Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 ...familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 × 10−7, allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 × 10−14 (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 × 10−5). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.
We mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as ...SGNE1), GREM1 and FMN1. We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P = 4.44 × 10−14).
Medical masks have inferior filtration efficiency and fit to filtering facepiece respirators (FFRs) but are widely used in healthcare and the community. These masks are intended for disposal after ...use but in the event of mask shortage re-use after reprocessing may be an option. We investigated eight reprocessing methods that each involved washing or soaking in liquid, are likely to eliminate respiratory viruses, and are safe and available in most community and healthcare settings.
Three brands of EN 14683 standards-compliant commercial medical mask were each reprocessed 10 times by one of eight methods. We measured filtration efficiency for poly-dispersed sodium chloride particles and pressure differential.
Compared with new medical masks, reprocessed masks had significantly reduced filtration efficiency. The reduction was mild-moderate (6.5-25.8%) after warm water wash, hot water soak or boiling water soak; and moderate-large (24.1-51.5%) after detergent, soap or laundry machine wash, or bleach soak. There were mixed and minor changes in pressure differential. Most reprocessed standards-compliant masks had better filtration efficiency than new non-standard commercial masks and then cotton and cotton-polyester mix fabric samples, even triple-layered fabrics.
High-quality commercial medical masks reprocessed 10 times by water immersion methods had better filtration efficiency than new non-standard masks and washable fabrics. These findings have particular relevance for community and low-resource healthcare settings.
Context: Leydig cell tumors (LCTs) are the most common non-germ-cell neoplasms of the testis. LCTs are often hormonally active and can result in precocious virilization or in adult feminization. We ...identified an LCT in an affected individual from a kindred with hereditary leiomyomatosis and renal cell cancer (HLRCC) and a germline fumarate hydratase (FH) mutation (N64T).
Objective: Our objective was to investigate the role of FH mutations in predisposition to LCTs.
Design: We tested for pathogenic effects of the N64T mutation and screened an additional 29 unselected adult LCTs for FH alterations. We also tested these LCTs for mutations in two genes, the LH/choriogonadotropin receptor (LHCGR) and the guanine nucleotide-binding protein α (GNAS) that had been implicated in LCT tumorigenesis.
Results: No mutations were found in GNAS, and one tumor had a LHCGR somatic substitution. In addition to the HLRCC case with the N64T germline FH mutation, we identified one other LCT with a previously unreported FH mutation (M411I). Both LCTs from these patients showed loss of the wild-type FH allele. Immunohistochemical and in situ hybridization analyses demonstrated activation of the hypoxia/angiogenesis pathway not only in the tumors belonging to the FH mutation carriers but also in several other mutation-negative LCTs.
Conclusions: Our study shows that some LCTs are caused by FH mutations and represents one of the first reports of germline mutations in any type of adult testicular tumor.
To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European ...descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10(-11). We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC.
To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 ...advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-β and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (Ptrend = 1.0 × 10−12).
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional ...loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 10(-10)). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.
This research abstracts a history of human-machine interaction to map the look, feel and sounds of a networked environment and what it is to exist within it. To do this, a cross-disciplinary ...examination of systems theory, art history, computational design and contemporary philosophy has been employed to chart the aesthetics of the network and to critically understand deterministic forces in the architectures of connection.With so much discussion about networked technologies predicated upon its future, it is vital to turn our heads back to historical examples of both technological innovation and how artists have engaged with it. This thesis examines key events in network culture, such as the implementation of the telegraph, the advent of the database, cybernetics, the Macy conferences and the world wide web alongside contextual responses from historical and contemporary art.What cultural influences are at work in the construction of the digital architectures set to shape this century? What is the aesthetic language used to explore and communicate these ideas? What is the form that information takes? This thesis explores the ways in which art making practices can help us understand the connected condition and the politics of a lived experience that is fundamentally embedded. It comprises a written thesis with documentation of an accompanying body of work, contextualised with historical and contemporary contributions to the fields of art, computational history and philosophy.I argue that knowledge pertaining to the semantics of innovation, the nature of information storage and the aesthetics of new systems in cryptography and transmission are being revealed in current art making practices and bring important, valuable insight to understanding the connected condition. This research determines that key characteristics of network aesthetics draw upon the cybernetic ideas of self-reflexivity, dissonance, poetic technicity, dynamic behaviour, the telematic and metaphor, but also stresses the importance of understanding less visible relationships between gender, labour and ethnicity in technological innovation.
Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be ...discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency MAF = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio OR = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.
To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 ...high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10−4 in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 × 10−13 overall; P = 6.9 × 10−12 replication), and rs16892766, at 8q23.3 (P = 3.3 × 10−18 overall; P = 9.6 × 10−17 replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.
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