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Background: Higher circulating carotenoids are associated with lower breast cancer risk. The underlying biology remains under-explored. Methods: We profiled 293 prediagnostic plasma metabolites in a nested case-control study (n = 887 cases) within the Nurses' Health Studies. Associations between circulating carotenoids and metabolites were identified using linear-mixed models (FDR = 0.05), and we further selected metabolites most predictive of carotenoids with LASSO. Metabolic signatures for carotenoids were calculated as weighted sums of LASSO selected metabolites. We further evaluated the metabolic signatures in relation to breast cancer risk using conditional logistic-regression. Results: We identified 48 to 110 metabolites associated with plasma levels of a-carotene, ß-carotene, ß-cryptoxanthin, estimated-vitamin-A-potential, lutein/zeaxanthin, and lycopene, which included primarily positively associated metabolites implicated in immune regulation (tryptophan), redox balance (plasmalogens, glutamine), epigenetic regulations (acetylated-/methylated-metabolites), and primarily inversely associated metabolites involved in ß-oxidation (carnitines; FDR = 0.05). The metabolomic signatures derived for ß-carotene (Q4 vs. Q1 relative risk RR = 0.74, Ptrend = 0.02), and estimated-vitamin-A-potential (Q4 vs. Q1 RR = 0.74, Ptrend = 0.02)--measured =10 years before diagnosis--were associated with lower breast cancer risk. Modest attenuations of RR for measured levels of ß-carotene and estimated-vitamin-A-potential were seen when we adjusted for their corresponding metabolic signatures. Conclusions: Metabolites involved in immune regulation, redox balance, membrane signaling, and ß-oxidation were associated with plasma carotenoids. Although some metabolites may reflect shared common food sources or compartmental colocalization with carotenoids, others may signal the underlying pathways of carotenoids-associated lowered breast cancer risk. Impact: Consumption of carotenoid-rich diet is associated with a wide-range of metabolic changes which may help to reduce breast cancer risk. [ABSTRACT FROM AUTHOR]

Mendelian randomization (MR) is often used to estimate effects of time-varying exposures on health outcomes using observational data. However, MR studies typically use a single measurement of exposure and apply conventional instrumental variable (IV) methods designed to handle time-fixed exposures. As such, MR effect estimates for time-varying exposures are often biased, and interpretations are unclear. We describe the instrumental conditions required for IV estimation with a time-varying exposure, and the additional conditions required to causally interpret MR estimates as a point effect, a period effect or a lifetime effect depending on whether researchers have measurements at a single or multiple time points. We propose methods to incorporate time-varying exposures in MR analyses based on g-estimation of structural mean models, and demonstrate its application by estimating the period effect of alcohol intake, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol on intermediate coronary heart disease outcomes using data from the Framingham Heart Study. We use this data example to highlight the challenges of interpreting MR estimates as causal effects, and describe other extensions of structural mean models for more complex data scenarios. [ABSTRACT FROM AUTHOR]

Background Diet is one of the modifiable risk factors for cognitive decline. However, studies on dietary protein intake and cognitive decline have remained limited and inconclusive. Objectives In this study, we aimed to investigate the associations between long-term dietary protein intake and subsequent subjective cognitive decline (SCD). Methods We included 49,493 women from the Nurses' Health Study (NHS) (1984–2006) and 27,842 men from the Health Professionals Follow-up Study (HPFS) (1986–2002). For the NHS, average dietary intake was calculated from 7 repeated semi-quantitative FFQs (SFFQs), and SCD was assessed in 2012 and 2014. For the HPFS, average dietary intake was calculated from 5 repeated SFFQs, and SCD was assessed in 2008 and 2012. Poisson regression was used to examine the associations between dietary protein, amino acids, and various protein food sources with subsequent SCD. Results Higher protein intake compared with total carbohydrates was associated with lower odds of SCD. When substituting 5% energy from protein for the equivalent percentage of energy from total carbohydrates, the pooled multivariable-adjusted ORs (95% CIs) were 0.89 (0.85, 0.94) for total protein, 0.89 (0.84, 0.94) for animal protein, and 0.74 (0.62, 0.88) for plant protein. When substituting 5% of energy from animal protein with plant protein, the OR was 0.84 (95% CI: 0.72, 0.97). For protein food sources, higher intakes of beans/legumes, fish, and lean poultry were significantly associated with lower odds of SCD, but higher intake of hotdogs was associated with higher odds of SCD. Conclusions Higher protein intake was associated with lower odds of SCD when compared isocalorically with carbohydrate. Plant protein sources were also associated with lower odds when compared with animal protein sources. Our findings suggest that adequate protein intake, and choices of protein sources could play a role in the maintenance of cognition and should be studied further. [ABSTRACT FROM AUTHOR]

Background The associations between nut consumption and cancer risk have not been extensively investigated. Objectives We aimed to examine the associations between nut consumption, especially specific types of nuts (peanut, tree nut, walnut, and tree nut other than walnut), and cancer risk. Methods Nut consumption was assessed by FFQ at baseline and updated every 2–4 y in the Nurses' Health Study (1980–2014), the Nurses' Health Study II (1991–2015), and the Health Professionals Follow-up Study (1986–2018). We examined the associations between the intake of total and specific types of nuts and risk of total cancer and common cancers, including lung, colorectal, breast, bladder, and aggressive prostate cancer. Cox proportional-hazards models were used to obtain the HRs and 95% CIs in each cohort as well as pooled. Results During 5,873,671 person-years of follow-up in 180,832 women and 45,560 men, we documented 44,561 incident cancer cases. As compared with nonconsumers, the pooled multivariable HRs of total nut consumption for ≥5 times/wk were 0.99 (95% CI: 0.94, 1.04; P -trend = 0.54) for total cancer, 0.88 (95% CI: 0.74, 1.04; P -trend = 0.18) for lung cancer, 1.07 (95% CI: 0.92, 1.26; P -trend = 0.89) for colorectal cancer, 0.90 (95% CI: 0.71, 1.14; P -trend = 0.65) for bladder cancer, 0.96 (95% CI: 0.85, 1.08; P -trend = 0.36) for breast cancer, and 1.18 (95% CI: 0.92, 1.51; P -trend = 0.52) for aggressive prostate cancer Conclusions In 3 large prospective cohorts, frequent nut consumption was not associated with risk of total cancer and common individual cancers. [ABSTRACT FROM AUTHOR]

A therapeutic effect of vitamin A supplementation on the course of photoreceptor degeneration, previously reported for patients with retinitis pigmentosa, was tested in two transgenic mouse models of this disease, each carrying a dominant rhodopsin mutation. The threonine-17 [right arrow] methionine (T17M) mutation is a class II rhodopsin mutation, characterized by a thermal instability/folding defect and minimal regeneration with the chromophore. The proline-347 [right arrow] serine (P347S) mutation belongs to class I, comprised of a smaller number of mutations that exhibit no recognized biochemical abnormality in vitro. In the present study, each of the two mouse models was fed a diet containing 2.5 mg of vitamin A palmitate (control) or 102.5 mg of vitamin A palmitate (high vitamin A) per kilogram of diet. Dark-adapted, full-field electroretinograms showed that the high vitamin A diet significantly reduced the rate of decline of a-wave and b-wave amplitudes in the T17M mice but had no significant effect on the decline of electroretinogram amplitude in the P347S mice. Correspondingly, histologic evaluation revealed that the treatment was associated with significantly longer photoreceptor inner and outer segments and a thicker outer nuclear layer in the T17M mice but had no effect on photoreceptor morphology in the P347S mice. In a separate series of experiments, the instability defect of the T17M mutant opsin expressed in vitro was partially alleviated by inclusion of 11-cis-retinal in the culture media. These results show that vitamin A supplementation slows the rate of photoreceptor degeneration caused by a class II rhodopsin mutation. Vitamin A supplementation may confer therapeutic benefit by stabilizing mutant opsins through increased availability of the chromophore.

The [Alpha] C protein of group B Streptococcus (GBS) is a major surface-associated antigen. Although its role in the biology and virulence of GBS has not been defined, it is opsonic and capable of eliciting protective immunity. The [Alpha] C protein is widely distributed among clinical isolates and is a potential protein carrier and antigen in conjugate vaccines to prevent GBS infections. The structural gene for the [Alpha] C protein, bca, has been cloned and sequenced. The protein encoded by bca is related to a class of surface-associated proteins of Gram-positive cocci involved in virulence and immunity. To investigate the potential roles of the [Alpha] C protein, bca null mutants were generated in which the bca gene was replaced with a kanamycin resistance cassette via homologous recombination using a novel shuttle/suicide vector. Studies of lethality in neonatal mice showed that the virulence of the bca null mutants was attenuated 5- to 7-fold when compared with the isogenic wild-type strain A909. Significant differences in mortality occurred in the first 24 h, suggesting that the role of the [Alpha] antigen is important in the initial stages of the infection. In contrast to A909, bca mutants were no longer killed by polymorphonuclear leukocytes in the presence of [Alpha]-specific antibodies in an in vitro opsonophagocytic assay. In contrast to previous studies, [Alpha] antigen expression does not appear to play a role in resistance to opsonophagocytosis in the absence of [Alpha]-specific antibodies. In addition, antibodies to the [Alpha] C protein did not passively protect neonatal mice from lethal challenge with bca mutants, suggesting that these epitopes are uniquely present within the [Alpha] antigen as expressed from the bca gene. Therefore, the [Alpha] C protein is important in the pathogenesis of GBS infection and is a target for protective immunity in the development of GBS vaccines.

Women may more effectively reduce their risk of heart disease by changing the fats they eat rather than simply eating less fat. In a 14-year study of 80,082 healthy nurses, fewer heart attacks and cardiac-related deaths occurred in those who ate more poly- and monounsaturated fats, and more cardiac events were associated with the consumption of saturated and hydrogenated (trans) fats. Substituting vegetable oils for animal-based and trans fats, rather than reducing overall fat intake, was the best strategy found in this group. Vegetable oils may help prevent heart disease.

Weight gain in adulthood may increase a woman's risk of developing breast cancer after menopause. This was one conclusion of a 16-year follow-up of 95,256 women participating in the Nurses' Health Study. During that time, 2,517 women developed breast cancer and 60% were postmenopausal. Weight gain during adulthood did not increase the risk of premenopausal breast cancer but increased the risk of postmenopausal breast cancer two-fold in women who did not use hormone therapy. Weight gain and hormone use combined were linked to one-third of postmenopausal breast cancer cases., Context.--Breast cancer is a major cause of mortality among women. It is important to identify modifiable risk factors for this disease. Objective.--To examine body mass index (BMI) at the age of 18 years and at midlife and adult weight change in relation to breast cancer incidence and mortality. Design.--Cohort study. Setting.--A cohort of 95 256 US female nurses aged 30 to 55 years who were followed up for 16 years. Main Outcome Measure.--Incident and fatal breast cancer. Results.--During 1 203498 person-years, 2517 incident breast cancers (60% postmenopausal) were documented. Higher current BMI was associated with lower breast cancer incidence before menopause and was minimally associated with incidence after menopause. However, a stronger positive relationship was seen among postmenopausal women who never used hormone replacement (relative risk=1.59 for BMI >31 kg/m[sup.2] vs is less than or equal to 20 kg/m[sup.2]; 95% confidence interval, 1.09-2.32; P for trend Conclusions.--Avoiding adult weight gain may contribute importantly to the prevention of breast cancer after menopause, particularly among women who do not use postmenopausal hormones. JAMA. 1997;278:1407-1411

Estrogen replacement therapy does not appear to significantly reduce mortality rates from heart disease in women who have a low risk of the disease. This is one of the conclusions of the Nurses' Health Study, which has followed 121,700 female nurses since 1976. By 1994, 3,637 had died. Those who used estrogen replacement therapy had a lower risk of death compared to those who never had. However, the increased risk of breast cancer in hormone users reduced that benefit over time. Hormone users with risk factors for heart disease benefitted the most, whereas those without risk factors benefitted little.