Clinical Chronobiology: Circadian Rhythms in Health and Disease

Abstract

Circadian rhythms (CRs) are entrainable endogenous rhythms that respond to external stimuli and regulate physiological functions. The suprachiasmatic nucleus (SCN) in the hypothalamus is the mammalian master clock that synchronizes all other tissue-specific peripheral clocks, primarily through gamma-aminobutyric acid (GABA) and vasoactive intestinal polypeptide (VIP). The SCN follows Earth's 24-hour cycle by light entrainment through the retinohypothalamic tract. At the cellular level, the core clock genes CLOCK, BMAL1, PER1–PER3, CRY1, and CRY2 regulate CRs in a negative feedback loop. The circadian disruption of the sleep–wake cycle manifests in at least six distinct clinical conditions. These are the circadian rhythm sleep–wake disorders (CRSWDs). Their diagnosis is made by history, sleep diaries, and actigraphy. Treatment involves a combination of timed light exposure, melatonin/melatonin agonists, and behavioral interventions. In addition, CR disturbances and subsequent misalignment can increase the risk of a variety of illnesses. These include infertility and menstrual irregularities as well as diabetes, obesity, fatty liver disease, and other metabolic syndromes. In addition, a disruption in the gut microbiome creates a proinflammatory environment. CR disturbances increase the risk for mood disorders, hence the utility of light-based therapies in depression. People with neurodegenerative disorders demonstrate significant disturbances in their CRs, and in their sleep–wake cycles. Circadian realignment therapies can also help decrease the symptomatic burden of these disorders. Certain epilepsy syndromes, such as juvenile myoclonic epilepsy (JME), have a circadian pattern of seizures. Circadian disturbances in epilepsy can be both the consequence and cause for breakthrough seizures. The immune system has its own CR. Disturbances in these due to shift work, for instance, can increase the risk of infections. CR disturbances can also increase the risk of cancer by impacting DNA repair, apoptosis, immune surveillance, and cell cycle regulation. Moreover, the timing of chemotherapeutic agents has been shown to increase their therapeutic impact in certain cancers.

Keywords

circadian rhythms - circadian rhythm sleep–wake disorders - chronobiology - suprachiasmatic nucleus - CLOCK genes - metabolism - mood disorders - immune disturbances - neurodegeneration - cancer - epilepsy

Publication History

Accepted Manuscript online:
17 February 2025

Article published online:
10 March 2025

• References

• 1 Mohawk JA, Takahashi JS. Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators. Trends Neurosci 2011; 34 (07) 349-358
• 2 Takahashi JS. Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet 2017; 18 (03) 164-179
• 3 Panda S. Circadian physiology of metabolism. Science 2016; 354 (6315) 1008-1015
• 4 Schwartz WJ, Klerman EB. Circadian neurobiology and the physiologic regulation of sleep and wakefulness. Neurol Clin 2019; 37 (03) 475-486
• 5 Leng Y, Musiek ES, Hu K, Cappuccio FP, Yaffe K. Association between circadian rhythms and neurodegenerative diseases. Lancet Neurol 2019; 18 (03) 307-318
• 6 Zarrinpar A, Chaix A, Yooseph S, Panda S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab 2014; 20 (06) 1006-1017
• 7 Vitaterna MH, Shimomura K, Jiang P. Genetics of circadian rhythms. Neurol Clin 2019; 37 (03) 487-504
• 8 Dollish HK, Tsyglakova M, McClung CA. Circadian rhythms and mood disorders: time to see the light. Neuron 2024; 112 (01) 25-40
• 9 Martchenko A, Martchenko SE, Biancolin AD, Brubaker PL. Circadian rhythms and the gastrointestinal tract: relationship to metabolism and gut hormones. Endocrinology 2020; 161 (12) bqaa167
• 10 Steele TA, St Louis EK, Videnovic A, Auger RR. Circadian rhythm sleep-wake disorders: a contemporary review of neurobiology, treatment, and dysregulation in neurodegenerative disease. Neurotherapeutics 2021; 18 (01) 53-74
• 11 Zee PC, Abbott SM. Circadian rhythm sleep-wake disorders. Continuum (Minneap Minn) 2020; 26 (04) 988-1002
• 12 Rosenwasser AM, Turek FW. Neurobiology of circadian rhythm regulation. Sleep Med Clin 2015; 10 (04) 403-412
• 13 Saini R, Jaskolski M, Davis SJ. Circadian oscillator proteins across the kingdoms of life: structural aspects. BMC Biol 2019; 17 (01) 13
• 14 Haque SN, Booreddy SR, Welsh DK. Effects of BMAL1 manipulation on the brain's master circadian clock and behavior. Yale J Biol Med 2019; 92 (02) 251-258
• 15 Koike N, Yoo SH, Huang HC. et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 2012; 338 (6105) 349-354
• 16 Rijo-Ferreira F, Takahashi JS. Genomics of circadian rhythms in health and disease. Genome Med 2019; 11 (01) 82
• 17 American Academy of Sleep Medicine (AASM). International Classification of Sleep Disorders. 3rd Edition, Text Revision (ICSD-3-TR).. AASM; 2023
• 18 Berry RB, Wagner MH. Sleep Medicine Pearls. 3rd ed.. Elsevier; 2015
• 19 Lewy AJ, Sack RL. Exogenous melatonin's phase-shifting effects on the endogenous melatonin profile in sighted humans: a brief review and critique of the literature. J Biol Rhythms 1997; 12 (06) 588-594
• 20 Burgess HJ, Revell VL, Molina TA, Eastman CI. Human phase response curves to three days of daily melatonin: 0.5 mg versus 3.0 mg. J Clin Endocrinol Metab 2010; 95 (07) 3325-3331
• 21 Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int 1992; 9 (05) 380-392
• 22 Duffy JF, Abbott SM, Burgess HJ. et al. Workshop report. Circadian rhythm sleep-wake disorders: gaps and opportunities. Sleep 2021; 44 (05) zsaa281
• 23 Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD). An update for 2015: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2015; 11 (10) 1199-1236
• 24 Mukhopadhyay S, Fineberg NA, Drummond LM. et al. Delayed sleep phase in severe obsessive-compulsive disorder: a systematic case-report survey. CNS Spectr 2008; 13 (05) 406-413
• 25 Murray JM, Sletten TL, Magee M. et al; Delayed Sleep on Melatonin (DelSoM) Study Group. Prevalence of circadian misalignment and its association with depressive symptoms in delayed sleep phase disorder. Sleep 2017;40(01):
• 26 Robillard R, Naismith SL, Rogers NL. et al. Delayed sleep phase in young people with unipolar or bipolar affective disorders. J Affect Disord 2013; 145 (02) 260-263
• 27 Snitselaar MA, Smits MG, Spijker J. ADHD symptoms in adults with delayed sleep phase disorder. Sleep Biol Rhythms 2019; 17: 11-18
• 28 Turner J, Drummond LM, Mukhopadhyay S. et al. A prospective study of delayed sleep phase syndrome in patients with severe resistant obsessive-compulsive disorder. World Psychiatry 2007; 6 (02) 108-111
• 29 Patke A, Murphy PJ, Onat OE. et al. Mutation of the human circadian clock gene CRY1 in familial delayed sleep phase disorder. Cell 2017; 169 (02) 203-215.e13
• 30 Micic G, Lovato N, Ferguson SA, Burgess HJ, Lack L. Circadian tau differences and rhythm associations in delayed sleep-wake phase disorder and sighted non-24-hour sleep-wake rhythm disorder. Sleep 2021; 44 (01) zsaa132
• 31 Abbott SM, Phillips AJ, Reid KJ, Cain SW, Zee PC. What's in a name? delayed by any other name is still a circadian disorder: a call for improved nomenclature for delayed sleep-wake phase disorder subtypes. Sleep 2023; 46 (11) zsad222
• 32 McGlashan EM, Burns AC, Murray JM. et al. The pupillary light reflex distinguishes between circadian and non-circadian delayed sleep phase disorder (DSPD) phenotypes in young adults. PLoS One 2018; 13 (09) e0204621
• 33 Czeisler CA, Duffy JF, Shanahan TL. et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 1999; 284 (5423) 2177-2181
• 34 Campbell SS, Murphy PJ. Delayed sleep phase disorder in temporal isolation. Sleep 2007; 30 (09) 1225-1228
• 35 Micic G, Lovato N, Gradisar M, Burgess HJ, Ferguson SA, Lack L. Circadian melatonin and temperature taus in delayed sleep-wake phase disorder and non-24-hour sleep-wake rhythm disorder patients: an ultradian constant routine study. J Biol Rhythms 2016; 31 (04) 387-405
• 36 Micic G, Lovato N, Gradisar M, Lack LC. Personality differences in patients with delayed sleep-wake phase disorder and non-24-h sleep-wake rhythm disorder relative to healthy sleepers. Sleep Med 2017; 30: 128-135
• 37 Sletten TL, Magee M, Murray JM. et al; Delayed Sleep on Melatonin (DelSoM) Study Group. Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: a double-blind, randomised clinical trial. PLoS Med 2018; 15 (06) e1002587
• 38 Musiek ES, Bhimasani M, Zangrilli MA, Morris JC, Holtzman DM, Ju YS. Circadian rest-activity pattern changes in aging and preclinical Alzheimer disease. JAMA Neurol 2018; 75 (05) 582-590
• 39 Jones CR, Campbell SS, Zone SE. et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med 1999; 5 (09) 1062-1065
• 40 Toh KL, Jones CR, He Y. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 2001; 291 (5506) 1040-1043
• 41 Chong SY, Ptáček LJ, Fu YH. Genetic insights on sleep schedules: this time, it's PERsonal. Trends Genet 2012; 28 (12) 598-605
• 42 Hida A, Kitamura S, Mishima K. Pathophysiology and pathogenesis of circadian rhythm sleep disorders. J Physiol Anthropol 2012; 31 (01) 7
• 43 Lee EK. Advanced sleep-wake disorder. In: Auger RR. ed. Circadian Rhythm Sleep-Wake Disorders. Spring, Cham; 2020: 109-122
• 44 Okechukwu CE. PERIOD3 gene P415A/H417R polymorphism-linked familial advanced sleep phase. Egypt J Med Hum Genet 2021; 22: 56
• 45 Shanware NP, Hutchinson JA, Kim SH, Zhan L, Bowler MJ, Tibbetts RS. Casein kinase 1-dependent phosphorylation of familial advanced sleep phase syndrome-associated residues controls PERIOD 2 stability. J Biol Chem 2011; 286 (14) 12766-12774
• 46 Xu Y, Padiath QS, Shapiro RE. et al. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 2005; 434 (7033) 640-644
• 47 Reid KJ, Chang AM, Dubocovich ML, Turek FW, Takahashi JS, Zee PC. Familial advanced sleep phase syndrome. Arch Neurol 2001; 58 (07) 1089-1094
• 48 Consens FB. Circadian rhythm sleep-wake disorders. Continuum (Minneap Minn) 2023; 29 (04) 1149-1166
• 49 Paine SJ, Fink J, Gander PH, Warman GR. Identifying advanced and delayed sleep phase disorders in the general population: a national survey of New Zealand adults. Chronobiol Int 2014; 31 (05) 627-636
• 50 Curtis BJ, Ashbrook LH, Young T. et al. Extreme morning chronotypes are often familial and not exceedingly rare: the estimated prevalence of advanced sleep phase, familial advanced sleep phase, and advanced sleep-wake phase disorder in a sleep clinic population. Sleep 2019; 42 (10) zsz148
• 51 Lack L, Wright H. The effect of evening bright light in delaying the circadian rhythms and lengthening the sleep of early morning awakening insomniacs. Sleep 1993; 16 (05) 436-443
• 52 Campbell SS, Dawson D, Anderson MW. Alleviation of sleep maintenance insomnia with timed exposure to bright light. J Am Geriatr Soc 1993; 41 (08) 829-836
• 53 Palmer JD, Francis JL, Pickard JD, Iannotti F. The efficacy and safety of aprotinin for hemostasis during intracranial surgery. J Neurosurg 2003; 98 (06) 1208-1216
• 54 Suhner AG, Murphy PJ, Campbell SS. Failure of timed bright light exposure to alleviate age-related sleep maintenance insomnia. J Am Geriatr Soc 2002; 50 (04) 617-623
• 55 Zee PC. Melantonin for the treatment of advanced sleep phase disorder. Sleep 2008; 31 (07) 923 , author reply 925
• 56 Abbott SM, Zee PC. Irregular sleep-wake rhythm disorder. Sleep Med Clin 2015; 10 (04) 517-522
• 57 Weaver DR, Stehle JH, Stopa EG, Reppert SM. Melatonin receptors in human hypothalamus and pituitary: implications for circadian and reproductive responses to melatonin. J Clin Endocrinol Metab 1993; 76 (02) 295-301
• 58 Pillar G, Shahar E, Peled N, Ravid S, Lavie P, Etzioni A. Melatonin improves sleep-wake patterns in psychomotor retarded children. Pediatr Neurol 2000; 23 (03) 225-228
• 59 Bjorvatn B. Shift-work disorder and treatment. In: Kushida CA. ed. Encyclopedia of Sleep and Circadian Rhythms. Academic Press; 2023: 617-623
• 60 Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA 2008; 299 (22) 2642-2655
• 61 Pavlova M. Circadian rhythm sleep-wake disorders. Continuum (Minneap Minn) 2017; 23 (4, Sleep Neurology): 1051-1063
• 62 Lockley SW, Skene DJ, Butler LJ, Arendt J. Sleep and activity rhythms are related to circadian phase in the blind. Sleep 1999; 22 (05) 616-623
• 63 Uchiyama M, Lockley SW. Non-24-hour sleep-wake rhythm disorder in sighted and blind patients. Sleep Med Clin 2015; 10 (04) 495-516
• 64 Flynn-Evans EE, Tabandeh H, Skene DJ, Lockley SW. Circadian rhythm disorders and melatonin production in 127 blind women with and without light perception. J Biol Rhythms 2014; 29 (03) 215-224
• 65 Lockley SW, Skene DJ, Arendt J, Tabandeh H, Bird AC, Defrance R. Relationship between melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab 1997; 82 (11) 3763-3770
• 66 Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H. Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab 1992; 75 (01) 127-134
• 67 Abbott SM, Choi J, Wilson J, Zee PC. Melanopsin-dependent phototransduction is impaired in delayed sleep-wake phase disorder and sighted non-24-hour sleep-wake rhythm disorder. Sleep 2021; 44 (02) zsaa184
• 68 Lockley SW. Non-24-h sleep-wake disorder in sighted and blind patients. In: Kushida CA. ed. Encyclopedia of Sleep and Circadian Rhythms. Academic Press; 2023: 624-631
• 69 Malkani RG, Abbott SM, Reid KJ, Zee PC. Diagnostic and treatment challenges of sighted non-24-hour sleep-wake disorder. J Clin Sleep Med 2018; 14 (04) 603-613
• 70 Tsujimura S, Ukai K, Ohama D, Nuruki A, Yunokuchi K. Contribution of human melanopsin retinal ganglion cells to steady-state pupil responses. Proc Biol Sci 2010; 277 (1693) 2485-2492
• 71 Adhikari P, Zele AJ, Feigl B. The post-illumination pupil response (PIPR). Invest Ophthalmol Vis Sci 2015; 56 (06) 3838-3849
• 72 Katz G, Knobler HY, Laibel Z, Strauss Z, Durst R. Time zone change and major psychiatric morbidity: the results of a 6-year study in Jerusalem. Compr Psychiatry 2002; 43 (01) 37-40
• 73 Cingi C, Emre IE, Muluk NB. Jetlag related sleep problems and their management: a review. Travel Med Infect Dis 2018; 24: 59-64
• 74 Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Jet lag: therapeutic use of melatonin and possible application of melatonin analogs. Travel Med Infect Dis 2008; 6 (1-2): 17-28
• 75 Eastman CI, Burgess HJ. How to travel the world without jet lag. Sleep Med Clin 2009; 4 (02) 241-255
• 76 Blum D. Jet lag type. In: Kushida CA. ed. Encyclopedia of Sleep and Circadian Rhythms. Academic Press; 2023: 632-635
• 77 Cheng P, Drake C. Shift work disorder. Neurol Clin 2019; 37 (03) 563-577
• 78 Burgess HJ, Sharkey KM, Eastman CI. Bright light, dark and melatonin can promote circadian adaptation in night shift workers. Sleep Med Rev 2002; 6 (05) 407-420
• 79 Smith MR, Fogg LF, Eastman CI. A compromise circadian phase position for permanent night work improves mood, fatigue, and performance. Sleep 2009; 32 (11) 1481-1489
• 80 Sagong C. Shift work disorder and treatment. In: Kushida CA. ed. Encyclopedia of Sleep and Circadian Rhythms. Academic Press; 2023: 636-643
• 81 Sallinen M, Härmä M, Akerstedt T, Rosa R, Lillqvist O. Promoting alertness with a short nap during a night shift. J Sleep Res 1998; 7 (04) 240-247
• 82 Schweitzer PK, Randazzo AC, Stone K, Erman M, Walsh JK. Laboratory and field studies of naps and caffeine as practical countermeasures for sleep-wake problems associated with night work. Sleep 2006; 29 (01) 39-50
• 83 Chellappa SL, Qian J, Vujovic N. et al. Daytime eating prevents internal circadian misalignment and glucose intolerance in night work. Sci Adv 2021; 7 (49) eabg9910
• 84 Liu B, Fan L, Wang Y. et al. Gut microbiota regulates host melatonin production through epithelial cell MyD88. Gut Microbes 2024; 16 (01) 2313769
• 85 Kulkarni SS, Singh O, Zigman JM. The intersection between ghrelin, metabolism and circadian rhythms. Nat Rev Endocrinol 2024; 20 (04) 228-238
• 86 Mills J, Kuohung W. Impact of circadian rhythms on female reproduction and infertility treatment success. Curr Opin Endocrinol Diabetes Obes 2019; 26 (06) 317-321
• 87 Summa KC, Vitaterna MH, Turek FW. Environmental perturbation of the circadian clock disrupts pregnancy in the mouse. PLoS One 2012; 7 (05) e37668
• 88 Kloss JD, Perlis ML, Zamzow JA, Culnan EJ, Gracia CR. Sleep, sleep disturbance, and fertility in women. Sleep Med Rev 2015; 22: 78-87
• 89 Reid KJ, Jaksa AA, Eisengart JB. et al. Systematic evaluation of Axis-I DSM diagnoses in delayed sleep phase disorder and evening-type circadian preference. Sleep Med 2012; 13 (09) 1171-1177
• 90 Antypa N, Vogelzangs N, Meesters Y, Schoevers R, Penninx BW. Chronotype associations with depression and anxiety disorders in a large cohort study. Depress Anxiety 2016; 33 (01) 75-83
• 91 Knutson KL, von Schantz M. Associations between chronotype, morbidity and mortality in the UK Biobank cohort. Chronobiol Int 2018; 35 (08) 1045-1053
• 92 Ehlers CL, Kupfer DJ, Frank E, Monk TH. Biological rhythms and depression: the role of zeitgebers and zeitstorers. Depression 1993; 1 (06) 285-293
• 93 Graw P, Kräuchi K, Wirz-Justice A, Pöldinger W. Diurnal variation of symptoms in seasonal affective disorder. Psychiatry Res 1991; 37 (01) 105-111
• 94 Leibenluft E, Turner EH, Feldman-Naim S, Schwartz PJ, Wehr TA, Rosenthal NE. Light therapy in patients with rapid cycling bipolar disorder: preliminary results. Psychopharmacol Bull 1995; 31 (04) 705-710
• 95 Stewart JW, Quitkin FM, Terman M, Terman JS. Is seasonal affective disorder a variant of atypical depression? Differential response to light therapy. Psychiatry Res 1990; 33 (02) 121-128
• 96 Wirz-Justice A, Quinto C, Cajochen C, Werth E, Hock C. A rapid-cycling bipolar patient treated with long nights, bedrest, and light. Biol Psychiatry 1999; 45 (08) 1075-1077
• 97 Frank E, Kupfer DJ, Thase ME. et al. Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch Gen Psychiatry 2005; 62 (09) 996-1004
• 98 Ehlers CL, Frank E, Kupfer DJ. Social zeitgebers and biological rhythms. A unified approach to understanding the etiology of depression. Arch Gen Psychiatry 1988; 45 (10) 948-952
• 99 Hood S, Amir S. The aging clock: circadian rhythms and later life. J Clin Invest 2017; 127 (02) 437-446
• 100 Turner PL, Mainster MA. Circadian photoreception: ageing and the eye's important role in systemic health. Br J Ophthalmol 2008; 92 (11) 1439-1444
• 101 Videnovic A, Noble C, Reid KJ. et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol 2014; 71 (04) 463-469
• 102 Brøndsted AE, Lundeman JH, Kessel L. Short wavelength light filtering by the natural human lens and IOLs—implications for entrainment of circadian rhythm. Acta Ophthalmol 2013; 91 (01) 52-57
• 103 Roccaro I, Smirni D. Fiat lux: the light became therapy. An overview on the bright light therapy in Alzheimer's disease sleep disorders. J Alzheimers Dis 2020; 77 (01) 113-125
• 104 Van Someren EJ, Swaab DF, Colenda CC, Cohen W, McCall WV, Rosenquist PB. Bright light therapy: improved sensitivity to its effects on rest-activity rhythms in Alzheimer patients by application of nonparametric methods. Chronobiol Int 1999; 16 (04) 505-518
• 105 Aziz NA, Pijl H, Frölich M. et al. Delayed onset of the diurnal melatonin rise in patients with Huntington's disease. J Neurol 2009; 256 (12) 1961-1965
• 106 Morton AJ, Wood NI, Hastings MH, Hurelbrink C, Barker RA, Maywood ES. Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease. J Neurosci 2005; 25 (01) 157-163
• 107 Zhang Y, Ren R, Yang L. et al. Sleep in Huntington's disease: a systematic review and meta-analysis of polysomongraphic findings. Sleep 2019; 42 (10) zsz154
• 108 Khyati M, Malik I, Agrawal N, Kumar V. Melatonin and curcumin reestablish disturbed circadian gene expressions and restore locomotion ability and eclosion behavior in Drosophila model of Huntington's disease. Chronobiol Int 2021; 38 (01) 61-78
• 109 Bernard C. Circadian/multidien molecular oscillations and rhythmicity of epilepsy (MORE). Epilepsia 2021; 62 (Suppl. 01) S49-S68
• 110 Leguia MG, Andrzejak RG, Rummel C. et al. Seizure cycles in focal epilepsy. JAMA Neurol 2021; 78 (04) 454-463
• 111 Maganti RK, Jones MV. Untangling a Web: basic mechanisms of the complex interactions between sleep, circadian rhythms, and epilepsy. Epilepsy Curr 2021; 21 (02) 105-110
• 112 Khan S, Nobili L, Khatami R. et al. Circadian rhythm and epilepsy. Lancet Neurol 2018; 17 (12) 1098-1108
• 113 Xu L, Guo D, Liu YY, Qiao DD, Ye JY, Xue R. Juvenile myoclonic epilepsy and sleep. Epilepsy Behav 2018; 80: 326-330
• 114 Kendis H, Baron K, Schuele SU, Patel B, Attarian H. Chronotypes in patients with epilepsy: does the type of epilepsy make a difference?. Behav Neurol 2015; 2015: 941354
• 115 Lightman SL, Conway-Campbell BL. Circadian and ultradian rhythms: clinical implications. J Intern Med 2024; 296 (02) 121-138
• 116 Olejniczak I, Oster H, Ray DW. Glucocorticoid circadian rhythms in immune function. Semin Immunopathol 2022; 44 (02) 153-163
• 117 Stenger S, Grasshoff H, Hundt JE, Lange T. Potential effects of shift work on skin autoimmune diseases. Front Immunol 2023; 13: 1000951
• 118 James SM, Honn KA, Gaddameedhi S, Van Dongen HPA. Shift work: disrupted circadian rhythms and sleep—implications for health and well-being. Curr Sleep Med Rep 2017; 3 (02) 104-112
• 119 Hazan G, Duek OA, Alapi H. et al. Biological rhythms in COVID-19 vaccine effectiveness in an observational cohort study of 1.5 million patients. J Clin Invest 2023; 133 (11) e167339
• 120 Ince LM, Barnoud C, Lutes LK. et al. Influence of circadian clocks on adaptive immunity and vaccination responses. Nat Commun 2023; 14 (01) 476
• 121 Abo SMC, Layton AT. Modeling the circadian regulation of the immune system: sexually dimorphic effects of shift work. PLOS Comput Biol 2021; 17 (03) e1008514
• 122 Zhou L, Zhang Z, Nice E, Huang C, Zhang W, Tang Y. Circadian rhythms and cancers: the intrinsic links and therapeutic potentials. J Hematol Oncol 2022; 15 (01) 21
• 123 Lee Y, Field JM, Sehgal A. Circadian rhythms, disease and chronotherapy. J Biol Rhythms 2021; 36 (06) 503-531
• 124 Lévi F, Zidani R, Misset JL. International Organization for Cancer Chronotherapy. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 1997; 350 (9079) 681-686
• 125 Focan C, Levi F, Kreutz F. et al. Continuous delivery of venous 5-fluorouracil and arterial 5-fluorodeoxyuridine for hepatic metastases from colorectal cancer: feasibility and tolerance in a randomized phase II trial comparing flat versus chronomodulated infusion. Anticancer Drugs 1999; 10 (04) 385-392
• 126 Roosendaal J, Jacobs BAW, Pluim D. et al. Phase I pharmacological study of continuous chronomodulated capecitabine treatment. Pharm Res 2020; 37 (05) 89
• 127 Mahalingam D, Wang JS, Hamilton EP. et al. Phase 1 open-label, multicenter study of first-in-class RORγ agonist LYC-55716 (cintirorgon): safety, tolerability, and preliminary evidence of antitumor activity. Clin Cancer Res 2019; 25 (12) 3508-3516
• 128 Lockhart AC, Bauer TM, Aggarwal C. et al. Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors. Invest New Drugs 2019; 37 (01) 87-97