| 1. |
- Couch, Fergus J., et al.
(author)
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
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Journal article (peer-reviewed)abstract
- Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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| 2. |
- Antoniou, Antonis C., et al.
(author)
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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:10, s. 885-892
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Journal article (peer-reviewed)abstract
- Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).
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| 3. |
- Hollestelle, Antoinette, et al.
(author)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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In: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Journal article (peer-reviewed)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 4. |
- Kurilshikov, Alexander, et al.
(author)
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Large-scale association analyses identify host factors influencing human gut microbiome composition
- 2021
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
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Journal article (peer-reviewed)abstract
- To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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| 5. |
- Lawrenson, Kate, et al.
(author)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 6. |
- Oehri, Jacqueline, et al.
(author)
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Vegetation type is an important predictor of the arctic summer land surface energy budget
- 2022
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Journal article (peer-reviewed)abstract
- Despite the importance of high-latitude surface energy budgets (SEBs) for land-climate interactions in the rapidly changing Arctic, uncertainties in their prediction persist. Here, we harmonize SEB observations across a network of vegetated and glaciated sites at circumpolar scale (1994–2021). Our variance-partitioning analysis identifies vegetation type as an important predictor for SEB-components during Arctic summer (June-August), compared to other SEB-drivers including climate, latitude and permafrost characteristics. Differences among vegetation types can be of similar magnitude as between vegetation and glacier surfaces and are especially high for summer sensible and latent heat fluxes. The timing of SEB-flux summer-regimes (when daily mean values exceed 0 Wm−2) relative to snow-free and -onset dates varies substantially depending on vegetation type, implying vegetation controls on snow-cover and SEB-flux seasonality. Our results indicate complex shifts in surface energy fluxes with land-cover transitions and a lengthening summer season, and highlight the potential for improving future Earth system models via a refined representation of Arctic vegetation types.
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| 7. |
- Zeng, Chenjie, et al.
(author)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Journal article (peer-reviewed)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Allesøe, Rosa Lundbye, et al.
(author)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Journal article (peer-reviewed)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 12. |
- Bizzotto, Roberto, et al.
(author)
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Processes Underlying Glycemic Deterioration in Type 2 Diabetes : An IMI DIRECT Study
- 2021
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In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 44:2, s. 511-518
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Journal article (peer-reviewed)abstract
- OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.
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| 13. |
- Bolton, Kelly L., et al.
(author)
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Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer
- 2012
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In: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 307:4, s. 382-390
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Journal article (peer-reviewed)abstract
- Context Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. Objective To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. Design, Setting, and Participants A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n=909) or BRCA2 (n=304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Main Outcome Measure Five-year overall mortality. Results The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P<.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P<.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P<.001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P<.001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity=.003). Conclusion Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis. JAMA. 2012;307(4):382-390
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| 14. |
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| 15. |
- Costello, David M., et al.
(author)
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Global patterns and controls of nutrient immobilization on decomposing cellulose in riverine ecosystems
- 2022
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In: Global Biogeochemical Cycles. - : John Wiley & Sons. - 0886-6236 .- 1944-9224. ; 36:3
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Journal article (peer-reviewed)abstract
- Microbes play a critical role in plant litter decomposition and influence the fate of carbon in rivers and riparian zones. When decomposing low-nutrient plant litter, microbes acquire nitrogen (N) and phosphorus (P) from the environment (i.e., nutrient immobilization), and this process is potentially sensitive to nutrient loading and changing climate. Nonetheless, environmental controls on immobilization are poorly understood because rates are also influenced by plant litter chemistry, which is coupled to the same environmental factors. Here we used a standardized, low-nutrient organic matter substrate (cotton strips) to quantify nutrient immobilization at 100 paired stream and riparian sites representing 11 biomes worldwide. Immobilization rates varied by three orders of magnitude, were greater in rivers than riparian zones, and were strongly correlated to decomposition rates. In rivers, P immobilization rates were controlled by surface water phosphate concentrations, but N immobilization rates were not related to inorganic N. The N:P of immobilized nutrients was tightly constrained to a molar ratio of 10:1 despite wide variation in surface water N:P. Immobilization rates were temperature-dependent in riparian zones but not related to temperature in rivers. However, in rivers nutrient supply ultimately controlled whether microbes could achieve the maximum expected decomposition rate at a given temperature. Collectively, we demonstrated that exogenous nutrient supply and immobilization are critical control points for decomposition of organic matter.
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| 16. |
- de Bel, Thomas, et al.
(author)
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Automated quantification of levels of breast terminal duct lobular (TDLU) involution using deep learning
- 2022
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In: npj Breast Cancer. - : Nature Portfolio. - 2374-4677. ; 8:1
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Journal article (peer-reviewed)abstract
- Convolutional neural networks (CNNs) offer the potential to generate comprehensive quantitative analysis of histologic features. Diagnostic reporting of benign breast disease (BBD) biopsies is usually limited to subjective assessment of the most severe lesion in a sample, while ignoring the vast majority of tissue features, including involution of background terminal duct lobular units (TDLUs), the structures from which breast cancers arise. Studies indicate that increased levels of age-related TDLU involution in BBD biopsies predict lower breast cancer risk, and therefore its assessment may have potential value in risk assessment and management. However, assessment of TDLU involution is time-consuming and difficult to standardize and quantitate. Accordingly, we developed a CNN to enable automated quantitative measurement of TDLU involution and tested its performance in 174 specimens selected from the pathology archives at Mayo Clinic, Rochester, MN. The CNN was trained and tested on a subset of 33 biopsies, delineating important tissue types. Nine quantitative features were extracted from delineated TDLU regions. Our CNN reached an overall dice-score of 0.871 (+/- 0.049) for tissue classes versus reference standard annotation. Consensus of four reviewers scoring 705 images for TDLU involution demonstrated substantial agreement with the CNN method (unweighted kappa = 0.747 +/- 0.01). Quantitative involution measures showed anticipated associations with BBD histology, breast cancer risk, breast density, menopausal status, and breast cancer risk prediction scores (p < 0.05). Our work demonstrates the potential to improve risk prediction for women with BBD biopsies by applying CNN approaches to generate automated quantitative evaluation of TDLU involution.
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| 17. |
- de Jong, Roelof S., et al.
(author)
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4MOST-4-metre Multi-Object Spectroscopic Telescope
- 2014
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In: Ground-based and Airborne Instrumentation for Astronomy V. - : SPIE. - 0277-786X .- 1996-756X. ; 9147
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Conference paper (peer-reviewed)abstract
- 4MOST is a wide-field, high-multiplex spectroscopic survey facility under development for the VISTA telescope of the European Southern Observatory (ESO). Its main science drivers are in the fields of galactic archeology, high-energy physics, galaxy evolution and cosmology. 4MOST will in particular provide the spectroscopic complements to the large area surveys coming from space missions like Gaia, eROSITA, Euclid, and PLATO and from ground-based facilities like VISTA, VST, DES, LSST and SKA. The 4MOST baseline concept features a 2.5 degree diameter field-of-view with similar to 2400 fibres in the focal surface that are configured by a fibre positioner based on the tilting spine principle. The fibres feed two types of spectrographs; similar to 1600 fibres go to two spectrographs with resolution R> 5000 (lambda similar to 390-930 nm) and similar to 800 fibres to a spectrograph with R> 18,000 (lambda similar to 392-437 nm & 515-572 nm & 605-675 nm). Both types of spectrographs are fixed-configuration, three-channel spectrographs. 4MOST will have an unique operations concept in which 5 year public surveys from both the consortium and the ESO community will be combined and observed in parallel during each exposure, resulting in more than 25 million spectra of targets spread over a large fraction of the southern sky. The 4MOST Facility Simulator (4FS) was developed to demonstrate the feasibility of this observing concept. 4MOST has been accepted for implementation by ESO with operations expected to start by the end of 2020. This paper provides a top-level overview of the 4MOST facility, while other papers in these proceedings provide more detailed descriptions of the instrument concept[1], the instrument requirements development[2], the systems engineering implementation[3], the instrument model[4], the fibre positioner concepts[5], the fibre feed[6], and the spectrographs[7].
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| 18. |
- Eriksen, Rebeca, et al.
(author)
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Dietary metabolite profiling brings new insight into the relationship between nutrition and metabolic risk : An IMI DIRECT study
- 2020
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In: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 58
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Journal article (peer-reviewed)abstract
- Background: Dietary advice remains the cornerstone of prevention and management of type 2 diabetes (T2D). However, understanding the efficacy of dietary interventions is confounded by the challenges inherent in assessing free living diet. Here we profiled dietary metabolites to investigate glycaemic deterioration and cardiometabolic risk in people at risk of or living with T2D. Methods: We analysed data from plasma collected at baseline and 18-month follow-up in individuals from the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohort 1 n = 403 individuals with normal or impaired glucose regulation (prediabetic) and cohort 2 n = 458 individuals with new onset of T2D. A dietary metabolite profile model (Tpred) was constructed using multivariable regression of 113 plasma metabolites obtained from targeted metabolomics assays. The continuous Tpred score was used to explore the relationships between diet, glycaemic deterioration and cardio-metabolic risk via multiple linear regression models. Findings: A higher Tpred score was associated with healthier diets high in wholegrain (β=3.36 g, 95% CI 0.31, 6.40 and β=2.82 g, 95% CI 0.06, 5.57) and lower energy intake (β=-75.53 kcal, 95% CI -144.71, -2.35 and β=-122.51 kcal, 95% CI -186.56, -38.46), and saturated fat (β=-0.92 g, 95% CI -1.56, -0.28 and β=–0.98 g, 95% CI -1.53, -0.42 g), respectively for cohort 1 and 2. In both cohorts a higher Tpred score was also associated with lower total body adiposity and favourable lipid profiles HDL-cholesterol (β=0.07 mmol/L, 95% CI 0.03, 0.1), (β=0.08 mmol/L, 95% CI 0.04, 0.1), and triglycerides (β=-0.1 mmol/L, 95% CI -0.2, -0.03), (β=-0.2 mmol/L, 95% CI -0.3, -0.09), respectively for cohort 1 and 2. In cohort 2, the Tpred score was negatively associated with liver fat (β=-0.74%, 95% CI -0.67, -0.81), and lower fasting concentrations of HbA1c (β=-0.9 mmol/mol, 95% CI -1.5, -0.1), glucose (β=-0.2 mmol/L, 95% CI -0.4, -0.05) and insulin (β=-11.0 pmol/mol, 95% CI -19.5, -2.6). Longitudinal analysis showed at 18-month follow up a higher Tpred score was also associated lower total body adiposity in both cohorts and lower fasting glucose (β=-0.2 mmol/L, 95% CI -0.3, -0.01) and insulin (β=-9.2 pmol/mol, 95% CI -17.9, -0.4) concentrations in cohort 2. Interpretation: Plasma dietary metabolite profiling provides objective measures of diet intake, showing a relationship to glycaemic deterioration and cardiometabolic health. Funding: This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115,317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and EFPIA companies.
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| 19. |
- Estrada, Karol, et al.
(author)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Journal article (peer-reviewed)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 20. |
- Frost, Robert, et al.
(author)
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Development of a Pelletron-based compact neutron source : At the Nuclear Applications Laboratory, Lund University
- 2023
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In: Journal of Neutron Research. - 1023-8166. ; 24:3-4, s. 281-287
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Journal article (peer-reviewed)abstract
- The Applied Nuclear Physics Group at Lund University is constructing a prototype CANS (Compact Accelerator-driven Neutron Source). The CANS is based around a 3 MV, single-ended, Pelletron accelerator, which is used to impinge a 2.8 MeV deuterium beam into a beryllium target. The anticipated neutron production will be on the order of 1010 n/s in 4π sr. A further upgrade to the ion source of the Pelletron is expected to increase neutron production to 1011 n/s. Neutron energies will be up to 9 MeV with peak emission at ∼5 MeV. Shielding and moderation will be provided by a large water tank surrounding the target, with three exit ports to allow neutrons of different energies to be directed to experiments. The design is supported by simulation results which predict fast-neutron fluxes of 9×104 to 5×106 n/cm2/s, and thermal-neutron fluxes of 1×104 to 5×104 n/cm2/s to be readily obtainable with a 10 µA deuteron beam.
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| 21. |
- Frost, Robert J. W., et al.
(author)
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Baseline measurements in the assessment of ESS-specific radionuclide uptake by crops cultivated in Southern Sweden
- 2024
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In: Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms. - 0168-583X. ; 556, s. 1-7
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Journal article (peer-reviewed)abstract
- The European Spallation Source, ESS, is a neutron research facility under construction in Lund, Southern Sweden. The Facility will produce neutrons by spallation, using a powerful linear accelerator to deliver protons to a tungsten target. In addition to the desired neutron production, a long list of radionuclides will be created as by-products of the nuclear reaction inside the target. The Swedish Radiation Safety Authority has established a list of the most relevant radionuclides, in terms of contribution to the effective dose to ESS workers and the general public, should an accidental release of irradiated target material occur. This list includes radionuclides that are not produced by the nuclear energy industry, in particular 178mHf, 182Ta, 187W, 148Gd and 173Lu. Ongoing research efforts aim to determine the best analytical methods to assess these exoticand often difficult-to-measure radionuclides in environmental samples. This work investigates the potential of X-ray fluorescence and time-of-flight elastic Recoil detection analysis for the assessment of soil samples, and the potential of particle induced X-ray emission for the assessment of crop samples. These techniques require only simple sample preparation steps and no chemical extraction, unlike the conventional environmental monitoring methods such as inductively-coupled plasma mass spectrometry, and show promise as complimentary methodsenabling fast sample throughput. This study focuses on the analysis of uncontaminated soil and crops, to provide baseline data, whilst simultaneously assessing the available measurement capabilities. For the X-ray fluorescence system used in this study, the method detection limit for W in soil was determined to be 0.147 ppth, and Zr which can be correlated with the migration of Hf was clearly measurable.
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| 22. |
- Frost, Robert J. W., et al.
(author)
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Preliminary results from a study of luminescent materials : For application in the beam imaging system at the ESS
- 2023
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In: Nuclear Instruments and Methods in Physics Research Section B. - : Elsevier. - 0168-583X .- 1872-9584. ; 540, s. 227-233
-
Journal article (peer-reviewed)abstract
- As part of the development of the beam imaging system at the European Spallation Source, luminescent screens have been fabricated by the flame spraying of scintillating materials onto stainless steel backings. A total of seven screens were produced, three of chromia alumina (Al2O3:Cr), two of YAG (Y3Al5O12:Ce) and two of a 50/50 mix of these. The properties of these screens under proton irradiation were evaluated using a2.55 MeV proton beam at currents of up to 10 μA. Irradiation times were up to 25 h per sample, during which luminescence-, spectrographic-, thermal- and current-data was sampled at a rate of 1 Hz. Preliminary results of these measurements are reported here; with a quantitative analysis presented for one of the chromia alumina screens and a qualitative comparison of all three material types. The luminescent yield for chromia alumina was determined to be around 2000 photons/MeV for a virgin screen, and was found to drop to 1.5% after 167 mC of proton irradiation. A recovery of the luminescence of chromia alumina to >60% was observed after beam current was reduced for an 8 h period. Observations indicate that the YAG and mixed composition screens retain higher luminescence than the chromia alumina even at temperatures of over 200 ◦C. It is indicated that the luminescence from YAG feeds the R-lines of chromia alumina in the mixed composition screens.
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| 23. |
- Gaudet, Mia M., et al.
(author)
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Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer
- 2010
-
In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 6:10
-
Journal article (peer-reviewed)abstract
- The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
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| 24. |
- Hamdi, Yosr, et al.
(author)
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Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3
- 2017
-
In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 161:1, s. 117-134
-
Journal article (peer-reviewed)abstract
- Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
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| 25. |
- Hin, Harold, et al.
(author)
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Clinical relevance of low serum vitamin B12 concentrations in older people : the Banbury B12 study
- 2006
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In: Age and Ageing. - London : Oxford University Press. - 0002-0729 .- 1468-2834. ; 35:4, s. 416-422
-
Journal article (peer-reviewed)abstract
- Background: low vitamin B12 concentrations are common in older people, but the clinical relevance of biochemical evidence of vitamin B12 deficiency in the absence of anaemia is uncertain. Objective: to examine associations of cognitive impairment, depression and neuropathy with blood measurements of vitamin B12 and folate status in older people. Design: cross-sectional study in general practice in Banbury, England. Participants: a total of 1,000 individuals aged 75 years or older living in the community. Results: low vitamin B12 concentrations were identified in 13% of older people and were associated with memory impairment and depression. After adjustment for age, sex and smoking, individuals with vitamin B12 or holotranscobalamin (holoTC) in the bottom compared with top quartiles had a 2-fold risk (OR = 2.17; 95% CI 1.11-4.27) and a 3-fold risk (OR = 3.02; 95% CI 1.31-6.98) of cognitive impairment, respectively. Low vitamin B12 status was also associated with missing ankle tendon jerks but not with depression. Treatment with vitamin B12 for 3 months corrected the biochemical abnormalities but had no effect on any of the clinical measurements. Conclusions: low vitamin B12 concentrations are associated with cognitive impairment and missing ankle tendon jerks in older people in the absence of anaemia. Large-scale trials of vitamin B12 supplementation are required to assess the clinical significance of these associations.
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| 26. |
- Hjorth, J. J. Johannes, et al.
(author)
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The microcircuits of striatum in silico
- 2020
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:17, s. 9554-9565
-
Journal article (peer-reviewed)abstract
- The basal ganglia play an important role in decision making and selection of action primarily based on input from cortex, thalamus, and the dopamine system. Their main input structure, striatum, is central to this process. It consists of two types of projection neurons, together representing 95% of the neurons, and 5% of interneurons, among which are the cholinergic, fast-spiking, and low threshold-spiking subtypes. The membrane properties, somadendritic shape, and intrastriatal and extrastriatal synaptic interactions of these neurons are quite well described in the mouse, and therefore they can be simulated in sufficient detail to capture their intrinsic properties, as well as the connectivity. We focus on simulation at the striatal cellular/microcircuit level, in which the molecular/subcellular and systems levels meet. We present a nearly full-scale model of the mouse striatum using available data on synaptic connectivity, cellular morphology, and electrophysiological properties to create a microcircuit mimicking the real network. A striatal volume is populated with reconstructed neuronal morphologies with appropriate cell densities, and then we connect neurons together based on appositions between neurites as possible synapses and constrain them further with available connectivity data. Moreover, we simulate a subset of the striatum involving 10,000 neurons, with input from cortex, thalamus, and the dopamine system, as a proof of principle. Simulation at this biological scale should serve as an invaluable tool to understand the mode of operation of this complex structure. This platform will be updated with new data and expanded to simulate the entire striatum.
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| 27. |
- Kirchhoff, Tomas, et al.
(author)
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Breast cancer risk and 6q22.33 : combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
- 2012
-
In: PLOS ONE. - : Public library of science. - 1932-6203. ; 7:6
-
Journal article (peer-reviewed)abstract
- Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
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| 28. |
- Koivula, Robert, et al.
(author)
-
Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : rationale and design of the epidemiological studies within the IMI DIRECT Consortium
- 2014
-
In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 57:6, s. 1132-1142
-
Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS:The DIRECT (Diabetes Research on Patient Stratification) Study is part of a European Union Framework 7 Innovative Medicines Initiative project, a joint undertaking between four industry and 21 academic partners throughout Europe. The Consortium aims to discover and validate biomarkers that: (1) predict the rate of glycaemic deterioration before and after type 2 diabetes onset; (2) predict the response to diabetes therapies; and (3) help stratify type 2 diabetes into clearly definable disease subclasses that can be treated more effectively than without stratification. This paper describes two new prospective cohort studies conducted as part of DIRECT.METHODS:Prediabetic participants (target sample size 2,200-2,700) and patients with newly diagnosed type 2 diabetes (target sample size ~1,000) are undergoing detailed metabolic phenotyping at baseline and 18 months and 36 months later. Abdominal, pancreatic and liver fat is assessed using MRI. Insulin secretion and action are assessed using frequently sampled OGTTs in non-diabetic participants, and frequently sampled mixed-meal tolerance tests in patients with type 2 diabetes. Biosamples include venous blood, faeces, urine and nail clippings, which, among other biochemical analyses, will be characterised at genetic, transcriptomic, metabolomic, proteomic and metagenomic levels. Lifestyle is assessed using high-resolution triaxial accelerometry, 24 h diet record, and food habit questionnaires.CONCLUSIONS/INTERPRETATION:DIRECT will yield an unprecedented array of biomaterials and data. This resource, available through managed access to scientists within and outside the Consortium, will facilitate the development of new treatments and therapeutic strategies for the prevention and management of type 2 diabetes
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| 29. |
- Koivula, Robert W., et al.
(author)
-
Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium
- 2019
-
In: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:9, s. 1601-1615
-
Journal article (peer-reviewed)abstract
- Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.
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| 30. |
- Koivula, Robert W., et al.
(author)
-
The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes : an IMI DIRECT study
- 2020
-
In: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 63:4, s. 744-756
-
Journal article (peer-reviewed)abstract
- Aims/hypothesis: It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). Methods: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. Results: The TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. Conclusions/interpretation: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.
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| 31. |
- Kotljarchuk, Andrej, 1968-
(author)
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In the Shadows of Poland and Russia : The Grand Duchy of Lithuania and Sweden in the European Crisis of the mid-17th century
- 2006
-
Doctoral thesis (other academic/artistic)abstract
- This book examines and analyses the Union between the Grand Duchy of Lithuania and Sweden signed in 1655 at Kėdainiai and the political crisis that followed. The union was a result of strong separatist dreams among the Lithuanian-Ruthenian Protestant elite led by the Radziwiłł family, and if implemented it would radically change the balance of power in the Baltic Sea region. The main legal point of the Union was the breach of Lithuanian federation with Poland and the establishment of a federation with Sweden. The Grand Duchy of Lithuania aspired to return to international relations as a self-governing subject. The Union meant a new Scandinavian alternative to Polish and Russian domination. The author places the events in the Grand Duchy of Lithuania in the general crisis that occurred in Europe in the middle of the 17th century characterized by a great number of wars, rebellions and civil wars from Portugal to Ukraine, and which builds the background to the crisis for Lithuania and Sweden. The research proved the importance of lesser powers in changing the geopolitical balance between the Great Powers. The conflict over Lithuania and Belarus was the main reason for the Swedish-Russian, Polish-Russian and Ukrainian-Russian wars. The failure of the Union with Sweden was caused by both internal and external factors. Internally, various ethnic, confessional and political groups within the nobility of Lithuania were split in favour of different foreign powers – from Muscovy to Transylvania. The external cause for the failure of the Union project was the failure of Swedish strategy. Sweden concentrated its activity to Poland, not to Lithuania. After the Union, Swedish authorities treated the Grand Duchy as an invaded country, not an equal. The Swedish administration introduced heavy taxation and was unable to control the brutality of the army. As a result Sweden was defeated in both Lithuania and Poland. Among the different economic, political and religious explanations of the general crisis, the case of Lithuania shows the importance of the political conflicts. For the separatists of Lithuania the main motive to turn against Poland and to promote alliance with Sweden, Russia or the Cossacks was the inability of Poland to shield the Grand Duchy from a Russian invasion.The Lithuanian case was a provincial rebellion led by the native nobility against their monarch, based on tradition of the previous independence and statehood period. It was not nationalism in its modern meaning, but instead a crisis of identity in the form of a conflict between Patria and Central Power. However, the cost of being a part of Sweden or Muscovy was greater than the benefit of political protection. Therefore, the pro-Polish orientation prevailed when Poland after 1658 recovered its military ability the local nobility regrouped around Warsaw. The Grand Duchy of Lithuania managed to remain on the political map of Europe, but at the price of general religious Catholization and cultural Polonization. After the crisis, the Grand Duchy of Lithuania gradually changed into a deep province of the Polish state.
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| 32. |
- Mauritzson, Nicholai, et al.
(author)
-
GEANT4-based calibration of an organic liquid scintillator
- 2022
-
In: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - : Elsevier BV. - 0168-9002. ; 1023
-
Journal article (peer-reviewed)abstract
- A light-yield calibration of an NE 213A organic liquid scintillator detector has been performed using bothmonoenergetic and polyenergetic gamma-ray sources. Scintillation light was detected in a photomultipliertube, and the corresponding pulses were subjected to waveform digitization on an event-by-event basis. Theresulting Compton edges have been analyzed using a GEANT4 simulation of the detector which models boththe interactions of the ionizing radiation as well as the transport of scintillation photons. The simulation is calibrated and also compared to well-established prescriptions used to determine the Compton edges,resulting ultimately in light-yield calibration functions. In the process, the simulation-based method produced information on the gain and intrinsic pulse-height resolution of the detector. It also facilitated a previously inaccessible understanding of the systematic uncertainties associated with the calibration of the scintillation-light yield. The simulation-based method was also compared to well-established numerical prescriptions for locating the Compton edges. Ultimately, the simulation predicted as much as 17% lower light-yield calibrations than the prescriptions. These calibrations indicate that approximately 35% of the scintillation light associated with a given gamma-ray reaches the photocathode. It is remarkable how well two 50 year old prescriptions for calibrating scintillation-light yield in organic scintillators have stood the test of time.
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| 33. |
- Mauritzson, N., et al.
(author)
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Light-yield response of liquid scintillators using 2-6 MeV tagged neutrons
- 2024
-
In: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier. - 0168-9002 .- 1872-9576. ; 1062
-
Journal article (peer-reviewed)abstract
- Knowledge of the neutron light -yield response is crucial to the understanding of scintillator-based neutron detectors. In this work, neutrons from 2-6 MeV have been used to study the scintillation light -yield response of the liquid scintillators NE 213A, EJ 305, EJ 331 and EJ 321P using event -by -event waveform digitization. Energy calibration was performed using a GEANT4 model to locate the edge positions of the Compton distributions produced by gamma -ray sources. The simulated light yield for neutrons from a PuBe source was compared to measured recoil proton distributions, where neutron energy was selected by time -of -flight. This resulted in an energy -dependent Birks parameterization to characterize the non-linear response to the lower energy neutrons. The NE 213A and EJ 305 results agree very well with existing data and are reproduced nicely by the simulation. New results for EJ 331 and EJ 321P, where the simulation also reproduces the data well, are presented.
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| 34. |
- Myhill, Robert, et al.
(author)
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On the P-T fO(2) stability of Fe4O5, Fe5O6 and Fe4O5-rich solid solutions
- 2016
-
In: Contributions to Mineralogy and Petrology. - : Springer Science and Business Media LLC. - 0010-7999 .- 1432-0967. ; 171:5
-
Journal article (peer-reviewed)abstract
- The high-pressure phases Fe4O5 and Fe506 have recently been added to the list of known iron oxides. As mixed -valence phases, it has been suggested that they could form in the Earth's mantle once the dominant minerals become saturated in ferric iron. The possibility that Fe4O5 could exist in the mantle is also supported by the fact that it forms extensive solid solutions with both Mg2+ and Cr3+. In this study, we present the results of high-pressure and high-temperature multi -anvil experiments performed between 5 and 24 GPa at 1000-1400 degrees C aimed at constraining the stability field of the Fe4O5 phase. We combine these results with published phase equilibria, equation of state and Fe Mg partitioning data to estimate the thermodynamic properties of Fe4O5, Fe5O6 and the (Mg,Fe)(2)Fe2O5 solid solution. Using our thermodynamic model, the oxygen fugacity at which the high-pressure iron oxides become stable is calculated and the redox stability of (Mg,Fe)(2)Fe2O5 in an assemblage of olivine and pyroxene is calculated as a function of the bulk Fe/(Fe + Mg) ratio. Fe4O5 and (Mg,Fe)(2)Fe2O5 are stable at oxygen fugacities higher than the diamond stability field and are, therefore, unlikely to be found as inclusions in diamonds. The stability field of Fe5O6, on the other hand, extends to oxygen fugacities compatible with diamond formation. Using the Mg Fe solid solution model, we show that Fe4O5-structured phases would be restricted to aluminium -poor environments in the mantle such as dunites or silica iron oxide rich sediments transported into the mantle via subduction.
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| 35. |
- Pédehontaa-Hiaa, Guillaume, et al.
(author)
-
How to detect radionuclides specific to the European Spallation Source in soil samples?
- 2023
-
In: Medical Physics in the Baltic States (2023) : Proceedings of the 16th International Conference on Medical Physics - Proceedings of the 16th International Conference on Medical Physics. ; , s. 115-120
-
Conference paper (peer-reviewed)abstract
- The European Spallation Source (ESS) is a neutron research facility under construction in southern Sweden. The facility will produce a wide range of radionuclides including 148Gd, 187W, 172Hf, 182Ta and 178nHf that could be released into the environment in an accident scenario. Detection limits for these contaminants in soil were estimated to be in the mg k-1 range for ICP-MS and <3 Bq per 200 ml soil for gamma-ray spectroscopy.
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| 36. |
- Pédehontaa-Hiaa, Guillaume, et al.
(author)
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Investigation of the limits of detection for specific radionuclides in soil from the European Spallation Source (ESS) using radiometric and mass spectrometric methods
- 2023
-
Reports (other academic/artistic)abstract
- This study provides information about the concentration of Tungsten (W), Hafnium (Hf) and Tantal (Ta) in the ESS soil and recommendations on the most appropriate sample preparation and measurement technique to assess contamination by these elements. The current levels of W, Hf and Ta measured in this study are in agreement with the estimated values from previous geological surveys. ICP MS showed low limits of detection for W, Hf and Ta and is thus an appropriate technique for environmental monitoring. However, the three metals are difficult to extract from soil and require the use of specific sample preparation methods (based on hydrofluoric acid for example). The transfer of stable W, Hf and Ta from soil to plant is poorly known and only a handful of publications can be found that are relevant to the plants grown around the ESS. The transfer of the radioisotopes of W, Hf and Ta in particular to animals (and man) is even less studied. However, the existing articles indicate a fast excretion of radio-W and radio-Ta while the excretion is slow for radio-Hf.The Minimum Detectable Activity (MDA) for gamma emitter released from the ESS facility will depend not only on the performances of the detection equipment but also on the composition of tungsten target at the time of the release. The determination of limits of detection of ESS related gamma emitters was performed using a strategy based on simulation of spectra. Semi-synthetic gamma spectra were obtained by combining real soil measurements with simulated data for mixtures of ESS radionuclides using the software Nucleonica. The simulation of 187W spectra was used as a proof of concept for the method. With this approach, it is possible to estimate limits of detection by gamma spectroscopy for a given target composition. The limits of detection of four relevant radionuclides were successfully determined for two different compositions of the ESS target and at three different activity concentrations in soil.
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| 37. |
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| 38. |
- Rebbeck, Timothy R., et al.
(author)
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Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women
- 2016
-
In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18:1
-
Journal article (peer-reviewed)abstract
- Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
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| 39. |
- Santangelo, James S., et al.
(author)
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Global urban environmental change drives adaptation in white clover
- 2022
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
-
Journal article (peer-reviewed)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
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| 40. |
- Tsakiris, Theofanis, et al.
(author)
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Correlation of optical transmittance and hydrogen concentration in Cr/V superlattices
- 2024
-
In: Nuclear Instruments and Methods in Physics Research Section B. - : Elsevier. - 0168-583X .- 1872-9584. ; 553
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Journal article (peer-reviewed)abstract
- We assess the linearity between the reduction of the optical transmittance in the wavelength range of 600–1000 nm and the hydrogen concentration in Cr/V hydrogenated superlattice structures, with a nominal Cr/V ratio of 2/14. The V layers, contained inside an epitaxial Cr/V superlattice, were exposed to gaseous H atmosphere. The hydrogen uptake, as well as the changes in their optical properties, due to the hydrogenation, were monitored through optical transmittance measurements. The resonant 1H(15N,αγ)12C nuclear reaction was used to obtain the hydrogen depth profile and to determine the average hydrogen concentration per host atom in the V layers. Linearity was experimentally confirmed between the change in optical transmittance in a wide wavelength range and the H concentration, showing that optical data can be used to extract the relative hydrogen concentration. Additionally, the changes in the optical transmittance of the superlattice were found to be more pronounced for incident light with a wavelength of 600 nm, while the corresponding optical changes in the wavelength range 700–1000 nm, presented negligible dependence on the wavelength.
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| 41. |
- Tsakiris, Theofanis, 1997-
(author)
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Investigation of hydrogenated V-based systems using ions and photons, a step towards in-situ IBA of metal hydrides
- 2024
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Licentiate thesis (other academic/artistic)abstract
- Metal hydrides, based on transition metals, are a promising class of materials for hydrogen storage purposes. Understanding the effects of finite size and the presence of surfaces and interfaces in thermodynamics of hydrogen in these materials is an important step towards engineering hydride-based storage systems. In this work, hydride systems based on vanadium were studied by means of ion beam analysis (IBA), x-ray diffraction (XRD) and optical experiments. A series of thin vanadium films was grown using magnetron sputtering, with the aim of optimizing the growth conditions of the vanadium layer and improving the crystallinity of the produced films. Moreover, the correlation between the optical transmittance and the hydrogen concentration, probed through nuclear reaction analysis (NRA), of a Cr/V superlattice was studied, as a part of an on-going, large-scale investigation of proximity effects. Finally, motivated by the implications caused by the loss of hydrogen during the ex-situ hydrogenation and ion irradiation, a gas-cell aiming at performing IBA with the sample immersed in gaseous environment was designed. The effect of silicon-rich nitride membranes, holding the pressure gradient between vacuum and atmospheric pressure, on the energy and angular distribution of the primary ion beam, was studied theoretically and experimentally, proving the possibility of conducting real-space crystallographic studies using the proposed setup.
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| 42. |
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| 43. |
- Walker, Logan C, et al.
(author)
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Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.
- 2010
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In: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-542X .- 1465-5411. ; 12:6
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Journal article (peer-reviewed)abstract
- Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.
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| 44. |
- Whitlow, Harry J., et al.
(author)
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Dynamic Analysis of major elements in biological tissue validating quantification of trace life elements in MeV ion beam microscopy
- 2024
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In: Nuclear Instruments and Methods in Physics Research Section B. - : Elsevier. - 0168-583X .- 1872-9584. ; 554
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Journal article (peer-reviewed)abstract
- MeV ion microprobe measurements of the lesser and trace life element concentrations in biological tissues are challenging because of complex spatial inhomogeneities in these types of samples. Measurements on ex vivo tissue sections require determination of the matrix element composition and the tissue section thickness. For these reasons, in this work, we adapted the Dynamic Analysis approach known from literature, to interpret the MeV ion microscopy data to determine concentrations of H, C, O, and N as well as the thickness of different tissue regions in Non Human Primate (NHP) mesenteric lymph node section. The results showed no strong variations of the matrix element contents regardless of section thickness variations in the tissue. The matrix information was used to quantify total-Ca molarities and a significant ∼30 mM Ca concentration hotspot was observed at the edge of sinus structure in the mesenteric lymph node as compared to the 3-4 mM total-Ca levels in the surrounding tissues. Thus, MeV ion microprobe imaging combined with dynamic analysis comprise a novel chemometric approach paving a way for quantitative analysis of similarly complicated animal and plant biological tissue sections.
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| 45. |
- Wolever, Thomas M S, et al.
(author)
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Measuring the glycemic index of foods: interlaboratory study.
- 2008
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In: The American journal of clinical nutrition. - 0002-9165 .- 1938-3207. ; 87:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Many laboratories offer glycemic index (GI) services. OBJECTIVE: We assessed the performance of the method used to measure GI. DESIGN: The GI of cheese-puffs and fruit-leather (centrally provided) was measured in 28 laboratories (n=311 subjects) by using the FAO/WHO method. The laboratories reported the results of their calculations and sent the raw data for recalculation centrally. RESULTS: Values for the incremental area under the curve (AUC) reported by 54% of the laboratories differed from central calculations. Because of this and other differences in data analysis, 19% of reported food GI values differed by >5 units from those calculated centrally. GI values in individual subjects were unrelated to age, sex, ethnicity, body mass index, or AUC but were negatively related to within-individual variation (P=0.033) expressed as the CV of the AUC for repeated reference food tests (refCV). The between-laboratory GI values (mean+/-SD) for cheese-puffs and fruit-leather were 74.3+/-10.5 and 33.2+/-7.2, respectively. The mean laboratory GI was related to refCV (P=0.003) and the type of restrictions on alcohol consumption before the test (P=0.006, r2=0.509 for model). The within-laboratory SD of GI was related to refCV (P<0.001), the glucose analysis method (P=0.010), whether glucose measures were duplicated (P=0.008), and restrictions on dinner the night before (P=0.013, r2=0.810 for model). CONCLUSIONS: The between-laboratory SD of the GI values is approximately 9. Standardized data analysis and low within-subject variation (refCV<30%) are required for accuracy. The results suggest that common misconceptions exist about which factors do and do not need to be controlled to improve precision. Controlled studies and cost-benefit analyses are needed to optimize GI methodology. The trial was registered at clinicaltrials.gov as NCT00260858.
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