Alpha-particle-induced complex chromosome exchanges transmitted through extra-thymic lymphopoiesis in vitro show evidence of emerging genomic instability

Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naïve T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure.This work was supported by the Department of Health, UK. Contract RRX95 (RMA NSDTG)

Motivating medical students to do research: a mixed methods study using Self-Determination Theory

BACKGROUND: It is widely accepted that all medical graduates should understand the uses and methods of rigorous research, with a need to promote research to graduates who will pursue an academic career. This study aimed to explore, identify and explain what motivates and demotivates medical students to do research. METHODS: A convergent parallel mixed methods study was conducted. Cross-sectional quantitative survey data (n = 579) and qualitative semi-structured interview findings (n = 23) data were separately collected and analysed. Informed by Self-Determination Theory (SDT), quantitative and qualitative findings were integrated to develop a model for the factors associated with medical students’ expressed motivation to do research, and related to clinical and research learning activities at different stages in an undergraduate medical program. RESULTS: Only 7.5 % of students had research experience prior to entering the program. Survey results revealed that students who had experienced exposure to the uncertainties of clinical practice through clerkships (Pre-Clinical (48 %) vs Clinical Years (64 %), p < 0.001), and a sense of achievement through supported compulsory research activities which were conducted as a team (Pre- Community Research (51 %) vs Post-Community Research (66 %), p < 0.001), were more likely to view future research activities positively. When integrated with qualitative findings using the three SDT domains of autonomy, competence and relatedness, eight major themes were identified: Self & Time, Career, Bureaucracy, Financial, Confidence, Clinical Relevance, Research as a Social Activity, and Personal Relevance. The findings suggest that motivation to do research is associated with increasing internalization of intrinsic motivators; in particular those associated with competence (Confidence) and relatedness (Clinical Relevance, Research as a Social Activity). CONCLUSIONS: SDT is useful for understanding the motivation of individuals and how curriculum can be designed to optimise motivation. Study findings suggest that well supported compulsory research activities that incorporate group learning and elements of choice may promote motivation to do research, and potentially, careers in research, even in a research naive student body. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12909-015-0379-1) contains supplementary material, which is available to authorized users

Sister chromatid exchanges occur in G2-irradiated cells

DNA double-strand breaks (DSBs) are arguably the most important lesions induced by ionizing radiation (IR) since unrepaired or misrepaired DSBs can lead to chromosomal aberrations and cell death. The two major pathways to repair IR-induced DSBs are non-homologous end-joining (NHEJ) and homologous recombination (HR). Perhaps surprisingly, NHEJ represents the predominant pathway in the G1 and G2 phases of the cell cycle, but HR also contributes and repairs a subset of IR-induced DSBs in G2. Following S-phase-dependent genotoxins, HR events give rise to sister chromatid exchanges (SCEs), which can be detected cytogenetically in mitosis. Here, we describe that HR occurring in G2-irradiated cells also generates SCEs in ∼50% of HR events. Since HR of IR-induced DSBs in G2 is a slow process, SCE formation in G2-irradiated cells requires several hours. During this time, irradiated S-phase cells can also reach mitosis, which has contributed to the widely held belief that SCEs form only during S phase. We describe procedures to measure SCEs exclusively in G2-irradiated cells and provide evidence that following IR cells do not need to progress through S phase in order to form SCEs