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| 4. |
- 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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| 5. |
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| 6. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 7. |
- Palin, K, et al.
(författare)
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Contribution of allelic imbalance to colorectal cancer
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 3664-
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Tidskriftsartikel (refereegranskat)abstract
- Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.
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| 9. |
- da Cunha, E., et al.
(författare)
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Measurements of the Dust Properties in z similar or equal to 1-3 Submillimeter Galaxies with ALMA
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 919:1
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Tidskriftsartikel (refereegranskat)abstract
- We present Atacama Large Millimeter/submillimeter Array (ALMA) 2 mm continuum observations of a complete and unbiased sample of 99 870 mu m selected submillimeter galaxies (SMGs) in the Extended Chandra Deep Field South (ALESS). Our observations of each SMG reach average sensitivities of 53 mu Jy beam(-1). We measure the flux densities for 70 sources, for which we obtain a typical 870 mu m-to-2 mm flux ratio of 14 +/- 5. We do not find a redshift dependence of this flux ratio, which would be expected if the dust emission properties of our SMGs were the same at all redshifts. By combining our ALMA measurements with existing Herschel/SPIRE observations, we construct a (biased) subset of 27 galaxies for which the cool dust emission is sufficiently well sampled to obtain precise constraints on their dust properties using simple isothermal models. Thanks to our new 2 mm observations, the dust emissivity index is well constrained and robust against different dust opacity assumptions. The median dust emissivity index of our SMGs is beta similar or equal to 1.9 +/- 0.4, consistent with the emissivity index of dust in the Milky Way and other local and high-redshift galaxies, as well as classical dust-grain model predictions. We also find a negative correlation between the dust temperature and beta, similar to low-redshift observational and theoretical studies. Our results indicate that beta similar or equal to 2 in high-redshift dusty star-forming galaxies, implying little evolution in dust-grain properties between our SMGs and local dusty galaxy samples, and suggesting that these high-mass and high-metallicity galaxies have dust reservoirs driven by grain growth in their interstellar medium.
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| 14. |
- Lyngsø Foged, Henning, et al.
(författare)
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Typical pitfalls leading to gaps between envisaged and realised impacts of manure and nutrient related projects - a gap analysis
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- SuMaNu is a thematic platform concerning nutrients and manure management, established “in order to strengthen the impact of projects’ outcomes in the selected thematic field”, especially via better integration of project results and conclusions into policies. The present gap analysis clarifies in this connection gaps between envisaged and realised impacts of seven projects to promote sustainable manure management, and specifies the impeding pitfalls, i.e. shortcomings and weaknesses that have caused the missing impact. The rationale behind the gap analysis is to help the design and implementation of future projects to achieve stronger impact. For this aim, it summarizes knowledge of selected projects' ability to produce results and recommendations and to communicate these to the end users for integration into policies. To conduct the gap analysis, an approach of deductive and theory-testing research was used based on a set of described and classified potential pitfalls in project design and implementation that could potentially lead to gaps between envisaged and realised policy impact of projects. Links between pitfall categories and implementation gaps were tested by the use of empirical data collected during this study. Six typical pitfalls were defined, and ten recommendations selected for the gap analysis. The analysis was as far as possible based on referenced documentation. Key target stakeholders representing Germany, Poland and Denmark as well as the BSR region were interviewed in order to increase the quality of the analysis and secure impartiality of the results. Generally, there were found gaps between envisaged and realised policy impacts. Out of the six classified pitfalls, not all projects had planned to create policy recommendations or impact among end users. The observed projects performed best with respect to producing planned results, whereas the most common pitfall was the ability to communicate these results. There were found considerable differences between the seven projects’ ability to support policy development and create impacts among end-users. It was among others concluded that projects are more likely to be integrated into policies and be implemented by end users if they adhere to some basic principles: 1) Objectives are SMART and in line with end-user needs; 2) Activities match the objectives and lead to the production of the foreseen results; and 3) Representatives of the administration and the end-users are directly involved in project partnerships and activities.
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| 15. |
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| 16. |
- Cajuso, T, et al.
(författare)
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Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4022-
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Tidskriftsartikel (refereegranskat)abstract
- Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We find highly variable retrotransposon activity among tumors and identify recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identify insertions in APC, likely to be tumor-initiating events. Insertions are positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions is independently associated with poor disease-specific survival.
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| 18. |
- 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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| 19. |
- Kaasinen, E, et al.
(författare)
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Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of the urinary bladder: A Nordic study
- 2003
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Ingår i: European Urology. - 1873-7560. ; 43:6, s. 637-645
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate whether, in patients with carcinoma in situ (CIS) of the urinary bladder, alternating instillation therapy with mitomycin C (MMC) and bacillus Calmette-Guerin (BCG) was more effective and less toxic than conventional BCG monotherapy. Methods: Patients were stratified prospectively for primary, secondary, and concomitant CIS and randomized to one of two regimens. Patients in the alternating group received six weekly intravesical instillations of MMC 40 mg, followed by alternating monthly instillations of BCG 120 mg and MMC for one year. In the monotherapy group, only BCG was instilled on the same schedule. Results: Of 323 enrolled patients, 304 were eligible for analysis. After an overall median follow-up of 56 months, the Kaplan-Meier disease-free estimate for BCG monotherapy was significantly better than that for alternating therapy (p = 0.03; log rank test). Risk for progression appeared lower in the BCG monotherapy group (p = 0.07) but no differences existed in survival. Besides the regimen, CIS category also predicted outcome to some extent. BCG monotherapy caused significantly more local side-effects and premature cessation of instillation treatment than did the alternating therapy. However, no differences were observed in the number of serious side-effects. Conclusion: One-year BCG monotherapy was more effective than the alternating therapy for reducing recurrence and compared well with the best regimens reported from substantially smaller series. The alternating therapy was better tolerated.
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| 22. |
- Kuisma, H, et al.
(författare)
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Parity associates with chromosomal damage in uterine leiomyomas
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 5448-
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Tidskriftsartikel (refereegranskat)abstract
- Mechanical forces in a constrained cellular environment were recently established as a facilitator of chromosomal damage. Whether this could contribute to tumorigenesis is not known. Uterine leiomyomas are common neoplasms that display relatively few chromosomal aberrations. We hypothesized that if mechanical forces contribute to chromosomal damage, signs of this could be seen in uterine leiomyomas from parous women. We examined the karyotypes of 1946 tumors, and found a striking overrepresentation of chromosomal damage associated with parity. We then subjected myometrial cells to physiological forces similar to those encountered during pregnancy, and found this to cause DNA breaks and a DNA repair response. While mechanical forces acting in constrained cellular environments may thus contribute to neoplastic degeneration, and genesis of uterine leiomyoma, further studies are needed to prove possible causality of the observed association. No evidence for progression to malignancy was found.
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| 23. |
- Mehine, M, et al.
(författare)
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Chromothripsis in uterine leiomyomas
- 2013
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Ingår i: The New England journal of medicine. - 1533-4406. ; 369:22, s. 2160-2161
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 26. |
- Sahu, B, et al.
(författare)
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Sequence determinants of human gene regulatory elements
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:3, s. 283-
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Tidskriftsartikel (refereegranskat)abstract
- DNA can determine where and when genes are expressed, but the full set of sequence determinants that control gene expression is unknown. Here, we measured the transcriptional activity of DNA sequences that represent an ~100 times larger sequence space than the human genome using massively parallel reporter assays (MPRAs). Machine learning models revealed that transcription factors (TFs) generally act in an additive manner with weak grammar and that most enhancers increase expression from a promoter by a mechanism that does not appear to involve specific TF–TF interactions. The enhancers themselves can be classified into three types: classical, closed chromatin and chromatin dependent. We also show that few TFs are strongly active in a cell, with most activities being similar between cell types. Individual TFs can have multiple gene regulatory activities, including chromatin opening and enhancing, promoting and determining transcription start site (TSS) activity, consistent with the view that the TF binding motif is the key atomic unit of gene expression.
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