The long time from exposure to potentially harmful chemicals until breast cancer occurrence poses challenges for designing etiologic studies and for implementing successful prevention programs. ...Growing evidence from animal and human studies indicates that distinct time periods of heightened susceptibility to endocrine disruptors exist throughout the life course. The influence of environmental chemicals on breast cancer risk may be greater during several windows of susceptibility (WOS) in a woman's life, including prenatal development, puberty, pregnancy, and the menopausal transition. These time windows are considered as specific periods of susceptibility for breast cancer because significant structural and functional changes occur in the mammary gland, as well as alterations in the mammary micro-environment and hormone signaling that may influence risk. Breast cancer research focused on these breast cancer WOS will accelerate understanding of disease etiology and prevention.
Despite the plausible heightened mechanistic influences of environmental chemicals on breast cancer risk during time periods of change in the mammary gland's structure and function, most human studies of environmental chemicals are not focused on specific WOS. This article reviews studies conducted over the past few decades that have specifically addressed the effect of environmental chemicals and metals on breast cancer risk during at least one of these WOS. In addition to summarizing the broader evidence-base specific to WOS, we include discussion of the NIH-funded Breast Cancer and the Environment Research Program (BCERP) which included population-based and basic science research focused on specific WOS to evaluate associations between breast cancer risk and particular classes of endocrine-disrupting chemicals-including polycyclic aromatic hydrocarbons, perfluorinated compounds, polybrominated diphenyl ethers, and phenols-and metals. We outline ways in which ongoing transdisciplinary BCERP projects incorporate animal research and human epidemiologic studies in close partnership with community organizations and communication scientists to identify research priorities and effectively translate evidence-based findings to the public and policy makers.
An integrative model of breast cancer research is needed to determine the impact and mechanisms of action of endocrine disruptors at different WOS. By focusing on environmental chemical exposure during specific WOS, scientists and their community partners may identify when prevention efforts are likely to be most effective.
There is a paucity of human data on exposure to blast traumatic brain injury (bTBI) and the corresponding systemic cytokine immune response at later time points (i.e., months, years) post-injury.
We ...conducted a repeated measures, case-control study, examining associations of serum levels of pro- and anti-inflammatory cytokines, measured both pre- and post-deployment with having mild and moderate/severe bTBI. Utilizing serum from the Department of Defense Serum Repository cytokines were measured via an ELISA-based array for 15 cytokines. We compared pre- vs. post-levels among mild cases, moderate/severe cases, and controls and carried out case-control comparisons, using paired t- tests and generalized linear models.
The average time between bTBI and post-deployment/bTBI serum among cases was 315.8 days. From pre- to post-deployment/bTBI, levels of interleukin 8 (IL-8) were decreased among both mild cases (μ = - 83.43 pg/ml; s.e. = 21.66) and moderate/severe cases (μ = - 107.67 pg/ml; s.e. = 28.74 pg/ml), while levels increased among controls (μ = 32.86 pg/ml; s.e. = 30.29). The same pattern occurred for matrix metallopeptidase 3 (MMP3), with levels decreasing for moderate/severe cases (μ = - 3369.24 pg/ml; s.e. = 1701.68) and increasing for controls (μ = 1859.60 pg/ml; s.e. = 1737.51) from pre- to post-deployment/bTBI. Evidence was also suggestive of case-control differences, from pre- to post-deployment/bTBI for interleukin 1 alpha (IL-1α), interleukin 4 (IL-4), and interleukin 6 (IL-6) among moderate/severe cases.
The findings of this longitudinal study indicate that in the chronic phase of bTBI, levels of IL-8 and MMP3 may be substantially lower than pre-injury. These results need confirmation in other studies, potentially those that account for treatment differences, which was not possible in our study.
Chronic neuropsychological sequelae following SARS-CoV-2 infection, including depression, anxiety, fatigue, and general cognitive difficulties, are a major public health concern. Given the potential ...impact of long-term neuropsychological impairment, it is important to characterize the frequency and predictors of this post-infection phenotype.
The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal study assessing the impact of SARS-CoV-2 infection in U.S. Military Healthcare System (MHS) beneficiaries, i.e. those eligible for care in the MHS including active duty servicemembers, dependents, and retirees. Four broad areas of neuropsychological symptoms were assessed cross-sectionally among subjects 1-6 months post-infection/enrollment, including: depression (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), fatigue (PROMIS® Fatigue 7a), and cognitive function (PROMIS® Cognitive Function 8a and PROMIS® Cognitive Function abilities 8a). Multivariable Poisson regression models compared participants with and without SARS-CoV-2 infection history on these measures, adjusting for sex, ethnicity, active-duty status, age, and months post-first positive or enrollment of questionnaire completion (MPFP/E); models for fatigue and cognitive function were also adjusted for depression and anxiety scores.
The study population included 2383 participants who completed all five instruments within six MPFP/E, of whom 687 (28.8%) had at least one positive SARS-CoV-2 test. Compared to those who had never tested positive for SARS-CoV-2, the positive group was more likely to meet instrument-based criteria for depression (15.4% vs 10.3%, p<0.001), fatigue (20.1% vs 8.0%, p<0.001), impaired cognitive function (15.7% vs 8.6%, p<0.001), and impaired cognitive function abilities (24.3% vs 16.3%, p<0.001). In multivariable models, SARS-CoV-2 positive participants, assessed at an average of 2.7 months after infection, had increased risk of moderate to severe depression (RR: 1.44, 95% CI 1.12-1.84), fatigue (RR: 2.07, 95% CI 1.62-2.65), impaired cognitive function (RR: 1.64, 95% CI 1.27-2.11), and impaired cognitive function abilities (RR: 1.41, 95% CI 1.15-1.71); MPFP/E was not significant.
Participants with a history of SARS-CoV-2 infection were up to twice as likely to report cognitive impairment and fatigue as the group without prior SARS-CoV-2 infection. These findings underscore the continued importance of preventing SARS-CoV-2 infection and while time since infection/enrollment was not significant through 6 months of follow-up, this highlights the need for additional research into the long-term impacts of COVID-19 to mitigate and reverse these neuropsychological outcomes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The underlying molecular mechanisms of PTSD are largely unknown. Distinct expression signatures for PTSD have been found, in particular for immune activation transcripts. DNA methylation may be ...significant in the pathophysiology of PTSD, since the process is intrinsically linked to gene expression. We evaluated temporal changes in DNA methylation in select promoter regions of immune system-related genes in U.S. military service members with a PTSD diagnosis, pre- and post-diagnosis, and in controls.
Cases (n = 75) had a post-deployment diagnosis of PTSD in their medical record. Controls (n = 75) were randomly selected service members with no PTSD diagnosis. DNA was extracted from pre- and post-deployment sera. DNA methylation (%5-mC) was quantified at specific CpG sites in promoter regions of insulin-like growth factor 2 (IGF2), long non-coding RNA transcript H19, interleukin-8 (IL8), IL16, and IL18 via pyrosequencing. We used multivariate analysis of variance and generalized linear models to calculate adjusted means (adjusted for age, gender, and race) to make temporal comparisons of %5-mC for cases (pre- to post-deployment) versus controls (pre- to post-deployment).
There were significant differences in the change of %5-mC pre- to post-deployment between cases and controls for H19 (cases: +0.57%, controls: -1.97%; p = 0.04) and IL18 (cases: +1.39%, controls: -3.83%; p = 0.01). For H19 the difference was driven by a significant reduction in %5-mC among controls; for IL18 the difference was driven by both a reduction in %5-mC among controls and an increase in %5-mC among cases. Stratified analyses revealed more pronounced differences in the adjusted means of pre-post H19 and IL18 methylation differences for cases versus controls among older service members, males, service members of white race, and those with shorter deployments (6-12 months).
In the study of deployed personnel, those who did not develop PTSD had reduced %5-mC levels of H19 and IL18 after deployment, while those who did develop PTSD had increased levels of IL18. Additionally, pre-deployment the people who later became cases had lower levels of IL18 %5-mC compared with controls. These findings are preliminary and should be investigated in larger studies.
Differences in ability to metabolize daidzein to equol might help explain inconsistent findings about isoflavones and breast cancer. We examined equol-producing status in relation to breast density, ...a marker of breast cancer risk, and evaluated whether an association of isoflavone intake with breast density differs by equol-producing status in a sample of Chinese immigrant women.
Participants were 224 women, ages 36 to 58 years, enrolled in a study on diet and breast density. All women completed dietary recall interviews, underwent a soy challenge to assess equol-producing status, and received a mammogram assessed for breast density using a computer-assisted method.
In our sample, 30% were classified as equol producers. In adjusted linear regression models, equol producers had significantly lower mean dense tissue area (32.8 vs. 37.7 cm(2), P = 0.03) and lower mean percent breast density (32% vs. 35%, P = 0.03) than nonproducers. Significant inverse associations of isoflavone intake with dense area and percent density were apparent, but only in equol producers (interaction P = 0.05 for both).
These results support the possibility that equol-producing status affects breast density and that effects of isoflavones on breast density depend on ability to metabolize daidzein to equol.
Although these findings warrant confirmation in a larger sample, they offer a possible explanation for the inconsistent findings about soy intake and breast density and possibly breast cancer risk as well. The findings further suggest the importance of identifying factors that influence equol-producing status and exploring appropriate targeting of interventions.
Background: Mammographic density is one of the strongest predictors of breast cancer risk. The mechanism by which breast density
increases breast cancer risk is unclear although it has been ...hypothesized that breast density reflects cumulative exposure
to estrogens.
Methods: To evaluate this hypothesis, we conducted a cross-sectional study among 520 postmenopausal women in the Nurses' Health
Study that examined the relation between circulating sex hormones and mammographic density. Women were postmenopausal and
not taking exogenous hormones at the time of blood collection and mammogram. Percent breast density was measured from digitized
mammograms using a computer-assisted method. Circulating estrone, estradiol, androstenedione, testosterone, DHEA, DHEA sulfate,
sex hormone–binding globulin, progesterone, and prolactin were measured in plasma.
Results: In contrast to the prior hypothesis, circulating estrogens were inversely related to percent mammographic density.
The mean percent mammographic density was 25.6% among women in the lowest quartile of circulating estradiol compared with
14.4% among women in the highest quartile Spearman correlation ( r ) = −0.22, P < 0.0001. Circulating estrogens alone explained 1% to 5% of the variation of mammographic density. Body mass index was positively
associated with circulating estradiol levels ( r = 0.45, P < 0.0001) and inversely related to percent mammographic density ( r = −0.51, P < 0.0001). After adjustment for body mass index, there was no association between estradiol and breast density ( r = 0.01, P = 0.81). Likewise, there was no relation between the other sex hormones measured or prolactin and mammographic density after
adjustment for body mass index.
Conclusion: These findings indicate that in postmenopausal women, mammographic density is independent of circulating sex hormone
levels.
Some studies have suggested that insulin-like growth factor (IGF) pathway is related to premenopausal breast density, one
of the strongest known breast cancer risk factors. This study was designed ...specifically to test the hypothesis that higher
levels of IGF-I and lower levels of IGF-binding protein (IGFBP)-3 are associated with high mammographic breast density among
premenopausal but not among postmenopausal women. A total of 783 premenopausal and 791 postmenopausal healthy women were recruited
during screening mammography examinations. Blood samples were collected at the time of mammography, and plasma IGF-I and IGFBP-3
levels were measured by ELISA. Mammographic breast density was estimated using a computer-assisted method. Spearman's partial
correlation coefficients ( r s ) were used to evaluate the associations. Adjusted mean breast density was assessed by joint levels of IGF-I and IGFBP-3 using
generalized linear models. Among premenopausal women, high levels of IGF-I and low levels of IGFBP-3 were independently correlated
with high breast density ( r s = 0.083; P = 0.021 and r s = −0.124; P = 0.0005, respectively). Correlation of IGF-I with breast density was stronger among women in the lowest tertile of IGFBP-3
than among those in the highest tertile of IGFBP-3 ( r s = 0.138; P = 0.027 and r s = −0.039; P = 0.530, respectively). In contrast, the correlation of IGFBP-3 with breast density was stronger among women in the highest
tertile of IGF-I than among those in the lowest tertile of IGF-I ( r s = −0.150; P = 0.016 and r s = −0.008; P = 0.904, respectively). Women in the combined top tertile of IGF-I and bottom tertile of IGFBP-3 had higher mean breast density
than those in the combined bottom tertile of IGF-I and top tertile of IGFBP-3 (53.8% versus 40.9%; P = 0.014). No significant association was observed among postmenopausal women. Our findings confirm that IGF-I and IGFBP-3
are associated with breast density among premenopausal women. They provide additional support for the idea that, among premenopausal
women, these growth factors may affect breast cancer risk, at least in part, through their influence on breast tissue morphology
as reflected on mammogram.
Cooking meats at high temperatures and for long duration produces heterocyclic amines and other mutagens. These meat-derived
mutagenic compounds have been hypothesized to increase risk of colorectal ...neoplasia, but prospective data are unavailable.
We examined the association between intakes of the heterocyclic amines 2-amino-3,8-dimethylimidazo4,5,- f quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo4,5- b pyridine (PhIP), 2-amino-3,4,8-trimethylimidazo4,5,- f quinoxaline (DiMeIQx), and meat-derived mutagenicity (MDM) and risk of distal colon adenoma using a cooking method questionnaire
administered in 1996 in the Health Professionals Follow-up Study cohort. Between 1996 and 2002, 581 distal colon adenoma cases
were identified. Higher intake of MDM was marginally associated with increased risk of distal adenoma fourth versus lowest
quintile: odds ratio (OR), 1.39; 95% confidence interval (95% CI), 1.05-1.84; highest versus lowest quintile: OR, 1.29; 95%
CI, 0.97-1.72; P trend = 0.08. Adjusting for total red meat or processed meat intake did not explain those associations. Our data also suggested
a positive association between higher MeIQx (highest versus lowest quintile: OR, 1.28; 95% CI, 0.95-1.71; P trend = 0.22) and risk of adenoma, but this association was attenuated after adjusting for processed meat intake. DiMeIQx and PhIP
did not seem to be associated with risk of adenoma. In conclusion, higher consumption of mutagens from meats cooked at higher
temperature and longer duration may be associated with higher risk of distal colon adenoma independent of overall meat intake.
Because mutagens other than heterocyclic amines also contribute to MDM, our results suggest that mutagens other than heterocyclic
amines in cooked meats may also play a role in increasing the risk of distal adenoma. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1120–5)
Avicenna’s proof for the existence of God (the Necessary Existent) in the Metaphysics of the Salvation relies on the claim that every possible existent shares a common cause. I argue that Avicenna ...has good reason to hold this claim given that he thinks that (1) every essentially ordered causal series originates in a first, common cause and that (2) every possible existent belongs to an essentially ordered series. Showing Avicenna’s commitment to 1 and 2 allows me to respond to Herbert Davidson’s and Richard Swinburne’s claim that Avicenna’s proof for the Necessary Existent is incomplete and fallacious.
Background: A better understanding of factors that affect breast density, one of the strongest breast cancer risk indicators,
may provide important clues about breast cancer etiology and prevention. ...This study evaluates the association of vitamin D
and calcium, from food and/or supplements, to breast density in premenopausal and postmenopausal women separately.
Methods: A total of 777 premenopausal and 783 post-menopausal women recruited at two radiology clinics in Quebec City, Canada,
in 2001 to 2002, completed a food frequency questionnaire to assess vitamin D and calcium. Breast density from screening mammograms
was assessed using a computer-assisted method. Associations between vitamin D or calcium and breast density were evaluated
using linear regression models. Adjusted means in breast density were assessed according to the combined daily intakes of
the two nutrients using generalized linear models.
Results: In premenopausal women, total intakes of vitamin D and calcium were inversely related to breast density ( β = −1.4; P = 0.004 for vitamin D; β = −0.8; P = 0.0004 for calcium). In multivariate linear regression, simultaneous increments in daily total intakes of 400 IU vitamin
D and 1,000 mg calcium were associated with an 8.5% (95% confidence interval, 1.8-15.1) lower mean breast density. The negative
association between dietary vitamin D intake and breast density tended to be stronger at higher levels of calcium intake and
vice versa. Among postmenopausal women, intakes of vitamin D and calcium were not associated with breast density.
Conclusion: These findings show that higher intakes of vitamin D and calcium from food and supplements are related to lower
levels of breast density among premenopausal women. They suggest that increasing intakes of vitamin D and calcium may represent
a safe and inexpensive strategy for breast cancer prevention.
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