Measurement of the Atmospheric Muon Spectrum from 20 to 3000 GeV

The absolute muon flux between 20 GeV and 3000 GeV is measured with the L3 magnetic muon spectrometer for zenith angles ranging from 0 degree to 58 degree. Due to the large exposure of about 150 m2 sr d, and the excellent momentum resolution of the L3 muon chambers, a precision of 2.3 % at 150 GeV in the vertical direction is achieved. The ratio of positive to negative muons is studied between 20 GeV and 500 GeV, and the average vertical muon charge ratio is found to be 1.285 +- 0.003 (stat.) +- 0.019 (syst.).Comment: Total 32 pages, 9Figure

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive as

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

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

Feasibilty Analysis for Hardware Acceleration of Pattern Recognition Algorithms

This thesis presents a feasibility analysis for hardware acceleration of the pattern recognition algorithms used by the Media Knowledge Engineering department at the Delft University of Technology. The feasibility analysis is conducted on a number of different algorithm classes. The Parzen Window algorithm appeared to be the most suitable option for acceleration when recongurable hardware is considered. The reason for this is that the Parzen Window consists of independent calculations that can be computed in parallel. It can be computed by execution of Custom Configured Hardware Units (CCU) in Field Programmable Gate Arrays (FPGAs). The feasibility analysis presented, gave insight in the question whether it is useful to implement these kind of algorithms in hardware. Our results showed that algorithms that have independent calculations and thus are able to be executed in parallel are strong candidates for hardware implementation, certainly when the design can be executed with integer calculations. Integer calculations reduce the complexity of hardware implementation, require smaller area on the FPGA, reduce the bandwidth of the calculations and can be computed faster than their floating point version. In the future our methodology can be reused for other algorithms that have a parallel structure.Microelectronics & Computer EngineeringElectrical Engineering, Mathematics and Computer Scienc

Variant VKORC1 and CYP2C9 Alleles in Patients with Diffuse Alveolar Hemorrhage Caused by Oral Anticoagulants

Diffuse alveolar hemorrhage (DAH) is a life-threatening bleeding complication that can occur as a result of oral anticoagulation therapy. We hypothesized that in patients treated with coumarins, alveolar hemorrhage is associated with vitamin K epoxide reductase (VKORC1) and cytochrome P450 (CYP) 2C9 (CYP2C9) variant alleles. In addition, in the case of acenocoumarol use, CYP2C19 allelic variants also play a role. During a 7-year period, data on patients using coumarins with confirmed DAH were gathered. Of 173 confirmed DAH cases, 75 received oral anticoagulants, and 63 (84%) of these 75 patients were included because their DNA was available. For genotyping the CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP2C19*3 (636G>A), VKORC1 (-1639G>A), and VKORC1 (1173C>T) single nucleotide polymorphisms (SNPs), real-time PCRs were performed. In 62 (98.4%) of 63 patients with DAH, variant alleles were found. In 51 (81.0%) of the 63 patients, VKORC1 allelic variants (20 homozygotes and 31 heterozygotes) were present. In 31 (49.2%) of the 63 DAH cases, CYP2C9 allelic variants (three homozygotes, 26 heterozygotes, and two compound heterozygotes) were observed, and in 20 (32.0%) of the 63 patients, variant alleles of both genes were observed. Genotyping of four SNPs for VKORC1 and CYP2C9 polymorphisms is useful in predicting a high probability of the occurrence of DAH in patients receiving oral anticoagulants. Early and timely use of genotyping is recommended to prevent a fatal outcome and to provide safer and more individualized anticoagulant therapy

The role of tumor necrosis factor alpha G-308A polymorphisms in the course of pulmonary sarcoidosis.

This study was designed to evaluate the relationship between the presence of tumor necrosis factor (TNF) polymorphisms, human leukocyte antigen (HLA)-DRB1*03 linkage and the prognosis of sarcoidosis. In a retrospective case-control study, TNF-alphaG-308A, TNF-alphaG-238A, lymphotoxin-alpha (LTA) and HLA-DRB1*03 were genotyped in 625 sarcoidosis patients. These patients were classified into 298 patients with persistent disease and 327 patients with non-persistent disease using chest X-ray (CXR) appearances and lung function parameters after at least 2 years of follow-up. The TNF-alpha-308A variant allele was observed in 25.5% of patients with persistent disease compared with 44.0% of patients with non-persistent disease. The corresponding odds ratio (OR) was 0.43 with a 95% confidence interval (CI) of 0.30-0.61. A strong linkage was found between TNF-alphaG-308A and HLA-DRB1*03 (OR = 0.03, 95% CI: 0.02-0.05). For TNF-alphaG-238A and LTA NcoI A252G, there were no statistically significant differences in the distribution of genotypes between the groups with and without persistent disease. The data indicate that presence of a TNF-alpha-308A variant allele and HLA-DRB1*03 were associated with a favorable prognosis. Because of the strong linkage between TNF-alphaG-308A and HLA-DRB1*03, genotyping of one simple and less expensive TNF-alpha single nucleotide polymorphism can be used to predict the prognosis of pulmonary sarcoidosis in clinical practice