10,202 results match your criteria Ataxia-telangiectasia


ATM-deficient neural precursors develop senescence phenotype with disturbances in autophagy.

Mech Ageing Dev 2020 Jul 1:111296. Epub 2020 Jul 1.

Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. Electronic address:

ATM is a kinase involved in DNA damage response (DDR), regulation of response to oxidative stress, autophagy and mitophagy. Mutations in the ATM gene in humans result in ataxi A-Telangiectasia disease (A-T) characterized by a variety of symptoms with neurodegeneration and premature ageing among them. Since brain is one of the most affected organs in A-T, we have focused on senescence of neural progenitor cells (NPCs) derived from A-T reprogrammed fibroblasts. Read More

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http://dx.doi.org/10.1016/j.mad.2020.111296DOI Listing

Resveratrol activates DNA damage response through inhibition of polo-like kinase 1 (PLK1) in natural killer/T cell lymphoma.

Ann Transl Med 2020 Jun;8(11):688

Key Laboratory of Medical Molecular Virology of Ministry of Education & Ministry of Health, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

Background: Extranodal natural killer/T cell lymphoma (NKTCL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis. Resveratrol (REV), a natural nontoxic pleiotropic agent, has antitumor effects, yet not being studied in NKTCL.

Methods: We performed immunohistochemical (IHC) staining with NKTCL tumor tissues. Read More

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http://dx.doi.org/10.21037/atm-19-4324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327334PMC

Caffeine as a tool for investigating the integration of Cdc25 phosphorylation, activity and ubiquitin-dependent degradation in .

Cell Div 2020 29;15:10. Epub 2020 Jun 29.

Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, Gothenburg, SE- 405 30 Sweden.

The evolutionarily conserved Cdc25 phosphatase is an essential protein that removes inhibitory phosphorylation moieties on the mitotic regulator Cdc2. Together with the Wee1 kinase, a negative regulator of Cdc2 activity, Cdc25 is thus a central regulator of cell cycle progression in . The expression and activity of Cdc25 is dependent on the activity of the Target of Rapamycin Complex 1 (TORC1). Read More

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http://dx.doi.org/10.1186/s13008-020-00066-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322915PMC

Targeting DNA Damage Repair Pathways in Pancreatic Adenocarcinoma.

Curr Treat Options Oncol 2020 Jun 29;21(8):62. Epub 2020 Jun 29.

Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN, 37232, USA.

Opinion Statement: Metastatic (and locally advanced) pancreatic adenocarcinoma (mPDA) represents a major challenge for the oncology community given the rising mortality burden from the disease and the preponderance of patients diagnosed with unresectable disease. Although systemic therapies have become more potent with the development of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel as first-line treatments, the median overall survival for patients treated with either of these regimens remains just above 1 year. A significant need exists to build upon the effectiveness of first-line regimens, incorporate tolerable maintenance treatments, and add effective later-line options for patients with this disease. Read More

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http://dx.doi.org/10.1007/s11864-020-00763-7DOI Listing

The Role of Ataxia Telangiectasia Mutant and Rad3-Related DNA Damage Response in Pathogenesis of Human Papillomavirus.

Pathogens 2020 Jun 23;9(6). Epub 2020 Jun 23.

Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China.

Human papillomavirus (HPV) infection leads to a variety of benign lesions and malignant tumors such as cervical cancer and head and neck squamous cell carcinoma. Several HPV vaccines have been developed that can help to prevent cervical carcinoma, but these vaccines are only effective in individuals with no prior HPV infection. Thus, it is still important to understand the HPV life cycle and in particular the association of HPV with human pathogenesis. Read More

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http://dx.doi.org/10.3390/pathogens9060506DOI Listing

Evaluation of Radiation Sensitivity in Patients with Hyper IgM Syndrome.

Immunol Invest 2020 Jun 25:1-17. Epub 2020 Jun 25.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences , Tehran, Iran.

Background: HIGM syndrome is a rare form of primary immunodeficiencies characterized by normal/increased amounts of serum IgM and decreased serum levels of other switched immunoglobulin classes. Since the affected patients are continuously infected with various types of pathogens and are susceptible for cancers, diagnostic and therapeutic tests including imaging techniques are recommended for the diagnosis and treatment of these patients, which predispose them to higher accumulated doses of radiation. Given the evidence of class switching recombination machinery defect and its association with an increased rate of DNA repair, we aimed to evaluate radiation sensitivity among a group of patients diagnosed with HIGM syndrome. Read More

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http://dx.doi.org/10.1080/08820139.2020.1779288DOI Listing

Roles of Chk2/CHEK2 in guarding against environmentally-induced DNA damage and replication-stress.

Environ Mol Mutagen 2020 Jun 24. Epub 2020 Jun 24.

Department of Cell Maintenance, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.

Checkpoint kinase 2 (human CHEK2; murine Chk2) is a critical mediator of the DNA damage response and has established roles in DNA Double Strand Break (DSB)-induced apoptosis and cell cycle arrest. DSBs may be invoked directly by ionizing radiation (IR) but may also arise indirectly from environmental exposures such as solar ultraviolet (UV) radiation. The primary forms of DNA damage induced by UV are DNA photolesions (such as cyclobutane pyrimidine dimers CPD and 6-4 photoproducts) which interfere with DNA synthesis and lead to DNA replication fork stalling. Read More

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http://dx.doi.org/10.1002/em.22397DOI Listing

Exploiting replicative stress in gynecological cancers as a therapeutic strategy.

Int J Gynecol Cancer 2020 Jun 22. Epub 2020 Jun 22.

National University Cancer Institute, Singapore

Elevated levels of replicative stress in gynecological cancers arising from uncontrolled oncogenic activation, loss of key tumor suppressors, and frequent defects in the DNA repair machinery are an intrinsic vulnerability for therapeutic exploitation. The presence of replication stress activates the DNA damage response and downstream checkpoint proteins including ataxia telangiectasia and Rad3 related kinase (ATR), checkpoint kinase 1 (CHK1), and WEE1-like protein kinase (WEE1), which trigger cell cycle arrest while protecting and restoring stalled replication forks. Strategies that increase replicative stress while lowering cell cycle checkpoint thresholds may allow unrepaired DNA damage to be inappropriately carried forward in replicating cells, leading to mitotic catastrophe and cell death. Read More

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http://dx.doi.org/10.1136/ijgc-2020-001277DOI Listing

Hereditary Predisposition to Hematopoietic Neoplasms: When Bloodline Matters for Blood Cancers.

Mayo Clin Proc 2020 Jul 19;95(7):1482-1498. Epub 2020 Jun 19.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN. Electronic address:

With the advent of precision genomics, hereditary predisposition to hematopoietic neoplasms- collectively known as hereditary predisposition syndromes (HPS)-are being increasingly recognized in clinical practice. Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms. However, evidence for hereditary predisposition is also apparent in lymphoid and plasma--cell neoplasms, with recent discoveries of germline variants in genes such as IKZF1, SH2B3, PAX5 (familial acute lymphoblastic leukemia), and KDM1A/LSD1 (familial multiple myeloma). Read More

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http://dx.doi.org/10.1016/j.mayocp.2019.12.013DOI Listing

Attenuation of ataxia telangiectasia mutated signalling mitigates age-associated intervertebral disc degeneration.

Aging Cell 2020 Jun 21. Epub 2020 Jun 21.

Ferguson Laboratory for Orthopedic and Spine Research, Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.

Previously, we reported that persistent DNA damage accelerates ageing of the spine, but the mechanisms behind this process are not well understood. Ataxia telangiectasia mutated (ATM) is a protein kinase involved in the DNA damage response, which controls cell fate, including cell death. To test the role of ATM in the human intervertebral disc, we exposed human nucleus pulposus (hNP) cells directly to the DNA damaging agent cisplatin. Read More

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http://dx.doi.org/10.1111/acel.13162DOI Listing

Variant ataxia-telangiectasia in a child presenting with laryngeal dystonia.

Turk J Pediatr 2020 ;62(3):491-494

Department of Pediatric, Neurology, İzmir Katip Celebi University, İzmir.

Background: Dystonia is a common hyperkinetic movement disorder in children; however, making an early and definitive diagnosis of dystonia can sometimes be challenging for clinicians.

Case: Herein, we report a case of a 16 years-old girl presenting with laryngeal dystonia due to compound heterozygosity of a known pathogenic and a novel variant in the ATM gene. Serum alpha-fetoprotein level was elevated. Read More

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http://dx.doi.org/10.24953/turkjped.2020.03.019DOI Listing
January 2020

Inhibitory effect of alpha-lipoic acid on mitochondrial dysfunction and interleukin-8 expression in interleukin-1beta-stimulated ataxia teleangiectasia fibroblasts.

J Physiol Pharmacol 2020 Feb 13;71(1). Epub 2020 Jun 13.

Department of Food and Nutrition, Brain Krea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, South Korea.

Ataxia telangiectasia (A-T) is an inherited neurodegenerative disease caused by mutation in the ataxia telangiectasia mutated (ATM) gene, leading to loss of function in the encoded protein ATM. Because ATM functions to reduce oxidative stress by up-regulating antioxidant enzymes, oxidative stress is a prevalent A-T phenotype and a mediator of the inflammation that drives A-T pathology. Reactive oxygen species (ROS) levels and the expression of pro-inflammatory cytokine interleukin-8 (IL-8) were higher in A-T cells than in normal cells. Read More

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http://dx.doi.org/10.26402/jpp.2020.1.15DOI Listing
February 2020

Ataxia-telangiectasia complicated with Hodgkin's lymphoma: A case report.

World J Clin Cases 2020 Jun;8(11):2387-2391

Department of Pediatrics (III), The Linyi People's Hospital, Linyi 276000, Shandong Province, China.

Background: Ataxia-telangiectasia (AT) is a rare, autosomal recessive, multisystem disorder. Because most clinicians have low awareness of the disease, only scarce reports of AT exist in the literature, especially of cases with lymphoma/leukemia.

Case Summary: A 7-year-old girl with a history of recurrent respiratory tract infections was referred to our department because of unstable walking for 5 years and enlarged neck nodes for 2-mo duration. Read More

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http://dx.doi.org/10.12998/wjcc.v8.i11.2387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281062PMC

Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling.

Antioxidants (Basel) 2020 Jun 12;9(6). Epub 2020 Jun 12.

Institute of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, Eötvös str. 6, H-6720 Szeged, Hungary.

Hybrid compounds combine fragments with complementary targets to achieve a common pharmacological goal. This approach represents an increasingly popular strategy for drug discovery. In this work, we aimed to design antitumor hybrid compounds based on an inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR)-dependent signaling, protoapigenone, and a pro-oxidant ferrocene or chalcone fragment. Read More

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http://dx.doi.org/10.3390/antiox9060519DOI Listing

HSV-1 Hijacks the Host DNA Damage Response in Corneal Epithelial Cells through ICP4-Mediated Activation of ATM.

Invest Ophthalmol Vis Sci 2020 Jun;61(6):39

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Purpose: Herpes simplex virus type I (HSV-1) infection of corneal epithelial cells activates ataxia telangiectasia mutated (ATM), an apical kinase in the host DNA damage response pathway, whose activity is necessary for the progression of lytic HSV-1 infection. The purpose of this study is to investigate the mechanism of ATM activation by HSV-1 in the corneal epithelium, as well as its functional significance.

Methods: Mechanistic studies were performed in cultured human corneal epithelial cell lines (hTCEpi, HCE), as well as in esophageal (EPC2) and oral (OKF6) cell lines. Read More

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http://dx.doi.org/10.1167/iovs.61.6.39DOI Listing

STK38 promotes ATM activation by acting as a reader of histone H4 ufmylation.

Sci Adv 2020 Jun 3;6(23):eaax8214. Epub 2020 Jun 3.

Division of Oncology, Mayo Clinic, Rochester, MN 55905, USA.

The ATM (ataxia-telangiectasia mutated) kinase is rapidly activated following DNA damage and phosphorylates its downstream targets to launch DDR signaling. Recently, we and others showed that UFM1 signaling promotes ATM activation. We further discovered that monoufmylation of histone H4 at Lys by UFM1-specific ligase 1 (UFL1) is an important step in the amplification of ATM activation. Read More

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http://dx.doi.org/10.1126/sciadv.aax8214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269669PMC

An Unusual Case of Metastatic Basal Cell Carcinoma of the Prostate: A Case Report and Literature Review.

Front Oncol 2020 27;10:859. Epub 2020 May 27.

Department of Oncology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin, China.

Primary basal cell carcinoma (BCC) is a rare prostate cancer. Currently, a standard treatment regime for BCC of the prostate is lacking and most patients have a poor prognosis. We reported on a patient with BCC of the prostate whose cancer metastasized after undergoing a radical prostatectomy and whose prognosis improved after treatment with etoposide. Read More

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http://dx.doi.org/10.3389/fonc.2020.00859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267053PMC

Heavy ion radiation-induced DNA damage mediates apoptosis via the Rpl27a-Rpl5-MDM2-p53/E2F1 signaling pathway in mouse spermatogonia.

Ecotoxicol Environ Saf 2020 Jun 11;201:110831. Epub 2020 Jun 11.

Department of Medical Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, China; School of Nuclear Science and Technology, University of Chinese Academy of Sciences, Beijing, 100039, China.

The risk of exposure to ionizing radiation (IR) environments has increased with the development of nuclear technology. IR exposure induces excessive apoptosis of the spermatogonia, which leads to male infertility. Spermatogonia apoptosis may be involved in ribosomal stress triggered by DNA damage following exposure to IR because ribosomal proteins (RPs) directly interact with mouse double minute 2 homolog (MDM2) to induce apoptosis. Read More

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http://dx.doi.org/10.1016/j.ecoenv.2020.110831DOI Listing

The RNA-associated MKT1 and MKT1L form alternative PBP1-containing complexes in .

J Biol Chem 2020 Jun 12. Epub 2020 Jun 12.

DKFZ-ZMBH Alliance, ZMBH, Germany.

Control of gene expression in kinetoplastids such as trypanosomes depends heavily on RNA-binding proteins that influence mRNA decay and translation. We previously showed that the trypanosome protein MKT1 forms a multicomponent protein complex: MKT1 interacts with PBP1, which in turn recruits LSM12 and poly(A)-binding protein. MKT1 is recruited to mRNAs by sequence-specific RNA-binding proteins, resulting in stabilization of the bound mRNA. Read More

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http://dx.doi.org/10.1074/jbc.RA120.013306DOI Listing

Tracking of Infused Mesenchymal Stem Cells in Injured Pulmonary Tissue in -Deficient Mice.

Cells 2020 Jun 10;9(6). Epub 2020 Jun 10.

Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescents, University Hospital, Goethe-University, 60596 Frankfurt am Main, Germany.

Pulmonary failure is the main cause of morbidity and mortality in the human chromosomal instability syndrome Ataxia-telangiectasia (A-T). Major phenotypes include recurrent respiratory tract infections and bronchiectasis, aspiration, respiratory muscle abnormalities, interstitial lung disease, and pulmonary fibrosis. At present, no effective pulmonary therapy for A-T exists. Read More

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http://dx.doi.org/10.3390/cells9061444DOI Listing

Targeting DNA Double-Strand Break Repair Enhances Radiosensitivity of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma to Photons and Protons.

Cancers (Basel) 2020 Jun 7;12(6). Epub 2020 Jun 7.

Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, 200 London Road, Liverpool L3 9TA, UK.

The response of head and neck squamous cell carcinoma (HNSCC) to radiotherapy depends on human papillomavirus type 16 (HPV) status, and where improved outcome and survival is observed in HPV-positive disease. However, strategies to further radiosensitise the tumours, particularly relatively radioresistant HPV-negative HNSCC, are actively being sought. The impact of targeting the major protein kinases involved in the signaling of DNA double-strand break (DSB) repair, namely ataxia telangiectasia-mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), and the catalytic subunit of DNA-dependent protein kinase (DNA-Pkcs), on the radiosensitisation of HNSCC cells was examined. Read More

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http://dx.doi.org/10.3390/cancers12061490DOI Listing

Immune competence and respiratory symptoms in patients with ataxia telangiectasia: A prospective follow-up study.

Clin Immunol 2020 Jun 3;217:108491. Epub 2020 Jun 3.

Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe University, Frankfurt, Germany. Electronic address:

Ataxia telangiectasia is a multi-system disorder characterized by progressive cerebellar ataxia, malignancies, chronic pulmonary disease and immunodeficiency. The aim of our study was to determine the immune competence and prevalence of respiratory infections and/or chronic cough in classical A-T patients compared to age-matched healthy controls.

Study Design: We recruited 20 classical A-T not treated by immunoglobulins and 21 healthy age-matched control patients. Read More

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http://dx.doi.org/10.1016/j.clim.2020.108491DOI Listing

RNF8 promotes high linear energy transfer carbon-ion-induced DNA double-stranded break repair in serum-starved human cells.

DNA Repair (Amst) 2020 Jul - Aug;91-92:102872. Epub 2020 May 20.

Gunma University Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Gunma, 371-8511, Japan. Electronic address:

The cell-killing effect of radiotherapy largely depends on unrepaired DNA double-stranded breaks (DSBs) or lethal chromosome aberrations induced by DSBs. Thus, the capability of DSB repair is critically important for the cancer-cell-killing effect of ionizing radiation. Here, we investigated the involvement of the DNA damage signaling factors ataxia telangiectasia mutated (ATM), ring finger protein 8 (RNF8), and RNF168 in quiescent G0/G1 cells, which are expressed in the majority of cell populations in tumors, after high linear energy transfer (LET) carbon-ion irradiation. Read More

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http://dx.doi.org/10.1016/j.dnarep.2020.102872DOI Listing

Multi-omics analysis of pathological changes in the amygdala of rats subjected to chronic restraint stress.

Behav Brain Res 2020 Jun 2;392:112735. Epub 2020 Jun 2.

West China School of Basic Medical Sciences & Forensic Science, Sichuan University, Chengdu, 610041 China; Department of Forensic Medicine, Hebei Medical University, Shijiazhuang, 050017 China. Electronic address:

Objective: Overwhelming stress potentially results in the occurrence of many mental diseases. The amygdala is one region in the brain targeted by stress. Recent studies have shown that changes in the amygdala of subjects under stress are related to depression, anxiety and post-traumatic stress disorder (PTSD). Read More

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http://dx.doi.org/10.1016/j.bbr.2020.112735DOI Listing

A Critical Role for ISGylation, Ubiquitination and, SUMOylation in Brain Damage: Implications for Neuroprotection.

Neurochem Res 2020 Jun 4. Epub 2020 Jun 4.

Pharma Division (Analytical Research and Development), Biological E. Limited, Turkapally-Shameerpet, Hyderabad, 500078, India.

Post-translational modification (PTMs) of proteins by ubiquitin and ubiquitin-like modifiers such as interferon-stimulated gene 15 (ISG15) and small ubiquitin-related modifier (SUMO) play a critical role in the regulation of brain pathophysiology. Protein ISGylation is a covalent attachment of ISG15 to its target proteins, which is a unique PTM among other ubiquitin-like modifiers. Although, ISG15 shares sequence homology to ubiquitin, yet the functional significance of protein ISGylation is distinct from ubiquitination and SUMOylation. Read More

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http://dx.doi.org/10.1007/s11064-020-03066-3DOI Listing

Targeting breast cancer stem-like cells using chloroquine encapsulated by a triphenylphosphonium-functionalized hyperbranched polymer.

Int J Pharm 2020 Jun 1;585:119465. Epub 2020 Jun 1.

Institute of Nanoscience and Nanotechnology, NCSR "Demokritos", 15310 Aghia Paraskevi, Greece. Electronic address:

Cancer stem cells (CSCs) have garnered increasing attention over the past decade, as they are believed to play a crucial role in tumor progression and drug resistance. Accumulating evidence provides insight into the function of autophagy in maintenance and survival of CSCs. Here, we studied the impact of a mitochondriotropic triphenylphosphonium-functionalized dendrimeric nanocarrier on cultured breast cancer cell lines, grown either as adherent cells or as mammospheres that mimic a stem-like phenotype. Read More

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http://dx.doi.org/10.1016/j.ijpharm.2020.119465DOI Listing
June 2020
3.650 Impact Factor

Inhibition of ATM Increases the Radiosensitivity of Uveal Melanoma Cells to Photons and Protons.

Cancers (Basel) 2020 May 28;12(6). Epub 2020 May 28.

Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, 200 London Road, Liverpool L3 9TA, UK.

Treatment of uveal melanoma (UM) is generally successful, with local primary tumour control being at 90%-95%. Localized radiotherapy in the form of plaque brachytherapy or proton beam radiotherapy is the most common treatment modality in the UK. However, the basic mechanisms of radiation response, DNA repair and tissue reactions in UM have not been well documented previously. Read More

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http://dx.doi.org/10.3390/cancers12061388DOI Listing

ATM-mediated DNA double-strand break response facilitated oncolytic Newcastle disease virus replication and promoted syncytium formation in tumor cells.

PLoS Pathog 2020 Jun 1;16(6):e1008514. Epub 2020 Jun 1.

Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute. Chinese Academy of Agricultural Science, Shanghai, P.R. China.

Deoxyribonucleic acid (DNA) damage response (DDR) is the fundamental cellular response for maintaining genomic integrity and suppressing tumorigenesis. The activation of ataxia telangiectasia-mutated (ATM) kinase is central to DNA double-strand break (DSB) for maintaining host-genome integrity in mammalian cells. Oncolytic Newcastle disease virus (NDV) can selectively replicate in tumor cells; however, its influence on the genome integrity of tumor cells is not well-elucidated. Read More

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http://dx.doi.org/10.1371/journal.ppat.1008514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263568PMC

Role of Blood Oxygen Saturation During Post-Natal Human Cardiomyocyte Cell Cycle Activities.

JACC Basic Transl Sci 2020 May 22;5(5):447-460. Epub 2020 Apr 22.

Shanghai Institute for Pediatric Congenital Heart Diseases, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Blood oxygen saturation (SaO) is one of the most important environmental factors in clinical heart protection. This study used human heart samples and human induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) to assess how SaO affects human CM cell cycle activities. The results showed that there were significantly more cell cycle markers in the moderate hypoxia group (SaO: 75% to 85%) than in the other 2 groups (SaO <75% or >85%). Read More

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http://dx.doi.org/10.1016/j.jacbts.2020.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251192PMC

Evaluation of awareness about primary immunodeficiencies among physicians before and after implementation of the educational program: A longitudinal study.

PLoS One 2020 29;15(5):e0233342. Epub 2020 May 29.

Department of Children's Diseases and Pediatric Surgery, I.Horbachevsky Ternopil National Medical University, Ternopil, Ukraine.

Increasing physicians' awareness is one of the main ways to improve early diagnosis of rare diseases. A survey among physicians of different specialties to evaluate the knowledge about primary immunodeficiencies (PID) was conducted in 2016 and in 2019 -before and after the implementation of an educational program. We compare responses from 82 doctors who participated in the 2016 survey, and 67 doctors who have taken part in the survey in 2019: pediatricians, general practitioners / family physicians and physicians of pediatric sub specialties. Read More

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233342PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259605PMC

Digitoxin inhibits HeLa cell growth through the induction of G2/M cell cycle arrest and apoptosis in vitro and in vivo.

Int J Oncol 2020 Aug 25;57(2):562-573. Epub 2020 May 25.

Formula‑pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.

Cervical cancer is the fourth most common gynecological malignancy affecting the health of women worldwide and the second most common cause of cancer‑related mortality among women in developing regions. Thus, the development of effective chemotherapeutic drugs for the treatment of cervical cancer has become an important issue in the medical field. The application of natural products for the prevention and treatment of various diseases, particularly cancer, has always attracted widespread attention. Read More

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http://dx.doi.org/10.3892/ijo.2020.5070DOI Listing

Emerging strategies to target cancer metabolism and improve radiation therapy outcomes.

Br J Radiol 2020 Jun 23:20200067. Epub 2020 Jun 23.

Department of Radiation Oncology, Wexner Medical Center and Comprehensive Cancer Center The Ohio State University Columbus, OH, USA.

Cancer-specific metabolic changes support the anabolic needs of the rapidly growing tumor, maintain a favorable redox balance, and help cells adapt to microenvironmental stresses like hypoxia and nutrient deprivation. Radiation is extensively applied in a large number of cancer treatment protocols but despite its curative potential, radiation resistance and treatment failures pose a serious problem. Metabolic control of DNA integrity and genomic stability can occur through multiple processes, encompassing cell cycle regulation, nucleotide synthesis, epigenetic regulation of gene activity, and antioxidant defenses. Read More

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http://dx.doi.org/10.1259/bjr.20200067DOI Listing

Biomarker-Guided Development of DNA Repair Inhibitors.

Mol Cell 2020 Jun 26;78(6):1070-1085. Epub 2020 May 26.

Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address:

Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Read More

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http://dx.doi.org/10.1016/j.molcel.2020.04.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316088PMC

rs622342 Polymorphism Predicts Insulin Resistance Improvement in Patients with Type 2 Diabetes Mellitus Treated with Metformin: A Cross-Sectional Study.

Int J Endocrinol 2020 8;2020:2975898. Epub 2020 May 8.

Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University, Ji'nan 250014, China.

Background: Metformin is the most widely used oral antidiabetic agent and can reduce insulin resistance (IR) effectively. Organic cation transporter 1 (encoded by ) is responsible for the transport of metformin, and ataxia-telangiectasia-mutated () is a gene relating to the DNA repair and cell cycle control. The aim of this study was to evaluate if the genetic variants in rs622342 and rs11212617 could be effective predictors of islet function improvement in patients with type 2 diabetes mellitus (T2DM) on metformin treatment. Read More

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http://dx.doi.org/10.1155/2020/2975898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231067PMC

Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells.

Oncogene 2020 Jun 23;39(25):4869-4883. Epub 2020 May 23.

Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.

The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Read More

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http://dx.doi.org/10.1038/s41388-020-1328-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299845PMC

The molecular genetics of cellular senescence in the context of organismal aging.

Cas Lek Cesk 2020 ;159(2):88-92

Cellular senescence is a physiological state generally defined as a stable arrest of proliferation by preventing the cells from cycling. Unlike terminally differentiated cells, that also do not show proliferative activity, cellular senescence is stress induced and blocks the proliferation of cells with theoretical ability to divide (such as progenitor, stem or cancer cells) due to the activity of specific signaling pathways. The number of senescent cells increases during the ontogenesis of an organism. Read More

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January 2020

Effect of epigallocatechin-3-gallate (EGCG) on embryos inseminated with oxidative stress-induced DNA damage sperm.

Syst Biol Reprod Med 2020 May 19:1-11. Epub 2020 May 19.

Reproductive Medicine Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.

Cryopreservation can induce damage in human spermatozoa through reactive oxygen species (ROS) generation. To reduce the potential risk of oxidative stress-induced sperm DNA damage, addition of different epigallocatechin-3-gallate (EGCG) concentrations were performed to determine the optimum concentration which was beneficial for IVF outcome for both fresh and frozen-thawed sperm. Next, the mouse sperm model exhibiting oxidative stress-induced DNA damage by exogenously treating with HO but overcoming the low fertilization rate of frozen-thawed sperm was used to investigate the effect of EGCG on the embryonic development and the potential EGCG-mediated effects on ataxia telangiectasia mutated (ATM) pSer-1981 in zygotes, the latter was known for leading to the activation of major kinases involved in the DNA repair pathway and the cell cycle checkpoint pathway. Read More

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http://dx.doi.org/10.1080/19396368.2020.1756525DOI Listing

Phosphorylation-Dependent Pin1 Isomerization of ATR: Its Role in Regulating ATR's Anti-apoptotic Function at Mitochondria, and the Implications in Cancer.

Front Cell Dev Biol 2020 30;8:281. Epub 2020 Apr 30.

Department of Cancer Biology, University of Toledo College of Medicine, Toledo, OH, United States.

Peptidyl-prolyl isomerization is an important post-translational modification of protein because proline is the only amino acid that can stably exist as and , while other amino acids are in the conformation in protein backbones. This makes prolyl isomerization a unique mechanism for cells to control many cellular processes. Isomerization is a rate-limiting process that requires a peptidyl-prolyl / isomerase (PPIase) to overcome the energy barrier between and isomeric forms. Read More

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http://dx.doi.org/10.3389/fcell.2020.00281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203486PMC

High Levels of ROS Impair Lysosomal Acidity and Autophagy Flux in Glucose-Deprived Fibroblasts by Activating ATM and Erk Pathways.

Biomolecules 2020 May 13;10(5). Epub 2020 May 13.

Department of Life Science, University of Seoul, Dongdaemun-gu, Seoulsiripdae-ro 163, Seoul 02504, Korea.

Under glucose deprivation, cells heavily mobilize oxidative phosphorylation to maintain energy homeostasis. This leads to the generation of high levels of ATP, as well as reactive oxygen species (ROS), from mitochondria. In nutrient starvation, autophagy is activated, likely to facilitate resource recycling, but recent studies suggest that autophagy flux is inhibited in cells undergoing glucose deprivation. Read More

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http://dx.doi.org/10.3390/biom10050761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277562PMC

Melanoma arising in a patient with ataxia-telangiectasia: A call for full skin examinations in this patient population.

Pediatr Dermatol 2020 May 15. Epub 2020 May 15.

Department of Dermatology, Henry Ford Health System, Detroit, MI, USA.

Ataxia-telangiectasia (A-T) is an autosomal recessive, multisystem disorder characterized by cerebellar ataxia and oculocutaneous telangiectasias that present in early childhood. Increased incidence of malignancy is also associated with A-T. Hematopoietic malignancies occur most commonly, with a majority being lymphoid cancers; however, there is a risk for other malignancies, such as breast, gastric, and other solid tumors. Read More

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http://dx.doi.org/10.1111/pde.14200DOI Listing

OsATM Safeguards Accurate Repair of Meiotic Double-Strand Breaks in Rice.

Plant Physiol 2020 Jul 13;183(3):1047-1057. Epub 2020 May 13.

Key Laboratory of Plant Functional Genomics of the Ministry of Education/Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding/Jiangsu Key Laboratory of Crop Genetics and Physiology/Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Agricultural College of Yangzhou University, Yangzhou 225009, China

ATAXIA TELANGIECTASIA-MUTATED (ATM) protein has been well studied for its roles in the DNA damage response. However, its role in meiosis has not been fully explored. Here, we characterized the functions of the rice () ATM homolog during meiosis. Read More

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http://dx.doi.org/10.1104/pp.20.00053DOI Listing
July 2020
6.841 Impact Factor

In Ataxia-Telangiectasia, Oral Betamethasone Administration Ameliorates Lymphocytes Functionality through Modulation of the IL-7/IL-7Rα Axis Paralleling the Neurological Behavior: A Comparative Report of Two Cases.

Immunol Invest 2020 May 13:1-9. Epub 2020 May 13.

Department of Translational Medical Sciences-Section of Pediatrics, Federico II University, Naples, Italy.

Ataxia-Telangiectasia (A-T) is characterized by cerebellar neurodegeneration and immunodeficiency. Recent studies suggest that very low glucocorticoids (GCs) doses may help improve A-T neurological phenotype in some patients. Interestingly, in GCs studies an unexpected improvement of lymphocytes proliferation in some A-T patients has been observed. Read More

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http://dx.doi.org/10.1080/08820139.2020.1761379DOI Listing
May 2020
1.903 Impact Factor

The p53-53BP1-Related Survival of A549 and H1299 Human Lung Cancer Cells after Multifractionated Radiotherapy Demonstrated Different Response to Additional Acute X-ray Exposure.

Int J Mol Sci 2020 May 8;21(9). Epub 2020 May 8.

School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Moscow Region, Russia.

Radiation therapy is one of the main methods of treating patients with non-small cell lung cancer (NSCLC). However, the resistance of tumor cells to exposure remains the main factor that limits successful therapeutic outcome. To study the molecular/cellular mechanisms of increased resistance of NSCLC to ionizing radiation (IR) exposure, we compared A549 (p53 wild-type) and H1299 (p53-deficient) cells, the two NSCLC cell lines. Read More

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http://dx.doi.org/10.3390/ijms21093342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246764PMC

Oocytes can efficiently repair DNA double-strand breaks to restore genetic integrity and protect offspring health.

Proc Natl Acad Sci U S A 2020 May 7;117(21):11513-11522. Epub 2020 May 7.

Ovarian Biology Laboratory, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia;

Female fertility and offspring health are critically dependent on an adequate supply of high-quality oocytes, the majority of which are maintained in the ovaries in a unique state of meiotic prophase arrest. While mechanisms of DNA repair during meiotic recombination are well characterized, the same is not true for prophase-arrested oocytes. Here we show that prophase-arrested oocytes rapidly respond to γ-irradiation-induced DNA double-strand breaks by activating Ataxia Telangiectasia Mutated, phosphorylating histone H2AX, and localizing RAD51 to the sites of DNA damage. Read More

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http://dx.doi.org/10.1073/pnas.2001124117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260990PMC

In Genetic Disorders, One Size Does Not Fit All.

Clin Pharmacol Ther 2020 May 5. Epub 2020 May 5.

Christopher J. Wohlberg, MD, LLC, Matlacha, Florida, USA.

In drug development, preclinical studies often do not predict human benefit. Why not, then, go right to the source-patients with rare diseases and, more importantly, with specific various genetic mutations that, in aggregate, define the phenotypic clinical disorder? In this issue, Genova et al. describe how induced pluripotent stem cells from patients with two genetic disorders (ataxia-telangiectasia and Aicardi-Goutières syndrome) can be used to better predict responses to immunosuppressive therapy. Read More

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http://dx.doi.org/10.1002/cpt.1851DOI Listing

DNA methylation and gene expression signatures are associated with ataxia-telangiectasia phenotype.

Sci Rep 2020 May 4;10(1):7479. Epub 2020 May 4.

Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

People with ataxia-telangiectasia (A-T) display phenotypic variability with regard to progression of immunodeficiency, sino-pulmonary disease, and neurologic decline. To determine the association between differential gene expression, epigenetic state, and phenotypic variation among people with A-T, we performed transcriptional and genome-wide DNA methylation profiling in patients with mild and classic A-T progression as well as healthy controls. RNA and genomic DNA were isolated from peripheral blood mononuclear cells for transcriptional and DNA methylation profiling with RNA-sequencing and modified reduced representation bisulfite sequencing, respectively. Read More

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http://dx.doi.org/10.1038/s41598-020-64514-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198504PMC
May 2020
5.078 Impact Factor

Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells.

Cancers (Basel) 2020 Apr 30;12(5). Epub 2020 Apr 30.

Gastrointestinal and Pancreatic Oncology Team, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 08036 Barcelona, Spain.

Tetraploidy, or whole-genome duplication, is a common phenomenon in cancer and preludes chromosome instability, which strongly correlates with disease progression, metastasis, and treatment failure. Therefore, it is reasonable to hypothesize that tetraploidization confers multidrug resistance. Nevertheless, the contribution of whole-genome duplication to chemo-radiotherapy resistance remains unclear. Read More

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http://dx.doi.org/10.3390/cancers12051118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281619PMC

Modeling Neurodegenerative Disorders in .

Int J Mol Sci 2020 Apr 26;21(9). Epub 2020 Apr 26.

Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA.

provides a powerful genetic model system in which to investigate the molecular mechanisms underlying neurodegenerative diseases. In this review, we discuss recent progress in modeling Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, Ataxia Telangiectasia, and neurodegeneration related to mitochondrial dysfunction or traumatic brain injury. We close by discussing recent progress using models of neural regeneration and how these are likely to provide critical insights into future treatments for neurodegenerative disorders. Read More

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http://dx.doi.org/10.3390/ijms21093055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246467PMC

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer.

Signal Transduct Target Ther 2020 May 1;5(1):60. Epub 2020 May 1.

Department of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, AMMS, 100850, Beijing, People's Republic of China.

Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. Read More

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http://dx.doi.org/10.1038/s41392-020-0150-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192953PMC