| 1. |
- Adams, Charleen, et al.
(author)
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Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study
- 2019
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In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:1, s. 208-216
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Journal article (peer-reviewed)abstract
- BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
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| 3. |
- Almquist, Joachim, 1980, et al.
(author)
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Unraveling the Pharmacokinetic Interaction of Ticagrelor and MEDI2452 (Ticagrelor Antidote) by Mathematical Modeling
- 2016
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In: CPT: Pharmacometrics and Systems Pharmacology. - : Wiley. - 2163-8306. ; 5:6, s. 313-323
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Journal article (peer-reviewed)abstract
- The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence.
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| 4. |
- Blau, Helen M., et al.
(author)
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Elastic substrates and methods of use in cell manipulation and culture
- 2010
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Patent (pop. science, debate, etc.)abstract
- Methods are provided for the ex vivo manipulation of cells, stem cells and other reproductive cells, by manipulating the cells in a container or device comprising an elastic substrate, wherein the substrate has an elasticity that mimics the elasticity of a native microenvironment of the cell.
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| 5. |
- Both, Adrianus, 1985-, et al.
(author)
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Growth and biochemical composition of Mytilus edulis when reared on effluent from a cod, Gadus morhua, aquaculture facility
- 2012
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In: Journal of Shellfish Research. - : National Shellfisheries Association. - 0730-8000 .- 1943-6319. ; 31:1, s. 79-85
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Journal article (peer-reviewed)abstract
- This study determined the growth and biochemical composition of blue mussels (Mytilus edulis) reared on effluent from Atlantic cod (Gadus morhua) and compared it with mussels reared on a standard shellfish diet. Feeding trials lasted 6 mo, and mussels were sampled on a monthly basis. Dry weight, ash-free dry weight, shell length, and condition index were all significantly higher in algae-fed mussels at the end of the experiment compared with effluent-fed mussels. The carbon content decreased for mussels fed both diets; however, their nitrogen and protein content increased, with effluent-fed mussels having significantly more nitrogen and protein than algae-fed mussels, suggesting that effluent can increase mussel growth. Total lipid and fatty acid (FA) content decreased for effluent-fed mussels at the end of the experiment. There were no significant differences in the lipid class composition between mussels fed the 2 diets. Mussels fed both diets significantly decreased in the amount of 14:0, 16:1ω7, 16:2ω4, 16:4ω1 and 20:5ω3, and effluent-fed mussels also decreased in 18:4ω3 and 21:5ω3, as well as increased in the amount of 17:1, the Zooplankton markers 20:1ω11 and 22:1ω11, and the dienoic nonmethylene-interrupted fatty acids (NMIDs) 20:2a and 22:2b. Significant differences in the amount of individual FAs between mussels fed the 2 diets included a larger amount of 18:2ω6 and 20:4ω6 in algae-fed mussels, and a significantly larger amount of 16:4ω1 in mussels fed effluent. Mussels fed both diets underwent significant increases in the proportion of bacterial FAs, ω6 FAs, Zooplankton markers, and NMIDs. Effluent-fed mussels had a significantly larger proportion of monounsaturated FAs, Zooplankton markers, and NMIDs, as well as a smaller proportion of polyunsaturated FAs, and ω3 and ω6 FAs than algae-fed mussels. The increased presence of Zooplankton markers supports the use of these FAs to track aquaculture wastes.
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| 6. |
- Both, Adrianus, 1985-, et al.
(author)
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Lipid composition of Mytilus edulis reared on organic waste from a Gadus morhua aquaculture facility
- 2011
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In: Aquatic Living Resources. - : EDP Sciences. - 0990-7440 .- 1765-2952. ; 24:3, s. 295-301
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Journal article (peer-reviewed)abstract
- The purpose of this study was to determine biochemical changes occurring in blue mussels (Mytilus edulis) fed effluent from an Atlantic cod (Gadus morhua) aquaculture facility over a period of ten weeks, compared to those in mussels fed a commercial shellfish diet and those supplied only filtered seawater. The total lipid and fatty acid content (mg g -1 wet weight) significantly decreased for mussels fed effluent during the experiment. The only change in the lipid class composition (% total lipid) at the end of the experiment was a significant increase in the proportion of acetone mobile polar lipids. There were several significant changes in the fatty acid composition (% total fatty acid) including an increase in the proportion of 18:1ω9, 18:2ω6, 20:4ω6, 21:5ω3 and the dienoic non-methylene-interrupted fatty acids 20:2a and 22:2b and significant decreases in the proportions of 16:0, 18:4ω3 and 20:5ω3. The increase in non-methylene interrupted dienes suggests that the amount of essential fatty acids in the effluent may be insufficient for optimal mussel growth. The presence of the terrestrial plant marker 18:2ω6 in both the fish feed and the effluent and its increased proportion in mussels fed effluent suggest that this fatty acid may have potential as a marker for aquaculture wastes.
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| 7. |
- Both, Adrianus, 1985-, et al.
(author)
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Physical and biochemical properties of effluent leaving an onshore Atlantic cod (Gadus morhua, Linnaeus 1758; Gadiformes: Gadidae) aquaculture facility and potential use in integrated multi-trophic aquaculture
- 2013
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In: Aquaculture Research. - : Hindawi Limited. - 1355-557X .- 1365-2109. ; 44:12, s. 1940-1951
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Journal article (peer-reviewed)abstract
- The physical and biochemical properties of Atlantic cod (Gadus morhua) wastes were analysed, and the waste remediation potential of blue mussels (Mytilus edulis) was assessed. Waste generated daily by Atlantic cod represented 24.9% of the cod feed added to the system. Particle distributions determined using a Coulter Multisizer and image analysis revealed that the majority of the particles in terms of numbers occupy the smaller size ranges; however, larger particles occupy a larger proportion of the volume. Effluent was composed of particles <70 μm (36%), 70-500 μm (31%) and particles >500 μm (33%) by weight. The amount of dissolved carbon and nitrogen associated with the effluent represented 3.1% and 3.7%, respectively, of the total feed added to the system daily. Particles <70 μm had significantly less organic matter, lipids and fatty acids and were expected to be ingested more by mussels than larger particles. The major lipid classes present in effluent were free fatty acids, triacylglycerols, phospholipids, acetone mobile polar lipids and sterol. Cod effluent contained two essential fatty acids DHA and EPA, a diatom marker (16:1ω7), as well as two zooplankton markers 22:1ω11 and 20:1ω9, which accumulated in mussels and may serve as markers for aquaculture wastes. Although only 36% of the effluent was of a size suitable for mussel ingestion, this size fraction has the greatest potential to spread to surrounding areas. These particulates may be useful as an alternate food source when natural seston is low.
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| 8. |
- Brandão, Andreia, et al.
(author)
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The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor
- 2020
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In: Cancers. - : MDPI AG. - 2072-6694. ; 12:11
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Journal article (peer-reviewed)abstract
- The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
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| 9. |
- Brandao, A, et al.
(author)
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The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor
- 2020
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In: Cancers. - : MDPI AG. - 2072-6694. ; 12:11
-
Journal article (peer-reviewed)abstract
- The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case–control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1–3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
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