| 1. |
- Fotouhi, Asal, et al.
(författare)
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Reduction of 8-oxodGTP in the nucleotide pool by hMTH1 leads to reduction in mutations in the human lymphoblastoid cell line TK6 exposed to UVA
- 2011
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Ingår i: Mutation research. - : Elsevier BV. - 0027-5107 .- 1873-135X. ; 715:1-2, s. 13-18
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Tidskriftsartikel (refereegranskat)abstract
- UVA has been suggested to play an important role in UV-induced mutagenesis. The mechanisms by which UVA induces mutations are still a matter of debate. Our aim was to investigate the protective capacity of hMTH1, a nucleotide pool sanitization enzyme with 8-oxodGTPase activity. Human B lymphoblastoid cells were stably transfected with shRNA directed against hMTH1. Clonogenic survival, mutations, intracellular and extracellular levels of 8-oxodG (8-oxo-7, 8-dihydro-2'-deoxyguanosine) and dG in the nucleotide pool of UVA-irradiated transfected and non-transfected cells were investigated. Mutations were determined in the thymidine kinase locus. Intracellular 8-oxodG and dG were measured using a modified ELISA and HPLC, respectively, after extraction of the nucleotide pool and conversion of nucleotides to their corresponding nucleosides. 8-oxodG in the medium was measured using ELISA. UVA-induced mutations were significantly higher while the survival was slightly lower in transfected compared to non-transfected cells. The increased mutation rate in transfected cells at increased exposure correlated with enhanced levels of 8-oxodG in the nucleotide pool, and a somewhat reduced level of 8-oxodG in the medium. The results indicate that the nucleotide pool is a significant target for UVA-induced mutations and implicates that hMTH1 plays an important role in protecting cells from UVA-induced oxidative stress.
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| 2. |
- Alvarez, Ignacio, et al.
(författare)
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Proteomic and Lipidomic Profiling of Calves Experimentally Co-Infected with Influenza D Virus and Mycoplasma bovis : Insights into the Host-Pathogen Interactions
- 2024
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Ingår i: Viruses. - : MDPI. - 1999-4915. ; 16:3
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Tidskriftsartikel (refereegranskat)abstract
- The role of Influenza D virus (IDV) in bovine respiratory disease remains unclear. An in vivo experiment resulted in increased clinical signs, lesions, and pathogen replication in calves co-infected with IDV and Mycoplasma bovis (M. bovis), compared to single-infected calves. The present study aimed to elucidate the host-pathogen interactions and profile the kinetics of lipid mediators in the airways of these calves. Bronchoalveolar lavage (BAL) samples collected at 2 days post-infection (dpi) were used for proteomic analyses by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, lipidomic analyses were performed by LC-MS/MS on BAL samples collected at 2, 7 and 14 dpi. Whereas M. bovis induced the expression of proteins involved in fibrin formation, IDV co-infection counteracted this coagulation mechanism and downregulated other acute-phase response proteins, such as complement component 4 (C4) and plasminogen (PLG). The reduced inflammatory response against M. bovis likely resulted in increased M. bovis replication and delayed M. bovis clearance, which led to a significantly increased abundance of oxylipids in co-infected calves. The identified induced oxylipids mainly derived from arachidonic acid; were likely oxidized by COX-1, COX-2, and LOX-5; and peaked at 7 dpi. This paper presents the first characterization of BAL proteome and lipid mediator kinetics in response to IDV and M. bovis infection in cattle and raises hypotheses regarding how IDV acts as a co-pathogen in bovine respiratory disease.
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| 3. |
- Dang, Li, et al.
(författare)
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Radioprotective effect of hypothermia on cells - a multiparametric approach to delineate the mechanisms
- 2012
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Ingår i: International Journal of Radiation Biology. - : Informa UK Limited. - 0955-3002 .- 1362-3095. ; 88:7, s. 507-514
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Low temperature (hypothermia) during irradiation of cells has been reported to have a radioprotective effect. The mechanisms are not fully understood. This study further investigates the possible mechanisms behind hypothermia-mediated radioprotection. Materials and methods: Human lymphoblastoid TK6 cells were incubated for 20 min at 0.8 or 37 degrees C and subsequently exposed to 1 Gy of gamma- or X-rays. The influence of ataxia telangiectasia mutated (ATM)-mediated double-strand break signalling and histone deacetylase-dependent chromatin condensation was investigated using the micronucleus assay. Furthermore, the effect of hypothermia was investigated at the level of phosphorylated histone 2AX (gamma H2AX) foci, clonogenic cell survival and micronuclei in sequentially-harvested cells. Results: The radioprotective effect of hypothermia (called the temperature effect [TE]) was evident only at the level of micronuclei at a single fixation time, was not influenced by the inhibition of ATM kinase activity and completely abolished by the histone deacetylase inhibition. No TE was seen at the level of gamma H2AX foci and cell survival. Conclusions: We suggest that low temperature during irradiation can induce a temporary cell cycle shift, which could lead to a reduced micronucleus frequency. Future experiments focused on cell cycle progression are needed to confirm this hypothesis.
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| 4. |
- Hall, C. Michael, et al.
(författare)
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Politics and the sustainable development goals : Tourism agenda 2030 perspective article
- 2023
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Ingår i: Tourism Review. - : Emerald Group Publishing Limited. - 1660-5373 .- 1759-8451. ; 78:2, s. 314-320
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Tidskriftsartikel (refereegranskat)abstract
- PurposeThe 2030 Agenda provides the normative framework for much contemporary thinking on sustainable tourism. This viewpoint paper aims to discuss the inherently political nature of the sustainable development goals (SDGs) and the implications for tourism and sustainability.Design/methodology/approachThis is a paper that highlights the political dimensions of positioning tourism within the SDGs.FindingsThis paper highlights continuing challenges in the broader politics of sustainable development in terms of the development of the 2030 Agenda and its implementation. It finds that the SDGs function as a form of metagovernance for sustainable development and sustainable tourism in particular.Originality/valueThis paper reinforces the importance of understanding the politics of the 2030 Agenda by locating sustainable tourism and the SDGs in the broader political context and the significance of metagovernance. In so doing, this paper contributes to continued theoretical debates on the framing of sustainable tourism that are key to understanding the politics of sustainable development and the winners and losers in the politics of tourism.
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| 5. |
- Hägglund, Sara, et al.
(författare)
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Pathogenesis, Host Innate Immune Response, and Aerosol Transmission of Influenza D Virus in Cattle
- 2019
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Ingår i: Journal of Virology. - 0022-538X .- 1098-5514. ; 93
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Tidskriftsartikel (refereegranskat)abstract
- The recently discovered influenza D virus (IDV) of the Orthomyxoviridae family has been detected in swine and ruminants with a worldwide distribution. Cattle are considered to be the primary host and reservoir, and previous studies suggested a tropism of IDV for the upper respiratory tract and a putative role in the bovine respiratory disease complex. This study aimed to characterize the pathogenicity of IDV in naive calves as well as the ability of this virus to transmit by air. Eight naive calves were infected by aerosol with a recent French isolate, D/bovine/France/5920/2014. Results show that IDV replicates not only in the upper respiratory tract but also in the lower respiratory tract (LRT), inducing moderate bronchopneumonia with restricted lesions of interstitial pneumonia. Inoculation was followed by IDV-specific IgG1 production as early as 10 days postchallenge and likely both Th1 and Th2 responses. Study of the innate immune response in the LRT of IDV-infected calves indicated the overexpression of pathogen recognition receptors and of chemokines CCL2, CCL3, and CCL4, but without overexpression of genes involved in the type I interferon pathway. Finally, virological examination of three aerosol-sentinel animals, housed 3 m apart from inoculated calves (and thus subject to infection by aerosol transmission), and IDV detection in air samples collected in different areas showed that IDV can be airborne transmitted and infect naive contact calves on short distances. This study suggests that IDV is a respiratory virus with moderate pathogenicity and probably a high level of transmission. It consequently can be considered predisposing to or a cofactor of respiratory disease.IMPORTANCE Influenza D virus (IDV), a new genus of the Orthomyxoviridae family, has a broad geographical distribution and can infect several animal species. Cattle are so far considered the primary host for IDV, but the pathogenicity and the prevalence of this virus are still unclear. We demonstrated that under experimental conditions (in a controlled environment and in the absence of coinfecting pathogens), IDV is able to cause mild to moderate disease and targets both the upper and lower respiratory tracts. The virus can transmit by direct as well as aerosol contacts. While this study evidenced overexpression of pathogen recognition receptors and chemokines in the lower respiratory tract, IDV-specific IgG1 production as early as 10 days postchallenge, and likely both Th1 and Th2 responses, further studies are warranted to better understand the immune responses triggered by IDV and its role as part of the bovine respiratory disease complex.
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| 6. |
- Näslund, Katarina, et al.
(författare)
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Authors’ response
- 2020
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Ingår i: Journal of Veterinary Diagnostic Investigation. - : SAGE Publications. - 1040-6387 .- 1943-4936. ; 32, s. 633-634
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 7. |
- Näslund, Katarina, et al.
(författare)
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Seroprevalence of influenza D virus in bulls in Argentina
- 2020
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Ingår i: Journal of Veterinary Diagnostic Investigation. - : SAGE Publications. - 1040-6387 .- 1943-4936. ; 32, s. 585-588
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Tidskriftsartikel (refereegranskat)abstract
- Influenza D virus (IDV) is considered a new agent involved in bovine respiratory disease (BRD). Based on seroprevalence studies or isolation from clinical samples, this virus has been detected on several continents and in several animal species, including cattle, pigs, camel, horses, and goats. We used an indirect in-house ELISA to detect anti-IDV antibodies in 165 serum samples from bulls on 116 farms in the province of La Pampa, Argentina. Eighty-five of 116 (73%) farms had at least 1 positive animal, and 112 of 165 (68%) of the analyzed samples were positive. There were no significant differences in the proportion of seropositive samples depending on the geographic region in which the samples were taken. Our results suggest that IDV infection is endemic in La Pampa; the clinical importance of IDV in Argentina remains to be investigated.
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| 8. |
- Sabouri, Mohammad, et al.
(författare)
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Increasing the resiliency of power systems in presence of GPS spoofing attacks: A data-driven deep-learning algorithm
- 2023
-
Ingår i: IET Generation, Transmission & Distribution. - : Institution of Engineering and Technology (IET). - 1751-8687 .- 1751-8695. ; 17:20, s. 4525-4540
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Tidskriftsartikel (refereegranskat)abstract
- The growing use of wireless technologies in power systems has raised concerns about cybersecurity, particularly regarding GPS spoofing attacks (GSAs). These attacks manipulate GPS data, leading to modifications in the phase angle of phasor measurement units (PMUs). In this paper, a Deep-learning GPS-Spoofing Counteraction (DLGSC) algorithm is proposed, utilizing PMU data for GSA detection and PMU data correction. The algorithm incorporates a recurrent neural network (RNN) and a set of long short-term memory (LSTM) units separately, for signal correction after attack detection. Unlike existing methods that struggle with simultaneous attacks or they are static methods, DLGSC tackles these challenges by leveraging deep learning techniques. By selecting appropriate features for GSA detection, DLGSC achieves accurate results. The algorithm is evaluated on standard IEEE 14-bus and IEEE 39-bus power systems, and its performance is compared to statistical, dynamic, and Deep Learning (DL) methods in the literature. Additionally, an experimental setup is designed to validate the algorithm in a laboratory environment. Results demonstrate the easy-implementable DLGSC algorithm's satisfactory real-time performance in various scenarios, such as load variations and noise, achieving over 98% accuracy. Notably, DLGSC is cable of detecting multiple GSAs on different PMUs.
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| 9. |
- Shakeri Manesh, Sara, 1982-, et al.
(författare)
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Cooperation of MTH1 and MYH proteins in response to oxidative stress induced by chronic γ-radiation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Mutation in the MYH gene has been suggested as a risk factor for colorectal cancer. MYH plays an important role in mutation avoidance induced by 8-oxo-G:A mispairs which may occur during oxidative stress. Oxidative stress has been suggested to be involved in several human disorders. In the present study we have exposed human lymphoblastoid TK6 cells to very low dose rates of γ-radiation to induce chronic oxidative stress. The aim of the study is to investigate the protective role of MYH and MTH1 against mutagenicity and cytotoxicity induced by chronic radiation in the cells with knockdown MYH or knockdown MYH/MTH1. The levels of MYH and/or MTH1 were knockdown permanently in cells using shRNA. Wild type and knockdown cells were exposed to chronic γ-radiation with the dose rates ranged from 1.4 to 30 mGy/h during growth. The cells were also subjected to an acute high dose rate. Growth rate, clonogenic survival and mutant frequency were analyzed in all cell types. A reduced level of cell growth and survival as well as an increased mutant frequency were observed in cells lacking both MYH and MTH1 proteins as compared to cells lacking only MYH and wild type cells. In conclusion, our results suggest that MYH and MTH1 cooperatively respond to oxidative stress induced by chronic radiation in human cells.
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| 10. |
- Shakeri Manesh, Sara, et al.
(författare)
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MTH1, an 8-oxo-2'-deoxyguanosine triphosphatase, and MYH, a DNA glycosylase, cooperate to inhibit mutations induced by chronic exposure to oxidative stress of ionising radiation
- 2017
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 32:3, s. 389-396
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Tidskriftsartikel (refereegranskat)abstract
- Our previous results showed that in addition to the immediate interaction of ionising radiation with DNA (direct and indirect effect), low-dose and chronic low-dose rate of irradiation induce endogenous oxidative stress. During oxidative stress, free radicals react with DNA, nucleoside triphosphates (dNTPs), proteins and lipids, and modify their structures. The MYH and MTH1 genes play important roles in preventing mutations induced by 8-hydroxy-guanine, which is an oxidised product of guanine. In this study, we used short-hairpin RNA to permanently knockdown MYH and MTH1 proteins in human lymphoblastoid TK6 cells. Knockdown and wild-type cells were chronically exposed to low dose rates of gamma-radiation (between 1.4 and 30 mGy/h). The cells were also subjected to acute doses delivered at a high-dose rate. Growth rate, extracellular 8-hydroxy-2'-deoxyguanosine, clonogenic cell survival and mutant frequencies were analysed in all cell types. A reduced level of cell growth and survival as well as increased mutant frequencies were observed in cells lacking both MYH and MTH1 proteins as compared to cells lacking only MYH and wild-type cells. To sum up, our results suggest that low-dose rates elevate oxidative stress. MTH1 together with MYH plays an important role in protection against mutations induced by modified dNTPs during chronic oxidative stress. In addition, we found no dose-rate effect at the level of mutations in the wild-type TK6 and MYH-KD cells. Our data interestingly indicate a dose-rate threshold for mutation induction in MTH1/MYH double knockdown cells.
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| 11. |
- Shakeri Manesh, Sara, et al.
(författare)
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Mutations and chromosomal aberrations in hMTH1-transfected and non-transfected TK6 cells after exposure to low dose rates of gamma radiation
- 2014
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Ingår i: Radiation and Environmental Biophysics. - : Springer Science and Business Media LLC. - 0301-634X .- 1432-2099. ; 53:2, s. 417-425
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to analyse the dose rate effect of gamma radiation at the level of mutations, chromosomal aberrations, and cell growth in TK6 cells with normal as well as reduced levels of hMTH1 protein. TK6 cells were exposed to gamma radiation at dose rates ranging from 1.4 to 30.0 mGy/h (chronic exposure) as well as 24 Gy/h (acute exposure). Cell growth, frequency of thymidine kinase mutants, and of chromosomal aberrations in painted chromosomes 2, 8, and 14 were analysed. A decline in cell growth and an increase in unstable-type chromosomal aberrations with increasing dose rate were observed in both cell lines. A dose rate effect was not seen on mutations or stable-type chromosomal aberrations in any of the two cell lines. Reduction in the hMTH1 protein does not influence the sensitivity of TK6 cells to gamma radiation. This result fits well with data of others generated with the same cell line.
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| 12. |
- Shakeri Manesh, Sara, 1982-
(författare)
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Role of MTH1 and MYH proteins in genotoxic effects of radiation
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Humans are constantly exposed to different types of radiations. It has been suggested that low dose and low dose rate of γ-radiation as well as ultra violet A (UVA) induce oxidative stress in cells that may promote mutations. The mechanisms behind radiation-induced oxidative stress and its relation to genotoxicity and cancer induction are not well understood. In the majority of investigations, the DNA molecule has been studied as the target for mutations, however the results obtained in our group point out that DNA bases in the cytoplasm could also be a significant target. MTH1 and MYH are two of the key proteins of the repair pathway that prevent mutations arising from oxidized DNA bases. In this thesis, we studied the role of MTH1 and MYH in genotoxicity of UVA and γ-radiation. The adaptive response to low dose rates of γ-radiation was also investigated. MTH1 and/or MYH were knockdown in human lymphoblastoid TK6 cells. The clonogenic survival, mutant frequency and chromosomal aberration assays were performed following UVA or γ-radiation exposure. Our results indicated that acute exposure to UVA or γ-radiation affects cell survival and also increases the mutant frequency above the background. The mutant frequency in MTH1 deficient cells was higher than that in wild types after UVA exposure. Following γ-radiation exposure, a higher mutant frequency was observed in the MYH and MTH1 deficient cells, in comparison to either MYH or MTH1 deficient or wild type cells. No dose rate effect of γ-radiation for mutations was observed. An adaptive response to γ-radiation was observed at the mutation level in MCF-10A cells but not at the survival level. In summary, our results suggest that; a) MYH and MTH1 cooperatively protect cells against genotoxic effects of γ-radiation; b) MTH1 protects cells from UVA-induced mutations; c) low dose rates of γ-radiation may induce an adaptive response at the mutation level; d) there is no dose rate effect for γ-radiation at the mutation level.
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| 13. |
- Shakeri Manesh, Sara, et al.
(författare)
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Studies of adaptive response and mutation induction in MCF-10A cells following exposure to chronic or acute ionizing radiation
- 2015
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Ingår i: Mutation research. - : Elsevier BV. - 0027-5107 .- 1873-135X. ; 780, s. 55-59
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Tidskriftsartikel (refereegranskat)abstract
- A phenomenon in which exposure to a low adapting dose of radiation makes cells more resistant to the effects of a subsequent high dose exposure is termed radio-adaptive response. Adaptive response could hypothetically reduce the risk of late adverse effects of chronic or acute radiation exposures in humans. Understanding the underlying mechanisms of such responses is of relevance for radiation protection as well as for the clinical applications of radiation in medicine. However, due to the variability of responses depending on the model system and radiation condition, there is a need to further study under what conditions adaptive response can be induced. In this study, we analyzed if there is a dose rate dependence for the adapting dose, assuming that the adapting dose induces DNA response/repair pathways that are dose rate dependent. MCF-10A cells were exposed to a 50 mGy adapting dose administered acutely (0.40 Gy/min) or chronically (1.4 mGy/h or 4.1 mGy/h) and then irradiated by high acute challenging doses. The endpoints of study include clonogenic cell survival and mutation frequency at X-linked hprt locus. In another series of experiment, cells were exposed to 100 mGy and 1 Gy at different dose rates (acutely and chronically) and then the mutation frequencies were studied. Adaptive response was absent at the level of clonogenic survival. The mutation frequencies were significantly decreased in the cells pre-exposed to 50 mGy at 1.4 mGy/h followed by 1 Gy acute exposure as challenging dose. Importantly, at single dose exposures (1 Gy or 100 mGy), no differences at the level of mutation were found comparing different dose rates.
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| 14. |
- Skiöld, Sara, et al.
(författare)
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Low doses of γ-radiation induce consistent protein expression changes in human leukocytes
- 2011
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Ingår i: International Journal of Low Radiation. - Inderscience Publishers. - 1477-6545 .- 1741-9190. ; 8:5/6, s. 374-387
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Tidskriftsartikel (refereegranskat)abstract
- Twenty percent of cancer patients experience adverse effects after radiotherapy. The therapeutic doses are adjusted to the most sensitive individuals, resulting in a suboptimal dose for many patients. At present there is no screening system available to predict individual radiosensitivity. The main aim of this study is to investigate differences in protein expression pathways induced by low doses of radiation in whole blood obtained from radiosensitive and non–radiosensitive patients. To address this aim, a protocol for exposure condition, dose and analysis of whole blood was developed. The conditions for handling blood samples were optimised. The optimal doses and post irradiation conditions were determined. We found that 1 mGy and 150 mGy significantly changed protein expression in leukocytes collected from the two donors. The result shows that the protocol developed is suitable for characterisation of proteomic profiles associated with low dose exposure of leukocytes.
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| 15. |
- Skiöld, Sara, 1981-
(författare)
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Radiation induced biomarkers of individual sensitivity to radiation therapy
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fifty percent of solid cancers are treated with radiation therapy (RT). The dose used in RT is adjusted to the most sensitive individuals so that not more than 5% of the patients will have severe adverse healthy tissue effects. As a consequence, the majority of the patients will receive a suboptimal dose, as they would have tolerated a higher total dose and received a better tumor control. Thus, if RT could be individualized based on radiation sensitivity (RS), more patients would be cured and the most severe adverse reactions could be avoided. At present the mechanisms behind RS are not known.The long term aim of this thesis was to develop diagnostic tools to assess the individual RS of breast cancer patients and to better understand the mechanisms behind the RS and radiation effects after low dose exposures. The approach was based on the hypothesis that biomarkers of individual RS, in terms of acute adverse skin reactions after breast cancer RT, can be found in whole blood that has been stressed by low doses of ionizing radiation (IR). To reach this goal two different approaches to identify biomarkers of RS have been investigated. A protocol for the analysis of differential protein expression in response to low dose in vitro irradiated whole blood was developed (paper I). This protocol was then used to investigate the proteomic profile of radiation sensitive and normo-sensitive patients, using isotope-coded protein labeled proteomics (ICPL). The results from the ICPL study (paper III) show that the two patient groups have different protein expression profiles both at the basal level and after IR. In paper II the potential biomarker 8-oxo-dG was investigated in serum after IR. The relative levels of IR induced 8-oxo-dG from radiation sensitive patients differ significantly from normo-sensitive patients. This indicates that the sensitive patients differ in their cellular response to IR and that 8-oxo-dG is a potential biomarker for RS.
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| 16. |
- Skiöld, Sara, et al.
(författare)
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Radiation-induced stress response in peripheral blood of breast cancer patients differs between patients with severe acute skin reactions and patients with no side effects to radiotherapy
- 2013
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Ingår i: Mutation research. Genetic toxicology and environmental mutagenesis. - : Elsevier BV. - 1383-5718 .- 1879-3592. ; 756:1-2, s. 152-157
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to compare the radiation-induced oxidative stress response in blood samples from breast cancer patients that developed severe acute skin reactions during the radiotherapy, with the response in blood samples from patients with no side effects. Peripheral blood was collected from 12 breast cancer patients showing no early skin reactions after radiotherapy (RTOG grade 0) and from 14 breast cancer patients who developed acute severe skin reactions (RTOG grade 3-4). Whole blood was irradiated with 0, 5 and 2000 mGy gamma-radiation and serum was isolated. The biomarker for oxidative stress, 8-oxo-dG, was analyzed in the serum by a modified ELISA. While a significant radiation-induced increase of serum 8-oxo-dG levels was observed in serum of the RTOG 0 patients, no increase was seen in serum of the RTOG 3-4 patients. The radiation induced increase in serum 8-oxo-dG levels after 5 mGy did not differ significantly from the increase observed for 2000 mGy in the RTOG 3-4 cohort, thus no dose response relation was observed. A receiver operating characteristic (ROC) value of 0.97 was obtained from the radiation-induced increase in 8-oxo-dG indicating that the assay could be used to identify patients with severe acute adverse reactions to radiotherapy. The results show that samples of whole blood from patients, classified as highly radiosensitive (RTOG 3-4) based on their skin reactions to radiotherapy, differ significantly in their oxidative stress response to ionizing radiation compared to samples of whole blood from patients with no skin reactions (RTOG 0). Extracellular 8-oxo-dG is primarily a biomarker of nucleotide damage and the results indicate that the patients with severe acute skin reactions differ in their cellular response to ionizing radiation at the level of induction of oxidative stress or at the level of repair or both.
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| 17. |
- Skiöld, Sara, et al.
(författare)
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Unique proteomic signature for radiation sensitive patients : a comparative study between normo-sensitive and radiation sensitive breast cancer patients
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Nearly every fourth person will be diagnosed with a cancer during their lifetime1 and approximately 50 percent of all cancers are treated with radiation therapy2. The therapy is adjusted to the most sensitive patients where 5 percent severe adverse acute healthy tissue effects are accepted. Twenty percent of all patients experience milder adverse effects from radiation therapy and there are indications that the patients with no signs of adverse effects have a higher probability of local reoccurrence of cancer within 5 years, indicating that they would have benefited from a higher dose of ionizing radiation (IR)3,4. If the individual radiation sensitivity could be determined before the start of radiation therapy, the dose could be personalized and the adverse effects reduced in sensitive patients. In addition, the probability to eradicate all cancer cells in normo-sensitive patients would increase. There is no generally accepted method available to diagnose radiation sensitivity before the start of the therapy and several studies on the mechanisms indicate that multifactorial mechanisms are involved.The long-term aim of this study is to identify biomarkers of radiation sensitivity to enable an individualized treatment. We have previously shown that radiation sensitive and normo-sensitive patients differ in their radiation induced 8-oxo-dG levels (a marker of oxidative stress). We hypothesized that this difference is due to different cellular capability to handle oxidative stress, were radiation sensitive patients doesn’t induce an oxidative stress response or are incapable of repairing oxidative stress related damages.To investigate the mechanisms behind radiation sensitivity 8 radiation sensitive (RTOG4) and 9 normo-sensitive (RTOG0) patients from a cohort of 2914 breast cancer patients with known normal tissue reactions after radiation therapy were selected. Whole blood was sampled and irradiated in vitro with 0, 1, or 150 mGy followed by 3 hour post-irradiation incubation at 37°C. The samples in the two groups were pooled to reduce individual variability not associated with radiation sensitivity responses. The protein expression profile of leukocytes was investigated with isotope-coded protein label (ICPL). First the differences in proteomic profiles of leukocytes isolated from normo-sensitive patients (RTOG 0) and extremely sensitive patients (RTOG 4) were investigated. Secondly, we analyzed leukocytes isolated from in vitro irradiated whole blood compared to non-irradiated whole blood within both groups. These two studies were done independent of each other using two different protein labeling methods.Here we show unique proteomic signatures separating the two groups both at the basal level (non-irradiated samples) and after doses of 1 and 150 mGy. Pathway analyses of both proteomic approaches suggest that oxidative stress response, coagulation properties and acute phase response are hallmarks of radiation sensitivity. Additionally the oxidative stress response can be linked mechanistically to our previous 8-oxo-dG study. Finally this investigation provides unique protein expression profiles which might be useful in future to predict radiation sensitivity.
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| 18. |
- Skiöld, Sara, et al.
(författare)
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Unique proteomic signature for radiation sensitive patients; a comparative study between normo-sensitive and radiation sensitive breast cancer patients
- 2015
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Ingår i: Mutation research. - : Elsevier BV. - 0027-5107 .- 1873-135X. ; 776, s. 128-135
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Tidskriftsartikel (refereegranskat)abstract
- Radiation therapy is a cornerstone of modern cancer treatment. Understanding the mechanisms behind normal tissue sensitivity is essential in order to minimize adverse side effects and yet to prevent local cancer reoccurrence. The aim of this study was to identify biomarkers of radiation sensitivity to enable personalized cancer treatment. To investigate the mechanisms behind radiation sensitivity a pilot study was made where eight radiation-sensitive and nine normo-sensitive patients were selected from a cohort of 2914 breast cancer patients, based on acute tissue reactions after radiation therapy. Whole blood was sampled and irradiated in vitro with 0, 1, or 150 mGy followed by 3 h incubation at 37 degrees C. The leukocytes of the two groups were isolated, pooled and protein expression profiles were investigated using isotope-coded protein labeling method (ICPL). First, leukocytes from the in vitro irradiated whole blood from normo-sensitive and extremely sensitive patients were compared to the non-irradiated controls. To validate this first study a second ICPL analysis comparing only the non-irradiated samples was conducted. Both approaches showed unique proteomic signatures separating the two groups at the basal level and after doses of 1 and 150 mGy. Pathway analyses of both proteomic approaches suggest that oxidative stress response, coagulation properties and acute phase response are hallmarks of radiation sensitivity supporting our previous study on oxidative stress response. This investigation provides unique characteristics of radiation sensitivity essential for individualized radiation therapy.
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| 19. |
- Sollazzo, Alice, et al.
(författare)
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Interaction of low and high LET radiation in TK6 cells-mechanistic aspects and significance for radiation protection
- 2016
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Ingår i: Journal of Radiological Protection. - : IOP Publishing. - 0952-4746 .- 1361-6498. ; 36:4, s. 721-735
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Tidskriftsartikel (refereegranskat)abstract
- Most environmental, occupational and medical exposures to ionising radiation are associated with a simultaneous action of different radiation types. An open question remains whether radiations of different qualities interact with each other to yield effects stronger than expected based on the assumption of additivity. It is possible that DNA damage induced by high linear energy transfer (LET) radiation will lead to an opening of the chromatin structure making the DNA more susceptible to attack by reactive oxygen species (ROS) generated by the low LET radiation. In such case, the effect of mixed beams should be strongly expressed in cells that are sensitive to ROS. The present investigation was carried out to test if cells with an impaired capacity to handle oxidative stress are particularly sensitive to the effect of mixed beams of alpha particles and x-rays. Clonogenic cell survival curves and mutant frequencies were analysed in TK6 wild type (wt) cells and in TK6 cells with a knocked down hMYH glycosylase. The results showed a synergistic effect of mixed beams on clonogenic cell survival of TK6(wt) but not TK6(MYH)-cells. The frequencies of mutants showed a high degree of interexperimental variability without any indications for synergistic effects of mixed beams. TK6(MYH)-cells were generally more tolerant to radiation exposure with respect to clonogenic cell survival but showed a strong increase in mutant frequency. The results demonstrate that exposure of wt cells to a mixed beam of alpha particles and x-rays leads to a detrimental effect which is stronger than expected based on the assumption of additivity. The role of oxidative stress in the reaction of cells to mixed beams remains unclear.
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| 20. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
-
Tidskriftsartikel (refereegranskat)
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