Dihydrobenz[e][1,4]oxazepin-2(3H)-ones, a new anthelmintic chemotype immobilising whipworm and reducing infectivity in vivo.

Trichuris trichiura is a human parasitic whipworm infecting around 500 million people globally, damaging the physical growth and educational performance of those infected. Current drug treatment options are limited and lack efficacy against the worm, preventing an eradication programme. It is therefore important to develop new treatments for trichuriasis. Using Trichuris muris, an established model for T. trichiura, we screened a library of 480 novel drug-like small molecules for compounds causing paralysis of the ex vivo adult parasite. We identified a class of dihydrobenz[e][1,4]oxazepin-2(3H)-one compounds with anthelmintic activity against T. muris. Further screening of structurally related compounds and resynthesis of the most potent molecules led to the identification of 20 active dihydrobenzoxazepinones, a class of molecule not previously implicated in nematode control. The most active immobilise adult T. muris with EC50 values around 25–50μM, comparable to the existing anthelmintic levamisole. The best compounds from this chemotype show low cytotoxicity against murine gut epithelial cells, demonstrating selectivity for the parasite. Developing a novel oral pharmaceutical treatment for a neglected disease and deploying it via mass drug administration is challenging. Interestingly, the dihydrobenzoxazepinone OX02983 reduces the ability of embryonated T. muris eggs to establish infection in the mouse host in vivo. Complementing the potential development of dihydrobenzoxazepinones as an oral anthelmintic, this supports an alternative strategy of developing a therapeutic that acts in the environment, perhaps via a spray, to interrupt the parasite lifecycle. Together these results show that the dihydrobenzoxazepinones are a new class of anthelmintic, active against both egg and adult stages of Trichuris parasites. They demonstrate encouraging selectivity for the parasite, and importantly show considerable scope for further optimisation to improve potency and pharmacokinetic properties with the aim of developing a clinical agent

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

The relationship between naevus count, memory function and telomere length in the Twins UK cohort

The presence of a skin–brain connection whereby alterations in the skin can inform on mechanisms underlying neurodegenerative diseases is increasingly recognized. In this study, we used a discovery (n = 321) and replication (n = 147) sample from the Twins UK population to test the association between naevus count and memory function, and its mediation by telomeres. Memory function was assessed in 1999 and 2009 using the paired associates learning test (PAL), while naevus count and leucocyte telomere length (LTL, assessed by the terminal restriction fragment assay) were measured once. Higher baseline naevus count was significantly associated with fewer errors at the baseline and follow-up PAL, as well as with change in PAL score over 10 years. This association was significantly attenuated after adjustment for LTL. The significant association between naevus count and PAL score was reproduced in the replication sample. These findings suggest that melanocytes might be used as model system to study the biological ageing pathways involved in neurodegeneration. © 2018 The Authors. Pigment Cell &amp; Melanoma Research Published by John Wiley &amp; Sons Lt

I eat therefore I am:an essay on human and animal mutuality

This essay provides an overview of seminal examples of Western thought (including the Bible, Plato, Hegel, Nietzsche, Freud and Heidegger) in which food features as a means to the conceptual differentiation of the human from the animal. Such an approach allows the emergence of a “structure” (in the Deleuzian sense) that seems to underlie the production of these distinctions. It is, paradoxically, human and animal mutuality – as this is manifested in their common need for, and consumption of, food – that has been utilised as their “differentiator” in the Western tradition and it is this, I argue, that renders possible the functions of what Agamben calls the “anthropological machine.

EORTC Melanoma Group achievements

Since its inception in 1969, the EORTC Melanoma Group has employed a multidisciplinary approach in the fight against melanoma and has registered significant achievements in many areas of melanoma treatment and research. The group showed that sentinel node (SN) tumor burden according to the Rotterdam Criteria and the microanatomic location were the most important prognostic factors for melanoma-specific survival and non-SN positivity in the completion lymph node dissection specimen. They demonstrated that extended schedule escalated dose temozolomide is feasible and has an acceptable safety profile. They also showed that the interferon-a targeted therapy should occur in a targeted patient population, and should probably not be offered to 70% of the patients that are currently being given this treatment. Through EORTC trial 18991, Sylatron™, pegylated interferon a-2b, for the treatment of melanoma patients with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy, was approved by the US FDA. The present article describes the achievements and future strategies of the Melanoma Group. © 2012 European Organisation for Research and Treatment of Cancer.SCOPUS: ar.jinfo:eu-repo/semantics/publishe