| 1. |
- Ferrucci, Veronica, et al.
(författare)
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Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1–TGF-β–OTX2–SNAIL via PTEN inhibitio
- 2018
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 141:5, s. 1300-1319
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Tidskriftsartikel (refereegranskat)abstract
- Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common ‘non-synonymous homozygous’ deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.
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| 2. |
- Laurie, Steven, et al.
(författare)
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The RD-Connect Genome-Phenome Analysis Platform : Accelerating diagnosis, research, and gene discovery for rare diseases
- 2022
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 43:6, s. 717-733
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Tidskriftsartikel (refereegranskat)abstract
- Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.
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| 3. |
- Lochmueller, Hanns, et al.
(författare)
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The Position of Neuromuscular Patients in Shared Decision Making. Report from the 235th ENMC Workshop : Milan, Italy, January 19-20, 2018
- 2019
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Ingår i: JOURNAL OF NEUROMUSCULAR DISEASES. - : IOS Press. - 2214-3599 .- 2214-3602. ; 6:1, s. 161-172
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Tidskriftsartikel (refereegranskat)abstract
- In the era of patient-centered medicine, shared decision-making (SDM) - in which healthcare professionals and patients exchange information and preferences and jointly reach a decision - has emerged as the gold standard model for the provision of formal healthcare. Indeed, in many geographical settings, patients are frequently invited to participate in choices concerning the design and delivery of their medical management. From a clinical perspective, benefits of this type of patient involvement encompass, for example, enhanced treatment satisfaction, improved medical compliance, better health outcomes, and maintained or promoted quality of life. Yet, although the theory and enactment of SDM in healthcare are well-described in the literature [1-3], comparatively less attention has been devoted to contextualizing questions relating to if, when, and how to include patients in decisions within medical research. In this context, patient involvement would be expected to be potentially relevant for and applicable to a wide range of activities and processes, from the identification of research priorities and development of grant applications, to the design of patient information and consent procedures, formulation of interventions, identification and recruitment of study sample populations, feasibility of a clinical trial, identification, selection, and specification of endpoints and outcomes in clinical trials and observational studies, data collection and analysis, and dissemination of results. To this end, 45 clinicians, healthcare professionals, researchers, patients, caregivers, and representatives from regulatory authorities and pharmaceutical companies from 15 different countries met to discuss the level of involvement of patients with neuromuscular diseases, specifically in the following settings of medical research for neuromuscular diseases: i) registries and biobanks; ii) clinical trials; and iii) regulatory processes. In this report, we present summaries of the talks that were given during the workshop, as well as discussion outcomes from the three topic areas listed above.
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| 4. |
- Pezzotta, A., et al.
(författare)
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Euclid preparation XLI. Galaxy power spectrum modelling in real space
- 2024
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 687
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the accuracy of the perturbative galaxy bias expansion in view of the forthcoming analysis of the Euclid spectroscopic galaxy samples. We compare the performance of a Eulerian galaxy bias expansion using state-of-the-art prescriptions from the effective field theory of large-scale structure (EFTofLSS) with a hybrid approach based on Lagrangian perturbation theory and high-resolution simulations. These models are benchmarked against comoving snapshots of the flagship I N-body simulation at z = (0.9, 1.2, 1.5, 1.8), which have been populated with H alpha galaxies leading to catalogues of millions of objects within a volume of about 58 h(-3) Gpc(3). Our analysis suggests that both models can be used to provide a robust inference of the parameters (h, omega c) in the redshift range under consideration, with comparable constraining power. We additionally determine the range of validity of the EFTofLSS model in terms of scale cuts and model degrees of freedom. From these tests, it emerges that the standard third-order Eulerian bias expansion - which includes local and non-local bias parameters, a matter counter term, and a correction to the shot-noise contribution - can accurately describe the full shape of the real-space galaxy power spectrum up to the maximum wavenumber of k(max) = 0.45 h Mpc(-1), and with a measurement precision of well below the percentage level. Fixing either of the tidal bias parameters to physically motivated relations still leads to unbiased cosmological constraints, and helps in reducing the severity of projection effects due to the large dimensionality of the model. We finally show how we repeated our analysis assuming a volume that matches the expected footprint of Euclid, but without considering observational effects, such as purity and completeness, showing that we can get constraints on the combination (h, omega c) that are consistent with the fiducial values to better than the 68% confidence interval over this range of scales and redshifts.
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| 5. |
- Thompson, Rachel, et al.
(författare)
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RD-Connect : An Integrated Platform Connecting Databases, Registries, Biobanks and Clinical Bioinformatics for Rare Disease Research
- 2014
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Ingår i: Journal of general internal medicine. - : Springer Science and Business Media LLC. - 0884-8734 .- 1525-1497. ; 29:S3, s. S780-S787
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Forskningsöversikt (refereegranskat)abstract
- Research into rare diseases is typically fragmented by data type and disease. Individual efforts often have poor interoperability and do not systematically connect data across clinical phenotype, genomic data, biomaterial availability, and research/trial data sets. Such data must be linked at both an individual-patient and whole-cohort level to enable researchers to gain a complete view of their disease and patient population of interest. Data access and authorization procedures are required to allow researchers in multiple institutions to securely compare results and gain new insights. Funded by the European Union's Seventh Framework Programme under the International Rare Diseases Research Consortium (IRDiRC), RD-Connect is a global infrastructure project initiated in November 2012 that links genomic data with registries, biobanks, and clinical bioinformatics tools to produce a central research resource for rare diseases.
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