| 1. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
- Rajewsky, N., et al.
(author)
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LifeTime and improving European healthcare through cell-based interceptive medicine
- 2020
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In: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 587:7834, s. 377-386
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Journal article (peer-reviewed)abstract
- LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.
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| 3. |
- Dujon, B, et al.
(author)
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The nucleotide sequence of Saccharomyces cerevisiae chromosome XV
- 1997
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 387:6632, s. 98-102
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Journal article (peer-reviewed)abstract
- Chromosome XV was one of the last two chromosomes of Saccharomyces cerevisiae to be discovered(1). It is the third-largest yeast chromosome after chromosomes XII and IV, and is very similar in size to chromosome VII. It alone represents 9% of the yeast genome (8% if ribosomal DNA is included). When systematic sequencing of chromosome XV was started, 93 genes or markers were identified, and most of them were mapped(2). However, very little else was known about chromosome XV which, in contrast to shorter chromosomes, had not been the object of comprehensive genetic or molecular analysis. It was therefore decided to start sequencing chromosome XV only in the third phase of the European Yeast Genome Sequencing Programme, after experience was gained on chromosomes III, XI and II (refs 3-5). The sequence of chromosome XV has been determined from a set of partly overlapping cosmid clones derived from a unique yeast strain, and physically mapped at 3.3-kilobase resolution before sequencing. As well as numerous new open reading frames (ORFs) and genes encoding tRNA or small RNA molecules, the sequence of 1,091,283 base pairs confirms the high proportion of orphan genes and reveals a number of ancestral and successive duplications with other yeast chromosomes.
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| 4. |
- Weinstein, John N., et al.
(author)
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The cancer genome atlas pan-cancer analysis project
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Research review (peer-reviewed)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 5. |
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| 6. |
- Drakvik, E., et al.
(author)
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Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment
- 2020
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In: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 134
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Journal article (peer-reviewed)abstract
- The number of anthropogenic chemicals, manufactured, by-products, metabolites and abiotically formed transformation products, counts to hundreds of thousands, at present. Thus, humans and wildlife are exposed to complex mixtures, never one chemical at a time and rarely with only one dominating effect. Hence there is an urgent need to develop strategies on how exposure to multiple hazardous chemicals and the combination of their effects can be assessed. A workshop, “Advancing the Assessment of Chemical Mixtures and their Risks for Human Health and the Environment” was organized in May 2018 together with Joint Research Center in Ispra, EU-funded research projects and Commission Services and relevant EU agencies. This forum for researchers and policy-makers was created to discuss and identify gaps in risk assessment and governance of chemical mixtures as well as to discuss state of the art science and future research needs. Based on the presentations and discussions at this workshop we want to bring forward the following Key Messages: • We are at a turning point: multiple exposures and their combined effects require better management to protect public health and the environment from hazardous chemical mixtures. • Regulatory initiatives should be launched to investigate the opportunities for all relevant regulatory frameworks to include prospective mixture risk assessment and consider combined exposures to (real-life) chemical mixtures to humans and wildlife, across sectors. • Precautionary approaches and intermediate measures (e.g. Mixture Assessment Factor) can already be applied, although, definitive mixture risk assessments cannot be routinely conducted due to significant knowledge and data gaps. • A European strategy needs to be set, through stakeholder engagement, for the governance of combined exposure to multiple chemicals and mixtures. The strategy would include research aimed at scientific advancement in mechanistic understanding and modelling techniques, as well as research to address regulatory and policy needs. Without such a clear strategy, specific objectives and common priorities, research, and policies to address mixtures will likely remain scattered and insufficient. © 2019 The Authors
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| 7. |
- Jordans, I. P.M., et al.
(author)
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Definition and sonographic reporting system for Cesarean scar pregnancy in early gestation : modified Delphi method
- 2022
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In: Ultrasound in Obstetrics and Gynecology. - : Wiley. - 0960-7692 .- 1469-0705. ; 59:4, s. 437-449
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Journal article (peer-reviewed)abstract
- Objective: To develop a standardized sonographic evaluation and reporting system for Cesarean scar pregnancy (CSP) in the first trimester, for use by both general gynecology and expert clinics. Methods: A modified Delphi procedure was carried out, in which 28 international experts in obstetric and gynecological ultrasonography were invited to participate. Extensive experience in the use of ultrasound to evaluate Cesarean section (CS) scars in early pregnancy and/or publications concerning CSP or niche evaluation was required to participate. Relevant items for the detection and evaluation of CSP were determined based on the results of a literature search. Consensus was predefined as a level of agreement of at least 70% for each item, and a minimum of three Delphi rounds were planned (two online questionnaires and one group meeting). Results: Sixteen experts participated in the Delphi study and four Delphi rounds were performed. In total, 58 items were determined to be relevant. We differentiated between basic measurements to be performed in general practice and advanced measurements for expert centers or for research purposes. The panel also formulated advice on indications for referral to an expert clinic. Consensus was reached for all 58 items on the definition, terminology, relevant items for evaluation and reporting of CSP. It was recommended that the first CS scar evaluation to determine the location of the pregnancy should be performed at 6–7 weeks' gestation using transvaginal ultrasound. The use of magnetic resonance imaging was not considered to add value in the diagnosis of CSP. A CSP was defined as a pregnancy with implantation in, or in close contact with, the niche. The experts agreed that a CSP can occur only when a niche is present and not in relation to a healed CS scar. Relevant sonographic items to record included gestational sac (GS) size, vascularity, location in relation to the uterine vessels, thickness of the residual myometrium and location of the pregnancy in relation to the uterine cavity and serosa. According to its location, a CSP can be classified as: (1) CSP in which the largest part of the GS protrudes towards the uterine cavity; (2) CSP in which the largest part of the GS is embedded in the myometrium but does not cross the serosal contour; and (3) CSP in which the GS is partially located beyond the outer contour of the cervix or uterus. The type of CSP may change with advancing gestation. Future studies are needed to validate this reporting system and the value of the different CSP types. Conclusion: Consensus was achieved among experts regarding the sonographic evaluation and reporting of CSP in the first trimester.
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| 8. |
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| 9. |
- El Kharraz, S., et al.
(author)
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The androgen receptor depends on ligand-binding domain dimerization for transcriptional activation
- 2021
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In: Embo Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 22:12
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Journal article (peer-reviewed)abstract
- Whereas dimerization of the DNA-binding domain of the androgen receptor (AR) plays an evident role in recognizing bipartite response elements, the contribution of the dimerization of the ligand-binding domain (LBD) to the correct functioning of the AR remains unclear. Here, we describe a mouse model with disrupted dimerization of the AR LBD (AR(Lmon/Y)). The disruptive effect of the mutation is demonstrated by the feminized phenotype, absence of male accessory sex glands, and strongly affected spermatogenesis, despite high circulating levels of testosterone. Testosterone replacement studies in orchidectomized mice demonstrate that androgen-regulated transcriptomes in AR(Lmon/Y) mice are completely lost. The mutated AR still translocates to the nucleus and binds chromatin, but does not bind to specific AR binding sites. In vitro studies reveal that the mutation in the LBD dimer interface also affects other AR functions such as DNA binding, ligand binding, and co-regulator binding. In conclusion, LBD dimerization is crucial for the development of AR-dependent tissues through its role in transcriptional regulation in vivo. Our findings identify AR LBD dimerization as a possible target for AR inhibition.
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| 10. |
- Regibo, S., et al.
(author)
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A background galaxy in the field of the beta Pictoris debris disk
- 2012
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 541, s. A3-
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Journal article (peer-reviewed)abstract
- Herschel images in six photometric bands show the thermal emission of the debris disk surrounding beta Pic. In the three PACS bands at 70 mu m, 100 mu m and 160 mu m and in the 250 mu m SPIRE band, the disk is well-resolved, and additional photometry is available in the SPIRE bands at 350 mu m and 500 mu m, where the disk is only marginally resolved. The SPIRE maps reveal a blob to the southwest of beta Pic, coinciding with submillimetre detection of excess emission in the disk. We investigated the nature of this blob. Our comparison of the colours, spectral energy distribution and size of the blob, the disk and the background sources shows that the blob is most likely a background source with a redshift between z = 1.0 and z = 1.6.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Rozenblatt-Rosen, O., et al.
(author)
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Building a high-quality Human Cell Atlas
- 2021
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In: Nature Biotechnology. - : Nature Research. - 1087-0156 .- 1546-1696. ; 39:2, s. 149-153
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Journal article (peer-reviewed)
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| 17. |
- Russell, Andrew J.C., et al.
(author)
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Regulators of male and female sexual development are critical for the transmission of a malaria parasite
- 2023
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In: Cell Host and Microbe. - : Cell Press. - 1931-3128 .- 1934-6069. ; 31:2, s. 305-319.e10
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Journal article (peer-reviewed)abstract
- Malaria transmission to mosquitoes requires a developmental switch in asexually dividing blood-stage parasites to sexual reproduction. In Plasmodium berghei, the transcription factor AP2-G is required and sufficient for this switch, but how a particular sex is determined in a haploid parasite remains unknown. Using a global screen of barcoded mutants, we here identify genes essential for the formation of either male or female sexual forms and validate their importance for transmission. High-resolution single-cell transcriptomics of ten mutant parasites portrays the developmental bifurcation and reveals a regulatory cascade of putative gene functions in the determination and subsequent differentiation of each sex. A male-determining gene with a LOTUS/OST-HTH domain as well as the protein interactors of a female-determining zinc-finger protein indicate that germ-granule-like ribonucleoprotein complexes complement transcriptional processes in the regulation of both male and female development of a malaria parasite.
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| 18. |
- van der Voet, Jan A., et al.
(author)
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Factors associated with longitudinal change of meniscal extrusion in overweight women without clinical signs of osteoarthritis
- 2021
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In: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 60:11, s. 5175-5184
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To identify variables associated with longitudinal change in meniscal extrusion, which might be used as possible targets for knee osteoarthritis (KOA) prevention. METHODS: In a high-risk population of middle-aged overweight women, meniscal extrusion was assessed with magnetic resonance imaging (1.5 T, coronal proton density, in-plane resolution 0.5 mm2, Sante DICOM Editor) at baseline and after 30 months. Outcomes were the absolute change in medial and lateral extrusion (mm) and relative change in extrusion (%). Based upon literature, 11 factors were hypothesized to be associated with longitudinal change. Generalized estimating equations were used to model the effect on meniscal change (P <0.05). RESULTS: In total, 677 knees of 343 women were available for analysis, with a mean age of 55.7 years (+/-3.2) and a mean BMI of 32.3 kg/m2 (+/-4.2). The greatest change in meniscal extrusion appeared medially with incident meniscal tear (4.4%; absolute 0.9 mm (95% CI: 0.3, 1.5; P =0.004); relative 14.5% (4.4, 24.7; 0.005)). Varus malalignment was associated with an increase of medial extrusion of 0.6 mm (37.6%; 0.1, 1.0; 0.009). A 5 kg/m2 higher baseline BMI was associated with absolute and relative increase of medial extrusion of 0.2 mm and 2.96% (0.1, 0.3; <0.001 and 1.3, 4.8; 0.002). Less explicit but significant changes in extrusion appeared with longitudinal change in BMI. CONCLUSION: Meniscal tears, varus malalignment and BMI were significantly associated with change in meniscal extrusion in middle-aged overweight women, providing viable therapeutic targets to prevent or reduce extrusion and thereby decelerate KOA development.
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| 19. |
- Weinsheimer, Shantel, et al.
(author)
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Integration of expression profiles and genetic mapping data to identify candidate genes in intracranial aneurysm.
- 2007
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 32:1, s. 45-57
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Journal article (peer-reviewed)abstract
- Intracranial aneurysm (IA) is a complex genetic disease for which, to date, 10 loci have been identified by linkage. Identification of the risk-conferring genes in the loci has proven difficult, since the regions often contain several hundreds of genes. An approach to prioritize positional candidate genes for further studies is to use gene expression data from diseased and nondiseased tissue. Genes that are not expressed, either in diseased or nondiseased tissue, are ranked as unlikely to contribute to the disease. We demonstrate an approach for integrating expression and genetic mapping data to identify likely pathways involved in the pathogenesis of a disease. We used expression profiles for IAs and nonaneurysmal intracranial arteries (IVs) together with the 10 reported linkage intervals for IA. Expressed genes were analyzed for membership in Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathways. The 10 IA loci harbor 1,858 candidate genes, of which 1,561 (84%) were represented on the microarrays. We identified 810 positional candidate genes for IA that were expressed in IVs or IAs. Pathway information was available for 294 of these genes and involved 32 KEGG biological function pathways represented on at least 2 loci. A likelihood-based score was calculated to rank pathways for involvement in the pathogenesis of IA. Adherens junction, MAPK, and Notch signaling pathways ranked high. Integration of gene expression profiles with genetic mapping data for IA provides an approach to identify candidate genes that are more likely to function in the pathology of IA.
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| 20. |
- Xu, D., et al.
(author)
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Are changes in meniscus volume and extrusion associated to knee osteoarthritis development? A structural equation model
- 2021
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In: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 29:10, s. 1426-1431
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Journal article (peer-reviewed)abstract
- Objective: To explore the interplay between (changes in) medial meniscus volume, meniscus extrusion and radiographic knee osteoarthritis (OA) development over 30 months follow-up (FU). Methods: Data from the PRevention of knee Osteoarthritis in Overweight Females study were used. This cohort included 407 middle-aged women with a body mass index ≥27 kg/m2, who were free of knee OA at baseline. Demographics were collected by questionnaires at baseline. All menisci at both baseline and FU were automatically segmented from MRI scans to obtain the meniscus volume and the change over time (delta volume). Baseline and FU meniscus body extrusion was quantitatively measured on mid-coronal proton density MR images. A structural equation model was created to assess the interplay between both medial meniscus volume and central extrusion at baseline, delta volume, delta extrusion, and incident radiographic knee OA at FU. Results: The structural equation modeling yielded a fair to good fit of the data. The direct effects of both medial meniscus volume and extrusion at baseline on incident OA were statistically significant (Estimate = 0.124, p = 0.029, and Estimate = 0.194, p < 0.001, respectively). Additional indirect effects on incident radiographic OA through delta meniscus volume or delta meniscus extrusion were not statistically significant. Conclusion: Baseline medial meniscus volume and extrusion were associated to incidence of radiographic knee OA at FU in middle-aged overweight and obese women, while their changes were not involved in these effects. To prevent knee OA, interventions might need to target the onset of meniscal pathologies rather than their progression.
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| 21. |
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