9,286 results match your criteria Ataxia-Telangiectasia


Aescin-induced reactive oxygen species play a pro-survival role in human cancer cells via ATM/AMPK/ULK1-mediated autophagy.

Acta Pharmacol Sin 2018 Jun 19. Epub 2018 Jun 19.

Department of General Surgery, The First People's Hospital of Wu Jiang, Suzhou, 215200, China.

Aescin, a natural mixture of triterpene saponins, has been reported to exert anticancer effect. Recent studies show that aescin increases intracellular reactive oxygen species (ROS) levels. However, whether the increased ROS play a role in the anticancer action of aescin remains to be explored. Read More

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June 2018
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Senataxin, A Novel Helicase at the Interface of RNA Transcriptome Regulation and Neurobiology: From Normal Function to Pathological Roles in Motor Neuron Disease and Cerebellar Degeneration.

Adv Neurobiol 2018 ;20:265-281

Department of Neurology, Duke University School of Medicine, Durham, NC, USA.

Senataxin (SETX) is a DNA-RNA helicase whose C-terminal region shows homology to the helicase domain of the yeast protein Sen1p. Genetic discoveries have established the importance of SETX for neural function, as recessive mutations in the SETX gene cause Ataxia with Oculomotor Apraxia type 2 (AOA2) (OMIM: 606002), which is the third most common form of recessive ataxia, after Friedreich's ataxia and Ataxia-Telangiectasia. In addition, rare, dominant SETX mutations cause a juvenile-onset form of Amyotrophic Lateral Sclerosis (ALS), known as ALS4. Read More

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January 2018

Scorpins in the DNA Damage Response.

Int J Mol Sci 2018 Jun 17;19(6). Epub 2018 Jun 17.

Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and James Comprehensive Cancer Center, Columbus, OH 43210, USA.

The DNA Damage Response (DDR) is a complex signaling network that comes into play when cells experience genotoxic stress. Upon DNA damage, cellular signaling pathways are rewired to slow down cell cycle progression and allow recovery. However, when the damage is beyond repair, cells activate complex and still not fully understood mechanisms, leading to a complete proliferative arrest or cell death. Read More

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PROMIDISα: a TCRα signature associated with immunodeficiencies caused by V(D)J recombination defects.

J Allergy Clin Immunol 2018 Jun 12. Epub 2018 Jun 12.

Laboratory "Genome Dynamics in the Immune System", INSERM UMR1163; Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France. Electronic address:

- Background: V(D)J recombination ensures the diversity of the adaptive immune system. While its complete defect causes Severe Combined Immunodeficiency (T-B-SCID), its suboptimal activity, is associated with a broad spectrum of immune manifestations such as late onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, in particular when it involves myelo-ablative conditioning regimen for hematopoietic stem cell transplantation (HSCT). Read More

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June 2018
1 Read

Microwave hyperthermia promotes caspase‑3-dependent apoptosis and induces G2/M checkpoint arrest via the ATM pathway in non‑small cell lung cancer cells.

Int J Oncol 2018 Jun 13. Epub 2018 Jun 13.

Center for Translational Medicine, Affiliated Hangzhou First People's Hospital of Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.

Post-operative microwave (MW) hyperthermia has been applied as an important adjuvant therapy to enhance the efficacy of traditional cancer treatment. A better understanding of the molecular mechanisms of MW hyperthermia may provide guided and further information on clinical hyperthermia treatment. In this study, we examined the effects of MW hyperthermia on non‑small cell lung carcinoma (NSCLC) cells in vitro, as well as the underlying mechanisms. Read More

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Targeting ATR in cancer.

Nat Rev Cancer 2018 Jun 13. Epub 2018 Jun 13.

Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

The chemical treatment of cancer started with the realization that DNA damaging agents such as mustard gas present notable antitumoural properties. Consequently, early drug development focused on genotoxic chemicals, some of which are still widely used in the clinic. However, the efficacy of such therapies is often limited by the side effects of these drugs on healthy cells. Read More

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The ATR inhibitor AZD6738 synergizes with gemcitabine in vitro and in vivo to induce pancreatic ductal adenocarcinoma regression.

Mol Cancer Ther 2018 Jun 11. Epub 2018 Jun 11.

Cancer Research UK Cambridge Institute, University of Cambridge.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers and overall survival rates have barely improved over the past five decades. The antimetabolite gemcitabine remains part of the standard-of-care, but shows very limited anti-tumor efficacy. Ataxia telangiectasia and Rad3-related protein (ATR), the apical kinase of the intra-S-phase DNA damage response (DDR), plays a central role in safeguarding cells from replication stress (RS) and can therefore limit the efficacy of antimetabolite drug therapies. Read More

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The identification of the ATR inhibitor VE-822 as a therapeutic strategy for enhancing cisplatin chemosensitivity in esophageal squamous cell carcinoma.

Cancer Lett 2018 Jun 8;432:56-68. Epub 2018 Jun 8.

Department of Thoracic Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People's Republic of China. Electronic address:

Inducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathway, which is dependent on the activation of ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), is essential for DNA damage repair, the maintenance of genomic stability and cell survival. Read More

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June 2018
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Ionizing Radiation-Induced Cellular Senescence in Normal, Non-transformed Cells and the Involved DNA Damage Response: A Mini Review.

Front Pharmacol 2018 22;9:522. Epub 2018 May 22.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

Cellular senescence is identified by a living cell in irreversible and persistent cell cycle arrest in response to various cellular stresses. Senescent cells secrete senescence-associated secretory phenotype factors that can amplify cellular senescence and alter the microenvironments. Radiotherapy, via ionizing radiation, serves as an effective treatment for local tumor control with side effects on normal cells, which can induce inflammation and fibrosis in irradiated and nearby regions. Read More

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Human Kinase/Phosphatase-Wide RNAi Screening Identified Checkpoint Kinase 2 as a Cellular Factor Facilitating Japanese Encephalitis Virus Infection.

Front Cell Infect Microbiol 2018 17;8:142. Epub 2018 May 17.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, causes acute encephalitis in humans with high mortality. Not much is known about the interactions between viral and cellular factors that regulate JEV infection. By using a kinase/phosphatase-wide RNAi screening approach, we identified a cell cycle-regulating molecule, checkpoint kinase 2 (CHK2), that plays a role in regulating JEV replication. Read More

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Elevated IgM levels as a marker for a unique phenotype in patients with Ataxia telangiectasia.

BMC Pediatr 2018 Jun 4;18(1):185. Epub 2018 Jun 4.

The Claudio Cohen Department of Pediatric Intensive Care, The Edmond and Lily Safra Children's Hospital, Tel- Hashomer, Israel.

Background: Ataxia telangiectasia (AT) is a rare, multi-systemic, genetic disorder. Mutations in the ATM gene cause dysfunction in cell-cycle, apoptosis and V (D) J recombination leading to neurodegeneration, cellular, humoral immunodeficiencies and predisposition to malignancies. Previous studies have suggested that a sub-group of AT patients with elevated IgM levels have a distinct and more severe phenotype. Read More

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Mitochondrial Dysfunctions Regulated Radioresistance through Mitochondria-to-Nucleus Retrograde Signaling Pathway of NF-κB/PI3K/AKT2/mTOR.

Radiat Res 2018 Jun 4. Epub 2018 Jun 4.

a   Department of Radiation and Medical Oncology.

We investigated the relationship between significantly different genes of the mitochondria-to-nucleus retrograde signaling pathway (RTG) in H1299 ρ cells (mtDNA depleted cell) and compared their radiosensitivity to that of parental ρ cells, to determine the possible intervention targets of radiosensitization. ρ cells were depleted of mitochondrial DNA by chronic culturing in ethidium bromide at low concentration. Radiosensitivity was analyzed using clonogenic assay. Read More

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Radiosensitizing effects of miR-18a-5p on lung cancer stem-like cells via downregulating both ATM and HIF-1α.

Cancer Med 2018 Jun 2. Epub 2018 Jun 2.

Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China.

Lung cancer is one of the main causes of cancer mortality globally. Most patients received radiotherapy during the course of disease. However, radioresistance generally occurs in the majority of these patients, leading to poor curative effect, and the underlying mechanism remains unclear. Read More

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Co-inhibition of Pol η and ATR sensitizes cisplatin-resistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair.

Acta Pharmacol Sin 2018 May 31. Epub 2018 May 31.

Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.

For the majority of patients with advanced non-small cell lung cancer (NSCLC), the standard of care remains platinum-based chemotherapy. However, cisplatin resistance is a big obstacle to the treatment, and elucidation of its mechanism is warranted. In this study, we showed that there was no difference in intracellular uptake of cisplatin or the removal of platinum-DNA adducts between a cisplatin-resistant NSCLC cell line (A549/DR) and a cisplatin-sensitive NSCLC cell line (A549). Read More

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May 2018
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Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair.

Cell Res 2018 May 29. Epub 2018 May 29.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Linker histone H1 is a master regulator of higher order chromatin structure, but its involvement in the DNA damage response and repair is unclear. Here, we report that linker histone H1.2 is an essential regulator of ataxia telangiectasia mutated (ATM) activation. Read More

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3F-Box protein 32 degrades ataxia telangiectasia and Rad3-related and regulates DNA damage response induced by gemcitabine in pancreatic cancer.

Oncol Lett 2018 Jun 28;15(6):8878-8884. Epub 2018 Mar 28.

Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.

Ataxia telangiectasia and Rad3-related (ATR) activates checkpoint kinase 1 (CHK1) following replication fork stalling, leading to cell cycle arrest. ATR-CHK1 pathway components are considered to be promising therapeutic targets to enhance the effectiveness of replication inhibitors. The present study revealed that F-Box protein 32 (FBXO32) regulated ATR expression in pancreatic cancer PANC-1 and MIA PaCa-2 cells. Read More

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Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase.

Blood Adv 2018 May;2(10):1157-1169

Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.

The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. Read More

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Camptothecin induces G/M phase arrest through the ATM-Chk2-Cdc25C axis as a result of autophagy-induced cytoprotection: Implications of reactive oxygen species.

Oncotarget 2018 Apr 24;9(31):21744-21757. Epub 2018 Apr 24.

Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea.

In the present study, we report that camptothecin (CPT) caused irreversible cell cycle arrest at the G/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 G/M phase arrest and moderately induced S phase arrest, indicating that the ROS is required for the regulation of CPT-induced G/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 G/M phase, indicating that Nrf2 delayed the S phase in response to CPT. Read More

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The major tegument protein of bovine herpesvirus-1, VP8, interacts with DNA damage response proteins and induces apoptosis.

J Virol 2018 May 16. Epub 2018 May 16.

VIDO-InterVac, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada

VP8, the UL47 gene product in bovine herpes virus-1 (BoHV-1), is a major tegument protein, essential for virus replication 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. Read More

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Orally bioavailable and blood-brain-barrier penetrating ATM inhibitor (AZ32) radiosensitizes intracranial gliomas in mice.

Mol Cancer Ther 2018 May 16. Epub 2018 May 16.

Department of Radiation Oncology, Virginia Commonwealth University

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. Read More

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Distinct roles of ATM and ATR in the regulation of ARP8 phosphorylation to prevent chromosome translocations.

Elife 2018 May 8;7. Epub 2018 May 8.

Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

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. Read More

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May 2018
2 Reads

Functional promoter rs189037 variant of is associated with decrease in lung diffusing capacity after irradiation for non-small-cell lung cancer.

Chronic Dis Transl Med 2018 Mar 16;4(1):59-66. Epub 2018 Mar 16.

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

Objective: Single-nucleotide polymorphisms (SNPs) in the ataxia telangiectasia-mutated gene 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 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. Read More

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March 2018
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Ataxia-Telangiectasia Mutated Kinase Is an Autophagic Balancer at The Onset of Heart Failure.

Authors:
Jun Yoshioka

Am J Physiol Heart Circ Physiol 2018 May 11. Epub 2018 May 11.

Molecular Cellular & Biomedical Sciences, City University of New York School of Medicine, United States.

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B-cell subsets imbalance and reduced expression of CD40 in ataxia-telangiectasia patients.

Allergol Immunopathol (Madr) 2018 May 5. Epub 2018 May 5.

Department of Pediatrics, Federal University of Sao Paulo Medical School, 598, Botucatu Street, Vila Clementino, São Paulo, SP 04023-062, Brazil. Electronic address:

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. Read More

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Neuroimmunology Research. A Report from the Cuban Network of Neuroimmunology.

Behav Sci (Basel) 2018 May 8;8(5). Epub 2018 May 8.

Las Tunas General Hospital, Post Office Box 27, Las Tunas 75100, Cuba.

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). Read More

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May 2018
2 Reads

Pediatric Ataxia: Focus on Chronic Disorders.

Semin Pediatr Neurol 2018 Apr 5;25:54-64. Epub 2018 Jan 5.

Departments of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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. Read More

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Ciclopirox activates ATR-Chk1 signaling pathway leading to Cdc25A protein degradation.

Genes Cancer 2018 Jan;9(1-2):39-52

Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.

Ciclopirox olamine (CPX), an off-patent anti-fungal drug, has been found to inhibit the G-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. Read More

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January 2018

Ataxia-telangiectasia gene () mutation heterozygosity in breast cancer: a narrative review.

Curr Oncol 2018 Apr 30;25(2):e176-e180. Epub 2018 Apr 30.

Department of Medicine, University of Toronto, Toronto, ON.

Background: Despite the fact that heterozygosity for a pathogenic 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 variant with respect to screening for breast and other malignancies, to choices for systemic therapy, and to decisions about radiation therapy.

Results: Given that the lifetime risk for breast cancer in women who are heterozygous for a pathogenic variant is likely greater than 25%, those women should undergo annual mammographic screening starting at least by 40 years of age. Read More

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Design, Synthesis, and Docking Studies of New Torin2 Analogs as Potential ATR/mTOR Kinase Inhibitors.

Molecules 2018 Apr 24;23(5). Epub 2018 Apr 24.

Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar-382355, Gujarat, India.

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. Read More

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ATR kinase inhibitors NVP-BEZ235 and AZD6738 effectively penetrate the brain after systemic administration.

Radiat Oncol 2018 Apr 23;13(1):76. Epub 2018 Apr 23.

Regenerative Medicine, Ospedale Policlinico San Martino, Genoa, Italy.

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 IC = 21 × 10 M in cells. AZD6738 does not target significantly PI3K/mTOR-related kinases but specifically inhibits ATR with IC = 74 × 10 M in cells. Read More

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April 2018
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MicroRNA-449a functions as a tumor suppressor in pancreatic cancer by the epigenetic regulation of ATDC expression.

Biomed Pharmacother 2018 Jul 24;103:782-789. Epub 2018 Apr 24.

Geriatric Respiratory Department, Xi'an NO.1 Hospital, First People's Hospital Affiliated to Xi'an Medical College, First Affiliated Hospital of Northwest University, Xi'an, Shaanxi Province, 710004, China.

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. Read More

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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-2 H-pyran-4-yl)-1,3-dihydro-2 H-imidazo[4,5- c]quinolin-2-one).

J Med Chem 2018 May 2;61(9):3823-3841. Epub 2018 May 2.

Oncology, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Drive , Waltham , Massachusetts 02451 , United States.

ATM inhibitors, such as 7, have demonstrated the antitumor 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 focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). Read More

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May 2018
5 Reads
5.45 Impact Factor

Histone chaperones play crucial roles in maintenance of stem cell niche during plant root development.

Plant J 2018 Jul 21;95(1):86-100. Epub 2018 May 21.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, International Associated Laboratory of CNRS-Fudan-HUNAU on Plant Epigenome Research, Department of Biochemistry, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai, 200438, China.

Stem cells in both plant and animal kingdoms reside in a specialized cellular context called the stem cell niche (SCN). SCN integrity is crucial for organism development. Here we show that the H3/H4 histone chaperone CHROMATIN ASSEMBLY FACTOR-1 (CAF-1) and the H2A/H2B histone chaperone NAP1-RELATED PROTEIN1/2 (NRP1/2) play synergistic roles in Arabidopsis root SCN maintenance. Read More

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July 2018
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Current and promising therapies in autosomal recessive ataxias.

CNS Neurol Disord Drug Targets 2018 Apr 18. Epub 2018 Apr 18.

Laval University and CHU de Quebec - Laval University, Axe neurosciences - Department of Medicine, Faculty of Medicine Quebec, Quebec. Canada.

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. Read More

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April 2018
1 Read

Utility of DNA, RNA, Protein, and Functional Approaches to Solve Cryptic Immunodeficiencies.

J Clin Immunol 2018 Apr 18;38(3):307-319. Epub 2018 Apr 18.

Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.

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. Read More

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April 2018
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Genetic testing for hereditary prostate cancer: Current status and limitations.

Cancer 2018 Apr 18. Epub 2018 Apr 18.

Department of Urology, Yale School of Medicine, New Haven, Connecticut.

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. Read More

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April 2018
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Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers.

Breast Cancer Res 2018 Apr 17;20(1):28. Epub 2018 Apr 17.

INSERM, U900, Paris, France.

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. Read More

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April 2018
2 Reads

A novel variant in ATM gene causes ataxia telangiectasia revealed by whole-exome sequencing.

Neurosciences (Riyadh) 2018 Apr;23(2):162-164

Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia. E-mail:

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. Read More

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Lead (Pb) induced ATM-dependent mitophagy via PINK1/Parkin pathway.

Toxicol Lett 2018 Jul 13;291:92-100. Epub 2018 Apr 13.

Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China. Electronic address:

Lead (Pb), a widely distributed environmental pollutant, is known to induce mitochondrial damage as well as autophagy in vitro and in vivo. In this study, we found that Pb could trigger mitophagy in both HEK293 cells and the kidney cortex of male Kunming mice. However, whether ataxia telangiectasis mutated (ATM) which is reported to be linked with PTEN-induced putative kinase 1 (PINK1)/Parkin pathway (a well-characterized mitophagic pathway) participates in the regulation of Pb-induced mitophagy and its exact role remains enigmatic. Read More

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July 2018
1 Read

Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer.

PLoS Genet 2018 04 16;14(4):e1007355. Epub 2018 Apr 16.

Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.

Considering that mutations in known prostate cancer (PrCa) predisposition genes, including those responsible for hereditary breast/ovarian cancer and Lynch syndromes, explain less than 5% of early-onset/familial PrCa, we have sequenced 94 genes associated with cancer predisposition using next generation sequencing (NGS) in a series of 121 PrCa patients. We found monoallelic truncating/functionally deleterious mutations in seven genes, including ATM and CHEK2, which have previously been associated with PrCa predisposition, and five new candidate PrCa associated genes involved in cancer predisposing recessive disorders, namely RAD51C, FANCD2, FANCI, CEP57 and RECQL4. Furthermore, using in silico pathogenicity prediction of missense variants among 18 genes associated with breast/ovarian cancer and/or Lynch syndrome, followed by KASP genotyping in 710 healthy controls, we identified "likely pathogenic" missense variants in ATM, BRIP1, CHEK2 and TP53. Read More

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Ataxia-Telangiectasia Mutated Kinase Deficiency Impairs Autophagic Response Early During Myocardial Infarction.

Am J Physiol Heart Circ Physiol 2018 Apr 13. Epub 2018 Apr 13.

Biomedical Sciences, East Tennessee State University, United States.

Ataxia-telangiectasia mutated kinase (ATM) is activated in response to DNA damage. We have previously shown that ATM plays a critical role in myocyte apoptosis and cardiac remodeling following myocardial infarction (MI). Here, we tested the hypothesis that ATM deficiency results in autophagic impairment in the heart early during MI. Read More

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April 2018
3 Reads

Insufficiency of DNA repair enzyme ATM promotes naive CD4 T-cell loss in chronic hepatitis C virus infection.

Cell Discov 2018 10;4:16. Epub 2018 Apr 10.

1Center of Excellence in Inflammation, Infectious Disease and Immunity, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614 USA.

T cells have a crucial role in viral clearance and vaccine response; however, the mechanisms regulating their responses to viral infections or vaccinations remain elusive. In this study, we investigated T-cell homeostasis, apoptosis, DNA damage, and repair machineries in a large cohort of subjects with hepatitis C virus (HCV) infection. We found that naive CD4 T cells in chronically HCV-infected individuals (HCV T cells) were significantly reduced compared with age-matched healthy subjects. Read More

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[Topoisomerase inhibitor upregulates MICA/B expression in breast cancer cells through ATM/ATR and NF-κB pathway].

Beijing Da Xue Xue Bao Yi Xue Ban 2018 Apr;50(2):318-325

Department of Hematology,Peking University First Hospital,Beijing 100034, China.

Objective: To investigate the effects of chemotherapeutic agents widely used in clinical practice on major histocompatibility complex class I-related chain A and B (MICA/B) expression in breast cancer cells, and to explore the molecular mechanisms involved.

Methods: We examined MICA/B mRNA and surface protein expressions in breast cancer cells treated with chemotherapeutic agents by real-time RT-PCR and flow cytometry respectively. The blocking effects of ataxia telangiectasia mutated and Rad3-related kinase (ATM/ATR) inhibitor caffeine and nuclear factor κB (NF-κB) inhibitor pynolidine dithiocarbamate (PDTC) on etoposide-upregulated MICA/B mRNA and surface protein expressions were investigated. Read More

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Assessing cardiovascular risk in ATM heterozygotes.

Rev Assoc Med Bras (1992) 2018 Feb;64(2):148-153

Pediatrics Department, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.

Objective: To evaluate the carotid intima-media complex (CIMC) thickness and lipid metabolism biomarkers associated with cardiovascular risk (CR) in parents of patients with ataxia-telangiectasia and verify an association with gender.

Method: A cross-sectional and controlled study with 29 ATM heterozygotes and 14 healthy controls. Biochemical tests and CIMC thickness measurement were performed. Read More

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February 2018
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RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer.

Ann Oncol 2018 May;29(5):1203-1210

Experimental Therapeutics Group.

Background: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. Read More

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A Case of Ataxia-telangiectasia Presented With Hemophagocytic Syndrome.

J Pediatr Hematol Oncol 2018 Apr 3. Epub 2018 Apr 3.

Department of Pediatric Allergy and Immunology, Faculty of Medicine, Ondokuz Mayis University, Samsun.

Ataxia-telangiectasia (A-T) is a multisystem disease caused by a genetic defect located on the long arm of chromosome 11 (11p22-23). The gene defect results in the loss of A-T-mutated protein, subsequently leading to unrepaired DNA fractures and defects in the signal transduction pathway. As a result, characteristic findings arise, including recurrent sinopulmonary infections, hypersensitivity against ionized radiation with the tendency to develop cancer related to progressive cerebellar ataxia, pathognomonic oculocutaneous telangiectasias, varying degrees of humoral and cellular immunodeficiency, and infertility. Read More

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April 2018
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Inhibition of DNA‑PK activity sensitizes A549 cells to X‑ray irradiation by inducing the ATM‑dependent DNA damage response.

Mol Med Rep 2018 Jun 29;17(6):7545-7552. Epub 2018 Mar 29.

College of Food Science and Technology, Bohai University, Jinzhou, Liaoning 121013, P.R. China.

Non‑small cell lung cancer (NSCLC) is radioresistant to X‑rays due to powerful cellular DNA damage repair mechanisms. DNA‑dependent protein kinase (DNA‑PK) is a key enzyme involved in DNA damage repair and the phenomenon and molecular mechanism of NSCLC radionsensitivity were investigated following inhibition of DNA‑PK activity. In the present study A549 cells were treated with the DNA‑PK inhibitor NU7026 and/or siRNA directed against ataxia telangiectasia mutated (ATM), followed by exposure to 4 Gy X‑ray irradiation. Read More

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June 2018
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Ataxia-Telangiectasia Mutated Kinase in the Control of Oxidative Stress, Mitochondria, and Autophagy in Cancer: A Maestro With a Large Orchestra.

Front Oncol 2018 16;8:73. Epub 2018 Mar 16.

Department of Biology, University of Rome "Tor Vergata", Rome, Italy.

Ataxia-telangiectasia mutated kinase (ATM) plays a central role in the DNA damage response (DDR) and mutations in its gene lead to the development of a rare autosomic genetic disorder, ataxia telangiectasia (A-T) characterized by neurodegeneration, premature aging, defects in the immune response, and higher incidence of lymphoma development. The ability of ATM to control genome stability several pointed to ATM as tumor suppressor gene. Growing evidence clearly support a significant role of ATM, in addition to its master ability to control the DDR, as principle modulator of oxidative stress response and mitochondrial homeostasis, as well as in the regulation of autophagy, hypoxia, and cancer stem cell survival. Read More

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March 2018
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Proteomics and transcriptomics analyses of ataxia telangiectasia cells treated with Dexamethasone.

PLoS One 2018 2;13(4):e0195388. Epub 2018 Apr 2.

Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.

Ataxia telangiectasia (A-T) is an incurable and rare hereditary syndrome. In recent times, treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this condition, but the molecular mechanism of action of these analogues remains unknown. Hence, the aim of this study was to gain insight into the molecular mechanism of action of glucocorticoid analogues in the treatment of A-T by investigating the role of Dexamethasone (Dexa) in A-T lymphoblastoid cell lines. Read More

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