| 111. |
- Krop, I, et al.
(författare)
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Lack of HIN-1 methylation in BRCAl-linked and "BRCA1-like" breast tumors
- 2003
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Ingår i: Cancer Research. - 1538-7445 .- 0008-5472. ; 63:9, s. 2024-2027
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Tidskriftsartikel (refereegranskat)abstract
- We recently identified a candidate tumor suppressor gene, HIN-1, that is silenced due to methylation in the majority of sporadic breast carcinomas and is localized to 5q33-qter, an area frequently lost in BRCA1 tumors and thought to harbor a BRCA1 modifier gene. To establish whether germ-line mutations in HIN-1 may influence breast cancer risk, we sequenced the HIN-1 coding region in 10 familial breast cancer patients with positive logarithm of the odds scores of at least one of the markers flanking HIN-1. We also sequenced the HIN-1 coding region in 15 BRCA1 and 35 sporadic breast tumors to determine whether HIN-1 is the target of the frequent 5q loss in BRCA1 tumors. No sequence alterations were found in any of the cases analyzed. However, analysis of HIN-1 promoter methylation status revealed that in striking contrast to sporadic cases, there is a nearly complete lack of HIN-1 methylation in BRCA1 tumors (P < 0.0001). Sporadic breast tumors with a "BRCA1-like" histopathological phenotype also demonstrated significantly lower frequency of HIN-1 promoter methylation (P = 0.01) compared with other cancer types, and there was also a difference among tumors based on their estrogen receptor and HER2 status (P = 0.006), suggesting that HIN-1 methylation patterns are associated with specific breast cancer subtypes.
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| 112. |
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| 113. |
- Lahti, K., et al.
(författare)
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Productivity Aspects in Submerged Arc Welding of Thick High-Strength Steels
- 2015
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Ingår i: Proceedings of IIW International Conference, High-Strength Materials. - Helsingfors. ; , s. 1-6-
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Konferensbidrag (refereegranskat)abstract
- A series of welding tests were made on 35 mm thick F500W high strength steel. This specific steel grade is developed for use in arctic conditions, especially in shipbuilding, and it has excellent impact toughness at temperatures down to -60°C. Submerged arc welding tests were performed using solid and flux-cored welding wire keeping the heat-input at levels typically recommended for thermo mechanically processed highstrengthsteels. Process improvement trials were even made using electrode extension (EE) allowing for higher melt-on rates without any increase in the heat input.However, as the chemical composition of F500W allows for higher heat input without risk for excessive grain growth, tests at higher heat inputs were also made as reference for additional ways to increase productivity. Three fundamental means for improving productivity were analyzed in this study: 1) use of solid or flux-cored wire, 2) effect of groove preparation, and 3) use ofelectrode extension. These all can be introduced without changes in heat input, and hence implementation to existing production systems is easy, economical and quick. Highest increase in productivity is gained by using electrode extension with optimized groove geometry. In the studied thickness of 35 mm, the number of runs was decrease by 60 % from 22 to 9 without increase in the heat input and with approved mechanical properties for this specific steel. Based on the outcome of this study, submerged arc welding can successfully be used for joining of this high strength steel with approved mechanical properties and high productivity.
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| 114. |
- Lahti, M., et al.
(författare)
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The required knowledge for lifespan mental health promotion and prevention for Master’s level mental health nurse education – the eMenthe project
- 2018
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Ingår i: International Journal of Health Promotion and Education. - Abingdon : Routledge. - 1463-5240 .- 2164-9545. ; 56:3, s. 143-154
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we address the kind of knowledge that is required for Master’s level nurse education for lifespan mental health promotion and prevention. Data were collected through structured interviews (N = 109). The interviews were conducted across five European countries. The data were analysed using a thematic content analysis approach. The findings show that Master’s level nurse education needs knowledge related to lifespan issues. Needs were raised in several issues like importance of increasing skills and knowledge of mental health workers. We conclude that there is a need to emphasise the knowledge required for mental health promotion and prevention for Master’s level nursing education across Europe. © 2018 Institute of Health Promotion and Education.
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| 115. |
- Lahti, R. A., et al.
(författare)
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Cause and manner of death and phase of the blood alcohol curve
- 2014
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Ingår i: Forensic Science International. - : Elsevier. - 0379-0738 .- 1872-6283. ; 244, s. 306-312
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Tidskriftsartikel (refereegranskat)abstract
- In a large number of forensic autopsies (N = 28,184) the concentrations of ethanol in femoral blood and bladder urine were determined and the urine-to-blood concentration ratios of ethanol were calculated. Based on the differences in ethanol concentration between urine and blood, the deaths were classified as having occurred during the absorptive, the peak or the post-absorptive phase of the blood-alcohol curve. Most people died in the post-absorptive phase, N = 24,223 (86%), whereas 1538 individuals (5.5%) were still absorbing alcohol and 2423 (8.6%) were at or close to the peak BAC at time of death. Both blood-alcohol concentration (BAC) and urine-alcohol concentration (UAC) were significantly higher in the post-absorptive phase (p less than 0.001). The proportions of people dying in the absorptive and peak phases increased with advancing age. The cause of death (CoD) and manner of death (MoD) according to death certificates were compared with phase of the blood-alcohol curve using amultinomial regression model with and without making adjustment for possible effects of age, gender and BAC. The relative risk (RR) and relative risk ratios (RRR) showed some associations between CoD and phase of the blood-alcohol curve. Undetermined MoD was significantly higher in the absorptive phase compared with the post-absorptive phase (RRR = 2.12). Deaths related to esophagus, stomach and duodenum (RRR = 2.04) and alcoholic liver diseases (RRR = 1.85) were significantly higher at or close to peak phase compared to the post-absorptive phase. Road-traffic fatalities were more prevalent in the peak BAC phase (RRR = 1.33) and deaths by accidental falls were less in the absorptive phase (RRR = 0.58) compared with the post-absorptive phase. The phase of alcohol intoxication seems relevant to consider by forensic experts when alcohol-related deaths are investigated.
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| 116. |
- Maddock, Jane, et al.
(författare)
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Vitamin D and cognitive function : A Mendelian randomisation study.
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. DHCR7(rs12785878), CYP2R1 rs12794714) and their combined synthesis score were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, p curvature ≤ 0.006), with much of the curvature attributed to a single study. DHCR7, CYP2R1, and the synthesis score were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for DHCR7 and CYP2R1, with no overall association observed for the synthesis score. Coefficients for the synthesis score and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.
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| 117. |
- McQuillan, Ruth, et al.
(författare)
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Evidence of Inbreeding Depression on Human Height
- 2012
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:7, s. e1002655-
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Tidskriftsartikel (refereegranskat)abstract
- Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.
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| 118. |
- Merid, Simon Kebede, et al.
(författare)
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Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age
- 2020
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Ingår i: Genome Medicine. - Stockholm : Karolinska Institutet, Dept of Clinical Science and Education, Södersjukhuset. - 1756-994X.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
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| 119. |
- Ndika, J, et al.
(författare)
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Epigenetic Differences in Long Non-coding RNA Expression in Finnish and Russian Karelia Teenagers With Contrasting Risk of Allergy and Asthma
- 2022
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Ingår i: Frontiers in allergy. - : Frontiers Media SA. - 2673-6101. ; 3, s. 878862-
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Tidskriftsartikel (refereegranskat)abstract
- Previously, we investigated skin microbiota and blood cell gene expression in Finnish and Russian teenagers with contrasting incidence of allergic conditions. The microbiota and transcriptomic signatures were distinctly different, with high Acinetobacter abundance and suppression of genes regulating innate immune response in healthy subjects.ObjectiveHere, we investigated long non-coding RNA (lncRNA) expression profiles of blood mononuclear cells (PBMC) from healthy and allergic subjects, to identify lncRNAs that act at the interphase of microbiome-mediated immune homeostasis in allergy/asthma.MethodsGenome-wide co-expression network analyses of blood cell lncRNA/mRNA expression was integrated with skin microbiota profiles of Finnish (69) and Russian (75) subjects. Selected lncRNAs were validated by stimulation of cohort-derived PBMCs and a macrophage cell model with birch pollen allergen (Betv1) or lipopolysaccharide, respectively.ResultsFinnish and Russian PBMCs were differentiated by 3,818 lncRNA transcripts. In the Finnish subjects with high prevalence of allergy and asthma, a subset of 37 downregulated lncRNAs (including, FAM155A-IT1 and LOC400958) were identified. They were part of a co-expression network with 20 genes known to be related to asthma and allergic rhinitis (R > 0.95). Incidentally, all these 20 genes were also components of pathways corresponding to cellular response to bacterium. The Finnish and Russian samples were also differentiated by the abundance of 176 bacterial OTU (operational taxonomic units). The subset of 37 lncRNAs, associated with allergy, was most correlated with the abundance of Acinetobacter (R > +0.5), Jeotgalicoccus (R > +0.5), Corynebacterium (R < −0.5) and Micrococcus (R < −0.5).ConclusionIn Finnish and Russian teenagers with contrasting allergy and asthma prevalence, epigenetic differences in lncRNA expression appear to be important components of the underlying microbiota-immune interactions. Unraveling the functions of the 37 differing lncRNAs may be the key to understanding microbiome-immune crosstalk, and to develop clinically relevant biomarkers.
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| 120. |
- Pervjakova, Natalia, et al.
(författare)
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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 31:19, s. 3377-3391
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Tidskriftsartikel (refereegranskat)abstract
- Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (p < 5x10-8) with GDM, mapping to/near MTNR1B (p = 4.3x10-54), TCF7L2 (p = 4.0x10-16), CDKAL1 (p = 1.6 × 10-14), CDKN2A-CDKN2B (p = 4.1x10-9) and HKDC1 (p = 2.9x10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.
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