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ataxia telangiectasia

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https://www.readbyqxmd.com/read/29774099/camptothecin-induces-g-2-m-phase-arrest-through-the-atm-chk2-cdc25c-axis-as-a-result-of-autophagy-induced-cytoprotection-implications-of-reactive-oxygen-species
#1
Rajapaksha Gedara Prasad Tharanga Jayasooriya, Matharage Gayani Dilshara, Ilandarage Menu Neelaka Molagoda, Cheol Park, Sang Rul Park, Seungheon Lee, Yung Hyun Choi, Gi-Young Kim
In the present study, we report that camptothecin (CPT) caused irreversible cell cycle arrest at the G2 /M phase, and was associated with decreased levels of cell division cycle 25C (Cdc25C) and increased levels of cyclin B1, p21, and phospho-H3. Interestingly, the reactive oxygen species (ROS) inhibitor, glutathione, decreased CPT-induced G2 /M phase arrest and moderately induced S phase arrest, indicating that the ROS is required for the regulation of CPT-induced G2 /M phase arrest. Furthermore, transient knockdown of nuclear factor-erythroid 2-related factor 2 (Nrf2), in the presence of CPT, increased the ROS' level and further shifted the cell cycle from early S phase to the G2 /M phase, indicating that Nrf2 delayed the S phase in response to CPT...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29769345/the-major-tegument-protein-of-bovine-herpesvirus-1-vp8-interacts-with-dna-damage-response-proteins-and-induces-apoptosis
#2
Sharmin Afroz, Ravendra Garg, Michel Fodje, Sylvia van Drunen Littel-van den Hurk
VP8, the UL47 gene product in bovine herpes virus-1 (BoHV-1), is a major tegument protein, essential for virus replication in vivo The major DNA damage response protein, ataxia telangiectasia mutated (ATM), phosphorylates Nijmegen breakage syndrome (NBS1) and structural maintenance of chromosome-1 (SMC1) proteins during the DNA damage response. VP8 was found to interact with ATM and NBS1 during transfection and BoHV-1 infection. However, VP8 did not interfere with phosphorylation of ATM in transfected or BoHV-1-infected cells...
May 16, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29769307/orally-bioavailable-and-blood-brain-barrier-penetrating-atm-inhibitor-az32-radiosensitizes-intracranial-gliomas-in-mice
#3
Jeremy Karlin, Jasmine Allen, Syed F Ahmad, Gareth Hughes, Victoria Sheridan, Rajesh Odedra, Paul Farrington, Elaine B Cadogan, Lucy C Riches, Antonio Garcia-Trinidad, Andrew G Thomason, Bhavika Patel, Jennifer Vincent, Alan Lau, Kurt G Pike, Thomas A Hunt, Amrita Sule, Nicholas C K Valerie, Laura Biddlestone-Thorpe, Jenna Kahn, Jason M Beckta, Nitai Mukhopadhyay, Bernard Barlaam, Sebastien L Degorce, Jason Kettle, Nicola Colclough, Joanne Wilson, Aaron Smith, Ian P Barrett, Li Zheng, Tianwei Zhang, Yingchun Wang, Kan Chen, Martin Pass, Stephen T Durant, Kristoffer Valerie
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 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 in vivo for efficacy and impact on tumor and healthy brain...
May 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29759113/distinct-roles-of-atm-and-atr-in-the-regulation-of-arp8-phosphorylation-to-prevent-chromosome-translocations
#4
Jiying Sun, Lin Shi, Aiko Kinomura, Atsuhiko Fukuto, Yasunori Horikoshi, Yukako Oma, Masahiko Harata, Masae Ikura, Tsuyoshi Ikura, Roland Kanaar, Satoshi Tashiro
Chromosomal translocations are hallmarks of various types of cancers and leukemias. However, the molecular mechanisms of chromosome translocations remain largely unknown. The ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, facilitates DNA repair to prevent chromosome abnormalities. Previously, we showed that ATM deficiency led to the 11q23 chromosome translocation, the most frequent chromosome abnormalities in secondary leukemia. Here, we show that ARP8, a subunit of the INO80 chromatin remodeling complex, is phosphorylated after etoposide treatment...
May 8, 2018: ELife
https://www.readbyqxmd.com/read/29756124/functional-promoter-rs189037-variant-of-atm-is-associated-with-decrease-in-lung-diffusing-capacity-after-irradiation-for-non-small-cell-lung-cancer
#5
Jose Luis Lopez Guerra, Yi-Peng Song, Quynh-Nhu Nguyen, Daniel R Gomez, Zhongxing Liao, Ting Xu
Objective: Single-nucleotide polymorphisms (SNPs) in the ataxia telangiectasia-mutated gene ATM have been linked with pneumonitis after radiotherapy for lung cancer but have not been evaluated in terms of pulmonary function impairment. Here we investigated potential associations between SNPs in ATM and changes in diffusing capacity of the lung for carbon monoxide (DLCO) in patients with non-small-cell lung cancer (NSCLC) after radiotherapy. Methods: From November 1998 through June 2009, 448 consecutive patients with inoperable primary NSCLC underwent definitive (≥60 Gy) radiotherapy, with or without chemotherapy...
March 2018: Chronic Diseases and Translational Medicine
https://www.readbyqxmd.com/read/29750568/ataxia-telangiectasia-mutated-kinase-is-an-autophagic-balancer-at-the-onset-of-heart-failure
#6
Jun Yoshioka
No abstract text is available yet for this article.
May 11, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29739685/b-cell-subsets-imbalance-and-reduced-expression-of-cd40-in-ataxia-telangiectasia-patients
#7
C T M Pereira, D C Bichuetti-Silva, N V F da Mota, R Salomão, M K C Brunialti, B T Costa-Carvalho
BACKGROUND: Ataxia-telangiectasia (AT) is a well-known primary immunodeficiency with recurrent sinopulmonary infections and variable abnormalities in both the humoral and cellular immune system. Dysfunctions in immunoglobulin production, reduced number of B cells, and B-cell receptor excision circles copies have been reported. We aimed to understand the immunological mechanisms involving the humoral compartment in AT patients by analysing peripheral blood B cells subsets, B-T lymphocyte cooperation through the expression of CD40 and CD40 ligand (CD40L), and cytokines involved in class-switch recombination production...
May 5, 2018: Allergologia et Immunopathologia
https://www.readbyqxmd.com/read/29738432/neuroimmunology-research-a-report-from-the-cuban-network-of-neuroimmunology
#8
María de Los Angeles Robinson-Agramonte, Lourdes Lorigados Pedre, Orlando Ramón Serrano-Barrera
Neuroimmunology can be traced back to the XIX century through the descriptions of some of the disease’s models (e.g., multiple sclerosis and Guillain Barret syndrome, amongst others). The diagnostic tools are based in the cerebrospinal fluid (CSF) analysis developed by Quincke or in the development of neuroimmunotherapy with the earlier expression in Pasteur’s vaccine for rabies. Nevertheless, this field, which began to become delineated as an independent research area in the 1940s, has evolved as an innovative and integrative field at the shared edges of neurosciences, immunology, and related clinical and research areas, which are currently becoming a major concern for neuroscience and indeed for all of the scientific community linked to it...
May 8, 2018: Behavioral Sciences
https://www.readbyqxmd.com/read/29735117/pediatric-ataxia-focus-on-chronic-disorders
#9
David R Lynch, Ashley McCormick, Kimberly Schadt, Elizabeth Kichula
Evaluation of a pediatric patient presenting with ataxia can be expensive and time consuming. Acute causes tend to have a clear developmental paradigm, but chronic presentations are more likely to be secondary to a genetic disorder, either one that primarily causes ataxia or that presents ataxia as one of a multitude of symptoms. Evaluation should focus on a quick diagnosis for those that have treatment options and for those that require other systemic monitoring. Friedreich ataxia is the most common, and genetic testing can easily confirm the suspicion...
April 2018: Seminars in Pediatric Neurology
https://www.readbyqxmd.com/read/29725502/ciclopirox-activates-atr-chk1-signaling-pathway-leading-to-cdc25a-protein-degradation
#10
Tao Shen, Hongyu Zhou, Chaowei Shang, Yan Luo, Yang Wu, Shile Huang
Ciclopirox olamine (CPX), an off-patent anti-fungal drug, has been found to inhibit the G1 -cyclin dependent kinases partly by increasing the phosphorylation and degradation of Cdc25A. However, little is known about the molecular target(s) of CPX responsible for Cdc25A degradation. Here, we show that CPX induced the degradation of Cdc25A neither by increasing CK1α or decreasing DUB3 expression, nor via activating GSK3β, but through activating Chk1 in rhabdomyosarcoma (Rh30) and breast carcinoma (MDA-MB-231) cells...
January 2018: Genes & Cancer
https://www.readbyqxmd.com/read/29719442/ataxia-telangiectasia-gene-atm-mutation-heterozygosity-in-breast-cancer-a-narrative-review
#11
K J Jerzak, T Mancuso, A Eisen
Background: Despite the fact that heterozygosity for a pathogenic ATM variant is present in 1%-2% of the adult population, clinical guidelines to inform physicians and genetic counsellors about optimal management in that population are lacking. Methods: In this narrative review, we describe the challenges and controversies in the management of women who are heterozygous for a pathogenic ATM variant with respect to screening for breast and other malignancies, to choices for systemic therapy, and to decisions about radiation therapy...
April 2018: Current Oncology
https://www.readbyqxmd.com/read/29695073/design-synthesis-and-docking-studies-of-new-torin2-analogs-as-potential-atr-mtor-kinase-inhibitors
#12
Althaf Shaik, Rashmi Bhakuni, Sivapriya Kirubakaran
Targeting DNA damage and response (DDR) pathway has become an attractive approach in cancer therapy. The key mediators involved in this pathway are ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia-mutated, Rad3-related kinase (ATR). These kinases induce cell cycle arrest in response to chemo- and radio-therapy and facilitate DNA repair via their major downstream targets. Targeting ATP-binding site of these kinases is currently under study. Torin2 is a second generation ATP competitive mTOR kinase inhibitor (EC50 = 250 pmol/L) with better pharmacokinetic profile...
April 24, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29685176/atr-kinase-inhibitors-nvp-bez235-and-azd6738-effectively-penetrate-the-brain-after-systemic-administration
#13
Guido Fròsina, Aldo Profumo, Daniela Marubbi, Diana Marcello, Jean Louis Ravetti, Antonio Daga
Ataxia Telangiectasia and Rad3 related protein (ATR) is a central mediator of the response to DNA damage that may cause the quiescent resistance of cancer initiating cells to genotoxic radiotherapy. NVP-BEZ235 is a dual PI3K/mTOR inhibitor that also effectively targets ATR with IC50  = 21 × 10- 9  M in cells. AZD6738 does not target significantly PI3K/mTOR-related kinases but specifically inhibits ATR with IC50  = 74 × 10- 9  M in cells. Both drugs have been proposed as radiosensitizers of different tumors including glioblastoma (GB), the most malignant brain tumor...
April 23, 2018: Radiation Oncology
https://www.readbyqxmd.com/read/29684857/microrna-449a-functions-as-a-tumor-suppressor-in-pancreatic-cancer-by-the-epigenetic-regulation-of-atdc-expression
#14
Feng Li, Jing Liang, Lu Bai
A growing body of evidence has suggested that microRNAs (miRNAs) play a pivotal role in the development and progression of pancreatic cancer. miRNA-449a (miR-449a) has attracted particular interest due to its critical role in regulating cancer biology in numerous cancer types. However, whether miR-449a is involved in the regulation of pancreatic cancer development and progression remains unknown. In this study, we aimed to investigate the expression pattern and potential biological function of miR-449a in pancreatic cancer...
April 20, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29683659/the-identification-of-potent-selective-and-orally-available-inhibitors-of-ataxia-telangiectasia-mutated-atm-kinase-the-discovery-of-azd0156-8-6-3-dimethylamino-propoxy-pyridin-3-yl-3-methyl-1-tetrahydro-2h-pyran-4-yl-1-3-dihydro-2h-imidazo-4-5-c-quinolin-2
#15
Kurt G Pike, Bernard Barlaam, Elaine Cadogan, Andrew Campbell, Yingxue Chen, Nicola Colclough, Nichola L Davies, Camila DeAlmeida, Sébastien L Degorce, Myriam Didelot, Allan Dishington, Richard Ducray, Stephen T Durant, Lorraine A Hassall, Jane L Holmes, Gareth D Hughes, Philip A MacFaul, Keith R Mulholland, Thomas M McGuire, Gilles Ouvry, Martin Pass, Graeme R Robb, Natalie Stratton, Zhenhua Wang, Joanne Wilson, Baochang Zhai, Kang Zhao, Nidal Al-Huniti
ATM inhibitors, such as 7, have demonstrated the anti-tumor potential of ATM inhibition when combined with DNA double strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focussed on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution)...
April 23, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29676235/current-and-promising-therapies-in-autosomal-recessive-ataxias
#16
Vincent Picher-Martel, Nicolas Dupre
BACKGROUND & OBJECTIVE: Ataxia is clinically characterized by unsteady gait and imbalance. Cerebellar disorders may arise from many causes such as metabolic diseases, stroke or genetic mutations. The genetic causes are classified by mode of inheritance and include autosomal dominant, X-linked and autosomal recessive ataxias. Many years have passed since the description of Friedreich's ataxia, the most common autosomal recessive ataxia, and mutations in many other genes have now been described...
April 18, 2018: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/29671115/utility-of-dna-rna-protein-and-functional-approaches-to-solve-cryptic-immunodeficiencies
#17
Margot A Cousin, Matthew J Smith, Ashley N Sigafoos, Jay J Jin, Marine I Murphree, Nicole J Boczek, Patrick R Blackburn, Gavin R Oliver, Ross A Aleff, Karl J Clark, Eric D Wieben, Avni Y Joshi, Pavel N Pichurin, Roshini S Abraham, Eric W Klee
PURPOSE: We report a female infant identified by newborn screening for severe combined immunodeficiencies (NBS SCID) with T cell lymphopenia (TCL). The patient had persistently elevated alpha-fetoprotein (AFP) with IgA deficiency, and elevated IgM. Gene sequencing for a SCID panel was uninformative. We sought to determine the cause of the immunodeficiency in this infant. METHODS: We performed whole-exome sequencing (WES) on the patient and parents to identify a genetic diagnosis...
April 18, 2018: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/29669169/genetic-testing-for-hereditary-prostate-cancer-current-status-and-limitations
#18
REVIEW
Jun Tu Zhen, Jamil Syed, Kevin Anh Nguyen, Michael S Leapman, Neeraj Agarwal, Karina Brierley, Xavier Llor, Erin Hofstatter, Brian Shuch
A significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Men who have multiple single-gene polymorphisms and a family history of prostate cancer have a significantly greater risk of developing prostate cancer. Numerous single-gene alterations have been confirmed to increase the risk of prostate cancer. These include breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively), mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and ataxia telangiectasia mutated (ATM)...
April 18, 2018: Cancer
https://www.readbyqxmd.com/read/29665859/morphology-and-genomic-hallmarks-of-breast-tumours-developed-by-atm-deleterious-variant-carriers
#19
Anne-Laure Renault, Noura Mebirouk, Laetitia Fuhrmann, Guillaume Bataillon, Eve Cavaciuti, Dorothée Le Gal, Elodie Girard, Tatiana Popova, Philippe La Rosa, Juana Beauvallet, Séverine Eon-Marchais, Marie-Gabrielle Dondon, Catherine Dubois d'Enghien, Anthony Laugé, Walid Chemlali, Virginie Raynal, Martine Labbé, Ivan Bièche, Sylvain Baulande, Jacques-Olivier Bay, Pascaline Berthet, Olivier Caron, Bruno Buecher, Laurence Faivre, Marc Fresnay, Marion Gauthier-Villars, Paul Gesta, Nicolas Janin, Sophie Lejeune, Christine Maugard, Sébastien Moutton, Laurence Venat-Bouvet, Hélène Zattara, Jean-Pierre Fricker, Laurence Gladieff, Isabelle Coupier, Georgia Chenevix-Trench, Janet Hall, Anne Vincent-Salomon, Dominique Stoppa-Lyonnet, Nadine Andrieu, Fabienne Lesueur
BACKGROUND: The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. METHODS: To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours...
April 17, 2018: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29664460/a-novel-variant-in-atm-gene-causes-ataxia-telangiectasia-revealed-by-whole-exome-sequencing
#20
Noufa A Alonazi, Khalid J Hundallah, Amal M Al Hashem, Sarar Mohamed
Ataxia-Telangiectasia (A-T) is an autosomal recessive disorder caused by variants in ATM gene and characterized by progressive neurologic impairment, cerebellar ataxia, and oculo-cutaneous telangiectasia. Immunodeficiency with a recurrent sinopulmonary infections are observed in patients with A-T. Here, we report a novel stop codon variant, c.5944 C>T (p.Gln1982*), revealed by whole-exome sequencing in a 9-year old boy. He presented with recurrent upper respiratory tract infections, failure to thrive, developmental delay, ataxic gait, and bulbar telangiectasia...
April 2018: Neurosciences: the Official Journal of the Pan Arab Union of Neurological Sciences
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