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Author Xiang, S.; Dauchy, R.T.; Hoffman, A.E.; Pointer, D.; Frasch, T.; Blask, D.E.; Hill, S.M.
Title Epigenetic inhibition of the tumor suppressor ARHI by light at night-induced circadian melatonin disruption mediates STAT3-driven paclitaxel resistance in breast cancer Type Journal Article
Year 2019 Publication Journal of Pineal Research Abbreviated Journal J Pineal Res
Volume 67 Issue 2 Pages (down) e12586
Keywords Animals; Human Health; Circadian Rhythm; Cancer; tumor suppression
Abstract Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) production by exposure to dim light at night (dLAN), as occurs with night shift work and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of breast cancer and resistance to tamoxifen and doxorubicin. Melatonin inhibition of human breast cancer chemo-resistance involves mechanisms including suppression of tumor metabolism and inhibition of kinases and transcription factors which are often activated in drug-resistant breast cancer. Signal Transducer and Activator of Transcription 3 (STAT3), frequently overexpressed and activated in Paclitaxel (PTX)-resistant breast cancer, promotes the expression of DNA methyltransferase one (DNMT1) to epigenetically suppresses the transcription of tumor suppressor Aplasia Ras homolog one (ARHI) which can sequester STAT3 in the cytoplasm to block PTX-resistance. We demonstrate that breast tumor xenografts in rats exposed to dLAN and circadian MLT disrupted express elevated levels of phosphorylated and acetylated STAT3, increased DNMT1, but reduced Sirtuin 1 (SIRT1) and ARHI. Furthermore, MLT and/or SIRT1 administration blocked/reversed Interleukin 6 (IL-6)-induced acetylation of STAT3 and its methylation of ARH1 to increase ARH1 mRNA expression in MCF-7 breast cancer cells. Finally, analyses of the I-SPY 1 trial demonstrates that elevated MT1 receptor expression is significantly correlated with pathologic complete response following neo-adjuvant therapy in breast cancer patients. This is the first study to demonstrate circadian disruption of MLT by dLAN driving intrinsic resistance to PTX via epigenetic mechanisms increasing STAT3 expression and that MLT administration can reestablish sensitivity of breast tumors to PTX and drive tumor regression.
Address Tulane Circadian Cancer Biology Group, New Orleans, Louisiana
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0742-3098 ISBN Medium
Area Expedition Conference
Notes PMID:31077613 Approved no
Call Number GFZ @ kyba @ Serial 2383
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Author Rahman, S.A.; Bibbo, C.; Olcese, J.; Czeisler, C.A.; Robinson, J.N.; Klerman, E.B.
Title Relationship between endogenous melatonin concentrations and uterine contractions in late third trimester of human pregnancy Type Journal Article
Year 2019 Publication Journal of Pineal Research Abbreviated Journal J Pineal Res
Volume 66 Issue 4 Pages (down) e12566
Keywords Human Health; Melatonin; Pregnancy
Abstract In humans, circulating levels of the hormone melatonin and the initiation of spontaneous labor are both higher at night than during the day. Since activation of uterine melatonin receptors can stimulate human in vitro uterine contractions and these receptors are only expressed on the uterine tissue of women in labor, we hypothesized that circulating melatonin concentrations would affect uterine contractions in vivo. We evaluated the impact of light-induced modulation of melatonin secretion on uterine contractions in women during late third-trimester (~36-39 weeks) of pregnancy in two inpatient protocols. We found a significant (p<0.05) positive linear association between circulating melatonin concentrations and the number of uterine contractions under both protocols. On average, uterine contractions increased between 1.4 to 2.1 contractions per 30 minutes for every 10 pg/ml*h increase in melatonin concentration. These findings have both basic science and clinical implications for pregnant women, since endogenous melatonin levels and melatonin receptor activity can be altered by light and/or pharmaceutical agents.
Address Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0742-3098 ISBN Medium
Area Expedition Conference
Notes PMID:30739346 Approved no
Call Number GFZ @ kyba @ Serial 2203
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Author Prayag, A.S.; Najjar, R.P.; Gronfier, C.
Title Melatonin suppression is exquisitely sensitive to light and primarily driven by melanopsin in humans Type Journal Article
Year 2019 Publication Journal of Pineal Research Abbreviated Journal J Pineal Res
Volume 66 Issue 4 Pages (down) e12562
Keywords Human Health; melatonin suppression; melanopic illuminance
Abstract INTRODUCTION: Light elicits a range of non-visual responses in humans. Driven predominantly by intrinsically photosensitive retinal ganglion cells (ipRGCs), but also by rods and/or cones, these responses include melatonin suppression. A sigmoidal relationship has been established between melatonin suppression and light intensity, however photoreceptoral involvement remains unclear. METHODS AND RESULTS: In this study, we first modelled the relationships between alpha-opic illuminances and melatonin suppression using an extensive dataset by Brainard and colleagues. Our results show that 1) melatonin suppression is better predicted by melanopic illuminance compared to other alpha-opic illuminances, 2) melatonin suppression is predicted to occur at levels as low as ~1.5 melanopic lux (melanopsin-weighted irradiance 0.2 muW/cm(2)), 3) saturation occurs at 305 melanopic lux (melanopsin-weighted irradiance 36.6 muW/cm(2)). We then tested this melanopsin-weighted illuminance response model derived from Brainard and colleagues' data and show that it predicts equally well melatonin suppression data from our laboratory, although obtained using different intensities and exposure duration. DISCUSSION: Together, our findings suggest that melatonin suppression by monochromatic lights is predominantly driven by melanopsin, and that it can be initiated at extremely low melanopic lux levels in experimental conditions. This emphasizes the concern of the non-visual impacts of low light intensities in lighting design and light-emitting devices. This article is protected by copyright. All rights reserved.
Address Lyon Neuroscience Research Center, Integrative Physiology of the Brain Arousal Systems, Waking team, Inserm UMRS 1028, CNRS UMR 5292, Universite Claude Bernard Lyon 1, Universite de Lyon, F-69000, Lyon, France
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0742-3098 ISBN Medium
Area Expedition Conference
Notes PMID:30697806 Approved no
Call Number GFZ @ kyba @ Serial 2186
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Author Phillips, A.J.K.; Vidafar, P.; Burns, A.C.; McGlashan, E.M.; Anderson, C.; Rajaratnam, S.M.W.; Lockley, S.W.; Cain, S.W.
Title High sensitivity and interindividual variability in the response of the human circadian system to evening light Type Journal Article
Year 2019 Publication Proceedings of the National Academy of Sciences of the United States of America Abbreviated Journal Proc Natl Acad Sci U S A
Volume 116 Issue 24 Pages (down) 12019-12024
Keywords Human Health; circadian rhythms; light sensitivity; circadian disruption; melatonin suppression; evening light
Abstract Before the invention of electric lighting, humans were primarily exposed to intense (>300 lux) or dim (<30 lux) environmental light-stimuli at extreme ends of the circadian system's dose-response curve to light. Today, humans spend hours per day exposed to intermediate light intensities (30-300 lux), particularly in the evening. Interindividual differences in sensitivity to evening light in this intensity range could therefore represent a source of vulnerability to circadian disruption by modern lighting. We characterized individual-level dose-response curves to light-induced melatonin suppression using a within-subjects protocol. Fifty-five participants (aged 18-30) were exposed to a dim control (<1 lux) and a range of experimental light levels (10-2,000 lux for 5 h) in the evening. Melatonin suppression was determined for each light level, and the effective dose for 50% suppression (ED50) was computed at individual and group levels. The group-level fitted ED50 was 24.60 lux, indicating that the circadian system is highly sensitive to evening light at typical indoor levels. Light intensities of 10, 30, and 50 lux resulted in later apparent melatonin onsets by 22, 77, and 109 min, respectively. Individual-level ED50 values ranged by over an order of magnitude (6 lux in the most sensitive individual, 350 lux in the least sensitive individual), with a 26% coefficient of variation. These findings demonstrate that the same evening-light environment is registered by the circadian system very differently between individuals. This interindividual variability may be an important factor for determining the circadian clock's role in human health and disease.
Address Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia sean.cain@monash.edu
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0027-8424 ISBN Medium
Area Expedition Conference
Notes PMID:31138694 Approved no
Call Number IDA @ intern @ Serial 2521
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Author Pilz, L.K.; Levandovski, R.; Oliveira, M.A.B.; Hidalgo, M.P.; Roenneberg, T.
Title Sleep and light exposure across different levels of urbanisation in Brazilian communities Type Journal Article
Year 2018 Publication Scientific Reports Abbreviated Journal Sci Rep
Volume 8 Issue 1 Pages (down) 11389
Keywords Human Health; Sleep
Abstract Quilombos are settlements originally founded by Africans and African descendants (Quilombolas) in remote parts of Brazil to escape slavery. Due to individual histories, Quilombos nowadays exhibit different states of industrialisation, making them ideal for studying the influence of electrification on daily behaviour. In a comparative approach, we aimed to understand whether and how human sleep changes with the introduction of artificial light. We investigated daily rest-activity-rhythms and sleep-patterns in the Quilombolas' by both wrist actimetry and the Munich ChronoType Questionnaire (MCTQ; the results of these two instruments correlated highly). Seven communities (MCTQ: N = 213/actimetry: N = 125) were compared in this study. Light exposure, phase of activity, sleep timing and duration differ across communities with various levels of urbanisation and histories of access to electricity. People living without electricity and those, who acquired it only very recently on average sleep earlier than those in more urbanised communities (mid-sleep about 1 hour earlier); sleep duration tends to be longer. Our results and those of others show that use of electricity and modern lifestyles have changed sleep behaviour. To understand the consequences of these changes for health, further studies are warranted.
Address Visiting Professor at UFRGS/CAPES, Porto Alegre, RS, Brazil. roenneberg@lmu.de
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 2045-2322 ISBN Medium
Area Expedition Conference
Notes PMID:30061685 Approved no
Call Number GFZ @ kyba @ Serial 1968
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