| 1. |
- Andreassi, Maria Grazia, et al.
(författare)
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A Longitudinal Study of Individual Radiation Responses in Pediatric Patients Treated with Proton and Photon Radiotherapy, and Interventional Cardiology : Rationale and Research Protocol of the HARMONIC Project
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 24:9, s. 8416-
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Tidskriftsartikel (refereegranskat)abstract
- The Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy (photon and proton) in Pediatrics (HARMONIC) is a five-year project funded by the European Commission that aimed to improve the understanding of the long-term ionizing radiation (IR) risks for pediatric patients. In this paper, we provide a detailed overview of the rationale, design, and methods for the biological aspect of the project with objectives to provide a mechanistic understanding of the molecular pathways involved in the IR response and to identify potential predictive biomarkers of individual response involved in long-term health risks. Biological samples will be collected at three time points: before the first exposure, at the end of the exposure, and one year after the exposure. The average whole-body dose, the dose to the target organ, and the dose to some important out-of-field organs will be estimated. State-of-the-art analytical methods will be used to assess the levels of a set of known biomarkers and also explore high-resolution approaches of proteomics and miRNA transcriptomes to provide an integrated assessment. By using bioinformatics and systems biology, biological pathways and novel pathways involved in the response to IR exposure will be deciphered.
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| 2. |
- Haghdoost, Siamak, 1968-
(författare)
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Biomarkers of oxidative stress and their application for assessment of individual radiosensitivity
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Radiotherapy is one of the most common therapeutic methods for treatment of many types of cancer. Despite many decades of development and experience there is much to improve, both in efficacy of treatment and to decrease the incidences of adverse healthy tissue reactions. Around 20 % of the radiotherapy patients show a broad range in the severity of normal tissue reactions to radiotherapy, and dose limits are governed by severe reactions in the most radiosensitive patients (< 5 %). Identification of patients with low, moderate or high clinical radiosensitivity before commencing of radiotherapy would allow individual adaptation of the maximum dose with an overall increase in the cure rate. Characterization of factors that may modify the biological effects of ionizing radiation has been a subject of intense research efforts. Still, there is no assay currently available that can reliably predict the clinical radiosensitivity. The aim of this work has been to investigate the role of oxidative stress in individual radiosensitivity and evaluate novel markers of radiation response, which could be adapted for clinical use.8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), a general marker of oxidative stress, is one of the major products of interaction of ionizing radiation with DNA and the nucleotide pool of the cell. As 8-oxo-dG is highly mutagenic due to incorrect base pairing with deoxyadenosine, various repair mechanisms recognize and remove 8-oxo-dG. The repaired lesions are released from cells to the extracellular milieu (serum, urine and cell culture medium) where they can be detected as markers for free radical reactions with the nucleic acids.Significant variations in background levels as well as in radiation induced levels of 8-oxo-dG in urine have been demonstrated in breast cancer patients (paper 1). Two major patterns were observed: high background and no therapy-related increase vs. low background and significant increase during radiotherapy for the radiosensitive and non radiosensitive patients respectively.Studies in paper 2 indicated major contribution of the nucleotide pool to the extracellular 8-oxo-dG levels. The results also implicated induction of prolonged endogenous oxidative stress in the irradiated cells. RNA “knock-down” experiments on the nucleotide pool sanitization enzyme hMTH1 in paper 3 lend further experimental evidence to this assumption.The applicability of 8-oxo-dG as a diagnostic marker of oxidative stress was demonstrated in paper 4. Studies on dialysis patients revealed a good correlation between inflammatory responses (known to be associated with persistent oxidative stress) and extracellular 8-oxo-dG.In summary, our results confirm that extracellular 8-oxo-dG is a sensitive in vivo biomarker of oxidative stress, primarily formed by oxidative damage of dGTP in the nucleotide pool with a potential to become a clinical tool for prediction of individual responses to radiotherapy.
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| 3. |
- Hammad, Mira, et al.
(författare)
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Roles of Oxidative Stress and Nrf2 Signaling in Pathogenic and Non-Pathogenic Cells : A Possible General Mechanism of Resistance to Therapy
- 2023
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Ingår i: Antioxidants. - 2076-3921. ; 12:7
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Forskningsöversikt (refereegranskat)abstract
- The coordinating role of nuclear factor erythroid-2-related factor 2 (Nrf2) in cellular function is undeniable. Evidence indicates that this transcription factor exerts massive regulatory functions in multiple signaling pathways concerning redox homeostasis and xenobiotics, macromolecules, and iron metabolism. Being the master regulator of antioxidant system, Nrf2 controls cellular fate, influencing cell proliferation, differentiation, apoptosis, resistance to therapy, and senescence processes, as well as infection disease success. Because Nrf2 is the key coordinator of cell defence mechanisms, dysregulation of its signaling has been associated with carcinogenic phenomena and infectious and age-related diseases. Deregulation of this cytoprotective system may also interfere with immune response. Oxidative burst, one of the main microbicidal mechanisms, could be impaired during the initial phagocytosis of pathogens, which could lead to the successful establishment of infection and promote susceptibility to infectious diseases. There is still a knowledge gap to fill regarding the molecular mechanisms by which Nrf2 orchestrates such complex networks involving multiple pathways. This review describes the role of Nrf2 in non-pathogenic and pathogenic cells.
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| 4. |
- Sangsuwan, Traimate, 1981-, et al.
(författare)
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Oxidative Stress Levels and DNA Repair Kinetics in Senescent Primary Human Fibroblasts Exposed to Chronic Low Dose Rate of Ionizing Radiation
- 2023
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Ingår i: Frontiers in Bioscience Landmark. - 2768-6701. ; 28:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Exposure to low dose rate (LDR) radiation may accelerate aging processes. Previously, we identified numerous LDR-induced pathways involved in oxidative stress (OS) and antioxidant systems, suggesting that these pathways protect against premature senescence (PS). This study aimed to investigate if there are differences between young replicative senescent (RS) and PS cells considering DNA repair kinetics, OS, and DNA damage localized in the telomeres. Methods: We established PS cells by culturing and passaging young primary fibroblasts exposed to LDR. Then, RS cells were established by culturing and passaging young fibroblasts until they stopped proliferating. Senescence was characterized by analyzing telomere length and senescence-associated β-galactosidase (SA-β-gal) staining. DNA damage and repair were evaluated with γH2AX foci formation; telomere identification was carried out using the fluorescence in situ hybridization (FISH) probe; and oxidative stress was assessed by measuring 8-oxo-dG in the medium. Results: The data indicate the following: young cells have a better ability to cope with LDR-induced oxidative stress; RS and PS have higher steady-state levels of DNA damage; RS have slower DNA repair kinetics; and PS/RS have elevated levels of telomeric DNA damage. Conclusion: Our main conclusion is that PS and RS differ regarding DNA repair kinetics and SA-β-gal levels.
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| 5. |
- Thierry-Chef, Isabelle, et al.
(författare)
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Health effects of ionising radiation in paediatrics undergoing either cardiac fluoroscopy or modern radiotherapy (The HARMONIC project)
- 2023
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Ingår i: The European Journal of Physics N (EPJ-N). - 2491-9292. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The use of ionising radiation (IR) for medical diagnosis and treatment procedures has had a major impact on the survival of paediatric patients. Although the benefits of these techniques lead to efficient health care, evaluation of potential associated long-term health effects is required. HARMONIC aims to better understand the increased risk of cancer and non-cancer effects after exposure to medical IR in children with cancer treated with modern external beam radiotherapy (EBRT) – radiation energy in MeV range – and in children with cardiac defects diagnosed and treated with cardiac fluoroscopy procedures (CFP) – radiation energy in keV range. The project investigates, among survivors of paediatric cancer, potential endocrine dysfunction, cardiovascular and neurovascular damage, health-related quality of life and second (and subsequent) primary cancer (SPC). The cardiac component builds a pooled cohort of approximately 90 000 paediatric patients who underwent CFP during childhood and adolescence to investigate cancer risk following exposure to IR and explore the potential effects of conditions predisposing to cancer. HARMONIC develops software tools to allow dose reconstruction in both EBRT and CFP to enable epidemiological investigations and future optimisation of treatments. With the creation of a biobank of blood and saliva samples, HARMONIC aims to provide a mechanistic understanding of radiation-induced adverse health effects and identify potential biomarkers that can predict these effects.
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