exercisers, +6.5%; controls, +13%; P=0.66). There was no evidence of effect modification by age, sex or body mass index.
A 12-month moderate-intensity exercise intervention did not affect levels of aMT6s.
Further research needs to focus on other potential mechanisms through which physical activity may reduce the risk of cancer.
PMCID: PMC4119501  PMID: 24859868
aMT6s; cancer; exercise; sedentary; sex hormones
2.  Effect of a 12-month Exercise Intervention on Serum Biomarkers of Angiogenesis in Postmenopausal Women: a randomized controlled trial 
Increased physical activity is associated with decreased risk of several types of cancer, but underlying mechanisms are poorly understood. Angiogenesis, where new blood vessels are formed, is common to adipose tissue formation/remodelling and tumor vascularization.
We examined effects of a 12-month 45 minutes/day, 5 days/week moderate-intensity aerobic exercise intervention, on four serum markers of angiogenesis in 173 sedentary, overweight, postmenopausal women, 50–75 years, randomized to intervention vs. stretching control. Circulating levels of positive regulators of angiogenesis (vascular endothelial growth factor (VEGF), osteopontin (OPN), plasminogen activator inhibitor-1 (PAI-1)); and the negative regulator pigment epithelium-derived factor (PEDF), were measured by immunoassay at baseline and 12-months. Changes were compared using generalized estimating equations, adjusting for baseline levels of analytes and BMI.
VEGF, OPN or PAI-1 levels did not differ by intervention arm. Participants randomized to exercise significantly reduced PEDF (−3.7%) vs. controls (+3.0%; P=0.009). Reductions in fat-mass were significantly associated with reductions in PAI-1 (Ptrend=0.03; Ptrend=0.02) and PEDF (Ptrend=0.002; Ptrend=0.01) compared to controls, or to those who gained any fat-mass respectively. There was a significant association between decreases in VO2max, and increased reductions in PEDF (Ptrend=0.03), compared to participants who increased their level of fitness.
Fat-loss reduces circulating PAI-1 and PEDF. Changes in VO2max are associated with alterations in PEDF, but these associations are complex.
Unexpected reductions in PEDF with decreasing fat-mass, and with decreasing VO2max, warrants further study, including examining effects of different types and intensities of exercise; and role of dietary weight-loss with and without exercise.
PMCID: PMC3976800  PMID: 24501378
Angiogenesis; exercise; VEGF; PAI-1; PEDF; osteopontin
3.  Change in Peripheral Blood Leukocyte Telomere Length and Mortality in Breast Cancer Survivors 
Progressive telomere shortening with cell division is a hallmark of aging. Short telomeres are associated with increased cancer risk, but there are conflicting reports about telomere length and mortality in breast cancer survivors.
We measured peripheral blood leukocyte telomere length at two time points in women enrolled in a multiethnic, prospective cohort of stage I to stage IIIA breast cancer survivors diagnosed between 1995 and 1999 with a median follow-up of 11.2 years. We evaluated associations between telomere length measured at mean 6 (baseline; LTL0; n = 611) and 30 months (LTL30; n = 478) after diagnosis and the change between those time points (n = 478), with breast cancer–specific and all-cause mortality using Cox proportional hazards models adjusted for possible confounders. Statistical tests were two-sided.
There were 135 deaths, of which 74 were due to breast cancer. Neither baseline nor 30-month telomere length was associated with either all-cause or breast cancer–specific mortality (LTL0: hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.67 to 1.02; HR = 0.88; 95% CI = 0.67 to 1.15; LTL30: HR = 0.78, 95% CI = 0.59 to 1.05; HR = 0.86; 95% = CI = 0.58 to 1.26, respectively). However, participants whose telomeres shortened between baseline and 30 months were at a statistically significantly increased risk of breast cancer–specific (HR = 3.03; 95% CI = 1.11 to 8.18) and all-cause mortality (HR = 2.38; 95% CI = 1.28 to 4.39) compared with participants whose telomeres lengthened. When follow-up was censored at 5-years after diagnosis, LTL0 (HR = 0.66; 95% CI = 0.45 to 0.96), LTL30 (HR = 0.51; 95% CI = 0.29 to 0.92), and change in telomere length (HR = 3.45; 95% CI = 1.11 to 10.75) were statistically significantly associated with all-cause mortality.
Telomere shortening was associated with increased risk of breast cancer–specific and all-cause mortality, suggesting that change in blood telomere length over time could be a biomarker of prognosis. Research on determinants of telomere length and change is needed.
PMCID: PMC3982887  PMID: 24627273
4.  Increasing Cervical Cancer Screening in the US-Mexico Border Region 
Hispanic women living on the US-México border experience health disparities, are less likely to access cervical cancer screening services, and have a higher rate of cervical cancer incidence compared to women living in non-border areas. Here we investigate the effects of an intervention delivered by community health workers (CHWs, known as lay health educators or Promotores de Salud in Spanish) on rates of cervical cancer screening in Hispanic women who were out of compliance with recommended screening guidelines.
Hispanic women out of compliance with screening guidelines, attending clinics in southern New México (NM), were identified using medical record review. All eligible women were offered the intervention. The study was conducted between 2009 and 2011, and data were analyzed in 2012. Setting/participants - 162 Hispanic women, resident in NM border counties, aged 29-80 years, who had not had a Pap test within the past 3 years. Intervention - A CHW-led, culturally appropriate, computerized education intervention. Main outcome measures - The percentage of women who underwent cervical cancer screening within 12 months of receiving the intervention. Change in knowledge of, and attitudes towards cervical cancer and screening as assessed by a baseline and follow-up questionnaire.
76.5% of women had a Pap test after the intervention. Women displayed increased knowledge about cervical cancer screening and about HPV.
A culturally appropriate promotora-led intervention is successful in increasing cervical cancer screening in at-risk Hispanic women on the US-México border.
PMCID: PMC4183147  PMID: 24689544
cervical cancer screening; community health workers; education intervention; health disparities; health promotion
6.  No effect of weight loss on LINE-1 methylation levels in peripheral blood leukocytes from postmenopausal overweight women 
Obesity (Silver Spring, Md.)  2014;22(9):2091-2096.
Obesity and weight-loss are associated with methylation patterns in specific genes, but their effect on Long Interspersed Nuclear Elements (LINE-1) methylation, a measure of global methylation is largely unknown.
Three hundred overweight/obese post-menopausal women (50–75 years) were part of a completed, 1-year randomized controlled trial, comparing independent and combined effects of a reduced-calorie weight-loss diet, and exercise program, vs. control. DNA was extracted from peripheral blood leukocytes collected at baseline and 12-months, and LINE-1 methylation analyzed by pyrosequencing. We compared mean changes between groups using generalized estimating equations and examined effects of weight-loss on LINE-1 methylation using stratified analyses (gained weight/no weight-loss (N=84); <5% (N=45); 5–10% (N=45); >10% of baseline weight-loss (N=126)) within each arm, adjusted by blood cell counts. We also examined associations between LINE-1 methylation and previously measured biomarkers, and anthropometrics.
No significant difference in LINE-1 methylation levels was detected in any intervention group vs. controls. The magnitude of weight-loss was not associated with LINE-1 methylation at 12-months. There were no associations between baseline characteristics of participants, or previously measured biomarkers, and LINE-1 methylation.
Our results suggest that lifestyle changes sufficient to significantly reduce weight over 12-months may not change LINE-1 DNA methylation levels.
PMCID: PMC4183146  PMID: 24930817
LINE-1 methylation; weight loss; randomized controlled trial
7.  Weight and metabolic effects of dietary weight loss and exercise interventions in postmenopausal antidepressant medication users and non-users: a randomized controlled trial 
Preventive medicine  2013;57(5):525-532.
Antidepressants may attenuate the effects of diet and exercise programs. We compared adherence and changes in body measures and biomarkers of glucose metabolism and inflammation between antidepressant users and non-users in a 12-month randomized controlled trial.
Overweight or obese, postmenopausal women were assigned to: diet (10% weight loss goal, N=118); moderate-to-vigorous aerobic exercise (225 minutes/week, N=117); diet+exercise (N=117); and control (N=87) in Seattle, WA 2005–2009. Women using antidepressants at baseline were classified as users (N=109). ANCOVA and generalized estimating equation approaches, respectively, were used to compare adherence (exercise amount, diet session attendance, and changes in percent calorie intake from fat, cardiopulmonary fitness, and pedometer steps) and changes in body measures (weight, waist and percent body fat) and serum biomarkers (glucose, insulin, homeostasis assessment-insulin resistance, and high-sensitivity C-reactive protein) between users and non-users. An interaction term (intervention × antidepressant use) tested effect modification.
There were no differences in adherence except diet session attendance was lower among users in the diet+exercise group (P<0.05 vs. non-users). Changes in body measures and serum biomarkers did not differ by antidepressant use (Pinteraction>0.05).
Dietary weight loss and exercise improved body measures and biomarkers of glucose metabolism and inflammation independent of antidepressant use.
PMCID: PMC3800227  PMID: 23859929
Obesity; weight loss intervention; antidepressants; diet; exercise
8.  Effects of individual and combined dietary weight loss and exercise interventions in postmenopausal women on adiponectin and leptin levels 
Journal of internal medicine  2013;274(2):163-175.
Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes, and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations.
Overweight/obese postmenopausal women (n=439) were randomized as follows: 1) a reduced calorie, weight loss diet (diet; N=118); 2) moderate-to-vigorous intensity aerobic exercise (exercise; N=117); 3) a combination of a reduced calorie, weight loss diet and moderate-to-vigorous intensity aerobic exercise (diet+exercise; N=117); or 4) control (N=87). The reduced calorie diet had a 10% weight loss goal. The exercise intervention consisted of 45 minutes of moderate-to-vigorous aerobic activity 5 days/week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay.
Adiponectin increased by 9.5 % in the diet group and 6.6 % in the diet+exercise group (both p≤0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet+exercise, −40.1%, p<0.0001; diet, −27.1%, p<0.0001; exercise, −12.7%, p=0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, p-trend=0.0002; diet+exercise, p-trend=0.0005) and directly associated with leptin (diet, p-trend<0.0001; diet+exercise, p-trend<0.0001).
Weight loss through diet or diet+exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet+exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin.
PMCID: PMC3738194  PMID: 23432360
adiponectin; leptin; randomized controlled trial; diet and exercise intervention
9.  Association Between Markers of Obesity and Progression From Barrett’s Esophagus to Esophageal Adenocarcinoma Adenocarcinoma 
Individuals with Barrett’s esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EA). Obesity contributes to development of BE and its progression to cancer. We investigated the roles of obesity-induced hyperinsulinemia and dysregulation of adipokines in these processes.
We measured fasting levels of glucose, insulin, leptin, and adiponectin in 392 patients enrolled in the Seattle BE Study. We calculated homeostatic model assessment (HOMA) scores (a measure of insulin sensitivity) and identified subjects with metabolic syndrome. We evaluated the association between these measures and risk of EA using Cox regression models adjusted for known risk factors.
Increasing HOMA scores were associated with increasing risk for EA; the strongest association was observed within the first 3 years after participants entered the study (hazard ratio (HR)=2.45; 95% confidence interval [CI], 1.43–4.1; Ptrend=.001). Leptin level was also significantly associated with increased risk of EA within 3 y (HR=2.51; 95% CI 1.09–5.81; Ptrend =0.03) and 6 y (HR=2.07; 95% CI 1.01–4.26; Ptrend=0.048) of baseline. The level of high molecular weight adiponectin had a non-linear inverse association with risk of EA; the strongest associations were observed in the second tertile (HR=0.34; 95% CI, 0.14–0.82). Metabolic syndrome was not associated with risk of EA.
Among patients with BE, increased levels of leptin and insulin resistance are associated with increased risk for EA, whereas increased level of high molecular weight adiponectin is inversely associated with EA. These biomarkers might be used to determine cancer risk among patients with BE.
PMCID: PMC3722274  PMID: 23466711
esophageal adenocarcinoma; Barrett’s esophagus; obesity; anthropometry; adipokines; leptin; adiponectin; HOMA; insulin sensitivity; metabolic syndrome; insulin resistance; esophageal cancer; overweight; body mass; cancer risk factor
10.  Effects of Dietary Weight Loss and Exercise on Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3 in Postmenopausal Women: A Randomized Controlled Trial 
High levels of insulin-like growth factor (IGF)-1 may increase the risk of common cancers in humans. We hypothesized that weight loss induced by diet and/or exercise would reduce IGF-1 in postmenopausal women. Four hundred and thirty nine overweight or obese (BMI ≥25kg/m2) women (50–75 y) were randomly assigned to: i) exercise (N=117), ii) dietary weight-loss (N=118), iii) diet + exercise (N=117), or iv) control (n=87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 min/day, 5 days/week of moderate-to-vigorous intensity activity. Fasting serum insulin-like growth factor (IGF)-1 and insulin-like growth factor binding protein (IGFBP)-3 were measured at baseline and 12 months by radioimmunoassay. Higher baseline BMI was associated with lower IGF-1 and IGF-1/IGFBP-3 molar ratio. While no significant changes in either IGF-1 or IGFBP-3 were detected in any intervention arm compared to control, the IGF-1/IGFBP-3 ratio increased significantly in the diet (+5.0%, p<0.01) and diet + exercise (+5.4%, p<0.01) groups compared to control. Greater weight loss was positively associated with change in both IGF-1 (ptrend=0.017) and IGF-1/IGFBP-3 ratio (ptrend<0.001) in the diet group, but inversely with change in IGFBP-3 in the diet + exercise group (ptrend=0.01). No consistent interaction effects with baseline BMI were detected. Modified IGF-1 bioavailability is unlikely to be a mechanism through which caloric restriction reduces cancer risk in postmenopausal women.
PMCID: PMC3732802  PMID: 23756654
lifestyle; intervention; obesity; energy balance; insulin
11.  Weight, inflammation, cancer-related symptoms and health-related quality of life among breast cancer survivors 
Maintaining weight is important for better prognosis of breast cancer survivors. The associations between weight and cancer-related symptoms are not known. We examined associations among weight, weight change, inflammation, cancer-related symptoms, and health-related quality of life (HRQOL) in a cohort of stage 0-IIIA breast cancer survivors. Participants were recruited on average 6 months (2–12 months) after diagnosis. Height, weight, and c-reactive protein (CRP) were assessed at approximately 30 months post-diagnosis; cancer-related symptoms (chest wall and arm symptoms, vasomotor symptoms, urinary incontinence, vaginal symptoms, cognition/mood problems, sleep, sexual interest/function), and HRQOL (SF-36) were assessed at approximately 40 months post-diagnosis. Weight was measured at baseline in a subset. Data on 661 participants were evaluable for body mass index (BMI); 483 were evaluable for weight change. We assessed associations between BMI (<25.0, 25.0–29.9, ≥30.0 kg/m2), post-diagnosis weight change (lost ≥5%, weight change <5%, gained ≥5%), and CRP (tertile) with cancer-related symptoms and HRQOL using analysis of covariance (ANCOVA). Higher symptoms scores indicate more frequent or severe symptoms. Higher HRQOL scores indicate better HRQOL. Compared with those with BMI<25kg/m2, women with BMI ≥30 kg/m2 had scores that were: increased for arm symptoms (+25.0%), urinary incontinence (+40.0%), tendency to nap (+18.9%) and poorer physical functioning (−15.6%, all p<0.05). Obese women had lower scores in trouble falling asleep (−9.9%; p<0.05). Compared with weight change <5%, participants with ≥5% weight gain had lower scores in physical functioning (−7.2%), role-physical (−15.5%) and vitality (−11.2%), and those with weight loss ≥5% had lower chest wall (−33.0%) and arm symptom scores (−35.5%, all p<0.05). Increasing CRP tertile was associated with worse scores for chest wall symptoms, urinary incontinence, physical functioning, role-physical, vitality and physical component summary scores (all Ptrend<0.05). Future studies should examine whether interventions to maintain a healthy weight and reduce inflammation could alleviate cancer-related symptoms and improve HRQOL.
PMCID: PMC3772666  PMID: 23797178
Breast cancer survivors; body weight; inflammation; cancer-related symptoms; quality of life
12.  Long-term physical activity trends in breast cancer survivors 
Physical activity is associated with reduced mortality and higher quality of life in breast cancer survivors; however, limited data on the prevalence of activity and long-term trends after diagnosis are available.
A multi-ethnic cohort of 631 women (18–64 years) with stage 0-IIIA breast cancer were followed for 10 years. Recreational aerobic activity (MET-hrs/week) was ascertained for the year before diagnosis (baseline), 24 months, 5 and 10 years after enrollment. Women were classified according to U.S. physical activity guidelines (≥150 mins/week moderate or ≥75 mins/week vigorous activity). The odds ratios (OR) for meeting guidelines at 5 and 10 years according to baseline factors was estimated using logistic regression. The change in MET-hrs/wk was predicted using linear regression.
Pre-diagnosis, 34% of women met physical activity guidelines; 34.0%, 39.5%, and 21.4% met guidelines at 24 months, 5 years, and 10 years post-enrollment, respectively. Fewer than 8% of survivors met guidelines at all follow-up periods. Over 10 years, recreational aerobic activity decreased by a mean(SD) 4.3(16.2) MET-hrs/wk.. Meeting guidelines pre-diagnosis was strongly associated with meeting guidelines at 5 years [OR (95% CI): 2.76 (1.85–4.1)] and 10 years [OR (95% CI): 3.35 (2.13–5.28)]. No other demographic or prognostic factors were significantly associated with the 10-year change in MET-hrs/wk.
The vast majority of early breast cancer survivors do not meet national exercise recommendations 10 years post-diagnosis.
Physical activity levels are low in breast cancer survivors across the 10 years post-diagnosis, yet the predictors of activity in this population remain poorly understood.
PMCID: PMC3688258  PMID: 23576689
exercise; women; cancer survivorship; lifestyle
13.  Independent and Combined Effects of Dietary Weight Loss and Exercise on Leukocyte Telomere Length in Postmenopausal Women 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20509.
Investigate the effects of 12 months of dietary weight loss and/or aerobic exercise on leukocyte telomere length in postmenopausal women.
Design and Methods
439 overweight or obese women (50–75 y) were randomized to: i) dietary weight loss (N=118); ii) aerobic exercise (N=117), iii) diet + exercise (N=117), or iv) control (N=87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 mins/day, 5 days/week of moderate-to-vigorous aerobic activity. Fasting blood samples were taken at baseline and 12 months. DNA was extracted from isolated leukocytes and telomere length was measured by quantitative-polymerase chain reaction (qPCR). Mean changes were compared between groups (intent-to-treat) using generalized estimating equations.
Baseline telomere length was inversely associated with age (r=−0.12 p<0.01) and positively associated with maximal oxygen uptake (r=0.11, p=0.03), but not with BMI or %body fat. Change in telomere length was inversely correlated with baseline telomere length (r=−0.47, p<0.0001). No significant difference in leukocyte telomere length was detected in any intervention group compared to controls, nor was the magnitude of weight loss associated with telomere length at 12 months.
Twelve-months of dietary weight loss and exercise did not change telomere length in postmenopausal women.
PMCID: PMC3786031  PMID: 23640743
caloric restriction; physical activity; lifestyle; ageing; chromosomes
14.  Influence of diet, exercise and serum vitamin D on sarcopenia in post-menopausal women 
To investigate the effects of 12 months of dietary weight loss and/or aerobic exercise on lean mass and the measurements defining sarcopenia in postmenopausal women, and to examine the potential moderating effect of serum 25-hydroxyvitamin D (25(OH)D) and age.
439 overweight and obese postmenopausal women were randomized to: diet modification (N=118); exercise (N=117), diet+exercise (N=117), or control (N=87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 mins/day, 5 days/week of moderate-to-vigorous intensity aerobic activity. Total and appendicular lean mass were quantified by dual Xray absorptiometry (DXA) at baseline and 12 months. A skeletal muscle index (SMI=appendicular lean mass (kg)/m2) and the prevalence of sarcopenia (SMI<5.67 kg/m2) were calculated. Serum 25(OH)D was assayed using a competitive chemiluminescent immunoassay.
Dietary weight loss resulted in a significant decrease in lean mass, and a borderline significant decrease in appendicular lean mass and SMI compared to controls. In contrast, aerobic exercise significantly preserved appendicular lean mass and SMI. Diet + exercise attenuated the loss of appendicular lean mass and SMI compared to diet alone, and did not result in significant loss of total- or appendicular lean mass compared to controls. Neither serum 25(OH)D nor age were significant moderators of the intervention effects.
Aerobic exercise added to dietary weight loss can attenuate the loss of appendicular lean mass during weight loss, and may be effective for the prevention and treatment of sarcopenia among overweight and obese postmenopausal women.
PMCID: PMC3594522  PMID: 23190588
caloric restriction; weight loss; 25-hydroxyvitamin D; ageing
15.  Injuries in Sedentary Individuals Enrolled in a 12-Month, Randomized, Controlled, Exercise Trial 
The risk of musculoskeletal injury with the introduction of moderate-to-vigorous exercise in sedentary adults is not well established. The purpose of this report is to examine the effect of a 12-month exercise intervention on musculoskeletal injury and bodily pain in predominately overweight, sedentary, men (n=102) and women (n=100), aged 40–75 years.
Participants were randomized to a moderate-to-vigorous aerobic exercise intervention (EX) (6 d/wk, 60 min/d, 60–85% max. heart rate) or usual lifestyle control (CON). Participants completed a self-report of musculoskeletal injury and body pain at baseline and 12-months.
The number of individuals reporting an injury (CON; 27% vs. EX; 28%, p= .95) did not differ by group. The most commonly injured site was lower leg/ankle/foot. The most common causes of injury were sports/physical activity, home maintenance or “other”. In the control group, bodily pain increased over the 12 months compared to the exercise group (CON −7.9, EX −1.4, p=.05). Baseline demographics and volume of exercise were not associated with injury risk.
Previously sedentary men and women randomized to a 12-month aerobic exercise intervention with a goal of 360 min/wk reported the same number of injuries as those in the control group and less bodily pain.
PMCID: PMC3960980  PMID: 22368219
musculoskeletal; physical activity; bodily pain; overweight
16.  Gene expression changes in adipose tissue with diet- and/or exercise-induced weight loss 
Adipose tissue plays a role in obesity-related cancers via increased production of inflammatory factors, steroid hormones, and altered adipokines. The impact of weight loss on adipose-tissue gene expression may provide insights into pathways linking obesity with cancer risk. We conducted an ancillary study within a randomized trial of diet, exercise, or combined diet+exercise vs. control among overweight/obese postmenopausal women. In 45 women, subcutaneous adipose-tissue biopsies were performed at baseline and after 6 months and changes in adipose-tissue gene expression were determined by microarray with an emphasis on pre-specified candidate pathways, as well as by unsupervised clustering of >37,000 transcripts (Illumina). Analyses were conducted first by randomization group, and then by degree of weight change at 6-months in all women combined. At 6 months, diet, exercise and diet+exercise participants lost a mean of 8.8 kg, 2.5 kg, and 7.9 kg (all p<0.05 vs. no change in controls). There was no significant change in candidate-gene expression by intervention group. In analysis by weight-change category, greater weight loss was associated a decrease in 17β-hydroxysteroid dehydrogenase-1 (HSD17B1, p-trend<0.01) and leptin (LEP, p-trend<0.01) expression, and marginally significant increased expression of estrogen receptor-1 (ESR1, p-trend=0.08) and insulin-like growth factor binding protein-3 (IGFBP3, p-trend=0.08). Unsupervised clustering revealed 83 transcripts with statistically significant changes. Multiple gene-expression changes correlated with changes in associated serum biomarkers. Weight-loss was associated with changes in adipose-tissue gene expression after 6 months, particularly in two pathways postulated to link obesity and cancer, i.e., steroid-hormone metabolism and IGF signaling.
PMCID: PMC3738189  PMID: 23341572
Adiposity; gene expression; obesity; weight-loss; exercise; diet; leptin; sex hormones; inflammation; adipokines; human; randomized-controlled trial
17.  Associations of insulin-like growth factor and insulin-like growth factor binding protein-3 with mortality in women with breast cancer 
Elevated circulating insulin-like growth factor-1 (IGF-1), a breast epithelial cell mitogen, is associated with breast cancer development. However, its association with breast cancer survival is not established. Circulating concentrations of IGF-1 are controlled via binding proteins, including IGF Binding Protein-3 (IGFBP-3), that may modulate the association of IGF1 with breast-cancer outcomes.
We measured IGF-1 and IGFBP-3 concentrations in serum from 600 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between IGF-1 and IGFBP-3, and as a ratio, modeled using quintile cut-points, with risk of breast cancer-specific (n=42 deaths) and all-cause mortality (n=87 deaths) using Cox proportional hazards models. In models adjusted for body mass index, ethnicity, tamoxifen use at time of blood draw, treatment received at diagnosis, and IGFBP-3, women in the highest quintile of IGF-1 level had an increased risk of all-cause mortality (Hazard Ratio (HR)=3.10 95% CI 1.21-7.93, p=0.02), although no dose-response association was evident. The IGF-1/IGFBP-3 ratio, an indicator of free IGF-I levels, was significantly associated with increasing risk of all-cause mortality (HR=2.83 95% CI 1.25-6.36 Ptrend=0.01, upper vs. lower quintile) in a fully adjusted model.
In conclusion, high serum levels of IGF-1 and the IGF-1/IGFBP-3 ratio were associated with increased risk of all-cause mortality in women with breast cancer. These results need to be confirmed in larger breast cancer survivor cohorts.
PMCID: PMC3764990  PMID: 22847383
IGF-1; IGFBP-3; breast cancer survival; mortality
18.  Exercise adherence, cardiopulmonary fitness and anthropometric changes improve exercise self-efficacy and health-related quality of life 
Regular exercise increases exercise self-efficacy and health-related quality of life (HRQOL); however, the mechanisms are unknown. We examined the associations of exercise adherence and physiological improvements with changes in exercise self-efficacy and HRQOL.
Middle-aged adults (N=202) were randomized to 12 months aerobic exercise (360 minutes/week) or control. Weight, waist circumference, percent body fat, cardiopulmonary fitness, HRQOL (SF-36), and exercise self-efficacy were assessed at baseline and 12 months. Adherence was measured in minutes/day from activity logs.
Exercise adherence was associated with reduced bodily pain, improved general health and vitality, and reduced role-emotional scores (Ptrend≤0.05). Increased fitness was associated with improved physical functioning, bodily pain and general health scores (Ptrend≤0.04). Reduced weight and percent body fat were associated with improved physical functioning, general health, and bodily pain scores (Ptrend<0.05). Decreased waist circumference was associated with improved bodily pain and general health but with reduced role-emotional scores (Ptrend≤0.05). High exercise adherence, increased cardiopulmonary fitness and reduced weight, waist circumference and percent body fat were associated with increased exercise self-efficacy (Ptrend<0.02).
Monitoring adherence and tailoring exercise programs to induce changes in cardiopulmonary fitness and body composition may lead to greater improvements in HRQOL and self-efficacy that could promote exercise maintenance.
PMCID: PMC3923574  PMID: 23036856
physical activity; intervention study; aerobic; physical fitness
19.  Risk Factors for Breast Cancer in Women Biopsied for Benign Breast Disease: A Nested Case-Control Study 
Cancer epidemiology  2010;34(1):34-39.
Women with a history of benign breast disease are at increased risk of subsequent breast cancer. However, few studies have examined whether established breast cancer risk factors other than histology are associated with an altered risk of breast cancer in women with benign breast disease. We used a nested case-control design within a large, multi-center cohort of women biopsied for benign breast disease (BBD) to estimate odds ratios for breast cancer in association with exposure to a range of personal and lifestyle factors.
Cases were women biopsied for BBD who subsequently developed breast cancer; controls were individually matched to cases on center and age at diagnosis and were women biopsied for BBD who did not develop breast cancer in the same follow-up interval as that for the cases. After excluding women with prevalent breast cancer, 1357 records (661 case records and 696 records) were available for analysis. We used conditional logistic regression to obtain crude and multivariable-adjusted estimates of the association between specific factors and risk of breast cancer.
In multivariable analyses age at first live birth, number of pregnancies, and postmenopausal status were inversely associated with risk of breast cancer. The odds ratio for women with age at first birth <25 years and >3 pregnancies, relative to nulliparous women, was 0.49, 95% confidence interval 0.13-0.79, and that for postmenopausal women relative to premenopausal women was 0.60, 95% 0.37-0.99.
Further study of personal factors influencing the risk of breast cancer in women with BBD may help to identify subgroups of the population at increased risk of invasive disease.
PMCID: PMC3889119  PMID: 20079704
benign breast disease; breast cancer; reproductive factors; hormone therapy
20.  History of weight cycling does not impede future weight loss or metabolic improvements in postmenopausal women 
Given that the repetitive loss and regain of body weight, termed weight cycling, is a prevalent phenomenon that has been associated with negative physiological and psychological outcomes, the purpose of this study was to investigate weight change and physiological outcomes in women with a lifetime history of weight cycling enrolled in a 12-month diet and/or exercise intervention.
439 overweight, inactive, postmenopausal women were randomized to: i) dietary weight loss with a 10% weight loss goal (N=118); ii) moderate-to-vigorous intensity aerobic exercise for 45 min/day, 5 days/week (n=117); ii) both dietary weight loss and exercise (n=117); or iv) control (n=87). Women were categorized as non-, moderate-(≥3 losses of ≥4.5 kg), or severe-cyclers (≥3 losses of ≥9.1 kg). Trend tests and linear regression were used to compare adherence and changes in weight, body composition, blood pressure, insulin, C-peptide, glucose, insulin resistance (HOMA-IR), C-reactive protein, leptin, adiponectin, and interleukin-6 between cyclers and non-cyclers.
Moderate (n=103) and severe (n=77) cyclers were heavier and had less favorable metabolic profiles than non-cyclers at baseline. There were, however, no significant differences in adherence to the lifestyle interventions. Weight-cyclers (combined) had a greater improvement in HOMA-IR compared to non-cyclers participating in the exercise only intervention (p=0.03), but no differences were apparent in the other groups.
A history of weight cycling does not impede successful participation in lifestyle interventions or alter the benefits of diet and/or exercise on body composition and metabolic outcomes.
PMCID: PMC3514598  PMID: 22898251
lifestyle intervention; insulin resistance; inflammation; adipokines
21.  Diabetes Prevention in Hispanics: Report From a Randomized Controlled Trial 
Hispanics are at increased risk of developing type 2 diabetes. Lifestyle interventions are effective in preventing diabetes and restoring glucose regulation.
We recruited Hispanic men and women (N = 320) who were residents of the Lower Yakima Valley, Washington, aged 18 years or older with hemoglobin A1c (HbA1c) levels higher than 6% to a parallel 2-arm randomized-controlled trial conducted from 2008 through 2012. The trial compared participants in the intervention arm, who received an immediate educational curriculum (n = 166), to participants in the control arm, who received a delayed educational curriculum (n = 154). The home-based curriculum consisted of 5 sessions led by community health workers and was designed to inform participants about diabetes, diabetes treatment, and healthy dietary and physical activity behaviors. Participants were randomly assigned to the intervention and control arms, and analysts were blinded as to participant arm. We evaluated intervention effects on HbA1c levels; frequency (times per week) of fruit and vegetable consumption; and frequency (times per week) of mild, moderate, and strenuous leisure-time physical activity. At baseline, 3 months, and 6 months after randomization, participants completed a questionnaire and provided a blood sample. Analysts were blinded to intervention arm.
The immediate intervention group (−0.64% [standard error (SE) 0.10]) showed a significant improvement in HbA1c scores (–37.5%, P = .04) compared with the delayed intervention group (–0.44%, P = .14). No significant changes were seen for dietary end points or changes in physical activity. We did observe a trend of greater increases in frequency of moderate and vigorous physical activity and a smaller increase in mild physical activity in the immediate intervention group than in the delayed intervention group.
This home-based intervention delivered by CHWs was associated with a clinically and statistically significant reduction in HbA1c levels in Hispanic adults with HbA1c levels higher than 6%.
PMCID: PMC3938962  PMID: 24576395
22.  Associations between null mutations in GSTT1 and GSTM1, the GSTP1 Ile105Val polymorphism, and mortality in breast cancer survivors 
SpringerPlus  2013;2:450.
Here we assessed associations between null mutations in glutathione-S-transferase (GST)T1 and GSTM1 genes, and the rs1695 polymorphism in GSTP1 (Ile105Val), and risk of breast cancer-specific (n=45) and all-cause (n=99) mortality in a multiethnic, prospective cohort of 533 women diagnosed with stage I-IIIA breast cancer in 1995–1999, enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study.
We measured the presence of the null mutation in GSTT1 and GSTM1, and the rs1695 polymorphism in GSTP1 by polymerase chain reaction. We assessed associations between breast-cancer specific and all-cause mortality using Cox proportional hazards models.
Participants with ER-negative tumors were more likely to be GSTT1 null (χ2=4.52; P=0.03), and African American women were more likely to be GSTM1 null (χ2=34.36; P<0.0001). Neither GSTM1 nor GSTT1 null mutations were associated with breast cancer-specific or all-cause mortality. In a model adjusted for body mass index, race/ethnicity, tumor stage and treatment received at diagnosis, the variant Val allele of rs1695 was associated with increased risk of all-cause (HR=1.81, 95% CI 1.16-2.82, P=0.008), but not breast cancer-specific mortality. The GSTT1 null mutation was associated with significantly higher levels of C-reactive protein.
GSTM1 and GSTT1 null genotypes had no effect on outcome; however the variant allele of rs1695 appears to confer increased risk for all-cause mortality in breast-cancer survivors.
Given the limited sample size of most studies examining associations between GST polymorphisms with breast cancer survival, and the lack of women undergoing more contemporary treatment protocols (treated prior to 1999), it may be helpful to re-examine this issue among larger samples of women diagnosed after the late 1990s, who all received some form of chemotherapy or radiotherapy.
PMCID: PMC3786079  PMID: 24083102
Glutathione-S-transferases; GSTT1; GSTM1; GSTP1; Polymorphisms; Breast cancer survival; Mortality
23.  Self-Monitoring and Eating-Related Behaviors Associated with 12-Month Weight Loss in Postmenopausal Overweight-to-Obese Women 
Lifestyle-based interventions, which typically promote various behavioral modification strategies, can serve as a setting for evaluating specific behaviors and strategies thought to promote or hinder weight loss. The aim of this study was to test the associations of self-monitoring (self-weighing, food journal completion) and eating-related (dietary intake, diet-related weight-control strategies, and meal patterns) behaviors with weight loss in a sample of postmenopausal overweight-to-obese women enrolled in a 12-month dietary weight loss intervention. Changes in body weight and adoption of self-monitoring and eating-related behaviors were assessed in 123 participants. Generalized linear models tested associations of these behaviors with 12-month weight change after adjusting for potential confounders. Mean percent weight loss was 10.7%. In the final model, completing more food journals was associated with a greater % weight loss (interquartile range, 3.7% greater weight loss; p<0.0001) while skipping meals (4.3% lower weight loss; p<0.05) and eating out for lunch (at least once a week, 2.5% lower weight loss; p<0.01) were associated with a lower amount of weight loss. These findings suggest that a greater focus on dietary self-monitoring, home-prepared meals, and consuming meals at regular intervals may improve 12-month weight loss among postmenopausal women enrolled in a dietary weight loss intervention.
PMCID: PMC3432675  PMID: 22795495
Women; behavioral strategies; eating behaviors; weight loss
24.  Metabolic, hormonal and immunological associations with global DNA methylation among postmenopausal women 
Epigenetics  2012;7(9):1020-1028.
DNA methylation is an epigenetic modification essential for the regulation of gene expression that has been implicated in many diseases, including cancer. Few studies have investigated the wide range of potential predictors of global DNA methylation, including biomarkers. Here, we investigated associations between DNA methylation and dietary factors, sex-steroid hormones, metabolic, lipid, inflammation, immune and one-carbon biomarkers. Data and baseline biomarker measurements were obtained from 173 overweight/obese postmenopausal women. Global DNA methylation in lymphocyte DNA was measured using the pyrosequencing assay for LINE-1 repeats. We used correlations and linear regression analyses to investigate associations between continuous data and DNA methylation, while t-tests were used for categorical data. Secondary analyses stratified by serum folate levels and multivitamin use were also conducted. There was little variability in LINE-1 methylation (66.3–79.5%). Mean LINE-1 methylation was significantly higher among women with elevated glucose levels. Mean LINE-1 methylation was also higher among women with high CD4+/CD8+ ratio, and lower among women with elevated vitamin B6, but neither reached statistical significance. In analyses stratified by folate status, DNA methylation was negatively associated with sex hormone concentrations (estrone, estradiol, testosterone and sex hormone binding globulin) among women with low serum folate levels (n = 53). Conversely, among women with high serum folate levels (n = 53), DNA methylation was positively associated with several immune markers (CD4/CD8 ratio, NK1656/lymphocytes and IgA). Results from this screening suggest that global DNA methylation is generally stable, with differential associations for sex hormones and immune markers depending on one-carbon status.
PMCID: PMC3515011  PMID: 22869041
DNA methylation; epigenetics; epidemiology; folate; glucose; metabolic; immune function; inflammation; post-menopausal; sex hormones; women
25.  Recruiting underrepresented groups into the Carbohydrates and Related Biomarkers (CARB) cancer prevention feeding study 
Contemporary clinical trials  2012;33(4):641-646.
Using data from a randomized, controlled feeding study, which aimed to recruit 88 participants (including 22 Hispanics and 22 African Americans), we examined strategies for recruiting individuals from underrepresented groups into research trials. Study eligibility criteria included participants who 1) were 18–45 years old; 2) had a body mass index (BMI) >18 < 24.9 or BMI > 28.0 <40.0; 3); had no preexisting health conditions; 4) were non-smoking; 5) had normal fasting blood glucose level (< 100 mg/dL); and 6) spoke English. Participants were recruited using two overarching methods: media-based strategies (flyers and posters, email announcements, announcements in local and campus newspapers, and the Internet) and in-person strategies (presentations in university classes and community events). Participants were enrolled March 2006–March 2009. We present the numbers of individuals requesting study information, completing pre-enrollment screening questionnaires, and enrolling in the study. A total of 1036 individuals requested study information, and 396 completed a pre-enrollment screening questionnaire; 90 enrolled in the study (22 Hispanics and 18 African Americans). Among enrolled participants, in-person recruitment strategies were reported by 39% of African Americans, 73% of Hispanics, and 30% of non-Hispanic Whites (P <0.001). In-person recruitment strategies were successful among Hispanics. Mass media recruitment strategies were successful among non-Hispanic Whites but enlisted relatively few Hispanic participants. Both strategies recruited nearly equal percentages of African Americans. These data suggest that different strategies are needed to effectively recruit racial/ethnic population subgroups into intervention studies.
PMCID: PMC3516589  PMID: 22504222
Patient recruitment; carbohydrate metabolism; Hispanic American; African American

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