62. The Radiotherapy of IMRT

Intensity Modulated Radiotherapy (IMRT) is going to revolutionise treatment planning and delivery of radiotherapy in the next few years. Although there are still technological constraints, IMRT allows delivery of a specified dose-distribution that is superior to what is realistically achievable with 3D conformal radiotherapy using standard techniques. This forces a re-think of the whole process of delivering radiotherapy. With our current technology, the physics has overtaken the biology and it appears that to realise the full potential of IMRT, a major research effort on the biological aspects of radiotherapy is needed. This goes far beyond traditional cellular radiobiology. New powerful assays in molecular biology and bioimaging will be key elements in the biological optimisation of radiotherapy. In this lecture, I will try to identify some of the research areas that will need to be further developed in order to get the full therapeutic benefit from IMRT

Stable isotope food-web analysis and mercury biomagnification in polar bears ( Ursus maritimus )

Mercury (Hg) biomagnification occurs in many ecosystems, resulting in a greater potential for toxicological effects in higher-level trophic feeders. However, Hg transport pathways through different food-web channels are not well known, particularly in high-latitude systems affected by the atmospheric Hg deposition associated with snow and ice. Here, we report on stable carbon and nitrogen isotope ratios, and Hg concentrations, determined for 26, late 19th and early 20th century, polar bear ( Ursus maritimus ) hair specimens, collected from catalogued museum collections. These data elucidate relationships between the high-latitude marine food-web structure and Hg concentrations in polar bears. The carbon isotope compositions of polar bear hairs suggest that polar bears derive nutrition from coupled food-web channels, based in pelagic and sympagic primary producers, whereas the nitrogen isotope compositions indicate that polar bears occupy > fourth-level trophic positions. Our results show a positive correlation between polar bear hair Hg concentrations and δ 15 N. Interpretation of the stable isotope data in combination with Hg concentrations tentatively suggests that polar bears participating in predominantly pelagic food webs exhibit higher mercury concentrations than polar bears participating in predominantly sympagic food webs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73930/1/j.1751-8369.2009.00114.x.pd

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

62. The Radiotherapy of IMRT

Intensity Modulated Radiotherapy (IMRT) is going to revolutionise treatment planning and delivery of radiotherapy in the next few years. Although there are still technological constraints, IMRT allows delivery of a specified dose-distribution that is superior to what is realistically achievable with 3D conformal radiotherapy using standard techniques. This forces a re-think of the whole process of delivering radiotherapy. With our current technology, the physics has overtaken the biology and it appears that to realise the full potential of IMRT, a major research effort on the biological aspects of radiotherapy is needed. This goes far beyond traditional cellular radiobiology. New powerful assays in molecular biology and bioimaging will be key elements in the biological optimisation of radiotherapy. In this lecture, I will try to identify some of the research areas that will need to be further developed in order to get the full therapeutic benefit from IMRT