A different methylation profile of circadian genes promoter in breast cancer patients according to clinicopathological features

ABSTRACT

One of the supposed mechanisms that may lead to breast cancer (BC) is an alteration of circadian gene expression and DNA methylation. We undertook an integrated approach to identify methylation pattern of core circadian promoter regions in BC patients with regard to clinical features. We performed a quantitative methylation-specific real-time PCR analysis of a promoter methylation profile in 107 breast tumor and matched non-tumor tissues. A panel of circadian genes CLOCK, BMAL1, PERIOD (PER1, 2, 3), CRYPTOCHROME (CRY1, 2) and TIMELESS as well as their association with clinicopathological characteristics were included in the analysis. Three out of the eight analyzed genes exhibited marked hypermethylation (PER1, 2, 3), whereas CLOCK, BMAL1, CRY2 showed significantly lower promoter CpG methylation in the BC tissues when compared to the non-tumor tissues. Among variously methylated genes we found an association between the elevated methylation level of PERs promoter region and molecular subtypes, histological subtypes and tumor grading of BC. Methylation status may be associated with a gene expression level of circadian genes in BC patients. An aberrant methylation pattern in circadian genes in BC may provide information that could be used as novel biomarkers in clinics and molecular epidemiology as well as play an important role in BC etiology.     

Melatonin Entrains Free‐running Blind People According to a Physiological Dose‐response Curve

The specific circadian role proposed for endogenous melatonin production was based on a study of sighted people who took low pharmacological doses (500 µg) of this chemical signal for the “biological night”: the magnitude and direction of the induced phase shifts were dependent on what time of day exogenous melatonin was administered and were described by a phase‐response curve that turned out to be the opposite of that for light. We now report that lower (physiological) doses of up to 300 µg can entrain (synchronize) free‐running circadian rhythms of 10 totally blind subjects that would otherwise drift later each day. The resulting log‐linear dose‐response curve in the physiological range adds support for a circadian function of endogenous melatonin in humans. Efficacy of exogenous doses in the physiological range are of clinical significance for totally blind people who will need to take melatonin daily over their entire lifetimes in order to remain entrained to the 24 h day. Left untreated, their free‐running endocrine, metabolic, behavioral, and sleep/wake cycles can be almost as burdensome as not having vision.     

Small Bowel and Plasma Gastrin Rhythms in Cats

The purpose of this experiment was to study the possible role of the gastric antrum and small bowel in the rhythm(s) of plasma gastrin. The cat was used as the laboratory animal. Three groups of cats were provided with a gastric fistula for the study of gastric acid and plasma gastrin rhythms. The first group (N = 7) served as controls. A second group (N = 3) was antrectomized and later subjected to a 80% small bowel resection. Gastric acid secretions were collected every 30 min from 0800 to 2400. Blood samples for determination of gastrin were drawn every 2hr from 0800 to 2400. In control animals a circadian (i.e.<24hr) and 3 ultradian (i.e.<24 hr) rhythms were detected for acid output. In the antrectomized cats, circadian and ultradian rhythms were documented. After small bowel resection circadian and ultradian rhythms in gastric acid secretion were observed. For plasma gastrin, circadian and ultradian rhythms were found in the control cats. In the antrectomized cats no rhythms were observed. After small bowel resection an ultradian rhythm reappeared in these antrectomized cats. Removal of the antrum in the cat induces disappearance of circadian and ultradian rhythms of plasma gastrin but fails to modify the acid rhythms. Small bowel resection results in the reappearance of an ultradian rhythm for plasma gastrin and a shift in acrophase for the circadian rhythm in acid secretion.     

Twice Daily Melatonin Peaks in Siberian but not Syrian Hamsters under 24 h Light:Dark:Light:Dark Cycles

The daily pattern of blood-borne melatonin varies seasonally under the control of a multi-oscillator circadian pacemaker. Here we examine patterns of melatonin secretion and locomotor activity in Siberian and Syrian hamsters entrained to bimodal LDLD8:4:8:4 and LD20:4 lighting schedules that facilitate novel temporal arrangements of component circadian oscillators. Under LDLD, both species robustly bifurcated wheel-running activity in distinct day scotophase (DS) and night scotophase (NS) bouts. Siberian hamsters displayed significant melatonin increases during each scotophase in LDLD, and in the single daily scotophase of LD20:4. The bimodal melatonin secretion pattern persisted in acutely extended 16 h scotophases. Syrian hamsters, in contrast, showed no significant increases in plasma melatonin during either scotophase of LDLD8:4:8:4 or in LD20:4. In this species, detectable levels were observed only when the DS of LDLD was acutely extended to yield 16 h of darkness. Established species differences in the phase lag of nocturnal melatonin secretion relative to activity onset may underlie the above contrast: In non-bifurcated entrainment to 24 h LD cycles, Siberian hamsters show increased melatonin secretion within ～2 h after activity onset, whereas in Syrian hamsters, detectable melatonin secretion phase lags activity onset and the L/D transition by at least 4?h. The present results provide new evidence indicating multi-oscillator regulation of the waveform of melatonin secretion, specifically, the circadian control of the onset, offset and duration of nocturnal secretion.     

Interrelationships between distinct circadian manifestations of possible bruxism,perceived stress,chronotype and social jetlag in a population of undergraduate students

ABSTRACT

This study investigates the recently hypothesized association between distinct circadian manifestations of possible bruxism in subjects with different chronotype profiles, social jetlag and levels of perceived stress. A cross-sectional study was performed by surveying dental students’ of Lithuanian University of Health Sciences. A survey instrument was designed and pilot tested for reliability and validity prior to full-scale administration. The instrument consisted of four sections: socio-demographic questions, bruxism-related items, the Perceived Stress Scale and the Munich ChronoType Questionnaire. The study included 228 students (82.5% females; mean age 22.67 ± 2.27). Awake grinding was significantly associated with later chronotype values (p = 0,039). Despite the lack of significance, binary regression models demonstrated that students with later chronotypes report higher rates of possible bruxism, especially as far as awake grinding (p = .170; OR = 1.89) and sleep grinding (p = .140; OR = 1.60) are concerned. There were no significant associations between perceived stress, social jetlag and bruxism. The scores of perceived stress did not correlate with chronotype values, although a high positive correlation was found between chronotype and social jetlag (r = 0.516, p = .000). It can be concluded that later chronotypes increase the odds for self-reported bruxism, and are significantly associated with higher rates of awake grinding and social jetlag. No interrelationships were found between perceived stress, possible bruxism and social jetlag.     

Circadian Time Organization of Professional Firemen: Desynchronization—Tau Differing from 24.0 Hours—Documented by Longitudinal Self-assessment of 16 Variables

We investigated the circadian synchronization/desynchronization (by field-study assessment of differences in period, τ, of 16 coexisting and well-documented rhythms) of 30 healthy firemen (FM) exposed to irregular, difficult, and stressful nocturnal work hours who demonstrated excellent clinical tolerance (allochronism). Three groups of FM were studied (A?=?12 FM on 24-h duty at the fire station; B?=?9 FM on 24-h duty at the emergency call center; C?=?9 day-shift administrative FM) of mostly comparable average age, body mass index, career duration, chronotype—morningness/eveningness, and trait of field dependence/independence. The self-assessed 16 circadian rhythms were (i) physiological ones of sleep-wake (sleep log), activity-rest (actography), body temperature (internal transmitter pill probe), right- and left-hand grip strength (hand dynamometer), systolic and diastolic blood pressure (BP) plus heart rate (ambulatory BP monitoring device); (ii) psychological ones (visual analog self-rating scales) of sleepiness, fatigue, fitness for work, and capacity to cope with aggressive social behavior; and (iii) cognitive ones of eye-hand skill and letter cancellation, entailing performance speed (tasks completed/unit time) and accuracy (errors). Data (4–6 time points/24?h; 2 591 480 values in total) were gathered continuously throughout two 8-d spans, one in winter 2010–2011 and one in summer 2011. Each of the resulting 938 unequal-interval time series was analyzed by a special power spectrum analysis to objectively determine the prominent τ. The desynchronization ratio (DR: number of study variables with τ?=?24.0?h/number of study variables?×?100) served to ascertain the strength/weakness of each rhythm per individual, group, and season. The field study confirmed, independent of group and season, coexistence of rather strong and weak circadian oscillators. Interindividual differences in DR were detected between groups and seasons (χ², correlation tests, analysis of variance [ANOVA]). Moreover, in each group, both in winter and summer, a normal distribution was observed in the number of FM with rhythms with τ?=?24.0?h, e.g., ranging from 5/16 (large desynchronization) to 16/16 (no desynchronization). Such a normal distribution with intraindividual stability over time (i.e., seasons) is consistent with the hypothesis of an inherited origin of a differential propensity to circadian desynchronization and which is supported by the distribution of τs in winter and summer following the Dian-Circadian Genetic Model, i.e., with τ?=?24.0?h, τ?=?24.0?h?+?n(0.8?h), and τ?=?24.0?h???n(0.8?h).     

Morningness–eveningness and treatment response in major depressive disorder

In a large, prospective, 8-week open study of 721 outpatients receiving agomelatine treatment for a current major depressive episode (MDE), morningness–eveningness (Composite Scale of Morningness) was assessed before and after treatment to investigate possible changes in morningness–eveningness after treatment and evaluate whether morningness–eveningness at baseline predicted treatment response. A change towards morningness was observed after treatment. This change was greater in responders than non-responders. Moreover, being a morning type at baseline was an independent predictor of response to treatment. Once thought to be a trait variable, morningness–eveningness is a potential treatment target that should be systematically assessed in MDE patients.     

Reviewing the Psychometric Properties of Contemporary Circadian Typology Measures

The accurate measurement of circadian typology (CT) is critical because the construct has implications for a number of health disorders. In this review, we focus on the evidence to support the reliability and validity of the more commonly used CT scales: the Morningness-Eveningness Questionnaire (MEQ), reduced Morningness-Eveningness Questionnaire (rMEQ), the Composite Scale of Morningness (CSM), and the Preferences Scale (PS). In addition, we also consider the Munich ChronoType Questionnaire (MCTQ). In terms of reliability, the MEQ, CSM, and PS consistently report high levels of reliability (>0.80), whereas the reliability of the rMEQ is satisfactory. The stability of these scales is sound at follow-up periods up to 13 mos. The MCTQ is not a scale; therefore, its reliability cannot be assessed. Although it is possible to determine the stability of the MCTQ, these data are yet to be reported. Validity must be given equal weight in assessing the measurement properties of CT instruments. Most commonly reported is convergent and construct validity. The MEQ, rMEQ, and CSM are highly correlated and this is to be expected, given that these scales share common items. The level of agreement between the MCTQ and the MEQ is satisfactory, but the correlation between these two constructs decreases in line with the number of “corrections” applied to the MCTQ. The interesting question is whether CT is best represented by a psychological preference for behavior or by using a biomarker such as sleep midpoint. Good-quality subjective and objective data suggest adequate construct validity for each of the CT instruments, but a major limitation of this literature is studies that assess the predictive validity of these instruments. We make a number of recommendations with the aim of advancing science. Future studies need to (1) focus on collecting data from representative samples that consider a number of environmental factors; (2) employ longitudinal designs to allow the predictive validity of CT measures to be assessed and preferably make use of objective data; (3) employ contemporary statistical approaches, including structural equation modeling and item-response models; and (4) provide better information concerning sample selection and a rationale for choosing cutoff points.     

Clocks for the city: circadian differences between forest and city songbirds

To keep pace with progressing urbanization organisms must cope with extensive habitat change. Anthropogenic light and noise have modified differences between day and night, and may thereby interfere with circadian clocks. Urbanized species, such as birds, are known to advance their activity to early morning and night hours. We hypothesized that such modified activity patterns are reflected by properties of the endogenous circadian clock. Using automatic radio-telemetry, we tested this idea by comparing activity patterns of free-living forest and city European blackbirds (Turdus merula). We then recaptured the same individuals and recorded their activity under constant conditions. City birds started their activity earlier and had faster but less robust circadian oscillation of locomotor activity than forest conspecifics. Circadian period length predicted start of activity in the field, and this relationship was mainly explained by fast-paced and early-rising city birds. Although based on only two populations, our findings point to links between city life, chronotype and circadian phenotype in songbirds, and potentially in other organisms that colonize urban habitats, and highlight that urban environments can significantly modify biologically important rhythms in wild organisms.