Comparison of RBE values of high- LET α-particles for the induction of DNA-DSBs, chromosome aberrations and cell reproductive death

<p>Abstract</p> <p>Background</p> <p>Various types of radiation effects in mammalian cells have been studied with the aim to predict the radiosensitivity of tumours and normal tissues, e.g. DNA double strand breaks (DSB), chromosome aberrations and cell reproductive inactivation. However, variation in correlations with clinical results has reduced general application. An additional type of information is required for the increasing application of high-LET radiation in cancer therapy: the Relative Biological Effectiveness (RBE) for effects in tumours and normal tissues. Relevant information on RBE values might be derived from studies on cells in culture.</p> <p>Methods</p> <p>To evaluate relationships between DNA-DSB, chromosome aberrations and the clinically most relevant effect of cell reproductive death, for ionizing radiations of different LET, dose-effect relationships were determined for the induction of these effects in cultured SW-1573 cells irradiated with gamma-rays from a Cs-137 source or with α-particles from an Am-241 source. RBE values were derived for these effects. Ionizing radiation induced foci (IRIF) of DNA repair related proteins, indicative of DSB, were assessed by counting gamma-H2AX foci. Chromosome aberration frequencies were determined by scoring fragments and translocations using premature chromosome condensation. Cell survival was measured by colony formation assay. Analysis of dose-effect relations was based on the linear-quadratic model.</p> <p>Results</p> <p>Our results show that, although both investigated radiation types induce similar numbers of IRIF per absorbed dose, only a small fraction of the DSB induced by the low-LET gamma-rays result in chromosome rearrangements and cell reproductive death, while this fraction is considerably enhanced for the high-LET alpha-radiation. Calculated RBE values derived for the linear components of dose-effect relations for gamma-H2AX foci, cell reproductive death, chromosome fragments and colour junctions are 1.0 ± 0.3, 14.7 ± 5.1, 15.3 ± 5.9 and 13.3 ± 6.0 respectively.</p> <p>Conclusions</p> <p>These results indicate that RBE values for IRIF (DNA-DSB) induction provide little valid information on other biologically-relevant end points in cells exposed to high-LET radiations. Furthermore, the RBE values for the induction of the two types of chromosome aberrations are similar to those established for cell reproductive death. This suggests that assays of these aberrations might yield relevant information on the biological effectiveness in high-LET radiotherapy.</p

Studies of the dose-effect relation

Dose-effect relations and, specifically, cell survival curves are surveyed with emphasis on the interplay of the random factors — biological variability, stochastic reaction of the cell, and the statistics of energy deposition —that co-determine their shape. The global parameters mean inactivation dose, , and coefficient of variance, V, represent this interplay better than conventional parameters. Mechanisms such as lesion interaction, misrepair, repair overload, or repair depletion have been invoked to explain sigmoid dose dependencies, but these notions are partly synonymous and are largely undistinguishable on the basis of observed dose dependencies. All dose dependencies reflect, to varying degree, the microdosimetric fluctuations of energy deposition, and these have certain implications, e.g. the linearity of the dose dependence at small doses, that apply regardless of unresolved molecular mechanisms of cellular radiation action

Science teachers' pedagogical content knowledge development during enactment of socioscientific curriculum materials

The purpose of this study is to provide insight into short‐term professionalization of teachers regarding teaching socioscientific issues (SSI). The study aimed to capture the development of science teachers' pedagogical content knowledge (PCK) for SSI teaching by enacting specially designed SSI curriculum materials. The study also explores indicators of stronger and weaker development of PCK for SSI teaching. Thirty teachers from four countries (Cyprus, Israel, Norway, and Spain) used one module (30-60 min lesson) of SSI materials. The data were collected through: (a) lesson preparation form (PCK‐before), (b) lesson reflection form (PCK‐after), (c) lesson observation table (PCK‐in‐action). The data analysis was based on the PCK model of Magnusson, Krajcik, and Borko (1999). Strong development of PCK for SSI teaching includes 'Strong interconnections between the PCK components,' 'Understanding of students'difficulties in SSI learning,' 'Suggesting appropriate instructional strategies,' and 'Focusing equally on science content and SSI skills.' Our findings point to the importance of these aspects of PCK development for SSI teaching. We argue that when professional development programs and curriculum materials focus on developing these aspects, they will contribute to strong PCK development for SSI teaching. The findings regarding the development in the components of PCK for SSI provide compelling evidence that science teachers can develop aspects of their PCK for SSI with the use of a single module. Most of the teachers developed their knowledge about students' understanding of science and instructional strategies. The recognition of student difficulties made the teacher consider specific teaching strategies which are in line with the learning objectives. There is an evident link between the development of PCK in instructional strategies and students' understanding of science for SSI teaching

RBE-LET relationships for different types of lethal radiation damage in mammalian cells: comparison with DNA dsb and an interpretation of differences in radiosensitivity

Relative biological effectiveness (RBE), as a function of linear energy transfer (LET), is evaluated for different types of damage contributing to mammalian cell reproductive death. Survival curves are analysed assuming a linear-quadratic dose dependence of lethal lesions. The linear term represents lethal damage due to single particle tracks, the quadratic term represents lethality due to interaction of lesions from independent tracks. RBE-LET relationships of single-track lethal damage, sublethal damage, potentially lethal damage and DNA double-strand breaks (dsb) are compared. Single-track lethal damage is shown to be composed of two components: damage that remains unrepaired in an interval between irradiation and assay, characterized by a very strong dependence on LET, with RBEs up to 20, and potentially lethal damage, which is weakly dependent on LET with RBEs < 3. Potentially lethal damage and sublethal damage depend similarly on LET as DNA dsb. The identification of these different components of damage leads to an interpretation of differences in radiosensitivity and in RBEs among various types of cell

Analysis of tumour responses by excision and in vitro assay of cellular clonogenic capacity.

A review is presented of the advantages and problems associated with the use of in vitro assays of cellular clonogenic capacity when used to analyse responses of tumours treated in vivo, either with radiation or chemotherapeutic agents. Three questions are considered: (1) Does the cell suspension obtained by the dispersion technique from various types of solid tumours provide an adequately random sample of the cells initially present in the tumour? (2) Are the properties of cells in suspensions obtained from solid tumours assayed in optimal conditions in vitro? (3) Are the properties expressed and analysed by in vitro techniques equivalent to the properties that the same cells would have expressed if they had been left in vivo, either in untreated or in treated tumours? It is concluded that the in vitro assay provides a valuable tool to analyse tumour responses but that the data obtained must be complemented by information on cell kinetics and other factors to obtain a complete description of tumour responses and to correlate them with tumour curability and growth delay