| 1. |
- Chantzi, Efthymia, et al.
(författare)
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COMBImage : a modular parallel processing framework for pairwise drug combination analysis that quantifies temporal changes in label-free video microscopy movies
- 2018
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Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: Large-scale pairwise drug combination analysis has lately gained momentum in drug discovery and development projects, mainly due to the employment of advanced experimental-computational pipelines. This is fortunate as drug combinations are often required for successful treatment of complex diseases. Furthermore, most new drugs cannot totally replace the current standard-of-care medication, but rather have to enter clinical use as add-on treatment. However, there is a clear deficiency of computational tools for label-free and temporal image-based drug combination analysis that go beyond the conventional but relatively uninformative end point measurements.Results: COMBImage is a fast, modular and instrument independent computational framework for in vitro pairwise drug combination analysis that quantifies temporal changes in label-free video microscopy movies. Jointly with automated analyses of temporal changes in cell morphology and confluence, it performs and displays conventional cell viability and synergy end point analyses. The image processing algorithms are parallelized using Google's MapReduce programming model and optimized with respect to method-specific tuning parameters. COMBImage is shown to process time-lapse microscopy movies from 384-well plates within minutes on a single quad core personal computer.This framework was employed in the context of an ongoing drug discovery and development project focused on glioblastoma multiforme; the most deadly form of brain cancer. Interesting add-on effects of two investigational cytotoxic compounds when combined with vorinostat were revealed on recently established clonal cultures of glioma-initiating cells from patient tumor samples. Therapeutic synergies, when normal astrocytes were used as a toxicity cell model, reinforced the pharmacological interest regarding their potential clinical use.Conclusions: COMBImage enables, for the first time, fast and optimized pairwise drug combination analyses of temporal changes in label-free video microscopy movies. Providing this jointly with conventional cell viability based end point analyses, it could help accelerating and guiding any drug discovery and development project, without use of cell labeling and the need to employ a particular live cell imaging instrument.
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| 2. |
- Chantzi, Efthymia, et al.
(författare)
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COMBImage2 : a parallel computational framework for higher-order drug combination analysis that includes automated plate design, matched filter based object counting and temporal data mining
- 2019
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Ingår i: BMC Bioinformatics. - : BMC. - 1471-2105. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pharmacological treatment of complex diseases using more than two drugs is commonplace in the clinic due to better efficacy, decreased toxicity and reduced risk for developing resistance. However, many of these higher-order treatments have not undergone any detailed preceding in vitro evaluation that could support their therapeutic potential and reveal disease related insights. Despite the increased medical need for discovery and development of higher-order drug combinations, very few reports from systematic large-scale studies along this direction exist. A major reason is lack of computational tools that enable automated design and analysis of exhaustive drug combination experiments, where all possible subsets among a panel of pre-selected drugs have to be evaluated.Results: Motivated by this, we developed COMBImage2, a parallel computational framework for higher-order drug combination analysis. COMBImage2 goes far beyond its predecessor COMBImage in many different ways. In particular, it offers automated 384-well plate design, as well as quality control that involves resampling statistics and inter-plate analyses. Moreover, it is equipped with a generic matched filter based object counting method that is currently designed for apoptotic-like cells. Furthermore, apart from higher-order synergy analyses, COMBImage2 introduces a novel data mining approach for identifying interesting temporal response patterns and disentangling higher- from lower- and single-drug effects.COMBImage2 was employed in the context of a small pilot study focused on the CUSP9v4 protocol, which is currently used in the clinic for treatment of recurrent glioblastoma. For the first time, all 246 possible combinations of order 4 or lower of the 9 single drugs consisting the CUSP9v4 cocktail, were evaluated on an in vitro clonal culture of glioma initiating cells.Conclusions: COMBImage2 is able to automatically design and robustly analyze exhaustive and in general higher-order drug combination experiments. Such a versatile video microscopy oriented framework is likely to enable, guide and accelerate systematic large-scale drug combination studies not only for cancer but also other diseases.
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| 3. |
- Dalmo, Erika, et al.
(författare)
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Growth-Inhibitory Activity of Bone Morphogenetic Protein 4 in Human Glioblastoma Cell Lines Is Heterogeneous and Dependent on Reduced SOX2 Expression
- 2020
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:7, s. 981-991
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme continues to have a dismal prognosis. Even though detailed information on the genetic aberrations in cell signaling and cell-cycle checkpoint control is available, no effective targeted treatment has been developed. Despite the advanced molecular defects, glioblastoma cells may have remnants of normal growth-inhibitory pathways, such as the bone morphogenetic protein (BMP) signaling pathway. We have evaluated the growth-inhibitory effect of BMP4 across a broad spectrum of patient samples, using a panel of 40 human glioblastoma initiating cell (GIC) cultures. A wide range of responsiveness was observed. BMP4 sensitivity was positively correlated with a proneural mRNA expression profile, high SOX2 activity, and BMP4-dependent upregulation of genes associated with inhibition of the MAPK pathway, as demonstrated by gene set enrichment analysis. BMP4 response in sensitive cells was mediated by the canonical BMP receptor pathway involving SMAD1/5/9 phosphorylation and SMAD4 expression. SOX2 was consistently downregulated in BMP4-treated cells. Forced expression of SOX2 attenuated the BMP4 sensitivity including a reduced upregulation of MAPK-inhibitory genes, implying a functional relationship between SOX2 downregulation and sensitivity. The results show an extensive heterogeneity in BMP4 responsiveness among GICs and identify a BMP4-sensitive subgroup, in which SOX2 is a mediator of the response.
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| 4. |
- Dalmo, Erika, et al.
(författare)
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Targeting SOX2 in glioblastoma cells reveals heterogeneity in SOX2 dependency
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma (GBM) is a lethal disease with no curative treatment. SOX2 is a stem cell transcription factor which is widely expressed across human GBM tumors. Downregulation of SOX2 inhibits tumor formation and its depletion leads to a complete stop of cell proliferation. Despite its known important role in GBM, there is a lack of SOX2 overexpression studies in human GBM cells cultured under stem cell conditions. Previous work in our lab suggests that SOX2 levels need to be precisely maintained for GBM cells to thrive. In this project, we have investigated how altered SOX2 expression affects primary human GBM lines. We found that elevated SOX2 expression inhibited proliferation in a dose-dependent manner in three out of four GBM cell lines. Global gene expression in the resistant line was shifted towards that of the proliferation-inhibited lines upon SOX2 induction. However, SOX2 induction also led to an increase in a GBM stem cell injury response phenotype, which was not present in proliferation-inhibited lines. Furthermore, CRISPR/Cas9-mediated SOX2 knockout revealed a SOX2 independence in the resistant cell line, where SOX2-negative cells could be propagated both in vitro and in vivo.
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| 5. |
- Darmanis, Spyros, et al.
(författare)
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Simultaneous Multiplexed Measurement of RNA and Proteins in Single Cells
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 14:2, s. 380-389
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Tidskriftsartikel (refereegranskat)abstract
- Significant advances have been made in methods to analyze genomes and transcriptomes of single cells, but to fully define cell states, proteins must also be accessed as central actors defining a cell's phenotype. Methods currently used to analyze endogenous protein expression in single cells are limited in specificity, throughput, or multiplex capability. Here, we present an approach to simultaneously and specifically interrogate large sets of protein and RNA targets in lysates from individual cells, enabling investigations of cell functions and responses. We applied our method to investigate the effects of BMP4, an experimental therapeutic agent, on early-passage glioblastoma cell cultures. We uncovered significant heterogeneity in responses to treatment at levels of RNA and protein, with a subset of cells reacting in a distinct manner to BMP4. Moreover, we found overall poor correlation between protein and RNA at the level of single cells, with proteins more accurately defining responses to treatment.
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| 6. |
- Edqvist, Per-Henrik D, et al.
(författare)
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Platelet-derived growth factor over-expression in retinal progenitors results in abnormal retinal vessel formation
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8, s. e42488-
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) plays an important role in development of the central nervous system, including the retina. Excessive PDGF signaling is associated with proliferative retinal disorders. We reported previously that transgenic mice in which PDGF-B was over-expressed under control of the nestin enhancer, nes/tk-PdgfB-lacZ, exhibited enhanced apoptosis in the developing corpus striatum. These animals display enlarged lateral ventricles after birth as well as behavioral aberrations as adults. Here, we report that in contrast to the relatively mild central nervous system phenotype, development of the retina is severely disturbed in nes/tk-PdgfB-lacZ mice.In transgenic retinas all nuclear layers were disorganized and photoreceptor segments failed to develop properly. Since astrocyte precursor cells did not populate the retina, retinal vascular progenitors could not form a network of vessels. With time, randomly distributed vessels resembling capillaries formed, but there were no large trunk vessels and the intraocular pressure was reduced. In addition, we observed a delayed regression of the hyaloid vasculature. The prolonged presence of this structure may contribute to the other abnormalities observed in the retina, including the defective lamination.
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| 7. |
- Gupta, Rajesh Kumar, et al.
(författare)
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Tumor-specific migration routes of xenotransplanted human glioblastoma cells in mouse brain
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- The migration of neural progenitor cells (NPCs) to their final destination during development follows well-defined pathways, such as along blood vessels. Cells originating from the highly malignant tumor glioblastoma (GBM) seem to exploit similar routes for infiltrating the brain parenchyma. In this report, we have examined the migration of GBM cells using three-dimensional high-resolution confocal microscopy in brain tumors derived from eight different human GBM cell lines xenografted into immunodeficient mice. The primary invasion routes identified were long-distance migration along white matter tracts and local migration along blood vessels. We found that GBM cells in the majority of tumors (6 out of 8) did not exhibit association with blood vessels. These tumors, derived from low lamin A/C expressing GBM cells, were comparatively highly diffusive and invasive. Conversely, in 2 out of 8 tumors, we noted perivascular invasion and displacement of astrocyte end-feet. These tumors exhibited less diffusive migration, grew as solid tumors, and were distinguished by elevated expression of lamin A/C. We conclude that the migration pattern of glioblastoma is distinctly tumor cell-specific. Furthermore, the ability to invade the confined spaces within white matter tracts may necessitate low expression of lamin A/C, contributing to increased nuclear plasticity. This study highlights the role of GBM heterogeneity in driving the aggressive growth of glioblastoma.
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| 8. |
- Kitambi, Satish Srinivas, et al.
(författare)
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Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule
- 2014
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 157:2, s. 313-328
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with marginal life expectancy. Based on the assumption that GBM cells gain functions not necessarily involved in the cancerous process, patient-derived glioblastoma cells (GCs) were screened to identify cellular processes amenable for development of targeted treatments. The quinine-derivative NSC13316 reliably and selectively compromised viability. Synthetic chemical expansion reveals delicate structure-activity relationship and analogs with increased potency, termed Vacquinols. Vacquinols stimulate death by membrane ruffling, cell rounding, massive macropinocytic vacuole accumulation, ATP depletion, and cytoplasmic membrane rupture of GCs. The MAP kinase MKK4, identified by a shRNA screen, represents a critical signaling node. Vacquinol-1 displays excellent in vivo pharmacokinetics and brain exposure, attenuates disease progression, and prolongs survival in a GBM animal model. These results identify a vulnerability to massive vacuolization that can be targeted by small molecules and point to the possible exploitation of this process in the design of anticancer therapies.
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| 9. |
- Larsson, Ida, et al.
(författare)
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Modeling glioblastoma heterogeneity as a dynamic network of cell states
- 2021
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Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 17:9
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Tidskriftsartikel (refereegranskat)abstract
- Tumor cell heterogeneity is a crucial characteristic of malignant brain tumors and underpins phenomena such as therapy resistance and tumor recurrence. Advances in single-cell analysis have enabled the delineation of distinct cellular states of brain tumor cells, but the time-dependent changes in such states remain poorly understood. Here, we construct quantitative models of the time-dependent transcriptional variation of patient-derived glioblastoma (GBM) cells. We build the models by sampling and profiling barcoded GBM cells and their progeny over the course of 3 weeks and by fitting a mathematical model to estimate changes in GBM cell states and their growth rates. Our model suggests a hierarchical yet plastic organization of GBM, where the rates and patterns of cell state switching are partly patient-specific. Therapeutic interventions produce complex dynamic effects, including inhibition of specific states and altered differentiation. Our method provides a general strategy to uncover time-dependent changes in cancer cells and offers a way to evaluate and predict how therapy affects cell state composition.
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| 10. |
- Niklasson, Johan, et al.
(författare)
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High morale and survival
- 2016
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Ingår i: Journal of Psychosomatic Research. - : Elsevier BV. - 0022-3999 .- 1879-1360. ; 85, s. 75-75
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 11. |
- Niklasson, Johan, et al.
(författare)
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High morale is associated with increased survival in the very old
- 2015
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Ingår i: Age and Ageing. - : Oxford University Press (OUP). - 0002-0729 .- 1468-2834. ; 44:4, s. 630-636
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: high morale is defined as future-oriented optimism. Previous research suggests that a high morale independently predicts increased survival among old people, though very old people have not been specifically studied.OBJECTIVE: to investigate whether high morale is associated with increased survival among very old people.SUBJECTS: the Umeå 85+/GErontological Regional DAtabase-study (GERDA) recruited participants aged 85 years and older in northern Sweden and western Finland during 2000-02 and 2005-07, of whom 646 were included in this study.METHODS: demographic, functional- and health-related data were collected in this population-based study through structured interviews and assessments carried out during home visits and from reviews of medical records. The 17-item Philadelphia Geriatric Center Morale Scale (PGCMS) was used to assess morale.RESULTS: the 5-year survival rate was 31.9% for participants with low morale, 39.4% for moderate and 55.6% for those with high morale. In an unadjusted Cox model, the relative risk (RR) of mortality was higher among participants with low morale (RR = 1.86, P < 0.001) and moderate morale (RR = 1.59, P < 0.001) compared with participants with high morale. Similar results were found after adjustment for age and gender. In a Cox model adjusted for several demographic, health- and function-related confounders, including age and gender, mortality was higher among participants with low morale (RR = 1.36, P = 0.032) than those with high morale. There was a similar but non-significant pattern towards increased mortality in participants with moderate morale (RR = 1.21, P value = 0.136).CONCLUSION: high morale is independently associated with increased survival among very old people.
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| 12. |
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| 13. |
- Niklasson, Johan, et al.
(författare)
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Higher morale is associated with lower risk of depressive disorders five years later among very old people
- 2017
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Ingår i: Archives of gerontology and geriatrics (Print). - : Elsevier BV. - 0167-4943 .- 1872-6976. ; 69, s. 61-68
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to investigate whether higher morale, i.e. future-oriented optimism, at baseline was associated with lower risk of depressive disorders five years later among very old people.Methods The Umeå85+/GErontological Regional Database, a population-based study with a longitudinal design, recruited participants in Sweden and Finland aged 85, 90 and ≥95 years. The sample in the present study included 647 individuals (89.1±4.4 years (Mean±SD), range 85-103). After five years, 216 were alive and agreed to a follow-up (92.6±3.4 years, range 90-104). The Philadelphia Geriatric Center Morale Scale (PGCMS) was used to assess morale. The depressive disorder diagnosis was determined according to DSM-IV based on medical records and interview data including assessment scales for depressive disorders. A number of sociodemographic, functional and health-related variables were analysed as possible confounders.Results For those with no depressive disorders at baseline, the only baseline variable significantly associated with depressive disorders five years later was the PGCMS score. A logistic regression model showed lower risk of depressive disorders five years later with higher baseline PGCMS scores (odds ratio 0.779 for one point increase in PGCMS, p<0.001). The association remained after adjusting for social isolation (p<0.1 association with depressive disorders five years later).Conclusion Our results indicate that the higher the morale, the lower the risk of depressive disorders five years later among very old people. The PGCMS seems to identify those very old individuals at increased risk of depressive disorders five years later. Preventive measures could befocused on this group.
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| 14. |
- Niklasson, Johan, et al.
(författare)
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Psychometric properties and feasibility of the Swedish version of the Philadelphia Geriatric Center Morale Scale
- 2015
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Ingår i: Quality of Life Research. - : Springer Science and Business Media LLC. - 0962-9343 .- 1573-2649. ; 24:11, s. 2795-2805
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Morale is related to psychological well-being and quality of life in older people. The Philadelphia Geriatric Center Morale Scale (PGCMS) is widely used to assess morale. The purpose of this study was to evaluate the psychometric properties and feasibility of the Swedish version of the 17-item PGCMS among very old people.METHODS: The Umea 85+/GERDA study included Swedish-speaking people aged 85, 90 and 95 years and older, from Sweden and Finland. Participants were interviewed in their own homes using a predefined set of questions. In the main sample, 493 individuals answered all 17 PGCMS items (aged 89.0 +/- 4.3 years). Another 105 answered between 1 and 16 questions (aged 89.6 +/- 4.4 years). A convenience sample was also collected, and 54 individuals answered all 17 PGCMS items twice (aged 84.7 +/- 6.7 years). The same assessor restated the questions within 1 week.RESULTS: Cronbach's alpha was 0.74 among those who answered all 17 questions in the main sample. Confirmatory factor analysis was used to test the construct validity of the most widely used version of the PGCMS, with 17 items and three factors, and showed a generally good fit. Among those answering between 1 and 17 PGCMS questions, 92.6 % (554/598) answered 16 or 17. The convenience sample was used for intra-rater test-retesting, and the intraclass correlation coefficient (ICC) was 0.89. The least significant change between two assessments, with 95 % confidence interval, was 3.53 PGCMS points.CONCLUSION: The Swedish version of the PGCMS seems to have satisfactory psychometric properties and feasibility among very old people.
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| 15. |
- Niklasson, Mia, et al.
(författare)
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BMP4 induction of a senescence-like phenotype in human glioblastoma cells is dependent on p21
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma (GBM) is a lethal disease and curative treatment is still lacking. BMP4 was initially suggested as a differentiation treatment of GBM, since it has been shown to induce astrocytic differentiation, but other reports have demonstrated that the response is reversible, variable among patient samples, and heterogeneous within the same cell line. To further interrogate the nature of the BMP4 proliferation-inhibitory response, we focused on cellular growth and senescence. BMP4 was found to induce a senescence-like phenotype in a SMAD-dependent manner in a subpopulation of GBM cells, demonstrated by induction of senescence-associated (SA)-β-gal, downregulation of lamin B1, as well as increased lysosomal mass, cell size and granularity, paralleled by an increase in p21 levels. To zoom in on the heterogeneity in BMP4 response within a cell culture, we used a therapy-sensitive/proneural-like (SENS/PN) clone and a therapy-resistant/mesenchymal-like (RES/MES) clone from the same tumor and saw a more prominent induction of a senescence-like phenotype in the RES/MES clone. Since the RES/MES clone showed higher basal levels of p21 and lower lamin B1 than the SENS/PN clone, we suggest that the expression of senescence markers is a component of the mesenchymal profile. Senolytic treatment ablated the SA-β-gal positive cells and normalized the p21 levels, and this enabled us to couple p21 upregulation to the senescence-like phenotype. In p21 knockout cells, BMP4-induced cell growth and SA-β-gal were abolished and lamin B1 was not down-regulated. SOX2, which in part mediates the inhibition of proliferation by BMP4, was down-regulated but still BMP4-treated p21 knockout cells proliferated faster than BMP4-treated wild-type cells. Altogether, this demonstrates that p21 signaling is crucial for BMP4-mediated induction of a senescence-like phenotype in GBM.
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| 16. |
- Niklasson, Mia, et al.
(författare)
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Enlarged lateral ventricles and aberrant behavior in mice overexpressing PDGF-B in embryonic neural stem cells
- 2010
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 316:17, s. 2779-2789
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) is important in central nervous system (CNS) development, and aberrant expression of PDGF and its receptors has been linked to developmental defects and brain tumorigenesis. We previously found that neural stem and progenitor cells in culture produce PDGF and respond to it by autocrine and/or paracrine signaling. We therefore aimed to examine CNS development after PDGF overexpression in neural stem cells in vivo. Transgenic mice were generated with PDGF-B under control of a minimal nestin enhancer element, which is specific for embryonic expression and will not drive adult expression in mice. The resulting mouse showed increased apoptosis in the developing striatum, which suggests a disturbed regulation of progenitor cells. Later in neurodevelopment, in early postnatal life, mice displayed enlarged lateral ventricles. This enlargement remained into adulthood and it was more pronounced in male mice than in transgenic female mice. Nevertheless, there was an overall normal composition of cell types and numbers in the brain and the transgenic mice were viable and fertile. Adult transgenic males, however, showed behavioral aberrations and locomotor dysfunction. Thus, a tightly regulated expression of PDGF during embryogenesis is required for normal brain development and function in mice.
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| 17. |
- Niklasson, Mia, et al.
(författare)
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Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
- 2017
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:7, s. 1741-1752
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Tidskriftsartikel (refereegranskat)abstract
- Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstreamsignaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas.
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| 18. |
- Niklasson, Mia, et al.
(författare)
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Mesenchymal transition and increased therapy resistance of glioblastoma cells is related to astrocyte reactivity
- 2019
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Ingår i: Journal of Pathology. - : WILEY. - 0022-3417 .- 1096-9896. ; 249:3, s. 295-307
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Tidskriftsartikel (refereegranskat)abstract
- Grade IV astrocytoma/glioblastoma multiforme (GBM) is essentially incurable, partly due to its heterogenous nature, demonstrated even within the glioma-initiating cell (GIC) population. Increased therapy resistance of GICs is coupled to transition into a mesenchymal (MES) cell state. The GBM MES molecular signature displays a pronounced inflammatory character and its expression vary within and between tumors. Herein, we investigate how MES transition of GBM cells relates to inflammatory responses of normal astroglia. In response to CNS insults astrocytes enter a reactive cell state and participate in directing neuroinflammation and subsequent healing processes. We found that the MES signature show strong resemblance to gene programs induced in reactive astrocytes. Likewise, astrocyte reactivity gene signatures were enriched in therapy-resistant MES-like GIC clones. Variable expression of astrocyte reactivity related genes also largely defined intratumoral GBM cell heterogeneity at the single-cell level and strongly correlated with our previously defined therapy-resistance signature (based on linked molecular and functional characterization of GIC clones). In line with this, therapy-resistant MES-like GIC secreted immunoregulatory and tissue repair related proteins characteristic of astrocyte reactivity. Moreover, sensitive GIC clones could be made reactive through long-term exposure to the proinflammatory cytokine interleukin 1 beta (IL1 beta). IL1 beta induced a slow MES transition, increased therapy resistance, and a shift in DNA methylation profile towards that of resistant clones, which confirmed a slow reprogramming process. In summary, GICs enter through MES transition a reactive-astrocyte-like cell state, connected to therapy resistance. Thus, from a biological point of view, MES GICs would preferably be called 'reactive GICs'. The ability of GBM cells to mimic astroglial reactivity contextualizes the immunomodulatory and microenvironment reshaping abilities of GBM cells that generate a tumor-promoting milieu. This insight will be important to guide the development of future sensitizing therapies targeting treatment-resistant relapse-driving cell populations as well as enhancing the efficiency of immunotherapies in GBM. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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| 19. |
- Näsman, Marina, et al.
(författare)
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Five-year change in morale is associated with negative life events in very old age
- 2019
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Ingår i: Aging & Mental Health. - : Routledge. - 1360-7863 .- 1364-6915. ; , s. 84-91
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The objectives were to study changes in morale in individuals 85 years and older, and to assess the effect of negative life events on morale over a five-year follow-up period.METHOD: The present study is based on longitudinal data from the Umeå85+/GERDA-study, including individuals 85 years and older at baseline (n = 204). Morale was measured with the Philadelphia Geriatric Center Morale Scale (PGCMS). Negative life events were assessed using an index including 13 negative life events occurring during the follow-up period. Linear regression was used for the multivariate analyses.RESULTS: The majority of the sample (69.1%) had no significant changes in morale during the five-year follow-up. However, the accumulation of negative life events was significantly associated with a greater decrease in PGCMS. A higher baseline PGCMS score did not attenuate the adverse effect negative life events had on morale.CONCLUSION: Morale seemed to be mainly stable in a five-year follow-up of very old people. It seems, nonetheless, that individuals are affected by negative life events, regardless of level of morale. Preventing negative life events and supporting individuals who experience multiple negative life events could have important implications for the care of very old people.
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| 20. |
- Segerman, Anna, et al.
(författare)
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Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 17:11, s. 2994-3009
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Tidskriftsartikel (refereegranskat)abstract
- Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuumof multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states.
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| 21. |
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| 22. |
- Xie, Yuan, et al.
(författare)
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The Human Glioblastoma Cell Culture Resource : Validated Cell Models Representing All Molecular Subtypes
- 2015
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 2:10, s. 1351-1363
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called gliomastem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional sub-types. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.
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| 23. |
- Öhlin, Jerry, et al.
(författare)
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Concurrent validity of the International Physical Activity Questionnaire adapted for adults aged ≥ 80 years (IPAQ-E 80 +) - tested with accelerometer data from the SilverMONICA study
- 2022
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Ingår i: Gait & Posture. - : Elsevier. - 0966-6362 .- 1879-2219. ; 92, s. 135-143
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Tidskriftsartikel (refereegranskat)abstract
- Background: Physical activity and sedentary behavior vary across the life span, and in very old people activity behavior can vary considerably over 24 h. A physical activity questionnaire adapted for this age group is lacking. This study was conducted to validate such a newly developed questionnaire suitable for use in very old people.Research question: Is the International Physical Activity Questionnaire adapted for adults aged ≥ 80 years (IPAQ-E 80 +) a valid measure of physical activity in very old people?Methods: Seventy-six participants (55.3% women) with a mean age of 84.4 ± 3.8 years wore accelerometers for ≥ 5 consecutive days, and completed the IPAQ-E 80 +. Spearman's rho and Bland-Altman plots were used to analyze the validity of IPAQ-E 80 + against accelerometer measures. Analyses were conducted for the separate items sitting, laying down at daytime and nighttime, walking, moderate to vigorous (MV) walking, and moderate to vigorous physical activity (MVPA), and the summary measures: total inactive time, sedentary time (i.e. lying down at daytime + sitting), total active time, and total MVPA + MV walking.Results: The IPAQ-E 80 + correlated with the accelerometer measures of total inactive- (r = 0.55, p < 0.001), sedentary- (r = 0.28, p = 0.015), walking- (r = 0.54 p < 0.001) and total active- (r = 0.60, p < 0.001) times, but not with measures of intensity of walking or physical activity; MV walking (r = 0.06, p = 0.58), MVPA (r = 0.17, p = 0.13).Significance: In this study the IPAQ-E 80 + showed fair to substantial correlations with accelerometers, and it therefore seems able to rank very old people according to levels of PA (total inactive-, sedentary-, and total active time, and walking time). The IPAQ-E 80 + seems promising for use in studies investigating associations between activity behavior and health in this population. Further investigation is needed to determine whether the IPAQ-E 80 + can accurately measure PA intensity.
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