Circadian rhythms in haematological malignancies: therapeutic potential and personalised interventions.

The circadian clock, a fundamental cellular mechanism, regulates the rhythmic expression of numerous genes and biological processes across various organs. Disruptions in this system, driven by genetic or environmental factors, have been reported to be involved in cancer progression. This review explores the role of the circadian clock in cancer hallmarks and its impact on cellular homeostasis within haematological malignancies.

Molecular characterization of the circadian clock in patients with Parkinson's disease-CLOCK4PD Study protocol.

Introduction: Circadian rhythms (CRs) orchestrate intrinsic 24-hour oscillations which synchronize an organism's physiology and behaviour with respect to daily cycles. CR disruptions have been linked to Parkinson's Disease (PD), the second most prevalent neurodegenerative disorder globally, and are associated to several PD-symptoms such as sleep disturbances. Studying molecular changes of CR offers a potential avenue for unravelling novel insights into the PD progression, symptoms, and can be further used for optimization of treatment strategies.

Molecular mechanisms of tumour development in glioblastoma: an emerging role for the circadian clock.

Glioblastoma is one of the most lethal cancers with current therapeutic options lacking major successes. This underlines the necessity to understand glioblastoma biology on other levels and use these learnings for the development of new therapeutic concepts. Mounting evidence in the field of circadian medicine points to a tight interplay between disturbances of the circadian system and glioblastoma progression.

Sex and age-dependent characterization of the circadian clock as a potential biomarker for physical performance: A prospective study protocol.

Introduction: Circadian rhythms (CR) regulate daily cycles in behavior, physiology and molecular processes. CRs are endogenous and vary across individuals. Seasonal changes can influence CR.

The circadian clock circuitry modulates leukemia initiating cell activity in T-cell acute lymphoblastic leukemia.

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, characterized by restricted cellular subsets with asymmetrically enriched leukemia initiating cell (LIC) activity. Nonetheless, it is still unclear which signaling programs promote LIC maintenance and progression.

Methods: Here, we evaluated the role of the biological clock in the regulation of the molecular mechanisms and signaling pathways impacting the cellular dynamics in T-ALL through an integrated experimental approach including gene expression profiling of shRNA-modified T-ALL cell lines and Chromatin Immunoprecipitation Sequencing (ChIP-Seq) of leukemic cells.

Circadian regulation in aging: Implications for spaceflight and life on earth.

Alterations in the circadian system are characteristic of aging on Earth. With the decline in physiological processes due to aging, several health concerns including vision loss, cardiovascular disorders, cognitive impairments, and muscle mass loss arise in elderly populations. Similar health risks are reported as "red flag" risks among astronauts during and after a long-term Space exploration journey.

Differential expression of the circadian clock network correlates with tumour progression in gliomas.

Background: Gliomas are tumours arising mostly from astrocytic or oligodendrocytic precursor cells. These tumours are classified according to the updated WHO classification from 2021 in 4 grades depending on molecular and histopathological criteria. Despite novel multimodal therapeutic approaches, the vast majority of gliomas (WHO grade III and IV) are not curable.

An integrative mathematical model for timing treatment toxicity and Zeitgeber impact in colorectal cancer cells.

Increasing evidence points to a role of the circadian clock in the regulation of cancer hallmarks with a strong impact on the understanding and treatment of this disease. Anti-cancer treatment can be personalized considering treatment timing. Here we present a new mathematical model based on data from three colorectal cancer cell lines and core-clock knock-outs, which couples the circadian and drug metabolism network, and that allows to determine toxicity profiles for a given drug and cell type.

TimeTeller for timing health: The potential of circadian medicine to improve performance, prevent disease and optimize treatment.

Circadian medicine, the study of the effects of time on health and disease has seen an uprising in recent years as a means to enhance health and performance, and optimize treatment timing. Our endogenous time generating system -the circadian clock- regulates behavioural, physiological and cellular processes. Disruptions of the clock, external factors like shift work or jet lag, or internal perturbations such as genetic alterations, are linked to an increased risk of various diseases like obesity, diabetes, cardiovascular diseases and cancer.

Skeletal muscle gene expression dysregulation in long-term spaceflights and aging is clock-dependent.

The circadian clock regulates cellular and molecular processes in mammals across all tissues including skeletal muscle, one of the largest organs in the human body. Dysregulated circadian rhythms are characteristic of aging and crewed spaceflight, associated with, for example, musculoskeletal atrophy. Molecular insights into spaceflight-related alterations of circadian regulation in skeletal muscle are still missing.

Molecular characterization of the circadian clock in paediatric leukaemia patients: a prospective study protocol.

Background: In many organisms, including humans, the timing of cellular processes is regulated by the circadian clock. At the molecular level the core-clock consists of transcriptional-translational-feedback loops including several genes such as BMAL1, CLOCK, PERs and CRYs generating circa 24-h rhythms in the expression of about 40% of our genes across all tissues. Previously these core-clock genes have been shown to be differentially expressed in various cancers.

Chronotherapy in Glioblastoma: state of the art and future perspectives.

Circadian rhythms regulate various processes in the human body, including drug metabolism. Chronotherapy optimizes treatment timing based on the circadian rhythm of the individual patient, such that the treatment efficacy is maximized, and adverse effects are minimized. It has been explored in different cancers with varying conclusions.

Antiproliferative Effects of Cynara Cardunculus in Colorectal Cancer Cells Are Modulated by the Circadian Clock.

The circadian clock generates 24 h rhythms in behavioural, cellular and molecular processes. Malfunctions of the clock are associated with enhanced susceptibility to cancer, worse treatment response and poor prognosis. Clock-controlled genes are involved in cellular processes associated with tumour development and progression including metabolism of drugs and the cell cycle.

Core-Clock Genes Regulate Proliferation and Invasion via a Reciprocal Interplay with MACC1 in Colorectal Cancer Cells.

The circadian clock coordinates the timing of several cellular processes including transcription, the cell cycle, and metabolism. Disruptions in the clock machinery trigger the abnormal regulation of cancer hallmarks, impair cellular homeostasis, and stimulate tumourigenesis. Here we investigated the role of a disrupted clock by knocking out or knocking down the core-clock (CC) genes , or in cancer progression (e.

Transcriptome analysis of clock disrupted cancer cells reveals differential alternative splicing of cancer hallmarks genes.

Emerging evidence points towards a regulatory role of the circadian clock in alternative splicing (AS). Whether alterations in core-clock components may contribute to differential AS events is largely unknown. To address this, we carried out a computational analysis on recently generated time-series RNA-seq datasets from three core-clock knockout (KO) genes (ARNTL, NR1D1, PER2) and WT of a colorectal cancer (CRC) cell line, and time-series RNA-seq datasets for additional CRC and Hodgkin's lymphoma (HL) cells, murine WT, Arntl KO, and Nr1d1/2 KO, and murine SCN WT tissue.

It's About Time: The Circadian Network as Time-Keeper for Cognitive Functioning, Locomotor Activity and Mental Health.

A variety of organisms including mammals have evolved a 24h, self-sustained timekeeping machinery known as the circadian clock (biological clock), which enables to anticipate, respond, and adapt to environmental influences such as the daily light and dark cycles. Proper functioning of the clock plays a pivotal role in the temporal regulation of a wide range of cellular, physiological, and behavioural processes. The disruption of circadian rhythms was found to be associated with the onset and progression of several pathologies including sleep and mental disorders, cancer, and neurodegeneration.

Analysis of more than 20,000 injuries in European professional football by using a citizen science-based approach: An opportunity for epidemiological research?

Objectives: It has been claimed that analyses of large datasets from publicly accessible, open-collaborated ("citizen science-based") online databases may provide additional insight into the epidemiology of injuries in professional football. However, this approach comes with major limitations, raising critical questions about the current trend of utilizing citizen science-based data. Therefore, we aimed to determine if citizen science-based health data from a popular online database on professional football players can be used for epidemiological research, i.

A Computational Analysis in a Cohort of Parkinson's Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes.

Increasing evidence suggests a role for circadian dysregulation in prompting disease-related phenotypes in mammals. Cancer and neurodegenerative disorders are two aging related diseases reported to be associated with circadian disruption. In this study, we investigated a possible effect of circadian disruption in Parkinson's disease (PD) and colorectal cancer (CRC).

A mathematical model of the circadian clock and drug pharmacology to optimize irinotecan administration timing in colorectal cancer.

Scheduling anticancer drug administration over 24 h may critically impact treatment success in a patient-specific manner. Here, we address personalization of treatment timing using a novel mathematical model of irinotecan cellular pharmacokinetics and -dynamics linked to a representation of the core clock and predict treatment toxicity in a colorectal cancer (CRC) cellular model. The mathematical model is fitted to three different scenarios: mouse liver, where the drug metabolism mainly occurs, and two human colorectal cancer cell lines representing an experimental system for human colorectal cancer progression.

Diurnal variations in the expression of core-clock genes correlate with resting muscle properties and predict fluctuations in exercise performance across the day.

Objectives: In this study, we investigated daily fluctuations in molecular (gene expression) and physiological (biomechanical muscle properties) features in human peripheral cells and their correlation with exercise performance.

Methods: 21 healthy participants (13 men and 8 women) took part in three test series: for the molecular analysis, 15 participants provided hair, blood or saliva time-course sampling for the rhythmicity analysis of core-clock gene expression via RT-PCR. For the exercise tests, 16 participants conducted strength and endurance exercises at different times of the day (9h, 12h, 15h and 18h).

Long-term continuous positive airway pressure treatment ameliorates biological clock disruptions in obstructive sleep apnea.

Background: Obstructive Sleep Apnea (OSA) is a highly prevalent and underdiagnosed sleep disorder. Recent studies suggest that OSA might disrupt the biological clock, potentially causing or worsening OSA-associated comorbidities. However, the effect of OSA treatment on clock disruption is not fully understood.

An Optimal Time for Treatment-Predicting Circadian Time by Machine Learning and Mathematical Modelling.

Tailoring medical interventions to a particular patient and pathology has been termed personalized medicine. The outcome of cancer treatments is improved when the intervention is timed in accordance with the patient's internal time. Yet, one challenge of personalized medicine is how to consider the biological time of the patient.

Circadian Dysregulation of the TGFβ/SMAD4 Pathway Modulates Metastatic Properties and Cell Fate Decisions in Pancreatic Cancer Cells.

Impairment of circadian rhythms impacts carcinogenesis. a clock-controlled gene and central component of the TGFβ canonical pathway, is frequently mutated in pancreatic ductal adenocarcinoma (PDA), leading to decreased survival. Here, we used an PDA model of SMAD4-positive and SMAD4-negative cells to investigate the interplay between circadian rhythms, the TGFβ canonical signaling pathway, and its impact on tumor malignancy.

The Rhythmicity of Clock Genes is Disrupted in the Choroid Plexus of the APP/PS1 Mouse Model of Alzheimer's Disease.

Background: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system.

Objective: The fact that circadian rhythm disruption is closely associated to Alzheimer's disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP.

Methods: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD.