Specialist Seminar – Hugh Tomlinson QC, Chair of ‘Hacked Off’: Leveson, Politicians and Effective Regulation of the Press: is it “bonkers” and will it happen?

In the wake of the hacking scandal and the Leveson Inquiry, the question of press regulation has generated a dynamic and divisive debate. Opponents of regulation emphasize that press freedom is vital to the operation of a democracy and should not be constrained by political forces. Yet those in favour of regulation point to the harms and abuses caused by an increasingly powerful press industry left unchecked

Anti-inflammatory mechanisms of the neutrophilreleased antimicrobial peptide α-defensins

Tissue homeostasis is necessary for optimal organ functioning. The onset of tissue trauma compromises the homeostatic environment resulting in widespread cell death with the likelihood of exposure to invading micro-organisms. Early stage elimination of microbes and immunomodulation is co-ordinated by leukocytes of the innate immune system of which neutrophils and macrophages play a pivotal role. Leukocyte-released pro-inflammatory factors are vital in the containment of infection but bring with it a degree of collateral tissue destruction. Thus cascading stages during inflammation must be tightly regulated to bring about timely tissue regeneration and regained homeostasis. However, chronic inflammatory diseases e.g. rheumatoid arthritis highlights the existence of defective regulation at numerous stages during this transition, often leading to debilitating disease progression. Recently published findings by our research group identified the anti-inflammatory properties of α-defensin - an anti-microbial peptide released from dying human neutrophils - on stimulated macrophages. Thus the main objective of my research was to gain an understanding into the molecular actions of α-defensins which inhibit the macrophage inflammatory potential. Strong evidence supported the propensity of α-defensins to inhibit both intracellular and secreted protein synthesis, as assessed by de novo 35S-radiolabeled Methionine incorporation. Inhibition was not attributed to endoplasmic reticulum stress events, a common diagnosis in the regulation of global translation. Supporting evidence using cell-free systems identified a fundamental block in translation with the inclusion of α-defensin. Biochemical studies linked the ability of α-defensin to bind non-specifically to oligonucleotide sequences. This binding potential was also demonstrated on ribosomal RNA (rRNA), impeding its migration through electrophoretic gels. Immunocytochemical assays proposed an emerging suggestion of α-defensins in macrophages concentrated in close proximity to ribosomes around the perinuclear region. Evidence of suggested defensin/ribosome accumulation after 24hrs after treatment were attempted but to date remained unconfirmed. Attempts to determine the fate of these proposed accumulations were inconclusive, assessed by autophagy assays and ribosome semiquantitation. This thesis describes for the first time an enhanced understanding into the intracellular inhibitory mechanisms of α-defensins on macrophages and possibly other cell types. Understanding the molecular impact of α-defensins provide key insights into this novel inflammatory regulator, with the potential to be utilized in future immunotherapies

Genome of the house fly, <i>Musca domestica</i> L., a global vector of diseases with adaptations to a septic environment

Background: Adult house flies, Musca domestica L., are mechanical vectors of more than 100 devastating diseases that have severe consequences for human and animal health. House fly larvae play a vital role as decomposers of animal wastes, and thus live in intimate association with many animal pathogens. Results: We have sequenced and analyzed the genome of the house fly using DNA from female flies. The sequenced genome is 691 Mb. Compared with Drosophila melanogaster, the genome contains a rich resource of shared and novel protein coding genes, a significantly higher amount of repetitive elements, and substantial increases in copy number and diversity of both the recognition and effector components of the immune system, consistent with life in a pathogen-rich environment. There are 146 P450 genes, plus 11 pseudogenes, in M. domestica, representing a significant increase relative to D. melanogaster and suggesting the presence of enhanced detoxification in house flies. Relative to D. melanogaster, M. domestica has also evolved an expanded repertoire of chemoreceptors and odorant binding proteins, many associated with gustation. Conclusions: This represents the first genome sequence of an insect that lives in intimate association with abundant animal pathogens. The house fly genome provides a rich resource for enabling work on innovative methods of insect control, for understanding the mechanisms of insecticide resistance, genetic adaptation to high pathogen loads, and for exploring the basic biology of this important pest. The genome of this species will also serve as a close out-group to Drosophila in comparative genomic studies

Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

Esophageal adenocarcinoma (EA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation, operating downstream of disease-associated exposures, is considered an important contributor to EA pathogenesis. Several risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), including symptomatic reflux, obesity, and smoking. The role of inherited genetic susceptibility remains an area of active investigation. To explore whether germline variation related to inflammatory processes influences susceptibility to BE/EA, we used data from a genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls. Our analysis included 7,863 single nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signaling, oxidative stress, human leukocyte antigen, and NFκB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. We identified a significant signal for the COX pathway in relation to BE risk (P=0.0059, FDR q=0.03), and in gene-level analyses found an association with MGST1 (microsomal glutathione-S-transferase 1; P=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Of these, four were subsequently confirmed (P<5.5 × 10−5) in a meta-analysis encompassing an independent set of 1,851 BE cases and 3,496 controls. Three of these SNPs (rs3852575, rs73112090, rs4149204) were associated with similar elevations in EA risk. This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/EA, and suggests that variants in MGST1 influence disease susceptibility

Stakeholder views on secondary findings in whole-genome and whole-exome sequencing:a systematic review of quantitative and qualitative studies

Purpose: As whole-exome and whole-genome sequencing (WES/WGS) move into routine clinical practice, it is timely to review data that might inform the debate around secondary findings (SF) and the development of policies that maximize participant benefit. Methods: We systematically searched for qualitative and quantitative studies that explored stakeholder views on SF in WES/WGS. Framework analysis was undertaken to identify major themes. Results: 44 articles reporting the views of 11,566 stakeholders were included. Stakeholders were broadly supportive of returning ‘actionable’ findings, but definitions of actionability varied. Stakeholder views on SF disclosure exist along a spectrum: potential WES/WGS recipients’ views were largely influenced by a sense of rights, while views of genomics professionals were informed by a sense of professional responsibility. Experience of genetic illness and testing resulted in greater caution about SF, suggesting that truly informed decisions require an understanding of the implications and limitations of WES/WGS and possible findings. Conclusion: This review suggests that bidirectional interaction during consent might best facilitate informed decision-making about SF, and that dynamic forms of consent, allowing for changing preferences, should be considered. Research exploring views from wider perspectives and from recipients who have received SF is critical if evidence-based policies are to be achieved.</p