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Impaired sleep and low daily activity levels increase the risk of developing metabolic syndrome (MS). Metformin (MET), an insulin sensitizer drug, is effective in regressing MS and has been recently studied as an adjuvant agent for managing sleep disorders. The present study aimed to assess whether 1,700 mg/day of MET treatment modifies sleep and daily activity levels in people with MS evaluated by Rest-Activity circadian Rhythm (RAR), which is the expression of 24 h of spontaneous activity parameters. A total of 133 subjects with MS, randomized into the MET (n = 65) or placebo (PLA, n = 68) group, underwent a clinical/anthropometric examination and carried out a continuous 7-day actigraphic monitoring to investigate sleep and RAR parameters at baseline and after 1 year of intervention. After 1 year of intervention, 105 subjects were analyzed. The MET group showed greater anthropometric and metabolic improvements compared with placebo, with a significant reduction in weight (p = 0.01), body mass index (p = 0.01), waist circumference (p = 0.03), and glucose (p < 0.001). With regard to sleep parameters, the MET group showed a significant increase in actual sleep time (p = 0.01) and sleep efficiency (p = 0.04) compared with placebo. There were no significant changes reported in the RAR parameters. Our study suggests that MET might be used as an adjuvant treatment for sleep disorders in people with MS.

Abstract The aim of the present study is to explore the potential association between sleep quality and physical activity (PA) in women carriers of BRCA1/2 mutations. 63 women completed the Pittsburgh Sleep Quality Index (PSQI) and Godin Shepard Leisure-Time Physical Activity Questionnaire (GSL-TPAQ) and were included in the present cross-sectional analysis. Globally, women showed a PSQI score of 7.0 ± 3.6 and a GSL-TPAQ score of 22.8 ± 18.3. Good sleepers (PSQI score ≤ 5) showed significantly higher PA levels compared to bad sleepers (PSQI score > 5). Women in the higher tertile of GSL-TPAQ total score (≥ 27 METs/week) have a prevalence ratio (PR) of being a good sleeper of 2.85 (1.25–6.52, 95% confidence intervals) compared to women in the lower tertile (≤ 11 METs/week). These results were consistent in BRCA1 and BRCA2 women. Considering each single question of PA intensity, the PR of being a good sleeper by unit of increase of MET/week was higher and significant in women engaged in strenuous and moderate intensity PA. These results suggests a direct association between PA and sleep quality in women carriers of BRCA mutations.

BackgroundBreast cancer onset is determined by a genetics-environment interaction. BRCA1/2 gene alterations are often genetically shared in familial context, but also food intake and hormonal assessment seem to influence the lifetime risk of developing this neoplasia. We previously showed the relationship between a six-months Mediterranean dietary intervention and insulin, glucose and estradiol levels in BRCA1/2 carrier subjects. The aim of the present study was to evidence the eventual influence of this dietary intervention on the relationship between circulating miRNA expression and metabolic parameters in presence of BRCA1/2 loss of function variants.MethodsPlasma samples of BRCA-women have been collected at the baseline and at the end of the dietary intervention. Moreover, subjects have been randomized in two groups: dietary intervention and placebo. miRNA profiling and subsequent ddPCR validation have been performed in all the subjects at both time points.ResultsddPCR analysis confirmed that five (miR-185-5p, miR-498, miR-3910, miR-4423 and miR-4445) of seven miRNAs, deregulated in the training cohort, were significantly up-regulated in subjects after dietary intervention compared with the baseline measurement. Interestingly, when we focused on variation of miRNA levels in the two timepoints, it could be observed that miR-4423, miR-4445 and miR-3910 expressions are positively correlated with variation in vitaminD level; whilst miR-185-5p difference in expression is related to HDL cholesterol variation.ConclusionsWe highlighted the synergistic effect of a healthy lifestyle and epigenetic regulation in BC through the modulation of specific miRNAs. Different miRNAs have been reported involved in the tumor onset acting as tumor suppressors by targeting tumor-associated genes that are often downregulated.

Existing epidemiological evidence regarding the potential role of (poly)phenol intake in prostate cancer (PCa) risk is scarce and, in the case of flavonoids, it has been suggested that their intake may increase PCa risk. We investigated the associations between the intake of the total and individual classes and subclasses of (poly)phenols and the risk of PCa, including clinically relevant subtypes. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort included 131,425 adult men from seven European countries. (Poly)phenol intake at baseline was assessed by combining validated center/country-specific dietary questionnaires and the Phenol-Explorer database. Multivariable-adjusted Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). In total, 6939 incident PCa cases (including 3501 low-grade and 710 high-grade, 2446 localized and 1268 advanced, and 914 fatal Pca cases) were identified during a mean follow-up of 14 years. No associations were observed between the total intake of (poly)phenols and the risk of PCa, either overall (HRlog2 = 0.99, 95% CI 0.94–1.04) or according to PCa subtype. Null associations were also found between all classes (phenolic acids, flavonoids, lignans, and stilbenes) and subclasses of (poly)phenol intake and the risk of PCa, overall and according to PCa subtype. The results of the current large prospective cohort study do not support any association between (poly)phenol intake and PCa incidence.

The female carriers of BRCA1/2 pathogenic variants (mutations) face a high lifetime risk of developing breast and/or ovarian cancer. However, the risk may differ depending on various genetic and non-genetic elements, including metabolic and hormonal factors. We previously showed that a 6-month Mediterranean dietary intervention trial reduced body weight and the levels of insulin-like growth factor I and other metabolic factors in BRCA mutation carriers. We also found that higher baseline levels of glucose and insulin were significantly associated with BRCA loss-of-function (LOF) variants. In this study, we evaluated whether the BRCA mutation type influences in a different way the metabolic and hormonal response to the dietary intervention in 366 female carriers. The LOF variant carriers randomized in the intervention group (IG) showed significantly higher changes in most considered parameters compared to the control group (CG). The nonsynonymous variant carriers in the IG showed similar changes, but none of them were statistically significant. Performing the “delta” analysis of differences (intention-to-treat analysis), we observed that in LOF variant carriers, the reduction of insulin levels was significantly more pronounced that in nonsynonymous variant carriers. These findings suggest that the changes in insulin levels might be modulated by a different response to the dietary intervention mediated by BRCA LOF variants.

IntroductionRecruitment is essential for the success of clinical trials. We are conducting a randomized clinical trial to test the effect of a Mediterranean dietary intervention with or without 1700 mg/day of metformin for the prevention of age-related chronic diseases, the MeMeMe trial (Trial registration number: EudraCT number: 2012-005427-32 ClinicalTrials.gov ID: NCT02960711). MeMeMe recruiting experience, highlighting strengths, limitations encountered and results is reported.Patients and methodsStatistical analysis focused on the reasons for withdrawal according to the recruitment method ("active" versus "passive" criterion) and the time of withdrawal. Logistic regression models were used to explore the associations between the risk of withdrawal and sex, recruitment method, randomization arm, and with markers of compliance to the intervention, such as one-year change in body weight.ResultsOut of 2035 volunteers, 660 (32.4%) were recruited "actively" and 1375 (67.6%) "passively". Among people who dropped out of the trial after randomization, there were 19.5% for the "active" and 22.0% for the "passive" method (p = 0.28). The risk of withdrawal was significantly higher in women (OR:1.91; 95% CI:1.17-3.12; p = 0.01), in volunteers older at recruitment (OR:1.25; 95% CI:1.07-1.45; p = 0.004), and in those with a higher BMI at baseline (OR:1.23; 95% CI:1.07-1.43; p = 0.004). Volunteers who lost at least 2 kg (the median weight change) in the first year of intervention were significantly less (53%) likely to withdraw from the trial (OR:0.48; 95% CI:0.30-0.75; p = 0.001).ConclusionOur findings suggest that the "passive" recruitment method was more effective than the "active" one to advance recruitment. The benefits of "passive" recruitment hardly outweighed the drawbacks.Trial registrationTrial registration number: EudraCT number: 2012-005427-32. ClinicalTrials.gov ID: NCT02960711.

BackgroundRandomized controlled clinical trials require management effort, involving huge organizational, economic and informatics investments. Information technology offers opportunities to approach clinical trial methodology in new ways. However, there are only a few reports of computerized data and drug management systems.ObjectiveThis paper describes a novel software created specifically for the management of a randomized trial of diet and metformin in people with metabolic syndrome (the Me.Me.Me. trial).MethodsMe.Me.Me. is an ongoing phase III randomized controlled trial in healthy people with metabolic syndrome to test the hypothesis that comprehensive lifestyle changes and/or metformin can prevent age-related chronic non-communicable diseases. To manage all the phases of the trial, we created a software which is a state pattern machine, user friendly, web-based, able to maintain the correct balance between randomization groups, and structured in various levels of security in order to guarantee the participant's privacy and compliance with the study protocol. The software achieves budget savings: drug management is not based on patients' packs, but on the actual need for drugs according to each participant's "state", with strict guidelines for the handling and supply of medication.ResultsThe trial is ongoing and recruitment will close on August 31, 2018. To date, 11737 bottles of metformin/placebo have been dispensed to 1054 randomized participants, with drug savings of 29.5%.ConclusionsA software which takes into account the "state" of participant might be a powerful resource for developing and managing clinical trials, helping avoid poor treatment allocation, and wastage of drugs and money.Me.me.me. trialEUDRACT no. 2012-005427-32. ClinicalTrials.gov Identifier: NCT02960711.

Background: Women carriers of BRCA1/2 mutations face a high lifetime risk (penetrance) of developing breast and/or ovarian cancer. Insulin-like growth factor I (IGF-I), body weight and markers of insulin resistance affect BRCA penetrance. We conducted a multicenter prospective two-armed (1:1) randomized controlled trial (NCT03066856) to investigate whether a Mediterranean dietary intervention with moderate protein restriction reduces IGF-I and other metabolic modulators of BRCA penetrance. Methods: BRCA carriers, with or without a previous cancer, aged 18–70 years and without metastases were randomly assigned to an active dietary intervention group (IG) or to a control group (CG). The primary endpoint of the intervention was the IGF-I reduction. Results: 416 women (216 in the IG and 200 in the CG) concluded the six-month dietary intervention. The IG showed significantly lowered serum levels of IGF-I (−11.3 ng/mL versus −1.3 ng/mL, p = 0.02), weight (−1.5 Kg versus −0.5 Kg, p < 0.001), waist circumference (−2 cm versus −0.7 cm, p = 0.01), hip circumference (−1.6 cm versus −0.5 cm, p = 0.01), total cholesterol (−10.2 mg/dL versus −3.6 mg/dL, p = 0.04) and triglycerides (−8.7 mg/dL versus + 5.5 mg/dL, p = 0.01) with respect to the CG. Conclusions: A Mediterranean dietary intervention with moderate protein restriction is effective in reducing IGF-I and other potential modulators of BRCA penetrance.

Women carriers of pathogenic variants (mutations) in the BRCA1/2 genes face a high lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). However, metabolic factors may influence BRCA penetrance. We studied the association of metabolic factors with BRCA1/2 variants and the risk effect of metabolic exposures in relation to the position of the mutations within the BRCA1/2. Overall, 438 women carriers of BRCA1/2 mutations, aged 18–70, with or without a previous diagnosis of BC/OC and without metastases, who joined our randomized dietary trial, were included in the study. The pathogenic variants were divided, according to their predicted effect, into loss of function (LOF) and nonsynonymous variants. The association between metabolic exposures and variants were analyzed by a logistic regression model. LOF variant carriers showed higher levels of metabolic parameters compared to carriers of nonsynonymous variants. LOF variant carriers had significantly higher levels of plasma glucose and serum insulin than nonsynonymous variant carriers (p = 0.03 and p < 0.001, respectively). This study suggests that higher insulin levels are significantly associated with LOF variants. Further investigations are required to explore the association of metabolic factors with LOF variants and the mechanisms by which these factors may affect BRCA-related cancer risk.

This study aimed to compare calculated nutrient intakes from two different food composition databases using data from the European prospective investigation into cancer and nutrition (EPIC) cohort. Dietary intake data of the EPIC cohort was recently matched to 150 food components from the U.S. nutrient database (USNDB). Twenty-eight of these nutrients were already included in the EPIC nutrient database (ENDB—based upon country specific food composition tables), and used for comparison. Paired sample t-tests, Pearson’s correlations (r), weighted kappa’s (κ) and Bland-Altman plots were used to compare the dietary intake of 28 nutrients estimated by the USNDB and the ENDB for 476,768 participants. Small but significant differences were shown between the USNDB and the ENDB for energy and macronutrient intakes. Moderate to very strong correlations (r = 0.60–1.00) were found for all macro- and micronutrients. A strong agreement (κ > 0.80) was found for energy, water, total fat, carbohydrates, sugar, alcohol, potassium and vitamin C, whereas a weak agreement (κ < 0.60) was found for starch, vitamin D and vitamin E. Dietary intakes estimated via the USNDB compare adequately with those obtained via the ENDB for most macro- and micronutrients, although the agreement was weak for starch, vitamin D and vitamin E. The USNDB will allow exposure assessments for 150 nutrients to investigate associations with disease outcomes within the EPIC cohort.

Background . Insulin resistance is associated with higher breast cancer (BC) penetrance in BRCA mutation carriers. Metabolic syndrome (MetS), an insulin resistance syndrome, can be reversed by adhering to the Mediterranean diet (MedDiet). In a dietary intervention trial on BRCA mutation carriers, we evaluated adherence to the MedDiet, and the association with the MetS, by analyzing data from the Mediterranean Diet Adherence Screener (MEDAS). Methods. BRCA mutation carriers, with or without BC, aged 18 to 70 years, were eligible for the trial. After the baseline examinations, women were randomized to a dietary intervention or to a control group. Both groups completed the MEDAS at baseline and at the end of the dietary intervention. Results . A total of 163 women completed the 6 months of dietary intervention. Compared with controls, the women in the intervention group significantly reduced their consumption of red meat ( P < .01) and commercial sweets ( P < .01) and their MEDAS score rose significantly (+1.3 vs +0.55, P = .02). The number of MetS parameters decreased with increasing points of adherence to the MEDAS score ( P = .01). In the intervention group, there was a significant association with the greater reduction of MetS. Conclusion. BRCA mutation carriers in the intervention group experienced greater improvement in their MedDiet and MetS parameters.

Background: Insulin-like growth factor I (IGF-I) and other markers of insulin resistance (IRm) might influence the penetrance of BRCA gene mutation. In a demonstration project on BRCA mutation carriers we tested the effect of the ‘Mediterranean diet’, with moderate protein restriction, on serum levels of IGF-I and IRm. Methods: BRCA mutation carriers, with or without breast cancer, aged 18–70 years and without metastases were eligible. After the baseline examinations, women were randomized to an active dietary intervention or to a control group. The intervention group attended six full days of life-style intervention activities (cookery classes followed by lunch, sessions of walking for 45 min and nutritional conferences) over the next six months. Results: 213 BRCA mutation carriers completed the six-month study. Women in the intervention group (110) showed major changes in all the parameters under study. They significantly lost weight (p < 0.001), fat mass (p = 0.002), with reduced hip circumference (p = 0.01), triglycerides (p = 0.02) and IGF-I (p = 0.02) compared with controls. They also had a significantly higher levels of insulin-like growth factor-binding protein 3 (IGFI-BP3) (p = 0.03) and a lower IGF-I/IGFI-BP3 ratio (p = 0.04). The reduction of serum levels of IGF-I was significantly associated with the reduction in the consumption of animal products (p = 0.04). Conclusions: Women in the intervention group showed significant improvements in IGF-I and in other IRm that might influence the penetrance of BRCA mutations.