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Abstract

Today's challenge for precision medicine involves the integration of the impact of molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements of tolerability and/or efficacy of medications through proper administration timing have been confirmed over the past decade for immunotherapy and chemotherapy against cancer, as well as for commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, and neurological conditions. Experimental and human studies have recently revealed sexually dimorphic circadian drug responses. Dedicated randomized clinical trials should now aim to issue personalized circadian timing recommendations for daily medical practice, integrating innovative technologies for remote longitudinal monitoring of circadian metrics, statistical prediction of molecular clock function from single-timepoint biopsies, and multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust circadian function, who would benefit most from personalized chronotherapy, need to be identified. Conversely, nonchronofit patients could benefit from the emerging pharmacological class of chronobiotics targeting the circadian clock.

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2024-01-23
2024-06-21
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Literature Cited

  1. 1.
    Halberg F. 1969. Chronobiology. Annu. Rev. Physiol. 31:675–725
    [Google Scholar]
  2. 2.
    Hastings MH, Reddy AB, Maywood ES. 2003. A clockwork web: circadian timing in brain and periphery, in health and disease. Nat. Rev. Neurosci. 4:649–61
    [Google Scholar]
  3. 3.
    Levi F, Schibler U. 2007. Circadian rhythms: mechanisms and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 47:593–628
    [Google Scholar]
  4. 4.
    Levi F, Okyar A, Dulong S, Innominato PF, Clairambault J. 2010. Circadian timing in cancer treatments. Annu. Rev. Pharmacol. Toxicol. 50:377–421
    [Google Scholar]
  5. 5.
    Dallmann R, Okyar A, Levi F. 2016. Dosing-time makes the poison: circadian regulation and pharmacotherapy. Trends Mol. Med. 22:430–45
    [Google Scholar]
  6. 6.
    Ballesta A, Innominato PF, Dallmann R, Rand DA, Levi FA. 2017. Systems chronotherapeutics. Pharmacol. Rev. 69:161–99
    [Google Scholar]
  7. 7.
    Bicker J, Alves G, Falcão A, Fortuna A. 2020. Timing in drug absorption and disposition: the past, present, and future of chronopharmacokinetics. Br. J. Pharmacol. 177:2215–39
    [Google Scholar]
  8. 8.
    Nahmias Y, Androulakis IP. 2021. Circadian effects of drug responses. Annu. Rev. Biomed. Eng. 23:203–24
    [Google Scholar]
  9. 9.
    Hesse J, Malhan D, Yalçin M, Aboumanify O, Basti A, Relógio A. 2020. An optimal time for treatment-predicting circadian time by machine learning and mathematical modelling. Cancers 12:3103
    [Google Scholar]
  10. 10.
    Kim D, Zavala E, Kim JK. 2020. Wearable technology and systems modeling for personalized chronotherapy. Curr. Opin. Syst. Biol. 21:9–15
    [Google Scholar]
  11. 11.
    Talamanca L, Naef F. 2020. How to tell time: advances in decoding circadian phase from omics snapshots. F1000Research 9:1150
    [Google Scholar]
  12. 12.
    Amorós-Figueras G, Jorge E, Alonso-Martin C, Traver D, Ballesta M et al. 2018. Endocardial infarct scar recognition by myocardial electrical impedance is not influenced by changes in cardiac activation sequence. Heart Rhythm 15:589–96
    [Google Scholar]
  13. 13.
    Vlachou D, Bjarnason GA, Giacchetti S, Lévi F, Rand DA. 2019. TimeTeller: a new tool for precision circadian medicine and cancer prognosis. bioRxiv 622050. https://doi.org/10.1101/622050
  14. 14.
    Cederroth CR, Albrecht U, Bass J, Brown SA, Dyhrfjeld-Johnsen J et al. 2019. Medicine in the fourth dimension. Cell Metab. 30:238–50
    [Google Scholar]
  15. 15.
    Schwartzberg L, Kim ES, Liu D, Schrag D. 2017. Precision oncology: who, how, what, when, and when not?. Am. Soc. Clin. Oncol. Educ. Book 37:160–69
    [Google Scholar]
  16. 16.
    Hesse J, Martinelli J, Aboumanify O, Ballesta A, Relógio A. 2021. A mathematical model of the circadian clock and drug pharmacology to optimize irinotecan administration timing in colorectal cancer. Comput. Struct. Biotechnol. J. 19:5170–83
    [Google Scholar]
  17. 17.
    Filipski E, King VM, Etienne MC, Li X, Claustrat B et al. 2004. Persistent twenty-four hour changes in liver and bone marrow despite suprachiasmatic nuclei ablation in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287:R844–51
    [Google Scholar]
  18. 18.
    Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH et al. 2004. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. PNAS 101:5339–46
    [Google Scholar]
  19. 19.
    Finger AM, Kramer A. 2021. Mammalian circadian systems: organization and modern life challenges. Acta Physiol. 231:e13548
    [Google Scholar]
  20. 20.
    Daiber A, Frenis K, Kuntic M, Li H, Wolf E et al. 2022. Redox regulatory changes of circadian rhythm by the environmental risk factors traffic noise and air pollution. Antioxid. Redox Signal. 37:679–703
    [Google Scholar]
  21. 21.
    Fougeray T, Polizzi A, Régnier M, Fougerat A, Ellero-Simatos S et al. 2022. The hepatocyte insulin receptor is required to program the liver clock and rhythmic gene expression. Cell Rep. 39:110674
    [Google Scholar]
  22. 22.
    Takahashi JS. 2017. Transcriptional architecture of the mammalian circadian clock. Nat. Rev. Genet. 18:164–79
    [Google Scholar]
  23. 23.
    Mauvoisin D, Gachon F. 2020. Proteomics in circadian biology. J. Mol. Biol. 432:3565–77
    [Google Scholar]
  24. 24.
    Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. 2014. A circadian gene expression atlas in mammals: implications for biology and medicine. PNAS 111:16219–24
    [Google Scholar]
  25. 25.
    Robles MS, Humphrey SJ, Mann M. 2017. Phosphorylation is a central mechanism for circadian control of metabolism and physiology. Cell Metab. 25:118–27
    [Google Scholar]
  26. 26.
    Mure LS, Le HD, Benegiamo G, Chang MW, Rios L et al. 2018. Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science 359:eaao0318
    [Google Scholar]
  27. 27.
    Anderson ST, FitzGerald GA. 2020. Sexual dimorphism in body clocks. Science 369:1164–65
    [Google Scholar]
  28. 28.
    Li XM, Mohammad-Djafari A, Dumitru M, Dulong S, Filipski E et al. 2013. A circadian clock transcription model for the personalization of cancer chronotherapy. Cancer Res. 73:7176–88
    [Google Scholar]
  29. 29.
    Talamanca L, Gobet C, Naef F. 2023. Sex-dimorphic and age-dependent organization of 24-hour gene expression rhythms in humans. Science 379:478–83
    [Google Scholar]
  30. 30.
    Wucher V, Sodaei R, Amador R, Irimia M, Guigó R. 2023. Day-night and seasonal variation of human gene expression across tissues. PLOS Biol. 21:e3001986
    [Google Scholar]
  31. 31.
    Mekbib T, Suen TC, Rollins-Hairston A, Smith K, Armstrong A et al. 2022. The ubiquitin ligase SIAH2 is a female-specific regulator of circadian rhythms and metabolism. PLOS Genet. 18:e1010305
    [Google Scholar]
  32. 32.
    Keller M, Mazuch J, Abraham U, Eom GD, Herzog ED et al. 2009. A circadian clock in macrophages controls inflammatory immune responses. PNAS 106:21407–12
    [Google Scholar]
  33. 33.
    Bourin P, Mansour I, Doinel C, Roué R, Rouger P, Levi F. 1993. Circadian rhythms of circulating NK cells in healthy and human immunodeficiency virus-infected men. Chronobiol. Int. 10:298–305
    [Google Scholar]
  34. 34.
    Dimitrov S, Benedict C, Heutling D, Westermann J, Born J, Lange T. 2009. Cortisol and epinephrine control opposing circadian rhythms in T cell subsets. Blood 113:5134–43
    [Google Scholar]
  35. 35.
    Lange T, Luebber F, Grasshoff H, Besedovsky L. 2022. The contribution of sleep to the neuroendocrine regulation of rhythms in human leukocyte traffic. Semin. Immunopathol. 44:239–54
    [Google Scholar]
  36. 36.
    Ackermann K, Revell VL, Lao O, Rombouts EJ, Skene DJ, Kayser M. 2012. Diurnal rhythms in blood cell populations and the effect of acute sleep deprivation in healthy young men. Sleep 35:933–40
    [Google Scholar]
  37. 37.
    Nguyen KD, Fentress SJ, Qiu Y, Yun K, Cox JS, Chawla A. 2013. Circadian gene Bmal1 regulates diurnal oscillations of Ly6Chi inflammatory monocytes. Science 341:1483–88
    [Google Scholar]
  38. 38.
    Silver AC, Arjona A, Walker WE, Fikrig E. 2012. The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity. Immunity 36:251–61
    [Google Scholar]
  39. 39.
    Ella K, Csépányi-Kömi R, Káldi K. 2016. Circadian regulation of human peripheral neutrophils. Brain Behav. Immun. 57:209–21
    [Google Scholar]
  40. 40.
    Bollinger T, Leutz A, Leliavski A, Skrum L, Kovac J et al. 2011. Circadian clocks in mouse and human CD4+ T cells. PLOS ONE 6:e29801
    [Google Scholar]
  41. 41.
    Nobis CC, Dubeau Laramée G, Kervezee L, De Sousa DM, Labrecque N, Cermakian N. 2019. The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways. PNAS 116:20077–86
    [Google Scholar]
  42. 42.
    Arjona A, Sarkar DK. 2006. Evidence supporting a circadian control of natural killer cell function. Brain Behav. Immun. 20:469–76
    [Google Scholar]
  43. 43.
    Labrecque N, Cermakian N. 2015. Circadian clocks in the immune system. J. Biol. Rhythms 30:277–90
    [Google Scholar]
  44. 44.
    Downton P, Early JO, Gibbs JE. 2020. Circadian rhythms in adaptive immunity. Immunology 161:268–77
    [Google Scholar]
  45. 45.
    Scheiermann C, Gibbs J, Ince L, Loudon A. 2018. Clocking in to immunity. Nat. Rev. Immunol. 18:423–37
    [Google Scholar]
  46. 46.
    Wang C, Lutes LK, Barnoud C, Scheiermann C. 2022. The circadian immune system. Sci. Immunol. 7:eabm2465
    [Google Scholar]
  47. 47.
    Palomino-Segura M, Hidalgo A. 2021. Circadian immune circuits. J. Exp. Med. 218:e20200798
    [Google Scholar]
  48. 48.
    Lasrado N, Jia T, Massilamany C, Franco R, Illes Z, Reddy J. 2020. Mechanisms of sex hormones in autoimmunity: focus on EAE. Biol. Sex Differ. 11:50
    [Google Scholar]
  49. 49.
    Beeson PB. 1994. Age and sex associations of 40 autoimmune diseases. Am. J. Med. 96:457–62
    [Google Scholar]
  50. 50.
    Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM et al. 2013. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339:1084–88
    [Google Scholar]
  51. 51.
    Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P et al. 2013. Gender bias in autoimmunity is influenced by microbiota. Immunity 39:400–12
    [Google Scholar]
  52. 52.
    Xie G, Wang X, Zhao A, Yan J, Chen W et al. 2017. Sex-dependent effects on gut microbiota regulate hepatic carcinogenic outcomes. Sci. Rep. 7:45232
    [Google Scholar]
  53. 53.
    Weger BD, Gobet C, Yeung J, Martin E, Jimenez S et al. 2019. The mouse microbiome is required for sex-specific diurnal rhythms of gene expression and metabolism. Cell Metab. 29:362–82.e8
    [Google Scholar]
  54. 54.
    Elderman M, de Vos P, Faas M. 2018. Role of microbiota in sexually dimorphic immunity. Front. Immunol. 9:1018
    [Google Scholar]
  55. 55.
    Belkaid Y, Hand TW. 2014. Role of the microbiota in immunity and inflammation. Cell 157:121–41
    [Google Scholar]
  56. 56.
    Zheng D, Liwinski T, Elinav E. 2020. Interaction between microbiota and immunity in health and disease. Cell Res. 30:492–506
    [Google Scholar]
  57. 57.
    Thaiss CA, Zmora N, Levy M, Elinav E. 2016. The microbiome and innate immunity. Nature 535:65–74
    [Google Scholar]
  58. 58.
    Roenneberg T, Pilz LK, Zerbini G, Winnebeck EC. 2019. Chronotype and social jetlag: a (self-) critical review. Biology 8:54
    [Google Scholar]
  59. 59.
    Bailey M, Silver R. 2014. Sex differences in circadian timing systems: implications for disease. Front. Neuroendocrinol. 35:111–39
    [Google Scholar]
  60. 60.
    Kennaway DJ. 2023. The dim light melatonin onset across ages, methodologies and sex and its relationship with morningness/eveningness. Sleep 46:zsad033
    [Google Scholar]
  61. 61.
    Komarzynski S, Bolborea M, Huang Q, Finkenstädt B, Lévi F. 2019. Predictability of individual circadian phase during daily routine for medical applications of circadian clocks. JCI Insight 4:e130423
    [Google Scholar]
  62. 62.
    Lévi F, Komarzynski S, Huang Q, Young T, Ang Y et al. 2020. Tele-monitoring of cancer patients' rhythms during daily life identifies actionable determinants of circadian and sleep disruption. Cancers 12:1938
    [Google Scholar]
  63. 63.
    Wittenbrink N, Ananthasubramaniam B, Münch M, Koller B, Maier B et al. 2018. High-accuracy determination of internal circadian time from a single blood sample. J. Clin. Investig. 128:3826–39
    [Google Scholar]
  64. 64.
    Vlachou D, Veretennikova M, Usselmann L, Vasilyev V, Ott S et al. 2023. TimeTeller: a tool to probe the circadian clock as a multigene dynamical system. bioRxiv 2023.03.14.532177. https://doi.org/10.1101/2023.03.14.532177
  65. 65.
    Hida A, Kitamura S, Katayose Y, Kato M, Ono H et al. 2014. Screening of clock gene polymorphisms demonstrates association of a PER3 polymorphism with morningness-eveningness preference and circadian rhythm sleep disorder. Sci. Rep. 4:6309
    [Google Scholar]
  66. 66.
    von Schantz M. 2008. Phenotypic effects of genetic variability in human clock genes on circadian and sleep parameters. J. Genet. 87:513–19
    [Google Scholar]
  67. 67.
    Komarzynski S, Huang Q, Innominato PF, Maurice M, Arbaud A et al. 2018. Inter-subject differences in circadian coordination captured in real time in healthy and cancerous individual persons during their daily routine using a mobile internet platform. J. Med. Internet. Res. 20:e204
    [Google Scholar]
  68. 68.
    Ozturk N, Ozturk D, Kavakli IH, Okyar A. 2017. Molecular aspects of circadian pharmacology and relevance for cancer chronotherapy. Int. J. Mol. Sci. 18:2168
    [Google Scholar]
  69. 69.
    Dong D, Yang D, Lin L, Wang S, Wu B. 2020. Circadian rhythm in pharmacokinetics and its relevance to chronotherapy. Biochem. Pharmacol. 178:114045
    [Google Scholar]
  70. 70.
    Dobrek L. 2021. Chronopharmacology in therapeutic drug monitoring-dependencies between the rhythmics of pharmacokinetic processes and drug concentration in blood. Pharmaceutics 13:1915
    [Google Scholar]
  71. 71.
    Nicolaides NC, Chrousos GP. 2020. Sex differences in circadian endocrine rhythms: clinical implications. Eur. J. Neurosci. 52:2575–85
    [Google Scholar]
  72. 72.
    Schwartz JB. 2003. The influence of sex on pharmacokinetics. Clin. Pharmacokinet. 42:107–21
    [Google Scholar]
  73. 73.
    Hunt CM, Westerkam WR, Stave GM. 1992. Effect of age and gender on the activity of human hepatic CYP3A. Biochem. Pharmacol. 44:275–83
    [Google Scholar]
  74. 74.
    Gorski JC, Jones DR, Haehner-Daniels BD, Hamman MA, O'Mara EM Jr., Hall SD. 1998. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin. Pharmacol. Ther. 64:133–43
    [Google Scholar]
  75. 75.
    Soldin OP, Chung SH, Mattison DR. 2011. Sex differences in drug disposition. J. Biomed. Biotechnol. 2011:187103
    [Google Scholar]
  76. 76.
    Soldin OP, Mattison DR. 2009. Sex differences in pharmacokinetics and pharmacodynamics. Clin. Pharmacokinet. 48:143–57
    [Google Scholar]
  77. 77.
    Murakami Y, Higashi Y, Matsunaga N, Koyanagi S, Ohdo S. 2008. Circadian clock-controlled intestinal expression of the multidrug-resistance gene mdr1a in mice. Gastroenterology 135:1636–44.e3
    [Google Scholar]
  78. 78.
    Dulong S, Ballesta A, Okyar A, Levi F. 2015. Identification of circadian determinants of cancer chronotherapy through in vitro chronopharmacology and mathematical modeling. Mol. Cancer Ther. 14:2154–64
    [Google Scholar]
  79. 79.
    Okamura A, Koyanagi S, Dilxiat A, Kusunose N, Chen JJ et al. 2014. Bile acid-regulated peroxisome proliferator-activated receptor-α (PPARα) activity underlies circadian expression of intestinal peptide absorption transporter PepT1/Slc15a1. J. Biol. Chem. 289:25296–305
    [Google Scholar]
  80. 80.
    Wada E, Koyanagi S, Kusunose N, Akamine T, Masui H et al. 2015. Modulation of peroxisome proliferator-activated receptor-α activity by bile acids causes circadian changes in the intestinal expression of Octn1/Slc22a4 in mice. Mol. Pharmacol. 87:314–22
    [Google Scholar]
  81. 81.
    Okyar A, Piccolo E, Ahowesso C, Filipski E, Hossard V et al. 2011. Strain- and sex-dependent circadian changes in abcc2 transporter expression: implications for irinotecan chronotolerance in mouse ileum. PLOS ONE 6:e20393
    [Google Scholar]
  82. 82.
    Okyar A, Kumar SA, Filipski E, Piccolo E, Ozturk N et al. 2019. Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity—implications for mechanistic pharmacokinetics modeling. Sci. Rep. 9:10505
    [Google Scholar]
  83. 83.
    Pácha J, Balounová K, Soták M. 2021. Circadian regulation of transporter expression and implications for drug disposition. Expert Opin. Drug Metab. Toxicol. 17:425–39
    [Google Scholar]
  84. 84.
    Zhang YK, Yeager RL, Klaassen CD. 2009. Circadian expression profiles of drug-processing genes and transcription factors in mouse liver. Drug Metab. Dispos. 37:106–15
    [Google Scholar]
  85. 85.
    Furtado A, Mineiro R, Duarte AC, Gonçalves I, Santos CR, Quintela T. 2022. The daily expression of ABCC4 at the BCSFB affects the transport of its substrate methotrexate. Int. J. Mol. Sci. 23:2443
    [Google Scholar]
  86. 86.
    Cui YJ, Cheng X, Weaver YM, Klaassen CD. 2009. Tissue distribution, gender-divergent expression, ontogeny, and chemical induction of multidrug resistance transporter genes (Mdr1a, Mdr1b, Mdr2) in mice. Drug Metab. Dispos. 37:203–10
    [Google Scholar]
  87. 87.
    Ando H, Yanagihara H, Sugimoto K, Hayashi Y, Tsuruoka S et al. 2005. Daily rhythms of P-glycoprotein expression in mice. Chronobiol. Int. 22:655–65
    [Google Scholar]
  88. 88.
    Radzialowski FM, Bousquet WF. 1968. Daily rhythmic variation in hepatic drug metabolism in the rat and mouse. J. Pharmacol. Exp. Ther. 163:229–38
    [Google Scholar]
  89. 89.
    Nair V, Casper R. 1969. The influence of light on daily rhythm in hepatic drug metabolizing enzymes in rat. Life Sci. 8:1291–98
    [Google Scholar]
  90. 90.
    Gachon F, Olela FF, Schaad O, Descombes P, Schibler U. 2006. The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab. 4:25–36
    [Google Scholar]
  91. 91.
    Lu YF, Jin T, Xu Y, Zhang D, Wu Q et al. 2013. Sex differences in the circadian variation of cytochrome p450 genes and corresponding nuclear receptors in mouse liver. Chronobiol. Int. 30:1135–43
    [Google Scholar]
  92. 92.
    Li XM, Metzger G, Filipski E, Lemaigre G, Lévi F. 1998. Modulation of nonprotein sulphydryl compounds rhythm with buthionine sulphoximine: relationship with oxaliplatin toxicity in mice. Arch. Toxicol. 72:574–79
    [Google Scholar]
  93. 93.
    DeBruyne JP, Weaver DR, Dallmann R. 2014. The hepatic circadian clock modulates xenobiotic metabolism in mice. J. Biol. Rhythms 29:277–87
    [Google Scholar]
  94. 94.
    Du K, Williams CD, McGill MR, Jaeschke H. 2014. Lower susceptibility of female mice to acetaminophen hepatotoxicity: role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase. Toxicol. Appl. Pharmacol. 281:58–66
    [Google Scholar]
  95. 95.
    Dulong S, Botelho de Souza LE, Machowiak J, Peuteman B, Duvallet G et al. 2022. Sex and circadian timing modulate oxaliplatin hematological and hematopoietic toxicities. Pharmaceutics 14:2465
    [Google Scholar]
  96. 96.
    Masubuchi Y, Nakayama J, Watanabe Y. 2011. Sex difference in susceptibility to acetaminophen hepatotoxicity is reversed by buthionine sulfoximine. Toxicology 287:54–60
    [Google Scholar]
  97. 97.
    Guha P, Heatherton KR, O'Connell KP, IS Alexander, Katz SC. 2022. Assessing the future of solid tumor immunotherapy. Biomedicines 10:655
    [Google Scholar]
  98. 98.
    Qian DC, Kleber T, Brammer B, Xu KM, Switchenko JM et al. 2021. Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study. Lancet Oncol. 22:1777–86
    [Google Scholar]
  99. 99.
    Karaboué A, Collon T, Pavese I, Bodiguel V, Cucherousset J et al. 2022. Time-dependent efficacy of checkpoint inhibitor nivolumab: results from a pilot study in patients with metastatic non-small-cell lung cancer. Cancers 14:896
    [Google Scholar]
  100. 100.
    Cortellini A, Barrichello APC, Alessi JV, Ricciuti B, Vaz VR et al. 2022. A multicentre study of pembrolizumab time-of-day infusion patterns and clinical outcomes in non-small-cell lung cancer: too soon to promote morning infusions. Ann. Oncol. 33:1202–4
    [Google Scholar]
  101. 101.
    Barrios CH, Montella TC, Ferreira CGM, De Marchi P, Coutinho LF et al. 2022. Time-of-day infusion of immunotherapy may impact outcomes in advanced non-small cell lung cancer patients (NSCLC). J. Clin. Oncol. 40:e21126
    [Google Scholar]
  102. 102.
    Rousseau A, Tagliamento M, Auclin E, Aldea M, Frelaut M et al. 2023. Clinical outcomes by infusion timing of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer. Eur. J. Cancer 182:107–14
    [Google Scholar]
  103. 103.
    Ortego I, Molina-Cerrillo J, Pinto A, Santoni M, Alonso-Gordoa T et al. 2022. Time-of-day infusion of immunotherapy in metastatic urothelial cancer (mUC): Should it be considered to improve survival outcomes?. J. Clin. Oncol. 40:e16541
    [Google Scholar]
  104. 104.
    Patel J, Draper A, Woo Y, Dhabaan L, Patel P et al. 2022. Impact of immunotherapy time-of-day infusion on overall survival in patients with metastatic renal cell carcinoma. J. Immunother. Cancer 10:A886
    [Google Scholar]
  105. 105.
    Centanni M, Moes D, Trocóniz IF, Ciccolini J, van Hasselt JGC. 2019. Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin. Pharmacokinet. 58:835–57
    [Google Scholar]
  106. 106.
    Otasowie CO, Tanner R, Ray DW, Austyn JM, Coventry BJ. 2022. Chronovaccination: harnessing circadian rhythms to optimize immunisation strategies. Front. Immunol. 13:977525
    [Google Scholar]
  107. 107.
    Zhang H, Liu Y, Liu D, Zeng Q, Li L et al. 2021. Time of day influences immune response to an inactivated vaccine against SARS-CoV-2. Cell Res. 31:1215–17
    [Google Scholar]
  108. 108.
    Fontova P, Colom H, Rigo-Bonnin R, van Merendonk LN, Vidal-Alabró A et al. 2021. Influence of the circadian timing system on tacrolimus pharmacokinetics and pharmacodynamics after kidney transplantation. Front. Pharmacol. 12:636048
    [Google Scholar]
  109. 109.
    Min DI, Chen HY, Fabrega A, Ukah FO, Wu YM et al. 1996. Circadian variation of tacrolimus disposition in liver allograft recipients. Transplantation 62:1190–92
    [Google Scholar]
  110. 110.
    Satoh S, Tada H, Murakami M, Tsuchiya N, Li Z et al. 2006. Circadian pharmacokinetics of mycophenolic acid and implication of genetic polymorphisms for early clinical events in renal transplant recipients. Transplantation 82:486–93
    [Google Scholar]
  111. 111.
    Conforti F, Pala L, Pagan E, Corti C, Bagnardi V et al. 2021. Sex-based differences in response to anti-PD-1 or PD-L1 treatment in patients with non-small-cell lung cancer expressing high PD-L1 levels. A systematic review and meta-analysis of randomized clinical trials. ESMO Open 6:100251
    [Google Scholar]
  112. 112.
    Ozturk N, Ozturk D, Pala-Kara Z, Kaptan E, Sancar-Bas S et al. 2018. The immune system as a chronotoxicity target of the anticancer mTOR inhibitor everolimus. Chronobiol. Int. 35:705–18
    [Google Scholar]
  113. 113.
    Ozturk N, Ozturk Civelek D, Sancar S, Kaptan E, Pala Kara Z, Okyar A 2021. Dosing-time dependent testicular toxicity of everolimus in mice. Eur. J. Pharm. Sci. 165:105926
    [Google Scholar]
  114. 114.
    Marcu LG. 2022. Developments on tumour site-specific chrono-oncology towards personalised treatment. Crit. Rev. Oncol. Hematol. 179:103803
    [Google Scholar]
  115. 115.
    Printezi MI, Kilgallen AB, Bond MJG, Štibler U, Putker M et al. 2022. Toxicity and efficacy of chronomodulated chemotherapy: a systematic review. Lancet Oncol. 23:e129–43
    [Google Scholar]
  116. 116.
    Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. 2023. Colorectal cancer statistics, 2023. CA Cancer J. Clin. 73:233–54
    [Google Scholar]
  117. 117.
    Lévi F, Zidani R, Misset JL. 1997. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 350:681–86
    [Google Scholar]
  118. 118.
    Lévi F, Misset JL, Brienza S, Adam R, Metzger G et al. 1992. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer. Cancer 69:893–900
    [Google Scholar]
  119. 119.
    Curé H, Chevalier V, Adenis A, Tubiana-Mathieu N, Niezgodzki G et al. 2002. Phase II trial of chronomodulated infusion of high-dose fluorouracil and l-folinic acid in previously untreated patients with metastatic colorectal cancer. J. Clin. Oncol. 20:1175–81
    [Google Scholar]
  120. 120.
    Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R et al. 2000. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 18:136–47
    [Google Scholar]
  121. 121.
    Innominato PF, Ballesta A, Huang Q, Focan C, Chollet P et al. 2020. Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: randomized multicenter EORTC 05011 trial. Cancer Med. 9:4148–59
    [Google Scholar]
  122. 122.
    Giacchetti S, Dugue PA, Innominato PF, Bjarnason GA, Focan C et al. 2012. Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis. Ann. Oncol. 23:3110–16
    [Google Scholar]
  123. 123.
    Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S et al. 2006. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J. Clin. Oncol. 24:3562–69
    [Google Scholar]
  124. 124.
    Innominato PF, Giacchetti S, Moreau T, Bjarnason GA, Smaaland R et al. 2013. Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer. Cancer 119:2564–73
    [Google Scholar]
  125. 125.
    Innominato PF, Giacchetti S, Bjarnason GA, Focan C, Garufi C et al. 2012. Prediction of overall survival through circadian rest-activity monitoring during chemotherapy for metastatic colorectal cancer. Int. J. Cancer 131:2684–92
    [Google Scholar]
  126. 126.
    Innominato PF, Giacchetti S, Moreau T, Smaaland R, Focan C et al. 2011. Prediction of survival by neutropenia according to delivery schedule of oxaliplatin-5-fluorouracil-leucovorin for metastatic colorectal cancer in a randomized international trial (EORTC 05963). Chronobiol. Int. 28:586–600
    [Google Scholar]
  127. 127.
    Innominato PF, Roche VP, Palesh OG, Ulusakarya A, Spiegel D, Levi FA. 2014. The circadian timing system in clinical oncology. Ann. Med. 46:191–207
    [Google Scholar]
  128. 128.
    Granda TG, D'Attino RM, Filipski E, Vrignaud P, Garufi C et al. 2002. Circadian optimisation of irinotecan and oxaliplatin efficacy in mice with Glasgow osteosarcoma. Br. J. Cancer 86:999–1005
    [Google Scholar]
  129. 129.
    Innominato PF, Lévi FA, Bjarnason GA. 2010. Chronotherapy and the molecular clock: clinical implications in oncology. Adv. Drug. Deliv. Rev. 62:979–1001
    [Google Scholar]
  130. 130.
    Sancar A, Van Gelder RN. 2021. Clocks, cancer, and chronochemotherapy. Science 371:eabb0738
    [Google Scholar]
  131. 131.
    Amiama-Roig A, Verdugo-Sivianes EM, Carnero A, Blanco JR. 2022. Chronotherapy: circadian rhythms and their influence in cancer therapy. Cancers 14:5071
    [Google Scholar]
  132. 132.
    Zhou J, Wang J, Zhang X, Tang Q. 2021. New insights into cancer chronotherapies. Front. Pharmacol. 12:741295
    [Google Scholar]
  133. 133.
    Damato AR, Herzog ED. 2022. Circadian clock synchrony and chronotherapy opportunities in cancer treatment. Semin. Cell Dev. Biol. 126:27–36
    [Google Scholar]
  134. 134.
    Gorbacheva VY, Kondratov RV, Zhang R, Cherukuri S, Gudkov AV et al. 2005. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex. PNAS 102:3407–12
    [Google Scholar]
  135. 135.
    Levi F, Focan C, Karaboue A, de la Valette V, Focan-Henrard D et al. 2007. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv. Drug Deliv. Rev. 59:1015–35
    [Google Scholar]
  136. 136.
    Focan C. 2002. Chronobiological concepts underlying the chronotherapy of human lung cancer. Chronobiol. Int. 19:253–73
    [Google Scholar]
  137. 137.
    Zhang PX, Jin F, Li ZL, Wu WL, Li YY et al. 2018. A randomized phase II trial of induction chemotherapy followed by cisplatin chronotherapy versus constant rate delivery combined with radiotherapy. Chronobiol. Int. 35:240–48
    [Google Scholar]
  138. 138.
    Li J, Chen R, Ji M, Zou SL, Zhu LN 2015. Cisplatin-based chronotherapy for advanced non-small cell lung cancer patients: a randomized controlled study and its pharmacokinetics analysis. Cancer Chemother. Pharmacol. 76:651–55
    [Google Scholar]
  139. 139.
    Kumar SA, Needham RJ, Abraham K, Bridgewater HE, Garbutt LA et al. 2021. Dose- and time-dependent tolerability and efficacy of organo-osmium complex FY26 and its tissue pharmacokinetics in hepatocarcinoma-bearing mice. Metallomics 13:mfaa003
    [Google Scholar]
  140. 140.
    Wagner AD, Oertelt-Prigione S, Adjei A, Buclin T, Cristina V et al. 2019. Gender medicine and oncology: report and consensus of an ESMO workshop. Ann. Oncol. 30:1914–24
    [Google Scholar]
  141. 141.
    Milano G, Etienne MC, Cassuto-Viguier E, Thyss A, Santini J et al. 1992. Influence of sex and age on fluorouracil clearance. J. Clin. Oncol. 10:1171–75
    [Google Scholar]
  142. 142.
    Chansky K, Benedetti J, Macdonald JS. 2005. Differences in toxicity between men and women treated with 5-fluorouracil therapy for colorectal carcinoma. Cancer 103:1165–71
    [Google Scholar]
  143. 143.
    Stein BN, Petrelli NJ, Douglass HO, Driscoll DL, Arcangeli G, Meropol NJ. 1995. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer 75:11–17
    [Google Scholar]
  144. 144.
    Cristina V, Mahachie J, Mauer M, Buclin T, Van Cutsem E et al. 2018. Association of patient sex with chemotherapy-related toxic effects: a retrospective analysis of the PETACC-3 trial conducted by the EORTC gastrointestinal group. JAMA Oncol. 4:1003–6
    [Google Scholar]
  145. 145.
    Spitschan M, Santhi N, Ahluwalia A, Fischer D, Hunt L et al. 2022. Science forum: sex differences and sex bias in human circadian and sleep physiology research. eLife 11:e65419
    [Google Scholar]
  146. 146.
    Bressolle F, Joulia JM, Pinguet F, Ychou M, Astre C et al. 1999. Circadian rhythm of 5-fluorouracil population pharmacokinetics in patients with metastatic colorectal cancer. Cancer Chemother. Pharmacol. 44:295–302
    [Google Scholar]
  147. 147.
    Kim DW, Byun JM, Lee JO, Kim JK, Koh Y. 2023. Chemotherapy delivery time affects treatment outcomes of female patients with diffuse large B cell lymphoma. JCI Insight 8:e164767
    [Google Scholar]
  148. 148.
    Ahowesso C, Li XM, Zampera S, Peteri-Brunback B, Dulong S et al. 2011. Sex and dosing-time dependencies in irinotecan-induced circadian disruption. Chronobiol. Int. 28:458–70
    [Google Scholar]
  149. 149.
    Haus E. 2007. Chronobiology of hemostasis and inferences for the chronotherapy of coagulation disorders and thrombosis prevention. Adv. Drug Deliv. Rev. 59:966–84
    [Google Scholar]
  150. 150.
    Chaudhary R, Sharma T, Tantry US, Asgar JA, Kundan P et al. 2022. Serial assessment of thrombogenicity and hemodynamics in patients with type II diabetes in a clinical research unit: evidence for circadian variations in clot formation. J. Thromb. Thrombolysis 54:393–400
    [Google Scholar]
  151. 151.
    Decousus HA, Croze M, Levi FA, Jaubert JG, Perpoint BM et al. 1985. Circadian changes in anticoagulant effect of heparin infused at a constant rate. Br. Med. J. 290:341–44
    [Google Scholar]
  152. 152.
    Brunner-Ziegler S, Jilma B, Schörgenhofer C, Winkler F, Jilma-Stohlawetz P et al. 2016. Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects. J. Thromb. Haemost. 14:316–23
    [Google Scholar]
  153. 153.
    Schoergenhofer C, Schwameis M, Brunner M, Zeitlinger M, Winkler F et al. 2015. Assessing the influence of diurnal variations and selective Xa inhibition on whole blood aggregometry. Scand. . J. Clin. Lab. Investig. 75:531–36
    [Google Scholar]
  154. 154.
    Soulban G, Labrecque G. 1989. Circadian rhythms of blood clotting time and coagulation factors II, VII, IX and X in rats. Life Sci. 45:2485–89
    [Google Scholar]
  155. 155.
    Shi J, Tong R, Zhou M, Gao Y, Zhao Y et al. 2022. Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation. Eur. Heart J. 43:2317–34
    [Google Scholar]
  156. 156.
    Gumz ML, Shimbo D, Abdalla M, Balijepalli RC, Benedict C et al. 2023. Toward precision medicine: circadian rhythm of blood pressure and chronotherapy for hypertension—2021 NHLBI Workshop report. Hypertension 80:503–22
    [Google Scholar]
  157. 157.
    Hermida RC, Hermida-Ayala RG, Smolensky MH, Mojón A, Fernández JR. 2021. Ingestion-time differences in the pharmacodynamics of hypertension medications: systematic review of human chronopharmacology trials. Adv. Drug. Deliv. Rev. 170:200–13
    [Google Scholar]
  158. 158.
    Ruben MD, Smith DF, FitzGerald GA, Hogenesch JB. 2019. Dosing time matters. Science 365:547–49
    [Google Scholar]
  159. 159.
    Hermida RC, Smolensky MH, Balan H, Castriotta RJ, Crespo JJ et al. 2021. Guidelines for the design and conduct of human clinical trials on ingestion-time differences—chronopharmacology and chronotherapy—of hypertension medications. Chronobiol. Int. 38:1–26
    [Google Scholar]
  160. 160.
    Hermida RC, Mojón A, Fernández JR, Hermida-Ayala RG, Crespo JJ et al. 2023. Elevated asleep blood pressure and non-dipper 24h patterning best predict risk for heart failure that can be averted by bedtime hypertension chronotherapy: a review of the published literature. Chronobiol. Int. 40:63–82
    [Google Scholar]
  161. 161.
    Irwin MR. 2019. Sleep and inflammation: partners in sickness and in health. Nat. Rev. Immunol. 19:702–15
    [Google Scholar]
  162. 162.
    Valenzuela PL, Carrera-Bastos P, Gálvez BG, Ruiz-Hurtado G, Ordovas JM et al. 2021. Lifestyle interventions for the prevention and treatment of hypertension. Nat. Rev. Cardiol. 18:251–75
    [Google Scholar]
  163. 163.
    Chou R, Dana T, Blazina I, Daeges M, Jeanne TL. 2016. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US preventive services task force. JAMA 316:2008–24
    [Google Scholar]
  164. 164.
    Hamprecht B, Nüssler C, Lynen F. 1969. Rhythmic changes of hydroxymethylglutaryl coenzyme a reductase activity in livers of fed and fasted rats. FEBS Lett. 4:117–21
    [Google Scholar]
  165. 165.
    Ness GC, Chambers CM. 2000. Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. Proc. Soc. Exp. Biol. Med. 224:8–19
    [Google Scholar]
  166. 166.
    Izquierdo-Palomares JM, Fernandez-Tabera JM, Plana MN, Añino Alba A, Gómez Álvarez P et al. 2016. Chronotherapy versus conventional statins therapy for the treatment of hyperlipidaemia. Cochrane Database Syst. Rev. 11:CD009462
    [Google Scholar]
  167. 167.
    Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S et al. 2020. Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metab. 31:92–104.e5
    [Google Scholar]
  168. 168.
    Ursini F, De Giorgi A, D'Onghia M, De Giorgio R, Fabbian F, Manfredini R 2021. Chronobiology and chronotherapy in inflammatory joint diseases. Pharmaceutics 13:1832
    [Google Scholar]
  169. 169.
    Levi F, Le Louarn C, Reinberg A 1985. Timing optimizes sustained-release indomethacin treatment of osteoarthritis. Clin. Pharmacol. Ther. 37:77–84
    [Google Scholar]
  170. 170.
    Arvidson NG, Gudbjörnsson B, Larsson A, Hällgren R. 1997. The timing of glucocorticoid administration in rheumatoid arthritis. Ann. Rheum. Dis. 56:27–31
    [Google Scholar]
  171. 171.
    Buttgereit F, Doering G, Schaeffler A, Witte S, Sierakowski S et al. 2008. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Lancet 371:205–14
    [Google Scholar]
  172. 172.
    Buttgereit F, Mehta D, Kirwan J, Szechinski J, Boers M et al. 2013. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann. Rheum. Dis. 72:204–10
    [Google Scholar]
  173. 173.
    To H, Yoshimatsu H, Tomonari M, Ida H, Tsurumoto T et al. 2011. Methotrexate chronotherapy is effective against rheumatoid arthritis. Chronobiol. Int. 28:267–74
    [Google Scholar]
  174. 174.
    Sion B, Bégou M. 2021. Can chronopharmacology improve the therapeutic management of neurological diseases?. Fundam. Clin. Pharmacol. 35:564–81
    [Google Scholar]
  175. 175.
    Klerman EB, Brager A, Carskadon MA, Depner CM, Foster R et al. 2022. Keeping an eye on circadian time in clinical research and medicine. Clin. Transl. Med. 12:e1131
    [Google Scholar]
  176. 176.
    Coogan AN, Thome J. 2011. Chronotherapeutics and psychiatry: setting the clock to relieve the symptoms. World J. Biol. Psychiatry 12:Suppl. 140–43
    [Google Scholar]
  177. 177.
    Ribeiro RFN, Cavadas C, Silva MMC. 2021. Small-molecule modulators of the circadian clock: pharmacological potentials in circadian-related diseases. Drug Discov. Today 26:1620–41
    [Google Scholar]
  178. 178.
    Rasmussen ES, Takahashi JS, Green CB. 2022. Time to target the circadian clock for drug discovery. Trends Biochem. Sci. 47:745–58
    [Google Scholar]
  179. 179.
    Hirota T, Lee JW, St. John PC, Sawa M, Iwaisako K et al. 2012. Identification of small molecule activators of cryptochrome. Science 337:1094–97
    [Google Scholar]
  180. 180.
    Dong Z, Zhang G, Qu M, Gimple RC, Wu Q et al. 2019. Targeting glioblastoma stem cells through disruption of the circadian clock. Cancer Discov. 9:1556–73
    [Google Scholar]
  181. 181.
    Humphries PS, Bersot R, Kincaid J, Mabery E, McCluskie K et al. 2018. Carbazole-containing amides and ureas: discovery of cryptochrome modulators as antihyperglycemic agents. Bioorg. Med. Chem. Lett. 28:293–97
    [Google Scholar]
  182. 182.
    Gul S, Rahim F, Isin S, Yilmaz F, Ozturk N et al. 2021. Structure-based design and classifications of small molecules regulating the circadian rhythm period. Sci. Rep. 11:18510
    [Google Scholar]
  183. 183.
    Chun SK, Jang J, Chung S, Yun H, Kim N-J et al. 2014. Identification and validation of cryptochrome inhibitors that modulate the molecular circadian clock. ACS Chem. Biol. 9:703–10
    [Google Scholar]
  184. 184.
    Gul S, Akyel YK, Gul ZM, Isin S, Ozcan O et al. 2022. Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice. Nat. Commun. 13:6742
    [Google Scholar]
  185. 185.
    Doruk YU, Yarparvar D, Akyel YK, Gul S, Taskin AC et al. 2020. A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude. J. Biol. Chem. 295:3518–31
    [Google Scholar]
  186. 186.
    Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ et al. 2012. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485:62–68
    [Google Scholar]
  187. 187.
    Sulli G, Rommel A, Wang X, Kolar MJ, Puca F et al. 2018. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553:351–55
    [Google Scholar]
  188. 188.
    He B, Nohara K, Park N, Park YS, Guillory B et al. 2016. The small molecule nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome. Cell Metab. 23:610–21
    [Google Scholar]
  189. 189.
    Hermida RC, Ayala DE, Mojón A, Fernández JR. 2010. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol. Int. 27:1629–51
    [Google Scholar]
  190. 190.
    Hermida RC, Crespo JJ, Domínguez-Sardiña M, Otero A, Moyá A et al. 2020. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur. Heart J. 41:4565–76
    [Google Scholar]
  191. 191.
    Reinberg A, Levi F. 1987. Clinical chronopharmacology with special reference to NSAIDs. Scand. J. Rheumatol. Suppl. 65:118–22
    [Google Scholar]
  192. 192.
    Lee Y, Lahens NF, Zhang S, Bedont J, Field JM, Sehgal A. 2019. G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment. PLOS Biol. 17:e3000228
    [Google Scholar]
  193. 193.
    Feillet C, Krusche P, Tamanini F, Janssens RC, Downey MJ et al. 2014. Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle. PNAS 111:9828–33
    [Google Scholar]
  194. 194.
    Roenneberg T, Kuehnle T, Juda M, Kantermann T, Allebrandt K et al. 2007. Epidemiology of the human circadian clock. Sleep Med. Rev. 11:429–38
    [Google Scholar]
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