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  1. Article ; Online: A molecular beacon approach to detecting RAD52 expression in response to DNA damage in human cells.

    Riches, Lucy C / Lynch, Anthony M / Gooderham, Nigel J

    Toxicology in vitro : an international journal published in association with BIBRA

    2010  Volume 24, Issue 2, Page(s) 652–660

    Abstract: Although DNA damage proteins are infrequently regulated at the transcriptional level, RAD52 mRNA levels appear to be significantly induced in human cells following methyl methanesulphonate (MMS) and Etoposide treatment. Studies have so far been limited ... ...

    Abstract Although DNA damage proteins are infrequently regulated at the transcriptional level, RAD52 mRNA levels appear to be significantly induced in human cells following methyl methanesulphonate (MMS) and Etoposide treatment. Studies have so far been limited to biochemical analysis of cellular extracts and we aimed to extend this observation to whole cells. To address this, we have developed a series of molecular beacon (MB) probes that fluoresce upon hybridising with RAD52 mRNA sequence. MB's are synthetic hairpin probes, which generate a significant fluorescent signal only upon hybridising complementary nucleotide. Three MB's are described herein, which display differential sensitivity, specificity and stability. In particular, the suitability of a texas red-labelled DNA MB (TR-MB), a dual-labelled (FAM-TAMRA) fluorescence resonance energy transfer-capable DNA MB (FRET-MB) and a FAM-labelled MB of 2'-O-methylated RNA backbone (FAM-MB) was investigated. We conclude that FAM-MB is most suitable for intracellular applications, and demonstrate a positive correlation between MB fluorescence intensity, RAD52 gene expression and both gamma ionising radiation and MMS concentration in human TK6 cells. RAD52 contribution to DNA repair has been ascribed to its role in homologous recombination (HR) and therefore we propose FAM-MB could be a potential tool for discriminating between substrates of HR and non-homologous end joining (NHEJ).
    MeSH term(s) Antineoplastic Agents, Alkylating/toxicity ; Antineoplastic Agents, Phytogenic/toxicity ; Biological Assay ; Cell Line, Tumor ; Cell-Free System ; DNA Breaks, Double-Stranded/drug effects ; DNA Repair ; Etoposide/toxicity ; Gene Expression Regulation/drug effects ; Humans ; Methyl Methanesulfonate/toxicity ; Rad52 DNA Repair and Recombination Protein/genetics ; Rad52 DNA Repair and Recombination Protein/metabolism
    Chemical Substances Antineoplastic Agents, Alkylating ; Antineoplastic Agents, Phytogenic ; RAD52 protein, human ; Rad52 DNA Repair and Recombination Protein ; Etoposide (6PLQ3CP4P3) ; Methyl Methanesulfonate (AT5C31J09G)
    Language English
    Publishing date 2010-03
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639064-x
    ISSN 1879-3177 ; 0887-2333
    ISSN (online) 1879-3177
    ISSN 0887-2333
    DOI 10.1016/j.tiv.2009.09.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2223: Show issues Location:
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  2. Article ; Online: Early events in the mammalian response to DNA double-strand breaks.

    Riches, Lucy C / Lynch, Anthony M / Gooderham, Nigel J

    Mutagenesis

    2008  Volume 23, Issue 5, Page(s) 331–339

    Abstract: Physical and chemical agents that induce DNA double-strand breaks (DSBs) are among the most potent mutagens. The mammalian cell response to DSB comprises a highly co-ordinated, yet complex network of proteins that have been categorized as sensors, signal ...

    Abstract Physical and chemical agents that induce DNA double-strand breaks (DSBs) are among the most potent mutagens. The mammalian cell response to DSB comprises a highly co-ordinated, yet complex network of proteins that have been categorized as sensors, signal transducers, mediators and effectors of damage and repair. While this provides an accessible classification system, review of the literature indicates that many proteins satisfy the criteria of more than one category, pointing towards a series of highly co-operative pathways with overlapping function. In summary, the MRE11-NBS1-RAD50 complex is necessary for achieving optimal activation of ataxia-telangiectasia-mutated (ATM) kinase, which catalyses a phosphorylation-mediated signal transduction cascade. Among the subset of proteins phosphorylated by ATM are histone H2AX (H2AX), mediator of damage checkpoint protein 1, nibrin (NBS1), P53-binding protein 1 and breast cancer protein 1, all of which subsequently redistribute into DSB-containing sub-nuclear compartments. Post-translational modification of DSB responding proteins achieves a rapid and reversible change in protein behaviour and mediates damage-specific interactions, hence imparting a high degree of vigilance to the cell. This review highlights events fundamental in maintaining genetic integrity with emphasis on early stages of the DSB response.
    MeSH term(s) Acid Anhydride Hydrolases ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; DNA Breaks, Double-Stranded ; DNA Repair Enzymes ; DNA-Binding Proteins/metabolism ; Histones/metabolism ; Humans ; MRE11 Homologue Protein ; Nuclear Proteins/metabolism ; Phosphopeptides ; Protein Serine-Threonine Kinases ; Protein Structure, Tertiary ; Telomere/enzymology ; Tumor Suppressor Proteins
    Chemical Substances Cell Cycle Proteins ; DNA-Binding Proteins ; H2AX protein, human ; Histones ; MRE11 protein, human ; NBN protein, human ; Nuclear Proteins ; Phosphopeptides ; Tumor Suppressor Proteins ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; MRE11 Homologue Protein (EC 3.1.-) ; Acid Anhydride Hydrolases (EC 3.6.-) ; RAD50 protein, human (EC 3.6.-) ; DNA Repair Enzymes (EC 6.5.1.-)
    Language English
    Publishing date 2008-07-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 632903-2
    ISSN 1464-3804 ; 0267-8357
    ISSN (online) 1464-3804
    ISSN 0267-8357
    DOI 10.1093/mutage/gen039
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2189: Show issues Location:
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  3. Article ; Online: Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically.

    Riches, Lucy C / Trinidad, Antonio G / Hughes, Gareth / Jones, Gemma N / Hughes, Adina M / Thomason, Andrew G / Gavine, Paul / Cui, Andy / Ling, Stephanie / Stott, Jonathan / Clark, Roger / Peel, Samantha / Gill, Pendeep / Goodwin, Louise M / Smith, Aaron / Pike, Kurt G / Barlaam, Bernard / Pass, Martin / O'Connor, Mark J /
    Smith, Graeme / Cadogan, Elaine B

    Molecular cancer therapeutics

    2019  Volume 19, Issue 1, Page(s) 13–25

    Abstract: AZD0156 is a potent and selective, bioavailable inhibitor of ataxia-telangiectasia mutated (ATM) protein, a signaling kinase involved in the DNA damage response. We present preclinical data demonstrating abrogation of irradiation-induced ATM signaling by ...

    Abstract AZD0156 is a potent and selective, bioavailable inhibitor of ataxia-telangiectasia mutated (ATM) protein, a signaling kinase involved in the DNA damage response. We present preclinical data demonstrating abrogation of irradiation-induced ATM signaling by low doses of AZD0156, as measured by phosphorylation of ATM substrates. AZD0156 is a strong radiosensitizer
    MeSH term(s) Animals ; Ataxia Telangiectasia Mutated Proteins/pharmacology ; Ataxia Telangiectasia Mutated Proteins/therapeutic use ; Cell Line, Tumor ; Humans ; Male ; Mice ; Mice, Nude ; Phthalazines/pharmacology ; Phthalazines/therapeutic use ; Piperazines/pharmacology ; Piperazines/therapeutic use ; Pyridines/pharmacology ; Pyridines/therapeutic use ; Quinolines/pharmacology ; Quinolines/therapeutic use ; Radiation-Sensitizing Agents/pharmacology ; Radiation-Sensitizing Agents/therapeutic use ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/pathology ; Triple Negative Breast Neoplasms/radiotherapy
    Chemical Substances Phthalazines ; Piperazines ; Pyridines ; Quinolines ; Radiation-Sensitizing Agents ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; AZD0156 (P5T0XWC07Z) ; olaparib (WOH1JD9AR8)
    Language English
    Publishing date 2019-09-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-18-1394
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5750: Show issues Location:
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  4. Article ; Online: Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice.

    Karlin, Jeremy / Allen, Jasmine / Ahmad, Syed F / Hughes, Gareth / Sheridan, Victoria / Odedra, Rajesh / Farrington, Paul / Cadogan, Elaine B / Riches, Lucy C / Garcia-Trinidad, Antonio / Thomason, Andrew G / Patel, Bhavika / Vincent, Jennifer / Lau, Alan / Pike, Kurt G / Hunt, Thomas A / Sule, Amrita / Valerie, Nicholas C K / Biddlestone-Thorpe, Laura /
    Kahn, Jenna / Beckta, Jason M / Mukhopadhyay, Nitai / Barlaam, Bernard / Degorce, Sebastien L / Kettle, Jason / Colclough, Nicola / Wilson, Joanne / Smith, Aaron / Barrett, Ian P / Zheng, Li / Zhang, Tianwei / Wang, Yingchun / Chen, Kan / Pass, Martin / Durant, Stephen T / Valerie, Kristoffer

    Molecular cancer therapeutics

    2018  Volume 17, Issue 8, Page(s) 1637–1647

    Abstract: Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that ... ...

    Abstract Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited central nervous system (CNS) bioavailability; thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested
    MeSH term(s) Administration, Oral ; Animals ; Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors ; Blood-Brain Barrier/metabolism ; Cell Line, Tumor ; Glioma/drug therapy ; Humans ; Mice ; Mice, Nude ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Radiation-Sensitizing Agents/pharmacology ; Radiation-Sensitizing Agents/therapeutic use
    Chemical Substances Protein Kinase Inhibitors ; Radiation-Sensitizing Agents ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Atm protein, mouse (EC 2.7.11.1)
    Language English
    Publishing date 2018-05-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-17-0975
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The effectiveness, acceptability and cost-effectiveness of psychosocial interventions for maltreated children and adolescents: an evidence synthesis.

    Macdonald, Geraldine / Livingstone, Nuala / Hanratty, Jennifer / McCartan, Claire / Cotmore, Richard / Cary, Maria / Glaser, Danya / Byford, Sarah / Welton, Nicky J / Bosqui, Tania / Bowes, Lucy / Audrey, Suzanne / Mezey, Gill / Fisher, Helen L / Riches, Wendy / Churchill, Rachel

    Health technology assessment (Winchester, England)

    2016  Volume 20, Issue 69, Page(s) 1–508

    Abstract: Background: Child maltreatment is a substantial social problem that affects large numbers of children and young people in the UK, resulting in a range of significant short- and long-term psychosocial problems.: Objectives: To synthesise evidence of ... ...

    Abstract Background: Child maltreatment is a substantial social problem that affects large numbers of children and young people in the UK, resulting in a range of significant short- and long-term psychosocial problems.
    Objectives: To synthesise evidence of the effectiveness, cost-effectiveness and acceptability of interventions addressing the adverse consequences of child maltreatment.
    Study design: For effectiveness, we included any controlled study. Other study designs were considered for economic decision modelling. For acceptability, we included any study that asked participants for their views.
    Participants: Children and young people up to 24 years 11 months, who had experienced maltreatment before the age of 17 years 11 months.
    Interventions: Any psychosocial intervention provided in any setting aiming to address the consequences of maltreatment.
    Main outcome measures: Psychological distress [particularly post-traumatic stress disorder (PTSD), depression and anxiety, and self-harm], behaviour, social functioning, quality of life and acceptability.
    Methods: Young Persons and Professional Advisory Groups guided the project, which was conducted in accordance with Cochrane Collaboration and NHS Centre for Reviews and Dissemination guidance. Departures from the published protocol were recorded and explained. Meta-analyses and cost-effectiveness analyses of available data were undertaken where possible.
    Results: We identified 198 effectiveness studies (including 62 randomised trials); six economic evaluations (five using trial data and one decision-analytic model); and 73 studies investigating treatment acceptability. Pooled data on cognitive-behavioural therapy (CBT) for sexual abuse suggested post-treatment reductions in PTSD [standardised mean difference (SMD) -0.44 (95% CI -4.43 to -1.53)], depression [mean difference -2.83 (95% CI -4.53 to -1.13)] and anxiety [SMD -0.23 (95% CI -0.03 to -0.42)]. No differences were observed for post-treatment sexualised behaviour, externalising behaviour, behaviour management skills of parents, or parental support to the child. Findings from attachment-focused interventions suggested improvements in secure attachment [odds ratio 0.14 (95% CI 0.03 to 0.70)] and reductions in disorganised behaviour [SMD 0.23 (95% CI 0.13 to 0.42)], but no differences in avoidant attachment or externalising behaviour. Few studies addressed the role of caregivers, or the impact of the therapist-child relationship. Economic evaluations suffered methodological limitations and provided conflicting results. As a result, decision-analytic modelling was not possible, but cost-effectiveness analysis using effectiveness data from meta-analyses was undertaken for the most promising intervention: CBT for sexual abuse. Analyses of the cost-effectiveness of CBT were limited by the lack of cost data beyond the cost of CBT itself.
    Conclusions: It is not possible to draw firm conclusions about which interventions are effective for children with different maltreatment profiles, which are of no benefit or are harmful, and which factors encourage people to seek therapy, accept the offer of therapy and actively engage with therapy. Little is known about the cost-effectiveness of alternative interventions.
    Limitations: Studies were largely conducted outside the UK. The heterogeneity of outcomes and measures seriously impacted on the ability to conduct meta-analyses.
    Future work: Studies are needed that assess the effectiveness of interventions within a UK context, which address the wider effects of maltreatment, as well as specific clinical outcomes.
    Study registration: This study is registered as PROSPERO CRD42013003889.
    Funding: The National Institute for Health Research Health Technology Assessment programme.
    MeSH term(s) Adolescent ; Antipsychotic Agents/therapeutic use ; Anxiety Disorders/therapy ; Child ; Child Abuse/psychology ; Child Abuse/therapy ; Child, Preschool ; Clinical Trials as Topic ; Cost-Benefit Analysis ; Depression/therapy ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Mental Disorders/epidemiology ; Mental Disorders/psychology ; Mental Disorders/therapy ; Models, Econometric ; Models, Psychological ; Object Attachment ; Psychotherapy/methods ; Quality of Life ; Resilience, Psychological ; Self-Injurious Behavior/therapy ; Stress Disorders, Post-Traumatic/therapy ; Stress, Psychological/therapy ; Substance-Related Disorders/psychology ; United Kingdom ; Young Adult
    Chemical Substances Antipsychotic Agents
    Language English
    Publishing date 2016-09-28
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2006765-3
    ISSN 2046-4924 ; 1366-5278
    ISSN (online) 2046-4924
    ISSN 1366-5278
    DOI 10.3310/hta20690
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5162: Show issues Location:
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  6. Article ; Online: The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models.

    Durant, Stephen T / Zheng, Li / Wang, Yingchun / Chen, Kan / Zhang, Lingli / Zhang, Tianwei / Yang, Zhenfan / Riches, Lucy / Trinidad, Antonio G / Fok, Jacqueline H L / Hunt, Tom / Pike, Kurt G / Wilson, Joanne / Smith, Aaron / Colclough, Nicola / Reddy, Venkatesh Pilla / Sykes, Andrew / Janefeldt, Annika / Johnström, Peter /
    Varnäs, Katarina / Takano, Akihiro / Ling, Stephanie / Orme, Jonathan / Stott, Jonathan / Roberts, Caroline / Barrett, Ian / Jones, Gemma / Roudier, Martine / Pierce, Andrew / Allen, Jasmine / Kahn, Jenna / Sule, Amrita / Karlin, Jeremy / Cronin, Anna / Chapman, Melissa / Valerie, Kristoffer / Illingworth, Ruth / Pass, Martin

    Science advances

    2018  Volume 4, Issue 6, Page(s) eaat1719

    Abstract: Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an ... ...

    Abstract Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC
    MeSH term(s) Animals ; Apoptosis/drug effects ; Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Brain Neoplasms/mortality ; Brain Neoplasms/pathology ; Cell Line, Tumor ; Cell Membrane Permeability ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Mice ; Phosphorylation ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Radiation Tolerance/drug effects ; Radiation-Sensitizing Agents/chemistry ; Radiation-Sensitizing Agents/pharmacology ; Signal Transduction/drug effects ; Treatment Outcome ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; X-Rays ; Xenograft Model Antitumor Assays
    Chemical Substances Protein Kinase Inhibitors ; Radiation-Sensitizing Agents ; Tumor Suppressor Protein p53 ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
    Language English
    Publishing date 2018-06-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.aat1719
    Database MEDical Literature Analysis and Retrieval System OnLINE

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