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- Purrington, Kristen S., et al.
(författare)
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Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer
- 2014
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 35:5, s. 1012-1019
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Tidskriftsartikel (refereegranskat)abstract
- In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 x 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 x 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 x 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 x 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
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- Ruifrok, Anneloes E, et al.
(författare)
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Study protocol : Differential effects of diet and physical activity based interventions in pregnancy on maternal and fetal outcomes: Individual patient data (IPD) meta-analysis and health economic evaluation
- 2014
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Ingår i: Systematic Reviews. - : Springer Science and Business Media LLC. - 2046-4053. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPregnant women who gain excess weight are at risk of complications during pregnancy and in the long term. Interventions based on diet and physical activity minimise gestational weight gain with varied effect on clinical outcomes. The effect of interventions on varied groups of women based on body mass index, age, ethnicity, socioeconomic status, parity, and underlying medical conditions is not clear. Our individual patient data (IPD) meta-analysis of randomised trials will assess the differential effect of diet- and physical activity-based interventions on maternal weight gain and pregnancy outcomes in clinically relevant subgroups of women.Methods/designRandomised trials on diet and physical activity in pregnancy will be identified by searching the following databases: MEDLINE, EMBASE, BIOSIS, LILACS, Pascal, Science Citation Index, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database. Primary researchers of the identified trials are invited to join the International Weight Management in Pregnancy Collaborative Network and share their individual patient data. We will reanalyse each study separately and confirm the findings with the original authors. Then, for each intervention type and outcome, we will perform as appropriate either a one-step or a two-step IPD meta-analysis to obtain summary estimates of effects and 95% confidence intervals, for all women combined and for each subgroup of interest. The primary outcomes are gestational weight gain and composite adverse maternal and fetal outcomes. The difference in effects between subgroups will be estimated and between-study heterogeneity suitably quantified and explored. The potential for publication bias and availability bias in the IPD obtained will be investigated. We will conduct a model-based economic evaluation to assess the cost effectiveness of the interventions to manage weight gain in pregnancy and undertake a value of information analysis to inform future research.
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- Zabriskie, Matthew S., et al.
(författare)
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BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia
- 2014
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 26:3, s. 428-442
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Tidskriftsartikel (refereegranskat)abstract
- Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph+) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph+ leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.
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- Carniato, S., et al.
(författare)
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Thomson-resonant interference effects in elastic x-ray scattering near the Cl K edge of HCl
- 2012
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 137:9, s. 094311-
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Tidskriftsartikel (refereegranskat)abstract
- We experimentally observed interference effects in elastic x-ray scattering from gas-phase HCl in the vicinity of the Cl Kedge. Comparison to theory identifies these effects as interference effects between non-resonant elastic Thomson scattering and resonant Raman scattering. The results indicate the non-resonant Thomson and resonant Raman contributions are of comparable strength. The measurements also exhibit strong polarization dependence, allowing an easy identification of the resonant and non-resonant contributions.
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- Vinuesa, Richardo, et al.
(författare)
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Aspect ratio effects in turbulent duct flows studied through direct numerical simulation
- 2014
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Ingår i: Journal of turbulence. - : Informa UK Limited. - 1468-5248 .- 1468-5248. ; 15:10, s. 677-706
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Tidskriftsartikel (refereegranskat)abstract
- Three-dimensional effects in turbulent duct flows, i.e., sidewall boundary layers and secondary motions, are studied by means of direct numerical simulation (DNS). The spectral element code Nek5000 is used to compute turbulent duct flows with aspect ratios 1-7 (at Re-b,Re- c = 2800, Re-tau,Re- c similar or equal to 180) and aspect ratio 1 (at Re-b,Re- c = 5600, Re-tau,Re- c similar or equal to 330), in streamwise-periodic boxes of length 25h. The total number of grid points ranges from 28 to 145 million, and the pressure gradient is adjusted iteratively in order to keep the same bulk Reynolds number in the centreplane with changing aspect ratio. Turbulence is initiated via a trip forcing active during the initial stages of the simulation, and the statistical convergence of the data is discussed both in terms of transient approach and averaging period. Spanwise variations in wall shear, mean-flow profiles, and turbulence statistics are analysed as a function of aspect ratio, and also compared with the spanwise-periodic channel (as idealisation of an infinite aspect ratio duct). The computations show good agreement with experimental measurements carried out in parallel at the Illinois Institute of Technology (IIT) in Chicago, and highlight the relevance of sidewall boundary layers and secondary vortices in the physics of the duct flow. The rich array of secondary vortices extending throughout the upper and lower walls of the duct, and their dependence on Reynolds number and aspect ratio, had not been reported in the literature before.
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