Search

Radon, a radioactive inert gas that comes from the decay of naturally occurring radioactive species, poses a substantial health risk due to its involvement in lung cancer carcinogenesis. This work proposes a metrological approach for determining radon exhalation rates from diverse building materials. This methodology employs an electrostatic collection chamber for alpha spectrometry of radon isotopic decay products. Experimental evaluations were conducted particularly focusing on volcanic gray tuff from Sant'Agata de' Goti (Campania region, Italy), a material commonly utilized in construction, to assess radon exhalation rates. The study aligns with Legislative Decree 101/2020, a transposition of European Directive 59/2013/Euratom, highlighting the need to identify materials with a high risk of radon exhalation. Moreover, this work supports the goals of the Italian National Radon Action Plan related to the aforementioned decree, aiming to develop methodologies for estimating radon exhalation rates from building materials and improving radioprotection practices. [ABSTRACT FROM AUTHOR]

The adult heart is made up of cardiomyocytes (CMs) that maintain pump function but are unable to divide and form new myocytes in response to myocardial injury. In contrast, the developmental cardiac tissue is made up of proliferative CMs that regenerate injured myocardium. In mammals, CMs during development are diploid and mononucleated. In response to cardiac maturation, CMs undergo polyploidization and binucleation associated with CM functional changes. The transition from mononucleation to binucleation coincides with unique metabolic changes and shift in energy generation. Recent studies provide evidence that metabolic reprogramming promotes CM cell cycle reentry and changes in ploidy and nucleation state in the heart that together enhances cardiac structure and function after injury. This review summarizes current literature regarding changes in CM ploidy and nucleation during development, maturation and in response to cardiac injury. Importantly, how metabolism affects CM fate transition between mononucleation and binucleation and its impact on cell cycle progression, proliferation and ability to regenerate the heart will be discussed. [ABSTRACT FROM AUTHOR]

The heart is a functional syncytium controlled by a delicate and sophisticated balance ensured by the tight coordination of its several cell subpopulations. Accordingly, cardiomyocytes together with the surrounding microenvironment participate in the heart tissue homeostasis. In the right atrium, the sinoatrial nodal cells regulate the cardiac impulse propagation through cardiomyocytes, thus ensuring the maintenance of the electric network in the heart tissue. Notably, the central nervous system (CNS) modulates the cardiac rhythm through the two limbs of the autonomic nervous system (ANS): the parasympathetic and sympathetic compartments. The autonomic nervous system exerts non-voluntary effects on different peripheral organs. The main neuromodulator of the Sympathetic Nervous System (SNS) is norepinephrine, while the principal neurotransmitter of the Parasympathetic Nervous System (PNS) is acetylcholine. Through these two main neurohormones, the ANS can gradually regulate cardiac, vascular, visceral, and glandular functions by turning on one of its two branches (adrenergic and/or cholinergic), which exert opposite effects on targeted organs. Besides these neuromodulators, the cardiac nervous system is ruled by specific neuropeptides (neurotrophic factors) that help to preserve innervation homeostasis through the myocardial layers (from epicardium to endocardium). Interestingly, the dysregulation of this neuro-signaling pathway may expose the cardiac tissue to severe disorders of different etiology and nature. Specifically, a maladaptive remodeling of the cardiac nervous system may culminate in a progressive loss of neurotrophins, thus leading to severe myocardial denervation, as observed in different cardiometabolic and neurodegenerative diseases (myocardial infarction, heart failure, Alzheimer's disease). This review analyzes the current knowledge on the pathophysiological processes involved in cardiac nervous system impairment from the perspectives of both cardiac disorders and a widely diffused and devastating neurodegenerative disorder, Alzheimer's disease, proposing a relationship between neurodegeneration, loss of neurotrophic factors, and cardiac nervous system impairment. This overview is conducive to a more comprehensive understanding of the process of cardiac neuro-signaling dysfunction, while bringing to light potential therapeutic scenarios to correct or delay the adverse cardiovascular remodeling, thus improving the cardiac prognosis and quality of life in patients with heart or neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Background: In Alzheimer's disease (AD), the characteristic cerebral amyloid β (Aβ) accumulation and tau pathology, are accompanied by a gradual loss of the two main neuromodulators, NGF and BDNF. This AD‐mediated derangement of the brain's neuro‐signaling pathways may extend to the periphery and, along with potential peripheral amyloid deposition, induce peripheral nervous system impairment, thus affecting other organs, including the heart. However, whether and how AD pathology affects cardiac physiology, neurotrophins, innervation, and heart amyloidosis is still undefined. Method: Here, we describe for the first‐time that cardiac remodeling and neuro‐signaling dysregulation are present in the hearts of Tg2576 mice, a widely used model of AD and cerebral amyloidosis. Results: Echocardiographic analysis showed significant deterioration of left ventricle function, as demonstrated by a decline of both ejection fraction and fraction shortening in 12‐month‐old Tg2576 mice compared to age‐matched WT littermates. The transgenic mice hearts presented an increase in interstitial fibrosis, with an accumulation of amyloid aggregates, including Aβ, associated with severe cardiac nervous system dysfunction. Tg2576 mice exhibited a depletion in cardiac nerve fiber density, both adrenergic (stained with tyrosine hydroxylase‐ TH) and regenerating nerve terminals (labeled with GAP‐43) compared to the WT mice. This myocardial denervation was accompanied by a decline in NGF and BDNF protein expression as well as GAP‐43 expression in both the brain and heart of Tg2576 mice. Likewise, both human neuroblastoma cells (SH‐SY5Y) and human cardiomyocytes (AC16) challenged with human Aβ‐40 or Aβ‐42 oligomers showed significant downregulation of both BDNF and GAP‐43 activity. Conclusion: Overall, this study highlights the deleterious impact of cerebral amyloidosis on the cardiac nervous system and heart physiology, providing potential therapeutic targets, such as neurotrophic factors, to prevent or limit the AD‐mediated degenerative mechanisms on the cardiovascular system. [ABSTRACT FROM AUTHOR]

The article discusses Estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative (ER+/HER2−), the most common subtype of breast cancer, accounting for up to 70% of all cases diagnosed. Mentions estrogen drives cell proliferation by inducing the expression of cyclin D1 and activating the cyclin-dependent kinase 4/6 (CDK4/6) pathway, in ER+ breast cancer. Informs relapses of ER+/ HER2- breast cancer remain a major problem, comprising 60% of metastatic breast cancer.

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER + breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B. RB1 loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER + breast cancer patients who develop resistance to CDK4/6i.

Developmental cardiac tissue is regenerative while operating under low oxygen. After birth, ambient oxygen is associated with cardiomyocyte cell cycle exit and regeneration. Likewise, cardiac metabolism undergoes a shift with cardiac maturation. Whether there are common regulators of cardiomyocyte cell cycle linking metabolism to oxygen tension remains unknown. The objective of the study is to determine whether mitochondrial UCP2 is a metabolic oxygen sensor regulating cardiomyocyte cell cycle. Neonatal rat ventricular myocytes (NRVMs) under moderate hypoxia showed increased cell cycle activity and UCP2 expression. NRVMs exhibited a metabolic shift toward glycolysis, reducing citrate synthase, mtDNA, mitochondrial membrane potential (ΔΨm), and DNA damage/oxidative stress, while loss of UCP2 reversed this phenotype. Next, WT and mice from a global UCP2-KO mouse line (UCP2KO) kept under hypoxia for 4 weeks showed significant decline in cardiac function that was more pronounced in UCP2KO animals. Cardiomyocyte cell cycle activity was reduced, while fibrosis and DNA damage was significantly increased in UCP2KO animals compared with WT under hypoxia. Mechanistically, UCP2 increased acetyl-CoA levels and histone acetylation, and it altered chromatin modifiers linking metabolism to cardiomyocyte cell cycle under hypoxia. Here, we show a potentially novel role for mitochondrial UCP2 as an oxygen sensor regulating cardiomyocyte cell cycle activity, acetyl-CoA levels, and histone acetylation in response to moderate hypoxia.