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Journal of Neurology, Neurosurgery, and... Feb 1964
Topics: Ataxia; Ataxia Telangiectasia; Child; Face; Palate; Sclera; South Africa; Telangiectasis
PubMed: 14123922
DOI: 10.1136/jnnp.27.1.38 -
The Journal of Veterinary Medical... Nov 2022Uncovering radiation toxicity is critical for the adaptation and expansion of advanced radiation therapies and for the development of novel cancer radiotherapy. In the...
Uncovering radiation toxicity is critical for the adaptation and expansion of advanced radiation therapies and for the development of novel cancer radiotherapy. In the near future, advanced radiotherapies, including heavy ion beam treatment, are expected to be applied in the treatment of dogs, but further basic research on the effects of radiation using canine normal and cancer cells is necessary to actually apply these techniques and achieve high therapeutic efficacy. The radiation sensitivity is varied by the activities of DNA damage response (DDR) and DNA repair. The development of radiosensitizers that target DDR- and DNA repair-kinases, like ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK), is progressing and is expected to be introduced into canine radiotherapy. However, there are no cytotoxicity reports on using the combination of radiation and these sensitizers as treatment in canine cells. In this study, we examined the cytotoxic effects of X-rays and/or radiosensitizers on the Madin-Darby canine kidney (MDCK) cell line. Our results show that X-rays suppress MDCK cell colony formation and proliferation in a dose-dependent manner. Additionally, our observations imply that the combination treatment with ATM inhibitor KU-55933 and DNA-PK inhibitor NU7441 significantly increased X-ray cytotoxicity in MDCK cells compared with the drugs alone. Furthermore, our findings further suggest that MDCK cells might be useful in clarifying the cytotoxicity in canine epithelial cells due to radiation and/or radiosensitizers, such as molecule-targeted drugs.
Topics: Dogs; Animals; DNA-Activated Protein Kinase; Ataxia Telangiectasia; Madin Darby Canine Kidney Cells; Ataxia Telangiectasia Mutated Proteins; DNA; Kidney; DNA Damage; Dog Diseases
PubMed: 36104184
DOI: 10.1292/jvms.22-0061 -
NeuroImage. Clinical 2020Ataxia Telangiectasia (A-T) is an inherited multisystem disorder with cerebellar neurodegeneration. The relationships between imaging metrics of cerebellar health and... (Observational Study)
Observational Study
BACKGROUND
Ataxia Telangiectasia (A-T) is an inherited multisystem disorder with cerebellar neurodegeneration. The relationships between imaging metrics of cerebellar health and neurological function across childhood in A-T are unknown, but may be important for determining timing and impact of therapeutic interventions.
PURPOSE
To test the hypothesis that abnormalities of cerebellar structure, physiology and cellular health occur in childhood A-T and correlate with neurological disability, we performed multiparametric cerebellar MRI and establish associations with disease status in childhood A-T.
METHODS
Prospective cross-sectional observational study. 22 young people (9 females / 13 males, age 6.6-17.8 years) with A-T and 24 matched healthy controls underwent 3-Tesla MRI with volumetric, diffusion and proton spectroscopic acquisitions. Participants with A-T underwent structured neurological assessment, and expression / activity of ataxia-telangiectasia mutated (ATM) kinase were recorded.
RESULTS
Ataxia-telangiectasia participants had cerebellar volume loss (fractional total cerebellar volume: 5.3% vs 8.7%, P < 0.0005, fractional 4th ventricular volumes: 0.19% vs 0.13%, P < 0.0005), that progressed with age (fractional cerebellar volumes, r = -0.66, P = 0.001), different from the control group (t = -4.88, P < 0.0005). The relationship between cerebellar volume and age was similar for A-T participants with absent ATM kinase production and those producing non-functioning ATM kinase. Markers of cerebellar white matter injury were elevated in ataxia-telangiectasia vs controls (apparent diffusion coefficient: 0.89 × 10 mm s vs 0.69 × 10 mm s, p < 0.0005) and correlated (age-corrected) with neurometabolite ratios indicating impaired neuronal viability (N-acetylaspartate:creatine r = -0.70, P < 0.001); gliosis (inositol:creatine r = 0.50, P = 0.018; combined glutamine/glutamate:creatine r = -0.55, P = 0.008) and increased myelin turnover (choline:creatine r = 0.68, P < 0.001). Fractional 4th ventricular volume was the only variable retained in the regression model predicting neurological function (adjusted r = 0.29, P = 0.015).
CONCLUSIONS
Quantitative MRI demonstrates cerebellar abnormalities in children with A-T, providing non-invasive measures of progressive cerebellar injury and markers reflecting neurological status. These MRI metrics may be of value in determining timing and impact of interventions aimed at altering the natural history of A-T.
Topics: Adolescent; Ataxia Telangiectasia; Cerebellum; Child; Cross-Sectional Studies; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Multimodal Imaging; Neuroimaging; Phenotype; Prospective Studies; White Matter
PubMed: 31855653
DOI: 10.1016/j.nicl.2019.102110 -
Biomedical Chromatography : BMC Nov 2022Ataxia-telangiectasia-mutated and Rad3-related (ATR) is master regulator of the DNA-damage response that, through multiple mechanisms, can promote cancer cell survival...
Ataxia-telangiectasia-mutated and Rad3-related (ATR) is master regulator of the DNA-damage response that, through multiple mechanisms, can promote cancer cell survival in response to replication stress from sources, including chemotherapy and radiation. Elimusertib (BAY-1895344) is an orally available small-molecule ATR inhibitor currently in preclinical and clinical development for cancer treatment. To support these studies and define elimusertib pharmacokinetics, we developed a HPLC-MS method for its quantitation. A 50-μL volume of plasma was subjected to acetonitrile protein precipitation and then chromatographic separation using a Phenomenex Polar-RP column (2 × 50 mm, 4 μm) and a gradient mobile phase consisting of 0.1% formic acid in acetonitrile and water during a 7-min run time. Mass spectrometric detection was achieved using a SCIEX 4000 triple-stage mass spectrometer with electrospray positive-mode ionization. With a stable isotopic internal standard, the assay was linear from 30 to 5000 ng/mL and proved to be both accurate (93.5-108.2%) and precise (<6.3% coefficient of variation) fulfilling criteria from the Food and Drug Administration guidance on bioanalytical method validation. This LC-MS/MS assay will support several ongoing clinical studies by defining elimusertib pharmacokinetics.
Topics: Acetonitriles; Ataxia Telangiectasia; Chromatography, Liquid; DNA; Humans; Protein Kinase Inhibitors; Reproducibility of Results; Tandem Mass Spectrometry; Water
PubMed: 35876841
DOI: 10.1002/bmc.5455 -
Autophagy Feb 2021Mitophagy is a selective process aimed at removing damaged or burned-out mitochondria; it is activated upon different stimuli and plays a fundamental role in preventing... (Review)
Review
Mitophagy is a selective process aimed at removing damaged or burned-out mitochondria; it is activated upon different stimuli and plays a fundamental role in preventing overproduction of reactive oxygen species (ROS) that might be generated by dysfunctional mitochondria. From this angle, mitophagy can be considered a fully-fledged antioxidant process. Such a surrogate antioxidant function is recently emerging, being shared among many molecular pathways and players that are usually not included among - and, formally, do not directly act as - antioxidants. ATM (ataxia telangiectasia mutated) is a prototype of this class of "neglected" antioxidants. In spite of its well-known role in DNA damage response, many phenotypes of ataxia telangiectasia (A-T) patients are, indeed, related to chronic oxidative stress, arguing for an additional antioxidant role of ATM. In a recent study, we discovered the mechanism through which ATM exerts antioxidant activity. In particular, we provided evidence that this involves ADH5/GSNOR (alcohol dehydrogenase 5 (class III), chi polypeptide), which, in turn, sustains mitophagy via PARK2 denitrosylation, and protects the cell from detrimental effects due to ROS.
Topics: Animals; Antioxidants; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Autophagy; Humans; Mitophagy; Reactive Oxygen Species
PubMed: 33292042
DOI: 10.1080/15548627.2020.1860490 -
The European Respiratory Journal Dec 2015
Topics: Ataxia Telangiectasia; Cough; Deglutition Disorders; Europe; Humans; Immunologic Deficiency Syndromes; Lung Diseases; Lung Diseases, Interstitial; Neurodegenerative Diseases; Pneumonia; Pulmonary Medicine; Recurrence; Respiratory Tract Infections; Sinusitis; Societies, Medical
PubMed: 26621885
DOI: 10.1183/13993003.01456-2015 -
PloS One 2022Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely...
BACKGROUND
Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely reported, there are no studies that give a comprehensive picture of this intriguing condition.
OBJECTIVES
Understand the natural history of ataxia-telangiectasia (A-T), as reported in scientific literature.
SEARCH METHODS
107 search terms were identified and divided into 17 searches. Each search was performed in PubMed, Ovid SP (MEDLINE) 1946-present, OVID EMBASE 1980 -present, Web of Science core collection, Elsevier Scopus, and Cochrane Library.
SELECTION CRITERIA
All human studies that report any aspect of A-T.
DATA COLLECTION AND ANALYSIS
Search results were de-duplicated, data extracted (including author, publication year, country of origin, study design, population, participant characteristics, and clinical features). Quality of case-control and cohort studies was assessed by the Newcastle-Ottawa tool. Findings are reported descriptively and where possible data collated to report median (interquartile range, range) of outcomes of interest.
MAIN RESULTS
1314 cases reported 2134 presenting symptoms. The most common presenting symptom was abnormal gait (1160 cases; 188 studies) followed by recurrent infections in classical ataxia-telangiectasia and movement disorders in variant ataxia-telangiectasia. 687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months).
CONCLUSIONS
This review demonstrates the multi-system involvement in A-T, confirms that neurological symptoms are the most frequent presenting features in classical A-T but variants have diverse manifestations. We found that most individuals with A-T have life limited to teenage or early adulthood. Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T. We recommend population-based studies to fill this evidence gap.
Topics: Adolescent; Adult; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cohort Studies; Humans; Movement Disorders; Mutation
PubMed: 35290391
DOI: 10.1371/journal.pone.0264177 -
The International Journal of... Jun 2022The DNA damage response is an integral part of a cells' ability to maintain genomic integrity by responding to and ameliorating DNA damage, or initiating cell death for...
The DNA damage response is an integral part of a cells' ability to maintain genomic integrity by responding to and ameliorating DNA damage, or initiating cell death for irrepairably damaged cells. This response is often hijacked by cancer cells to evade cell death allowing mutant cells to persist, as well as in the development of treatment resistance to DNA damaging agents such as chemotherapy and radiation. Prostate cancer (PCa) cells often exhibit alterations in DNA damage response genes including ataxia telangiectasia mutated (ATM), correlating with aggressive disease phenotype. The recent success of Poly (ADP-ribose) polymerase (PARP) inhibition has led to several clinically approved PARP inhibitors for the treatment of men with metastatic PCa, however a key limitation is the development of drug resistance and relapse. An alternative approach is selectively targeting ATM and ataxia telangiectasia and Rad3-related (ATR) which, due to their position at the forefront of the DDR, represent attractive pharmacological targets. ATR inhibition has been shown to act synergistically with PARP inhibition and other cancer treatments to enhance anti-tumour activity. ATM-deficiency is a common characteristic of PCa and a synthetic lethal relationship exists between ATM and ATR, with ATR inhibition inducing selective cell death in ATM-deficient PCa cells. The current research highlights the feasibility of therapeutically targeting ATR in ATM-deficient prostate tumours and in combination with other treatments to enhance overall efficacy and reduce therapeutic resistance. ATM also represents an important molecular biomarker to stratify patients into targeted treatment groups and aid prognosis for personalised medicine.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; DNA Damage; Humans; Male; Neoplasm Recurrence, Local; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms
PubMed: 35609768
DOI: 10.1016/j.biocel.2022.106230 -
Frontiers in Immunology 2021Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative multisystem disorder. A minority of AT patients can present late-onset atypical presentations...
Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative multisystem disorder. A minority of AT patients can present late-onset atypical presentations due to unknown mechanisms. The demographic, clinical, immunological and genetic data were collected by direct interview and examining the Iranian AT patients with late-onset manifestations. We also conducted a systematic literature review for reported atypical AT patients. We identified three Iranian AT patients (3/249, 1.2% of total registry) with later age at ataxia onset and slower neurologic progression despite elevated alpha-fetoprotein levels, history of respiratory infections, and immunological features of the syndrome. Of note, all patients developed autoimmunity in which a decrease of naïve T cells and regulatory T cells were observed. The literature searches also summarized data from 73 variant AT patients with atypical presentation indicating biallelic mild mutations mainly lead to an atypical phenotype with an increased risk of cancer. Variant AT patients present with milder phenotype or atypical form of classical symptoms causing under- or mis- diagnosis. Although missense mutations are more frequent, an atypical presentation can be associated with deleterious mutations due to unknown modifying factors.
Topics: Adolescent; Adult; Ataxia; Ataxia Telangiectasia; Child; Child, Preschool; Female; Humans; Iran; Male; Mutation, Missense; Phenotype; T-Lymphocytes, Regulatory; Young Adult; alpha-Fetoproteins
PubMed: 35095854
DOI: 10.3389/fimmu.2021.779502 -
Blood May 2013In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many... (Review)
Review
In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells, ataxia telangiectasia mutated (ATM) is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high-molecular-weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell-signaling pathways involved in cell-cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense-mediated decay, and others. Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients-children and adults alike-which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. An exciting recent development is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses.
Topics: Adult; Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA Breaks, Double-Stranded; DNA Damage; DNA-Binding Proteins; Humans; Mitochondria; Models, Biological; Oxidation-Reduction; Oxidative Stress; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 23440242
DOI: 10.1182/blood-2012-09-456897