| 1. |
- Orlando, Ludovic, et al.
(författare)
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Recalibrating Equus evolution using the genome sequence of an early Middle Pleistocene horse
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 499:7456, s. 74-
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Tidskriftsartikel (refereegranskat)abstract
- The rich fossil record of equids has made them a model for evolutionary processes(1). Here we present a 1.12-times coverage draft genome from a horse bone recovered from permafrost dated to approximately 560-780 thousand years before present (kyr BP)(2,3). Our data represent the oldest full genome sequence determined so far by almost an order of magnitude. For comparison, we sequenced the genome of a Late Pleistocene horse (43 kyr BP), and modern genomes of five domestic horse breeds (Equus ferus caballus), a Przewalski's horse (E. f. prze-walskii) and a donkey (E. asinus). Our analyses suggest that the Equus lineage giving rise to all contemporary horses, zebras and donkeys originated 4.0-4.5 million years before present (Myr BP), twice the conventionally accepted time to the most recent common ancestor of the genus Equus(4,5). We also find that horse population size fluctuated multiple times over the past 2 Myr, particularly during periods of severe climatic changes. We estimate that the Przewalski's and domestic horse populations diverged 38-72 kyr BP, and find no evidence of recent admixture between the domestic horse breeds and the Przewalski's horse investigated. This supports the contention that Przewalski's horses represent the last surviving wild horse population(6). We find similar levels of genetic variation among Przewalski's and domestic populations, indicating that the former are genetically viable and worthy of conservation efforts. We also find evidence for continuous selection on the immune system and olfaction throughout horse evolution. Finally, we identify 29 genomic regions among horse breeds that deviate from neutrality and show low levels of genetic variation compared to the Przewalski's horse. Such regions could correspond to loci selected early during domestication.
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| 2. |
- Rasmussen, Morten, et al.
(författare)
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Ancient human genome sequence of an extinct Palaeo-Eskimo
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 463:7282, s. 757-762
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Tidskriftsartikel (refereegranskat)abstract
- We report here the genome sequence of an ancient human. Obtained from ∼4,000-year-old permafrost-preserved hair, the genome represents a male individual from the first known culture to settle in Greenland. Sequenced to an average depth of 20×, we recover 79% of the diploid genome, an amount close to the practical limit of current sequencing technologies. We identify 353,151 high-confidence single-nucleotide polymorphisms (SNPs), of which 6.8% have not been reported previously. We estimate raw read contamination to be no higher than 0.8%. We use functional SNP assessment to assign possible phenotypic characteristics of the individual that belonged to a culture whose location has yielded only trace human remains. We compare the high-confidence SNPs to those of contemporary populations to find the populations most closely related to the individual. This provides evidence for a migration from Siberia into the New World some 5,500 years ago, independent of that giving rise to the modern Native Americans and Inuit.
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| 3. |
- Allesøe, Rosa Lundbye, et al.
(författare)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 4. |
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| 5. |
- Andersson, Anders-Petter, 1969-
(författare)
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Interaktiv musikkomposition
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation, titled Interactive Music Composition, is a practice based Ph.D. thesis in the field of Musicology. The purpose is to explore if and how one can compose computer based interactive music, that is musically satisfying for an interacting audience, consisting of both laymen and skilled musicians. The text describes the design and reflection in two interactive music installations: Do-Be-DJ, open-air installation in a public park, and, Mufi, with modular and moveable interface. Based on methods and perspectives in Musicology and Interaction Design, a composition model for interactive music is developed. The model investigates the experience dimensions listen, explore, compose and collaborate. It also investigates the design dimensions of interaction, narrative structure, composition rule and sound node. The conceptual approach is to apply improvisation and composition methods from jazz, pop and groove based music on interactive music. It also uses the concepts of openess in musical structures and interpretation, musical mediation of actions and meaning and everyday use of music, when composing interactive music. The dissertation contributes to an understanding of how to create composition techniques for interactive music, such as: Direct, varied and shifting response. It reflects on the change in meaning of the musicological terms composition, improvisation, musical work, listener, musician and audience. And on the interaction design terms interaction, gameplay, system and user. The term co-creator is used to describe an actively, interacting and collaborating person, to complement traditional terms like audience, performer and user.
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| 6. |
- Andersson, Robin, 1980-
(författare)
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Decoding the Structural Layer of Transcriptional Regulation : Computational Analyses of Chromatin and Chromosomal Aberrations
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gene activity is regulated at two separate layers. Through structural and chemical properties of DNA – the primary layer of encoding – local signatures may enable, or disable, the binding of proteins or complexes of them with regulatory potential to the DNA. At a higher level – the structural layer of encoding – gene activity is regulated through the properties of higher order DNA structure, chromatin, and chromosome organization. Cells with abnormal chromosome compaction or organization, e.g. cancer cells, may thus have perturbed regulatory activities resulting in abnormal gene activity. Hence, there is a great need to decode the transcriptional regulation encoded in both layers to further our understanding of the factors that control activity and life of a cell and, ultimately, an organism. Modern genome-wide studies with those aims rely on data-intense experiments requiring sophisticated computational and statistical methods for data handling and analyses. This thesis describes recent advances of analyzing experimental data from quantitative biological studies to decipher the structural layer of encoding in human cells. Adopting an integrative approach when possible, combining multiple sources of data, allowed us to study the influences of chromatin (Papers I and II) and chromosomal aberrations (Paper IV) on transcription. Combining chromatin data with chromosomal aberration data allowed us to identify putative driver oncogenes and tumor-suppressor genes in cancer (Paper IV). Bayesian approaches enabling the incorporation of background information in the models and the adaptability of such models to data have been very useful. Their usages yielded accurate and narrow detection of chromosomal breakpoints in cancer (Papers III and IV) and reliable positioning of nucleosomes and their dynamics during transcriptional regulation at functionally relevant regulatory elements (Paper II). Using massively parallel sequencing data, we explored the chromatin landscapes of human cells (Papers I and II) and concluded that there is a preferential and evolutionary conserved positioning at internal exons nearly unaffected by the transcriptional level. We also observed a strong association between certain histone modifications and the inclusion or exclusion of an exon in the mature gene transcript, suggesting a functional role in splicing.
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| 7. |
- Cordova, R., et al.
(författare)
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Dietary intake of advanced glycation end products (AGEs) and changes in body weight in European adults
- 2020
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Ingår i: European Journal of Nutrition. - : Springer Berlin/Heidelberg. - 1436-6207 .- 1436-6215. ; 59, s. 2893-2904
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Advanced glycation end products (AGEs) can be formed in foods by the reaction of reducing sugars with proteins, and have been shown to induce insulin resistance and obesity in experimental studies. We examined the association between dietary AGEs intake and changes in body weight in adults over an average of 5 years of follow-up.Methods: A total of 255,170 participants aged 25–70 years were recruited in ten European countries (1992–2000) in the PANACEA study (Physical Activity, Nutrition, Alcohol, Cessation of smoking, Eating out of home in relation to Anthropometry), a sub-cohort of the EPIC (European Prospective Investigation into Cancer and Nutrition). Body weight was measured at recruitment and self-reported between 2 and 11 years later depending on the study center. A reference database for AGEs was used containing UPLC–MS/MS-measured Nε-(carboxymethyl)-lysine (CML), Nε-(1-carboxyethyl)-lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) in 200 common European foods. This reference database was matched to foods and decomposed recipes obtained from country-specific validated dietary questionnaires in EPIC and intake levels of CEL, CML, and MG-H1 were estimated. Associations between dietary AGEs intake and body weight change were estimated separately for each of the three AGEs using multilevel mixed linear regression models with center as random effect and dietary AGEs intake and relevant confounders as fixed effects.Results: A one-SD increment in CEL intake was associated with 0.111 kg (95% CI 0.087–0.135) additional weight gain over 5 years. The corresponding additional weight gain for CML and MG-H1 was 0.065 kg (0.041–0.089) and 0.034 kg (0.012, 0.057), respectively. The top six food groups contributing to AGEs intake, with varying proportions across the AGEs, were cereals/cereal products, meat/processed meat, cakes/biscuits, dairy, sugar and confectionary, and fish/shellfish.Conclusion: In this study of European adults, higher intakes of AGEs were associated with marginally greater weight gain over an average of 5 years of follow-up.
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| 8. |
- Davies, Siwan M, et al.
(författare)
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Identification of the Fugloyarbanki tephra in the NGRIP ice-core: a key tie-point for marine and ice-core sequences during the last glacial period
- 2008
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Ingår i: Journal of Quaternary Science. - : Wiley. - 0267-8179 .- 1099-1417. ; 23:5, s. 409-414
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Tidskriftsartikel (refereegranskat)abstract
- A visible tephra horizon in the NGRIP ice core has been identified by geochemical analysis as the Fugloyarbanki Tephra, a widespread marker horizon in marine cores from the Faroe Islands area and the northern North Atlantic. An age of 26 740 ± 390 yr b2k (1σ uncertainty) is derived for this tephra according to the new Greenland Ice Core Chronology (GICC05) based on multi-parameter counting of annual layers. Detection of this tephra for the first time within the NGRIP ice core provides a key tie-point between marine and ice-core records during the transition between MIS 3 and 2. Identification of this volcanic event within the Greenland records demonstrates the future potential of using tephrochronology to precisely correlate palaeoarchives in widely separated localities that span the last glacial period, as well as providing a potential method for examining the extent of the radiocarbon marine reservoir effect at this time.
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| 9. |
- Hougaard, Jesper Leth, et al.
(författare)
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The nerve fibre layer symmetry test: computerized evaluation of human retinal nerve fibre layer thickness as measured by optical coherence tomography
- 2004
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Ingår i: Acta Ophthalmologica Scandinavica. - : Wiley. - 1395-3907 .- 1600-0420. ; 82:4, s. 410-418
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To present and test a new interpretative concept, the nerve fibre layer symmetry test (NST), for computerized evaluation of retinal nerve fibre layer thickness (RNFLT) as measured by optical coherence tomography (OCT) in glaucoma. Methods: The NST concept was constructed and tested in a pilot study. A total of 32 healthy and 40 age-matched glaucomatous eyes were included and examined by OCT, computerized perimetry, RNFL/disc photography, tonometry and a general ophthalmologic examination. Results: The observed NST sensitivity and specificity were high, at 38/40 eyes (95%) and 32/32 eyes (100%), respectively, and 40/40 eyes (100%), and 31/32 eyes (97%), respectively, when correcting the OCT RNFLT measurement for the influence of variability in image signal/quality. The NST sensitivity was 8-10% higher than the single most sensitive traditional OCT RNFLT parameter; this difference was not statistically significant in this small sample. Conclusion: The NST showed high specificity and sensitivity for detection of RNFLT attenuation indicating early to severe glaucoma. Although promising, the NST needs to be further developed and validated in larger study samples and in patients with various stages of glaucomatous damage.
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| 10. |
- Häfner, Sophia J., et al.
(författare)
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Ribosomal RNA 2′-O-methylation dynamics impact cell fate decisions
- 2023
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Ingår i: Developmental Cell. - 1534-5807. ; 58:17, s. 9-1609
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Tidskriftsartikel (refereegranskat)abstract
- Translational regulation impacts both pluripotency maintenance and cell differentiation. To what degree the ribosome exerts control over this process remains unanswered. Accumulating evidence has demonstrated heterogeneity in ribosome composition in various organisms. 2′-O-methylation (2′-O-me) of rRNA represents an important source of heterogeneity, where site-specific alteration of methylation levels can modulate translation. Here, we examine changes in rRNA 2′-O-me during mouse brain development and tri-lineage differentiation of human embryonic stem cells (hESCs). We find distinct alterations between brain regions, as well as clear dynamics during cortex development and germ layer differentiation. We identify a methylation site impacting neuronal differentiation. Modulation of its methylation levels affects ribosome association of the fragile X mental retardation protein (FMRP) and is accompanied by an altered translation of WNT pathway-related mRNAs. Together, these data identify ribosome heterogeneity through rRNA 2′-O-me during early development and differentiation and suggest a direct role for ribosomes in regulating translation during cell fate acquisition.
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| 11. |
- Immerstrand, Charlotte, et al.
(författare)
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Conjugated-polymer micro- and milliactuators for biological applications
- 2002
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Ingår i: MRS bulletin. - : Springer Science and Business Media LLC. - 0883-7694 .- 1938-1425. ; 27:6, s. 461-464
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Tidskriftsartikel (refereegranskat)abstract
- The development of new conjugated-polymer tools for the study of the biological realm, and for use in a clinical setting, is reviewed in this article. Conjugated-polymer actuators, based on the changes of volume of the active conjugated polymer during redox transformation, can be used in electrolytes employed in cell-culture media and in biological fluids such as blood, plasma, and urine. Actuators ranging in size from 10 μm to 100 μm suitable for building structures to manipulate single cells are produced with photolithographic techniques. Larger actuators may be used for the manipulation of blood vessels and biological tissue.
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| 12. |
- Ingvarsson, Johan, et al.
(författare)
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Detection of pancreatic cancer using antibody microarray-based serum protein profiling
- 2008
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Ingår i: Proteomics. - : Wiley. - 1615-9861 .- 1615-9853. ; 8:11, s. 2211-2219
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Tidskriftsartikel (refereegranskat)abstract
- The driving force behind oncoproteomics is to identify protein signatures that are associated with a particular malignancy. Here, we have used a recombinant scFv antibody microarray in an attempt to classify sera derived from pancreatic adenocarcinoma patients versus healthy subjects. Based on analysis of nonfractionated, directly labeled, whole human serum proteomes we have identified a protein signature based on 19 nonredundant analytes, that discriminates between cancer patients and healthy subjects. Furthermore, a potential protein signature, consisting of 21 protein analytes, could be defined that was shown to be associated with cancer patients having a life expectancy of <12 months. Taken together, the data suggest that antibody microarray analysis of complex proteomes will be a useful tool to define disease associated protein signatures.
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| 13. |
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| 14. |
- Jacobs, Kevin B, et al.
(författare)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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| 15. |
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| 16. |
- Käll, Lukas, et al.
(författare)
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A combined transmembrane topology and signal peptide prediction method
- 2004
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 338:5, s. 1027-1036
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Tidskriftsartikel (refereegranskat)abstract
- An inherent problem in transmembrane protein topology prediction and signal peptide prediction is the high similarity between the hydrophobic regions of a transmembrane helix and that of a signal peptide, leading to cross-reaction between the two types of predictions. To improve predictions further, it is therefore important to make a predictor that aims to discriminate between the two classes. In addition, topology information can be gained when successfully predicting a signal Peptide leading a trans' membrane protein since it dictates that the N terminus of the mature protein must be on the non-cytoplasmic side of the membrane. Here, we present Phobius, a combined transmembrane protein topology and signal peptide predictor. The predictor is based on a hidden Markov model (HMM) that models the different sequence regions of a signal peptide and the different regions of a transmembrane protein in a series of interconnected states. Training was done on a newly assembled and curated dataset. Compared to TMHMM and SignalP, errors coming from cross-prediction between transmembrane segments and signal peptides were reduced substantially by Phobius. False classifications of signal peptides were reduced from 26.1% to 3.9% and false classifications of transmembrane helices were reduced from 19.0%, to 7.7%. Phobius was applied to the proteomes of Honzo sapiens and Escherichia coli. Here we also noted a drastic reduction of false classifications compared to TMHMM/SignalP, suggesting that Phobius is well suited for whole-genome annotation of signal peptides and transmembrane regions. The method is available at http://phobius.cgb.ki.se/ as well as at http://phobius.binf.ku.dk/.
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| 17. |
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| 18. |
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| 19. |
- Liu, Zhaoxu, et al.
(författare)
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Somatostatin effects on the proteome of the LNCaP cell-line
- 2007
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Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 30:5, s. 1173-1179
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Tidskriftsartikel (refereegranskat)abstract
- Some clinical results indicate that somatostatin (sms) might be useful in the treatment of advanced prostate cancer (HRPC). Because of its transient in vivo half-life only more stable derivatives of sms are of interest in this context. Recent studies have shown that natural sms can be conjugated to a carbohydrate (smsdx) with preservation of sms-like effects on the prostatic tumor cell proteome. The present study identifies some of the affected proteins in an effort to elucidate pathways and proteins that might be of importance for the potential usefulness of sms treatment in HRPC. After incubating the LNCaP cell-line with sms14/smsdx, comparative proteomics was used for analysing and identifying affected proteins. Protein expression patterns were analysed with two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Catalytic mitochondrial and mitochondrial-associated proteins were significantly affected (fold change approximately 2 or higher) and they were in general up-regulated. Apoptosis-related proteins were both up-regulated (VDAC1, VDAC2) and down-regulated (PRDX2, TCTP). The fold change was >2 for PRDX2 and <2 for the others. There was a strong agreement between sms and smsdx on the up- and down-regulation of proteins. Sms/smsdx triggered up-regulation of catalytic mitochondrial proteins and seemed to affect apoptosis-related proteins. This could indicate important pathways on which smsdx might be able to curb the progression of HRPC. The results encourage a pending clinical phase II study.
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| 20. |
- Londoño, Catalina, et al.
(författare)
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Polyphenol intake and epithelial ovarian cancer risk in the European prospective investigation into cancer and nutrition (Epic) study
- 2021
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Ingår i: Antioxidants. - : MDPI. - 2076-3921. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Despite some epidemiological evidence on the protective effects of polyphenol intake on epithelial ovarian cancer (EOC) risk from case-control studies, the evidence is scarce from prospective studies and non-existent for several polyphenol classes. Therefore, we aimed to investigate the associations between the intake of total, classes and subclasses of polyphenols and EOC risk in a large prospective study. The study was conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which included 309,129 adult women recruited mostly from the general population. Polyphenol intake was assessed through validated country-specific dietary questionnaires and the Phenol-Explorer database. During a mean follow-up of 14 years, 1469 first incident EOC cases (including 806 serous, 129 endometrioid, 102 mucinous, and 67 clear cell tumours) were identified. In multivariable-adjusted Cox regression models, the hazard ratio in the highest quartile of total polyphenol intake compared with the lowest quartile (HRQ4vsQ1 ) was 1.14 (95% CI 0.94–1.39; p-trend = 0.11). Similarly, the intake of most classes and subclasses of polyphenols were not related to either overall EOC risk or any EOC subtype. A borderline statistically significant positive association was observed between phenolic acid intake (HRQ4vsQ1 = 1.20, 95% CI 1.01–1.43; p-trend = 0.02) and EOC risk, especially for the serous subtype and in women with obesity, although these associations did not exceed the Bonferroni correction threshold. The current results do not support any association between polyphenol intake and EOC in our large European prospective study. Results regarding phenolic acid intake need further investigation.
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| 21. |
- McKee, Lauren, 1985-, et al.
(författare)
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Introducing endo-xylanase activity into an exo-acting arabinofuranosidase that targets side chains
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATIONAL ACADEMY OF SCIENCES. - 0027-8424 .- 1091-6490. ; 109:17
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Tidskriftsartikel (refereegranskat)abstract
- The degradation of the plant cell wall by glycoside hydrolases is central to environmentally sustainable industries. The major polysaccharides of the plant cell wall are cellulose and xylan, a highly decorated beta-1,4-xylopyranose polymer. Glycoside hydrolases displaying multiple catalytic functions may simplify the enzymes required to degrade plant cell walls, increasing the industrial potential of these composite structures. Here we test the hypothesis that glycoside hydrolase family 43 (GH43) provides a suitable scaffold for introducing additional catalytic functions into enzymes that target complex structures in the plant cell wall. We report the crystal structure of Humicola insolens AXHd3 (HiAXHd3), a GH43 arabinofuranosidase that hydrolyses O3-linked arabinose of doubly substituted xylans, a feature of the polysaccharide that is recalcitrant to degradation. HiAXHd3 displays an N-terminal five-bladed beta-propeller domain and a C-terminal beta-sandwich domain. The interface between the domains comprises a xylan binding cleft that houses the active site pocket. Substrate specificity is conferred by a shallow arabinose binding pocket adjacent to the deep active site pocket, and through the orientation of the xylan backbone. Modification of the rim of the active site introduces endo-xylanase activity, whereas the resultant enzyme variant, Y166A, retains arabinofuranosidase activity. These data show that the active site of HiAXHd3 is tuned to hydrolyse arabinofuranosyl or xylosyl linkages, and it is the topology of the distal regions of the substrate binding surface that confers specificity. This report demonstrates that GH43 provides a platform for generating bespoke multifunctional enzymes that target industrially significant complex substrates, exemplified by the plant cell wall.
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| 22. |
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| 23. |
- Papadimitriou, Nikos, et al.
(författare)
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A nutrient-wide association study for risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition and the Netherlands Cohort Study
- 2020
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Ingår i: European Journal of Nutrition. - : Springer Nature. - 1436-6207 .- 1436-6215. ; 59:7, s. 2929-2937
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive.Methods: A nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR < 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS).Results: A total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS.Conclusions: Our findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature.
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| 24. |
- Pedersen, Helle Krogh, et al.
(författare)
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A computational framework to integrate high-throughput '-omics' datasets for the identification of potential mechanistic links
- 2018
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Ingår i: Nature Protocols. - : Nature Publishing Group. - 1754-2189 .- 1750-2799. ; 13:12, s. 2781-2800
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Tidskriftsartikel (refereegranskat)abstract
- We recently presented a three-pronged association study that integrated human intestinal microbiome data derived from shotgun-based sequencing with untargeted serum metabolome data and measures of host physiology. Metabolome and microbiome data are high dimensional, posing a major challenge for data integration. Here, we present a step-by-step computational protocol that details and discusses the dimensionality-reduction techniques used and methods for subsequent integration and interpretation of such heterogeneous types of data. Dimensionality reduction was achieved through a combination of data normalization approaches, binning of co-abundant genes and metabolites, and integration of prior biological knowledge. The use of prior knowledge to overcome functional redundancy across microbiome species is one central advance of our method over available alternative approaches. Applying this framework, other investigators can integrate various '-omics' readouts with variables of host physiology or any other phenotype of interest (e.g., connecting host and microbiome readouts to disease severity or treatment outcome in a clinical cohort) in a three-pronged association analysis to identify potential mechanistic links to be tested in experimental settings. Although we originally developed the framework for a human metabolome-microbiome study, it is generalizable to other organisms and environmental metagenomes, as well as to studies including other -omics domains such as transcriptomics and proteomics. The provided R code runs in ~1 h on a standard PC.
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| 25. |
- Petersen, Anders Ø., et al.
(författare)
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Conjugated C-6 hydroxylated bile acids in serum relate to human metabolic health and gut Clostridia species
- 2021
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge about in vivo effects of human circulating C-6 hydroxylated bile acids (BAs), also called muricholic acids, is sparse. It is unsettled if the gut microbiome might contribute to their biosynthesis. Here, we measured a range of serum BAs and related them to markers of human metabolic health and the gut microbiome. We examined 283 non-obese and obese Danish adults from the MetaHit study. Fasting concentrations of serum BAs were quantified using ultra-performance liquid chromatography-tandem mass-spectrometry. The gut microbiome was characterized with shotgun metagenomic sequencing and genome-scale metabolic modeling. We find that tauro- and glycohyocholic acid correlated inversely with body mass index (P = 4.1e-03, P = 1.9e-05, respectively), waist circumference (P = 0.017, P = 1.1e-04, respectively), body fat percentage (P = 2.5e-03, P = 2.3e-06, respectively), insulin resistance (P = 0.051, P = 4.6e-4, respectively), fasting concentrations of triglycerides (P = 0.06, P = 9.2e-4, respectively) and leptin (P = 0.067, P = 9.2e-4). Tauro- and glycohyocholic acids, and tauro-a-muricholic acid were directly linked with a distinct gut microbial community primarily composed of Clostridia species (P = 0.037, P = 0.013, P = 0.027, respectively). We conclude that serum conjugated C-6-hydroxylated BAs associate with measures of human metabolic health and gut communities of Clostridia species. The findings merit preclinical interventions and human feasibility studies to explore the therapeutic potential of these BAs in obesity and type 2 diabetes.
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| 26. |
- Rapin, Nicolas, et al.
(författare)
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Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients
- 2014
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 123:6, s. 894-904
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression profiling has been used extensively to characterize cancer, identify novel subtypes, and improve patient stratification. However, it has largely failed to identify transcriptional programs that differ between cancer and corresponding normal cells and has not been efficient in identifying expression changes fundamental to disease etiology. Here we present a method that facilitates the comparison of any cancer sample to its nearest normal cellular counterpart, using acute myeloid leukemia (AML) as a model. We first generated a gene expression-based landscape of the normal hematopoietic hierarchy, using expression profiles from normal stem/progenitor cells, and next mapped the AML patient samples to this landscape. This allowed us to identify the closest normal counterpart of individual AML samples and determine gene expression changes between cancer and normal. We find the cancer vs normal method (CvN method) to be superior to conventional methods in stratifying AML patients with aberrant karyotype and in identifying common aberrant transcriptional programs with potential importance for AML etiology. Moreover, the CvN method uncovered a novel poor-outcome subtype of normal-karyotype AML, which allowed for the generation of a highly prognostic survival signature. Collectively, our CvN method holds great potential as a tool for the analysis of gene expression profiles of cancer patients.
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| 27. |
- Rohrmann, S., et al.
(författare)
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Smoking and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition
- 2013
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 108:3, s. 708-714
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Tidskriftsartikel (refereegranskat)abstract
- Background: Smoking is not associated with prostate cancer incidence in most studies, but associations between smoking and fatal prostate cancer have been reported. Methods: During 1992 and 2000, lifestyle information was assessed via questionnaires and personal interview in a cohort of 145112 European men. Until 2009, 4623 incident cases of prostate cancer were identified, including 1517 cases of low-grade, 396 cases of high grade, 1516 cases of localised, 808 cases of advanced disease, and 432 fatal cases. Multivariable Cox proportional hazards regression models were used to examine the association of smoking status, smoking intensity, and smoking duration with the risk of incident and fatal prostate cancer. Results: Compared with never smokers, current smokers had a reduced risk of prostate cancer (RR = 0.90, 95% CI: 0.83-0.97), which was statistically significant for localised and low-grade disease, but not for advanced or high-grade disease. In contrast, heavy smokers (25+ cigarettes per day) and men who had smoked for a long time (40+ years) had a higher risk of prostate cancer death (RR = 1.81, 95% CI: 1.11-2.93; RR = 1.38, 95% CI: 1.01-1.87, respectively). Conclusion: The observation of an increased prostate cancer mortality among heavy smokers confirms the results of previous prospective studies.
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| 28. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 29. |
- Traulsen, Lisbet Krogh, et al.
(författare)
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Determinants of persistent asthma in young adults
- 2018
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Ingår i: European clinical respiratory journal. - : Informa UK Limited. - 2001-8525. ; 5:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of the study was to evaluate determinants for the prognosis of asthma in a population-based cohort of young adults. Design: The study was a nine-year clinical follow up of 239 asthmatic subjects from an enriched population-based sample of 1,191 young adults, aged 20-44 years, who participated in an interviewer-administered questionnaire and clinical examination at baseline in 2003-2006. From the interview, an asthma score was generated as the simple sum of affirmative answers to five main asthma-like symptoms in order to analyse symptoms of asthma as a continuum. The clinical examination comprised spirometry, bronchial challenge or bronchodilation, and skin prick test. Results: Among the 239 individuals with asthma at baseline 164 (69%) had persistent asthma at follow up, while 68 (28%) achieved remission of asthma and seven (3%) were diagnosed with COPD solely. Determinants for persistent asthma were use of medication for breathing within the last 12 months: Short-acting beta-adrenoceptor agonists (SABA) only (OR 3.39; 95%CI: 1.47-7.82) and inhaled corticosteroids (ICS) and/or long-acting beta-adrenoceptor agonists (LABA) (8.95; 3.87-20.69). Stratified by age of onset determinants for persistence in individuals with early-onset asthma (age less than 16 years) were FEV₁ below predicted (7.12; 1.61-31.50), asthma score at baseline (2.06; 1.15-3.68) and use of ICS and/or LABA within 12 months (9.87; 1.95-49.98). In individuals with late-onset asthma the determinant was use of ICS and/or LABA within 12 months (6.84; 2.09-22.37). Conclusions: Pulmonary function below predicted, severity of disease expressed by asthma score and use of ICS and/or LABA were all determinants for persistent early-onset asthma, whereas only use of ICS and/or LABA was a determinant in late-onset asthma. A high asthma score indicated insufficient disease control in a substantial proportion of these young adults.
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| 30. |
- Traulsen, Lisbet Krogh, et al.
(författare)
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Risk factors for incident asthma and COPD in a cohort of young adults
- 2018
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Ingår i: Clinical Respiratory Journal. - : Wiley. - 1752-6981. ; 12:3, s. 1021-1029
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The aim of the study was to describe potential shared risk factors for incident asthma and COPD in a population-based, 9-year follow-up study. Methods: From a cohort of 1191 individuals, aged 20-44, who participated in baseline survey including spirometry, bronchial challenge, and skin prick test (SPT) 742 subjects (62%) were reexamined at follow-up in 2012-2014. Results: A total of 27 incident cases of asthma and 22 cases of COPD were identified at follow-up corresponding to an incidence rate of 5.8 (95% CI 3.9-8.4) and 3.5 (2.2-5.3) per 1000 person years, respectively. Among the identified COPD cases a total of 12 were Asthma-COPD Overlap Syndrome (ACOS). Atopy defined by positive SPT was a risk factor for asthma in males (OR 7.54; 95% CI 1.24-45.90), whereas risk factors in females were nasal allergy (3.81; 1.20-12.11), FEV1<100% predicted (3.96; 1.07-14.62) and parental asthma (3.06; 1.00-9.40). Risk factors for COPD in males were bronchial hyperresponsiveness (23.13; 1.41-380.50) and FEV1<100% predicted (all male cases had FEV1<100% predicted) and in females current smoking (3.34; 1.16-9.59) and asthma at baseline (5.21; 1.48-18.34). Conclusions: No shared risk factors for incident asthma and COPD were found. Despite low power when stratifying by sex risk factors for incident asthma and COPD emphasize considerable gender differences.
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| 31. |
- van Roekel, Eline H., et al.
(författare)
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Circulating metabolites associated with alcohol intake in the european prospective investigation into cancer and nutrition cohort
- 2018
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the metabolites associated with alcohol consumption may provide insights into the metabolic pathways through which alcohol may affect human health. We studied associations of alcohol consumption with circulating concentrations of 123 metabolites among 2974 healthy participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Alcohol consumption at recruitment was self-reported through dietary questionnaires. Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQTMp180 kit). Data were randomly divided into discovery (2/3) and replication (1/3) sets. Multivariable linear regression models were used to evaluate confounder-adjusted associations of alcohol consumption withmetabolite concentrations. Metabolites significantly related to alcohol intake in the discovery set (FDR q-value < 0.05) were further tested in the replication set (Bonferroni-corrected p-value < 0.05). Of the 72metabolites significantly related to alcohol intake in the discovery set, 34 were also significant in the replication analysis, including three acylcarnitines, the amino acid citrulline, four lysophosphatidylcholines, 13 diacylphosphatidylcholines, seven acyl-alkylphosphatidylcholines, and six sphingomyelins. Our results confirmed earlier findings that alcohol consumption was associated with several lipid metabolites, and possibly also with specific acylcarnitines and amino acids. This provides further leads for future research studies aiming at elucidating the mechanisms underlying the effects of alcohol in relation to morbid conditions.
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| 32. |
- Wadt, Karin A W, et al.
(författare)
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Molecular characterization of melanoma cases in denmark suspected of genetic predisposition.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.
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| 33. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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