| 61. |
- Stepien, M., et al.
(författare)
-
Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study
- 2021
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 148:3, s. 609-625
-
Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed forN1-acetylspermidine, isatin,p-hydroxyphenyllactic acid, tyrosine, sphingosine,l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, gamma-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.
|
|
| 62. |
- Vimaleswaran, K. S., et al.
(författare)
-
Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts
- 2013
-
Ingår i: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 10:2
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n=123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p=6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p=6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p=0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p=0.88; metabolism score, p=0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p=0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
|
|
| 63. |
|
|
| 64. |
- Zheng, J., et al.
(författare)
-
Mendelian Randomization Analysis Reveals a Causal Influence of Circulating Sclerostin Levels on Bone Mineral Density and Fractures
- 2019
-
Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 34:10, s. 1824-1836
-
Tidskriftsartikel (refereegranskat)abstract
- In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (beta = 0.20, p = 4.6 x 10(-49)) and GALNT1 (beta = 0.11 per G allele, p = 4.4 x 10(-11)). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (beta = -0.12, 95% confidence interval [CI] -0.20 to -0.05) and eBMD (beta = -0.12, 95% CI -0.14 to -0.10), and a positive relationship with fracture risk (beta = 0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. (c) 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.
|
|
| 65. |
- Agarwalla, S.K., et al.
(författare)
-
EUROnu-WP6 2010 Report
- 2012
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This is a summary of the work done by the Working Package 6 (Physics) of the EU project "EUROnu" during the second year of activity of the project.
|
|
| 66. |
|
|
| 67. |
- Buckland, G., et al.
(författare)
-
Healthy lifestyle index and risk of gastric adenocarcinoma in the EPIC cohort study
- 2015
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 137:3, s. 598-606
-
Tidskriftsartikel (refereegranskat)abstract
- Several modifiable lifestyle factors, including smoking, alcohol, certain dietary factors and weight are independently associated with gastric cancer (GC); however, their combined impact on GC risk is unknown. We constructed a healthy lifestyle index to investigate the joint influence of these behaviors on GC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The analysis included 461,550 participants (662 first incident GC cases) with a mean follow-up of 11.4 years. A healthy lifestyle index was constructed, assigning 1 point for each healthy behavior related to smoking status, alcohol consumption and diet quality (represented by the Mediterranean diet) for assessing overall GC and also body mass index for cardia GC and 0 points otherwise. Risk of GC was calculated using Cox proportional hazards regression models while adjusting for relevant confounders. The highest versus lowest score in the healthy lifestyle index was associated with a significant lower risk of GC, by 51% overall (HR 0.49 95% CI 0.35, 0.70), by 77% for cardia GC (HR 0.23 95% CI 0.08, 0.68) and by 47% for noncardia GC (HR 0.53 (95% CI 0.32, 0.87), p-trends<0.001. Population attributable risk calculations showed that 18.8% of all GC and 62.4% of cardia GC cases could have been prevented if participants in this population had followed the healthy lifestyle behaviors of this index. Adopting several healthy lifestyle behaviors including not smoking, limiting alcohol consumption, eating a healthy diet and maintaining a normal weight is associated with a large decreased risk of GC. What's new? Several modifiable lifestyle factors, including smoking status, alcohol consumption, diet quality and weight, have been independently associated with gastric cancer. Behavioral patterns often cluster, however, lifestyle scores can be used to analyse overlapping risk factors. In this study, the authors used a healthy-lifestyle index to evaluate the combined effects of all of the above factors on the risk of developing gastric cancer (GC). They found that following a healthy lifestyle dramatically decreases the burden of gastric cancer.
|
|
| 68. |
- Burgman, A., et al.
(författare)
-
The ESSnuSB Design Study: Overview and Future Prospects
- 2023
-
Ingår i: Universe. - : MDPI. - 2218-1997. ; 9:8
-
Forskningsöversikt (refereegranskat)abstract
- ESSnuSB is a design study for an experiment to measure the CP violation in the leptonic sector at the second neutrino oscillation maximum using a neutrino beam driven by the uniquely powerful ESS linear accelerator. The reduced impact of systematic errors on sensitivity at the second maximum allows for a very precise measurement of the CP violating parameter. This review describes the fundamental advantages of measurement at the second maximum, the necessary upgrades to the ESS linac in order to produce a neutrino beam, the near and far detector complexes, and the expected physics reach of the proposed ESSnuSB experiment, concluding with the near future developments aimed at the project realization.
|
|
| 69. |
- Burgman, A., et al.
(författare)
-
The European Spallation Source neutrino super-beam conceptual design report
- 2022
-
Ingår i: The European Physical Journal Special Topics. - : Springer Nature. - 1951-6355 .- 1951-6401. ; 231:21, s. 3779-3955
-
Forskningsöversikt (refereegranskat)abstract
- A design study, named ESSνSB for European Spallation Source neutrino Super Beam, has been carried out during the years 2018–2022 of how the 5 MW proton linear accelerator of the European Spallation Source under construction in Lund, Sweden, can be used to produce the world’s most intense long-baseline neutrino beam. The high beam intensity will allow for measuring the neutrino oscillations near the second oscillation maximum at which the CP violation signal is close to three times higher than at the first maximum, where other experiments measure. This will enable CP violation discovery in the leptonic sector for a wider range of values of the CP violating phase δCPδCP and, in particular, a higher precision measurement of δCPδCP. The present Conceptual Design Report describes the results of the design study of the required upgrade of the ESS linac, of the accumulator ring used to compress the linac pulses from 2.86 ms to 1.2 μs, and of the target station, where the 5 MW proton beam is used to produce the intense neutrino beam. It also presents the design of the near detector, which is used to monitor the neutrino beam as well as to measure neutrino cross sections, and of the large underground far detector located 360 km from ESS, where the magnitude of the oscillation appearance of νe from νμ is measured. The physics performance of the ESSνSB research facility has been evaluated demonstrating that after 10 years of data-taking, leptonic CP violation can be detected with more than 5 standard deviation significance over 70% of the range of values that the CP violation phase angle δCPδCP can take and that δCPδCP can be measured with a standard error less than 8° irrespective of the measured value of δCPδCP. These results demonstrate the uniquely high physics performance of the proposed ESSνSBESSνSB research facility.
|
|
| 70. |
- Chen, Y. H., et al.
(författare)
-
Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases
- 2023
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 55, s. 44-53
-
Tidskriftsartikel (refereegranskat)abstract
- Metabolic processes can influence disease risk and provide therapeutic targets. By conducting genome-wide association studies of 1,091 blood metabolites and 309 metabolite ratios, we identified associations with 690 metabolites at 248 loci and associations with 143 metabolite ratios at 69 loci. Integrating metabolite-gene and gene expression information identified 94 effector genes for 109 metabolites and 48 metabolite ratios. Using Mendelian randomization (MR), we identified 22 metabolites and 20 metabolite ratios having estimated causal effect on 12 traits and diseases, including orotate for estimated bone mineral density, alpha-hydroxyisovalerate for body mass index and ergothioneine for inflammatory bowel disease and asthma. We further measured the orotate level in a separate cohort and demonstrated that, consistent with MR, orotate levels were positively associated with incident hip fractures. This study provides a valuable resource describing the genetic architecture of metabolites and delivers insights into their roles in common diseases, thereby offering opportunities for therapeutic targets.
|
|
