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1.  Dominant-Negative CK2α Induces Potent Effects on Circadian Rhythmicity  
PLoS Genetics  2008;4(1):e12.
Circadian clocks organize the precise timing of cellular and behavioral events. In Drosophila, circadian clocks consist of negative feedback loops in which the clock component PERIOD (PER) represses its own transcription. PER phosphorylation is a critical step in timing the onset and termination of this feedback. The protein kinase CK2 has been linked to circadian timing, but the importance of this contribution is unclear; it is not certain where and when CK2 acts to regulate circadian rhythms. To determine its temporal and spatial functions, a dominant negative mutant of the catalytic alpha subunit, CK2αTik, was targeted to circadian neurons. Behaviorally, CK2αTik induces severe period lengthening (∼33 h), greater than nearly all known circadian mutant alleles, and abolishes detectable free-running behavioral rhythmicity at high levels of expression. CK2αTik, when targeted to a subset of pacemaker neurons, generates period splitting, resulting in flies exhibiting both long and near 24-h periods. These behavioral effects are evident even when CK2αTik expression is induced only during adulthood, implicating an acute role for CK2α function in circadian rhythms. CK2αTik expression results in reduced PER phosphorylation, delayed nuclear entry, and dampened cycling with elevated trough levels of PER. Heightened trough levels of per transcript accompany increased protein levels, suggesting that CK2αTik disturbs negative feedback of PER on its own transcription. Taken together, these in vivo data implicate a central role of CK2α function in timing PER negative feedback in adult circadian neurons.
Author Summary
The molecular mechanism that governs organization of physiology and behavior into 24-h rhythms is a conserved transcriptional feedback process that is strikingly similar across distinct phyla. Notably, cyclic phosphorylation of negative feedback regulators is critical to time molecular rhythms. Indeed, mutation of a putative phosphoacceptor site in the human PERIOD2 gene, a key negative regulator, is associated with Advanced Sleep Phase Syndrome. This study reveals a critical role for the protein kinase CK2 for setting the period of behavioral and molecular oscillations in Drosophila. Circadian phenotypes due to CK2 disruption are due to a direct requirement in adult circadian pacemakers. These findings further demonstrate that CK2 modification of the negative feedback regulator PERIOD alters its cyclical phosphorylation, protein abundance, nuclear translocation, and transcriptional repression activity. These studies place CK2 as a central kinase in circadian timing.
PMCID: PMC2211540  PMID: 18208335
2.  The relationship between fatigue and light exposure during chemotherapy 
Fatigue is one of the most common and distressing complaints among cancer patients, not only during radiation and chemotherapy, but also for months to years after the completion of treatment. Fatigue interferes with patients’ daily lives, reduces their quality of life, and is often a significant reason why patients discontinue treatment. We hypothesized that some of the fatigue may be related to disrupted circadian rhythms and low light exposure. The main objective of this study therefore was to investigate the association between fatigue and light exposure among patients with breast cancer.
As part of a larger, ongoing prospective study on fatigue, sleep, and circadian rhythms in patients with breast cancer, an analysis of 63 women newly diagnosed with stage I–IIIA breast cancer and scheduled to receive four cycles of adjuvant or neoadjuvant anthracycline-based chemotherapy was conducted. Data were collected before and during weeks 1, 2, and 3 of cycle 1 and cycle 4. Fatigue was assessed using the Short Form of Multidimensional Fatigue Symptom Inventory. Light exposure was recorded with a wrist actigraph.
There were significant correlations between fatigue levels and light exposure (r=−0.28 to −0.45) within both cycle 1 and cycle 4, such that higher levels of fatigue were associated with less light exposure. There were also significant correlations between changes in light exposure and changes in fatigue within the first 2 weeks of each cycle (r=−0.28 to −0.52).
Increased fatigue was significantly correlated with decreased light exposure among patients with breast cancer. Although the cause and effect of exacerbated fatigue and decreased light exposure cannot be confirmed by the current study, and lower light exposure may just in part be due to the fatigued patients spending less time outdoors in bright light, two hypotheses are proposed about the mechanisms by which light may alleviate the fatigue of patients with breast cancer. These results suggest the need for prospective intervention studies of light therapy for breast-cancer-related fatigue.
PMCID: PMC1599705  PMID: 15864659
Breast cancer; Fatigue; Light; Chemotherapy
3.  Chronic Interferon-Alpha Administration Disrupts Sleep Continuity and Depth in Patients with Hepatitis C: Association with Fatigue, Motor Slowing and Increased Evening Cortisol 
Biological psychiatry  2010;68(10):942-949.
Consequences of chronic exposure to cytokines of the innate immune system on sleep in humans and the association of cytokine-induced sleep alterations with behavior, motor performance and cortisol secretion are unknown.
Thirty-one patients with hepatitis C without pre-existing sleep disorders underwent nighttime polysomnography, daytime multiple sleep latency testing, behavioral assessments, neuropsychological testing and serial blood sampling at baseline and after ~12 weeks of either treatment with the innate immune cytokine, interferon (IFN)-alpha (n=19) or no treatment (n=12). Fatigue and sleepiness were assessed using the Multidimensional Fatigue Inventory and Epworth Sleepiness Scale.
IFN-alpha administration led to significant increases in wake after sleep onset and significant decreases in Stage 3/4 sleep and sleep efficiency. REM latency and Stage 2 sleep were significantly increased during IFN-alpha treatment. Decreases in Stage 3/4 sleep and increases in REM latency were associated with increases in fatigue, whereas decreases in sleep efficiency were associated with reduced motor speed. Increased wake after sleep onset was associated with increased evening plasma cortisol. Despite IFN-alpha-induced increases in fatigue, daytime sleepiness did not increase. In fact, IFN-alpha-treated patients exhibited decreased propensity to fall asleep during daytime nap opportunities.
Chronic exposure to an innate immune cytokine reduced sleep continuity and depth, and induced a sleep pattern consistent with insomnia and hyperarousal. These data suggest that innate immune cytokines may provide a mechanistic link between disorders associated with chronic inflammation including medical and/or psychiatric illnesses and insomnia, which in turn is associated with fatigue, motor slowing and altered cortisol.
PMCID: PMC2937202  PMID: 20537611
Sleep; insomnia; hyperarousal; polysomnography; fatigue; depression; interferon-alpha; hepatitis C; neuropsychology; cortisol; cytokines
4.  Circadian function in patients with advanced non-small-cell lung cancer 
British Journal of Cancer  2005;93(11):1202-1208.
This study aimed to evaluate whether patients with advanced non-small-cell lung cancer experience disrupted rest–activity daily rhythms, poor sleep quality, weakness, and maintain attributes that are linked to circadian function such as fatigue. This report describes the rest–activity patterns of 33 non-small-cell lung cancer patients who participated in a randomised clinical trial evaluating the benefits of melatonin. Data are reported on circadian function, health-related quality of life (QoL), subjective sleep quality, and anxiety/depression levels prior to randomisation and treatment. Actigraphy data, an objective measure of circadian function, demonstrated that patients' rest–activity circadian function differs significantly from control subjects. Our patients reported poor sleep quality and high levels of fatigue. Ferrans and Powers QoL Index instrument found a high level of dissatisfaction with health-related QoL. Data from the European Organization for Research and Treatment for Cancer reported poor capacity to fulfil the activities of daily living. Patients studied in the hospital during or near chemotherapy had significantly more abnormal circadian function than those studied in the ambulatory setting. Our data indicate that measurement of circadian sleep/activity dynamics should be accomplished in the outpatient/home setting for a minimum of 4–7 circadian cycles to assure that they are most representative of the patients' true condition. We conclude that the daily sleep/activity patterns of patients with advanced lung cancer are disturbed. These are accompanied by marked disruption of QoL and function. These data argue for investigating how much of this poor functioning and QoL are actually caused by this circadian disruption, and, whether behavioural, light-based, and or pharmacologic strategies to correct the circadian/sleep activity patterns can improve function and QoL.
PMCID: PMC2361523  PMID: 16265345
circadian function; non-small-cell lung cancer; rest/activity function; sleep quality; quality of life; actigraphy
5.  The effect of MELatOnin on Depression, anxietY, cognitive function and sleep disturbances in patients with breast cancer. The MELODY trial: protocol for a randomised, placebo-controlled, double-blinded trial 
BMJ Open  2012;2(1):e000647.
Breast cancer represents about one-third of all cancer diagnoses and accounts for about 15% of cancer deaths in women. Many of these patients experience depression, anxiety, sleep disturbances and cognitive dysfunction. This may adversely affect quality of life and also contribute to morbidity and mortality. Melatonin is a regulatory circadian hormone having, among others, a hypnotic and an antidepressive effect. It has very low toxicity and very few adverse effects compared with the more commonly used antidepressants and hypnotics.
Methods and analysis
The objective of this double-blind, randomised, placebo-controlled trial is to investigate whether treatment with oral melatonin has a prophylactic or ameliorating effect on depressive symptoms, anxiety, sleep disturbances and cognitive dysfunction in women with breast cancer. Furthermore, the authors will examine whether a specific clock-gene, PER3, is correlated with an increased risk of depressive symptoms, sleep disturbances or cognitive dysfunction. The MELODY trial is a prospective double-blinded, randomised, placebo-controlled trial in which the authors intend to include 260 patients. The primary outcome is depressive symptoms measured by the Major Depression Inventory. The secondary outcomes are anxiety measured by a Visual Analogue Scale, total sleep time, sleep efficiency, sleep latency and periods awake measured by actigraphy and changes in cognitive function measured by a neuropsychological test battery. Tertiary outcomes are fatigue, pain, well-being and sleep quality/quantity measured by Visual Analogue Scale and sleep diary and sleepiness measured by the Karolinska Sleepiness Scale. The PER3 genotype is also to be determined in blood samples.
Article summary
This is a protocol article on the MELODY trial. The objective of this double-blind randomized, placebo-controlled trial is to investigate whether daily treatment with 6 mg oral melatonin has a prophylactic or ameliorating effect on depressive symptoms, anxiety, sleep disturbances and cognitive dysfunction in women with breast cancer. Furthermore to examine whether a specific clock-gene PER3 is correlated with an increased risk of depressive symptoms, sleep disturbances or cognitive dysfunction.
PMCID: PMC3278491  PMID: 22240653
6.  Predictors of fatigue in obstructive sleep apnea 
The objective of this study was to determine potential inflammatory predictors of fatigue in obstructive sleep apnea (OSA).
Materials and methods
Fifty-six women and men untreated OSA patients had their sleep monitored with polysomnography. Fatigue was assessed by the Multidimensional Fatigue Symptom Inventory-Short Form. Depressed mood was assessed by the Center for Epidemiologic Studies-Depression Scale. Blood was drawn to assess circulating levels of Interleukin-6 (IL-6) and soluble tumor necrosis factor receptor I (sTNF-RI). Age, gender, body mass index (BMI), blood pressure, OSA severity, depressed mood, and inflammatory biomarkers were entered into a hierarchical multiple linear regression analysis predicting self-reported fatigue.
Approximately 42% of the patients reported significant amounts of fatigue. Higher BMI (p=0.014), greater depressed mood (p=0.004), and higher sTNF-RI levels (p=0.033) were independent predictors of fatigue in the final model (full model R2=.571; p=.003). Age, gender, blood pressure and apnea severity were unrelated to fatigue.
The findings suggest that in addition to depressed mood, fatigue in OSA may be associated with increased body weight and elevated levels of the proinflammatory cytokine receptor sTNF-RI. The findings support a linkage between the widely reported fatigue in OSA and a sleep-related component of inflammation.
PMCID: PMC2633300  PMID: 18516635
Obstructive sleep apnea; Fatigue; Cytokines; Body mass index; Depression
7.  Circadian Clock Genes Per1 and Per2 Regulate the Response of Metabolism-Associated Transcripts to Sleep Disruption 
PLoS ONE  2012;7(12):e52983.
Human and animal studies demonstrate that short sleep or poor sleep quality, e.g. in night shift workers, promote the development of obesity and diabetes. Effects of sleep disruption on glucose homeostasis and liver physiology are well documented. However, changes in adipokine levels after sleep disruption suggest that adipocytes might be another important peripheral target of sleep. Circadian clocks regulate metabolic homeostasis and clock disruption can result in obesity and the metabolic syndrome. The finding that sleep and clock disruption have very similar metabolic effects prompted us to ask whether the circadian clock machinery may mediate the metabolic consequences of sleep disruption. To test this we analyzed energy homeostasis and adipocyte transcriptome regulation in a mouse model of shift work, in which we prevented mice from sleeping during the first six hours of their normal inactive phase for five consecutive days (timed sleep restriction – TSR). We compared the effects of TSR between wild-type and Per1/2 double mutant mice with the prediction that the absence of a circadian clock in Per1/2 mutants would result in a blunted metabolic response to TSR. In wild-types, TSR induces significant transcriptional reprogramming of white adipose tissue, suggestive of increased lipogenesis, together with increased secretion of the adipokine leptin and increased food intake, hallmarks of obesity and associated leptin resistance. Some of these changes persist for at least one week after the end of TSR, indicating that even short episodes of sleep disruption can induce prolonged physiological impairments. In contrast, Per1/2 deficient mice show blunted effects of TSR on food intake, leptin levels and adipose transcription. We conclude that the absence of a functional clock in Per1/2 double mutants protects these mice from TSR-induced metabolic reprogramming, suggesting a role of the circadian timing system in regulating the physiological effects of sleep disruption.
PMCID: PMC3532432  PMID: 23285241
8.  Pre-treatment Symptom Cluster in Breast Cancer Patients is Associated with Worse Sleep, Fatigue and Depression during Chemotherapy 
Psycho-oncology  2009;18(2):187-194.
The concept of symptom clusters is relatively new in cancer patients' symptom management. This study, which spanned four cycles of chemotherapy, combined three commonly seen pre-treatment symptoms in cancer patients (i.e., sleep disturbances, fatigue and depression) into one symptom cluster, to explore the associations between pre-treatment cluster categories and longitudinal profiles of these same symptoms during chemotherapy.
This was a prospective study. Seventy-six women with newly diagnosed stage I–III breast cancer, scheduled to receive at least four cycles of adjuvant or neoadjuvant anthracycline-based chemotherapy participated. Data were collected at seven time points before and during treatment. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). Fatigue was measured with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). Depressive symptoms were measured with the Center of Epidemiological Studies-Depression (CES-D). Patients were divided into three groups based on the number of symptoms they experienced before the start of chemotherapy (i.e., no symptoms, 1–2 symptoms or all three symptoms) and a symptom cluster index (SCI) was computed.
All women reported worse sleep, more fatigue and more depressive symptoms during treatment compared to baseline (all p's <0.01); however, those women with a higher symptom cluster index (i.e., more symptoms pre-treatment) continued to experience worse symptoms during treatment compared to those who began with fewer symptoms (all p's <0.01).
A higher clinically relevant-based pre-treatment symptom cluster was associated with more sleep disturbances, greater fatigue and more depressive symptoms during chemotherapy. Specific interventions for these pre-treatment symptoms may improve the frequency and severity of these same symptoms during chemotherapy, when they are most severe and most disruptive to quality of life.
PMCID: PMC2762479  PMID: 18677716
breast cancer; symptom cluster; sleep disturbances; fatigue; depression
9.  Serotonin and Corticosterone Rhythms in Mice Exposed to Cigarette Smoke and in Patients with COPD: Implication for COPD-Associated Neuropathogenesis 
PLoS ONE  2014;9(2):e87999.
The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD.
PMCID: PMC3919731  PMID: 24520342
10.  The role of circadian clock genes in mental disorders 
The study of molecular clock mechanisms in psychiatric disorders is gaining significant interest due to data suggesting that a misalignment between the endogenous circadian system and the sleep-wake cycle might contribute to the clinical status of patients suffering from a variety of psychiatric disorders. Sleep disturbances in major depressive disorder (MDD) are characterized by increased sleep latency, poorer sleep efficiency, reduced latency to the first rapid eye movement (REM) sleep episode, and early-morning awakening, but there is little data to indicate a role of circadian clock genes in MDD. There is also relatively little information regarding the role of clock genes in anxiety. In contrast, a significant amount of evidence gathered in bipolar disorder (BPD) patients suggests a circadian rhythm disorder, namely an advanced circadian rhythm and state-dependent alterations of REM sleep latency. Most research on the role of clock genes in BPD has focused on polymorphisms of CLOCK, but the lithium target GSK3 may also play a significant role. A circadian phase shift is also theorized to contribute to the pathophysiology of winter seasonal affective disorder (SAD). Certain allelic combinations of NPAS2, PER3, and BMAL1 appear to contribute to the risk of SAD. In chronic shizophrenia, disturbances of sleep including insomnia and reduced sleep efficiency have been observed. Genetic studies have found associations with CLOCK, PER1, PER3, and TIMELESS. Sleep and circadian changes associated with dementia due to Alzheimer's disease suggest a functional change in the circadian master clock, which is supported by postmortem studies of clock gene expression in the brain.
PMCID: PMC3202489  PMID: 17969870
clock gene; mental disorder; mental health; major depressive disorder; bipolar affective disorder; seasonal affective disorder; schizophrenia; Alzheimer's disease; sleep-wake cycle; rest-activity cycle; single-nucleotide polymorphism
11.  Circadian rhythm sleep disorders in patients with multiple sclerosis and its association with fatigue: A case-control study 
Circadian rhythm sleep disorders are a presentation of sleep disorders in patients with multiple sclerosis (MS). This study aims to compare this problem in MS patients with healthy people and to determine its association with chronic fatigue in MS patients.
Materials and Methods:
A case-control study was performed on 120 MS patients and 60 healthy subjects matched for age and sex, in 2009 in MS Clinic Alzahra Hospital. Sleep quality, rhythm and fatigue severity were assessed using PSQI (Pittsburgh sleep quality index) and FSS (Fatigue severity Scale) questionnaires, respectively. Its reliability and validity has been confirmed in several studies (Cronbach's alpha = 0.83). This index has seven sections including patient's assessment of his/her sleep, sleep duration, efficacy of routine sleep, sleep disorders, use of hypnotic medication, and dysfunction in daily activities.
Circadian rhythm sleep disorder was more frequent in MS patients relative to healthy subjects (P: 0.002). It was higher in MS patients with severe fatigue relative to MS patients with mild fatigue (P: 0.05). Fatigue severity was 49.9 ± 8.2 and 22.5 ± 7.4 in the first and second group, respectively. PSQI index was 7.9 ± 4.5 in patients with severe fatigue and 5.9 ± 4.5 in patients with mild fatigue and 4.5 ± 2.4 in the control group (P: 0.0001).
Circadian rhythm sleep disorders are more frequent in MS patients and those with fatigue. Recognition and management of circadian rhythm sleep disorders in MS patients, especially those with fatigue may be helpful in improving care of these patients.
PMCID: PMC3743326  PMID: 23961292
Chronic fatigue; circadian rhythm sleep disorder; fatigue severity scale; multiple sclerosis; Pittsburg sleep quality index
12.  The relationship between fatigue and sleep in cancer patients: a review 
European journal of cancer care  2001;10(4):245-255.
Fatigue is a major complaint among cancer patients, yet it is unknown whether cancer-related fatigue experienced during the day relates to sleep/wake cycles or to the quality and quantity of sleep obtained at night. Although it is not well defined or well understood at present, cancer-related fatigue is generally regarded as a form of tiredness that does not improve following rest or sleep. Objectively recorded sleep and biological rhythms have not been well investigated in these patients, but it appears that most cancer patients may in fact not be getting a good night’s sleep. Evidence is accumulating that sleep is often disturbed in cancer patients, probably owing to a variety of causes. We posit that some degree of cancer-related fatigue experienced during the day may relate to sleep/wake cycles or to the quality and quantity of sleep obtained at night. Different components or dimensions of fatigue (physical, attentional/cognitive, emotional/affective, etc.) are probably associated in some way with disrupted sleep and desynchronized sleep/wake rhythms. These associations may change in measurable ways prior to treatment, during treatment and after treatment completion. In cancer patients, as in other medically ill patients, sleep that is inadequate or unrefreshing may be important not only to the expression of fatigue, but to the patients’ quality of life and their tolerance to treatment, and may influence the development of mood disorders and clinical depression. This review summarizes the state of the literature on fatigue, sleep and circadian rhythms.
PMCID: PMC2951731  PMID: 11806675
sleep; fatigue; cancer; circadian rhythms; chronotherapy
13.  Deregulated expression of circadian clock genes in gastric cancer 
BMC Gastroenterology  2014;14:67.
Gastric cancer (GC), an aggressive malignant tumor of the alimentary tract, is a leading cause of cancer-related death. Circadian rhythm exhibits a 24-hour variation in physiological processes and behavior, such as hormone levels, metabolism, gene expression, sleep and wakefulness, and appetite. Disruption of circadian rhythm has been associated with various cancers, including chronic myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, endometrial carcinoma, and breast cancer. However, the expression of circadian clock genes in GC remains unexplored.
In this study, the expression profiles of eight circadian clock genes (PER1, PER2, PER3, CRY1, CRY2, CKIϵ, CLOCK, and BMAL1) of cancerous and noncancerous tissues from 29 GC patients were investigated using real-time quantitative reverse-transcriptase polymerase chain reaction and validated through immunohistochemical analysis.
We found that PER2 was significantly up-regulated in cancer tissues (p < 0.005). Up-regulated CRY1 expression was significantly correlated with more advanced stages (stage III and IV) (p < 0.05).
Our results suggest deregulated expressions of circadian clock genes exist in GC and circadian rhythm disturbance may be associated with the development of GC.
PMCID: PMC3992139  PMID: 24708606
Gastric cancer; Circadian clock genes; Circadian rhythm
14.  Polymorphisms in the circadian expressed genes PER3 and ARNTL2 are associated with diurnal preference and GNβ3 with sleep measures 
Journal of Sleep Research  2014;23(5):595-604.
Sleep and circadian rhythms are intrinsically linked, with several sleep traits, including sleep timing and duration, influenced by both sleep homeostasis and the circadian phase. Genetic variation in several circadian genes has been associated with diurnal preference (preference in timing of sleep), although there has been limited research on whether they are associated with other sleep measurements. We investigated whether these genetic variations were associated with diurnal preference (Morningness–Eveningness Questionnaire) and various sleep measures, including: the global Pittsburgh Sleep Quality index score; sleep duration; and sleep latency and sleep quality. We genotyped 10 polymorphisms in genes with circadian expression in participants from the G1219 sample (n = 966), a British longitudinal population sample of young adults. We conducted linear regressions using dominant, additive and recessive models of inheritance to test for associations between these polymorphisms and the sleep measures. We found a significant association between diurnal preference and a polymorphism in period homologue 3 (PER3) (P < 0.005, recessive model) and a novel nominally significant association between diurnal preference and a polymorphism in aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) (P < 0.05, additive model). We found that a polymorphism in guanine nucleotide binding protein beta 3 (GNβ3) was associated significantly with global sleep quality (P < 0.005, recessive model), and that a rare polymorphism in period homologue 2 (PER2) was associated significantly with both sleep duration and quality (P < 0.0005, recessive model). These findings suggest that genes with circadian expression may play a role in regulating both the circadian clock and sleep homeostasis, and highlight the importance of further studies aimed at dissecting the specific roles that circadian genes play in these two interrelated but unique behaviours.
PMCID: PMC4320759  PMID: 24635757
circadian expressed genes; genetic association; single nucleotide polymorphisms; sleep duration; sleep quality
15.  A comparison of disrupted sleep patterns in women with cancer-related fatigue and postmenopausal women without cancer (Resubmission) 
Fatigue and disrupted sleep often coexist and both are prominent clinical problems in cancer affecting quality of life. Disrupted sleep patterns are likely related to cancer-related fatigue. The relationship needs further investigation. This study aimed to characterize and compare disrupted sleep patterns in fatigued breast cancer patients receiving chemotherapy with postmenopausal women without a history of cancer. Anxiety levels were also examined.
Data for this secondary analysis came from two studies. Global sleep quality and state anxiety were self-reported by 30 fatigued female breast cancer chemotherapy outpatients and 32 non-cancer postmenopausal women using Pittsburgh Sleep Quality Index (PSQI) and State-Trait Anxiety Inventory, respectively.
Fatigued breast cancer patients showed significant sleep difficulties, characterized by prolonged sleep onset latency (M= 54.3, SD= 49.2 minutes) and frequent nighttime awakenings, despite 40% of the patients using sleep medications three or more times a week. Compared to the non-cancer comparison group, fatigued patients reported significantly longer sleep latency (p=0.041), more use of sleep medications (p=0.006), and higher total PSQI scores (p=0.005). State anxiety levels did not differ between the two groups (p=0.88).
Sleep is disrupted in fatigued breast cancer women undergoing chemotherapy. Nearly all fatigued patients (97%) had trouble sleeping (global PSQI scores >5), indicating significant difficulties in overall sleep quality among those patients. Knowledge of the nature of sleep disruption among cancer patients may contribute to CRF symptom management leading to tailored interventions designed to improve sleep quality in cancer patients thereby managing fatigue and improving quality of life.
PMCID: PMC3117033  PMID: 21093372
symptom management; cancer-related fatigue; disrupted sleep patterns; breast cancer
16.  Fatigue in patients with COPD participating in a pulmonary rehabilitation program 
Fatigue is a distressing, complex, multidimensional sensation common in individuals with chronic obstructive pulmonary disease (COPD). While fatigue negatively impacts functional performance and quality of life, there has been little study of the fatigue that affects participants in pulmonary rehabilitation programs. The purpose of this study was to examine the emotional, behavioral, cognitive, and physical dimensions of fatigue and their relationships to dyspnea, mental health, sleep, and physiologic factors.
Patients and methods
A convenience sample of 42 pulmonary rehabilitation participants with COPD completed self-report questionnaires which measured dimensions of fatigue using the Multidimensional Fatigue Inventory, anxiety and depression using the Hospital Anxiety and Depression Scale, and sleep quality using the Pittsburgh Sleep Quality Index. Data on other clinical variables were abstracted from pulmonary rehabilitation program health records.
Almost all (95.3%) participants experienced high levels of physical fatigue. High levels of fatigue were also reported for the dimensions of reduced activity (88.1%), reduced motivation (83.3%), mental fatigue (69.9%), and general fatigue (54.5%). Close to half (42.9%) of participants reported symptoms of anxiety, while almost one quarter (21.4%) reported depressive symptoms. Age was related to the fatigue dimensions of reduced activity (ρ = 0.43, P < 0.01) and reduced motivation (ρ = 0.31, P < 0.05). Anxiety was related to reduced motivation (ρ = −0.47, P < 0.01). Fatigue was not associated with symptoms of depression, sleep quality, gender, supplemental oxygen use, smoking status, or Medical Research Council dyspnea scores.
Fatigue (particularly the physical and reduced motivation dimensions of fatigue) was experienced by almost all participants with COPD attending this pulmonary rehabilitation program. Fatigue affected greater proportions of participants than either anxiety or depression. The high prevalence of fatigue may impact on enrolment, participation, and attrition in pulmonary rehabilitation programs. Further investigation of the nature, correlates, and impact of fatigue in this population is required.
PMCID: PMC2962297  PMID: 21037955
COPD; fatigue; pulmonary rehabilitation; anxiety; depression; sleep quality
17.  Fatigue and Circadian Activity Rhythms in Breast Cancer Patients Before and After Chemotherapy: A Controlled Study 
Fatigue (Abingdon, Eng. Print)  2013;1(1-2):12-26.
Breast cancer (BC) patients often experience cancer-related fatigue (CRF) before, during, and after their chemotherapy. Circadian rhythms are 24-hour cycles of behavior and physiology that are generated by internal pacemakers and entrained by zeitgebers (e.g., light). A few studies have suggested a relationship between fatigue and circadian rhythms in some clinical populations.
One hundred and forty-eight women diagnosed with stage I-III breast cancer and scheduled to receive at least four cycles of adjuvant or neoadjuvant chemotherapy, and 61 controls (cancer-free healthy women) participated in this study. Data were collected before (Baseline) and after four cycles of chemotherapy (Cycle-4). Fatigue was assessed with the Short Form of Multidimensional Fatigue Symptom Inventory (MFSI-SF); circadian activity rhythm (CAR) was recorded with wrist actigraphy (six parameters included: amplitude, acrophase, mesor, up-mesor, down-mesor and F-statistic). A mixed model analysis was used to examine changes in fatigue and CAR parameters compared to controls, and to examine the longitudinal relationship between fatigue and CAR parameters in BC patients.
More severe CRF (total and subscale scores) and disrupted CAR (amplitude, mesor and F-statistic) were observed in BC patients compared to controls at both Baseline and Cycle-4 (all p's<0.05); BC patients also experienced more fatigue and decreased amplitude and mesor, as well as delayed up-mesor time at Cycle-4 compared to Baseline (all p's<0.05). The increased total MFSI-SF scores were significantly associated with decreased amplitude, mesor and F-statistic (all p's<0.006).
CRF exists and CAR is disrupted even before the start of chemotherapy. The significant relationship between CRF and CAR indicate possible underlying connections. Re-entraining the disturbed CAR using effective interventions such as bright light therapy might also improve CRF.
PMCID: PMC3568994  PMID: 23412418
breast cancer; fatigue; circadian activity rhythm; chemotherapy
18.  Impact of paroxetine on sleep problems in 426 cancer patients receiving chemotherapy: A trial from the University of Rochester Cancer Center Community Clinical Oncology Program 
Sleep medicine  2012;13(9):1184-1190.
Sleep problems are a frequent distressing symptom in cancer patients, yet little is known about their treatment. Sleep problems and depression frequently co-occur, leading healthcare professionals to treat depression with the expectation that sleep problems will also improve. The purpose of this study was to compare the effect of paroxetine to placebo on sleep problems via a secondary data analysis of a RCT designed to compare the effects of paroxetine to placebo on fatigue in cancer patients undergoing chemotherapy. A previously published report found a significant effect of paroxetine on depression in this cohort.
A total of 426 patients were randomized following Cycle 2 of chemotherapy to receive either 20 mg of paroxetine or placebo. Sleep problems were assessed using questions from the Hamilton Depression Inventory three times during chemotherapy.
A total of 217 patients received paroxetine and 209 received placebo. Significantly fewer patients taking paroxetine reported sleep problems compared to patients on placebo (Paroxetine 79% versus Placebo 88%; p < 0.05). These differences remained significant even after controlling for baseline sleep problems and depression (p < 0.05).
Paroxetine had a significant benefit on sleep problems in both depressed and non-depressed cancer patients. However, rates of sleep problems remained high even among those effectively treated for depression with paroxetine. There is a need to develop and deliver sleep-specific interventions to effectively treat sleep-related side effects of cancer treatments. These findings suggest that sleep problems and depression are prevalent and co-morbid. Cancer progression, its response to treatment, and overall patient survival are intricately linked to host factors, such as inflammatory response and circadian rhythms, including sleep/wake cycles. Sleep problems and depression are modifiable host factors that can influence inflammation and impact cancer progression and quality of life. Future research should focus on discovering the pathogenesis of sleep dysregulation and depression in cancer so that better treatment approaches can be developed to ameliorate these symptoms.
PMCID: PMC3664933  PMID: 22858235
19.  Arousal frequency is associated with increased fatigue in obstructive sleep apnea 
Fatigue is an important and often underemphasized symptom in patients with obstructive sleep apnea (OSA). Sleep fragmentation, i.e., arousals and disruptions in sleep architecture, is common in patients with OSA and may potentially contribute to their fatigue. We hypothesized that arousal frequency and changes in sleep architecture contribute to the fatigue experienced by patients with OSA.
Seventy-three patients with diagnosed but untreated OSA (AHI ≥ 15) were enrolled in this study. A baseline polysomnogram was obtained, and fatigue was measured with the Multidimensional Fatigue Symptom Inventory-short form (MFSI-sf). We evaluated the association between fatigue and arousals and various polysomongraphic variables, including sleep stages and sleep efficiency.
Significant correlations between MFSI-sf subscale scores and various arousal indices were noted. Emotional fatigue scores were associated with total arousal index (r = 0.416, p = .021), respiratory movement arousal index (r = 0.346, p = .025), and spontaneous movement arousal index (r = 0.378, p = .025). Physical fatigue scores were associated with total arousal index (r = 0.360, p = .033) and respiratory movement arousal index (r = 0.304, p = .040). Percent of stage 1 sleep and REM sleep were also associated with physical and emotional fatigue scores. Hierarchal linear regression analysis demonstrated that emotional fatigue scores were independently associated with spontaneous movement arousals after controlling for age, body mass index, depression, and sleep apnea severity.
These findings suggest that arousals may contribute to the fatigue seen in patients with OSA.
PMCID: PMC2764080  PMID: 19319586
Obstructive sleep apnea; Fatigue; Sleep architecture; Arousals
20.  Sleep and Circadian Rhythms in Spousally Bereaved Seniors 
Chronobiology international  2008;25(1):83-98.
A laboratory study of sleep and circadian rhythms was undertaken in 28 spousally bereaved seniors (≥60 yrs) at least four months after the loss event. Measures taken included two nights of polysomnography (second night used), ∼36 h of continuous core body temperature monitoring, and four assessments of mood and alertness throughout a day. Preceding the laboratory study, two-week diaries were completed, allowing the assessment of lifestyle regularity using the 17-item Social Rhythm Metric (SRM) and the timing of sleep using the Pittsburgh Sleep Diary (PghSD). Also completed were questionnaires assessing level of grief (Texas Revised Inventory of Grief [TRIG] and Index of Complicated Grief [ICG]), subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI]), morningness-eveningness (Composite Scale of Morningness [CSM]), and clinical interview yielding a Hamilton Depression Rating Scale (HDRS) score. Grief was still present, as indicated by an average TRIG score of about 60. On average, the bereaved seniors habitually slept between ∼23:00 and ∼06:40 h, achieving ∼6 h of sleep with a sleep efficiency of ∼80%. They took about 30 min to fall asleep, and had their first REM episode after 75 min. About 20% of their sleep was in Stage REM, and about 3% in Stages 3 or 4 (slow wave sleep). Their mean PSQI score was 6.4. Their circadian temperature rhythms showed the usual classic shape with a trough at ∼01:00 h, a fairly steep rise through the morning hours, and a more gradual rise to mid-evening, with an amplitude of ∼0.8°C. In terms of lifestyle regularity, the mean regularity (SRM) score was 3.65 (slightly lower than that usually seen in seniors). Mood and alertness showed time-of-day variation with peak alertness in the late morning and peak mood in the afternoon. Correlations between outcome sleep/circadian variables and level of grief (TRIG score) were calculated; there was a slight trend for higher grief to be associated with less time spent asleep (p = 0.07) and reduced alertness at 20:00 h (p = 0.05). Depression score was not correlated with TRIG score (p > 0.20). When subjects were divided into groups by the nature of their late spouse's death (expected/after a long-term chronic illness [n = 18] versus unexpected [n = 10]), no differences emerged in any of the variables. In conclusion, when studied at least four months after the loss event, there appears to be some sleep disruption in spousally bereaved seniors. However, this disruption does not appear to be due to bereavement-related disruptions in the circadian system.
PMCID: PMC2806655  PMID: 18293151
Bereavement; Widow; Sleep; Circadian rhythms
21.  Ras-Mediated Deregulation of the Circadian Clock in Cancer 
PLoS Genetics  2014;10(5):e1004338.
Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.
Author Summary
Living systems possess an endogenous time-generating system – the circadian clock - accountable for a 24 hours oscillation in the expression of about 10% of all genes. In mammals, disruption of oscillations is associated to several diseases including cancer. In this manuscript, we address the following question: what are the elicitors of a disrupted clock in cancer? We applied a systems biology approach to correlate experimental, bioinformatics and modelling data and could thereby identify key genes which discriminate strong and weak oscillators among cancer cell lines. Most of the discriminative genes play important roles in cell cycle regulation, DNA repair, immune system and metabolism and are involved in oncogenic pathways such as the RAS/MAPK. To investigate the potential impact of the Ras oncogene in the circadian clock we generated experimental models harbouring conditionally active Ras oncogenes. We put forward a direct correlation between the perturbation of Ras oncogene and an effect in the expression of clock genes, found by means of mathematical simulations and validated experimentally. Our study shows that perturbations of a single oncogene are sufficient to deregulate the mammalian circadian clock and opens new ways in which the circadian clock can influence disease and possibly play a role in therapy.
PMCID: PMC4038477  PMID: 24875049
22.  Systematic Analysis of Circadian Genes in a Population-Based Sample Reveals Association of TIMELESS with Depression and Sleep Disturbance 
PLoS ONE  2010;5(2):e9259.
Disturbances in the circadian pacemaker system are commonly found in individuals with depression and sleep-related problems. We hypothesized that some of the canonical circadian clock genes would be associated with depression accompanied by signs of disturbed sleep, early morning awakening, or daytime fatigue. We tested this hypothesis in a population-based sample of the Health 2000 dataset from Finland, including 384 depressed individuals and 1270 controls, all with detailed information on sleep and daytime vigilance, and analyzed this set of individuals with regard to 113 single-nucleotide polymorphisms of 18 genes of the circadian system. We found significant association between TIMELESS variants and depression with fatigue (D+FAT+) (rs7486220: pointwise P = 0.000099, OR = 1.66; corrected empirical P for the model of D+FAT+  = 0.0056; haplotype ‘C-A-A-C’ of rs2291739-rs2291738-rs7486220-rs1082214: P = 0.0000075, OR = 1.72) in females, and association to depression with early morning awakening (D+EMA+) (rs1082214: pointwise P = 0.0009, OR = 2.70; corrected empirical P = 0.0374 for the model D+EMA+; haplotype ‘G-T’ of rs7486220 and rs1082214: P = 0.0001, OR = 3.01) in males. There was significant interaction of gender and TIMELESS (for example with rs1082214, P = 0.000023 to D+EMA+ and P = 0.005 to D+FAT+). We obtained supported evidence for involvement of TIMELESS in sleeping problems in an independent set of control individuals with seasonal changes in mood, sleep duration, energy level and social activity in females (P = 0.036, ® = 0.123 for rs1082214) and with early morning awakening or fatigue in males (P = 0.038 and P = 0.0016, respectively, for rs1082214). There was also some evidence of interaction between TIMELESS and PER1 in females to D+FAT+ as well as between TIMELESS and ARNTL, RORA or NR1D1 in males to D+EMA+. These findings support a connection between circadian genes and gender-dependent depression and defective sleep regulation.
PMCID: PMC2823770  PMID: 20174623
23.  Inflammatory Cytokines are Associated with the Development of Symptom Burden in Patients with NSCLC Undergoing Concurrent Chemoradiation Therapy 
Brain, behavior, and immunity  2010;24(6):968-974.
Elevations in cancer treatment-induced circulating inflammatory cytokines may be partially responsible for the development of significant symptom burden (e.g., pain, fatigue, distress, disturbed sleep) during concurrent chemoradiation therapy (CXRT). Sixty-two patients undergoing CXRT for locally advanced non-small cell lung cancer (NSCLC) reported symptoms weekly for 15 weeks via the M. D. Anderson Symptom Inventory (MDASI). Serum inflammatory cytokines were assessed weekly during therapy via enzyme-linked immunosorbent assay. Dynamic changes in cytokines and associated symptom profiles were estimated using mixed-effect models. MDASI symptom severity increased gradually as CXRT dose accumulated and peaked at week 8. Serum concentrations of interleukin (IL)-6, IL-10, and serum soluble receptor 1 for tumor necrosis factor (sTNF-R1) increased significantly by week 8 (all p < .05). During CXRT, controlled for age, sex, race, body mass index, cancer recurrence, previous treatment status, total radiotherapy dose, and CXRT delivery technique, an increase in sTNF-R1 was significantly related to an increase in the mean score for all 15 MDASI symptoms (estimate, 1.74; SE, 0.69; p < .05) and to a larger radiation dose to normal lung volume (estimate, 1.77; SE, 0.71; p < .01); an increase in serum IL-6 was significantly related to increased mean severity for the five most severe symptoms (pain, fatigue, disturbed sleep, lack of appetite, sore throat) (estimate, 0.32; SE, 0.16; p < .05). These results suggest a role for over-expressed pro-inflammatory cytokines in significant worsening of symptoms in NSCLC patients undergoing CXRT, and warrant further study to identify biological targets for ameliorating treatment-related symptom burden.
PMCID: PMC2897921  PMID: 20353817
Symptom; inflammatory cytokines; MDASI; NSCLC; chemoradiation; mixed-effect model
24.  Serum sTNFR1, IL6, and the Development of Fatigue in Patients with Gastrointestinal Cancer Undergoing Chemoradiation Therapy 
Brain, Behavior, and Immunity  2012;26(5):699-705.
Although evidence of inflammation and fatigue has been noted in cancer survivors, whether inflammation is linked to the expression of fatigue and other symptoms arising from concurrent chemoradiation therapy (CXRT) has not been well studied. Patients undergoing CXRT for locally advanced colorectal or esophageal cancer (n = 103) reported multiple symptoms weekly via the M. D. Anderson Symptom Inventory (MDASI) from start of therapy. Serum samples were collected weekly to examine changes in inflammatory markers (interleukin [IL]-6, IL-8, IL-10, IL-1 receptor antagonist [IL-1RA], vascular endothelial growth factor [VEGF], and soluble receptor 1 for tumor necrosis factor [sTNF-R1]) via enzyme-linked immunosorbent assay. Relationships between symptom severity and inflammatory-marker concentration levels were estimated using mixed-effect regression analysis, controlled for week of therapy, age, sex, body mass index, pre-CXRT tumor stage, pre-CXRT chemotherapy, pre-CXRT statin use, and type of cancer. Fatigue was the most severe symptom over time, its development profile shared with pain, distress, drowsiness, poor appetite, and disturbed sleep. sTNF-R1 and IL-6 shared a similar pattern of symptom development, with significant increase during CXRT and decrease after completion of CXRT. Serum concentrations of sTNF-R1 were positively associated over time with the severity of fatigue (p = .00097), while sTNF-R1 and IL-6 were positively related to the severity of a component score of the six most severe symptoms (both p < .0001). This longitudinal study suggests a role for over-expressed sTNF-R1 and IL-6 in the development of fatigue and other severe sickness symptoms during CXRT in patients with colorectal or esophageal cancer.
PMCID: PMC3355215  PMID: 22251605
fatigue; symptoms; sickness behavior; cytokines; cancer; inflammation; MDASI; chemoradiation
25.  Disrupting Circadian Homeostasis of Sympathetic Signaling Promotes Tumor Development in Mice 
PLoS ONE  2010;5(6):e10995.
Cell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Period1 and 2 (Per) or Cryptochrome1 and 2 (Cry) are deficient in cell cycle regulation and Per2 mutant mice are cancer-prone. However, it remains unclear how circadian rhythm in cell proliferation is generated in vivo and why disruption of circadian rhythm may lead to tumorigenesis.
Methodology/Principal Findings
Mice lacking Per1 and 2, Cry1 and 2, or one copy of Bmal1, all show increased spontaneous and radiation-induced tumor development. The neoplastic growth of Per-mutant somatic cells is not controlled cell-autonomously but is dependent upon extracellular mitogenic signals. Among the circadian output pathways, the rhythmic sympathetic signaling plays a key role in the central-peripheral timing mechanism that simultaneously activates the cell cycle clock via AP1-controlled Myc induction and p53 via peripheral clock-controlled ATM activation. Jet-lag promptly desynchronizes the central clock-SNS-peripheral clock axis, abolishes the peripheral clock-dependent ATM activation, and activates myc oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice.
Tumor suppression in vivo is a clock-controlled physiological function. The central circadian clock paces extracellular mitogenic signals that drive peripheral clock-controlled expression of key cell cycle and tumor suppressor genes to generate a circadian rhythm in cell proliferation. Frequent disruption of circadian rhythm is an important tumor promoting factor.
PMCID: PMC2881876  PMID: 20539819

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