BRCA1 and BRCA2 Gene Expression: Diurnal Variability and Influence of Shift Work

BRCA1 and BRCA2 genes are involved in DNA double-strand break repair and related to breast cancer. Shift work is associated with biological clock alterations and with a higher risk of breast cancer. The aim of this study was to investigate the variability of expression of BRCA genes through the day in healthy subjects and to measure BRCA expression levels in shift workers. The study was approached in two ways. First, we examined diurnal variation of BRCA1 and BRCA2 genes in lymphocytes of 15 volunteers over a 24-hour period. Second, we measured the expression of these genes in lymphocytes from a group of shift and daytime workers. The change in 24-hour expression levels of BRCA1 and BRCA2 genes was statistically significant, decreasing from the peak at midday to the lowest level at midnight. Lower levels for both genes were found in shift workers compared to daytime workers. Diurnal variability of BRCA1 and BRCA2 expression suggests a relation of DNA double-strand break repair system with biological clock. Lower levels of BRCA1 and BRCA2 found in shift workers may be one of the potential factors related to the higher risk of breast cancer.

Fecal Microbiota Transplantation for Clostridium difficile Infection: A One-Center Experience.

BACKGROUND: Clostridium difficile is a gram-positive, anaerobic, and spore-forming bacillus, which is responsible for the majority of antibiotic-associated diarrhea and colitis. OBJECTIVE: Determine if fecal microbiota transplantation (FMT) is effective in a population sample from Connecticut. METHODS: We report the clinical experience of 92 consecutive patients from one gastroenterology practice in central Connecticut treated by colonoscopy with FMT for infection with Clostridium difficile from 2012 to 2017. The analyses are based on clinical follow-up up to 3 months after the FMT procedure and on medical chart review. RESULTS: Overall, complete recovery occurred in 86% of patients. As previously reported in a limited number of previous studies, community-acquired cases were more common than hospital-acquired cases, and community-acquired cases were more likely to be female. CONCLUSIONS: Consistent with some previous reports, we found the following: the source of the donor for FMT did not make a difference in recovery: material from nonrelatives was as effective as from close relatives; and the presence of multiple comorbidities did not make a difference in recovery: patients with 2 or more comorbidities did as well as those with one or none.

Kernel density analysis reveals a halo pattern of breast cancer incidence in Connecticut.

Breast cancer (BC) incidence rates in Connecticut are among the highest in the United States, and are unevenly distributed within the state. Our goal was to determine whether artificial light at night (ALAN) played a role. Using BC records obtained from the Connecticut Tumor Registry, we applied the double kernel density (DKD) estimator to produce a continuous relative risk surface of a disease throughout the State. A multi-variate analysis compared DKD and census track estimates with population density, fertility rate, percent of non-white population, population below poverty level, and ALAN levels. The analysis identified a "halo" geographic pattern of BC incidence, with the highest rates of the disease observed at distances 5-15 km from the state's major cities. The "halo" was of high-income communities, with high ALAN, located in suburban fringes of the state's main cities.

Bioavailable serum estradiol may alter radiation risk of postmenopausal breast cancer: a nested case-control study.

PURPOSE: Ionizing radiation and high levels of circulating estradiol are known breast cancer carcinogens. We investigated the risk of first primary postmenopausal breast cancer in relation to the combined effects of whole-body ionizing radiation exposure and prediagnostic levels of postmenopausal sex hormones, particularly bioavailable estradiol (bE2). MATERIALS AND METHODS: A nested case-control study of 57 incident breast cancer cases matched with 110 controls among atomic bomb survivors. Joint effects of breast radiation dose and circulating levels of sex hormones were assessed using binary regression and path analysis. RESULTS AND CONCLUSION: Radiation exposure, higher levels of bE2, testosterone and progesterone, and established reproductive risk factors were positively associated with postmenopausal breast cancer risk. A test for mediation of the effect of radiation via bE2 level suggested a small (14%) but significant mediation (p = 0.004). The estimated interaction between radiation and bE2 was large but not significant (interaction = 3.86; p = 0.32). There is accumulating evidence that ionizing radiation not only damages DNA but also alters other organ systems. While caution is needed, some portion of the radiation risk of postmenopausal breast cancer appeared to be mediated through bE2 levels, which may be evidence for cancer risks due to both direct and indirect effects of radiation.

Proximal Aberrant Crypt Foci Associate with Synchronous Neoplasia and Are Primed for Neoplastic Progression.

Aberrant crypt foci (ACF) are the earliest morphologically identifiable lesion found within the human colon. Despite their relatively high frequency in the distal colon, few studies have examined the molecular characteristics of ACF within the proximal colon. In the following study, clinical participants (n = 184) were screened for ACF using high-definition chromoendoscopy with contrast dye-spray. Following pathologic confirmation, ACF biopsies were subjected to laser capture microdissection (LCM), and epithelial cells were evaluated for somatic mutations with a customized colorectal cancer mutation panel using DNA-mass spectrometry. Samples were further characterized for microsatellite instability (MSI). Logistic models were used to associate proximal ACF with synchronous (detected during the same procedure) neoplasia. Thirty-nine percent of participants had at least one histologically confirmed proximal ACF. Individuals with a proximal ACF were significantly more likely to present with a synchronous neoplasm (P = 0.001), and specifically, a proximal, tubular, or tubulovillous adenoma (multivariable OR = 2.69; 95% confidence interval, 1.12-6.47; P = 0.027). Proximal ACF were more likely to be dysplastic (52%) compared with distal ACF (13%; P < 0.0001). Somatic mutations to APC, BRAF, KRAS, NRAS, and ERBB2 were detected in 37% of proximal ACF. Hyperplastic ACF were more often MSI-high, but there were no differences in MSI status observed by colonic location. In summary, ACF are identified in the proximal colons of approximately 40% of individuals undergoing chromoendoscopy and more often in patients with synchronous proximal adenomas.Implications: This study provides the most complete set of data, to date, that ACF represent the earliest step in the adenoma-carcinoma sequence but remain below the detection limit of conventional endoscopy.Visual Overview: http//mcr.accrjournals.org/content/molcanres/16/3/486/F1.large.jpg Mol Cancer Res; 16(3); 486-95. ©2017 AACR.

Metformin Use in Practice: Compliance With Guidelines for Patients With Diabetes and Preserved Renal Function.

IN BRIEF Several contraindications limit the use of metformin, most notably the risk of lactic acidosis. This article reports on an examination of a population of patients with diabetes with preserved renal function to evaluate provider compliance with guidelines on metformin use and to identify factors that contributed when practice diverged from recommendations. It found that metformin was withheld from approximately one-third of these patients because of 1) an existent contraindication to metformin, 2) patient behavior or preference, or 3) provider preference or bias based on patient or personal factors. Although providers generally follow current recommendations for the use of metformin, deviations from guidelines in practice are common.

Health consequences of electric lighting practices in the modern world: A report on the National Toxicology Program's workshop on shift work at night, artificial light at night, and circadian disruption.

The invention of electric light has facilitated a society in which people work, sleep, eat, and play at all hours of the 24-hour day. Although electric light clearly has benefited humankind, exposures to electric light, especially light at night (LAN), may disrupt sleep and biological processes controlled by endogenous circadian clocks, potentially resulting in adverse health outcomes. Many of the studies evaluating adverse health effects have been conducted among night- and rotating-shift workers, because this scenario gives rise to significant exposure to LAN. Because of the complexity of this topic, the National Toxicology Program convened an expert panel at a public workshop entitled "Shift Work at Night, Artificial Light at Night, and Circadian Disruption" to obtain input on conducting literature-based health hazard assessments and to identify data gaps and research needs. The Panel suggested describing light both as a direct effector of endogenous circadian clocks and rhythms and as an enabler of additional activities or behaviors that may lead to circadian disruption, such as night-shift work and atypical and inconsistent sleep-wake patterns that can lead to social jet lag. Future studies should more comprehensively characterize and measure the relevant light-related exposures and link these exposures to both time-independent biomarkers of circadian disruption and biomarkers of adverse health outcomes. This information should lead to improvements in human epidemiological and animal or in vitro models, more rigorous health hazard assessments, and intervention strategies to minimize the occurrence of adverse health outcomes due to these exposures.

Rotating Night-Shift Work and the Risk of Breast Cancer in the Nurses' Health Studies.

In 2007, the International Agency for Research on Cancer declared shift work that involved circadian disruption to be a "probable" carcinogen (group 2A), noting that human evidence was limited. Using data from 2 prospective cohort studies, the Nurses' Health Study (1988-2012; n = 78,516) and Nurses' Health Study II (1989-2013; n = 114,559), we examined associations between rotating night-shift work and breast cancer risk. In the 2 cohorts, there were a total of 9,541 incident invasive breast malignancies and 24 years of follow-up. In the Nurses' Health Study, women with 30 years or more of shift work did not have a higher risk of breast cancer (hazard ratio (HR) = 0.95, 95% confidence interval (95% CI): 0.77, 1.17; P for trend = 0.63) compared with those who never did shift work, although follow-up occurred primarily after retirement from shift work. Among participants in the Nurses' Health Study II, who were younger than participants in the other cohort, the risk of breast cancer was significantly higher in women with 20 years or more of shift work at baseline, reflecting young-adult exposure (HR = 2.15, 95% CI: 1.23, 3.73; P for trend = 0.23), and was marginally significantly higher for women with 20 years or more of cumulative shift work when we used updated exposure information (HR = 1.40, 95% CI: 1.00, 1.97; P for trend = 0.74). In conclusion, long-term rotating night-shift work was associated with a higher risk of breast cancer, particularly among women who performed shift work during young adulthood. Further studies should explore the role of shift work timing on breast cancer risk.

Letter in reference to: "Short-term effects of night shift work on breast cancer risk: a cohort study of payroll data".

There are major flaws with the analyses in the Vistisen et al (1) cohort study examining if night shift work is a short-term risk factor for breast cancer. The crucial problem is the potential for exposure misclassification, which is very high. The authors' definition of day shift is "≥3 hours of work between 06:00-20:00 hours". This means that a worker on an 8-hour shift that begins at 03:00 hours would be classified as a day rather than night shift worker because he/she worked only two hours between 24:00-05:00 hours. Similarly, a second shifter might start work at 17:00 but not get off until 01:00 and yet still be classified as a "day shift" worker. This does not make sense as a baseline comparison group "unexposed" to work during the night hours. A sensible classification system would be to define "day shift" as any shift that begins after 07:00 and ends before 18:00 hours. This is straightforward and avoids all of the ambiguities inherent in the definition used by the authors. In addition, the authors claim that the "inception population" is less likely to have had past prior non-day work hours. However, this group has an average age of >35 years. It is inconceivable that all of these women were new graduates who started a public health sector job for the first time. Rather, the majority must surely have worked elsewhere for many years but then started in the regions covered only after 2006. This topic is too important, and this cohort too valuable, not to carefully define the baseline comparison group of "day workers" in a sensible manner. All the inferences rely crucially on this definition. The authors have the data to define the day-working baseline group in a way that avoids these obvious biases. That is why it is so frustrating that the authors chose to conduct the analyses as they did, with a highly flawed definition of "day work", when they could have done so much better. A highly flawed epidemiological report is worse than no report at all because it misleads the scientific community and the public. Reference 1. Vistisen HT, Garde AH, Frydenberg M, Christiansen P, Hansen ÅM, Hansen J, Bonde JPE, Kolstad HA. Short-term effects of night shift work on breast cancer risk: a cohort study of payroll data. Scand J Work Environ Health - online first. http://dx.doi.org/10.5271/sjweh.3603.

Light at night and breast cancer incidence in Connecticut: An ecological study of age group effects.

The aim of this study was to test the prediction that within the state of Connecticut, USA, communities with high nighttime outdoor light level would have higher breast cancer incidence rates. Breast cancer cases were identified from the Connecticut Tumor Registry, the oldest within the United States, for years 2005 and 2009 and geocoded to the 829 census tracts in the state. Nighttime light level (LAN) was obtained from the Defense Meteorological Satellite Program (DMSP), 1996/97 satellite image, providing a 10-year lag. Regression models were used incorporating the LAN levels and census level data on potential confounders for the whole female population of the state, and for separate age groups. Light level emerged as a significant predictor of breast cancer incidence. After taking account of several potential confounders, the excess risk in the highest LAN level census tracts compared to the lowest was about 63% (RR=1.63; 95% CI=1.41, 1.89). The association of LAN with breast cancer incidence weakened with age; the association was strongest among premenopausal women.

Circadian disruption and health: Shift work as a harbinger of the toll taken by electric lighting.

Electric light is one of the signature inventions of human beings. A problem, however, is that electric light can confuse our endogenous circadian rhythmicity. It has now become apparent that circadian biology is fundamental to the functioning and adaptation of almost all life forms. In the modern world, everyone is exposed to electric light during the day and night, and thereby can experience some level of circadian disruption. Perhaps as a canary in the coal mine, study of people whose work hours include nighttime (shift workers) is beginning to yield insights on the adverse health effects of circadian disruption from electric light.

Mortality risk from comorbidities independent of triple-negative breast cancer status: NCI-SEER-based cohort analysis.

PURPOSE: A comparatively high prevalence of comorbidities among African-American/Blacks (AA/B) has been implicated in disparate survival in breast cancer. There is a scarcity of data, however, if this effect persists when accounting for the adverse triple-negative breast cancer (TNBC) subtype which occurs at threefold the rate in AA/B compared to white breast cancer patients. METHODS: We reviewed charts of 214 white and 202 AA/B breast cancer patients in the NCI-SEER Connecticut Tumor Registry who were diagnosed in 2000-2007. We employed the Charlson Co-Morbidity Index (CCI), a weighted 17-item tool to predict risk of death in cancer populations. Cox survival analyses estimated hazard ratios (HRs) for all-cause mortality in relation to TNBC and CCI adjusting for clinicopathological factors. RESULTS: Among patients with SEER local stage, TNBC increased the risk of death (HR 2.18, 95 % CI 1.14-4.16), which was attenuated when the CCI score was added to the model (Adj. HR 1.50, 95 % CI 0.74-3.01). Conversely, the adverse impact of the CCI score persisted when controlling for TNBC (Adj. HR 1.49, 95 % CI 1.29-1.71; per one point increase). Similar patterns were observed in SEER regional stage, but estimated HRs were lower. AA/B patients with a CCI score of ≥3 had a significantly higher risk of death compared to AA/B patients without comorbidities (Adj. HR 5.65, 95 % CI 2.90-11.02). A lower and nonsignificant effect was observed for whites with a CCI of ≥3 (Adj. HR 1.90, 95 % CI 0.68-5.29). CONCLUSIONS: comorbidities at diagnosis increase risk of death independent of TNBC, and AA/B patients may be disproportionately at risk.

Affect, emotion dysregulation and sleep quality among low-income women.

OBJECTIVES: To examine the underlying mechanisms through which steady state emotions, specifically affect and emotion regulation, influence sleep quality among young adult low-income women. DESIGN: Cross-sectional. SETTING: Stress and Health Study (2006-2012) in southeast Texas. PARTICIPANTS: A subgroup (n=392) of racially and ethnically diverse young adult women ages 18-31. MEASUREMENTS: Participants provided measures of positive and negative affect, difficulties in emotion regulation, and sleep quality. Structural equation models were designed to identify differential mediating roles of emotion dysregulation in the association between both positive and negative affect and sleep quality. RESULTS: The relationship between positive affect and improved sleep quality operated completely through domains of emotion regulation (ß= -0.054, 95% CI: -0.08 to -0.03), whereas the adverse effects of negative affect exhibited both direct (ß= 0.142, 95% CI: 0.06 to 0.23) and indirect (ß= 0.124, 95% CI: 0.08 to 0.16) effects on poor sleep. Negative affect was associated with poor sleep quality via two pathways-it directly influenced sleep quality and it indirectly influenced sleep quality among women experiencing difficulties in emotion regulation. CONCLUSIONS: Therapies targeting improvement and maintenance of healthy emotion regulation domains, while delineating the positive affect state from the negative affect state, may lessen the burden of poor sleep quality among low-income women.

Colorectal polyp prevention by daily aspirin use is abrogated among active smokers.

PURPOSE: Based on suggestive findings from a recent study of high-risk Japanese patients, we sought to determine whether the risk of colorectal polyps associated with smoking may be modified by daily use of aspirin in an analysis of a large US screening population. METHODS: This is a cross-sectional study of 2,918 consecutive colonoscopy patients at a university hospital over a 30-month period. Data were abstracted from electronic medical records. Multivariate models of polyp counts were used to examine the competing risks of smoking and aspirin use. Models were further stratified by polyp location (proximal vs. distal) and pathologic subtype (dysplastic vs. serrated). RESULTS: Incidental rate of polyps was higher among active smokers [incidence rate ratio (IRR) 1.72; 95 % confidence interval (CI) 1.46-2.02] and lower among daily aspirin users (IRR 0.73; 95 % CI 0.61-0.86) compared to those who used neither. Smoking interacts significantly with aspirin use resulting in loss of aspirin protection (IRR 1.69; 95 % CI 1.28-2.24). Stratified analyses demonstrate that aspirin specifically reduces the risk of traditional dysplastic adenomas (IRR 0.72; 95 % CI 0.61-0.86) not serrated/hyperplastic polyps (IRR 0.92; 95 % CI 0.72-1.17) and that the modification of aspirin protection by smoking is primarily observed within the distal colorectum (p < 0.03). CONCLUSIONS: We report for the first time, in a typical risk US clinical population, a lack of protective association of aspirin for polyps among active smokers. Future prospective studies are recommended to confirm this mitigating effect in order to improve the precision of the growing evidence base about the chemopreventive benefit of aspirin in colorectal cancer.

Circadian Modulation of 8-Oxoguanine DNA Damage Repair.

The DNA base excision repair pathway is the main system involved in the removal of oxidative damage to DNA such as 8-Oxoguanine (8-oxoG) primarily via the 8-Oxoguanine DNA glycosylase (OGG1). Our goal was to investigate whether the repair of 8-oxoG DNA damage follow a circadian rhythm. In a group of 15 healthy volunteers, we found a daily variation of Ogg1 expression and activity with higher levels in the morning compared to the evening hours. Consistent with this, we also found lower levels of 8-oxoG in morning hours compared to those in the evening hours. Lymphocytes exposed to oxidative damage to DNA at 8:00 AM display lower accumulation of 8-oxoG than lymphocytes exposed at 8:00 PM. Furthermore, altered levels of Ogg1 expression were also observed in a group of shift workers experiencing a deregulation of circadian clock genes compared to a control group. Moreover, BMAL1 knockdown fibroblasts with a deregulated molecular clock showed an abolishment of circadian variation of Ogg1 expression and an increase of OGG1 activity. Our results suggest that the circadian modulation of 8-oxoG DNA damage repair, according to a variation of Ogg1 expression, could render humans less susceptible to accumulate 8-oxoG DNA damage in the morning hours.

Electric light, particularly at night, disrupts human circadian rhythmicity: is that a problem?

Over the past 3 billion years, an endogenous circadian rhythmicity has developed in almost all life forms in which daily oscillations in physiology occur. This allows for anticipation of sunrise and sunset. This physiological rhythmicity is kept at precisely 24 h by the daily cycle of sunlight and dark. However, since the introduction of electric lighting, there has been inadequate light during the day inside buildings for a robust resetting of the human endogenous circadian rhythmicity, and too much light at night for a true dark to be detected; this results in circadian disruption and alters sleep/wake cycle, core body temperature, hormone regulation and release, and patterns of gene expression throughout the body. The question is the extent to which circadian disruption compromises human health, and can account for a portion of the modern pandemics of breast and prostate cancers, obesity, diabetes and depression. As societies modernize (i.e. electrify) these conditions increase in prevalence. There are a number of promising leads on putative mechanisms, and epidemiological findings supporting an aetiologic role for electric lighting in disease causation. These include melatonin suppression, circadian gene expression, and connection of circadian rhythmicity to metabolism in part affected by haem iron intake and distribution.

Sleep Quality Among Low-Income Young Women in Southeast Texas Predicts Changes in Perceived Stress Through Hurricane Ike.

STUDY OBJECTIVES: To document the time course of perceived stress among women through the period of a natural disaster, to determine the effect of sleep quality on this time course, and to identify risk factors that predict higher levels of perceived stress. DESIGN: Longitudinal study from 2006-2012. SETTING: Community-based family planning clinics in southeast Texas. PARTICIPANTS: There were 296 women aged 18-31 y who experienced Hurricane Ike, September 2008. MEASUREMENTS AND RESULTS: Cohen Perceived Stress Scale (PSS) was administered every 2 mo from 6 mo before to 12 mo after Hurricane Ike. Sleep quality was assessed 1 mo after Hurricane Ike using the Pittsburg Sleep Quality Index (PSQI). Good sleep was defined as a PSQI summary score < 5, and poor sleep as a score ≥ 5. Hurricane Ike stressors (e.g., property damage, subjective stressors) and pre-Ike lifetime major life events and emotional health (e.g., emotional dysregulation, self-control) were also assessed. RESULTS: Over the entire period of 18 mo (6 mo before and 12 mo after the hurricane), perceived stress was significantly higher among poor sleepers compared to good sleepers, and only good sleepers showed a significant decrease in perceived stress after Hurricane Ike. In addition, a higher level of perceived stress was positively associated with greater Ike damage among poor sleepers, whereas this correlation was not observed among good sleepers. In the final multivariate longitudinal model, Ike-related subjective stressors as well as baseline major life events and emotional dysregulation among poor sleepers predicted higher levels of perceived stress over time; among good sleepers, additional factors such as lower levels of self-control and having a history of a psychiatric disorder also predicted higher levels of perceived stress. CONCLUSIONS: Sleep quality after Hurricane Ike, an intense natural disaster producing substantial damage, impacted changes in perceived stress over time. Our findings suggest the possibility that providing victims of disasters with effective interventions to improve sleep quality could help to reduce their perceived stress over time.

Adverse events in cancer patients with sickle cell trait or disease: case reports.

PURPOSE: Given the relatively high prevalence of sickle cell trait and disease among African Americans and established racial disparities in cancer outcomes, we reviewed the literature regarding adverse events in cancer patients with these hematologic genotypes. Erythrocyte sickling can result from extreme hypoxia and other physiologic stressors, as might occur during cancer therapy. Further, tumoral hypoxia, a poor prognostic and predictive factor, could lead to a cycle of local sickling and increased hypoxia. METHODS: A search of PubMed produced 150 publications, most of which were excluded because of incidental relevance. Eleven case reports of patients diagnosed from 1993 to 2013 were reviewed. RESULTS: Two reports of patients with sickle cell trait describe an abundance of sickled erythrocytes within tumors, and a third report describes sickling-related events requiring multiday hospitalization. Eight reports of patients with sickle cell disease delineated multiorgan failure, vaso-occlusive crises, and rapid renal deterioration. Hypothesized triggers are delayed clearance of anticancer agents attributable to baseline kidney damage, activation of vasoadherent neutrophils from treatment to counter chemotherapy-induced neutropenia, hypoxia from general anesthesia, and intratumoral hypoxia. CONCLUSION: Clinical implications include pretreatment genotyping for prophylaxis, dose adjustment, and enhanced patient monitoring. With the current lack of high-quality evidence, however, the scope of poor outcomes remains unknown.