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    Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks.
    J Immunol 2017 Feb 17. Epub 2017 Feb 17.
    Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104;
    Mammalian cells have evolved a common DNA damage response (DDR) that sustains cellular function, maintains genomic integrity, and suppresses malignant transformation. In pre-B cells, DNA double-strand breaks (DSBs) induced at Igκ loci by the Rag1/Rag2 (RAG) endonuclease engage this DDR to modulate transcription of genes that regulate lymphocyte-specific processes. We previously reported that RAG DSBs induced at one Igκ allele signal through the ataxia telangiectasia mutated (ATM) kinase to feedback-inhibit RAG expression and RAG cleavage of the other Igκ allele. Read More

    The DNA damage response promotes polyomavirus JC infection by nucleus to cytoplasm NF- kappaB activation.
    Virol J 2017 Feb 15;14(1):31. Epub 2017 Feb 15.
    Center for Neurovirology, Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
    Background: Infection of glial cells by human neurotropic polyomavirus JC (JCV), the causative agent of the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML), rapidly inflicts damage to cellular DNA. This activates DNA damage response (DDR) signaling including induction of expression of DNA repair factor Rad51. We previously reported that Rad51 co-operates with the transcription factor NF-κB p65 to activate JCV early transcription. Read More

    Genomic profiling of acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis.
    Leukemia 2017 Feb 15. Epub 2017 Feb 15.
    Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Read More

    FANCD2 Binds Human Papillomavirus Genomes and Associates with a Distinct Set of DNA Repair Proteins to Regulate Viral Replication.
    MBio 2017 Feb 14;8(1). Epub 2017 Feb 14.
    Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
    The life cycle of human papillomavirus (HPV) is dependent on the differentiation state of its host cell. HPV genomes are maintained as low-copy episomes in basal epithelial cells and amplified to thousands of copies per cell in differentiated layers. Replication of high-risk HPVs requires the activation of the ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR) DNA repair pathways. Read More

    Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks.
    Oncotarget 2017 Feb 7. Epub 2017 Feb 7.
    Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
    DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a distinct factor in the non-homologous end-joining (NHEJ) pathway involved in DNA double-strand break (DSB) repair. We examined the crosstalk between key proteins in the DSB NHEJ repair pathway and cell cycle regulation and found that mouse embryonic fibroblast (MEF) cells deficient in DNA-PKcs or Ku70 were more vulnerable to ionizing radiation (IR) compared with wild-type cells and that DSB repair was delayed. γH2AX was associated with phospho-Ataxia-telangiectasia mutated kinase (Ser1987) and phospho-checkpoint effector kinase 1 (Ser345) foci for the arrest of cell cycle through the G2/M phase. Read More

    ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.
    Transl Oncol 2017 Feb 6;10(2):190-196. Epub 2017 Feb 6.
    Department of Biochemistry & Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada; Department on Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada. Electronic address:
    The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Read More

    The Clinical Significance of Complete Class Switching Defect in Ataxia Telangiectasia Patients.
    Expert Rev Clin Immunol 2017 Feb 4. Epub 2017 Feb 4.
    a Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.
    Objectives: Ataxia telangiectasia (AT) is a primary immunodeficiency associated with recurrent infections. We aimed to investigate clinical and immunological classification in AT patients who suffer from a different spectrum of humoral immune defects.

    Methods: AT patients were categorized according to the ability of class switching and patients with hyper IgM (HIgM) profile were defined as class switching defect (CSD). Read More

    Evaluation of [(18)F]-ATRi as PET tracer for in vivo imaging of ATR in mouse models of brain cancer.
    Nucl Med Biol 2017 Jan 16;48:9-15. Epub 2017 Jan 16.
    Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA; Weill Cornell Medical College, New York, NY, 10065, USA. Electronic address:
    Rationale: Ataxia telangiectasia and Rad3-related (ATR) threonine serine kinase is one of the key elements in orchestrating the DNA damage response (DDR). As such, inhibition of ATR can amplify the effects of chemo- and radiation-therapy, and several ATR inhibitors (ATRi) have already undergone clinical testing in cancer. For more accurate patient selection, monitoring and staging, real-time in vivo imaging of ATR could be invaluable; the development of appropriate imaging agents has remained a major challenge. Read More

    AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM-deficiency in gastric cancer cells.
    Mol Cancer Ther 2017 Jan 30. Epub 2017 Jan 30.
    Seoul National University College of Medicine.
    Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect (HRD). The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer. In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. Read More

    Discovery of pyrazolopyrimidine derivatives as novel inhibitors of ataxia telangiectasia and rad3 related protein (ATR).
    Bioorg Med Chem Lett 2017 Feb 16;27(4):750-754. Epub 2017 Jan 16.
    Medivation, Now Pfizer Inc., 525 Market Street, 36th Floor, San Francisco, CA 94105, United States. Electronic address:
    The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K. Read More

    Ataxia-telangiectasia: Immunodeficiency and survival.
    Clin Immunol 2017 Jan 24. Epub 2017 Jan 24.
    Department of Neurology - Pediatric Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
    Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. Read More

    New diagnosis of atypical ataxia-telangiectasia in a 17-year-old boy with T-cell acute lymphoblastic leukemia and a novel ATM mutation.
    J Hum Genet 2017 Jan 26. Epub 2017 Jan 26.
    Institute for Cancer Genetics, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
    Ataxia-telangiectasia (A-T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM gene. Typically, it presents in early childhood with progressive cerebellar dysfunction along with immunodeficiency and oculocutaneous telangiectasia. An increased risk of malignancy is also associated with the syndrome and, rarely, may be the presenting feature in small children. Read More

    DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neurogenesis.
    J Neurosci 2017 Jan;37(4):893-905
    Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105,
    The DNA damage response (DDR) orchestrates a network of cellular processes that integrates cell-cycle control and DNA repair or apoptosis, which serves to maintain genome stability. DNA-PKcs (the catalytic subunit of the DNA-dependent kinase, encoded by PRKDC), ATM (ataxia telangiectasia, mutated), and ATR (ATM and Rad3-related) are related PI3K-like protein kinases and central regulators of the DDR. Defects in these kinases have been linked to neurodegenerative or neurodevelopmental syndromes. Read More

    Ataxia telangiectasia in Turkey: multisystem involvement of 91 patients.
    World J Pediatr 2017 Jan 25. Epub 2017 Jan 25.
    Department of Pediatric Infectious Diseases and Clinical Immunology, Istanbul Medical Faculty, Istanbul University., Istanbul, Turkey.
    Background: Ataxia telangiectasia (AT) is a genetically based multisystemic disorder. We aimed to make a comprehensive evaluation of multisystem involvement in AT by describing clinical features and outcome of 91 patients.

    Methods: Medical records of the patients who were diagnosed and followed by a multidisciplinary approach during a 27-year period (1988-2015) were reviewed retrospectively. Read More

    Regulation of human polλ by ATM-mediated phosphorylation during non-homologous end joining.
    DNA Repair (Amst) 2017 Jan 17. Epub 2017 Jan 17.
    Departamento Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, Sevilla 41092, Spain; Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla/CSIC, Sevilla 41092, Spain. Electronic address:
    DNA double strand breaks (DSBs) trigger a variety of cellular signaling processes, collectively termed the DNA-damage response (DDR), that are primarily regulated by protein kinase ataxia-telangiectasia mutated (ATM). Among DDR activated processes, the repair of DSBs by non-homologous end joining (NHEJ) is essential. The proper coordination of NHEJ factors is mainly achieved through phosphorylation by an ATM-related kinase, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the molecular basis for this regulation has yet to be fully elucidated. Read More

    Age-Dependent Oxidative DNA Damage Does Not Correlate with Reduced Proliferation of Cardiomyocytes in Humans.
    PLoS One 2017 18;12(1):e0170351. Epub 2017 Jan 18.
    Department of Thoracic and Cardiovascular Surgery, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
    Background: Postnatal human cardiomyocyte proliferation declines rapidly with age, which has been suggested to be correlated with increases in oxidative DNA damage in mice and plays an important role in regulating cardiomyocyte proliferation. However, the relationship between oxidative DNA damage and age in humans is unclear.

    Methods: Sixty right ventricular outflow myocardial tissue specimens were obtained from ventricular septal defect infant patients during routine congenital cardiac surgery. Read More

    Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes.
    J Cell Physiol 2017 Jan 18. Epub 2017 Jan 18.
    Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, Naples, Italy.
    Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD), and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Read More

    Divergence of cAMP signaling pathways mediating augmented nucleotide excision repair and pigment induction in melanocytes.
    Exp Dermatol 2017 Jan 17. Epub 2017 Jan 17.
    University of Kentucky College of Medicine Markey Cancer Center, 800 Rose Street, Lexington, KY, 40536.
    Loss-of-function melanocortin 1 receptor (MC1R) polymorphisms are common in UV-sensitive fair-skinned individuals and are associated with blunted cAMP second messenger signaling and higher lifetime risk of melanoma because of diminished ability of melanocytes to cope with UV damage. cAMP signaling positions melanocytes to resist UV injury by up-regulating synthesis of UV-blocking eumelanin pigment and by enhancing the repair of UV-induced DNA damage. cAMP enhances melanocyte nucleotide excision repair (NER), the genome maintenance pathway responsible for the removal of mutagenic UV photolesions, through cAMP-activated protein kinase (protein kinase A)-mediated phosphorylation of the ataxia telangiectasia mutated and Rad3 related (ATR) protein on the S435 residue. Read More

    The depletion of ATM inhibits colon cancer proliferation and migration via B56γ2-mediated Chk1/p53/CD44 cascades.
    Cancer Lett 2017 Apr 14;390:48-57. Epub 2017 Jan 14.
    School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China. Electronic address:
    Ataxia-telangiectasia mutated (ATM) protein kinase is a major guardian of genomic stability, and its well-established function in cancer is tumor suppression. Here, we report an oncogenic role of ATM. Using two isogenic sets of human colon cancer cell lines that differed only in their ATM status, we demonstrated that ATM deficiency significantly inhibits cancer cell proliferation, migration, and invasion. Read More

    A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes.
    Cancer 2017 Jan 13. Epub 2017 Jan 13.
    Fox Chase Cancer Center, Philadelphia, Pennsylvania.
    Background: As panel testing becomes more common in clinical practice, it is important to understand the prevalence and trends associated with the pathogenic variants (PVs) identified. This is especially true for genetically heterogeneous cancers, such as breast cancer (BC), in which PVs in different genes may be associated with various risks and cancer subtypes. The authors evaluated the outcomes of genetic testing among women who had a personal history of BC. Read More

    Ataxia Telangiectasia and Juvenile Idiopathic Arthritis.
    Pediatrics 2017 Feb 12;139(2). Epub 2017 Jan 12.
    Children's Hospital Zagreb, Zagreb, Croatia.
    We report, to the best of our knowledge, the first case of a child with typical ataxia telangiectasia (A-T) who developed juvenile idiopathic arthritis (JIA). The patient was a 15-year-old boy with A-T who presented with noninfectious polyarthritis. A-T is a rare, autosomal recessive disorder characterized by cerebellar atrophy, oculocutaneous telangiectasia, immunodeficiency, radiosensitivity, and predisposition to cancer. Read More

    The Mre11-Nbs1 Interface Is Essential for Viability and Tumor Suppression.
    Cell Rep 2017 Jan;18(2):496-507
    Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. Electronic address:
    The Mre11 complex (Mre11, Rad50, and Nbs1) is integral to both DNA repair and ataxia telangiectasia mutated (ATM)-dependent DNA damage signaling. All three Mre11 complex components are essential for viability at the cellular and organismal levels. To delineate essential and non-essential Mre11 complex functions that are mediated by Nbs1, we used TALEN-based genome editing to derive Nbs1 mutant mice (Nbs1(mid) mice), which harbor mutations in the Mre11 interaction domain of Nbs1. Read More

    Ferulic acid (FA) abrogates γ-radiation induced oxidative stress and DNA damage by up-regulating nuclear translocation of Nrf2 and activation of NHEJ pathway.
    Free Radic Res 2017 Jan 11;51(1):47-63. Epub 2017 Jan 11.
    a Department of Physiology , Centre for Nanoscience and Nanotechnology and Centre with Potential for Excellence in Particular Area (CPEPA), University of Calcutta , Kolkata , West Bengal , India.
    The present study was aimed to evaluate the radioprotective effect of ferulic acid (FA), a naturally occurring plant flavonoid in terms of DNA damage and damage related alterations of repair pathways by gamma radiation. FA was administered at a dose of 50 mg/kg body weight for five consecutive days prior to exposing the swiss albino mice to a single dose of 10 Gy gamma radiation. Ionising radiation induces oxidative damage manifested by decreased expression of Cu, Zn-SOD (SOD stands for super oxide dismutase), Mn-SOD and catalase. Read More

    Integrating Gene Correction in the Reprogramming and Transdifferentiation Processes: A One-Step Strategy to Overcome Stem Cell-Based Gene Therapy Limitations.
    Stem Cells Int 2016 15;2016:2725670. Epub 2016 Dec 15.
    Medical Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea.
    The recent advent of induced pluripotent stem cells (iPSCs) and gene therapy tools has raised the possibility of autologous cell therapy for rare genetic diseases. However, cellular reprogramming is inefficient in certain diseases such as ataxia telangiectasia, Fanconi anemia, LIG4 syndrome, and fibrodysplasia ossificans progressiva syndrome, owing to interference of the disease-related genes. To overcome these therapeutic limitations, it is necessary to fundamentally correct the abnormal gene during or prior to the reprogramming process. Read More

    Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome.
    Redox Biol 2016 Dec 28;11:375-383. Epub 2016 Dec 28.
    Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37 Str., 15-295 Bialystok, Poland. Electronic address:
    Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Read More

    Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia.
    Arterioscler Thromb Vasc Biol 2017 Jan 5. Epub 2017 Jan 5.
    From the School of Basic Medicine, Shandong University, Shandong University, Jinan, Shandong Province, China (Q.Y., S.P., W.Z., X.G., J.W., Y.L., F.J.); Key Laboratory of Cardiovascular Remodeling and Function Research & The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (X.W.); and Department of Cardiology, Qing Dao Central Hospital, Qing Dao, Shandong Province, China (Y.Z.).
    Objective: RNA polymerase I (Pol I)-dependent rRNA synthesis is a determinant factor in ribosome biogenesis and thus cell proliferation. The importance of dysregulated Pol I activity in cardiovascular disease, however, has not been recognized. Here, we tested the hypothesis that specific inhibition of Pol I might prevent arterial injury-induced neointimal hyperplasia. Read More

    Contribution of canonical nonhomologous end joining to chromosomal rearrangements is enhanced by ATM kinase deficiency.
    Proc Natl Acad Sci U S A 2017 Jan 5;114(4):728-733. Epub 2017 Jan 5.
    Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, Duarte, CA 91010;
    A likely mechanism of chromosomal rearrangement formation involves joining the ends from two different chromosomal double-strand breaks (DSBs). These events could potentially be mediated by either of two end-joining (EJ) repair pathways [canonical nonhomologous end joining (C-NHEJ) or alternative end joining (ALT-EJ)], which cause distinct rearrangement junction patterns. The relative role of these EJ pathways during rearrangement formation has remained controversial. Read More

    Collateral damage: insights into bacterial mechanisms that predispose host cells to cancer.
    Nat Rev Microbiol 2017 02 3;15(2):109-128. Epub 2017 Jan 3.
    Centre d'Immunologie de Marseille-Luminy Parc Scientifique et Technologique de Luminy, Case 906, 13288 Marseille Cedex 09, France.
    Infections are estimated to contribute to 20% of all human tumours. Viruses are known to induce cell transformation, but evidence has also linked bacteria, such as Helicobacter pylori and Salmonella enterica subsp. enterica serovar Typhi, to different cancer types. Read More

    Mec1/ATR, the Program Manager of Nucleic Acids Inc.
    Genes (Basel) 2016 Dec 28;8(1). Epub 2016 Dec 28.
    Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
    Eukaryotic cells are equipped with surveillance mechanisms called checkpoints to ensure proper execution of cell cycle events. Among these are the checkpoints that detect DNA damage or replication perturbations and coordinate cellular activities to maintain genome stability. At the forefront of damage sensing is an evolutionarily conserved molecule, known respectively in budding yeast and humans as Mec1 (Mitosis entry checkpoint 1) and ATR (Ataxia telangiectasia and Rad3-related protein). Read More

    Activation of ATR-Chk1 pathway facilitates EBV-mediated transformation of primary tonsillar B-cells.
    Oncotarget 2017 Jan;8(4):6461-6474
    Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zürich, Zürich, Switzerland.
    Primary infection of the immunocompromised host with the oncovirus Epstein-Barr virus (EBV) that targets mainly B-cells is associated with an increased risk for EBV-associated tumors. The early events subsequent to primary infection with potential for B-cell transformation are poorly studied. Here, we modeled in vitro the primary infection by using B-cells isolated from tonsils, the portal of entry of EBV, since species specificity of EBV hampers modeling in experimental animals. Read More

    Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex.
    Hum Mol Genet 2016 Dec 25. Epub 2016 Dec 25.
    Department of Biochemistry and Biomedical Research, McMaster University, HSC 4N54, 1200 Main Street West, Hamilton, Canada L8N3Z5
    Huntington's disease (HD) is an age-dependent neurodegenerative disease. DNA repair pathways have recently been implicated as the most predominant modifiers of age of onset in HD patients. We report that endogenous huntingtin protein directly participates in oxidative DNA damage repair. Read More

    Ataxia-telangiectasia mutated interactor regulates head and neck cancer metastasis via KRas expression.
    Oral Oncol 2016 Dec 21. Epub 2016 Dec 21.
    Angiogenesis Research Center, National Taiwan University, Taiwan; Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:
    Objectives: Relapse is the most serious problem affecting the morbidity and mortality rates of patients with head and neck squamous cell carcinoma (HNSCC). Although HNSCC has been studied for several decades, the exact mechanism of cancer recurrence remains unclear.

    Materials And Methods: ataxia-telangiectasia mutated interactor (ATMIN) messenger RNA(mRNA) expression was detected in HNSCC samples by quantitative RT-PCR, and was analyzed with patients' clinical outcomes by Kaplan-Meier analyses. Read More

    Audiological findings in children with ataxia-telangiectasia (A-T) syndrome.
    Int J Pediatr Otorhinolaryngol 2017 Jan 15;92:94-98. Epub 2016 Nov 15.
    Assistant Professor of Audiology, Otorhinolaryngology Department, Faculty of Medicine, Tanta University, Egypt.
    Aim: To assess peripheral and central hearing in children with A-T.

    Method: 3 children diagnosed with A-T according to the diagnostic criteria for A-T of the European Society for Immunodeficiencies. Involuntary movements were seen in the form of chorea-athetosis together with tremors. Read More

    Three-Dimensional Architecture of the Human BRCA1-A Histone Deubiquitinase Core Complex.
    Cell Rep 2016 Dec;17(12):3099-3106
    Structural Biology of DNA-Damage Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address:
    BRCA1 is a tumor suppressor found to be mutated in hereditary breast and ovarian cancer and plays key roles in the maintenance of genomic stability by homologous recombination repair. It is recruited to damaged chromatin as a component of the BRCA1-A deubiquitinase, which cleaves K63-linked ubiquitin chains attached to histone H2A and H2AX. BRCA1-A contributes to checkpoint regulation, repair pathway choice, and HR repair efficiency through molecular mechanisms that remain largely obscure. Read More

    A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype.
    Hum Mol Genet 2016 Dec 22. Epub 2016 Dec 22.
    The University of Queensland Centre for Clinical Research, Herston, Qld, Australia
    Ataxia-telangiectasia (A-T), an autosomal recessive disease caused by mutations in the ATM gene is characterised by cerebellar atrophy and progressive neurodegeneration which has been poorly recapitulated in Atm mutant mice. Consequently, pathways leading to neurodegeneration in A-T are poorly understood. We describe here the generation of an Atm knockout rat model that does not display cerebellar atrophy but instead paralysis and spinal cord atrophy, reminiscent of that seen in older patients and milder forms of the disorder. Read More

    Aging of the Immune System. Mechanisms and Therapeutic Targets.
    Ann Am Thorac Soc 2016 Dec;13(Supplement_5):S422-S428
    Department of Medicine, Stanford University Medical School, Stanford, California.
    Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Read More

    ATM mutations for surgeons.
    Fam Cancer 2016 Dec 17. Epub 2016 Dec 17.
    Division of Surgical Oncology, Department of Surgery, The Ohio State University College of Medicine, N908 Doan Hall, 410 W 10th Ave, Columbus, OH, 43210, USA.
    The ataxia-telangiectasia mutated (ATM) gene encodes a protein kinase involved in DNA repair. Heterozygotic carriers are at an increased risk of developing breast cancer. As the use of genetic testing increases, identification of at-risk patients will also increase. Read More

    DNA damage response in nephrotoxic and ischemic kidney injury.
    Toxicol Appl Pharmacol 2016 Oct 27. Epub 2016 Oct 27.
    Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China; Department of Cellular Biology & Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA. Electronic address:
    DNA damage activates specific cell signaling cascades for DNA repair, cell cycle arrest, senescence, and/or cell death. Recent studies have demonstrated DNA damage response (DDR) in experimental models of acute kidney injury (AKI). In cisplatin-induced AKI or nephrotoxicity, the DDR pathway of ATR/Chk2/p53 is activated and contributes to renal tubular cell apoptosis. Read More

    Induction of a Cellular DNA Damage Response by Porcine Circovirus Type 2 Facilitates Viral Replication and Mediates Apoptotic Responses.
    Sci Rep 2016 Dec 16;6:39444. Epub 2016 Dec 16.
    Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, No. 9 Shuguang Garden Middle Road, Haidian District, Beijing 100097, China.
    Cellular DNA damage response (DDR) triggered by infection of DNA viruses mediate cell cycle checkpoint activation, DNA repair, or apoptosis induction. In the present study, infection of porcine circovirus type 2 (PCV2), which serves as a major etiological agent of PCV2-associated diseases (PCVAD), was found to elicit a DNA damage response (DDR) as observed by the phosphorylation of H2AX and RPA32 following infection. The response requires active viral replication, and all the ATM (ataxia telangiectasia-mutated kinase), ATR (ATM- and Rad3-related kinase), and DNA-PK (DNA-dependent protein kinase) are the transducers of the DDR signaling events in the PCV2-infected cells as demonstrated by the phosphorylation of ATM, ATR, and DNA-PK signalings as well as reductions in their activations after treatment with specific kinase inhibitors. Read More

    DNA repair in the trinucleotide repeat disorders.
    Lancet Neurol 2017 Jan;16(1):88-96
    UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
    Background: Inherited diseases caused by unstable repeated DNA sequences are rare, but together represent a substantial cause of morbidity. Trinucleotide repeat disorders are severe, usually life-shortening, neurological disorders caused by nucleotide expansions, and most have no disease-modifying treatments. Longer repeat expansions are associated with genetic anticipation (ie, earlier disease onset in successive generations), although the differences in age at onset are not entirely accounted for by repeat length. Read More

    EGb 761 protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury and exerts inhibitory effect on ATM pathway.
    J Microbiol Biotechnol 2016 Dec 14. Epub 2016 Dec 14.
    Department of Cardiovascular Surgery, Nanyang Affiliated Hospital of Zhengzhou University, Nanyang Central Hospital; No.312 Gongnong Road, Nanyang, Henan Province, China.
    Ginkgo biloba extract (EGb 761) has been widely clinically used to reduce myocardial ischemia reperfusion injury (MIRI). Microvascular endothelial cells (MVECs) may be a proper cellular model in vitro for the effect and mechanism study against MIRI. However, the effect of EGb 761 on MVECs resisting hypoxia/reoxygenation (H/R) injury is little reported. Read More

    Colorectal Choriocarcinoma in a Patient with Probable Lynch Syndrome.
    Front Oncol 2016 29;6:252. Epub 2016 Nov 29.
    Cantonal Hospital Baselland, Institute of Pathology , Liestal , Switzerland.
    Background: Personalized therapy of colorectal cancer is influenced by morphological, molecular, and host-related factors. Here, we report the comprehensive clinicopathological and molecular analysis of an extra-gestational colorectal choriocarcinoma in a patient with probable Lynch syndrome.

    Case Presentation: A 61-year-old female with history of gastric cancer at age 36 presented with a transmurally invasive tumor of the right hemicolon and liver metastasis. Read More

    Low-dose irradiation promotes proliferation of the human breast cancer MDA-MB-231 cells through accumulation of mutant P53.
    Int J Oncol 2017 Jan 6;50(1):290-296. Epub 2016 Dec 6.
    Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
    Low-dose irradiation (LDIR) has been proven to have differential biological effects on normal mammalian somatic cells and cancer cells. Our previous study showed that p53 gene status is a critical factor regulating the effect of LDIR on cancer cells. We investigated the effect of LDIR on the breast cancer cell line MDA-MB-231 that harbors a mutant p53 gene, and the normal breast fibroblast cell line Hs 578Bst. Read More

    Cutis tricolor: a literature review and report of five new cases.
    Quant Imaging Med Surg 2016 Oct;6(5):525-534
    Department of Medical and Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Section of Radiology, University of Catania, Catania, Italy.
    Background: Cutis tricolor is a skin abnormality consisting in a combination of congenital hyper- and hypopigmented skin lesions (in the form of paired macules, patches or streaks) in close proximity to each other in a background of normal skin. It is currently regarded as a twin-spotting (mosaic) phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far either: (I) as an purely cutaneous trait; (II) as a part of a complex malformation phenotype (Ruggieri-Happle syndrome, RHS) including distinct facial features, eye (cataract), skeletal (skull and vertebral defects, and long bones dysplasia), nervous system (corpus callosum, cerebellar and white matter anomalies, cavum vergae and holoprosencephaly) and systemic abnormalities; (III) as a distinct type with multiple, disseminated smaller skin macules (cutis tricolor parvimaculata); and (IV) in association with other skin disturbances [e. Read More

    Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM.
    Mol Cell 2017 Jan 8;65(1):91-104. Epub 2016 Dec 8.
    Howard Hughes Medical Institute, University of Texas at Austin, Austin, TX 78712, USA; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA; Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA. Electronic address:
    Ataxia-telangiectasia mutated (ATM) regulates the DNA damage response as well as DNA double-strand break repair through homologous recombination. Here we show that ATM is hyperactive when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is chemically inhibited or when the DNA-PKcs gene is deleted in human cells. Pre-incubation of ATM protein with active DNA-PKcs also significantly reduces ATM activity in vitro. Read More

    Ex vivo encapsulation of dexamethasone sodium phosphate into human autologous erythrocytes using fully automated biomedical equipment.
    Int J Pharm 2017 Jan 7;517(1-2):175-184. Epub 2016 Dec 7.
    EryDel SpA, via Sasso 36, 61029, Urbino (PU), Italy; Department of Biomolecular Sciences, University of Urbino "Carlo Bo", via Saffi 2, 61029, Urbino (PU), Italy. Electronic address:
    Erythrocyte-based drug delivery systems are emerging as potential new solutions for the release of drugs into the bloodstream. The aim of the present work was to assess the performance of a fully automated process (EDS) for the ex-vivo encapsulation of the pro-drug dexamethasone sodium phosphate (DSP) into autologous erythrocytes in compliance with regulatory requirements. The loading method was based on reversible hypotonic hemolysis, which allows the opening of transient pores in the cell membrane to be crossed by DSP. Read More

    Nano-Mechanical Characterization of Ataxia Telangiectasia Cells Treated with Dexamethasone.
    Cell Biochem Biophys 2016 Dec 8. Epub 2016 Dec 8.
    Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
    Ataxia telangiectasia is a rare genetic disease and no therapy is currently available. Glucocorticoid analogues have been shown to improve the neurological symptoms of treated patients. In the present study ataxia telangiectasia and wild type cells were used as a cellular model and treated with dexamethasone. Read More

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