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      Biological effectiveness of very high gamma dose rate and its implication for radiological protection

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          Abstract

          Many experimental studies are carried out to compare biological effectiveness of high dose rate (HDR) with that of low dose rate (LDR). The rational for this is the uncertainty regarding the value of the dose rate effectiveness factor (DREF) used in radiological protection. While a LDR is defined as 0.1 mGy/min or lower, anything above that is seen as HDR. In cell and animal experiments, a dose rate around 1 Gy/min is usually used as representative for HDR. However, atomic bomb survivors, the reference cohort for radiological protection, were exposed to tens of Gy/min. The important question is whether gamma radiation delivered at very high dose rate (VHDR—several Gy/min) is more effective in inducing DNA damage than that delivered at HDR. The aim of this investigation was to compare the biological effectiveness of gamma radiation delivered at VHDR (8.25 Gy/min) with that of HDR (0.38 Gy/min or 0.79 Gy/min). Experiments were carried out with human peripheral mononuclear cells (PBMC) and the human osteosarcoma cell line U2OS. Endpoints related to DNA damage response were analysed. The results show that in PBMC, VHDR is more effective than HDR in inducing gene expression and micronuclei. In U2OS cells, the repair of 53BP1 foci was delayed after VHDR indicating a higher level of damage complexity, but no VHDR effect was observed at the level of micronuclei and clonogenic cell survival. We suggest that the DREF value may be underestimated when the biological effectiveness of HDR and LDR is compared.

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          Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.

          Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.
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            The in vitro micronucleus technique.

            M Fenech (2000)
            The study of DNA damage at the chromosome level is an essential part of genetic toxicology because chromosomal mutation is an important event in carcinogenesis. The micronucleus assays have emerged as one of the preferred methods for assessing chromosome damage because they enable both chromosome loss and chromosome breakage to be measured reliably. Because micronuclei can only be expressed in cells that complete nuclear division a special method was developed that identifies such cells by their binucleate appearance when blocked from performing cytokinesis by cytochalasin-B (Cyt-B), a microfilament-assembly inhibitor. The cytokinesis-block micronucleus (CBMN) assay allows better precision because the data obtained are not confounded by altered cell division kinetics caused by cytotoxicity of agents tested or sub-optimal cell culture conditions. The method is now applied to various cell types for population monitoring of genetic damage, screening of chemicals for genotoxic potential and for specific purposes such as the prediction of the radiosensitivity of tumours and the inter-individual variation in radiosensitivity. In its current basic form the CBMN assay can provide, using simple morphological criteria, the following measures of genotoxicity and cytotoxicity: chromosome breakage, chromosome loss, chromosome rearrangement (nucleoplasmic bridges), cell division inhibition, necrosis and apoptosis. The cytosine-arabinoside modification of the CBMN assay allows for measurement of excision repairable lesions. The use of molecular probes enables chromosome loss to be distinguished from chromosome breakage and importantly non-disjunction in non-micronucleated binucleated cells can be efficiently measured. The in vitro CBMN technique, therefore, provides multiple and complementary measures of genotoxicity and cytotoxicity which can be achieved with relative ease within one system. The basic principles and methods (including detailed scoring criteria for all the genotoxicity and cytotoxicity end-points) of the CBMN assay are described and areas for future development identified.
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              Confidence intervals rather than P values: estimation rather than hypothesis testing.

              Overemphasis on hypothesis testing--and the use of P values to dichotomise significant or non-significant results--has detracted from more useful approaches to interpreting study results, such as estimation and confidence intervals. In medical studies investigators are usually interested in determining the size of difference of a measured outcome between groups, rather than a simple indication of whether or not it is statistically significant. Confidence intervals present a range of values, on the basis of the sample data, in which the population value for such a difference may lie. Some methods of calculating confidence intervals for means and differences between means are given, with similar information for proportions. The paper also gives suggestions for graphical display. Confidence intervals, if appropriate to the type of study, should be used for major findings in both the main text of a paper and its abstract.
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                Author and article information

                Contributors
                andrzej.wojcik@su.se
                Journal
                Radiat Environ Biophys
                Radiat Environ Biophys
                Radiation and Environmental Biophysics
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0301-634X
                1432-2099
                1 June 2020
                1 June 2020
                2020
                : 59
                : 3
                : 451-460
                Affiliations
                [1 ]GRID grid.10548.38, ISNI 0000 0004 1936 9377, Department of Molecular Biosciences, Centre for Radiation Protection Research, The Wenner-Gren Institute, , Stockholm University, ; Svante Arrhenius väg 20C, 106 91 Stockholm, Sweden
                [2 ]GRID grid.411821.f, ISNI 0000 0001 2292 9126, Department of Radiobiology and Immunology, Institute of Biology, , Jan Kochanowski University, ; Kielce, Poland
                Author information
                http://orcid.org/0000-0002-3951-774X
                Article
                852
                10.1007/s00411-020-00852-z
                7368856
                32488310
                09b5f95b-3223-43ff-b51f-7890534a925e
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 December 2019
                : 25 May 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100011759, Strålsäkerhetsmyndigheten;
                Award ID: 2016-2423
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004200, Stiftelsen Olle Engkvist Byggmästare;
                Award ID: 184-510
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2020

                Biophysics
                dose rate,gene expression,micronuclei,dna damage response
                Biophysics
                dose rate, gene expression, micronuclei, dna damage response

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