Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges

Traceability of values for catalytic activity concentration of enzymes : a certified reference material for aspartate transaminase

Background: A new reference material for the liver enzyme aspartate transaminase (AST) (L-aspartate: 2-oxoglutarate-aminotransferase, EC 2.6.1.1), also called aspartate aminotransferase (ASAT), has been developed under the code ERM-AD457/IFCC. This certified reference material (CRM) for AST has been produced from a human type recombinant AST expressed in Escherichia coli and a buffer containing bovine serum albumin, and has been lyophilised. Methods: The homogeneity and the stability of the material have been tested and the catalytic activity concentration has been characterised by 12 laboratories using the reference procedure for AST at 37 degrees C from the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Results: The certified catalytic activity concentration and certified uncertainty of AST in the reconstituted material are (1.74 +/- 0.05) mkat/L or (104.6 +/- 2.7) U/L (with a coverage factor k = 2; 95% confidence interval). Conclusions: Both the certified value and uncertainty are traceable to the International System of Units (SI). The material is aiming to control the IFCC reference procedure for AST at 37 degrees C, which will then be used to assign values to calibrants and control materials. The present paper highlights the scientific challenges and innovations which were encountered during the development of this new CRM

The Calvin Lab : bio-organic chemistry group at the University of California, Berkeley, 1945-1963 /

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Early allopolyploid evolution in the post-neolithic Brassica napus oilseed genome

Oilseed rape (Brassica napus L.) was formed 3c7500 years ago by hybridization between B. rapa and B. oleracea, followed by chromosome doubling, a process known as allopolyploidy. Together with more ancient polyploidizations, this conferred an aggregate 72x genome multiplication since the origin of angiosperms and high gene content.We examined the B. napus genome and the consequences of its recent duplication. The constituent An and Cn subgenomes are engaged in subtle structural, functional, and epigenetic cross-talk, with abundant homeologous exchanges. Incipient gene loss and expression divergence have begun. Selection in B. napus oilseed types has accelerated the loss of glucosinolate genes, while preserving expansion of oil biosynthesis genes. These processes provide insights into allopolyploid evolution and its relationship with crop domestication and improvement.Erratum published in Vol 345, no. 6202 September 2014 DOI: 10.1126/science.1260782Peer reviewed: YesNRC publication: Ye

Genome-wide association study identifies novel loci predisposing to cutaneous melanoma

We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 x 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma

Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study

To provide a global, up-to-date picture of the prevalence, treatment, and outcomes of Candida bloodstream infections in intensive care unit patients and compare Candida with bacterial bloodstream infection. DESIGN: A retrospective analysis of the Extended Prevalence of Infection in the ICU Study (EPIC II). Demographic, physiological, infection-related and therapeutic data were collected. Patients were grouped as having Candida, Gram-positive, Gram-negative, and combined Candida/bacterial bloodstream infection. Outcome data were assessed at intensive care unit and hospital discharge. SETTING: EPIC II included 1265 intensive care units in 76 countries. PATIENTS: Patients in participating intensive care units on study day. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Of the 14,414 patients in EPIC II, 99 patients had Candida bloodstream infections for a prevalence of 6.9 per 1000 patients. Sixty-one patients had candidemia alone and 38 patients had combined bloodstream infections. Candida albicans (n = 70) was the predominant species. Primary therapy included monotherapy with fluconazole (n = 39), caspofungin (n = 16), and a polyene-based product (n = 12). Combination therapy was infrequently used (n = 10). Compared with patients with Gram-positive (n = 420) and Gram-negative (n = 264) bloodstream infections, patients with candidemia were more likely to have solid tumors (p < .05) and appeared to have been in an intensive care unit longer (14 days [range, 5-25 days], 8 days [range, 3-20 days], and 10 days [range, 2-23 days], respectively), but this difference was not statistically significant. Severity of illness and organ dysfunction scores were similar between groups. Patients with Candida bloodstream infections, compared with patients with Gram-positive and Gram-negative bloodstream infections, had the greatest crude intensive care unit mortality rates (42.6%, 25.3%, and 29.1%, respectively) and longer intensive care unit lengths of stay (median [interquartile range]) (33 days [18-44], 20 days [9-43], and 21 days [8-46], respectively); however, these differences were not statistically significant. CONCLUSION: Candidemia remains a significant problem in intensive care units patients. In the EPIC II population, Candida albicans was the most common organism and fluconazole remained the predominant antifungal agent used. Candida bloodstream infections are associated with high intensive care unit and hospital mortality rates and resource use

Runaway electron beam control

Post-disruption runaway electron (RE) beams in tokamaks with large current can cause deep melting of the vessel and are one of the major concerns for ITER operations. Consequently, a considerable effort is provided by the scientific community in order to test RE mitigation strategies. We present an overview of the results obtained at FTU and TCV controlling the current and position of RE beams to improve safety and repeatability of mitigation studies such as massive gas (MGI) and shattered pellet injections (SPI). We show that the proposed RE beam controller (REB-C) implemented at FTU and TCV is effective and that current reduction of the beam can be performed via the central solenoid reducing the energy of REs, providing an alternative/parallel mitigation strategy to MGI/SPI. Experimental results show that, meanwhile deuterium pellets injected on a fully formed RE beam are ablated but do not improve RE energy dissipation rate, heavy metals injected by a laser blow off system on low-density flat-top discharges with a high level of RE seeding seem to induce disruptions expelling REs. Instabilities during the RE beam plateau phase have shown to enhance losses of REs, expelled from the beam core. Then, with the aim of triggering instabilities to increase RE losses, an oscillating loop voltage has been tested on RE beam plateau phase at TCV revealing, for the first time, what seems to be a full conversion from runaway to ohmic current. We finally report progresses in the design of control strategies at JET in view of the incoming SPI mitigation experiments

Real-time-capable prediction of temperature and density profiles in a tokamak using RAPTOR and a first-principle-based transport model

The RAPTOR code is a control-oriented core plasma profile simulator with various applications in control design and verification, discharge optimization and real-time plasma simulation. To date, RAPTOR was capable of simulating the evolution of poloidal flux and electron temperature using empirical transport models, and required the user to input assumptions on the other profiles and plasma parameters. We present an extension of the code to simulate the temperature evolution of both ions and electrons, as well as the particle density transport. A proof-of-principle neural-network emulation of the quasilinear gyrokinetic QuaLiKiz transport model is coupled to RAPTOR for the calculation of first-principle-based heat and particle turbulent transport. These extended capabilities are demonstrated in a simulation of a JET discharge. The multi-channel simulation requires ∼0.2 s to simulate 1 second of a JET plasma, corresponding to ∼20 energy confinement times, while predicting experimental profiles within the limits of the transport model. The transport model requires no external inputs except for the boundary condition at the top of the H-mode pedestal. This marks the first time that simultaneous, accurate predictions of Te, Tiand nehave been obtained using a first-principle-based transport code that can run in faster-than-real-time for present-day tokamaks