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| 2. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 3. |
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| 4. |
- Ferreira, MA, et al.
(författare)
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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1741-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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| 5. |
- Dork, T, et al.
(författare)
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Two truncating variants in FANCC and breast cancer risk
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 12524-
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Tidskriftsartikel (refereegranskat)abstract
- Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
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| 11. |
- Guenot, Diego, et al.
(författare)
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Probing electron correlation on the attosecond time scale
- 2014
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Ingår i: High Intensity Lasers and High Field Phenomena, HILAS 2014. - 9781557529954
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Konferensbidrag (refereegranskat)abstract
- We present experimental measurements and theoretical calculations of single and double ionization time delays in various noble gases using an interferometric method. The measured delays allow us to extract information on the electron correlation.
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| 14. |
- Barillot, T., et al.
(författare)
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Attosecond time delays in C-60 valence photoemissions at the giant plasmon
- 2015
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6596 .- 1742-6588. ; 635, s. 112074-112074
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Konferensbidrag (refereegranskat)abstract
- We perform time-dependent local density functional calculations of the time delay in C-60 HOMO and HOMO-1 photoionization at giant plasmon energies. A semiclassical model is used to develop further insights.
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| 16. |
- Dahlstrom, M, et al.
(författare)
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Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is the most common neurodegenerative disorder and results in severe neurodegeneration and progressive cognitive decline. Neurotrophins are growth factors involved in the development and survival of neurons, but also in underlying mechanisms for memory formation such as hippocampal long-term potentiation. Our aim was to identify small molecules with stimulatory effects on the signaling of two neurotrophins, the nerve growth factor (NGF) and the brain derived neurotrophic factor (BDNF). To identify molecules that could potentiate neurotrophin signaling, 25,000 molecules were screened, which led to the identification of the triazinetrione derivatives ACD855 (Ponazuril) and later on ACD856, as positive allosteric modulators of tropomyosin related kinase (Trk) receptors. ACD855 or ACD856 potentiated the cellular signaling of the neurotrophin receptors with EC50 values of 1.9 and 3.2 or 0.38 and 0.30 µM, respectively, for TrkA or TrkB. ACD855 increased acetylcholine levels in the hippocampus by 40% and facilitated long term potentiation in rat brain slices. The compounds acted as cognitive enhancers in a TrkB-dependent manner in several different behavioral models. Finally, the age-induced cognitive dysfunction in 18-month-old mice could be restored to the same level as found in 2-month-old mice after a single treatment of ACD856. We have identified a novel mechanism to modulate the activity of the Trk-receptors. The identification of the positive allosteric modulators of the Trk-receptors might have implications for the treatment of Alzheimer’s diseases and other diseases characterized by cognitive impairment.
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| 17. |
- Dooley, James, et al.
(författare)
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Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 48, s. 519-527
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.
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| 28. |
- Hagg-Holmberg, S., et al.
(författare)
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The role of blood pressure in risk of ischemic and hemorrhagic stroke in type 1 diabetes
- 2019
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Ingår i: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundHypertension is one of the strongest risk factors for stroke in the general population, while systolic blood pressure has been shown to independently increase the risk of stroke in type 1 diabetes. The aim of this study was to elucidate the association between different blood pressure variables and risk of stroke in type 1 diabetes, and to explore potential nonlinearity of this relationship.MethodsWe included 4105 individuals with type 1 diabetes without stroke at baseline, participating in the nationwide Finnish Diabetic Nephropathy Study. Mean age at baseline was 37.411.9years, median duration of diabetes 20.9 (interquartile range 11.5-30.4) years, and 52% were men. Office systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Based on these pulse pressure (PP) and mean arterial pressure (MAP) were calculated. Strokes were classified based on medical and autopsy records, as well as neuroimaging. Cox proportional hazard models were performed to study how the different blood pressure variables affected the risk of stroke and its subtypes.ResultsDuring median follow-up time of 11.9 (9.21-13.9) years, 202 (5%) individuals suffered an incident stroke; 145 (72%) were ischemic and 57 (28%) hemorrhagic. SBP, DBP, PP, and MAP all independently increased the risk of any stroke. SBP, PP, and MAP increased the risk of ischemic stroke, while SBP, DBP, and MAP increased the risk of hemorrhagic stroke. SBP was strongly associated with stroke with a hazard ratio of 1.20 (1.11-1.29)/10mmHg. When variables were modeled using restricted cubic splines, the risk of stroke increased linearly for SBP, MAP, and PP, and non-linearly for DBP.Conclusions The different blood pressure variables are all independently associated with increased risk of stroke in individuals with type 1 diabetes. The risk of stroke, ischemic stroke, and hemorrhagic stroke increases linearly at blood pressure levels less than the current recommended treatment guidelines.
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| 32. |
- Xia, CY, et al.
(författare)
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Hodgkin Lymphoma Monozygotic Triplets Reveal Divergences in DNA Methylation Signatures
- 2020
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 10, s. 598872-
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Tidskriftsartikel (refereegranskat)abstract
- We studied DNA methylation profiles in four different cell populations from a unique constellation of monozygotic triplets in whom two had developed Hodgkin Lymphoma (HL). We detected shared differences in DNA methylation signatures when comparing the two HL-affected triplets with the non-affected triplet. The differences were observed in naïve B-cells and marginal zone-like B-cells. DNA methylation differences were also detected when comparing each of the HL-affected triplets against each other. Even though we cannot determine whether treatment and/or disease triggered the observed differences, we believe our data are important on behalf of forthcoming studies, and that it might provide important clues for a better understanding of HL pathogenesis.
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| 37. |
- Jimenez-Galan, A., et al.
(författare)
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Phase Measurement of a Fano Resonance Using Tunable Attosecond Pulses
- 2015
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 635, s. 092137-092137
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Konferensbidrag (refereegranskat)abstract
- We study photoionization of argon atoms close to the 3s(2)3p(6) -> 3s(1)3p(6)4p Fano resonance using an attosecond pulse train and a weak infrared probe field. An interferometric technique combined with tunable attosecond pulses allows us to determine the phase of the photoionization amplitude as a function of photon energy. We interpret the experimental results using an analytical two-photon model based on the Fano formalism and obtain quantitative agreement.
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| 38. |
- Larsen, P, et al.
(författare)
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Synthesis of [C-11]iodomethane by iodination of [C-11]methane
- 1997
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Ingår i: APPLIED RADIATION AND ISOTOPES. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0969-8043. ; 48:2, s. 153-157
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- [C-11]iodomethane was synthesized by iodination of[C-11]methane with iodine. The reaction was carried out in a system where [C-11]methane, helium and iodine vapours were mixed and heated. The formed [C-11]iodomethane was continuously removed from the reac
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| 40. |
- Luostarinen, T., et al.
(författare)
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Human papillomavirus, other sexually transmitted infections and risk of cervical cancer : A Nordic Joint Study
- 2011
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Ingår i: IEA World Congress of Epidemiology, 7–11 August 2011, Edinburgh International Conference Centre, Edinburgh, Scotland. - : BMJ. ; 65, s. A266-A266
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Konferensbidrag (refereegranskat)abstract
- Introduction: Human papillomavirus (HPV) is considered necessary cause of invasive cervical cancer (ICC), but relations between different HPV types and other sexually transmitted infections in cervical carcinogenesis are unresolved. The CCRPB-EU Network conducted a large study, aiming to assess how major high- and low-risk HPV types, 16, 18 and 6, and possible cofactors, Chlamydia trachomatis and herpes simplex virus type 2 (HSV-2), interact in the aetiology of cervical cancer. Methods: A case-control study was nested in four Nordic serum banks containing serum samples from approximately 1 000 000 women. Linkage to cancer registries resulted to 604 ICC cases diagnosed after serum sampling. Five controls were matched to bank, age at sampling and storage time. IgG antibodies specific for HPV types, C trachomatis and HSV-2 were determined, and tobacco smoke exposure measured by serum cotinine, and HPV DNA in cancer tissue PCR-tested. ORs were estimated by conditional logistic regression, and adjusted for cotinine and for HPV16, HPV18 and C trachomatis, when applicable. Results: Seropositivity for HPV16 did not confer any increased risk for HPV18 DNA positive cancer and HPV18 seropositivity had no association with HPV16 DNA positive cancer. HPV6 had no effect on its own but an antagonistic joint effect with HPV16. HSV-2 had little or no association. C trachomatis had a strongly increased risk for cervical cancer, which remained also among HPV18 seropositives. Conclusions: Type-specific HPV DNA persistence is important in cervical carcinogenesis. HSV-2 is possibly not a cofactor, but C trachomatis is probably a strong cofactor for ICC.
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| 41. |
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| 42. |
- Toivola, J., et al.
(författare)
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Overexpression of chloroplast NADPH-dependent thioredoxin reductase in Arabidopsis enhances leaf growth and elucidates in vivo function of reductase and thioredoxin domains
- 2013
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Ingår i: Frontiers in Plant Science. - : Frontiers Media SA. - 1664-462X. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Plant chloroplasts have versatile thioredoxin systems including two thioredoxin reductases and multiple types of thioredoxins. Plastid-localized NADPH-dependent thioredoxin reductase (NTRC) contains both reductase (NTRd) and thioredoxin (TRXd) domains in a single polypeptide and forms homodimers. To study the action of NTRC and NTRC domains in vivo, we have complemented the ntrc knockout line of Arabidopsis with the wild type and full-length NTRC genes, in which 2-Cys motifs either in NTRd, or in TRXd were inactivated. The ntrc line was also transformed either with the truncated NTRd or TRXd alone. Overexpression of wild-type NTRC promoted plant growth by increasing leaf size and biomass yield of the rosettes. Complementation of the ntrc line with the full-length NTRC gene containing an active reductase but an inactive TRXd, or vice versa, recovered wild-type chloroplast phenotype and, partly, rosette biomass production, indicating that the NTRC domains are capable of interacting with other chloroplast thioredoxin systems. Overexpression of truncated NTRd or TRXd in ntrc background did not restore wild-type phenotype. Modeling of the three-dimensional structure of the NTRC dimer indicates extensive interactions between the NTR domains and the TRX domains further stabilize the dimeric structure. The long linker region between the NTRd and TRXd, however, allows flexibility for the position of the TRXd in the dimer. Supplementation of the TRXd in the NTRC homodimer model by free chloroplast thioredoxins indicated that TRXf is the most likely partner to interact with NTRC. We propose that overexpression of NTRC promotes plant biomass yield both directly by stimulation of chloroplast biosynthetic and protective pathways controlled by NTRC and indirectly via free chloroplast thioredoxins. Our data indicate that overexpression of chloroplast thiol redox-regulator has a potential to increase biofuel yield in plant and algal species suitable for sustainable bioenergy production.
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| 43. |
- van Zuydam, Natalie, et al.
(författare)
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Genome-Wide Association Study of Peripheral Artery Disease
- 2021
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 2574-8300. ; 14:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant (P-association <= 5x10(-8)) associations with PAD in 449 548 (N-cases=12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], P-diabetes=2.5x10(-9), P-interactionwithdiabetes=5.3x10(-7)). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], P-smokers=9.3x10(-10), P-interactionwithsmoking=3.9x10(-5)). Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
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