Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy

Cell, Journal Year: 2024, Volume and Issue: 187(11), P. 2690 - 2702.e17

Published: May 1, 2024

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control tumor growth response to immunotherapy. Here, we show in murine human cancers that these exhibit circadian oscillations, driven by both endogenous clock leukocytes rhythmic leukocyte infiltration, which depends on endothelial cells microenvironment. To harness rhythms therapeutically, demonstrate efficacy chimeric antigen receptor cell therapy immune checkpoint blockade can be improved adjusting time treatment during day. Furthermore, time-of-day-dependent signatures models predict overall survival patients with melanoma correlate anti-PD-1 therapy. Our data functional significance dynamics microenvironment suggest importance leveraging features improving future clinical trial design patient care.

Language: Английский

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The dim light melatonin onset across ages, methodologies, and sex and its relationship with morningness/eveningness

SLEEP, Journal Year: 2023, Volume and Issue: 46(5)

Published: Feb. 17, 2023

Abstract The onset of melatonin secretion, the dim light (DLMO), is a tool for determining phase circadian timing system. Although small studies have investigated impacts age and methods calculating DLMO, there no DLMO reference range. In current study, saliva from 3579 participants 121 published plasma 818 healthy controls 31 (aged 3–73 years) were analyzed. subset 53 papers (1749 participants), individual Morningness Eveningness Questionaire (MEQ) scores obtained authors or mined publications range was constructed. Saliva earliest in children to 10 years latest around 20 thereafter advanced with by 30 min oldest participants. Melatonin assay calculation had little effect on determination DLMO. correlated (p < 0.001) MEQ score; lower associated later increased age, reflecting tendency toward morningness. An evaluation 14 clinically diagnosed patients living delayed sleep–wake disorder (mean ages revealed mean within albeit at late extreme. Peak levels 179 high degree variability groups, but only decline between 50 lowest after 70 years.

Language: Английский

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Circadian disruption, clock genes, and metabolic health

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(14)

Published: July 14, 2024

A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal human to suggest that expression core circadian genes, such locomotor output cycles kaput gene (CLOCK), brain muscle ARNT-Like 1 (BMAL1), period (PER), cyptochrome (CRY), consequent hundreds genes integral regulation cellular metabolism. These represent potential pathophysiological pathways linking adverse health outcomes, including obesity, syndrome, type 2 diabetes. Here, we aim summarize select in vivo models compare these results with epidemiologic findings advance understanding existing foundational mechanistic links between altered clock contributions health-related pathologies. Findings have important implications treatment, prevention, control pathologies leading causes death disability, diabetes, cardiovascular disease, cancer.

Language: Английский

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Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(7)

Published: Feb. 6, 2024

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular rhythms noncancerous cancerous human tissues their clinical relevance are largely unknown. We reconstructed informatically, integrating locally collected, time-stamped biopsies with public datasets. For tissue, inflammatory, epithelial–mesenchymal transition (EMT), estrogen responsiveness pathways show modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes organization. Luminal A organoids informatic ordering of luminal samples exhibit continued, albeit dampened reprogrammed rhythms. CYCLOPS magnitude, a measure global rhythm strength, varied widely among samples. Cycling EMT pathway genes was markedly increased high-magnitude tumors. Surprisingly, patients tumors had reduced 5-y survival. Correspondingly, 3D cultures invasion following disruption. This study links cancer EMT, metastatic potential, prognosis.

Language: Английский

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Circadian disruption and human health: A bidirectional relationship

European Journal of Neuroscience, Journal Year: 2018, Volume and Issue: 51(1), P. 567 - 583

Published: Dec. 14, 2018

Abstract Circadian rhythm disorders have been classically associated with of abnormal timing the sleep–wake cycle, however circadian dysfunction can play a role in wide range pathology, ranging from increased risk for cardiometabolic disease and malignancy shift workers, prompting need new field focused on larger concept medicine. The relationship between disruption human health is bidirectional, changes amplitude often preceding classical symptoms neurodegenerative disorders. As our understanding importance grows, we to develop better clinical techniques identifying rhythms also based strategies management. Overall this review highlights bring time all aspects medicine, emphasizing medicine as prime example both personalized precision

Language: Английский

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The µMCTQ: An Ultra-Short Version of the Munich ChronoType Questionnaire

Journal of Biological Rhythms, Journal Year: 2019, Volume and Issue: 35(1), P. 98 - 110

Published: Dec. 3, 2019

Individuals vary in how their circadian system synchronizes with the cyclic environment (zeitgeber). Assessing these differences “phase of entrainment”—often referred to as chronotype—is an important procedure laboratory experiments and epidemiological studies but is also increasingly applied medicine, both diagnosis therapy. While biochemical measurements (e.g., dim-light melatonin onset [DLMO]) internal time are still gold standard, they laborious, expensive, mostly rely on special conditions dim light). Chronotype estimation form questionnaires useful approximating timing individual’s clock. They simple, inexpensive, location independent administrable on- offline) can therefore be easily administered many individuals. The Munich ChronoType Questionnaire (MCTQ) established instrument assess chronotype by asking subjects about sleep-wake-behavior. Here we present a shortened version MCTQ, µMCTQ, for use situations which length critical, such large cohort studies. µMCTQ contains only core module standard MCTQ (stdMCTQ), was adapted from 17 6 essential questions, allowing quick assessment other related parameters social jetlag sleep duration. results correspond well ones collected stdMCTQ externally validated actimetry DLMO, assessed at home (no measure compliance). Sleep onset, midpoint sleep, µMCTQ-derived marker showed slight deviations toward earlier times when compared (<35 min). good test-retest reliability correlated significantly phase markers (DLMO), especially taken work-free days. Because its brevity, represents ideal tool estimate individual time-critical contexts, individualized medicine.

Language: Английский

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Population-level rhythms in human skin with implications for circadian medicine

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(48), P. 12313 - 12318

Published: Oct. 30, 2018

Skin is the largest organ in body and serves important barrier, regulatory, sensory functions. The epidermal layer shows rhythmic physiological responses to daily environmental variation (e.g., DNA repair). We investigated role of circadian clock transcriptional regulation epidermis using a hybrid experimental design, which limited set human subjects (n = 20) were sampled throughout 24-h cycle larger population 219) once. found robust oscillator at level pairwise correlations clock-associated genes 298 samples. then used CYCLOPS reconstruct temporal order all samples, identified hundreds rhythmically expressed epidermis. compared these results with published time-series skin data from mice strong concordance phase across species for both transcripts pathways. Furthermore, like blood, readily accessible potential source biomarkers. Using ZeitZeiger, we biomarker that capable reporting within 3 hours single sample. In summary, show rhythms persist scale describe path develop single-sample

Language: Английский

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Novel Approaches for Assessing Circadian Rhythmicity in Humans: A Review

Journal of Biological Rhythms, Journal Year: 2020, Volume and Issue: 35(5), P. 421 - 438

Published: July 23, 2020

The temporal organization of molecular and physiological processes is driven by environmental behavioral cycles as well self-sustained circadian oscillators. Quantification phase, amplitude, period, disruption oscillators essential for understanding their contribution to sleep-wake disorders, social jet lag, interindividual differences in entrainment, the development chrono-therapeutics. Traditionally, assessment human system, output SCN particular, has required collection long time series univariate markers such melatonin or core body temperature. Data were collected specialized laboratory protocols designed control influences on rhythmicity. These are time-consuming, expensive, not practical assessing status patients participants epidemiologic studies. Novel approaches parameters peripheral have been developed. They based machine learning mathematical model-informed analyses features extracted from 1 a few samples high-dimensional data, transcriptomes, metabolomes, long-term simultaneous recording activity, light exposure, skin temperature, heart rate vitro approaches. Here, we review whether these successfully quantify central indexed gold standard markers. Although several perform under entrained conditions when sleep occurs at night, methods either worse other shift work they assessed any than entrainment thus do yet know how robust are. hold promise medicine, chrono-therapeutics, chrono-epidemiology. There remains need validate against markers, individuals all sexes ages, patient populations, and, which displaced.

Language: Английский

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Chronotype and Social Jetlag - a (self-)critical review

Published: May 8, 2019

The Munich ChronoType Questionnaire (MCTQ) has now been available for more than 15 years; its original publication cited 1,240 times (Google Scholar, May 2019); online version, which was until July 2017, produced almost 300,000 entries from all over the world (MCTQ database). MCTQ gone through several versions, translated into 13 languages and validated against other objective measures of daily timing in independent studies. Besides being used as a method to correlate circadian features human biology with factors &ndash; ranging health issues geographical gave rise quantifying old wisdoms, like &ldquo;teenagers are late&rdquo; new concepts, social jetlag. Some MCTQ&rsquo;s simplicity some view it critically; is time have self-critical on MCTQ, address misunderstandings give definitions about MCTQ-derived chronotype concept

Language: Английский

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Genetics of the human circadian clock and sleep homeostat

Neuropsychopharmacology, Journal Year: 2019, Volume and Issue: 45(1), P. 45 - 54

Published: Aug. 10, 2019

Language: Английский

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