Collagen degradation and neutrophilic infiltration: a vicious circle in inflammatory bowel disease

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

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

The LHCb upgrade I

The LHCb upgrade represents a major change of the experiment. The detectors have been almost completely renewed to allow running at an instantaneous luminosity five times larger than that of the previous running periods. Readout of all detectors into an all-software trigger is central to the new design, facilitating the reconstruction of events at the maximum LHC interaction rate, and their selection in real time. The experiment's tracking system has been completely upgraded with a new pixel vertex detector, a silicon tracker upstream of the dipole magnet and three scintillating fibre tracking stations downstream of the magnet. The whole photon detection system of the RICH detectors has been renewed and the readout electronics of the calorimeter and muon systems have been fully overhauled. The first stage of the all-software trigger is implemented on a GPU farm. The output of the trigger provides a combination of totally reconstructed physics objects, such as tracks and vertices, ready for final analysis, and of entire events which need further offline reprocessing. This scheme required a complete revision of the computing model and rewriting of the experiment's software

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

Evidence for a self-enforcing inflammation in neutrophil-mediated chronic diseases

In summary, this thesis provides evidence for the self-sustaining role of neutrophils in the inflammatory state in the pathogenesis of COPD and CD. In active disease, neutrophils release proteolytic enzymes that breakdown collagen. One of the collagen fragments can be neutrophilic chemoattractant N-ac-PGP, which leads to enhanced neutrophil inflammation and further inflammation. In COPD, cigarette smoking initiates a vicious circle of events leading to collagen breakdown, PGP generation and PGP-induced neutrophilic transmigration (fig. 1). This PGP generation can also play a significant role in the pathogenesis of CD, since neutrophils from CD patients generate higher amounts of PGP from whole collagen under basal conditions than neutrophils from healthy controls. It was proposed that intestinal damage initiates a vicious circle of events leading to collagen breakdown, PGP generation and PGP-induced neutrophilic transmigration (fig. 2). Since N-ac-PGP likely plays a significant role in both chronic diseases, N-ac-PGP is a very interesting drug target. Medication such as CXCR2 antagonists or MMP and PE inhibitors could be provided to tackle the sustained neutrophilic inflammation

The malleability of mate selection in speed-dating events

This study examined to what extent individual mate selectivity could be explained by characteristics of the mating market. Specifically, we hypothesized that females’ selectivity would be more malleable, or context-dependent, than males’ mate selectivity (cf. Baumeister, 2000; Gangestad & Simpson, 2000). In a series of 22 speed-dating events in which 546 adults aged 22-42 years participated, we investigated whether the proportion of available potential mates (i.e., male-female ratio), which sex rotated during the speed-date event (i.e., approached the other sex), and mate qualities of same-sex competitors affected individuals’ selectivity, as indexed by the proportion of no’s given during the speed-dating events. Results from multilevel analyses demonstrated that, as hypothesized, event characteristics explained mate selectivity only for females. Specifically, women with a lower facial attractiveness and more deviant body mass index (BMI) values were overall less selective, but this trend was only present in speed-dating events characterized by higher intrasex competition—when females rotated or when other females in the event were more attractive or had healthier BMI. The findings partially support the idea of "erotic plasticity" in females, demonstrating that females’ mate selectivity is more malleable and dependent on context than males’ mate selectivity

Targeting chemokine receptors in chronic inflammatory diseases: An extensive review

The traffic of the different types of immune cells is an important aspect in the immune response. Chemokines are soluble peptides that are able to attract cells by interaction with chemokine receptors on their target cells. Several different chemokines and receptors exist enabling the specific trafficking of different immune cells. In chronic inflammatory disorders there is abundance of immune cells present at the inflammatory site. This review focuses on the role of chemokine receptors in chronic inflammatory disorders of the lungs, intestine, joints, skin and nervous system and the potential of targeting these receptors as therapeutic intervention in these disorders. © 2011 Elsevier Inc. All rights reserved