Search Our Scientific Publications & Authors

Ann Neurol 2018 Dec 14. Epub 2018 Dec 14.

Ataxia Telangiectasia Service, Respiratory Support and Sleep Centre, Papworth Hospital. Papworth Everard, Cambridge, CB23 3RE, UK.

Objective: Variant Ataxia-Telangiectasia is caused by mutations that allow some retained ATM kinase activity. Here, we describe the clinical features of the largest established cohort of individuals with variant Ataxia-Telangiectasia and explore genotype-phenotype correlations.

Methods: Cross-sectional data were collected retrospectively. Read More

Cerebellum 2018 Dec 6. Epub 2018 Dec 6.

Department of Neurology, Neurology Service, Cleveland VA Medical Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, 44110, USA.

Ataxia-telangiectasia is the second most common autosomal recessive hereditary ataxia, with an estimated incidence of 1 in 100,000 births. Besides ataxia and ocular telangiectasias, eye movement abnormalities have long been associated with this disorder and is frequently present in almost all patients. A handful of studies have described the phenomenology of ocular motor deficits in ataxia-telangiectasia. Read More

Biochem Biophys Res Commun 2018 Dec 3. Epub 2018 Dec 3.

Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address:

Castration-resistant prostate cancer (CRPC) lacks effective treatment, and studies have shown that PARPi inhibitors, such as Olaparib, are somewhat effective; however, the efficacy of Olaparib in CRPC still needs to be further improved. Nitrogen permease regulator-like 2 (NPRL2) is reported to be a tumor suppressor candidate gene and is closely related to the DNA repair pathway, which can affect the sensitivity of many chemotherapeutic drugs. However, there is no research on whether NPRL2 is associated with sensitivity to Olaparib. Read More

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Ataxia telangiectasia mutated and Rad3-related (ATR) kinase is a key factor activated by DNA damage and replication stress. An alternative pathway for ATR activation has been proposed to occur via stalled RNA polymerase II (RNAPII). However, how RNAPII might signal to activate ATR remains unknown. Read More

Anim Cells Syst (Seoul) 2018 9;22(6):400-406. Epub 2018 Oct 9.

Research Institute for Basic Science and Division of Biological Science, Wonkwang University, Iksan, Korea.

Ultraviolet B (UVB) radiation induces skin damage, skin matrix degradation, and wrinkle formation through photochemical reaction and oxidative stress. Therefore, protecting the skin from UVB can prevent skin aging. In this study, we investigated the effects of a mixture (RA) of Rg2, a ginsenoside, and astaxanthin, an antioxidant, on the responses of HaCaT cells exposed to UVB (700 J/m). Read More

Oncogene 2018 Dec 7. Epub 2018 Dec 7.

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Ataxia telangiectasia mutated and RAD3 related (ATR) protein kinase plays critical roles in ensuring DNA replication, DNA repair, and cell cycle control in response to replication stress, making ATR inhibition a promising therapeutic strategy for cancer treatment. To identify genes whose loss makes tumor cells hypersensitive to ATR inhibition, we performed CRISPR/Cas9-based whole-genome screens in 3 independent cell lines treated with a highly selective ATR inhibitor, AZD6738. These screens uncovered a comprehensive genome-wide profile of ATR inhibitor sensitivity. Read More

Oncogene 2018 Dec 10. Epub 2018 Dec 10.

Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA.

There is increasing evidence that genomic instability is a prerequisite for cancer progression. Here we show that SIM2s, a member of the bHLH/PAS family of transcription factors, regulates DNA damage repair through enhancement of homologous recombination (HR), and prevents epithelial-mesenchymal transitions (EMT) in an Ataxia-telangiectasia mutated (ATM)-dependent manner. Mechanistically, we found that SIM2s interacts with ATM and is stabilized through ATM-dependent phosphorylation in response to IR. Read More

Orv Hetil 2018 Dec;159(49):2065-2072

I. Gyermekgyógyászati Klinika, Semmelweis Egyetem, Általános Orvostudományi Kar Budapest, Bókay J. u. 53., 1083.

Experimental and clinical data suggest a complex interaction between the endocrine and immune systems. However, only few epidemiological studies are available dealing with endocrine complications in different types of primary immunodeficiency diseases. It is well documented that there is a close association between immunodeficiency syndromes and the development of autoimmune disorders. Read More

Orv Hetil 2018 Dec;159(49):2057-2064

Szent László Kórház Telephely, Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet Budapest, Albert Flórián út 5-7., 1097.

The number of primary immune deficiencies exceeds 350, approximately a quarter of them having neurological implications. Severe central nervous system infections may occur in an even higher proportion. Beyond listing in a table of all diseases with a neurological impact, the author gives detailed analysis of one typical disorder. Read More

Hum Reprod 2018 Dec 6. Epub 2018 Dec 6.

Institute of Cell Biology and Genes and Development Group, CDBS Hugh Robson Building, University of Edinburgh, Edinburgh, UK.

Study Question: Does ovarian follicle activation by phosphatase homologue of chromosome-10 (PTEN) inhibition affect DNA damage and repair in bovine oocytes and granulosa cells?

Summary Answer: PTEN inhibition promotes bovine non-growing follicle activation but results in increased DNA damage and impaired DNA repair capacity in ovarian follicles in vitro.

What Is Known Already: Inhibition of PTEN is known to activate primordial follicles but may compromise further developmental potential. In breast cancer cells, PTEN inhibition represses nuclear translocation of breast cancer susceptibility 1 (BRCA1) and Rad51; this impairs DNA repair resulting in an accumulation of damaged DNA, which contributes to cell senescence. Read More

Int J Radiat Oncol Biol Phys 2018 Nov 30. Epub 2018 Nov 30.

Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address:

Purpose: Roberts Syndrome (RBS) is a rare recessively-transmitted developmental disorder characterized by growth retardation, craniofacial abnormalities and truncation of limbs. All affected individuals to date have mutations in the ESCO2 (Establishment of cohesion 2) gene, a key regulator of the cohesin complex, which is involved in sister chromatid cohesion and DNA double-strand break (dsb) repair. Here we characterize DNA damage responses (DDRs) for the first time in a RBS-affected family. Read More

Neurology 2018 Nov 30. Epub 2018 Nov 30.

From the Department of Neurology-Pediatric Neurology (N.J.H.v.O., M.A.A.P.W.) and Department of Neurology (N.J.H.v.O., J.v.G., B.P.C.v.d.W.), Donders Institute for Brain, Cognition and Behaviour, Donders Center for Medical Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Neurology (A.H.), Addenbrookes Hospital, Cambridge; Institute of Cancer & Genomic Sciences (A.M.R.T.), University of Birmingham, UK; Department of Internal Medicine (M.v.D.), Radboud University Medical Center, Nijmegen; Department of Pediatric Infectious Diseases and Immunology (C.M.R.W.), Amalia Children's Hospital and Radboud Institute for Molecular Life Sciences, and Department of Pediatrics, Radboudumc Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.

Objective: To describe and classify the neurologic trajectories in patients with mild neurologic forms of ataxia telangiectasia (A-T) from the Dutch A-T cohort, combined with patients reported in the literature.

Methods: Clinical, genetic, and laboratory data of 14 patients with mild neurologic phenotypes of A-T from the Dutch cohort were analyzed and combined with corresponding data from the literature. A mild neurologic phenotype was defined by a later onset, nonataxia presenting or dominant feature, or slower progression compared to the classic A-T phenotype. Read More

Front Immunol 2018 20;9:2703. Epub 2018 Nov 20.

Institute of Biopathology and Regenerative Medicine, Center for Biomedical Research, University of Granada, Granada, Spain.

Ataxia-telangiectasia (A-T) is a complex disease arising from mutations in the gene (Ataxia-Telangiectasia Mutated), which plays crucial roles in repairing double-strand DNA breaks (DSBs). Heterogeneous immunodeficiency, extreme radiosensitivity, frequent appearance of tumors and neurological degeneration are hallmarks of the disease, which carries high morbidity and mortality because only palliative treatments are currently available. Gene therapy was effective in animal models of the disease, but the large size of the cDNA required the use of HSV-1 or HSV/AAV hybrid amplicon vectors, whose characteristics make them unlikely tools for treating A-T patients. Read More

Cancer Res Treat 2018 Dec 3. Epub 2018 Dec 3.

Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Purpose: The DNA damage response (DDR) is a multi-complex network of signaling pathways involved in DNA damage repair, cell cycle checkpoints, and apoptosis. In the case of biliary tract cancer (BTC), the strategy of DDR targeting has not been evaluated, even though many patients have DNA repair pathway alterations. The purpose of this study was to test the DDR-targeting strategy in BTC using an ataxia-telangiectasia and Rad3-related (ATR) inhibitor. Read More

Mar Drugs 2018 Nov 30;16(12). Epub 2018 Nov 30.

Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.

11-Dehydrosinulariolide, an active compound that is isolated from the cultured soft coral , has been suggested to show anti-tumor biological characteristics according to previous studies. However, its potential effect on small cell lung cancer (SCLC) remains unknown. The present study investigates the underlying mechanism for the treatment of SCLC in vitro and in vivo. Read More

Cancer Res 2018 Dec 29;78(24):6713-6716. Epub 2018 Nov 29.

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan.

Glioblastoma (GBM) is a highly aggressive form of cancer that is resistant to standard therapy with concurrent radiation and temozolomide, two agents that work by inducing DNA damage. An underlying cause of this resistance may be a subpopulation of cancer stem-like cells that display a heightened DNA damage response (DDR). Although this DDR represents an attractive therapeutic target for overcoming the resistance of GBMs to radiotherapy, until now, the cause of this DDR upregulation has not been understood. Read More

Mol Med Rep 2018 Nov 20. Epub 2018 Nov 20.

College of Life Science and Bioengineering, School of Science, Beijing Jiaotong University, Beijing 100044, P.R. China.

Natural killer (NK) cells recognize stress‑activated NK group 2, member D (NKG2D) ligands in tumors. In the present study, the expression levels of NKG2D ligands were examined in four lung cancer cell lines (A549, PLA801D, NCI‑H157 and NCI‑H520). In the A549 cells, the expression of MHC class I polypeptiderelated sequence (MIC)A/B and UL16 binding protein (ULBP)1 was weak, the expression of ULBP2 was typical, and neither ULBP3 nor ULBP4 were expressed. Read More

Biochemistry (Mosc) 2018 Sep;83(9):1040-1045

Research Center of Neurology, Moscow, 125367, Russia.

The prevalent form of familial parkinsonism is caused by mutations in the LRRK2 gene encoding for the mitochondrial protein kinase. In the review, we discuss possible causes of appearance of tetraploid cells in neuronal precursors obtained from induced pluripotent stem cells from patients with the LRRK2-associated form of parkinsonism after genome editing procedure. As LRRK2 protein participates in cell proliferation and maintenance of the nuclear envelope, spindle fibers, and cytoskeleton, mutations in the LRRK2 gene can affect protein functions and lead, via various mechanisms, to the mitotic machinery disintegration and chromosomal aberration. Read More

DNA Repair (Amst) 2018 Nov 13. Epub 2018 Nov 13.

Department of Pathology & Translational Pathobiology, LSU Health Sciences Center Shreveport, Shreveport, Louisiana, 71130, United States. Electronic address:

The ataxia telangiectasia-mutated and Rad3-related (ATR) serine/threonine kinase plays a central role in the repair of replication-associated DNA damage, the maintenance of S and G2/M-phase genomic stability, and the promotion of faithful mitotic chromosomal segregation. A number of stimuli activate ATR, including persistent single-stranded DNA at stalled replication folks, R loop formation, hypoxia, ultraviolet light, and oxidative stress, leading to ATR-mediated protein phosphorylation. Recently, hydrogen sulfide (HS), an endogenous gasotransmitter, has been found to regulate multiple cellular processes through complex redox reactions under similar cell stress environments. Read More

Life Sci Alliance 2018 Jun 21;1(3):e201800096. Epub 2018 Jun 21.

Institut de Génétique Humaine, Centre National de la Recherche Scientifique, Université de Montpellier, Montpellier, France.

The DNA damage response (DDR) ensures cellular adaptation to genotoxic insults. In the crowded environment of the nucleus, the assembly of productive DDR complexes requires multiple protein modifications. How the apical E1 ubiquitin activation enzyme UBA1 integrates spatially and temporally in the DDR remains elusive. Read More

Life Sci Alliance 2018 Jun 22;1(3):e201800021. Epub 2018 Jun 22.

Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

The synaptonemal complex is a proteinaceous structure essential for meiotic recombination, and its components have been assumed to play a role exclusively in the germ line. However, SYCE2, a component constituting the synaptonemal complex, is expressed at varying levels in somatic cells. Considering its potent protein-binding activities, it may be possible that SYCE2 plays a somatic role by affecting nuclear functions. Read More

Biol Blood Marrow Transplant 2018 Nov 7;24(11):2245-2249. Epub 2018 Jul 7.

Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland.

Ataxia-telangiectasia (A-T) syndrome is an autosomal recessive chromosomal breakage syndrome caused by mutation of the ataxia-telangiectasia mutated gene manifested by progressive neurodegeneration, telangiectasias of sclera and skin, immune deficiency with sinopulmonary infections, and increased incidence of lymphoid malignancies and solid tumors. Three children with A-T underwent allogeneic stem cell transplantation (SCT) using protocols for Fanconi anemia. All 3 patients were engrafted with a mixed donor-recipient chimerism, but the full donor engraftment was observed in the T lymphocyte compartment. Read More

Virology 2018 Nov 16;527:47-56. Epub 2018 Nov 16.

Department of Microbiology, Pearson Hall, Miami University, 700 E. High Street, Oxford, OH 45056, United States; Cell Molecular and Structural Biology Program, Miami University, Oxford, OH 45056, United States. Electronic address:

Adenovirus (Ad) type 5 (Ad5) E4 deletion mutants including H5dl1007 (E4-) induce a DNA damage response (DDR) that activates the kinase ataxia-telangiectasia mutated (ATM), which can interfere with efficient viral DNA replication. We find that localization of active phosphorylated ATM (pATM) to E4- viral replication centers (VRCs) is important for its inhibitory effect. ATM is necessary for localization of RNF8 and 53BP1 to E4 mutant VRCs, while recruitment of DDR factors Mre11, Mdc1 and γH2AX is ATM-independent, raising the possibility that ATM may affect viral chromatin at VRCs. Read More

Mutat Res 2018 Dec 1;836(Pt B):122-126. Epub 2018 Jun 1.

Postgraduate Program in Pharmacy, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Laboratory of Genetics, University Hospital, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. Electronic address:

Ataxi A-T elangiectasia (AT) is a multisystem, complex and rare disease inherited in an autosomal recessive manner. Homozygous individuals have a variety of pathological manifestations, however, heterozygotes only present a higher risk of developing cancer. We evaluated the background levels of DNA damage (basal damage) and cell response to bleomycin or ionizing radiation using Comet assay and the cytokinesis-block micronucleus (CBMN) test in individuals with AT, their parents and controls. Read More

Pharmacogenomics 2018 Nov 16;19(17):1335-1344. Epub 2018 Oct 16.

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China.

Aim: To investigate the association between SNPs in DNA damage response pathways and toxicities following I radiotherapy of differentiated thyroid cancer (DTC). Materials & methods: We identified 22 functional SNPs of genes in DNA damage response pathways. MassArray was used to sequence SNP genotypes in 203 DTC patients. Read More

Med Phys 2018 Nov;45(11):e1111-e1122

Trento Institute for Fundamental Physics Applications, National Institute for Nuclear Physics, Trento, Italy.

Purpose: Radiogenomics is the study of genomic changes that underlie the radioresponse of normal and tumor tissues. And while this is generally regarded as a whole genome approach, one must keep in mind the impact of single gene biology on radioresponse, (ataxia telangiectasia, Nijmegen breakage syndrome).

Methods: This review begins with the association of single nucleotide polymorphisms in the DNA with adverse normal tissue events to the prediction of therapeutic outcome after radiotherapy. Read More

Front Immunol 2018 29;9:2495. Epub 2018 Oct 29.

Division for Stem Cell Transplantation and Immunology, Children's Hospital, Goethe-Universität Frankfurt am Main, Frankfurt, Germany.

Ataxia telangiectasia (A-T) is a primary immunodeficiency with mutations in the gene encoding the A-T mutated (ATM) protein that interacts with immune, hematopoietic, and endocrine targets resulting in broad multi-systemic clinical manifestations with a devastating outcome. Apart from a progressive neurodegenerative disorder, A-T leads to significantly increased susceptibility to malignancies. It is a matter of discussion whether pre-emptive allogeneic hematopoietic stem cell transplantation (alloHSCT) using a reduced intensity conditioning regimen would be an option to restore immune-competence and prevent malignancy, as shown in animal models, because conventional treatment protocols of malignant diseases using radio- and/or chemotherapy have a high rate of therapy-related morbidity and mortality in these patients. Read More

Biochem Biophys Rep 2018 Dec 30;16:115-121. Epub 2018 Oct 30.

Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Deamination of 5-methyl cytosine is a major cause of cancer-driver mutations in inflammation-associated cancers. The deaminase APOBEC3B is expressed in these cancers and causes mutations under replication stress; however, the mechanisms by which APOBEC3B mediates deamination and its association with genomic disorders are still unclear. Here, we show that APOBEC3B is stabilized to induce deamination reaction in response to DNA double-strand breaks (DSBs), resulting in the formation of long-lasting DSBs. Read More

Biochem Biophys Res Commun 2018 Dec 5;506(4):1052-1058. Epub 2018 Nov 5.

Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, College of Preventive Medicine, Third Military Medical University, Gaotanyan Street 30(#), Shapingba, Chongqing, 400038, China. Electronic address:

As compared with 2D cell line cultures, 3D intestinal organoids are better at maximally recapitulating the physiological features of stem cells in vivo. However, the complex 3D structure is an obstacle which must be objectively and automatically evaluated to assess colony growth and regeneration. Meanwhile, no internal standard currently exists for evaluating the size of heterogeneities in organoids or defining those regenerating colonies. Read More

Biochem Biophys Res Commun 2018 Dec 4;506(4):983-989. Epub 2018 Nov 4.

Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. Electronic address:

Cell proliferation is regulated not only by soluble chemical factors but also by mechanical cues surrounding cells. Mechanical stretch of extracellular substrates is known to promote cell proliferation by driving exit from the G phase and entry into the S phase. Here, we report that planer compression of extracellular substrates induces cell cycle arrest in the S phase. Read More

Mol Clin Oncol 2018 Nov 17;9(5):493-498. Epub 2018 Sep 17.

Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.

Ataxia-telangiectasia (A-T) is an infrequent autosomal recessive disorder that involves multiple systems and is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent respiratory infections, and a tendency to develop lymphoid malignancies. A-T is caused by mutations in the ATM gene, with >1,000 mutations reported to date and gradually increasing in number. Patients with A-T have an increased incidence of cancers. Read More

MBio 2018 Nov 6;9(6). Epub 2018 Nov 6.

Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany

Cervical and ovarian cancers exhibit characteristic mutational signatures that are reminiscent of mutational processes, including defective homologous recombination (HR) repair. How these mutational processes are initiated during carcinogenesis is largely unclear. infections are epidemiologically associated with cervical and ovarian cancers. Read More

J Neuroinflammation 2018 Nov 6;15(1):308. Epub 2018 Nov 6.

Division of Life Science and State Key Laboratory of Molecular Neurobiology, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.

Background: Inflammation plays a critical role in accelerating the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) and ataxia telangiectasia (A-T). In A-T mouse models, LPS-induced neuroinflammation advances the degenerative changes found in cerebellar Purkinje neurons both in vivo and in vitro. In the current study, we ask whether ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), can have the opposite effect and delay the symptoms of the disease. Read More

Int J Mol Sci 2018 Nov 2;19(11). Epub 2018 Nov 2.

Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Werner Syndrome (WS) is an autosomal recessive disorder characterized by the premature development of aging features. Individuals with WS also have a greater predisposition to rare cancers that are mesenchymal in origin. Werner Syndrome Protein (WRN), the protein mutated in WS, is unique among RecQ family proteins in that it possesses exonuclease and 3' to 5' helicase activities. Read More

Mutat Res 2018 Dec 8;836(Pt A):117-123. Epub 2018 May 8.

Dipartimento di Medicina Clinica e Molecolare, Facoltà di Medicina e Psicologia, "Sapienza" Università di Roma, Via di Grottarossa 1035, 00189 Roma, Italy.

The ataxia telangiectasia mutated (ATM) protein is a pivotal multifunctional protein kinase predominantly involved in DNA damage response, as well as in maintaining overall functional integrity of the cells. Apart from playing its major role in regulating the cellular response to DNA damage, ATM, when mutated, can additionally determine oxidative stress, metabolic syndrome, mitochondrial dysfunction and neurodegeneration. In the present paper we aim to investigate the levels of oxidative stress potentially induced by the oxidizing rodent renal carcinogen KBrO in ATM-defective lymphoblastoid cell lines (LCLs) established from four classical AT patients (with different ATM mutations), one AT variant with reduced hypersensitivity to X rays, obligate AT heterozygotes and wild type intrafamilial control. Read More

Mutat Res 2018 Dec 15;836(Pt A):109-116. Epub 2018 Jun 15.

Department of Ecological and Biological Sciences (DEB), University of Tuscia, Via San Camillo de Lellis snc, 01100, Viterbo, Italy. Electronic address:

Ataxia telangiectasia is a rare autosomal recessive genome instability syndrome caused by mutations in the Ataxia Telangiectasia Mutated gene and characterized by a very high sensitivity to agents inducing double strand breaks such as ionizing radiation. In cells derived from ataxia telangiectasia patients a prominent enhancement of chromosomal aberrations is revealed as a consequence of this radiosensitivity characteristic, arising from defective DNA repair for a small fraction of breaks localized in the less accessible heterochromatin. Moreover, the signaling mediated by ataxia telangiectasia protein kinase also modifies chromatin structure. Read More

J Cell Biochem 2018 Nov 1. Epub 2018 Nov 1.

Department of Orthopedic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Osteosarcoma (OS) is a primary malignant bone tumor with high morbidity. Developing new therapeutic approaches with neoadjuvant is of great interest in OS treatment. Reportedly, ataxia telangiectasia mutated (ATM)/ataxia telangiectasia and radiation resistance gene 3 related (ATR)-p53 signaling is considered as a critical DNA damage signaling pathway sensitizing cancer cells to chemotherapies; while wild-type p53-induced phosphatase 1 (WIP1), an oncogene overexpressed in diverse cancers, has been regarded as a critical inhibitor in the ATM/ATR-p53 DNA damage signaling pathway. Read More

Br J Cancer 2018 Nov 2;119(10):1233-1243. Epub 2018 Nov 2.

Translational Sciences, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.

Background: AZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangiectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage.

Methods: We used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue.

Results: We found moderate pRAD50 baseline levels across cancer indications. Read More

BMC Cancer 2018 Nov 1;18(1):1060. Epub 2018 Nov 1.

Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China.

Background: Ataxia telangiectasia mutated (ATM) gene plays a key role in response to DNA lesions and is related to the invasion and metastasis of malignancy. Epidemiological studies have indicated associations between ATM rs1801516 polymorphism and different types of cancer, but their results are inconsistent. To further evaluate the effect of ATM rs1801516 polymorphism on cancer risk, we conducted this meta-analysis. Read More

Biochemistry 2018 Nov 12;57(47):6592-6603. Epub 2018 Nov 12.

Discipline of Biological Engineering , Indian Institute of Technology Gandhinagar , Gandhinagar - 382355 , Gujarat , India.

DNA damage response (DDR) pathways form an integral part of the body's repair machinery, and ATR (ataxia-telangiectasia and Rad3-related kinase) protein is one of the key mediators in the DDR pathway that helps in maintaining genomic integrity. A growing body of evidence suggests that inhibition of ATR can help sensitize tumor cells to combinatorial treatment. However, specific ATR kinase inhibitors have largely remained elusive until now. Read More

Mov Disord Clin Pract 2018 Jan-Feb;5(1):89-91. Epub 2017 Dec 3.

Department of Neurology and Center of Clinical Neuroscience First Faculty of Medicine Charles University and General Faculty Hospital Prague Czech Republic.

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312564-sup-v001_1. Read More

Cell Oncol (Dordr) 2018 Oct 26. Epub 2018 Oct 26.

Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, 410210, India.

Purpose: Previously we have shown, using a primary glioblastoma (GBM) cell model, that a subpopulation of innately radiation resistant (RR) GBM cells survive radiotherapy and form multinucleated and giant cells (MNGCs) by homotypic fusions. We also showed that MNGCs may cause relapse. Here, we set out to explore whether molecular characteristics of RR cells captured from patient-derived primary GBM cultures bear clinical relevance. Read More

Trends Cancer 2018 Nov 9;4(11):755-768. Epub 2018 Oct 9.

Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia; LFR2O, Institute Gustave Roussy, Villejuif, France; Lomonosov Moscow State University, Moscow, Russia.

Synthetic lethality occurs when simultaneous perturbations of two genes or molecular processes result in a loss of cell viability. The number of known synthetically lethal interactions is growing steadily. We review here synthetically lethal interactions of ataxia-telangiectasia mutated (ATM), ATM- and Rad3-related (ATR), and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Read More

DNA Repair (Amst) 2018 Dec 11;72:10-17. Epub 2018 Oct 11.

The David and Inez Myers Laboratory for Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, New York, United States. Electronic address:

The genome instability syndrome, ataxia-telangiectasia (A-T) is caused by null mutations in the ATM gene, that lead to complete loss or inactivation of the gene's product, the ATM protein kinase. ATM is the primary mobilizer of the cellular response to DNA double-strand breaks (DSBs) - a broad signaling network in which many components are ATM targets. The major clinical feature of A-T is cerebellar atrophy, characterized by relentless loss of Purkinje and granule cells. Read More

J Med Chem 2018 Nov 10;61(22):9889-9907. Epub 2018 Nov 10.

Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.

The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Read More

F1000Res 2018 10;7:1233. Epub 2018 Aug 10.

CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), (FPS) Fundacion Progreso y Salud, Sevilla, Andalucia, 41092, Spain.

Photoreceptors, light-sensing neurons in retina, are central to vision. Photoreceptor cell death (PCD) is observed in most inherited and acquired retinal dystrophies. But the underlying molecular mechanism of PCD is unclear. Read More

Neurogenetics 2018 Dec 21;19(4):237-255. Epub 2018 Oct 21.

Division for Neurology, Department for Children and Adolescents, Goethe University, 60590, Frankfurt am Main, Germany.

Autosomal recessive ataxia telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency, and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the ataxia telangiectasiamutated (ATM) gene, a serine-threonine protein kinase involved in DNA damage response and excitatory neurotransmission. The selective vulnerability of cerebellar Purkinje neurons (PN) to A-T is not well understood. Read More

J Pediatr Hematol Oncol 2018 Oct 18. Epub 2018 Oct 18.

Department of Pediatrics, Division of Pediatric Hematology, Faculty of Medicine, Hacettepe University, Ankara.

A unique consanguineous family with 2 genomic instability disorders, Fanconi anemia and ataxia telangiectasia, revealed exceptional combinations of null mutations in the FANCA and ATM genes. Two siblings with Fanconi anemia had novel homozygous consecutive microdeletions (c.1361-1370delCCTCCTTTGG, c. Read More

Cerebellum 2018 Oct 18. Epub 2018 Oct 18.

Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 100 Cambridge Street, Suite 2000, Boston, MA, 02114, USA.

Ataxia-telangiectasia (AT) is an autosomal recessive, multisystem disease causing cerebellar ataxia, mucocutaneous telangiectasias, immunodeficiency, and malignancies. A pilot study reported cognitive and behavioral manifestations characteristic of the cerebellar cognitive affective / Schmahmann syndrome (CCAS). We set out to test and further define these observations because a more comprehensive understanding of the spectrum of impairments in AT is essential for optimal management. Read More

J Biol Chem 2018 Dec 16;293(49):19025-19037. Epub 2018 Oct 16.

From the Markey Cancer Center and

Blunted melanocortin 1 receptor (MC1R) signaling promotes melanocyte genomic instability in part by attenuating cAMP-mediated DNA repair responses, particularly nucleotide excision repair (NER), which recognizes and clears mutagenic photodamage. cAMP-enhanced NER is mediated by interactions between the ataxia telangiectasia-mutated and Rad3-related (ATR) and xeroderma pigmentosum complementation group A (XPA) proteins. We now report a critical role for sirtuin 1 (SIRT1) in regulating ATR-mediated phosphorylation of XPA. Read More