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- Almstedt, Elin, 1988-, et al.
(författare)
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Integrative discovery of treatments for high-risk neuroblastoma
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.
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| 2. |
- Almstedt, Elin, et al.
(författare)
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Real-time evaluation of glioblastoma growth in patient-specific zebrafish xenografts
- 2021
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 24:5, s. 726-738
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patient-derived xenograft (PDX) models of glioblastoma (GBM) are a central tool for neuro-oncology research and drug development, enabling the detection of patient-specific differences in growth, and in vivo drug response. However, existing PDX models are not well suited for large-scale or automated studies. Thus, here, we investigate if a fast zebrafish-based PDX model, supported by longitudinal, AI-driven image analysis, can recapitulate key aspects of glioblastoma growth and enable case-comparative drug testing.Methods: We engrafted 11 GFP-tagged patient-derived GBM IDH wild-type cell cultures (PDCs) into 1-day-old zebrafish embryos, and monitored fish with 96-well live microscopy and convolutional neural network analysis. Using light-sheet imaging of whole embryos, we analyzed further the invasive growth of tumor cells.Results: Our pipeline enables automatic and robust longitudinal observation of tumor growth and survival of individual fish. The 11 PDCs expressed growth, invasion and survival heterogeneity, and tumor initiation correlated strongly with matched mouse PDX counterparts (Spearman R = 0.89, p < 0.001). Three PDCs showed a high degree of association between grafted tumor cells and host blood vessels, suggesting a perivascular invasion phenotype. In vivo evaluation of the drug marizomib, currently in clinical trials for GBM, showed an effect on fish survival corresponding to PDC in vitro and in vivo marizomib sensitivity.Conclusions: Zebrafish xenografts of GBM, monitored by AI methods in an automated process, present a scalable alternative to mouse xenograft models for the study of glioblastoma tumor initiation, growth, and invasion, applicable to patient-specific drug evaluation.
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| 5. |
- Krona, Cecilia, et al.
(författare)
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GLIOBLASTOMA GROWTH IS SHAPED BY INVASION ROUTE-SPECIFIC FUNCTIONAL SIGNATURES
- 2023
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Ingår i: Neuro-Oncology. - 1522-8517. ; 25:Supplement: 5, MODL-16
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- One of the defining features of glioblastomas (GBMs) is the capacity for invasive growth along multiple anatomical pathways in the brain. GBM is well-studied on a genetic and molecular level, but clinically relevant and experimentally tractable models of invasive growth are largely lacking. Here, we report an integrated study of patient-matched information, genomic- and molecular profiles with growth in mouse brains to expose treatments and biomarkers associated with glioblastoma invasion and recurrence. In total, 64 patient-derived cell lines (PDCLs) were injected into the striatum of n ≥ 4 mice each. The 45 tumor-forming PDCLs were each scored for 10 distinct growth characteristics (n = 182 mice). The repertoire of phenotypes was highly divergent, and our material included clear cases of perivascular route invasion, white matter route invasion, perineuronal satellitosis, and gliosarcoma. We explored if cellular pathways, monitored by RNA-sequencing, could account for these differences. GSEA highlighted a positive enrichment for highly proliferative proneural tumors characterized by Notch activation, neuronal signaling, and epigenetic gene regulatory programs in the tumor-initiating lines. Transcriptional signatures were also strongly predictive of route-specific invasion. Diffuse invasion was predominantly seen in classical-subtype PDCLs with astrocytic or outer radial glia-like signatures. Proneural PDCLs, in turn, grew as solid tumors with an invasive peripheral region around vasculature, and mesenchymal tumors were more demarcated. To explore the therapeutic implications of our findings, we used our data-driven method (TargetTranslator, Nat Comm 2020) to predict the drug vulnerabilities of different types of invasive glioblastoma. Defined GBM tumors with perivascular invasion are characterized by increased IGFR1, MAPK/ERK, PI3K/AKT/mTOR, and JAK2 signaling. Diffusively growing GBM tumors, on the other hand, depend more on Wnt/β-catenin signaling, neuronal signaling, and active inflammatory response. Using a sphere invasion assay, we confirm that targeting both PI3K- and Wnt signaling selectively reduces glioblastoma invasion, highlighting their therapeutic potential.
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| 8. |
- Martin, Lene, 1953-, et al.
(författare)
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Test-retest variation in macular thickness measurements with the Heidelberg Retina Tomograph
- 2012
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Ingår i: Clinical and experimental optometry. - : Informa UK Limited. - 0816-4622 .- 1444-0938. ; 95:5, s. 515-521
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The aim was to evaluate the test-retest variation of macular thickness measurements using the Heidelberg Retina Tomograph (HRT3) Retina Module and compare it with the Stratus optical coherence tomography (OCT). As no normative data has been published for the HRT Retina Module, a secondary purpose was to obtain reference values for this technique. Methods: Thirty healthy subjects and nine patients with macular oedema were examined. The healthy subjects underwent five examinations by two experienced examiners at two different occasions. The patients with maculopathy were examined twice by one examiner on one occasion. All measurements were made with both the HRT3 and the Stratus OCT and the macular thickness measurements were used for calculations of thetest-retest variation. Results: In healthy subjects the coefficient of variation (CV) ranged from 4.5 to 8.8 per cent with the HRT3 and from 0.6 to 1.5 per cent with the Stratus OCT. In the nine patients withmacular oedema, the HRT CV ranged from 7.9 to16.6 per cent and for OCT from 1.1 to 2.5 per cent. The intra-class correlation in the central area for intra-observer/intra-visit in healthy subjects was 0.78 with the HRT3 and 0.93 with the Stratus OCT. Corresponding values for the patients with macular oedema were 0.64 with the HRT3 and 1.0 with the Stratus OCT. Mean macular thickness was significantly larger in all areas measured with the HRT3 compared with the Stratus OCT. No significant correlations were found between the thickness values from the different instruments. Conclusion: In this study, macular thickness was measured with two different techniques. The HRT3 showed lower repeatability and reproducibility as well as a higher CV compared with the Stratus OCT in both healthy subjects and patients with macular oedema. This difference might be of clinical relevance, even though the nine patients with maculopathy in the current study showed abnormal results with both methods.
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| 9. |
- Molnar, Anna, et al.
(författare)
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Central macular thickness in 6.5-year-old children born extremely preterm is strongly associated with gestational age even when adjusted for risk factors
- 2017
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Ingår i: Retina. - : Lippincott Williams & Wilkins. - 0275-004X .- 1539-2864. ; 37:12, s. 2281-2288
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:To assess the macular thickness in 6.5-year-old children born extremelypreterm (EPT) in comparison with children born at term and to investigate risk factorsassociated with the macular thickness in the preterm group.Methods:A population-based study of 6.5-year-old children born before the gestationalage of 27 weeks and age-matched control subjects. Macular assessments with opticalcoherence tomography were performed, and the results were compared with neonatal riskfactors and sex.Results:Adequate optical coherence tomography measurements were obtained from134 children born EPT (mean gestational age of 25 weeks [range 23–26]) and 145 controlsubjects. The mean (range) of central macula thickness was significantly increased (P,0.001)in the EPT group (right eyes: 282mm [238–356], left eyes: 283mm[229–351]), compared withthe control group (right eyes: 249mm [208–293], left eyes: 248mm[207–290]). A multiple linearmixed model analysis of the EPT group revealed gestational age, retinopathy of prematurity,and male gender as important risk factors for an increased macular thickness. The macularthickness decreased by 3.9mm per gestational week, when adjusted for retinopathy of pre-maturity and sex.Conclusion:Extremely preterm birth constitutes a substantial risk factor for a thickcentral macula, even when adjusted for retinopathy of prematurity and male gender.
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| 10. |
- Rosén, Emil
(författare)
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Modeling glioblastoma growth patterns and their mechanistic origins
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma (GBM) is the most common and aggressive primary brain cancer. GBM cells migrate away from the primary lesion and invade healthy brain tissue. The invading cells escape surgical resection, radiotherapy and develop resistance to chemotherapy. Consequently, despite treatment, recurrence is inevitable, and survival is only 14 months. For this purpose, we conducted four studies where we integrated experimental data from extensive patient material with image analysis and mathematical modeling.In study 1, we developed a tool, TargetTranslator, integrating different data modalities to identify new treatments. We implemented an image analysis pipeline to validate our results using a deep artificial neural network to quantify neuroblastoma cell differentiation.In study 2, we integrated the zebrafish and image analysis from study 1 to develop a high-throughput in vivo assay. Zebrafish were orthotopically injected with GBM cells, and each fish's tumor growth and vital status were automatically measured. We characterized the in vivo proliferation rate, survival, and treatment response to the drug marizomib for several patient-derived cell cultures. Light-sheet imaging also revealed two distinct growth types. The first set of cell cultures grew as bulk tumors, whereas the second set invaded vasculature as single cells.In study 3, we used the image analysis from study 1, coupled with an agent-based model to estimate in vitro cell migration and proliferation from single end-point images. The method was validated by a time series data set and applied to a large high-content drug screen of GBM cells. We identified three promising candidates for reducing GBM cell migration. The method can estimate migration on any end-point images of adherent cells without any additional experimental cost.Study 4 characterized the growth and invasive patterns of 45 patient-derived GBM cell cultures in orthogonal mouse xenografts. We found that up to four independent axes of variation could describe the phenotypes and were associated with distinct transcriptomic pathways. The transcriptomic pathways were in part associated with common genomic alterations and subtypes in GBM. We further identified a particularly aggressive GBM phenotype.In conclusion, this thesis was interdisciplinary and aimed to measure survival, invasion, and morphology from extensive patient material. The work had given us new insight into GBM invasion and growth and developed several scalable models suitable for evaluating new therapies.
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