443 results on '"Martin F. Lavin"'
Search Results
2. Supplementary Figure 5 from A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells
- Author
-
Martin F. Lavin, David G. Walker, Kathleen S. Ensbey, Amanda W. Kijas, Sergei Kozlov, Angus Harding, Bryan W. Day, Tara L. Roberts, and Yi Chieh Lim
- Abstract
PDF file, 340K, Rad51 foci formation to measure homologous recombination repair in glioma initiaitng cells.
- Published
- 2023
3. Supplementary Figure 1 from A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells
- Author
-
Martin F. Lavin, David G. Walker, Kathleen S. Ensbey, Amanda W. Kijas, Sergei Kozlov, Angus Harding, Bryan W. Day, Tara L. Roberts, and Yi Chieh Lim
- Abstract
PDF file, 478K, Long-term proliferation and tumourigenicity in glioma initiating cells.
- Published
- 2023
4. Data from A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells
- Author
-
Martin F. Lavin, David G. Walker, Kathleen S. Ensbey, Amanda W. Kijas, Sergei Kozlov, Angus Harding, Bryan W. Day, Tara L. Roberts, and Yi Chieh Lim
- Abstract
Glioblastoma multiforme (GBM) is the most common form of brain tumor with a poor prognosis and resistance to radiotherapy. Recent evidence suggests that glioma-initiating cells play a central role in radioresistance through DNA damage checkpoint activation and enhanced DNA repair. To investigate this in more detail, we compared the DNA damage response in nontumor forming neural progenitor cells (NPC) and glioma-initiating cells isolated from GBM patient specimens. As observed for GBM tumors, initial characterization showed that glioma-initiating cells have long-term self-renewal capacity. They express markers identical to NPCs and have the ability to form tumors in an animal model. In addition, these cells are radioresistant to varying degrees, which could not be explained by enhanced nonhomologous end joining (NHEJ). Indeed, NHEJ in glioma-initiating cells was equivalent, or in some cases reduced, as compared with NPCs. However, there was evidence for more efficient homologous recombination repair in glioma-initiating cells. We did not observe a prolonged cell cycle nor enhanced basal activation of checkpoint proteins as reported previously. Rather, cell-cycle defects in the G1–S and S-phase checkpoints were observed by determining entry into S-phase and radioresistant DNA synthesis following irradiation. These data suggest that homologous recombination and cell-cycle checkpoint abnormalities may contribute to the radioresistance of glioma-initiating cells and that both processes may be suitable targets for therapy. Mol Cancer Ther; 11(9); 1863–72. ©2012 AACR.
- Published
- 2023
5. Supplementary Figure 3 from A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells
- Author
-
Martin F. Lavin, David G. Walker, Kathleen S. Ensbey, Amanda W. Kijas, Sergei Kozlov, Angus Harding, Bryan W. Day, Tara L. Roberts, and Yi Chieh Lim
- Abstract
PDF file, 416K, The effect of IR on neurosphere size and apoptosis.
- Published
- 2023
6. Supplementary Methods and Figure Legend from A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells
- Author
-
Martin F. Lavin, David G. Walker, Kathleen S. Ensbey, Amanda W. Kijas, Sergei Kozlov, Angus Harding, Bryan W. Day, Tara L. Roberts, and Yi Chieh Lim
- Abstract
PDF file, 139K.
- Published
- 2023
7. Supplementary Figure 6 from A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells
- Author
-
Martin F. Lavin, David G. Walker, Kathleen S. Ensbey, Amanda W. Kijas, Sergei Kozlov, Angus Harding, Bryan W. Day, Tara L. Roberts, and Yi Chieh Lim
- Abstract
PDF file, 244K, BRCA1 foci demonstrate similar kinetics to Rad51 foci after exposure to ionizing radiation.
- Published
- 2023
8. Supplementary Figure 2 from A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells
- Author
-
Martin F. Lavin, David G. Walker, Kathleen S. Ensbey, Amanda W. Kijas, Sergei Kozlov, Angus Harding, Bryan W. Day, Tara L. Roberts, and Yi Chieh Lim
- Abstract
PDF file, 388K, Glioma initiating cells are capable of forming different lineages.
- Published
- 2023
9. DNA damage rather than type I IFN signaling is the primary mediator of neural dysfunction in Aicardi-Goutières syndrome after RNASEH2 disruption
- Author
-
Martin F. Lavin and Abrey J. Yeo
- Subjects
General Neuroscience - Published
- 2021
10. Toxins from Sea-Squirts
- Author
-
Dianne J. Watters, Clifford J. Hawkins, and Martin F. Lavin
- Published
- 2022
11. Snake Venom Hydrogels as a Rapid Hemostatic Agent for Uncontrolled Bleeding (Adv. Healthcare Mater. 15/2022)
- Author
-
Ramanathan Yegappan, Jan Lauko, Zhao Wang, Martin F. Lavin, Amanda W. Kijas, and Alan E. Rowan
- Subjects
Biomaterials ,Biomedical Engineering ,Pharmaceutical Science - Published
- 2022
12. Snake Venom Hydrogels as a Rapid Hemostatic Agent for Uncontrolled Bleeding
- Author
-
Ramanathan Yegappan, Jan Lauko, Zhao Wang, Martin F. Lavin, Amanda W. Kijas, and Alan E. Rowan
- Subjects
Biomaterials ,Fibrinolysis ,Biomedical Engineering ,Humans ,Pharmaceutical Science ,Hemorrhage ,Hydrogels ,Blood Coagulation ,Hemostatics ,Snake Venoms - Abstract
Uncontrolled bleeding from traumatic injury remains the leading cause of preventable death with loss of balance between blood clotting (coagulation) and blood clot breakdown (fibrinolysis). A major limitation of existing hemostatic agents is that they require a functioning clotting system to control the bleeding and are largely based on gauze delivery scaffolds. Herein, a novel rapid wound sealant, composed of two recombinant snake venom proteins, the procoagulant ecarin, to rapidly initiate blood clotting and the antifibrinolytic textilinin, to prevent blood clot breakdown within a synthetic thermoresponsive hydrogel scaffold is developed. In vitro, it is demonstrated that clotting is rapidly initiated with only nanomolar concentrations of venom protein and clot breakdown is effectively inhibited by textilinin. A stable clot is formed within 60 s compared to normal clot formation in 8 min. In vivo studies reveal that the snake venom hydrogel rapidly controls warfarin-induced bleeding, reducing the bleed volume from 48% to 12% and has demonstrated immune compatibility. A new class of hemostatic agents that achieve formation of rapid and stable blood clots even in the presence of blood thinners is demonstrated here.
- Published
- 2022
13. miRNA-34c-5p targets Fra-1 to inhibit pulmonary fibrosis induced by silica through p53 and PTEN/PI3K/Akt signaling pathway
- Author
-
Xinru Pang, Haojun Shi, Xiaoshu Chen, Chao Li, Bin Shi, Abrey J. Yeo, Martin F. Lavin, Qiang Jia, Hua Shao, Juan Zhang, and Gongchang Yu
- Subjects
Epithelial-Mesenchymal Transition ,Health, Toxicology and Mutagenesis ,Pulmonary Fibrosis ,PTEN Phosphohydrolase ,Dust ,General Medicine ,Management, Monitoring, Policy and Law ,Toxicology ,Silicon Dioxide ,Fibrosis ,MicroRNAs ,Phosphatidylinositol 3-Kinases ,Humans ,Tumor Suppressor Protein p53 ,Proto-Oncogene Proteins c-akt ,Proto-Oncogene Proteins c-fos ,Cell Proliferation ,Signal Transduction - Abstract
Silica dust particles are representative of air pollution and long-term inhalation of silicon-containing dust through the respiratory tract can cause pulmonary fibrosis. Epithelial-mesenchymal transformation (EMT) plays an important role in the development of fibrosis. This process can relax cell-cell adhesion complexes and enhance cell migration and invasion properties of these cells. Dysregulation of microRNA-34c (miR-34c) is highly correlated with organ fibrosis including pulmonary fibrosis. In this study, we found that miR-34c-5p could alleviate the occurrence and development of silica-mediated EMT. Fos-related antigen 1 was identified as a functional target of miR-34c-5p by bioinformatics analysis and the dual luciferase gene reporting assay. Importantly, chemically induced up-regulation of hsa-miR-34c-5p correlated inversely with the expression of Fra-1 and further exploration found that the miR-34c-5p/Fra-1 axis inhibits the activation of the phosphatase and tensin homolog deleted on chromosome 10/phosphatidylinositol-4,5-bisphosphate3-kinase/protein kinase B (PTEN/PI3K/AKT) signaling pathway. In addition, through interaction with PTEN/p53 it inhibits the proliferation and migration of human bronchial epithelial cells stimulated by silica, and promotes cell apoptosis, thereby preventing EMT. This finding provides a promising biomarker for the diagnosis and prognosis of pulmonary fibrosis. Furthermore, overexpression of miR-34c-5p represents a potential therapeutic approach.
- Published
- 2022
14. Editorial: Cancer Therapeutics: Targeting DNA Repair Pathways
- Author
-
Amila Suraweera, James A. L. Brown, Yi Chieh Lim, and Martin F. Lavin
- Subjects
genomic ,QH301-705.5 ,repair ,DNA repair ,cancer ,double strand break ,stability ,Biology (General) ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Molecular Biology ,Biochemistry - Published
- 2022
15. The hallmarks of aging in Ataxia-Telangiectasia
- Author
-
Julio Aguado, Cecilia Gómez-Inclán, Hannah C. Leeson, Martin F. Lavin, Yosef Shiloh, and Ernst J. Wolvetang
- Subjects
Aging ,Ataxia Telangiectasia ,Neurology ,Humans ,Aging, Premature ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Molecular Biology ,Biochemistry ,Genomic Instability ,Biotechnology ,DNA Damage - Abstract
Ataxia-telangiectasia (A-T) is caused by absence of the catalytic activity of ATM, a protein kinase that plays a central role in the DNA damage response, many branches of cellular metabolism, redox and mitochondrial homeostasis, and cell cycle regulation. A-T is a complex disorder characterized mainly by progressive cerebellar degeneration, immunodeficiency, radiation sensitivity, genome instability, and predisposition to cancer. It is increasingly recognized that the premature aging component of A-T is an important driver of this disease, and A-T is therefore an attractive model to study the aging process. This review outlines the current state of knowledge pertaining to the molecular and cellular signatures of aging in A-T and proposes how these new insights can guide novel therapeutic approaches for A-T.
- Published
- 2022
16. Correction of ATM mutations in iPS cells from two ataxia-telangiectasia patients restores DNA damage and oxidative stress responses
- Author
-
U Wang Lei, Abrey J. Yeo, Keerat Junday, Ashmitha Sundarrajan, Michelle Pewarchuk, Hannah C Leeson, Amanda W. Kijas, Ernst J. Wolvetang, Sarah L. Withey, Dmitry A. Ovchinnikov, and Martin F. Lavin
- Subjects
Mitochondrial ROS ,DNA Repair ,DNA damage ,Induced Pluripotent Stem Cells ,Ataxia Telangiectasia Mutated Proteins ,Biology ,medicine.disease_cause ,Frameshift mutation ,Ataxia Telangiectasia ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Missense mutation ,Phosphorylation ,Molecular Biology ,Gene ,Cells, Cultured ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Mutation ,Recovery of Function ,General Medicine ,medicine.disease ,Cell biology ,Oxidative Stress ,030220 oncology & carcinogenesis ,Ataxia-telangiectasia ,DNA Damage - Abstract
Patients with ataxia-telangiectasia (A-T) lack a functional ATM kinase protein and exhibit defective repair of DNA double-stranded breaks and response to oxidative stress. We show that CRISPR/Cas9-assisted gene correction combined with piggyBac (PB) transposon-mediated excision of the selection cassette enables seamless restoration of functional ATM alleles in induced pluripotent stem cells from an A-T patient carrying compound heterozygous exonic missense/frameshift mutations, and from a patient with a homozygous splicing acceptor mutation of an internal coding exon. We show that the correction of one allele restores expression of ~ 50% of full-length ATM protein and ameliorates DNA damage-induced activation (auto-phosphorylation) of ATM and phosphorylation of its downstream targets, KAP-1 and H2AX. Restoration of ATM function also normalizes radiosensitivity, mitochondrial ROS production and oxidative-stress-induced apoptosis levels in A-T iPSC lines, demonstrating that restoration of a single ATM allele is sufficient to rescue key ATM functions. Our data further show that despite the absence of a functional ATM kinase, homology-directed repair and seamless correction of a pathogenic ATM mutation is possible. The isogenic pairs of A-T and gene-corrected iPSCs described here constitute valuable tools for elucidating the role of ATM in ageing and A-T pathogenesis.
- Published
- 2020
17. RAD50 regulates mitotic progression independent of DNA repair functions
- Author
-
Martin F. Lavin, Girmay Asgedom, Axel Schambach, Thilo Dörk, Kristine Bousset, Anna Vatselia, Lea Völkening, Holger Bastians, and Detlev Schindler
- Subjects
0301 basic medicine ,DNA Repair ,Cell division ,DNA repair ,Mitosis ,Biology ,Biochemistry ,Ataxia Telangiectasia ,03 medical and health sciences ,0302 clinical medicine ,Live cell imaging ,Genetics ,medicine ,Humans ,DNA Breaks, Double-Stranded ,Fibroblast ,Molecular Biology ,MRE11 Homologue Protein ,Kinase ,Acid Anhydride Hydrolases ,Cell biology ,DNA-Binding Proteins ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,medicine.anatomical_structure ,MRN complex ,Rad50 ,biological phenomena, cell phenomena, and immunity ,030217 neurology & neurosurgery ,Biotechnology - Abstract
The Mre11A/RAD50/NBN complex (MRN) is an essential regulator of the cellular damage response after DNA double-strand breaks (DSBs). More recent work has indicated that MRN may also impact on the duration of mitosis. We show here that RAD50-deficient fibroblasts exhibit a marked delay in mitotic progression that can be rescued by lentiviral transduction of RAD50. The delay was observed throughout all mitotic phases in live cell imaging using GFP-labeled H2B as a fluorescent marker. In complementation assays with RAD50 phosphorylation mutants, modifications at Ser635 had little effect on mitotic progression. By contrast with RAD50, fibroblast strains deficient in ATM or NBN did not show a significant slowing of mitotic progression. Ataxia-telangiectasia-like disorder (ATLD) fibroblasts with nuclease-deficient MRE11A (p.W210C) tended to show slower mitosis, though by far not as significant as RAD50-deficient cells. Inhibitor studies indicated that ATM kinase activity might not grossly impact on mitotic progression, while treatment with MRE11A inhibitor PFM39 modestly prolonged mitosis. Inhibition of ATR kinase significantly prolonged mitosis but this effect was mostly independent of RAD50 status. Taken together, our data unravel a mitotic role of RAD50 that can be separated from its known functions in DNA repair.
- Published
- 2019
18. Thymic stromal lymphopoietin (TSLP) and Toluene-diisocyanate-induced airway inflammation: Alleviation by TSLP neutralizing antibody
- Author
-
Qiang Jia, Abrey J. Yeo, Xiaoqun Wang, Cunxiang Bo, Yu Zhang, Linlin Sai, Hua Shao, Martin F. Lavin, Cheng Peng, and Gongchang Yu
- Subjects
Adult ,Male ,0301 basic medicine ,Thymic stromal lymphopoietin ,Anti-Inflammatory Agents ,Inflammation ,Toxicology ,Immunoglobulin E ,03 medical and health sciences ,0302 clinical medicine ,Thymic Stromal Lymphopoietin ,Occupational Exposure ,medicine ,Animals ,Humans ,Lung ,Asthma ,Inhalation Exposure ,Mice, Inbred BALB C ,Bronchus ,biology ,Inhalation ,medicine.diagnostic_test ,business.industry ,Interleukin-17 ,Pneumonia ,General Medicine ,Middle Aged ,respiratory system ,medicine.disease ,Antibodies, Neutralizing ,respiratory tract diseases ,Cross-Sectional Studies ,030104 developmental biology ,medicine.anatomical_structure ,Bronchoalveolar lavage ,Case-Control Studies ,Immunology ,biology.protein ,Cytokines ,Inflammation Mediators ,Toluene 2,4-Diisocyanate ,medicine.symptom ,business ,Occupational asthma ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Toluene-diisocyanate (TDI) is mainly used in the manufacturing process of polyurethane foams, and is a potent inducer of occupational asthma characterized by airway inflammation and airway hyperreactivity. Thymic stromal lymphopoietin (TSLP) plays an important role in the development of asthma, and correlating with the differentiation of Th2 and Th17 cells. However, the role of TSLP in TDI-induced asthma remains unclear. In this study, 96 TDI-exposed workers as well as a mouse model of TDI-induced asthma were investigated. The air exposure assessment result of TDI in the workplace showed that workers were exposed to inhalation of a very high concentration of TDI, approximately 8 times the recommended level, leading to a decrease in pulmonary function and an increase in inflammatory cells, as well as TSLP and IgE levels in the supernatant of sputum obtained from exposed workers. In order to further investigate the role of TSLP in the pathogenesis of TDI-induced asthma, a mouse model of TDI-induced asthma was also employed. Histopathological analysis of mouse lung and bronchus showed an obvious infiltration of inflammatory cells around the bronchus. The levels of inflammatory cells, IFN-γ, IL-4 and IL-17 in bronchoalveolar lavage fluid (BALF), the expression levels of TSLP protein and ROR-γt and IL-17 mRNA in mouse lung tissues were also significantly increased. However, after treatment with TSLP neutralizing antibody (TSLP-Ab), the degree of pulmonary and bronchial inflammation in mice was significantly alleviated, and the levels of inflammatory cells, IFN-γ, IL-4 and IL-17 in BALF, and the expression levels of ROR-γt and IL-17 mRNA in lung tissue were significantly decreased. Our data shows that TSLP plays an important role in the pathogenesis of TDI-induced asthma, and that TSLP-Ab can effectively alleviate TDI-induced airway inflammation of asthma.
- Published
- 2019
19. Rapid serum tube technology overcomes problems associated with use of anticoagulants
- Author
-
Lambro A. Johnson, Martin F. Lavin, Goce Dimeski, Paul P. Masci, Kong-Nan Zhao, Michael Grant, and John de Jersey
- Subjects
anticoagulants ,Analyte ,Clinical Biochemistry ,analytes ,prothrombin activators ,serum ,030204 cardiovascular system & hematology ,complex mixtures ,03 medical and health sciences ,0302 clinical medicine ,Prothrombinase ,Humans ,Medicine ,Blood Coagulation ,030304 developmental biology ,Whole blood ,0303 health sciences ,Chromatography ,medicine.diagnostic_test ,Heparin ,business.industry ,Biochemistry (medical) ,Original Articles ,Thromboelastography ,Clotting time ,Coagulation ,Snake venom ,Prothrombin ,Blood Coagulation Tests ,business ,circulatory and respiratory physiology ,medicine.drug - Abstract
Introduction: Failure to obtain complete blood clotting in serum is a common laboratory problem. Our aim was to determine whether snake prothrombin activators are effective in clotting blood and producing quality serum for analyte measurement in anticoagulated patients. Materials and methods: Whole blood clotting was studied in a total of 64 blood samples (41 controls, 20 Warfarin patients, 3 anticoagulated patients using snake venom prothrombin activator (OsPA)) with plain tubes. Coagulation was analysed using a visual assay, Hyland-Clotek and thromboelastography. Healthy control blood was spiked with a range of anticoagulants to determine the effectiveness of OsPa-induced clotting. A paired analysis of a Dabigatran patient and a control investigated the effectiveness of the OsPA clotting tubes. Biochemical analytes (N = 31) were determined for 7 samples on chemistry and immunoassay analysers and compared with commercial tubes. Results: Snake venom prothrombin activators efficiently coagulated blood and plasma spiked with heparin and commonly used anticoagulants. Clotting was observed in the presence of anticoagulants whereas no clotting was observed in BDRST tubes containing 3 U/mL of heparin. Snake venom prothrombin activator enhanced heparinised blood clotting by shortening substantially the clotting time and improving significantly the strength of the clot. Comparison of 31 analytes from the blood of five healthy and two anticoagulated participants gave very good agreement between the analyte concentrations determined. Conclusions: Our results showed that the snake venom prothrombin activators OsPA and PtPA efficiently coagulated recalcified and fresh bloods with or without added anticoagulants. These procoagulants produced high quality serum for accurate analyte measurement.
- Published
- 2019
20. An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T)
- Author
-
Robert G. Parton, Martin F. Lavin, Magtouf Gatei, David Coman, Kok Leong Chong, Abrey J. Yeo, and G.N. Subramanian
- Subjects
Mitochondrion ,medicine.disease_cause ,Endoplasmic Reticulum ,Ataxia-telangiectasia ,chemistry.chemical_compound ,Ataxia Telangiectasia ,Endoplasmic reticulum–mitochondrial interaction ,Mitophagy ,medicine ,Humans ,Glycolysis ,Heptanoate (C7) ,Molecular Biology ,Internal medicine ,Cells, Cultured ,Nutrient deprivation ,Chemistry ,Endoplasmic reticulum ,Cell Biology ,medicine.disease ,RC31-1245 ,Triheptanoin ,Cell biology ,Mitochondria ,Anaerobic glycolysis ,ATM ,Original Article ,Mitochondrial dysfunction ,Oxidative stress - Abstract
Background ATM, the protein defective in the human genetic disorder, ataxia-telangiectasia (A-T) plays a central role in response to DNA double-strand breaks (DSBs) and in protecting the cell against oxidative stress. We showed that A-T cells are hypersensitive to metabolic stress which can be accounted for by a failure to exhibit efficient endoplasmic reticulum (ER)-mitochondrial signalling and Ca2+ transfer in response to nutrient deprivation resulting in mitochondrial dysfunction. The objective of the current study is to use an anaplerotic approach using the fatty acid, heptanoate (C7), a metabolic product of the triglyceride, triheptanoin to correct the defect in ER-mitochondrial signalling and enhance cell survival of A-T cells in response to metabolic stress. Methods We treated control cells and A-T cells with the anaplerotic agent, heptanoate to determine their sensitivity to metabolic stress induced by inhibition of glycolysis with 2- deoxyglucose (2DG) using live-cell imaging to monitor cell survival for 72 h using the Incucyte system. We examined ER-mitochondrial signalling in A-T cells exposed to metabolic stress using a suite of techniques including immunofluorescence staining of Grp75, ER-mitochondrial Ca2+ channel, the VAPB-PTPIP51 ER-mitochondrial tether complexes as well as proximity ligation assays between Grp75-IP3R1 and VAPB1-PTPIP51 to establish a functional interaction between ER and mitochondria. Finally, we also performed metabolomic analysis using LC-MS/MS assay to determine altered levels of TCA intermediates A-T cells compared to healthy control cells. Results We demonstrate that heptanoate corrects all aspects of the defective ER-mitochondrial signalling observed in A-T cells. Heptanoate enhances ER-mitochondrial contacts; increases the flow of calcium from the ER to the mitochondrion; restores normal mitochondrial function and mitophagy and increases the resistance of ATM-deficient cells and cells from A-T patients to metabolic stress-induced killing. The defect in mitochondrial function in ATM-deficient cells was accompanied by more reliance on aerobic glycolysis as shown by increased lactate dehydrogenase A (LDHA), accumulation of lactate, and reduced levels of both acetyl CoA and ATP which are all restored by heptanoate. Conclusions We conclude that heptanoate corrects metabolic stress in A-T cells by restoring ER-mitochondria signalling and mitochondrial function and suggest that the parent compound, triheptanoin, has immense potential as a novel therapeutic agent for patients with A-T., Highlights • The fatty acid heptanoate rescues cell killing after nutrient deprivation in A-T cells. • Heptanoate enhances endoplasmic reticulum (ER)-mitochondrial contacts. • Normal mitochondrial function and mitophagy are restored in A-T cells by heptanoate. • Heptanoate shifts A-T cells to more reliance on oxidative phosphorylation.
- Published
- 2021
21. Microcrystalline silica particles induce inflammatory response via pyroptosis in primary human respiratory epithelial cells
- Author
-
Jiayin Sun, Abrey J. Yeo, Hua Shao, Bing Han, Peng Li, Cheng Peng, Martin F. Lavin, Zhongjun Du, Chao Li, Shangya Chen, and Xiao Geng
- Subjects
Inflammasomes ,Health, Toxicology and Mutagenesis ,Respiratory System ,Inflammation ,Management, Monitoring, Policy and Law ,Toxicology ,Pathogenesis ,Silicosis ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Pyroptosis ,Humans ,Chemistry ,Inflammasome ,Epithelial Cells ,General Medicine ,respiratory system ,medicine.disease ,Silicon Dioxide ,Cell biology ,MicroRNAs ,MRNA Sequencing ,Toxicity ,medicine.symptom ,Signal transduction ,medicine.drug - Abstract
The mechanism of the sterile inflammatory response in the respiratory tract induced by exposure to sterile particles has not been fully elucidated. The aim of our study is to explore the earlier events in initiating inflammatory response at molecular and cellular level in primary cultured human airway epithelial cells (AEC) exposed to silica particles in order to provide information for earlier diagnosis and prevention of silica particle-induced toxicity as well as possible information on the genesis of silicosis. We isolated primary AEC from three healthy adults and treated them with silica particles at different concentrations for 48 h. We found evidence for silica-induced inflammasome activation by the co-localization of Caspase-1 and NLRP3, as well as increased levels of IL-1β and IL-18. Lactate dehydrogenase and NucGreen analysis proved the occurrence of pyroptosis. High throughput mRNA sequencing showed that the inflammatory response and NF-κB signaling pathways were significantly enriched in gene ontology and Kyoto encyclopedia of genes and genomes analysis, and pyroptosis-related genes were up-regulated. The miR-455-3p and five lncRNAs (LOC105375913, NEAT1, LOC105375181, LOC100506098, and LOC105369370) were verified as key factors related to the mechanism by ceRNA network analysis. LOC105375913 was first discovered to be associated with inflammation in AEC. These data suggest that microcrystalline silica can induce significant inflammation and pyroptosis in human primary AEC through NLRP3 inflammasome pathway and NF-κB signaling pathway at both the gene and protein levels, and the possible mechanism could be miR-455-3p mediated ceRNA hypothesis. Our data provide a method for the studies of the respiratory toxicity of fine particulate matter and the pathogenesis of early silicosis. The miR-455-3p and five lncRNAs related ceRNA network might be the toxicity mechanism of microcrystalline silica particles to AEC.
- Published
- 2021
22. Potential Application of Recombinant Snake Prothrombin Activator Ecarin in Blood Diagnostics
- Author
-
Kong-Nan, Zhao, Paul, Masci, Goce, Dimeski, Lambro, Johnson, Michael, Grant, John, de Jersey, and Martin F, Lavin
- Subjects
recombinant ecarin ,blood clotting ,clotting of anticoagulated blood ,high quality serum ,Endopeptidases ,Animals ,Humans ,Anticoagulants ,Prothrombin ,Snakes ,Thrombosis ,Viper Venoms ,Molecular Biology ,Biochemistry ,Thromboplastin - Abstract
We describe here the purification and cloning of a codon-optimized form of the snake prothrombin activator ecarin from the saw scaled viper (Echis carinatus) expressed in mammalian cells. Expression of recombinant ecarin (rEcarin) was carried out in human embryonic kidney cells (HEK) cells under conditions for the development and performance of a novel and scalable recombinant snake ecarin to industry standards. Clotting performance of the rEcarin was established in recalcified citrated whole blood, plasma, and fresh whole blood and found to be comparable to native ecarin (N-Ecarin). Furthermore, hemolysis was observed with N-Ecarin at relatively high doses in both recalcified citrated and fresh whole blood, while clotting was not observed with rEcarin, providing an important advantage for the recombinant form. In addition, rEcarin effectively clotted both recalcified citrated whole blood and fresh whole blood containing different anticoagulants including heparin, warfarin, dabigatran, Fondaparinux, rivaroxaban and apixaban, forming firm clots in the blood collection tubes. These results demonstrate that rEcarin efficiently clots normal blood as well as blood spiked with high concentrations of anticoagulants and has great potential as an additive to blood collection tubes to produce high quality serum for analyte analysis in diagnostic medicine.
- Published
- 2022
23. Ataxia Telangiectasia iPSC line generated from a patient olfactory biopsy identifies novel disease-causing mutations
- Author
-
Zoe Hunter, Martin F. Lavin, Harman Kaur Chaggar, Ernst J. Wolvetang, Alan Mackay-Sim, and Hannah C Leeson
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Cerebellum ,QH301-705.5 ,Biopsy ,Induced Pluripotent Stem Cells ,Disease ,Progressive neurodegeneration ,Ataxia Telangiectasia Mutated Proteins ,Biology ,Ataxia Telangiectasia ,medicine ,Humans ,Biology (General) ,Induced pluripotent stem cell ,medicine.diagnostic_test ,Neurodegeneration ,Cell Biology ,General Medicine ,medicine.disease ,medicine.anatomical_structure ,Ataxia-telangiectasia ,Mutation ,Cancer research ,Ipsc line ,Developmental Biology - Abstract
Ataxia Telangiectasia is a rare autosomal recessive disorder caused by a mutated ATM gene. The most debilitating symptom of Ataxia Telangiectasia is the progressive neurodegeneration of the cerebellum, though the molecular mechanisms driving this degeneration remains unclear. Here we describe the generation and validation of an induced pluripotent stem cell (iPSC) line from an olfactory biopsy from a patient with Ataxia Telangiectasia. Sequencing identified two previously unreported disease-causing mutations in the ATM gene. This line can be used to generate 2D and 3D patient-specific neuronal models enabling investigations into the mechanisms underlying neurodegeneration.
- Published
- 2021
24. Metformin Attenuates Silica-Induced Pulmonary Fibrosis by Activating Autophagy via the AMPK-mTOR Signaling Pathway
- Author
-
Cheng Peng, Shu-Xian Li, Qiang Jia, Abrey J. Yeo, Juan Zhang, Gongchang Yu, Chao Li, Xin-Ru Pang, Hua Shao, and Martin F. Lavin
- Subjects
Pharmacology ,autophagy ,pulmonary fibrosis ,Chemistry ,Autophagy ,Inflammation ,RM1-950 ,medicine.disease ,AMPK-mTOR ,Metformin ,Proinflammatory cytokine ,Silicosis ,Fibrosis ,silica ,Pulmonary fibrosis ,medicine ,Cancer research ,Pharmacology (medical) ,Tumor necrosis factor alpha ,Therapeutics. Pharmacology ,medicine.symptom ,metformin ,medicine.drug - Abstract
Long-term exposure to crystalline silica particles leads to silicosis characterized by persistent inflammation and progressive fibrosis in the lung. So far, there is no specific treatment to cure the disease other than supportive care. In this study, we examined the effects of metformin, a prescribed drug for type || diabetes on silicosis and explored the possible mechanisms in an established rat silicosis model in vivo, and an in vitro co-cultured model containing human macrophages cells (THP-1) and human bronchial epithelial cells (HBEC). Our results showed that metformin significantly alleviated the inflammation and fibrosis of lung tissues of rats exposed to silica particles. Metformin significantly reduced silica particle-induced inflammatory cytokines including transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in rat lung tissue and HBEC culture supernatant. The protein levels of Vimentin and α-smooth muscle actin (α-SMA) were significantly decreased by metfomin while expression level of E-cadherin (E-Cad) increased. Besides, metformin increased the expression levels of phosphorylated adenosine 5′-monophosphate (AMP)-activated protein kinase (p-AMPK), microtubule-associated protein (MAP) light chain 3B (LC3B) and Beclin1 proteins, and reduced levels of phosphorylated mammalian target of rapamycin (p-mTOR) and p62 proteins in vivo and in vitro. These results suggest that metformin could inhibit silica-induced pulmonary fibrosis by activating autophagy through the AMPK-mTOR pathway.
- Published
- 2021
25. Metformin Attenuates Silica-Induced Pulmonary Fibrosis by Activating Autophagy
- Author
-
Shu-Xian, Li, Chao, Li, Xin-Ru, Pang, Juan, Zhang, Gong-Chang, Yu, Abrey J, Yeo, Martin F, Lavin, Hua, Shao, Qiang, Jia, and Cheng, Peng
- Subjects
Pharmacology ,autophagy ,pulmonary fibrosis ,silica ,metformin ,AMPK-mTOR ,Original Research - Abstract
Long-term exposure to crystalline silica particles leads to silicosis characterized by persistent inflammation and progressive fibrosis in the lung. So far, there is no specific treatment to cure the disease other than supportive care. In this study, we examined the effects of metformin, a prescribed drug for type || diabetes on silicosis and explored the possible mechanisms in an established rat silicosis model in vivo, and an in vitro co-cultured model containing human macrophages cells (THP-1) and human bronchial epithelial cells (HBEC). Our results showed that metformin significantly alleviated the inflammation and fibrosis of lung tissues of rats exposed to silica particles. Metformin significantly reduced silica particle-induced inflammatory cytokines including transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in rat lung tissue and HBEC culture supernatant. The protein levels of Vimentin and α-smooth muscle actin (α-SMA) were significantly decreased by metfomin while expression level of E-cadherin (E-Cad) increased. Besides, metformin increased the expression levels of phosphorylated adenosine 5′-monophosphate (AMP)-activated protein kinase (p-AMPK), microtubule-associated protein (MAP) light chain 3B (LC3B) and Beclin1 proteins, and reduced levels of phosphorylated mammalian target of rapamycin (p-mTOR) and p62 proteins in vivo and in vitro. These results suggest that metformin could inhibit silica-induced pulmonary fibrosis by activating autophagy through the AMPK-mTOR pathway.
- Published
- 2021
26. SMG1 heterozygosity exacerbates haematopoietic cancer development in Atm null mice by increasing persistent DNA damage and oxidative stress
- Author
-
Hui-Chi Lai, Cheok Soon Lee, Yi Chieh Lim, Uda Ho, Simon H. Apte, John Luff, Martin F. Lavin, Hazel Quek, Alexander James, and Tara L. Roberts
- Subjects
0301 basic medicine ,Heterozygote ,Lymphoma ,DNA damage ,Carcinogenesis ,medicine.medical_treatment ,Longevity ,Ataxia Telangiectasia Mutated Proteins ,Kaplan-Meier Estimate ,Biology ,Protein Serine-Threonine Kinases ,medicine.disease_cause ,Loss of heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,medicine ,cancer ,Animals ,Lung cancer ,Cells, Cultured ,Mice, Knockout ,Cancer ,Cell Biology ,Original Articles ,Fibroblasts ,medicine.disease ,Embryo, Mammalian ,Mice, Inbred C57BL ,Haematopoiesis ,Oxidative Stress ,030104 developmental biology ,Cytokine ,inflammation ,Gamma Rays ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Cancer research ,Molecular Medicine ,Original Article ,Oxidative stress - Abstract
Suppressor of morphogenesis in genitalia 1 (SMG1) and ataxia telangiectasia mutated (ATM) are members of the PI3‐kinase like–kinase (PIKK) family of proteins. ATM is a well‐established tumour suppressor. Loss of one or both alleles of ATM results in an increased risk of cancer development, particularly haematopoietic cancer and breast cancer in both humans and mouse models. In mice, total loss of SMG1 is embryonic lethal and loss of a single allele results in an increased rate of cancer development, particularly haematopoietic cancers and lung cancer. In this study, we generated mice deficient in Atm and lacking one allele of Smg1, Atm−/−Smg1gt/+ mice. These mice developed cancers more rapidly than either of the parental genotypes, and all cancers were haematopoietic in origin. The combined loss of Smg1 and Atm resulted in a higher level of basal DNA damage and oxidative stress in tissues than loss of either gene alone. Furthermore, Atm−/−Smg1gt/+ mice displayed increased cytokine levels in haematopoietic tissues compared with wild‐type animals indicating the development of low‐level inflammation and a pro‐tumour microenvironment. Overall, our data demonstrated that combined loss of Atm expression and decreased Smg1 expression increases haematopoietic cancer development.
- Published
- 2019
27. Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity
- Author
-
Claire E. Wainwright, Martin F. Lavin, Lutz Krause, Abrey J. Yeo, Emmanuelle Fantino, Anna Henningham, Sally Galbraith, and Peter D. Sly
- Subjects
0301 basic medicine ,medicine.medical_treatment ,lcsh:Medicine ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,Pulmonary fibrosis ,medicine ,lcsh:Science ,Multidisciplinary ,Innate immune system ,business.industry ,Respiratory disease ,lcsh:R ,Inflammasome ,medicine.disease ,3. Good health ,respiratory tract diseases ,030104 developmental biology ,Cytokine ,Ataxia-telangiectasia ,Immunology ,lcsh:Q ,business ,030217 neurology & neurosurgery ,Oxidative stress ,medicine.drug - Abstract
Respiratory disease is a major cause of morbidity and mortality in patients with ataxia-telangiectasia (A-T) who are prone to recurrent sinopulmonary infections, bronchiectasis, pulmonary fibrosis, and pulmonary failure. Upper airway infections are common in patients and S. pneumoniae is associated with these infections. We demonstrate here that the upper airway microbiome in patients with A-T is different from that to healthy controls, with S. pneumoniae detected largely in patients only. Patient-specific airway epithelial cells and differentiated air-liquid interface cultures derived from these were hypersensitive to infection which was at least in part due to oxidative damage since it was partially reversed by catalase. We also observed increased levels of the pro-inflammatory cytokines IL-8 and TNF-α (inflammasome-independent) and a decreased level of the inflammasome-dependent cytokine IL-β in patient cells. Further investigation revealed that the ASC-Caspase 1 signalling pathway was defective in A-T airway epithelial cells. These data suggest that the heightened susceptibility of these cells to S. pneumoniae infection is due to both increased oxidative damage and a defect in inflammasome activation, and has implications for lung disease in these patients.
- Published
- 2019
28. Hesperetin attenuates silica‑induced lung injury by reducing oxidative damage and inflammatory response
- Author
-
Linlin Shao, Abrey J. Yeo, Jinguo Fang, Juan Zhang, Shu-Xian Li, Yanqin Chen, Hua Shao, Martin F. Lavin, and Gongchang Yu
- Subjects
0301 basic medicine ,Cancer Research ,Antioxidant ,medicine.medical_treatment ,Lung injury ,Pharmacology ,medicine.disease_cause ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,Pulmonary fibrosis ,medicine ,oxidative stress ,rat ,lung injury ,chemistry.chemical_classification ,biology ,Chemistry ,hesperetin ,Glutathione peroxidase ,fibrosis ,Hesperetin ,Articles ,inflammatory response ,General Medicine ,Malondialdehyde ,medicine.disease ,030104 developmental biology ,silica ,030220 oncology & carcinogenesis ,biology.protein ,Oxidative stress - Abstract
Oxidative stress and the inflammatory response are two important mechanisms of silica-induced lung injury. Hesperetin (HSP) is a natural flavonoid compound that is found in citrus fruits and has been indicated to exhibit strong antioxidant and anti-inflammatory properties. The current study evaluated the protective effect of HSP on lung injury in rats exposed to silica. The results indicated that the degree of alveolitis and pulmonary fibrosis in the HSP-treated group was significantly decreased compared with the silica model group. The content of hydroxyproline (HYP) was also revealed to decrease overall in the HSP treated group compared with the silica model group, indicating that the degree of pulmonary fibrosis was decreased compared with the silica model group. The present study also demonstrated that HSP reduced oxidation levels of malondialdehyde (MDA) and increased the activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-PX). Total antioxidant capacity (T-AOC) was also increased following HSP treatment, indicating that HSP can alleviate oxidative stress in the lung tissue of silica-exposed rats. In addition, HSP was revealed to inhibit the synthesis and secretion of fibrogenic factor TGF-β1, reduce the production of pro-inflammatory cytokines IL-1β, IL-4, TNF-α and increase the levels of anti-inflammatory factors IFN-γ and IL-10. The current study demonstrated that HSP can effectively attenuate silica-induced lung injury by reducing oxidative damage and the inflammatory response.
- Published
- 2021
29. The spectrum of ATM gene mutations in Iranian patients with ataxia-telangiectasia
- Author
-
Asghar Aghamohammadi, Martin F. Lavin, Fereshte Salami, Tannaz Moeini Shad, Samaneh Delavari, Mahya Mehrmohamadi, Parisa Amirifar, Soraya Moamer, Salar Pashangzadeh, Mohammad Reza Ranjouri, Reza Yazdani, Seyed Mohammad Akrami, and Hassan Abolhassani
- Subjects
medicine.medical_specialty ,Immunology ,Hepatosplenomegaly ,Ataxia Telangiectasia Mutated Proteins ,Iran ,03 medical and health sciences ,Ataxia Telangiectasia ,0302 clinical medicine ,Lower respiratory tract infection ,Internal medicine ,Genotype ,medicine ,Immunology and Allergy ,Humans ,030212 general & internal medicine ,Child ,Immunodeficiency ,Exome sequencing ,business.industry ,Genetic disorder ,medicine.disease ,Phenotype ,030228 respiratory system ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Ataxia-telangiectasia ,Mutation ,medicine.symptom ,business ,Progressive disease - Abstract
BACKGROUND Ataxia-telangiectasia (A-T) is a rare genetic disorder characterized by a distinct range of clinical manifestations, including progressive ataxia, immunodeficiency, and radiosensitivity. METHODS Clinical data, laboratory results, and genetic data were collected from forty-three A-T patients. Whole-exome sequencing and Sanger sequencing were done for the patients clinically diagnosed as suffering from A-T. Based on the phenotype severity of the disease, patients were divided into severe and mild subgroups. RESULTS The median (IQR) age of diagnosis in this cohort was 5 (3-7) years, and various types of clinical manifestations, including fever (P =.005), lower respiratory tract infection (P = .033), diarrhea (P = .014), and hepatosplenomegaly (P = .032), were significantly higher among patients diagnosed with the severe phenotype. Our results showed a correlation between phenotype severity and mutation type. The chance of having severe phenotype in patients who have severe mutations, including frameshift and nonsense, was 7.3 times higher than in patients who were categorized in the mild genotype group (odds ratio = 7.3, P = .006). Thirty-four types of mutations including 9 novel mutations were observed in our study. CONCLUSION Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time the broad spectrum of mutations and phenotypes in Iranian A-T patients, which is required for carrier detection and reducing the burden of disease in the future using the patients' families and for the public healthcare system.
- Published
- 2021
30. Author response for 'The spectrum of ATM gene mutations in Iranian patients with ataxia‐telangiectasia'
- Author
-
Parisa Amirifar, Martin F. Lavin, Mahya Mehrmohamadi, Asghar Aghamohammadi, Hassan Abolhassani, Soraya Moamer, Samaneh Delavari, Fereshte Salami, Seyed Mohammad Akrami, Tannaz Moeini Shad, Reza Yazdani, Mohammad Reza Ranjouri, and Salar Pashangzadeh
- Subjects
Atm gene ,business.industry ,Ataxia-telangiectasia ,Cancer research ,Medicine ,business ,medicine.disease - Published
- 2021
31. Combined immunodeficiencies with associated or syndromic features
- Author
-
Hans D. Ochs, Reza Yazdani, Zahra Chavoshzadeh, Hassan Abolhassani, Marzieh Tavakol, Martin F. Lavin, Sepideh Darougar, Alireza Shafiei, and Ahmad Vosughi Motlagh
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,medicine.disease ,Dyskeratosis ,Combined immunodeficiencies ,medicine.anatomical_structure ,Immune system ,Failure to thrive ,medicine ,Primary immunodeficiency ,Vitamin B12 ,medicine.symptom ,business ,B cell ,Immunodeficiency - Abstract
Combined immune deficiencies (CIDs) are a heterogeneous group of inherited immune disorders characterized by impaired development, function, or both of T lymphocytes, with variable B cell defects. Among CIDs, a group of disorders is associated with syndromic features. The term CID syndromes apply to disorders in which other clinical features are present in addition to immunodeficiency. CID with associated or syndromic features comprises nine major categories including congenital thrombocytopenia, DNA repair defects, immunoosseous dysplasias (IODs), thymic defects with additional congenital anomalies, hyper-immunoglobulin E syndromes, dyskeratosis congenital, defects of vitamin B12 and folate metabolism, anhidrotic epidermodysplasia with ID and others. Most patients belonging to this group of primary immunodeficiency disorders manifest severe infections caused by opportunistic organisms, chronic diarrhea, failure to thrive, and recurrent and chronic respiratory infections. These patients present with less severe complications in the first year of life than severe CID patients, as evidence of immunodeficiency may be initially absent, whereas other clinical complications are present. Because syndromic CID can present initially with nonimmunologic manifestation, the various medical specialists involved in these cases should be aware of the signs and symptoms of this PID category.
- Published
- 2021
32. Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia
- Author
-
Robert G. Parton, Magtouf Gatei, David Coman, Kok Leong Chong, Romal Stewart, Abrey J. Yeo, Ernst J. Wolvetang, Martin F. Lavin, Adam D. Brown, Dongxiu Zou, Sarah L. Withey, and Michael B. Kastan
- Subjects
Multidisciplinary ,Functional Aspects of Cell Biology ,Chemistry ,Endoplasmic reticulum ,Cell Biology ,Mitochondrion ,medicine.disease ,Organizational Aspects of Cell Biology ,Article ,Cell biology ,mitochondrial fusion ,Mitophagy ,Organelle ,Ataxia-telangiectasia ,medicine ,lcsh:Q ,lcsh:Science ,Homeostasis ,Function (biology) - Abstract
Summary There is evidence that ATM mutated in ataxia-telangiectasia (A-T) plays a key role in protecting against mitochondrial dysfunction, the mechanism for which remains unresolved. We demonstrate here that ATM-deficient cells are exquisitely sensitive to nutrient deprivation, which can be explained by defective cross talk between the endoplasmic reticulum (ER) and the mitochondrion. Tethering between these two organelles in response to stress was reduced in cells lacking ATM, and consistent with this, Ca2+ release and transfer between ER and mitochondria was reduced dramatically when compared with control cells. The impact of this on mitochondrial function was evident from an increase in oxygen consumption rates and a defect in mitophagy in ATM-deficient cells. Our findings reveal that ER-mitochondrial connectivity through IP3R1-GRP75-VDAC1, to maintain Ca2+ homeostasis, as well as an abnormality in mitochondrial fusion defective in response to nutrient stress, can account for at least part of the mitochondrial dysfunction observed in A-T cells., Graphical Abstract, Highlights • Hypersensitivity to glucose deprivation in ATM-deficient cells • Defective ER-mitochondrion cross talk after nutrient stress in these cells • Markedly reduced Ca2+ transfer between these two organelles in ATM-deficient cells • Mitochondrial dysfunction in response to nutrient stress in the absence of ATM, Cell Biology; Organizational Aspects of Cell Biology; Functional Aspects of Cell Biology
- Published
- 2021
33. Premature ovarian ageing following heterozygous loss of Senataxin
- Author
-
Martin F. Lavin, Hayden Homer, and Goutham Narayanan Subramanian
- Subjects
0301 basic medicine ,Heterozygote ,endocrine system ,Embryology ,Ataxia ,DNA damage ,Period (gene) ,Ovarian ageing ,Primary Ovarian Insufficiency ,Biology ,medicine.disease_cause ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Animals ,Genetic Predisposition to Disease ,Ovarian follicle ,Oculomotor apraxia ,Ovarian Reserve ,Molecular Biology ,Cells, Cultured ,Mice, Knockout ,Mutation ,030219 obstetrics & reproductive medicine ,Age Factors ,DNA Helicases ,Obstetrics and Gynecology ,Heterozygote advantage ,Cell Biology ,medicine.disease ,Multifunctional Enzymes ,In Vitro Oocyte Maturation Techniques ,Mice, Inbred C57BL ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Reproductive Medicine ,Oocytes ,Female ,medicine.symptom ,Infertility, Female ,RNA Helicases ,DNA Damage ,Developmental Biology - Abstract
Premature loss of ovarian activity before 40 years of age is known as primary ovarian insufficiency (POI) and occurs in ∼1% of women. A more subtle decline in ovarian activity, known as premature ovarian ageing (POA), occurs in ∼10% of women. Despite the high prevalence of POA, very little is known regarding its genetic causation. Senataxin (SETX) is an RNA/DNA helicase involved in repair of oxidative stress-induced DNA damage. Homozygous mutation of SETX leads to the neurodegenerative disorder, ataxia oculomotor apraxia type 2 (AOA2). There have been reports of POI in AOA2 females suggesting a link between SETX and ovarian ageing. Here, we studied female mice lacking either one (Setx+/−) or both (Setx−/−) copies of SETX over a 12- to 14-month period. We find that DNA damage is increased in oocytes from 8-month-old Setx+/− and Setx−/− females compared with Setx+/+ oocytes leading to a marked reduction in all classes of ovarian follicles at least 4 months earlier than typically occurs in female mice. Furthermore, during a 12-month long mating trial, Setx+/− and Setx−/− females produced significantly fewer pups than Setx+/+ females from 7 months of age onwards. These data show that SETX is critical for preventing POA in mice, likely by preserving DNA integrity in oocytes. Intriguingly, heterozygous Setx loss causes an equally severe impact on ovarian ageing as homozygous Setx loss. Because heterozygous SETX disruption is less likely to produce systemic effects, SETX compromise could underpin some cases of insidious POA.
- Published
- 2020
34. The spectrum of ATM gene mutations in Iranian patients with ataxia-telangiectasia
- Author
-
Hassan Abolhassani, Soraya Moamer, Tannaz Moeini Shad, Asghar Aghamohammadi, Mohammad Reza Ranjouri, Mahya Mehrmohamadi, Martin F. Lavin, Parisa Amirifar, Samaneh Delavari, Fereshte Salami, Reza Yazdani, Seyed Mohammad Akrami, and Salar Pashangzadeh
- Subjects
medicine.medical_specialty ,business.industry ,Genetic disorder ,Hepatosplenomegaly ,medicine.disease ,Frameshift mutation ,Internal medicine ,Genotype ,Ataxia-telangiectasia ,medicine ,medicine.symptom ,business ,Progressive disease ,Exome sequencing ,Immunodeficiency - Abstract
Background: Ataxia-telangiectasia (A-T) is a rare genetic disorder characterized by a distinct range of clinical manifestations, including progressive ataxia, immunodeficiency, and radiosensitivity. Methods: Clinical data, laboratory results, and genetic data were collected from forty-three A-T patients. Whole exome sequencing and Sanger sequencing were done for the patients clinically diagnosed as suffering from A-T. Based on the phenotype severity of the disease, patients were divided into severe and mild sub-groups. Results: The median (IQR) age of diagnosis in this cohort was 5 (3-7) years and various types of clinical manifestations, including fever (p= 0.005), lower respiratory tract infection (p= 0.033), diarrhea (p= 0.014), and hepatosplenomegaly (p= 0.032) were significantly higher amongst patients diagnosed with the severe phenotype. Our results showed a strong correlation between phenotype severity and mutation type. The chance of having severe phenotype in patients who have severe mutations, including frameshift and nonsense, was 7.3 times higher compared to patients who were categorized in the mild genotype group (odds ratio= 7.3, p= 0.006). Thirty-four types of mutations including 9 novel mutations, were observed in our study. Conclusion: Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time, the broad spectrum of mutations and phenotypes in Iranian A-T patients which are required for carrier detection and reducing the burden of disease in future using the patients’ families and for the public health care system. Keywords: Ataxia-telangiectasia (A-T), ATM, Whole-exome sequencing, Class switching recombination (CSR), phenotype severity.
- Published
- 2020
35. Venom of the Red-Bellied Black Snake
- Author
-
Rachael Y M, Ryan, Viviana P, Lutzky, Volker, Herzig, Taylor B, Smallwood, Jeremy, Potriquet, Yide, Wong, Paul, Masci, Martin F, Lavin, Glenn F, King, J Alejandro, Lopez, Maria P, Ikonomopoulou, and John J, Miles
- Subjects
CD4-Positive T-Lymphocytes ,Elapid Venoms ,Lipopolysaccharides ,immunosuppression ,TNF ,Antigen-Presenting Cells ,red-bellied black snake ,Article ,CD4+ T cells ,Pseudechis porphyriacus ,Animals ,Cytokines ,Humans ,Elapidae ,Immunosuppressive Agents ,snake venom - Abstract
Venoms act with remarkable specificity upon a broad diversity of physiological targets. Venoms are composed of proteins, peptides, and small molecules, providing the foundation for the development of novel therapeutics. This study assessed the effect of venom from the red-bellied black snake (Pseudechis porphyriacus) on human primary leukocytes using bead-based flow cytometry, mixed lymphocyte reaction, and cell viability assays. We show that venom treatment had a significant immunosuppressive effect, inhibiting the secretion of interleukin (IL)-2 and tumor necrosis factor (TNF) from purified human T cells by 90% or greater following stimulation with mitogen (phorbol 12-myristate 13-acetate and ionomycin) or via cluster of differentiation (CD) receptors, CD3/CD28. In contrast, venom treatment did not inhibit TNF or IL-6 release from antigen-presenting cells stimulated with lipopolysaccharide. The reduced cytokine release from T cells was not associated with inhibition of T cell proliferation or reduction of cell viability, consistent with an anti-inflammatory mechanism unrelated to the cell cycle. Deconvolution of the venom using reverse-phase HPLC identified four fractions responsible for the observed immunosuppressive activity. These data suggest that compounds from P. porphyriacus venom may be potential drug leads for T cell-associated conditions such as graft versus host disease, rheumatoid arthritis, and inflammatory bowel disease.
- Published
- 2020
36. Venom of the Red-Bellied Black Snake Pseudechis porphyriacus Shows Immunosuppressive Potential
- Author
-
John J. Miles, Viviana P. Lutzky, Volker Herzig, Maria P. Ikonomopoulou, Paul Pantaleone Masci, Martin F. Lavin, Jeremy Potriquet, Yide Wong, Glenn F. King, J. Alejandro Lopez, Rachael Y. M. Ryan, and Taylor B. Smallwood
- Subjects
Pseudechis ,Health, Toxicology and Mutagenesis ,medicine.medical_treatment ,T cell ,TNF ,lcsh:Medicine ,Venom ,red-bellied black snake ,CD4+ T cells ,Pharmacology ,Toxicology ,03 medical and health sciences ,medicine ,Viability assay ,030304 developmental biology ,snake venom ,0303 health sciences ,immunosuppression ,biology ,Cluster of differentiation ,Chemistry ,030302 biochemistry & molecular biology ,lcsh:R ,CD28 ,biology.organism_classification ,Pseudechis porphyriacus ,Cytokine ,medicine.anatomical_structure ,Snake venom - Abstract
Venoms act with remarkable specificity upon a broad diversity of physiological targets. Venoms are composed of proteins, peptides, and small molecules, providing the foundation for the development of novel therapeutics. This study assessed the effect of venom from the red-bellied black snake (Pseudechis porphyriacus) on human primary leukocytes using bead-based flow cytometry, mixed lymphocyte reaction, and cell viability assays. We show that venom treatment had a significant immunosuppressive effect, inhibiting the secretion of interleukin (IL)-2 and tumor necrosis factor (TNF) from purified human T cells by 90% or greater following stimulation with mitogen (phorbol 12-myristate 13-acetate and ionomycin) or via cluster of differentiation (CD) receptors, CD3/CD28. In contrast, venom treatment did not inhibit TNF or IL-6 release from antigen-presenting cells stimulated with lipopolysaccharide. The reduced cytokine release from T cells was not associated with inhibition of T cell proliferation or reduction of cell viability, consistent with an anti-inflammatory mechanism unrelated to the cell cycle. Deconvolution of the venom using reverse-phase HPLC identified four fractions responsible for the observed immunosuppressive activity. These data suggest that compounds from P. porphyriacus venom may be potential drug leads for T cell-associated conditions such as graft versus host disease, rheumatoid arthritis, and inflammatory bowel disease.
- Published
- 2020
37. Author Correction: Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity
- Author
-
Claire E. Wainwright, Martin F. Lavin, Sally Galbraith, Anna Henningham, Peter D. Sly, Emmanuelle Fantino, Lutz Krause, and Abrey J. Yeo
- Subjects
Male ,Adolescent ,Inflammasomes ,Science ,Ataxia Telangiectasia Mutated Proteins ,Nose ,Pneumococcal Infections ,Oxidative damage ,Ataxia Telangiectasia ,Medicine ,Humans ,Author Correction ,Child ,Lung ,Cells, Cultured ,Inflammation ,Multidisciplinary ,Innate immune system ,business.industry ,Cell Differentiation ,Epithelial Cells ,medicine.disease ,Immunity, Innate ,Oxidative Stress ,Streptococcus pneumoniae ,Case-Control Studies ,Child, Preschool ,Ataxia-telangiectasia ,Immunology ,Female ,Airway ,business - Abstract
Respiratory disease is a major cause of morbidity and mortality in patients with ataxia-telangiectasia (A-T) who are prone to recurrent sinopulmonary infections, bronchiectasis, pulmonary fibrosis, and pulmonary failure. Upper airway infections are common in patients and S. pneumoniae is associated with these infections. We demonstrate here that the upper airway microbiome in patients with A-T is different from that to healthy controls, with S. pneumoniae detected largely in patients only. Patient-specific airway epithelial cells and differentiated air-liquid interface cultures derived from these were hypersensitive to infection which was at least in part due to oxidative damage since it was partially reversed by catalase. We also observed increased levels of the pro-inflammatory cytokines IL-8 and TNF-α (inflammasome-independent) and a decreased level of the inflammasome-dependent cytokine IL-β in patient cells. Further investigation revealed that the ASC-Caspase 1 signalling pathway was defective in A-T airway epithelial cells. These data suggest that the heightened susceptibility of these cells to S. pneumoniae infection is due to both increased oxidative damage and a defect in inflammasome activation, and has implications for lung disease in these patients.
- Published
- 2020
38. Oocytes mount a noncanonical DNA damage response involving APC-Cdh1–mediated proteolysis
- Author
-
Martin F. Lavin, Goutham Narayanan Subramanian, Jessica Greaney, Olivier J. Becherel, Hayden Homer, and Zhe Wei
- Subjects
DNA damage ,Biology ,medicine.disease_cause ,Article ,Anaphase-Promoting Complex-Cyclosome ,Cdh1 Proteins ,03 medical and health sciences ,chemistry.chemical_compound ,DNA biology ,Mice ,0302 clinical medicine ,medicine ,Animals ,Cell cycle and division ,Cyclin B1 ,Mitosis ,Cells, Cultured ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Cyclin-dependent kinase 1 ,030219 obstetrics & reproductive medicine ,DNA Helicases ,RNA ,Cell Biology ,Cadherins ,Multifunctional Enzymes ,Cell biology ,Mice, Inbred C57BL ,chemistry ,Proteolysis ,Oocytes ,Phosphorylation ,Female ,Oxidative stress ,DNA ,RNA Helicases ,DNA Damage - Abstract
Using an in vivo model of DNA damage involving Senataxin knockout mice along with in vitrogenotoxic treatments, Subramanian et al. identify a DNA damage response in oocytes that builds slowly following damage induction and is mediated by increased APC-Cdh1–mediated cyclin B1 proteolysis., In mitotic cells, DNA damage induces temporary G2 arrest via inhibitory Cdk1 phosphorylation. In contrast, fully grown G2-stage oocytes readily enter M phase immediately following chemical induction of DNA damage in vitro, indicating that the canonical immediate-response G2/M DNA damage response (DDR) may be deficient. Senataxin (Setx) is involved in RNA/DNA processing and maintaining genome integrity. Here we find that mouse oocytes deleted of Setx accumulate DNA damage when exposed to oxidative stress in vitro and during aging in vivo, after which, surprisingly, they undergo G2 arrest. Moreover, fully grown wild-type oocytes undergo G2 arrest after chemotherapy-induced in vitro damage if an overnight delay is imposed following damage induction. Unexpectedly, this slow-evolving DDR is not mediated by inhibitory Cdk1 phosphorylation but by APC-Cdh1–mediated proteolysis of the Cdk1 activator, cyclin B1, secondary to increased Cdc14B-dependent APC-Cdh1 activation and reduced Emi1-dependent inhibition. Thus, oocytes are unable to respond immediately to DNA damage, but instead mount a G2/M DDR that evolves slowly and involves a phosphorylation-independent proteolytic pathway.
- Published
- 2020
39. Clinical potential of ATM inhibitors
- Author
-
Abrey J. Yeo and Martin F. Lavin
- Subjects
0301 basic medicine ,DNA Repair ,DNA damage ,Health, Toxicology and Mutagenesis ,Cell ,Antineoplastic Agents ,Genotoxic Stress ,Ataxia Telangiectasia Mutated Proteins ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplasms ,Genetics ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Phosphorylation ,Molecular Biology ,Mechanism (biology) ,Cancer ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Ataxia-telangiectasia ,Cancer cell ,Mutation ,Cancer research ,DNA ,DNA Damage - Abstract
The protein defective in the human genetic disorder ataxia-telangiectasia, ATM, plays a central role in responding to DNA double strand breaks and other lesions to protect the genome against DNA damage and in this way minimize the risk of mutations that can lead to abnormal cellular behaviour. Its function in normal cells is to protect the cell against genotoxic stress but inadvertently it can assist cancer cells by providing resistance against chemotherapeutic agents and thus favouring tumour growth and survival. However, it is now evident that ATM also functions in a DNA damage-independent fashion to protect the cell against other forms of stress such as oxidative and nutrient stress and this non-canonical mechanism may also be relevant to cancer susceptibility in individuals who lack a functional ATM gene. Thus the use of ATM inhibitors to combat resistance in tumours may extend beyond a role for this protein in the DNA damage response. Here, we provide some background on ATM and its activation and investigate the efficacy of ATM inhibitors in treating cancer.
- Published
- 2020
40. Epimedium Polysaccharide Ameliorates Benzene-Induced Aplastic Anemia in Mice
- Author
-
Qiang Jia, Ru Han, Ping Cui, Jin He, Martin F. Lavin, Gongchang Yu, and Cheng Peng
- Subjects
chemistry.chemical_classification ,0303 health sciences ,Reactive oxygen species ,Article Subject ,Pharmacology ,medicine.disease ,Peripheral blood mononuclear cell ,03 medical and health sciences ,Subcutaneous injection ,Other systems of medicine ,0302 clinical medicine ,medicine.anatomical_structure ,Complementary and alternative medicine ,chemistry ,Apoptosis ,030220 oncology & carcinogenesis ,medicine ,Peripheral blood cell ,Hemoglobin ,Bone marrow ,Aplastic anemia ,RZ201-999 ,030304 developmental biology ,Research Article - Abstract
Benzene (BZ) is an important occupational and environmental pollutant. Exposure to BZ may cause aplastic anemia which is characterized as bone marrow hematopoietic failure. In order to reduce the harmful effects of this pollutant, it is necessary to identify additional preventative measures. In this study, we investigated the protective effects of epimedium polysaccharide (EPS), a natural compound with antioxidant and immune-enhancing potency, on aplastic anemia induced by benzene exposure in mice. Male CD-1 mice were randomly divided into five groups including control, BZ (880 mg/kg), LE (EPS low-dose, 20 mg/kg + BZ), ME (EPS middle-dose, 100 mg/kg + BZ), and HE (EPS high-dose, 200 mg/kg + BZ) groups. Animals were exposed to BZ by subcutaneous injection in the presence or absence of EPS via oral administration. All mice were treated 3 times a week for 8 consecutive weeks to develop a mouse model of benzene-induced aplastic anemia (BIAA). Results showed that BZ induced a significant decrease in both white and red blood cells, platelet counts, and hemoglobin level compared with that in the control group (p<0.01). Treatment of EPS led to a protective effect against these changes particularly in the highest-dose group (HE, p<0.01). EPS also recovered the decreased number of nucleated cells in peripheral blood cell smears and femur biopsies by BZ exposure. The increased level of reactive oxygen species (ROS) in bone marrow mononuclear cells (BMMNCs) in mice from the BZ group was significantly lower (p<0.01) in the mice from the highest concentration of EPS (HE) group when compared with that from the control group. In addition, BZ exposure led to a significant increase in the apoptosis rate in BMMNCs which was prevented by EPS in a dose-dependent manner (p<0.01). The antiapoptosis effect of EPS was through reversing apoptotic proteins such as BAX, Caspase-9 and Caspase-3, and Bcl-2. Finally, EPS treatment partially restored the levels of T cells and the different subtypes except CD80+ and CD86+ compared with the BZ group (HE, p<0.05). These results suggest that EPS has protective effects against BIAA via antioxidative stress, immune modulation, and antiapoptosis mechanisms.
- Published
- 2020
- Full Text
- View/download PDF
41. Impaired Endoplasmic Reticulum (ER)-Mitochondrial Signaling in Ataxia-Telangiectasia Contributes to Mitochondrial Dysfunction
- Author
-
Abrey J. Yeo, Martin F. Lavin, Chong L. Kok, Magtouf Gatei, David Coman, Ernst J. Wolvetang, Robert G. Parton, Romal Stewart, Michael B. Kastan, Sarah L. Withey, Adam D. Brown, and Dongxiu Zou
- Subjects
mitochondrial fusion ,Chemistry ,Endoplasmic reticulum ,Mitophagy ,Ataxia-telangiectasia ,medicine ,Wild type ,Mitochondrion ,medicine.disease ,VDAC1 ,Homeostasis ,Cell biology - Abstract
Ataxia-telangiectasia (A-T) mutated (ATM) plays a central role in the response to DNA double strand breaks (DNA DSB) but there is increasing evidence that it has a key role in protecting against mitochondrial dysfunction, the mechanism for which remains unresolved. We demonstrate here that A-T cells are also exquisitely sensitive to metabolic stress which can be explained by defective cross-talk between the endoplasmic reticulum (ER) and the mitochondrion through the mitochondrial–associated membrane (MAM). We showed that formation of a molecular bridge between the voltage-dependent calcium channel (VDAC1) and the inositol 1,4,5 trisphosphate receptor type 1 (IP3R1), mediated by the mitochondrial chaperone GRP75, is defective in A-T cells after nutrient stress. Tethering between these two organelles in response to stress, as determined by number of ER-mitochondrial contact sites, was reduced in A-T cells and consistent with this, Ca2+ release and transfer between ER and mitochondria was reduced dramatically compared to wild type cells. The impact of this on mitochondrial function was evident from an increase in oxygen consumption rates and a defect in mitophagy in ATM-deficient cells after glucose deprivation. Our findings reveal that ER- mitochondrial connectivity through IP3R1-GRP75-VDAC1, to maintain Ca2+ homeostasis, as well as an abnormality in mitochondrial fusion is defective in A-T cells in response to nutrient stress which can account for at least part of the mitochondrial dysfunction observed in A-T cells.
- Published
- 2020
42. Next-generation rapid serum tube technology using prothrombin activator coagulant: fast, high-quality serum from normal samples
- Author
-
Goce Dimeski, Paul P. Masci, John de Jersey, Lambro A. Johnson, Kong-Nan Zhao, Martin F. Lavin, and Michael Grant
- Subjects
030213 general clinical medicine ,Analyte ,Clinical Biochemistry ,030204 cardiovascular system & hematology ,Fibrinogen ,03 medical and health sciences ,0302 clinical medicine ,Thrombin ,Prothrombinase ,medicine ,Animals ,Humans ,Blood Coagulation ,Whole blood ,Blood Specimen Collection ,Chromatography ,medicine.diagnostic_test ,Coagulants ,Chemistry ,Biochemistry (medical) ,General Medicine ,Healthy Volunteers ,Thromboelastography ,Coagulation ,Immunoassay ,Prothrombin ,Blood Coagulation Tests ,Snake Venoms ,medicine.drug - Abstract
Background Incomplete blood clotting or latent clotting in serum is a common laboratory problem, especially for patients on anticoagulant therapy or when serum tubes are centrifuged before clotting is completed. We describe a novel approach to producing high-quality serum using snake venom prothrombin activator complex (OsPA) as an additive in blood collection tubes for non-anticoagulated (normal) individuals. Methods Plasma clotting assays were performed using a Hyland-Clotek instrument. Blood clotting was visually observed, and thromboelastography was also performed to determine the important parameters of coagulation. Thrombin generation was assayed using the chromogenic substrate S-2238, and biochemical analytes in the serum were determined on chemistry and immunoassay analysers. Fibrinogen was determined by either ELISA or Clauss fibrinogen assay. Results We initially showed that OsPA had strong coagulation activity in clotting not only recalcified citrated plasma and recalcified citrated whole blood, but also fresh whole blood in a clinical setting. The use of TEG clearly showed improved speed of clotting and generation of a firmer clot. We also showed that the use of OsPA to produce serum did not interfere with the determination of commonly measured biochemical analytes. The underlying clotting mechanism involves a burst of thrombin production at the initial stages of the clotting process upon contact with prothrombin in blood. Conclusions These results demonstrate rapid generation of high-quality serum, contributing to faster turnaround times with standardised quality samples, for accurate analyte determinations in normal individuals.
- Published
- 2018
43. Understanding the mechanisms of silica nanoparticles for nanomedicine
- Author
-
Yingwen Mu, Hua Shao, Cheng Peng, Ziyuan Li, Zhongjun Du, and Martin F. Lavin
- Subjects
Pore size ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Nanotechnology ,02 engineering and technology ,silica nanoparticles ,010402 general chemistry ,01 natural sciences ,Silica nanoparticles ,Drug Delivery Systems ,biocompatibility ,Biomedicine ,Emerging Technologies ,Drug discovery ,business.industry ,Photothermal therapy ,021001 nanoscience & nanotechnology ,Silicon Dioxide ,0104 chemical sciences ,Nanoscale Systems in Biology ,Nanomedicine ,Pharmaceutical Preparations ,Advanced Review ,Drug delivery ,Nanoparticles ,Advanced Reviews ,0210 nano-technology ,business - Abstract
As a consequence of recent progression in biomedicine and nanotechnology, nanomedicine has emerged rapidly as a new discipline with extensive application of nanomaterials in biology, medicine, and pharmacology. Among the various nanomaterials, silica nanoparticles (SNPs) are particularly promising in nanomedicine applications due to their large specific surface area, adjustable pore size, facile surface modification, and excellent biocompatibility. This paper reviews the synthesis of SNPs and their recent usage in drug delivery, biomedical imaging, photodynamic and photothermal therapy, and other applications. In addition, the possible adverse effects of SNPs in nanomedicine applications are reviewed from reported in vitro and in vivo studies. Finally, the potential opportunities and challenges for the future use of SNPs are discussed. This article is categorized under:Nanotechnology Approaches to Biology > Nanoscale Systems in BiologyTherapeutic Approaches and Drug Discovery > Emerging Technologies, Schematic diagram of silica nanoparticles applied to different nanomedicine.
- Published
- 2019
44. Cutaneous Granulomatosis and Class Switching Defect as a Presenting Sign in Ataxia-Telangiectasia: First Case from the National Iranian Registry and Review of the Literature
- Author
-
Asghar Aghamohammadi, Martin F. Lavin, Reza Yazdani, Parisa Amirifar, Hassan Abolhassani, Tannaz Moeini Shad, Alireza Ghanadan, and Soheila Sotoudeh
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Biopsy ,Immunology ,Ataxia Telangiectasia Mutated Proteins ,Iran ,Pathogenesis ,03 medical and health sciences ,Ataxia Telangiectasia ,0302 clinical medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Registries ,Telangiectasia ,Immunodeficiency ,Genetic Association Studies ,Skin ,Cancer predisposition ,business.industry ,Immunoglobulins, Intravenous ,General Medicine ,medicine.disease ,Dermatology ,Immunoglobulin Class Switching ,030104 developmental biology ,Phenotype ,Treatment Outcome ,Immunoglobulin class switching ,030220 oncology & carcinogenesis ,Ataxia-telangiectasia ,Mutation ,Primary immunodeficiency ,Female ,Elevated igm ,medicine.symptom ,business - Abstract
Ataxia-telangiectasia (A-T) is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency and cancer predisposition, caused by mutations in the ataxia telangiectasia mutated (ATM) gene. The clinical and immunological manifestations of A-T are very heterogeneous, especially at an early age, leading to frequent misdiagnosis. Cutaneous granulomas with unknown pathogenesis occur uncommonly in a minority of A-T patients. We herein report an unusual case of a 13-year-old girl with A-T who presented severe clinical manifestations, including multiple granulomatous lesions of the skin and a class switch defect phenotype. This patient is the first Iranian A-T case with cutaneous granulomatosis and immunodeficiency. In addition, the literature on skin granulomas in all previously reported A-T patients is reviewed indicating an increased frequency of elevated IgM level and female dominancy in this selected group of patients.
- Published
- 2019
45. Design and Clinical Verification of Surface-Enhanced Raman Spectroscopy Diagnostic Technology for Individual Cancer Risk Prediction
- Author
-
Hema Samaratunga, Renee S. Richards, Paul N. Mainwaring, Kevin M. Koo, Yuling Wang, Matt Trau, Matthew J. Roberts, John Yaxley, Martin F. Lavin, G. Coughlin, Jing Wang, Aine Farrell, Robert A. Gardiner, and Patrick Teloken
- Subjects
Adult ,Male ,medicine.medical_specialty ,Scoring system ,Surface Properties ,General Physics and Astronomy ,02 engineering and technology ,Spectrum Analysis, Raman ,010402 general chemistry ,01 natural sciences ,Clinical biomarker ,Risk Factors ,Diagnostic technology ,Biomarkers, Tumor ,medicine ,Humans ,General Materials Science ,Medical physics ,Aged ,business.industry ,General Engineering ,Human patient ,Clinical performance ,Prostatic Neoplasms ,Equipment Design ,Middle Aged ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,0210 nano-technology ,Cancer risk ,business ,Clinical evaluation ,Biopsy findings - Abstract
The use of emerging nanotechnologies, such as plasmonic nanoparticles in diagnostic applications, potentially offers opportunities to revolutionize disease management and patient healthcare. Despite worldwide research efforts in this area, there is still a dearth of nanodiagnostics which have been successfully translated for real-world patient usage due to the predominant sole focus on assay analytical performance and lack of detailed investigations into clinical performance in human samples. In a bid to address this pressing need, we herein describe a comprehensive clinical verification of a prospective label-free surface-enhanced Raman scattering (SERS) nanodiagnostic assay for prostate cancer (PCa) risk stratification. This contribution depicts a roadmap of (1) designing a SERS assay for robust and accurate detection of clinically validated PCa RNA targets; (2) employing a relevant and proven PCa clinical biomarker model to test our nanodiagnostic assay; and (3) investigating the clinical performance on independent training ( n = 80) and validation ( n = 40) cohorts of PCa human patient samples. By relating the detection outcomes to gold-standard patient biopsy findings, we established a PCa risk scoring system which exhibited a clinical sensitivity and specificity of 0.87 and 0.90, respectively [area-under-curve of 0.84 (95% confidence interval: 0.81-0.87) for differentiating high- and low-risk PCa] in the validation cohort. We envision that our SERS nanodiagnostic design and clinical verification approach may aid in the individualized prediction of PCa presence and risk stratification and may overall serve as an archetypical strategy to encourage comprehensive clinical evaluation of nanodiagnostic innovations.
- Published
- 2018
46. ATM inhibition prevents interleukin-6 from contributing to the proliferation of glioblastoma cells after ionizing radiation
- Author
-
Carolin Offenhäuser, Tara L. Roberts, Shazrul Fazry, Yi Chieh Lim, Martin F. Lavin, Hazel Quek, Bryan W. Day, and Andrew W. Boyd
- Subjects
0301 basic medicine ,Cancer Research ,Cell Survival ,DNA damage ,medicine.medical_treatment ,Cell ,Ataxia Telangiectasia Mutated Proteins ,Radiation Tolerance ,Cell Line ,Central Nervous System Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Neural Stem Cells ,Radiation, Ionizing ,Radioresistance ,medicine ,Humans ,RNA, Messenger ,Interleukin 6 ,Cell Proliferation ,Cell Death ,biology ,Interleukin-6 ,Kinase ,business.industry ,Receptors, Interleukin-6 ,Neural stem cell ,Radiation therapy ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,Neurology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Neurology (clinical) ,Glioblastoma ,business ,DNA Damage - Abstract
Glioblastoma (GBM) is a highly fatal disease with a 5 year survival rate of less than 22%. One of the most effective treatment regimens to date is the use of radiotherapy which induces lethal DNA double-strand breaks to prevent tumour growth. However, recurrence occurs in the majority of patients and is in-part a result of robust radioresistance mechanisms. In this study, we demonstrate that the multifunctional cytokine, interleukin-6 (IL-6), confers a growth advantage in GBM cells but does not have the same effect on normal neural progenitor cells. Further analysis showed IL-6 can promote radioresistance in GBM cells when exposed to ionising radiation. Ablation of the Ataxia-telangiectasia mutated serine/threonine kinase that is recruited and activated by DNA double-strand breaks reverses the effect of radioresistance and re-sensitised GBM to DNA damage thus leading to increase cell death. Our finding suggests targeting the signaling cascade of DNA damage response is a potential therapeutic approach to circumvent IL-6 from promoting radioresistance in GBM.
- Published
- 2018
47. PIKKing a way to regulate inflammation
- Author
-
Yi Chieh Lim, Martin F. Lavin, Tara L. Roberts, and Hazel Quek
- Subjects
0301 basic medicine ,DNA Repair ,DNA damage ,Immunology ,Cell ,Inflammation ,Biology ,Genome ,Transcriptome ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Animals ,Humans ,Immunology and Allergy ,Innate immune system ,Kinase ,Cell Biology ,Immunity, Innate ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Immune System ,030220 oncology & carcinogenesis ,medicine.symptom ,DNA Damage ,Signal Transduction - Abstract
The phosphoinositide-3-kinase like kinases are a family of very large protein kinases. These PI3-kinase like kinase (PIKK) proteins have well-established roles in detection and repair of damage to the genome, regulation of the transcriptome and cellular metabolism. Recently there has emerged, evidence for links between these proteins and inflammation. While some of these links come from an increased understanding of the impacts of damage to the cell on inflammatory responses, others suggest that PIKK proteins also have direct roles in regulation of immune responses. Particularly evident is the link between DNA damage and innate immune response pathways. Here, we review recent findings on the PIKK family of proteins and how they impact on inflammation, particularly activation of the innate immune system.
- Published
- 2017
48. Therapeutic targets and investigated treatments for Ataxia-Telangiectasia
- Author
-
Kate Sinclair, Peter D. Sly, Amanda W. Kijas, Claire E. Wainwright, Martin F. Lavin, Ernst J. Wolvetang, and Abrey J. Yeo
- Subjects
0301 basic medicine ,business.industry ,Health Policy ,Neurodegeneration ,Cancer ,medicine.disease ,Bioinformatics ,Clinical trial ,03 medical and health sciences ,Liver disease ,030104 developmental biology ,Immune system ,Lung disease ,Ataxia-telangiectasia ,Immunology ,medicine ,Pharmacology (medical) ,Stem cell ,business ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) - Abstract
Introduction: Ataxia-Telangiectasia (A-T) is an autosomal recessive multisystem disease affecting the brain, immune system, lungs, liver and also characterised by an enhanced risk of lymphoid and other tumours. At present there is no cure for A-T with management relying on supportive care using symptom-specific medications. Identification of the gene defective in this syndrome, ATM, and further characterization of the disorder together with greater insight into the function of the ATM protein has provided greater opportunity for the development of potential therapies. Areas covered: Here we review conventional as well as more recently developed approaches to manage the symptoms of patients with A-T. In addition we explore ongoing and potential strategies for therapy involving gene correction, stem cells and use of antioxidants and anti-inflammatory agents. Expert opinion: Prevention or arrest of the progressive neurodegeneration, the most debilitating feature of A-T, represents a major goal in the development of a cure for this disorder. However, since lung disease and increased risk of cancer are responsible for the majority of mortality in A-T, a greater understanding of these pathologies together with more effective approaches to treatment is required in the overall management of patients.
- Published
- 2016
49. Simultaneous targeting of DNA replication and homologous recombination in glioblastoma with a polyether ionophore
- Author
-
Zara C. Bruce, Rochelle C.J. D’Souza, Baek Kim, Yi Chieh Lim, Kum Kum Khanna, Andrew W. Boyd, Mark J. Coster, Jason K. Cullen, Petra Hamerlik, Valentina Cianfanelli, Lisa Maria Wiesmueller, Adrian P. Wiegmans, Kathleen S. Ensbey, Brett W. Stringer, Amanda W. Kijas, Rosalind L. Jeffree, Fanny J. Lombard, Fiona M. Smith, Tara L. Roberts, Bijan Mahboubi, Carolin Offenhäuser, Martin F. Lavin, Bryan W. Day, Hazel Quek, Terrance Grant Johns, and Amanda L. Bain
- Subjects
DNA Replication ,Cancer Research ,DNA damage ,DNA repair ,Population ,homologous recombination ,Mice, SCID ,chemistry.chemical_compound ,Mice ,In vivo ,Mice, Inbred NOD ,Radioresistance ,Drug Discovery ,Autophagy ,Medicine ,Animals ,Humans ,education ,Salinomycin ,Pyrans ,education.field_of_study ,Ionophores ,business.industry ,Brain Neoplasms ,Editorials ,Recombinational DNA Repair ,Xenograft Model Antitumor Assays ,Oncology ,chemistry ,Basic and Translational Investigations ,Cancer research ,Neoplastic Stem Cells ,Neurology (clinical) ,Homologous recombination ,business ,Glioblastoma ,Ex vivo - Abstract
Background Despite significant endeavor having been applied to identify effective therapies to treat glioblastoma (GBM), survival outcomes remain intractable. The greatest nonsurgical benefit arises from radiotherapy, though tumors typically recur due to robust DNA repair. Patients could therefore benefit from therapies with the potential to prevent DNA repair and synergize with radiotherapy. In this work, we investigated the potential of salinomycin to enhance radiotherapy and further uncover novel dual functions of this ionophore to induce DNA damage and prevent repair. Methods In vitro primary GBM models and ex vivo GBM patient explants were used to determine the mechanism of action of salinomycin by immunoblot, flow cytometry, immunofluorescence, immunohistochemistry, and mass spectrometry. In vivo efficacy studies were performed using orthotopic GBM animal xenograft models. Salinomycin derivatives were synthesized to increase drug efficacy and explore structure-activity relationships. Results Here we report novel dual functions of salinomycin. Salinomycin induces toxic DNA lesions and prevents subsequent recovery by targeting homologous recombination (HR) repair. Salinomycin appears to target the more radioresistant GBM stem cell–like population and synergizes with radiotherapy to significantly delay tumor formation in vivo. We further developed salinomycin derivatives which display greater efficacy in vivo while retaining the same beneficial mechanisms of action. Conclusion Our findings highlight the potential of salinomycin to induce DNA lesions and inhibit HR to greatly enhance the effect of radiotherapy. Importantly, first-generation salinomycin derivatives display greater efficacy and may pave the way for clinical testing of these agents.
- Published
- 2019
50. Regulation of RNA degradation pathways during the lipopolysaccharide response in Macrophages
- Author
-
John Luff, Alexander James, Uda Ho, Hui-Chi Lai, Tara L. Roberts, Paul de Souza, Martin F. Lavin, and Hazel Quek
- Subjects
0301 basic medicine ,Exonuclease ,Lipopolysaccharides ,RNA Stability ,Immunology ,Nonsense-mediated decay ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Transcription (biology) ,Gene expression ,Immunology and Allergy ,Animals ,Post-transcriptional regulation ,Messenger RNA ,Sequence Analysis, RNA ,Macrophages ,RNA ,Proteins ,Reproducibility of Results ,Cell Biology ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,biology.protein - Abstract
The innate immune response to LPS is highly dynamic yet tightly regulated. The majority of studies of gene expression have focussed on transcription. However, it is also important to understand how post-transcriptional pathways are regulated in response to inflammatory stimuli as the rate of RNA degradation relative to new transcription is important for overall expression. RNA decay pathways include nonsense-mediated decay, the RNA decay exosome, P-body localized deadenylation, decapping and degradation, and AU-rich element targeted decay mediated by tristetraprolin. Here, bone marrow-derived Mϕs were treated with LPS over a time course of 0, 2, 6, and 24 h and the transcriptional profiles were analyzed by RNA sequencing. The data show that components of RNA degradation pathways are regulated during an LPS response. Processing body associated decapping enzyme DCP2 and regulatory subunit DCP1A, and 5′ exonuclease XRN1 and sequence specific RNA decay pathways were upregulated. Nonsense mediated decay was also increased in response to LPS induced signaling, initially by increased activation and at later timepoints at the mRNA and protein levels. This leads to increased nonsense mediated decay efficiency across the 24 h following LPS treatment. These findings suggest that LPS activation of Mϕs results in targeted regulation of RNA degradation pathways in order to change how subsets of mRNAs are degraded during an inflammatory response.
- Published
- 2019
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.