A novel retinoblastoma therapy from genomic and epigenetic analyses.

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss

External beam radiation therapy and enadenotucirev: inhibition of the DDR and mechanisms of radiation-mediated virus increase

Ionising radiation causes cell death through the induction of DNA damage, particularly double-stranded DNA (dsDNA) breaks. Evidence suggests that adenoviruses inhibit proteins involved in the DNA damage response (DDR) to prevent recognition of double-stranded viral DNA genomes as cellular dsDNA breaks. We hypothesise that combining adenovirus treatment with radiotherapy has the potential for enhancing tumour-specific cytotoxicity through inhibition of the DDR and augmentation of virus production. We show that EnAd, an Ad3/Ad11p chimeric oncolytic adenovirus currently being trialled in colorectal and other cancers, targets the DDR pathway at a number of junctures. Infection is associated with a decrease in irradiation-induced 53BP1 and Rad51 foci formation, and in total DNA ligase IV levels. We also demonstrate a radiation-associated increase in EnAd production in vitro and in a pilot in vivo experiment. Given the current limitations of in vitro techniques in assessing for synergy between these treatments, we adapted the plaque assay to allow monitoring of viral plaque size and growth and utilised the xCELLigence cell adhesion assay to measure cytotoxicity. Our study provides further evidence on the interaction between adenovirus and radiation in vitro and in vivo and suggests these have at least an additive, and possibly a synergistic, impact on cytotoxicity

Renouncing the Single Image: Photography and the Realism of Abstraction

This essay addresses the issue of the relationship between abstraction and realism that it argues is at stake in the rejection of any primacy accorded to the single image, in favour of a sequencing of photographs according to certain, often novelistic and epic ideas of narrative form. Setting out from the opening text of Allan Sekula’s Fish Story, the article explores the competing tendencies towards what Georg Lukács termed ‘narration’ and ‘description’ as these are traced throughout Sekula's project (in part through a comparison with the contrasting works of Andreas Gursky). The essay concludes by suggesting the ways in which it is the irreducible actuality of abstraction within the concrete everydayness of capitalism's social world that means that all photographic ‘realism’ is intrinsically ‘haunted’ by a certain spectre of that ‘self-moving substance in the ‘shape of money’, as Marx calls it, or of the abstract form of capital itself

A history of high-power laser research and development in the United Kingdom

The first demonstration of laser action in ruby was made in 1960 by T. H. Maiman of Hughes Research Laboratories, USA. Many laboratories worldwide began the search for lasers using different materials, operating at different wavelengths. In the UK, academia, industry and the central laboratories took up the challenge from the earliest days to develop these systems for a broad range of applications. This historical review looks at the contribution the UK has made to the advancement of the technology, the development of systems and components and their exploitation over the last 60 years

Relationship between alcohol-attributable disease and socioeconomic status, and the role of alcohol consumption in this relationship: a systematic review and meta-analysis

Background: Studies show that alcohol consumption appears to have a disproportionate impact on people of low socioeconomic status. Further exploration of the relationship between alcohol consumption, socioeconomic status and the development of chronic alcohol-attributable diseases is therefore important to inform the development of effective public health programmes. Methods: We used systematic review methodology to identify published studies of the association between socioeconomic factors and mortality and morbidity for alcohol-attributable conditions. To attempt to quantify differences in the impact of alcohol consumption for each condition, stratified by SES, we (i) investigated the relationship between SES and risk of mortality or morbidity for each alcohol-attributable condition, and (ii) where, feasible explored alcohol consumption as a mediating or interacting variable in this relationship. Results: We identified differing relationships between a range of alcohol-attributable conditions and socioeconomic indicators. Pooled analyses showed that low, relative to high socioeconomic status, was associated with an increased risk of head and neck cancer and stroke, and in individual studies, with hypertension and liver disease. Conversely, risk of female breast cancer tended to be associated with higher socioeconomic status. These findings were attenuated but held when adjusted for a number of known risk factors and other potential confounding factors. A key finding was the lack of studies that have explored the interaction between alcohol-attributable disease, socioeconomic status and alcohol use. Conclusions: Despite some limitations to our review, we have described relationships between socioeconomic status and a range of alcohol-attributable conditions, and explored the mediating and interacting effects of alcohol consumption where feasible. However, further research is needed to better characterise the relationship between socioeconomic status alcohol consumption and alcohol-attributable disease risk so as to gain a greater understanding of the mechanisms and pathways that influence the differential risk in harm between people of low and high socioeconomic status

From Sacred to Scientific: Epic Religion, Spectacular Science, and Charlton Heston’s Science Fiction Cinema

This paper analyses how long-1960s cinema responded to and framed public discourses surrounding religion and science. This approach allows for a discussion that extends beyond a critical study of the scholarly debates that surround the place of religion in science during a transitional period. Charlton Heston was an epic actor who went from literally playing God in The Ten Commandments (1956) to playing “god” as a messianic scientist in The Omega Man (1971). Best known for playing Moses, Heston became an unlikely science-based cinema star during the early 1970s. He was re-imagined as a scientist, but the religiosity of his established persona was inescapable. Heston and the science-based films he starred in capitalized upon the utopian promises of real science, and also the fears of the vocal activist counterculture. Planet of the Apes (1968), Omega Man (1971), Soylent Green (1973), and other science-based films made between 1968-1977 were bleak countercultural warnings about excessive consumerism, uncontrolled science, nuclear armament, irreversible environmental damage, and eventual human extinction. In this paper I argue that Heston’s transition from biblical epic star to science-fiction anti-hero represents the way in which the role and interpretation of science changed in post-classical cinema. Despite the shift from religious epic to science-based spectacle, religion remained a faithful component of Hollywood output indicating the ongoing connection between science and religion in US culture. I will consider the transition from sacred to science-based narratives and how religion was utilised across the production process of films that commented upon scientific advances

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead