Facilitating the analysis of a UK national blood service supply chain using distributed simulation

In an attempt to investigate blood unit ordering policies, researchers have created a discrete-event model of the UK National Blood Service (NBS) supply chain in the Southampton area of the UK. The model has been created using Simul8, a commercial-off-the-shelf discrete-event simulation package (CSP). However, as more hospitals were added to the model, it was discovered that the length of time needed to perform a single simulation severely increased. It has been claimed that distributed simulation, a technique that uses the resources of many computers to execute a simulation model, can reduce simulation runtime. Further, an emerging standardized approach exists that supports distributed simulation with CSPs. These CSP Interoperability (CSPI) standards are compatible with the IEEE 1516 standard The High Level Architecture, the defacto interoperability standard for distributed simulation. To investigate if distributed simulation can reduce the execution time of NBS supply chain simulation, this paper presents experiences of creating a distributed version of the CSP Simul8 according to the CSPI/HLA standards. It shows that the distributed version of the simulation does indeed run faster when the model reaches a certain size. Further, we argue that understanding the relationship of model features is key to performance. This is illustrated by experimentation with two different protocols implementations (using Time Advance Request (TAR) and Next Event Request (NER)). Our contribution is therefore the demonstration that distributed simulation is a useful technique in the timely execution of supply chains of this type and that careful analysis of model features can further increase performance

Common variants at theCHEK2gene locus and risk of epithelial ovarian cancer

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.Other Research Uni

Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Cells from NBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from ataxia telangiectasia. We describe the positional cloning of a gene encoding a novel protein, nibrin. It contains two modules found in cell cycle checkpoint proteins, a forkhead-associated domain adjacent to a breast cancer carboxy-terminal domain. A truncating 5 bp deletion was identified in the majority of NBS patients, carrying a conserved marker haplotype. Five further truncating mutations were identified in patients with other distinct haplotypes. The domains found in nibrin and the NBS phenotype suggest that this disorder is caused by defective responses to DNA double-strand breaks