Effect of physical exercise on immune, inflammatory, cardiometabolic biomarkers, and fatty acids of breast cancer survivors: results from the MAMA_MOVE Gaia After Treatment trial.

PURPOSE: Physical exercise has positive effects on clinical outcomes of breast cancer survivors such as quality of life, fatigue, anxiety, depression, body mass index, and physical fitness. We aimed to study its impact on immune, inflammatory, cardiometabolic, and fatty acids (FA) biomarkers. METHODS: An exploratory sub-analysis of the MAMA_MOVE Gaia After Treatment trial (NCT04024280, registered July 18, 2019) was performed. Blood sample collections occurred during the control phase and at eight weeks of the intervention phase. Samples were subjected to complete leukocyte counts, cytokine, and cardiometabolic marker evaluation using flow cytometry, enzyme-linked immunoassays, and gas chromatography. RESULTS: Ninety-three percent of the 15 participants had body mass index ≥ 25 kg/m2. We observed a decrease of the plasmatic saturated FA C20:0 [median difference - 0.08% (p = 0.048); mean difference - 0.1 (95%CI - 0.1, - 0.0)], positively associated with younger ages. A tendency to increase the saturated FA C18:0 and the ratio of unsaturated/saturated FA and a tendency to decrease neutrophils (within the normal range) and interferon-gamma were observed. CONCLUSIONS: Positive trends of physical exercise on circulating immune cells, inflammatory cytokines, and plasmatic FA were observed. Larger studies will further elucidate the implications of physical exercise on metabolism. These exploratory findings may contribute to future hypothesis-driven research and contribute to meta-analyses.

Doxorubicin Dose-Dependent Impact on Physiological Balance-A Holistic Approach in a Rat Model.

Doxorubicin (DOX) is commonly used in several chemotherapies to treat various cancers, but it is known to cause cardiotoxicity and cardiac symptoms. Autonomic dysfunction is thought to contribute to the cardiotoxic effects of DOX, but the specific dose required to disrupt homeostatic processes is still unclear and is influenced by numerous factors. This study aimed to investigate how the DOX dosage affects autonomic function and physiological parameters, to elucidate the neurocardiac mechanisms underlying the observed cardiovascular side effects. Wistar rats were treated with DOX for four weeks and divided into three dosing groups: DOX8 (2 mg/kg/week), DOX16 (4 mg/kg/week), and DOX20 (5 mg/kg/week). A control group received NaCl 0.9% saline (1 mL/kg/week). In an acute experiment, we recorded blood pressure (BP), electrocardiogram, heart rate (HR), and respiratory rate (RF). Baroreflex gain and chemoreflex sensitivity were calculated, and cardiac tissue was analyzed with picrosirius histochemistry to measure collagen content. Our results showed that the LF/HF ratio, indicative of autonomic activity, was altered along with hypotension and bradycardia at a cumulative DOX dose threshold of 16 mg/kg. We observed a positive correlation between DOX dose and BP, HR, urinary norepinephrine, LF/HF ratio, and fibrotic heart area. Lower LF/HF ratios were associated with high DOX doses, reflecting drug-induced impairment of autonomic control of HR. This study provides valuable insights into the dose-dependent effects of DOX on physiological parameters and the development of cardiovascular dysfunction. These findings are critical, which is important for optimizing the management and therapeutic strategies for patients undergoing DOX-based chemotherapy.

Adaptive changes in the DNA damage response during skeletal muscle cell differentiation.

DNA double-strand breaks (DSBs) trigger specialized cellular mechanisms that collectively form the DNA damage response (DDR). In proliferating cells, the DDR serves the function of mending DNA breaks and satisfying the cell-cycle checkpoints. Distinct goals exist in differentiated cells that are postmitotic and do not face cell-cycle checkpoints. Nonetheless, the distinctive requirements and mechanistic details of the DDR in differentiated cells are still poorly understood. In this study, we set an in vitro differentiation model of human skeletal muscle myoblasts into multinucleated myotubes that allowed monitoring DDR dynamics during cell differentiation. Our results demonstrate that myotubes have a prolonged DDR, which is nonetheless competent to repair DSBs and render them significantly more resistant to cell death than their progenitors. Using live-cell microscopy and single-molecule kinetic measurements of transcriptional activity, we observed that myotubes respond to DNA damage by rapidly and transiently suppressing global gene expression and rewiring the epigenetic landscape of the damaged nucleus. Our findings provide novel insights into the DDR dynamics during cellular differentiation and shed light on the strategy employed by human skeletal muscle to preserve the integrity of the genetic information and sustain long-term organ function after DNA damage.

Single-molecule imaging of transcription at damaged chromatin.

How DNA double-strand breaks (DSBs) affect ongoing transcription remains elusive due to the lack of single-molecule resolution tools directly measuring transcription dynamics upon DNA damage. Here, we established new reporter systems that allow the visualization of individual nascent RNAs with high temporal and spatial resolution upon the controlled induction of a single DSB at two distinct chromatin locations: a promoter-proximal (PROP) region downstream the transcription start site and a region within an internal exon (EX2). Induction of a DSB resulted in a rapid suppression of preexisting transcription initiation regardless of the genomic location. However, while transcription was irreversibly suppressed upon a PROP DSB, damage at the EX2 region drove the formation of promoter-like nucleosome-depleted regions and transcription recovery. Two-color labeling of transcripts at sequences flanking the EX2 lesion revealed bidirectional break-induced transcription initiation. Transcriptome analysis further showed pervasive bidirectional transcription at endogenous intragenic DSBs. Our data provide a novel framework for interpreting the reciprocal interactions between transcription and DNA damage at distinct chromatin regions.