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- Kaasinen, E, et al.
(författare)
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Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1252-
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Tidskriftsartikel (refereegranskat)abstract
- Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.
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- Dunlop, Malcolm G, et al.
(författare)
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Cumulative impact of 10 common genetic variants on colorectal cancer risk in 42,333 individuals from eight populations
- 2012
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Ingår i: Gut. - Stockholm : Karolinska Institutet, Dept of Molecular Medicine and Surgery. - 1468-3288 .- 0017-5749.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. DESIGN: Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39 266) and in combination with gender, age and FH (n=11 324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. RESULTS: The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2×10(-16)), confirmed in external validation sets (Sweden p=1.2×10(-6), Finland p=2×10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk. CONCLUSION: Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.
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- Kainu, T, et al.
(författare)
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Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
- 2000
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 97:17, s. 9603-9608
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Tidskriftsartikel (refereegranskat)abstract
- A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
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- Georgitsi, Marianthi, et al.
(författare)
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Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia.
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:8, s. 3321-5
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients.OBJECTIVE: Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.DESIGN: Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.SETTING: The study was conducted at nonprofit academic research and medical centers.PATIENTS: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.MAIN OUTCOME MEASURES: We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features.RESULTS: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.CONCLUSIONS: Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.
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- Heinonen, HR, et al.
(författare)
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Global metabolomic profiling of uterine leiomyomas
- 2017
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 117:12, s. 1855-1864
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Tidskriftsartikel (refereegranskat)
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- Spindlberger, L., et al.
(författare)
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Optical Properties of Vanadium in 4H Silicon Carbide for Quantum Technology
- 2019
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Ingår i: Physical Review Applied. - : AMER PHYSICAL SOC. - 2331-7019. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- We study the optical properties of tetravalent-vanadium impurities in 4H silicon carbide. Light emission from two crystalline sites is observed at wavelengths of 1.28 and 1.33 mu m, with optical lifetimes of 163 and 43 ns, respectively, which remains stable up to 50 and 20 K, respectively. Moreover, spectrally broad photoluminescence is observed up to room temperature. Group-theory and ab initio density-functional supercell calculations enable unequivocal site assignment and shed light on the spectral features of the defects. Specifically, our numerical simulations indicate that the site assignment is reversed with respect to previous assumptions. Our calculations show that vanadium in silicon carbide has highly favorable properties for the generation of single photons in the telecommunication wavelength regime. Combined with the available electronic and nuclear degrees of freedom, vanadium presents all the ingredients required for a highly efficient spin-photon interface.
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- Vartanyan, Sergey L., et al.
(författare)
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Collection of radiocarbon dates on the mammoths (Mammuthus primigenius) and other genera of Wrangel Island, northeast Siberia, Russia
- 2008
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Ingår i: Quaternary Research. - : Cambridge University Press (CUP). - 0033-5894 .- 1096-0287. ; 70:1, s. 51-59
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Tidskriftsartikel (refereegranskat)abstract
- We present and discuss a full list of radiocarbon dates for woolly mammoth and other species of the Mammoth fauna available from Wrangel Island, northeast Siberia, Russia. Most of the radiocarbon dates are published here for the first time. Of the 124 radiocarbon dates on mammoth bone, 106 fall between 3700 and 9000 yr ago. We believe these dates bracket the period of mammoth isolation oil Wrangel Island and their ultimate extinction, which we attribute to natural causes. The absence of dates between 9-12 ka probably indicates a period when mammoths were absent from Wrangel Island. Long bone dimensions of Holocene mammoths from Wrangel Island indicate that these animals were comparable in size to those on the mainland, although they were not large animals, neither can they be classified as dwarfs. Occurrence of mammoth Holocene refugia on the mainland is suggested. Based on other species of the Mammoth fauna that have also been radiocarbon on Wrangel Island, including horse, bison, musk ox and woolly rhinoceros, it appears that the mammoth was the only species of that fauna that inhabited Wrangel Island in the mid-Holocene.
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- Clark, R., et al.
(författare)
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Developing a robust self evaluation framework for active learning : The first stage of an ERASMUS+ project (QAEMarketPlace4HEI)
- 2015
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Ingår i: Proceedings of the 43rd SEFI Annual Conference 2015 - Diversity in Engineering Education: An Opportunity to Face the New Trends of Engineering, SEFI 2015. - : European Society for Engineering Education (SEFI). - 9782873520120
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Konferensbidrag (refereegranskat)abstract
- In ensuring the quality of learning and teaching in Higher Education, self-evaluation is an important component of the process. An example would be the approach taken within the CDIO community whereby self-evaluation against the CDIO standards is part of the quality assurance process. Eight European universities (Reykjavik University, Iceland; Turku University of Applied Sciences, Finland; Aarhus University, Denmark; Helsinki Metropolia University of Applied Sciences, Finland; Umeå University, Sweden; Telecom Bretagne, France; Aston University, United Kingdom; Queens University Belfast, United Kingdom) are engaged in an EU funded Erasmus + project that is exploring the quality assurance process associated with active learning.
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- Karhu, Elisa, et al.
(författare)
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Exercise and gastrointestinal symptoms : running-induced changes in intestinal permeability and markers of gastrointestinal function in asymptomatic and symptomatic runners
- 2017
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Ingår i: European Journal of Applied Physiology. - : Springer. - 1439-6319 .- 1439-6327. ; 117:12, s. 2519-2526
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Tidskriftsartikel (refereegranskat)abstract
- Athletes frequently experience gastrointestinal (GI) symptoms during training and competition. Although the prevalence of exercise-induced GI symptoms is high, the mechanisms leading to GI distress during exercise are not fully understood. The aim of this study was to identify running-induced changes in intestinal permeability and markers of GI function and investigate their association with gastrointestinal symptoms. We recruited 17 active runners who we allocated as either asymptomatic or symptomatic based on their history of experiencing GI symptoms during running. The participants took part in a running test where they were asked to run for 90 min at 80% of their best 10 km race speed. Intestinal permeability was measured at baseline and after the running test. Levels of serum intestinal fatty acid-binding protein (I-FABP), zonulin, bacterial lipopolysaccharide (LPS), and fecal calprotectin were also measured at baseline and after the running test. Running induced a significant increase in intestinal permeability and serum I-FABP concentration but there were no differences between asymptomatic and symptomatic runners. Serum LPS activity did not change from baseline following the running test but the symptomatic group exhibited higher LPS activity at baseline compared to the asymptomatic runners. Running for 90 min at a challenging pace causes small intestinal damage and increases intestinal permeability. However, these alterations in GI function do not appear to correlate with the development of GI symptoms during running.
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