Guidance on the use of MRI for treatment planning in radiotherapy clinical trials

The aim of this article is to propose meaningful guidance covering the technical and safety issues involved when designing or conducting radiotherapy clinical trials that use MRI for treatment planning. The complexity of imaging requirements will depend on the trial aims, design and MRI methods used.The use of MRI within the RT pathway is becoming more prevalent and clinically appropriate as access to MRI increases, treatment planning systems become more versatile and potential indications for MRI-planning in RT are documented. Novel MRI-planning opportunities are often initiated and validated within clinical trials.The guidance in this document is intended to assist researchers designing RT clinical trials involving MRI, so that they may provide sufficient information about the appropriate methods to be used for image acquisition, post-processing and quality assurance such that participating sites complete MRI to consistent standards. It has been produced in collaboration with the National Radiotherapy Trials Quality Assurance Group (RTTQA).As the use of MRI in RT is developed, it is highly recommended for researchers writing clinical trial protocols to include imaging guidance as part of their clinical trial documentation covering the trial-specific requirements for MRI procedures. Many of the considerations and recommendations in this guidance may well apply to MR-guided treatment machines, where clinical trials will be crucial. Similarly, many of these recommendations will apply to the general use of MRI in RT, outside of clinical trials.This document contains a large number of recommendations, not all of which will be relevant to any particular trial. Designers of RT clinical trials must therefore take this into account. They must also use their own judgement as to the appropriate compromise between accessibility of the trial and its technical rigour

Gender differences in the clinical management of patients with angina pectoris: a cross-sectional survey in primary care

Non peer reviewedPublisher PD

Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies

Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA(A) receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNAIG, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.Peer reviewe

Resource-dependent attenuation of species interactions during bacterial succession

Bacterial communities are vital for many economically and ecologically important processes. The role of bacterial community composition in determining ecosystem functioning depends critically on interactions among bacterial taxa. Several studies have shown that, despite a predominance of negative interactions in communities, bacteria are able to display positive interactions given the appropriate evolutionary or ecological conditions. We were interested in how interspecific interactions develop over time in a naturalistic setting of low resource supply rates. We assembled aquatic bacterial communities in microcosms and assayed the productivity (respiration and growth) and substrate degradation while tracking community composition. The results demonstrated that while bacterial communities displayed strongly negative interactions during the early phase of colonisation and acclimatisation to novel biotic and abiotic factors, this antagonism declined over time towards a more neutral state. This was associated with a shift from use of labile substrates in early succession to use of recalcitrant substrates later in succession, confirming a crucial role of resource dynamics in linking interspecific interactions with ecosystem functioning

Varying constants, Gravitation and Cosmology

Fundamental constants are a cornerstone of our physical laws. Any constant varying in space and/or time would reflect the existence of an almost massless field that couples to matter. This will induce a violation of the universality of free fall. It is thus of utmost importance for our understanding of gravity and of the domain of validity of general relativity to test for their constancy. We thus detail the relations between the constants, the tests of the local position invariance and of the universality of free fall. We then review the main experimental and observational constraints that have been obtained from atomic clocks, the Oklo phenomenon, Solar system observations, meteorites dating, quasar absorption spectra, stellar physics, pulsar timing, the cosmic microwave background and big bang nucleosynthesis. At each step we describe the basics of each system, its dependence with respect to the constants, the known systematic effects and the most recent constraints that have been obtained. We then describe the main theoretical frameworks in which the low-energy constants may actually be varying and we focus on the unification mechanisms and the relations between the variation of different constants. To finish, we discuss the more speculative possibility of understanding their numerical values and the apparent fine-tuning that they confront us with.Comment: 145 pages, 10 figures, Review for Living Reviews in Relativit