6541 Background: B-cell acute lymphoblastic leukaemia (B-ALL) is the most common paediatric malignancy. While cure rates exceed 90%, treatment remains intensive and is frequently associated with relapse, toxicity, and long-term adverse effects. The circadian clock regulates DNA repair, metabolism, immune function, and drug pharmacokinetics—processes central to cancer therapy. Although treatment timing has been shown to influence outcomes in childhood ALL, the molecular circadian landscape of malignant versus healthy hematopoietic cells in paediatric patients remains unexplored. Methods: We performed an integrated molecular and clinical circadian profiling study in paediatric ALL patients (N=7) and age-matched healthy controls (N=10). Peripheral blood, bone marrow, and saliva samples were collected at diagnosis. CD19⁺ (leukemic B cells) and paired CD19⁻ (non-B cells) populations were isolated and used to establish an internal, patient-specific circadian baseline. Expression of ~800 cancer-, immune-, and clock-related genes was quantified using NanoString SPRINT technology. Rhythmicity parameters (acrophase, amplitude, MESOR), differential expression, and machine-learning–based classification were integrated with longitudinal clinical and physiological data. Results: Malignant CD19⁺ cells exhibited marked circadian dysregulation compared with paired CD19⁻ cells from the same patients. Core clock architecture was altered specifically in leukemic cells, including disrupted BMAL1–PER2 phase relationships and reduced rhythmic amplitude. CD19 expression itself displayed cell-type–specific circadian modulation, with higher amplitude and phase variability in CD19⁺ cells. In contrast, CD19⁻ cells retained more coherent circadian organization, supporting their use as an internal normalization reference. Preliminary analyses suggest that the degree of circadian misalignment between CD19⁺ and CD19⁻ compartments correlates with treatment dynamics, including early response and therapy duration. Conclusions: Our findings reveal profound, cell-intrinsic circadian disruption in paediatric B-ALL and demonstrate that comparing malignant CD19⁺ cells against paired non-malignant CD19⁻ cells enables robust detection of clock dysregulation. These results provide a molecular framework for developing circadian biomarkers and support the rational design of chronotherapy strategies aimed at optimising efficacy while minimising toxicity in paediatric leukaemia.

Circadian rhythms play a crucial role in maintaining cardiovascular homeostasis, orchestrating fluctuations in blood pressure, heart rate variability, endothelial function, and systemic vascular tone. Disruptions of the circadian clock -arising from ageing, genetic predisposition, or environmental and lifestyle factors- can significantly elevate the risk of cardiovascular diseases, including hypertension, atherosclerosis, heart failure, and arrhythmias. This review examines the role of circadian regulation in cardiovascular physiology, from molecular clock networks and clock-controlled gene regulation to systemic cardiovascular physiology and clinical translation. We discuss how circadian disruption affects blood pressure, heart rate variability, and vascular health, through mechanisms including inflammation, mitochondrial dysfunction, and metabolic dysregulation. We further position circadian biology within the broader context of cardiovascular ageing and the molecular mechanisms that drive age-associated cardiovascular decline.Special attention is given to the role of inflamm-ageing in promoting atherosclerosis and acute cardiovascular events, as well as the impact of desynchrony between central and peripheral clocks on disease severity. Additionally, we highlight the circadian regulation of genes implicated in cardiovascular ageing and disease. Finally, we explore emerging research on the clinical implications of circadian misalignment, with a focus on therapeutic strategies such as chronotherapy, time-restricted eating, and physical activity. By integrating current evidence, this review provides a comprehensive perspective on leveraging circadian rhythms for the prevention and management of cardiovascular diseases.

The circadian clock plays a crucial role in regulating the timing of numerous physiological processes. Its dysregulation has severe implications for the organism’s homeostasis and is among the main characteristics of aging. As women age and transition through menopause, disruptions in circadian rhythms may occur, leading to symptoms such as insomnia, mood changes, or altered energy levels. In this prospective non-randomized cohort study, we seek to characterize and better understand circadian clock alterations in women across various stages of their reproductive cycle, both with and without daily routine alterations (e.g., specific diet, light exposure). Understanding the intricate relationship between circadian rhythms and female health during the aging process is essential for developing targeted interventions to mitigate symptoms and promote overall well-being in menopausal women. Findings from this study will be used to devise tailored circadian rhythm assessments and interventions for women, facilitating the alleviation of menopause-related symptoms and promoting healthy aging.

The aim of the present study was to identify blood-based biomarkers that could predict individual VO2max improvement before the start of an artificial altitude training camp. In an exploratory intervention study, 15 young highly trained athletes from the German Athletics Federation completed a 21-day Live High – Train Low program at an artificial altitude house, which simulated an altitude of 800 km·h (approximately 1.900–2.500 m) under normobaric hypoxia. V̇O₂max was measured pre- and post-intervention, and blood parameters were collected at six time points (pre, post and four times at altitude. The pre measurement functioned as baseline and was used for the predictive model. Altitude training led to a mean V̇O₂max increase of 2.1 mL · kg⁻¹ · min⁻¹ (+ 3.1

Introduction Altitude training is a method among endurance athletes to enhance performance via hypoxia-induced adaptations, However, individual responses vary significantly, with some athletes even showing performance decrements. Iron metabolism and immune function may influence these adaptations, as hypoxia-induced erythropoiesis increases systemic iron demand, potentially affecting immune cells reliant on iron. This study investigated the interplay between hematological, iron, and immune parameters under controlled hypoxic conditions. Methods 15 elite endurance athletes participated in a 21-day live-high-train-low training camp in an artificial normobaric altitude house. Blood samples were collected pre- and post-camp and at four intermediate time points to measure hematological variables, iron metabolism markers, and immune parameters. Pre- and post-performance was assessed via VO₂max tests. Statistical analyses included paired t-tests, Wilcoxon rank-sum test, Spearman correlations, and Granger causality analysis to explore systemic temporal interactions. Results VO₂max increased significantly (p < 0.05) with large interindividual variability (2.4 ± 3.5 ml/min/kg). Hemoglobin, erythrocytes, and sTfR showed significant increases over time (p < 0.05), while ferritin peaked early and declined post-camp. Myeloperoxidase and lactoferrin exhibited dynamic correlations with iron parameters (p < 0.05), reflecting competition between erythropoiesis and immune function for iron. The structure of the Granger causality network places transferrin in a central role, highlighting iron metabolism as one key regulator of these adaptations. Discussion Artificial altitude training induces systemic physiological changes involving hematological, iron, and immune systems. Controlled hypoxic conditions enable detailed exploration of these underlying interactions, providing insights into optimizing altitude training strategies for endurance performance enhancement.

BACKGROUND:Ovarian cancer is among the most lethal malignancies in women. The advent of PARP inhibitors (PARPi) has improved outcomes. However, treatment-related toxicity remains a critical challenge, impacting patient quality of life and treatment adherence. METHODS:In a circadian sub-study of the MAMOC trial-a double-blind, phase III study-42 patients (FIGO stage IIIA-IV) were randomised in a 2:1 ratio to receive rucaparib or placebo. In a subset of these patients, we performed differential gene expression and rhythmicity analysis on up to 800 genes, including clock and clock-controlled genes. Machine learning algorithms and mathematical modelling were employed to simulate patient-specific toxicity profiles and to explore correlations between gene expression patterns and treatment-related side effects. FINDINGS:Our analysis revealed significant disruptions in circadian rhythms, specifically in the expression of the core clock genes BMAL1 and PER2, following treatment. These disruptions strongly correlated with the severity and frequency of side effects, including nausea and fatigue, displaying opposite trends between the placebo and rucaparib-treated groups. K-means clustering successfully distinguished rucaparib-treated patients from those receiving placebo based on BMAL1 phase and gene expression profiles. In addition, rucaparib therapy also altered the expression of several clock-controlled genes, including SIRT1, BRCA1, BRCA2, and TP53. Notably, our data suggest that individual differences in circadian rhythms may lead to distinct 24-h toxicity profiles among patients. INTERPRETATION:These findings suggest that circadian rhythm dysregulation may contribute to the toxicity of PARPi therapy. Aligning treatment timing with circadian rhythms could mitigate these adverse effects, and improve patient outcomes. FUNDING:This study was funded by the Dr. Rolf Schwiete Stiftung and the MSH Medical School Hamburg, Germany. The MAMOC trial (ClinicalTrials.gov: NCT04227522) was funded by Clovis Oncology, United States.

The success of fracture healing relies on overlapping but coordinated cellular and molecular events. Characterizing an outline of differential gene regulation throughout successful healing is essential for identifying crucial phase-specific markers and may serve as the basis for engineering these in challenging healing situations. This study analyzed the healing progression of a standard closed femoral fracture model in C57BL/6N (age = 8 weeks) wild-type male mice. The fracture callus was assessed across various days post fracture (D = days 0, 3, 7, 10, 14, 21, and 28) by microarray, with D0 serving as a control. Histological analyses were carried out on samples from D7 until D28 to support the molecular findings. Microarray analysis revealed a differential regulation of immune response, angiogenesis, ossification, extracellular matrix regulation, mitochondrial and ribosomal genes during healing. In-depth analysis showed differential regulation of mitochondrial and ribosomal genes during the initial phase of healing. Furthermore, the differential gene expression showed an essential role of Serpin Family F Member 1 over the well-known Vascular Endothelial Growth Factor in angiogenesis, especially during the inflammatory phase. The significant upregulation of matrix metalloproteinase 13 and bone sialoprotein from D3 until D21 asserts their importance in bone mineralization. The study also shows type I collagen around osteocytes located in the ossified region at the periosteal surface during the first week of healing. Histological analysis of matrix extracellular phosphoglycoprotein and extracellular signal-regulated kinase stressed their roles in bone homeostasis and the physiological bone-healing process. This study reveals previously unknown and novel candidates, that could serve as a target for specific time points in healing and to remedy cases of impaired healing.

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. Here, we investigated potential functional consequences of clock disruptions on skeletal muscle using published omics datasets obtained from spaceflights and other clock-altering, external (fasting and exercise), or internal (aging) conditions on Earth. Our analysis identified alterations of the clock network and skeletal muscle-associated pathways, as a result of spaceflight duration in mice, which resembles aging-related gene expression changes observed in humans on Earth (e.g., ATF4 downregulation, associated with muscle atrophy). Furthermore, according to our results, external factors such as exercise or fasting lead to molecular changes in the core-clock network, which may compensate for the circadian disruption observed during spaceflights. Thus, maintaining circadian functioning is crucial to ameliorate unphysiological alterations and musculoskeletal atrophy reported among astronauts.

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. However, little is known about the common molecular alterations underlying terrestrial aging and space-related aging in astronauts, and controversial conclusions have been recently reported. In light of the regulatory role of the circadian clock in the maintenance of human health, we review here the overlapping role of the circadian clock both on aging on Earth and spaceflight with a focus on the four most affected systems: visual, cardiovascular, central nervous, and musculoskeletal systems. In this review, we briefly introduce the regulatory role of the circadian clock in specific cellular processes followed by alterations in those processes due to aging. We next summarize the known molecular alterations associated with spaceflight, highlighting involved clock-regulated genes in space flown Drosophila, nematodes, small mammals, and astronauts. Finally, we discuss common genes that are altered in terms of their expression due to aging on Earth and spaceflight. Altogether, the data elaborated in this review strengthen our hypothesis regarding the timely need to include circadian dysregulation as an emerging hallmark of aging on Earth and beyond.

Osseointegration is a prerequisite for the long-term success of implants. Titanium implants are preferred for their biocompatibility and mechanical properties. Nonetheless, the need for early and immediate loading requires enhancing these properties by adding bioactive coatings. In this preclinical study, extracellular matrix properties and cellular balance at the implant/bone interface was examined. Polyelectrolyte multilayers of chitosan and gelatin or with chitosan and Hyaluronic acid fabricated on titanium alloy using a layer-by-layer self-assembly process were compared with native titanium alloy. The study aimed to histologically evaluate bone parameters that correlate to the biomechanical anchorage enhancement resulted from bioactive coatings of titanium implants in a rat animal model. Superior collagen fiber arrangements and an increased number of active osteocytes reflected a significant improvement of bone matrix quality at the bone interface of the chitosan/gelatin-coated titan implants over chitosan/hyaluronic acid-coated and native implants. Furthermore, the numbers and localization of osteoblasts and osteoclasts in the reparative and remodeling phases suggested a better cellular balance in the chitosan/Gel-coated group over the other two groups. Investigating the micro-mechanical properties of bone tissue at the interface can elucidate detailed discrepancies between different promising bioactive coatings of titanium alloys to maximize their benefit in future medical applications.

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 ARNTL, PER2 or NR1D1 in cancer progression (e.g., cell proliferation and invasion) using colorectal cancer (CRC) cell lines HCT116, SW480 and SW620, from different progression stages with distinct clock phenotypes, and identified mechanistic links from the clock to altered cancer-promoting cellular properties. We identified MACC1 (metastasis-associated in colon cancer 1), a known driver for metastasis and an EMT (epithelial-to-mesenchymal transition)-related gene, to be significantly differentially expressed in CC manipulated cells and analysed the effect of MACC1 manipulation (knockout or overexpression) in terms of circadian clock phenotype as well as cancer progression. Our data points to a bi-directional MACC1-circadian clock interplay in CRC, via CC genes. In particular, knocking out MACC1 reduced the period of oscillations, while its overexpression increased it. Interestingly, we found the MACC1 protein to be circadian expressed in HCT116 WT cells, which was disrupted after the knockout of CC genes, and identified a MACC1-NR1D1 protein–protein interaction. In addition, MACC1 manipulation and CC knockout altered cell invasion properties of HCT116 cells, pointing to a regulation of clock and cancer progression in CRC, possibly via the interaction of MACC1 with core-clock 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. The deletion of individual core-clock genes resulted in the loss of circadian expression in crucial spliceosome components such as SF3A1 (in ARNTL KO ), SNW1 (in NR1D1 KO ), and HNRNPC (in PER2 KO ), which led to a differential pattern of KO-specific AS events. All HCT116 KO cells showed a rhythmicity loss of a crucial spliceosome gene U2AF1 , which was also not rhythmic in higher progression stage CRC and HL cancer cells. AS analysis revealed an increase in alternative first exon events specific to PER2 and NR1D1 KO in HCT116 cells, and a KO-specific change in expression and rhythmicity pattern of AS transcripts related to cancer hallmarks genes including FGFR2 in HCT116_ ARNTL KO , CD44 in HCT116_ NR1D1 KO , and MET in HCT116_ PER2 KO . KO-specific changes in rhythmic properties of known spliced variants of these genes (e.g. FGFR2 IIIb/ FGFR2 IIIc) correlated with epithelial-mesenchymal-transition signalling. Altogether, our bioinformatic analysis highlights a role for the circadian clock in the regulation of AS, and reveals a potential impact of clock disruption in aberrant splicing in cancer hallmark genes.

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.e. in providing results comparable to other data sources used in previously published studies. Design: Retrospective database analysis. Methods: Transfermarkt.com (Transfermarkt; Hamburg; Germany) is a publicly accessible online database on various data of professional football players. All information provided in the section "injury history" of football players from the top five European leagues over a period of ten seasons (2009/10-2018/19) was analyzed. Frequency, characteristics, and incidence of injuries were reported according to seasons and countries, and results compared with three previously published databases (a scientific injury surveillance, a media-based study, and an insurance database). Results: Overall, 21,598 injuries of 11,507 players were analyzed from the Transfermarkt.com database. Incidence was 0.63 injuries per player-season (95% confidence interval 0.62 to 0.64) but significant differences between subgroups (countries, years) were found. In comparison to other databases, citizen science-based data was associated with lower injury incidences and higher proportions of severe injuries. Conclusions: With few exceptions (e.g., severe injuries), the use of citizen science-based health data on professional football players cannot be recommended at present for epidemiological research. (c) 2021 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Biofeedback was reported as an effective concept for bruxism treatment, through increasing patient’s awareness of the habit. During bruxing both ear canals become tighter, therefore, an in-ear device can provide biofeedback. The in-ear device is fitted to the ear canal in physiological status, during bruxing the ear-canal tightens resulting in stress on the canal walls and unpleasant feeling. Subsequently, patients stop their bruxing habit. The aim of this study is to provide first clinical evidence that in-ear devices have a positive impact on relieving bruxism in patients. Despite the low number of patients, this early study was designed as a controlled prospective study. The trial included seven female patients with a median age of 47.3 years (23–64 years). Only two patients implemented their devices for eight and seven months, respectively. One patient reported a relief in her symptoms, like headaches and pain intensity during the night, by 50% after three month and 80% after six months. Despite the limited number of participants, the study reflects a potential of Intra-aural devices as effective biofeedback devices in treating bruxism.

Periprosthetic femoral fracture (PFF) is a devastating complication. Here, the authors aimed to determine the influence of the timing of surgery as a risk factor for mortality and poor postoperative outcome in patients suffering from PFF. A retrospective descriptive analysis of patients treated for PFF between January 2010 and March 2018 was performed. In addition to patient and treatment characteristics, we assessed mortality rates and postoperative functional outcome by using the Harris Hip and WOMAC score. One-year mortality after PFF was 10.7%. Delayed surgery after 48 h did not negatively influence mortality after PFF. The postoperative hospital stay did not influence the mortality rate, nor did it correlate with medical scores of comorbidities, general health or functionalities. Cementation of stem correlated negatively with the WOMAC score. Deceased patients had a higher Charlson Comorbidity Index (CCI) score, while American society of Anaesthesiologists (ASA) scores did not show a significant difference. There were no differences between ORIF and revision arthroplasty. In conclusion, delayed surgery after 48 h does not negatively influence mortality after PFF. The CCI seems to be a suitable tool to assess patients' risk for increased mortality after PFF, while the usually used ASA score is not able to achieve a relevant risk assessment.