1. |
- Householder, John Ethan, et al.
(författare)
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One sixth of Amazonian tree diversity is dependent on river floodplains
- 2024
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Ingår i: NATURE ECOLOGY & EVOLUTION. - 2397-334X. ; 8, s. 901-911
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Tidskriftsartikel (refereegranskat)abstract
- Amazonia's floodplain system is the largest and most biodiverse on Earth. Although forests are crucial to the ecological integrity of floodplains, our understanding of their species composition and how this may differ from surrounding forest types is still far too limited, particularly as changing inundation regimes begin to reshape floodplain tree communities and the critical ecosystem functions they underpin. Here we address this gap by taking a spatially explicit look at Amazonia-wide patterns of tree-species turnover and ecological specialization of the region's floodplain forests. We show that the majority of Amazonian tree species can inhabit floodplains, and about a sixth of Amazonian tree diversity is ecologically specialized on floodplains. The degree of specialization in floodplain communities is driven by regional flood patterns, with the most compositionally differentiated floodplain forests located centrally within the fluvial network and contingent on the most extraordinary flood magnitudes regionally. Our results provide a spatially explicit view of ecological specialization of floodplain forest communities and expose the need for whole-basin hydrological integrity to protect the Amazon's tree diversity and its function.
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2. |
- Luize, Bruno Garcia, et al.
(författare)
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Geography and ecology shape the phylogenetic composition of Amazonian tree communities
- 2024
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Ingår i: JOURNAL OF BIOGEOGRAPHY. - 0305-0270 .- 1365-2699. ; 51:7, s. 1163-1184
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Amazonia hosts more tree species from numerous evolutionary lineages, both young and ancient, than any other biogeographic region. Previous studies have shown that tree lineages colonized multiple edaphic environments and dispersed widely across Amazonia, leading to a hypothesis, which we test, that lineages should not be strongly associated with either geographic regions or edaphic forest types. Location: Amazonia. Taxon: Angiosperms (Magnoliids; Monocots; Eudicots). Methods: Data for the abundance of 5082 tree species in 1989 plots were combined with a mega-phylogeny. We applied evolutionary ordination to assess how phylogenetic composition varies across Amazonia. We used variation partitioning and Moran's eigenvector maps (MEM) to test and quantify the separate and joint contributions of spatial and environmental variables to explain the phylogenetic composition of plots. We tested the indicator value of lineages for geographic regions and edaphic forest types and mapped associations onto the phylogeny. Results: In the terra firme and v & aacute;rzea forest types, the phylogenetic composition varies by geographic region, but the igap & oacute; and white-sand forest types retain a unique evolutionary signature regardless of region. Overall, we find that soil chemistry, climate and topography explain 24% of the variation in phylogenetic composition, with 79% of that variation being spatially structured (R-2 = 19% overall for combined spatial/environmental effects). The phylogenetic composition also shows substantial spatial patterns not related to the environmental variables we quantified (R-2 = 28%). A greater number of lineages were significant indicators of geographic regions than forest types. Main Conclusion: Numerous tree lineages, including some ancient ones (>66 Ma), show strong associations with geographic regions and edaphic forest types of Amazonia. This shows that specialization in specific edaphic environments has played a long-standing role in the evolutionary assembly of Amazonian forests. Furthermore, many lineages, even those that have dispersed across Amazonia, dominate within a specific region, likely because of phylogenetically conserved niches for environmental conditions that are prevalent within regions.
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3. |
- ter Steege, Hans, et al.
(författare)
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Mapping density, diversity and species-richness of the Amazon tree flora
- 2023
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Ingår i: COMMUNICATIONS BIOLOGY. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Using 2.046 botanically-inventoried tree plots across the largest tropical forest on Earth, we mapped tree species-diversity and tree species-richness at 0.1-degree resolution, and investigated drivers for diversity and richness. Using only location, stratified by forest type, as predictor, our spatial model, to the best of our knowledge, provides the most accurate map of tree diversity in Amazonia to date, explaining approximately 70% of the tree diversity and species-richness. Large soil-forest combinations determine a significant percentage of the variation in tree species-richness and tree alpha-diversity in Amazonian forest-plots. We suggest that the size and fragmentation of these systems drive their large-scale diversity patterns and hence local diversity. A model not using location but cumulative water deficit, tree density, and temperature seasonality explains 47% of the tree species-richness in the terra-firme forest in Amazonia. Over large areas across Amazonia, residuals of this relationship are small and poorly spatially structured, suggesting that much of the residual variation may be local. The Guyana Shield area has consistently negative residuals, showing that this area has lower tree species-richness than expected by our models. We provide extensive plot meta-data, including tree density, tree alpha-diversity and tree species-richness results and gridded maps at 0.1-degree resolution. A study mapping the tree species richness in Amazonian forests shows that soil type exerts a strong effect on species richness, probably caused by the areas of these forest types. Cumulative water deficit, tree density and temperature seasonality affect species richness at a regional scale.
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4. |
- Kattge, Jens, et al.
(författare)
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TRY plant trait database - enhanced coverage and open access
- 2020
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Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Tidskriftsartikel (refereegranskat)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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5. |
- de Oliveira, Andressa Souza, et al.
(författare)
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Antifungal activity of sustainable histone deacetylase inhibitors against planktonic cells and biofilms of Candida spp. and Cryptococcusneoformans
- 2023
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Ingår i: Medical Mycology. - : Oxford University Press (OUP). - 1369-3786 .- 1460-2709. ; 61:8
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Tidskriftsartikel (refereegranskat)abstract
- The limited therapeutic options for fungal infections and the increased incidence of fungal strains resistant to antifungal drugs, especially Candida spp., require the development of new antifungal drugs and strategies. Histone deacetylase inhibitors (HDACi), like vorinostat, have been studied in cancer treatment and have antifungal effects, acting alone or synergistically with classical antifungals. Here we investigated the antifungal activity of two novel sustainable HDACi (LDT compounds) based on vorinostat structure. Molecular docking simulation studies reveal that LDT compounds can bind to Class-I HDACs of Candida albicans, C. tropicalis, and Cryptococcus neoformans, which showed similar binding mode to vorinostat. LDT compounds showed moderate activity when tested alone against fungi but act synergistically with antifungal azoles against Candida spp. They reduced biofilm formation by more than 50% in C. albicans (4 µg/mL), with the main action in fungal filamentation. Cytotoxicity of the LDT compounds against RAW264.7 cells was evaluated and LDT536 demonstrated cytotoxicity only at the concentration of 200 µmol/L, while LDT537 showed IC50 values of 29.12 µmol/L. Our data indicated that these sustainable and inexpensive HDACi have potential antifungal and antibiofilm activities, with better results than vorinostat, although further studies are necessary to better understand the mechanism against fungal cells.
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9. |
- Barjesteh van Waalwijk van Doorn-Khosrovani, Sahar, et al.
(författare)
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PCM4EU and PRIME-ROSE : Collaboration for implementation of precision cancer medicine in Europe
- 2024
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Ingår i: Acta Oncologica. - 1651-226X .- 1651-226X. ; 63, s. 385-391
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful. PATIENTS AND METHODS: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe. RESULTS: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients. ble from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.
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10. |
- Caronna, Edoardo, et al.
(författare)
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Redefining migraine prevention: early treatment with anti-CGRP monoclonal antibodies enhances response in the real world
- 2024
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Ingår i: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY. - 0022-3050 .- 1468-330X.
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Tidskriftsartikel (refereegranskat)abstract
- Background Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months. Methods European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as >= 50% and >= 75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response. Results Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models. Conclusions This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success.
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11. |
- Cirino, Glauber, et al.
(författare)
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Observations of Manaus urban plume evolution and interaction with biogenic emissions in GoAmazon 2014/5
- 2018
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Ingår i: Atmospheric Environment. - : Elsevier BV. - 1352-2310 .- 1873-2844. ; 191, s. 513-524
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Tidskriftsartikel (refereegranskat)abstract
- As part of the Observations and Modeling of the Green Ocean Amazon (GoAmazon 2014/5) Experiment, detailed aerosol and trace gas measurements were conducted near Manaus, a metropolis located in the central Amazon Basin. Measurements of aerosol particles and trace gases were done downwind Manaus at the sites T2 (Tiwa Hotel) and T3 (Manacapuru), at a distance of 8 and 70 km from Manaus, respectively. Based on in-plume measurements closer to Manaus (site T2), the chemical signatures of city emissions were used to improve the interpretation of pollutant levels at the T3 site. We derived chemical and physical properties for the city's atmospheric emission ensemble, taking into account only air masses impacted by the Manaus plume at both sites, during the wet and dry season Intensive Operating Periods (IOPs). At T2, average concentrations of aerosol number (CN), CO and SO2 were 5500 cm(-3) (between 10 and 490 nm), 145 ppb and 0.60 ppb, respectively, with a typical ratio ACN/ACO of 60-130 particles cm(-3) ppb(-1). The aerosol scattering (at RH < 60%) and absorption at 637 nm at T2 ranged from 10 to 50 M m(-1) and 5-10 M m(-1), respectively, leading to a mean single scattering albedo (SSA) of 0.70. In addition to identifying periods dominated by Manaus emissions at both T2 and T3, the plume transport between the two sampling sites was studied using back trajectory calculations. Results show that the presence of the Manaus plume at site T3 was important mainly during the daytime and at the end of the afternoons. During time periods directly impacted by Manaus emissions, an average aerosol number concentration of 3200 cm(-3) was measured at T3. Analysis of plume evolution between T2 and T3 indicates a transport time of 4-5 h. Changes of submicron organic and sulfate aerosols ratios relative to CO (Delta OA/Delta CO and Delta SO4/Delta CO, respectively) indicate significant production of secondary organic aerosol (SOA), corresponding to a 40% mass increase in OA and a 30% in SO4 mass concentration. Similarly, during air mass arrival at T3 the SSA increased to 0.83 from 0.70 at T2, mainly associated with an increase in organic aerosol concentration. Aerosol particle size distributions show a strong decrease in the Aitken nuclei mode (10-100 nm) during the transport from T2 to T3, in particular above 30 nm, as a result of efficient coagulation processes into larger particles. A decrease of 30% in the particle number concentration and an increase of about 50 nm in geometric mean diameter were observed from T2 to T3 sites. The study of the evolution of aerosol properties downwind of the city of Manaus improves our understanding of how coupling of anthropogenic and biogenic sources may be impacting the sensitive Amazonian atmosphere.
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12. |
- Gordinho, Luís de Oliveira, et al.
(författare)
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Song divergence between subspecies of reed bunting is more pronounced in singing styles under sexual selection
- 2015
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Ingår i: Animal Behaviour. - : Elsevier BV. - 1095-8282 .- 0003-3472. ; 107, s. 221-231
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Tidskriftsartikel (refereegranskat)abstract
- Song divergence between populations of a species can lead to reproductive isolation and speciation. However, birds may have different singing styles used in distinct social contexts, and songs of each style may change at different rates over time and space. Here, we tested whether song divergence between subspecies of reed bunting, Emberiza schoeniclus, differs with singing style, by comparing song traits of its three singing styles among three subspecies breeding in northern and western Europe. We show that the two singing styles under sexual selection (dawn and fast songs, related to obtaining extrapair and social mates, respectively) diverged significantly more than the slow songs (used as an all-clear signal to nest- attending social females). Multiple song traits differed significantly between the subspecies in all singing styles, with E. s. lusitanica generally being intermediate between E. s. schoeniclus and E. s. witherbyi, and the pattern of song complexity opposing the expected latitudinal gradient (of increasing complexity with increasing latitude). Cluster analyses of populations indicate that sexually selected singing styles are better for discriminating subspecies, describing a scenario of a major split in song features between the migratory, northern E. s. schoeniclus and the two resident, southern subspecies, rather than a clinal variation. The greater song divergence in fast and dawn singing styles suggests that sexual selection may be playing an important role in the incipient speciation of reed buntings.
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13. |
- Governa, Valeria, et al.
(författare)
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Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 119:9
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic strategies directed at the tumor surfaceome (TS), including checkpoint inhibitor blocking antibodies, antibody drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cells, provide a new armament to fight cancer. However, a remaining bottleneck is the lack of strategies to comprehensively interrogate patient tumors for potential TS targets. Here, we have developed a platform (tumor surfaceome mapping [TS-MAP]) integrated with a newly curated TS classifier (SURFME) that allows profiling of primary 3D cultures and intact patient glioma tumors with preserved tissue architecture. Moreover, TS-MAP specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. In high-grade gliomas that remain among the most aggressive forms of cancer, we show that cellular spatial organization (2D vs. 3D) fundamentally transforms the surfaceome and endocytome (e.g., integrins, proteoglycans, semaphorins, and cancer stem cell markers) with general implications for target screening approaches, as exemplified by an ADC targeting EGFR. The TS-MAP platform was further applied to profile the surfaceome and endocytome landscape in a cohort of freshly resected gliomas. We found a highly diverse TS repertoire between patient tumors, not directly associated with grade and histology, which highlights the need for individualized approaches. Our data provide additional layers of understanding fundamental to the future development of immunotherapy strategies, as well as procedures for proteomics-based target identification and selection. The TS-MAP platform should be widely applicable in efforts aiming at a better understanding of how to harness the TS for personalized immunotherapy.
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14. |
- Neto, Júlio Manuel, et al.
(författare)
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Stable isotopes reveal differences in diet among reed bunting subspecies that vary in bill size
- 2017
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Ingår i: Journal of Avian Biology. - : Wiley. - 0908-8857. ; 48:2, s. 284-294
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Tidskriftsartikel (refereegranskat)abstract
- Reed bunting Emberiza schoeniclus subspecies vary considerably in bill size and shape and seem to be at an early stage of speciation, in which bill might be indirectly causing reproductive isolation. Hence, we evaluated whether bill size, as well as age and sex, are associated with foraging niche in three west European subspecies of reed bunting: the thin-billed schoeniclus, the intermediate-billed lusitanica and the thick-billed witherbyi. Blood sampling was undertaken at three sites in southwest Europe during the winter (when these subspecies co-occur), and stable isotope analyses (carbon and nitrogen) were performed to assess their foraging niches. Stable isotope analyses of potential food items confirmed uniform baseline isotopic composition among sites. schoeniclus showed a significantly broader isotopic niche than lusitanica and witherbyi, which seemed otherwise similar despite the fact that witherbyi is more divergent in bill traits. Stable isotope ratios were consistent with the latter two subspecies feeding on C3-plant-feeding insects, whereas schoeniclus diet also included C4 plant material. Despite its lower sexual dimorphism, sex and age differences were found only in schoeniclus, but these differences vary between locations in a complex manner. Our results suggest that bill size and shape differentiated between northern, migratory and southern, resident subspecies as a consequence of natural selection through competition during the winter, which is now reflected in isotopic niche divergence between subspecies. The potential roles of sexual selection, reed thickness and summer temperature on the difference in bill size (and greater sexual dimorphism) between lusitanica and witherbyi are discussed.
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15. |
- Offer, Svenja, et al.
(författare)
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Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration
- 2019
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Ingår i: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 38
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPrimary brain tumors, in particular glioblastoma (GBM), remain among the most challenging cancers. Like most malignant tumors, GBM is characterized by hypoxic stress that triggers paracrine, adaptive responses, such as angiogenesis and macrophage recruitment, rescuing cancer cells from metabolic catastrophe and conventional oncological treatments. The unmet need of strategies to efficiently target tumor “stressness” represents a strong clinical motivation to better understand the underlying mechanisms of stress adaptation. Here, we have investigated how lipid loading may be involved in the paracrine crosstalk between cancer cells and the stromal compartment of the hypoxic tumor microenvironment.MethodsRegions from patient GBM tumors with or without the lipid loaded phenotype were isolated by laser capture microdissection and subjected to comparative gene expression analysis in parallel with cultured GBM cells with or without lipid loading. The potential involvement of extracellular lipids in the paracrine crosstalk with stromal cells was studied by immunoprofiling of the secretome and functional studies in vitro as well as in various orthotopic GBM mouse models, including hyperlipidemic ApoE−/− mice. Statistical analyses of quantitative experimental methodologies were performed using unpaired Student’s T test. For survival analyses of mouse experiments, log-rank test was used, whereas Kaplan-Meier was performed to analyze patient survival.ResultsWe show that the lipid loaded niche of GBM patient tumors exhibits an amplified hypoxic response and that the acquisition of extracellular lipids by GBM cells can reinforce paracrine activation of stromal cells and immune cells. At the functional level, we show that lipid loading augments the secretion of e.g. VEGF and HGF, and may potentiate the cross-activation of endothelial cells and macrophages. In line with these data, in vivo studies suggest that combined local tumor lipid loading and systemic hyperlipidemia of ApoE−/− mice receiving a high fat diet induces tumor vascularization and macrophage recruitment, and was shown to significantly decrease animal survival.ConclusionsTogether, these data identify extracellular lipid loading as a potentially targetable modulator of the paracrine adaptive response in the hypoxic tumor niche and suggest the contribution of the distinct lipid loaded phenotype in shaping the glioma microenvironment.
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16. |
- Taskén, Kjetil, et al.
(författare)
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Single point of entry to the European precision cancer medicine trial network PRIME-ROSE
- 2024
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 1527-7755 .- 0732-183X. ; 42:16
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Konferensbidrag (refereegranskat)abstract
- Background: Over the last decades, there has been a surge in the development and approval of targeted drugs and immunotherapies for treating cancer patients, as seen by the 757 % increase in approvals by the FDA for new cancer treatments since 2000 (1). This has significantly impacted cancer care and contributed to improving overall survival in various cancer subgroups. However, access to these new treatments is constrained by the market access strategy of the patent-owning company and available knowledge of treatment effects. Only a few treatments have received pan-cancer approval from EMA or FDA, and most drugs receive market authorization per indication. As a result, there is a widening access gap between patients with different cancer types (2). Methods: Exploring the effect of biomarker-driven treatments in new cancer subtypes requires the ability to find patients with rare biomarkers. PRIME-ROSE is a European precision medicine network comprising 11 ongoing or soon-to-start national DRUP-like clinical trials testing registered drugs outside their current label (www.prime-rose.eu). Patients with relevant tumor biomarkers are identified and treated with matched drugs available in each trial’s drug portfolio. The ambition is to swiftly and systematically evaluate the effectiveness of approved precision cancer medicines in new indications through pragmatic trial designs and with RWE control cohorts, ensuring expansion into all relevant patient groups to maximize societal benefit. This is particularly relevant for rare cancers, which are enriched in precision medicine trials (3). Results: In PRIME-ROSE, the trials now share and aggregate data to build evidence faster and more effectively impact patient care by addressing key challenges in precision cancer medicine implementation (increasing the recruitment area to 71 million inhabitants). This will significantly reduce the time for filling treatment cohorts and contribute to closing the indication/drug-specific knowledge gap. In fact, several pharmaceutical companies have already shown their interest in and commitment to participating in PRIME-ROSE, as it offers the unique advantage of entering the trials in the network simultaneously (single point of entry) and with a floating allocation of treatment slots between trials, increasing efficiency in finding patients with specific biomarkers to fill treatment cohorts. Conclusions: A unified entry point to the PRIME-ROSE network is feasible and can facilitate building the knowledge base faster for label expansion and/or country-specific approvals/ reimbursement. National multi-stakeholder ecosystems that include pragmatic, RWE-controlled DRUP-like clinical trials may advance precision medicine implementation.
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