Ageing as a risk factor for neurodegenerative disease

Nature Reviews Neurology, Год журнала: 2019, Номер 15(10), С. 565 - 581

Опубликована: Сен. 9, 2019

Язык: Английский

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Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

Cell Metabolism, Год журнала: 2018, Номер 27(6), С. 1176 - 1199

Опубликована: Июнь 1, 2018

Язык: Английский

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Biomarkers of Cellular Senescence and Skin Aging

Frontiers in Genetics, Год журнала: 2018, Номер 9

Опубликована: Авг. 23, 2018

Cellular senescence is an irreversible growth arrest that occurs as a result of different damaging stimuli, including DNA damage, telomere shortening and dysfunction or oncogenic stress. Senescent cells exert pleotropic effect on development, tissue aging regeneration, inflammation, wound healing tumor suppression. Strategies to remove senescent from tissues preneoplastic lesions can delay lead increased healthspan. However, significant hurdle in the field has been identification universal biomarker facilitates unequivocal detection quantification cell types vitro vivo. Mammalian skin largest organ human body consists compartments. Skin provides physical barrier against harmful microbes, toxins protects us ultraviolet radiation. Increasing evidence suggests accumulate chronologically- photoaged skin; may contribute age-related changes pathologies. Here, we highlight current biomarkers detect review their utility context aging. In particular, discuss efficacy within compartments types, how they myriad manifestations

Язык: Английский

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DNA damage checkpoint kinases in cancer

Expert Reviews in Molecular Medicine, Год журнала: 2020, Номер 22

Опубликована: Янв. 1, 2020

Abstract DNA damage response (DDR) pathway prevents high level endogenous and environmental being replicated passed on to the next generation of cells via an orchestrated integrated network cell cycle checkpoint signalling repair pathways. Depending type damage, where in it occurs different pathways are involved, with ATM-CHK2-p53 controlling G1 or ATR-CHK1-Wee1 S G2/M checkpoints. Loss control is common cancer through TP53, ATM mutations, Rb loss cyclin E overexpression, providing a stronger rationale for targeting S/G2 This review will focus ATM-CHK2-p53-p21 ATR-CHK1-WEE1 ongoing efforts target these patient benefit.

Язык: Английский

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Cellular functions of the protein kinase ATM and their relevance to human disease

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 22(12), С. 796 - 814

Опубликована: Авг. 24, 2021

Язык: Английский

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Chromosome instability syndromes

Nature Reviews Disease Primers, Год журнала: 2019, Номер 5(1)

Опубликована: Сен. 19, 2019

Язык: Английский

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DNA damage—how and why we age?

eLife, Год журнала: 2021, Номер 10

Опубликована: Янв. 29, 2021

Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, increased risk morbidity and mortality. Many factors contribute aging, such as time-dependent accumulation macromolecular damage, including DNA damage. The integrity nuclear genome essential for cellular, tissue, organismal health. damage constant threat because nucleic acids are chemically unstable under physiological conditions vulnerable attack by endogenous environmental factors. To combat this, all organisms possess highly conserved mechanisms detect repair Persistent (genotoxic stress) triggers signaling cascades drive cells into apoptosis or senescence avoid replicating damaged genome. drawback these cancer avoidance promote aging. Here, we review evidence plays causal role We also provide genotoxic stress linked other cellular processes implicated drivers mitochondrial metabolic dysfunction, altered proteostasis inflammation. These links between genetic code pillars aging support notion could be root

Язык: Английский

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Ataxia‐telangiectasia: A review of clinical features and molecular pathology

Pediatric Allergy and Immunology, Год журнала: 2019, Номер 30(3), С. 277 - 288

Опубликована: Янв. 27, 2019

Abstract Ataxia‐telangiectasia (A‐T) is an autosomal recessive primary immunodeficiency (PID) disease that caused by mutations in ataxia‐telangiectasia mutated ( ATM ) gene encoding a serine/threonine protein kinase. A‐T patients represent broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases. This congenital disorder has phenotypic heterogeneity, the severity symptoms varies different based on progression. The principal role nuclear coordination cellular signaling pathways response DNA double‐strand breaks, oxidative stress, cell cycle checkpoint. pathogenesis not limited damage (DDR) pathway, it other functions mainly hematopoietic cells neurons. adjusts organelles such as mitochondria peroxisomes also regulates angiogenesis glucose metabolisms. However, (especially viability) need further investigations. In this review, we described nucleus cytoplasm, its association with some formation neurologic, immunologic, vascular, pulmonary, metabolic, dermatologic complications.

Язык: Английский

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Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers

Cancer Prevention Research, Год журнала: 2021, Номер 14(4), С. 433 - 440

Опубликована: Янв. 28, 2021

Abstract Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate PV cancer risks independent family history. analysis included patients referred for hereditary testing with a multi-gene panel (N = 627,742). Cancer carriers 4,607) were adjusted history using multivariable logistic regression reported as ORs 95% confidence intervals (CIs). Subanalyses c.7271T>G missense conducted. Moderate-to-high pancreatic (OR, 4.21; CI, 3.24–5.47), prostate 2.58; 1.93–3.44), gastric 2.97; 1.66–5.31), invasive ductal breast 2.03; 1.89–2.19) cancers estimated carriers. Notably, was associated higher 3.76; 2.76–5.12) than other truncating PVs. Low-to-moderate seen carcinoma situ 1.80; 1.61–2.02), male 1.72; 1.08–2.75), ovarian 1.57; 1.35–1.83), colorectal 1.49; 1.24–1.79), melanoma 1.46; 1.18–1.81). PVs multiple and, while professional society guidelines support that eligible increased screening, screening may also be warranted. is high cancer, 3- 4-fold increase supports consideration strategies prevention and/or early detection. Prevention Relevance: pathogenic These results indicate some common previously appreciated warranted variants.

Язык: Английский

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A framework for individualized splice-switching oligonucleotide therapy

Nature, Год журнала: 2023, Номер 619(7971), С. 828 - 836

Опубликована: Июль 12, 2023

Abstract Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases 1 , but the systematic identification such remains challenge. Here we performed whole-genome sequencing analyses characterize variation in 235 (from 209 families) ataxia-telangiectasia, severely debilitating and life-threatening recessive disorder 2,3 yielding complete molecular diagnosis almost all individuals. We developed predictive taxonomy assess amenability each individual splice-switching ASO intervention; 9% 6% had variants that were ‘probably’ or ‘possibly’ amenable splice modulation, respectively. Most deep intronic regions are inaccessible exon-targeted sequencing. ASOs successfully rescued mis-splicing ATM cellular signalling patient fibroblasts for two recurrent variants. In pilot clinical study, one these was child who been diagnosed ataxia-telangiectasia soon after birth, showed good tolerability without serious adverse events three years. Our study provides framework prospective might benefit from therapeutic approach involving ASOs.

Язык: Английский

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