Dietary flavonoid intake and incidence of erectile dysfunction

Background: The predominant etiology for erectile dysfunction (ED) is vascular, however limited data are available on the role of diet. A higher intake of several flavonoids reduces diabetes and cardiovascular disease (CVD) risk but no studies have examined associations between flavonoids and erectile function.   Objective: To examine the relationship between habitual flavonoid sub-class intakes and incidence of ED.   Methods: We conducted a prospective study among 25,096 men from the Health Professionals Follow-up Study. Total flavonoid and subclass intakes were calculated from food frequency questionnaires collected every 4 years. Participants rated their erectile function in 2000 (with historical reporting from 1986) and again in 2004 and 2008.   Results: During 10 years of follow-up, 35.6% reported incident ED. After multivariate adjustment, including classic CVD risk factors, several sub-classes were associated with reduced ED incidence; specifically flavones (RR 0.91:95%CI=0.85,0.97; p-trend=0.006), flavanones (RR 0.89;95%CI=0.83,0.95; p-trend=0.0009), and anthocyanins (RR 0.91;95%CI=0.85,0.98; p-trend=0.002) comparing extreme intakes. The results remained significant after additional adjustment for a composite dietary intake score. In analyses stratified by age, a higher intake of flavanones, anthocyanins and flavones was significantlyassociated with a reduction in risk of erectile dysfunction only in men <70 years old and not older men (11-16% reduction in risk (p - interaction 0.002, 0.03, 0.007 for flavones, flavanones and anthocyanins respectively). In food-based analysis, higher total fruit intake, major sources of anthocyanins and flavanones, was associated with 14% reduction in risk of ED (RR 0.86;95%CI=0.79,0.92; p=0.002).The American Journal of Clinical Nutrition AJCN/2015/122010 Version 3.    Conclusions : These data suggest that a higher habitual intake of specific 24 flavonoid-rich foods are associated with reduced ED incidence. Intervention trials are needed to further examine the impact of increasing intakes of commonly consumed flavonoid-rich foods on men’s health

Pan-cancer classifications of tumor histological images using deep learning

Histopathological images are essential for the diagnosis of cancer type and selection of optimal treatment. However, the current clinical process of manual inspection of images is time consuming and prone to intra- and inter-observer variability. Here we show that key aspects of cancer image analysis can be performed by deep convolutional neural networks (CNNs) across a wide spectrum of cancer types. In particular, we implement CNN architectures based on Google Inception v3 transfer learning to analyze 27815 H&E slides from 23 cohorts in The Cancer Genome Atlas in studies of tumor/normal status, cancer subtype, and mutation status. For 19 solid cancer types we are able to classify tumor/normal status of whole slide images with extremely high AUCs (0.995±0.008). We are also able to classify cancer subtypes within 10 tissue types with AUC values well above random expectations (micro-average 0.87±0.1). We then perform a cross-classification analysis of tumor/normal status across tumor types. We find that classifiers trained on one type are often effective in distinguishing tumor from normal in other cancer types, with the relationships among classifiers matching known cancer tissue relationships. For the more challenging problem of mutational status, we are able to classify TP53 mutations in three cancer types with AUCs from 0.65-0.80 using a fully-trained CNN, and with similar cross-classification accuracy across tissues. These studies demonstrate the power of CNNs for not only classifying histopathological images in diverse cancer types, but also for revealing shared biology between tumors. We have made software available at: https://github.com/javadnoorb/HistCNNFirst author draf

Dietary flavonoid intake and weight maintenance: three prospective cohorts of 124,086 US men and women followed for up to 24 years

Objective: To examine whether dietary intake of specific flavonoid sub-classes is associated with weight change over time, including flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, and flavonoid polymers. Design: Three prospective cohort studies. Setting: Health professionals in the United States. Participants: 124,086 men and women participating in the Health Professionals Follow-up Study (HPFS), Nurses’ Health Study (NHS), and Nurses’ Health Study II (NHS II). Main outcome measure: Self-reported change in weight over multiple 4-year time intervals between 1986 and 2011. Results: Increased consumption of most flavonoid sub-classes, including flavonols, flavan-3-ols, anthocyanins, and flavonoid polymers was inversely associated with weight change over 4-year time intervals, after adjustment for simultaneous changes in other lifestyle factors including other aspects of diet, smoking status, and physical activity. In the pooled results, the greatest magnitude of association was observed for anthocyanins (-0.22 lbs, 95% CI -0.30 to -0.15 lbs per additional SD/day, 10 mg), flavonoid polymers (-0.18 lbs, 95% CI -0.28 to -0.08 lbs per additional SD/day, 138 mg), and flavonols (-0.16 lbs, 95% CI -0.26 to -0.06 lbs per additional SD/day, 7 mg). After additional adjustment for fiber intake associations remained significant for anthocyanins, proanthocyanidins, and total flavonoid polymers but were attenuated and no longer statistically significant for other sub-classes. Conclusions: Higher intake of foods rich in flavonols, flavan-3-ols, anthocyanins, and flavonoid polymers, may contribute to weight maintenance in adulthood, and may help to refine dietary recommendations for the prevention of obesity and its potential sequelae

Habitual intake of flavonoid subclasses and risk of colorectal cancer in two large prospective cohorts

Background: Flavonoids inhibit the growth of colon cancer cells in vitro. In a secondary analysis of a randomized controlled trial, the Polyp Prevention Trial, a higher intake of one sub-class, flavonols, was significantly associated with reduced risk of recurrent advanced adenoma. Most previous prospective studies on colorectal cancer evaluated only a limited number of flavonoid sub-classes and intake ranges, yielding inconsistent results.  Objective: To examine whether higher habitual dietary intakes of flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols and anthocyanins) are associated with lower risk of colorectal cancer.  Design: Using data from validated food frequency questionnaires administered every four years and an updated flavonoid food composition database flavonoid intakes were calculated for 42,478 male participants from the Health Professionals Follow-up Study and for 76,364 female participants from the Nurses’ Health Study.  Results: During up to 26 years of follow-up, 2,519 colorectal cancer cases (1,061 in men, 1,458 in women) were documented. Intakes of flavonoid subclasses were not associated with risk of colorectal cancer in either cohort. Pooled multivariable adjusted relative risks (95% confidence interval) comparing the highest with the lowest quintile were 1.04 (0.91, 1.18) for flavonols; 1.01 (0.89, 1.15) for flavones; 0.96 (0.84, 1.10) for flavanones; 1.07 (0.95, 1.21) for flavan-3-ols; and 0.98 (0.81, 1.19) for anthocyanins (all p-values for heterogeneity by sex >0.19). In subsite analyses, flavonoid intake was also not associated with colon or rectal cancer risk.  Conclusion: Our findings do not support the hypothesis that a higher habitual intake of any flavonoid sub-class decreases the risk of colorectal cancer

Association Between Passive and Active Smoking and Incident Type 2 Diabetes in Women

OBJECTIVE: Accumulating evidence has identified a positive association between active smoking and the risk of diabetes, but previous studies had limited information on passive smoking or changes in smoking behaviors over time. This analysis examined the association between exposure to passive smoke, active smoking, and the risk of incident type 2 diabetes among women. RESEARCH DESIGN AND METHODS: This is a prospective cohort study of 100,526 women in the Nurses’ Health Study who did not have prevalent diabetes in 1982, with follow-up for diabetes for 24 years. RESULTS: We identified 5,392 incident cases of type 2 diabetes during 24 years of follow-up. Compared with nonsmokers with no exposure to passive smoke, there was an increased risk of diabetes among nonsmokers who were occasionally (relative risk [RR] 1.10 [95% CI 0.94–1.23]) or regularly (1.16 [1.00–1.35]) exposed to passive smoke. The risk of incident type 2 diabetes was increased by 28% (12–50) among all past smokers. The risk diminished as time since quitting increased but still was elevated even 20–29 years later (1.15 [1.00–1.32]). Current smokers had the highest risk of incident type 2 diabetes in a dose-dependent manner. Adjusted RRs increased from 1.39 (1.17–1.64) for 1–14 cigarettes per day to 1.98 (1.57–2.36) for ≥25 cigarettes per day compared with nonsmokers with no exposure to passive smoke. CONCLUSIONS: Our study suggests that exposure to passive smoke and active smoking are positively and independently associated with the risk of type 2 diabetes

Alcohol Consumption, Mediating Biomarkers, and Risk of Type 2 Diabetes Among Middle-Aged Women

OBJECTIVE—The purpose of this study was to investigate whether adiponectin concentrations and biomarkers of inflammation, endothelial dysfunction, and insulin resistance mediate the association between alcohol consumption and diabetes. RESEARCH DESIGN AND METHODS—In a nested case-control study of 705 women with incident diabetes and 787 matched control subjects, we examined the adjusted relationship between baseline alcohol consumption and risk of diabetes before and after adjustment for markers of inflammation/endothelial dysfunction (C-reactive protein, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, tumor necrosis factor-α receptor 2, and interleukin-6), fasting insulin, and adiponectin concentrations. RESULTS—Alcohol consumption was associated with a decreased risk of diabetes (odds ratio per 12.5 g/day increment in alcohol use 0.58; 95% CI 0.49–0.69; P 2% of the observed relationship. Without adjustment for BMI, these biomarkers individually explained slightly more of the association, but <10% in all cases. Adiponectin accounted for 25% in a fully adjusted model and for 29% without adjustment for BMI. CONCLUSIONS—In this population of women, alcohol consumption was inversely associated with risk of type 2 diabetes. Adiponectin appeared to be a mediator of this association, but circulating biomarkers of inflammation, endothelial dysfunction, and fasting insulin did not explain this association. These results suggest that further research is needed into the potentially mediating roles of other biomarkers affected by alcohol consumption

Fluorescent Oxidation Products and Risk of Coronary Heart Disease: A Prospective Study in Women

Background: Oxidative stress is implicated in the etiology of coronary heart disease (CHD). New measures to capture oxidative stress are warranted. Fluorescent oxidation products (FlOPs) can be measured in plasma and have been shown to reflect levels of oxidative stress and to predict risk of CHD in men over 6 years of follow‐up. The objective of this study is to determine whether measures of FlOPs are associated with risk of CHD in women over an extended follow‐up period. Methods and Results: We measured FlOP by spectrofluorometer in a nested case–control study within the Nurses' Health Study, with baseline blood collection in 1990 and follow‐up of 397 incident CHD cases through 2004 matched 1:2 with controls. Level of FlOPs was independently associated with CHD. The relative risk across extreme quintiles was 1.64 (95% confidence interval [CI], 1.06 to 2.53) when adjusted for lifestyle factors, lipids and C‐reactive protein (P trend across quintiles=0.01). A slightly stronger association was observed when analyses were restricted to women fasting >8 hours at blood draw (RR, 1.91; 95% CI, 1.16 to 3.15). In exploratory time to event analyses, high levels of FlOPs measured ≥5 years before the CHD event, but not closer to the CHD event, were associated with the risk of CHD. Conclusions: Higher levels of FlOPs were associated with the risk of CHD in women. The association appeared strongest for long‐term prediction of CHD events

Hemoglobin A1c Is Associated With Increased Risk of Incident Coronary Heart Disease Among Apparently Healthy, Nondiabetic Men and Women

Background: Hemoglobin A1c (HbA1c), a time‐integrated marker of glycemic control, predicts risk of coronary heart disease (CHD) among diabetics. Few studies have examined HbA1c and risk of CHD among women and men without clinically elevated levels or previously diagnosed diabetes. Methods and Results: We conducted parallel nested case–control studies among women (Nurses' Health Study) and men (Health Professionals Follow‐up Study). During 14 and 10 years of follow‐up, 468 women and 454 men developed incident nonfatal myocardial infarction (MI) and fatal CHD. Controls were matched 2:1 based on age, smoking, and date of blood draw. For these analyses, participants with a history of diabetes or HbA1c levels ≥6.5% at baseline were excluded. Compared with HbA1c of 5.0% to 3.0 mg/L had a 2.5‐fold higher risk of CHD compared with participants in the lowest categories of both biomarkers. Conclusions: Our findings suggest that HbA1c is associated with CHD risk among apparently healthy, nondiabetic women and men and may be an important early clinical marker of disease risk

Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy

Phosphatase and tensin homolog (PTEN) loss is associated with genomic instability. APE1 is a key player in DNA base excision repair (BER) and an emerging drug target in cancer. We have developed small molecule inhibitors against APE1 repair nuclease activity. In the current study we explored a synthetic lethal relationship between PTEN and APE1 in melanoma. Clinicopathological significance of PTEN mRNA and APE1 mRNA expression was investigated in 191 human melanomas. Preclinically, PTEN-deficient BRAF-mutated (UACC62, HT144, and SKMel28), PTEN-proficient BRAF-wildtype (MeWo), and doxycycline-inducible PTEN-knockout BRAF-wildtype MeWo melanoma cells were DNA repair expression profiled and investigated for synthetic lethality using a panel of four prototypical APE1 inhibitors. In human tumours, low PTEN mRNA and high APE1 mRNA was significantly associated with reduced relapse free and overall survival. Pre-clinically, compared to PTEN-proficient cells, PTEN-deficient cells displayed impaired expression of genes involved in DNA double strand break (DSB) repair. Synthetic lethality in PTEN-deficient cells was evidenced by increased sensitivity, accumulation of DSBs and induction of apoptosis following treatment with APE1 inhibitors. We conclude that PTEN deficiency is not only a promising biomarker in melanoma, but can also be targeted by a synthetic lethality strategy using inhibitors of BER, such as those targeting APE1