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- Derksen, J. W. G., et al.
(författare)
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Real-world evidence contributions to European medicines agency's safety and efficacy evaluations of oncology targeted therapies between 2018-2022
- 2023
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Ingår i: Annals of Oncology. - : Elsevier. - 0923-7534 .- 1569-8041. ; 34:Suppl. 2, s. S930-S930
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: While Real-world Evidence (RWE) has documented value for safety monitoring and disease epidemiology, its objective contribution to safety and efficacy evaluations for regulatory purposes is still unclear. Here, we aim to describe the prevalence and type of RWE considered by European Medicines Agency (EMA) as contribution to efficacy and safety-related evidence generation among approved oncology targeted therapies...Methods: On March 10, 2023, we screened the medicines listing of EMA to identify all anti-cancer targeted therapies for solid malignancies with a decision date (initial marketing authorizations and extension of indications) between 2018-2022. We screened the European public assessment reports (EPARs) using a standardized approach to collect data on RWE. When generated pre-authorization, the RWE contribution to the final regulatory decision was classified as definitive, supportive, or non-supportive. For...Results: Out of a total of 1976 medicines, we identified 55 oncology targeted therapies, corresponding to 75 EPARs (indications), which are described in the table. The use of RWE in regulatory deliberations occurred in 24/75 (32%) EPARs, increasing from 30% in 2018-2020, to 34% in 2021-2022. Pre-authorization RWE was described in 20/24 (83%) EPARs, among which none were definitive, 8 RWE studies (in 7 EPARs) non-supportive, and 20 RWE studies (in 15 EPARs) were supportive of the decision. Published RWE...Conclusions: Over the past 5 years, RWE involvement in the approval of oncology targeted therapies in Europe tends to increase, with the majority being supportive for EMA regulatory decision making complementary to traditional clinical trials...
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- Bonetti, A, et al.
(författare)
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RADICL-seq identifies general and cell type-specific principles of genome-wide RNA-chromatin interactions
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 1018-
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Tidskriftsartikel (refereegranskat)abstract
- Mammalian genomes encode tens of thousands of noncoding RNAs. Most noncoding transcripts exhibit nuclear localization and several have been shown to play a role in the regulation of gene expression and chromatin remodeling. To investigate the function of such RNAs, methods to massively map the genomic interacting sites of multiple transcripts have been developed; however, these methods have some limitations. Here, we introduce RNA And DNA Interacting Complexes Ligated and sequenced (RADICL-seq), a technology that maps genome-wide RNA–chromatin interactions in intact nuclei. RADICL-seq is a proximity ligation-based methodology that reduces the bias for nascent transcription, while increasing genomic coverage and unique mapping rate efficiency compared with existing methods. RADICL-seq identifies distinct patterns of genome occupancy for different classes of transcripts as well as cell type–specific RNA-chromatin interactions, and highlights the role of transcription in the establishment of chromatin structure.
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- Castelo-Branco, A., et al.
(författare)
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Treatment patterns in patients with multiple sclerosis : a single hospital cohort study in Sweden
- 2021
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 27:Suppl. 2, s. 732-732
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: An increasing number of disease-modifying therapies (DMT) for multiple sclerosis (MS) has led to switching between treatments.Objectives: In a Swedish MS cohort study, we analysed switching treatment patterns, including prescribed symptomatic medications, before and after an MS diagnosis.Methods: A national incident MS cohort diagnosed in 2008–2016 in the Swedish National Patient Register was linked to the national Prescribed Drug Register. A subcohort in the electronic medical records (EMR) of the Karolinska University Hospital was analysed for medication usage.Results: Patients with an MS diagnosis in the EMR cohort (n=1289) were identified (female, 68.2%; mean age (standard deviation), 38.8 (12.2) years). Prescribed symptomatic medications in the year before cohort entry included analgesics (23.2%), antidepressants (13.9%), opioids (13.4%), systemic corticosteroids (11.2%), and anxiolytics (10.0%). In the 4 years after cohort entry, medications included analgesics (65.2%), systemic antibacterials (55.9%), anti-inflammatory and antirheumatics (50.1%), antidepressants (34.8%), anxiolytics (21.1%), antiepileptics (19.1%) and ophthalmic drugs (16.6%). Of 1289 patients, 1040 were prescribed a DMT (80.7%). Median time (months, interquartile range) to first usage of new DMTs by age group was 1.71, 0.82–4.30 (<40 years); 1.87, 0.95–7.00 (40–59 years); and 3.96, 1.15–12.16 (⩾60 years). The most common DMTs (n=patients) were first-line (n=1054): interferons (55.9%), rituximab (15.7%), dimethyl fumarate (9.1%), natalizumab (7.4%), glatiramer acetate (7.1%), fingolimod (3.5%); second-line (n=551): rituximab (29.4%), natalizumab (19.4%), dimethyl fumarate (17.6%), fingolimod (16.3%), glatiramer acetate (7.8%), interferons (3.1%), teriflunomide (2.2%); third-line (n=184): rituximab (51.1%), natalizumab (13.0%), interferons (9.8%), fingolimod (9.8%), dimethyl fumarate (6.0%).Conclusions: These data indicate high usage of prescribed symp-tomatic medications before and after the MS diagnosis, which may indicate the consequences of prodromal and early sympto-matic MS. Most patients were treated with a DMT within months of diagnosis, with predominant initial use of interferons, and switching to more potent agents in later lines of therapy. Prescribing patterns are changing and expected to evolve further with earlier use of powerful agents.
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- Zhang, D, et al.
(författare)
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Spatial epigenome-transcriptome co-profiling of mammalian tissues
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 616:7955, s. 113-122
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Tidskriftsartikel (refereegranskat)abstract
- Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context1–5. However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue features were identified by either spatial epigenome or spatial transcriptome we also observed distinct patterns, suggesting their differential roles in defining cell states. Linking epigenome to transcriptome pixel by pixel allows the uncovering of new insights in spatial epigenetic priming, differentiation and gene regulation within the tissue architecture. These technologies are of great interest in life science and biomedical research.
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| 19. |
- Zhang, D, et al.
(författare)
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Spatial epigenome-transcriptome co-profiling of mammalian tissues
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615616:79547955, s. 113-122
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Tidskriftsartikel (refereegranskat)abstract
- Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context1–5. However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue features were identified by either spatial epigenome or spatial transcriptome we also observed distinct patterns, suggesting their differential roles in defining cell states. Linking epigenome to transcriptome pixel by pixel allows the uncovering of new insights in spatial epigenetic priming, differentiation and gene regulation within the tissue architecture. These technologies are of great interest in life science and biomedical research.
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