| 1. |
- Gustavsson, Bengt, et al.
(författare)
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Functional analysis of a variant of the thyrotropin receptor gene in a family with Graves' disease
- 1995
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Ingår i: Molecular and Cellular Endocrinology. - 0303-7207 .- 1872-8057. ; 111:2, s. 167-173
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Tidskriftsartikel (refereegranskat)abstract
- Nucleotide sequence analysis of PCR fragments corresponding to the TSH-receptor (TSHR) amplified from genomic DNA collected from the four members of a family, two of which had Graves' thyrotoxicosis, revealed a nucleotide substitution in the first position of codon 36 of the TSH-receptor gene in the two patients. The nucleotide substitution was from G to C, leading to a 36D-->36H change (D36H) in the predicted amino acid sequence of the receptor. The altered sequence was also found in DNA obtained from their mother, but not in DNA from their father. We stably expressed the two receptor variants in NIH 3T3 cells, by transfection of cDNA encoding the wildtype (WT) and D36H variants of the TSHR. Neither the binding of 125I-TSH nor the responsiveness to TSH measured as cAMP formation, appeared to be different in the TSHR-D36H compared to the TSHR-WT. Furthermore, the D36H-receptor also became desensitized when exposed to TSH as did the WT-receptor.
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| 2. |
- Dillner, Joakim, et al.
(författare)
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Svensk konsensus om vaccination mot cervixcancer. Vaccinprogram bör införas i grundskolan med sikte på att utrota HPV16/18
- 2006
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Ingår i: Läkartidningen. - 0023-7205. ; 103:44, s. 9-3377
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Tidskriftsartikel (refereegranskat)abstract
- Vaccination against the Human Papillomavirus (HPV) has recently been approved as a means to prevent cervical cancer. The Swedish Institute for Infectious Disease Control and the Swedish Society for Obstetrics & Gynecology arranged a consensus conference to discuss design of future cervical cancer prevention programs. Conclusions include that preventive programs should aim at eradication of oncogenic HPV 16/18 infection and that the potentially preventable cervical cancers should no longer occur. Necessary prerequisites include adoption of a population-based vaccination program in primary school, an HPV vaccination registry and coordination of cervical cancer preventive efforts on vaccination and cervical screening.
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| 3. |
- Glimelius, Bengt, et al.
(författare)
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U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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| 4. |
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| 5. |
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| 6. |
- 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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| 7. |
- Simanainen, J., et al.
(författare)
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Analysis of mutations in exon 1 of the human thyrotropin receptor gene : high frequency of the D36H and P52T polymorphic variants
- 1999
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Ingår i: Thyroid. - 1050-7256 .- 1557-9077. ; 9:1, s. 7-11
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate the N-terminal part (the translated part of exon 1) of the human thyrotropin receptor (TSHR) for the presence of mutations. Patients with Graves' disease (n = 160) and healthy controls (blood donors; n = 140) were screened using single-stranded conformational polymorphism (SSCP) in combination with restriction enzyme digestion for the two previously known mutations in this part of the receptor, viz. D36H and P52T TSHR-variants. We did not find any novel mutation in this region. However, D36H and P52T variants were found both in the TSHR of Graves' patients and in the healthy controls. The overall frequency of the D36H-receptor variant was 5.0% (15/300) and of the P52T-receptor, 7.3% (22/300). There was no major difference in the frequency for either of the TSHR alleles between the 2 groups. Thus, these 2 polymorphic variants of the TSHR seem to occur in a relatively high frequency in the population.
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| 8. |
- Afrakhte, Mozhgan, et al.
(författare)
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Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members
- 1998
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 249:2, s. 505-11
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Tidskriftsartikel (refereegranskat)abstract
- Smad6 and Smad7 function as intracellular antagonists in transforming growth factor-beta (TGF-beta) signaling. Here we report the isolation of human Smad6, which is closely related to Smad7. Smad6 and Smad7 mRNAs were differentially expressed in lung cancer cell lines and were rapidly and directly induced by TGF-beta1, activin and bone morphogenetic protein-7. Cross-talk between TGF-beta and other signaling pathways was demonstrated by the finding that epidermal growth factor (EGF) induced the expression of inhibitory SMAD mRNA. Moreover, whereas the phorbol ester PMA alone had no effect, it potentiated the TGF-beta1-induced expression of Smad7 mRNA. Ectopic expression of anti-sense Smad7 RNA was found to increase the effect of TGF-beta1, supporting its role as a negative regulator in TGF-beta signaling. Thus, expression of inhibitory Smads is induced by multiple stimuli, including the various TGF-beta family members, whose action they antagonize.
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| 9. |
- Agarwal, Prasoon, et al.
(författare)
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CGGBP1 mitigates cytosine methylation at repetitive DNA sequences
- 2015
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Results: Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. Conclusions: The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.
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| 10. |
- Agarwal, Prasoon, et al.
(författare)
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Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs
- 2016
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Ingår i: Cell Cycle. - : Informa UK Limited. - 1538-4101 .- 1551-4005. ; 15:12, s. 1558-1571
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Tidskriftsartikel (refereegranskat)abstract
- CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.
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| 11. |
- Allen, Marie, et al.
(författare)
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Origin of the U87MG glioma cell line : Good news and bad news
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:354
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Tidskriftsartikel (refereegranskat)abstract
- Human tumor-derived cell lines are indispensable tools for basic and translational oncology. They have an infinite life span and are easy to handle and scalable, and results can be obtained with high reproducibility. However, a tumor-derived cell line may not be authentic to the tumor of origin. Two major questions emerge: Have the identity of the donor and the actual tumor origin of the cell line been accurately determined? To what extent does the cell line reflect the phenotype of the tumor type of origin? The importance of these questions is greatest in translational research. We have examined these questions using genetic profiling and transcriptome analysis in human glioma cell lines. We find that the DNA profile of the widely used glioma cell line U87MG is different from that of the original cells and that it is likely to be a bona fide human glioblastoma cell line of unknown origin.
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| 12. |
- Andrae, Johanna, et al.
(författare)
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A 1.8kb GFAP-promoter fragment is active in specific regions of theembryonic CNS
- 2001
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Ingår i: Mechanisms of Development. - 0925-4773 .- 1872-6356. ; 107:1-2, s. 181-5
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Tidskriftsartikel (refereegranskat)abstract
- The intermediate filament glial fibrillary acidic protein (GFAP) constitutes the major cytoskeletal protein in astrocytes (J. Neuroimmunol. 8 (1985) 203) and is traditionally referred to as a specific marker for astrocytes. To identify early glial precursors, we created GFAPpromoter-lacZ transgenic mice, using a 1.8kb 5' fragment of human GFAP. The expression of the transgene was first detected in the neuroepithelium at embryonic day 9.5. It was further found in the ventricular zone of the developing telencephalon, in the cerebellar primordium, trigeminal ganglia, and radial glia. Later, scattered beta-gal+ cells were seen in pons, brain stem and glia limitans. The results indicate that GFAP activity is regulated in a region-specific manner during central nervous system (CNS) development and that the gene is turned on in different cell types independently.
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| 13. |
- Antoni, Gunnar, et al.
(författare)
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In Vivo Visualization of Amyloid Deposits in the Heart with C-11-PIB and PET
- 2013
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 54:2, s. 213-220
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Tidskriftsartikel (refereegranskat)abstract
- Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-C-11]2-(4'-methylamino-phenyl)-6-hydroxybenzothiazole (C-11-PIB) PET is used in the evaluation of brain amyloidosis. We evaluated the potential use of C-11-PIB PET in systemic amyloidosis affecting the heart. Methods: Patients (n = 10) diagnosed with systemic amyloidosis-including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type- and healthy volunteers (n = 5) were investigated with PET/CT using C-11-PIB to study cardiac amyloid deposits and with C-11-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention. Results: Myocardial C-11-PIB uptake was visually evident in all patients 15-25 min after injection and was not seen in any volunteer. A significant difference in C-11-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with C-11-PIB. No correlation between C-11-PIB retention index and myocardial blood flow as measured with C-11-acetate was found on the global level, whereas a positive correlation on the segmental level was seen in a single patient. Conclusion: C-11-PIB and PET could be a method to study systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.
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| 14. |
- Attarha, Sanaz, et al.
(författare)
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Mast cells modulate proliferation, migration and sternness of glioma cells through downregulation of GSK3 beta expression and inhibition of STAT3 activation
- 2017
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Ingår i: Cellular Signalling. - : Elsevier BV. - 0898-6568 .- 1873-3913. ; 37, s. 81-92
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) heterogeneity is the main obstacle to efficient treatment due to the existence of sub population of cells with increased tumorigenicity and network of tumor associated parenchymal cells in the tumor microenvironment. We previously demonstrated that mast cells (MCs) infiltrate mouse and human gliomas in response to variety of signals in a glioma grade-dependent manner. However, the role of MCs in glioma development and the mechanisms behind MCs-glioma cells interaction remain unidentified. In the present study, we show that MCs upon activation by glioma cells produce soluble factors including IL-6, which are documented to be involved in cancer-related activities. We observe 'tumor educated' MCs decrease glioma cell proliferation and migration, reduce self-renewal capacity and expression of stemness markers but in turn promote glioma cell differentiation. 'Tumor educated' MC derived mediators exert these effects via inactivation of STAT3 signaling pathway through GSK3 beta down-regulation. We identified 'tumor educated' MC derived IL-6 as one of the contributors among the complex mixture of MCs mediators, to be partially involved in the observed MC induced biological effect on glioma cells. Thus, MC mediated abolition of STAT3 signaling hampers glioma cell proliferation and migration by suppressing their stemness and inducing differentiation via down-regulation of GSK3 beta expression. Targeting newly identified inflammatory MC-STAT3 axis could contribute to patient tailored therapy and unveil potential future therapeutic opportunities for patients.
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| 15. |
- Babateen, Omar, et al.
(författare)
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Etomidate, propofol and diazepam potentiate GABA-evoked GABAA currents in a cell line derived from Human glioblastoma
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 748, s. 101-107
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Tidskriftsartikel (refereegranskat)abstract
- GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit α2, α3, α5, β1, β2, β3, δ, γ3, π, and θ mRNAs in the U3047MG cell line. Whole-cell GABA-activated currents were recorded and the half-maximal concentration (EC50) for the GABA-activated current was 36μM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1μM) and the general anesthetics etomidate and propofol (50μM). In line with the expressed GABAA receptors containing at least the α3β3θ subunits, the receptors were highly sensitive to etomidate (EC50=55nM). Immunocytochemistry identified expression of the α3 and β3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells.
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| 16. |
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| 17. |
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| 18. |
- Bergström, J.Daniel, et al.
(författare)
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Epidermal growth factor receptor signaling activates Met in human anaplastic thyroid carcinoma cells
- 2000
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 259:1, s. 293-299
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Tidskriftsartikel (refereegranskat)abstract
- Overexpression of Met is a common finding in thyroid carcinomas. Recently, we reported on overexpression and ligand-independent constitutive activation of Met in anaplastic thyroid carcinoma cells. In the present study we have investigated a putative mechanism for this phenomenon. Cell lines with constitutively activated Met expressed both TGF-alpha mRNA and protein. Western blot analysis revealed expression of receptors for epidermal growth factor (EGFR) in all carcinoma cell lines; in tumor cells with elevated levels of TGF-alpha mRNA there was a constitutive tyrosine phosphorylation of the EGFRs. Preincubation of carcinoma cells with suramin decreased EGFR activation and downregulated Met expression as well as the ligand-independent phosphorylation of Met. Similar results were obtained with a EGFR tyrosine kinase inhibitor, AG 1478. The MEK inhibitor U0126 had an even more pronounced effect compared to AG 1478, indicating a Ras/MAPK-mediated signal in the regulation of Met expression and activation. Inhibition of EGFR signaling also decreased proliferation of the anaplastic thyroid carcinoma cells. Thus, aberrant activation of EGFRs may lead to an overexpression and activation of Met, which may be of importance for the malignant phenotype of anaplastic thyroid carcinomas.
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| 19. |
- Blume-Jensen, Peter, et al.
(författare)
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Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis
- 1991
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Ingår i: EMBO Journal. - 0261-4189 .- 1460-2075. ; 10:13, s. 4121-4128
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Tidskriftsartikel (refereegranskat)abstract
- The proto-oncogene c-kit is allelic with the murine white spotting (W) locus and encodes a transmembrane protein tyrosine kinase that is structurally related to the receptors for platelet-derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1). Recently the ligand for the c-kit product, stem cell factor (SCF), was identified in both transmembrane and soluble forms. In order to examine the mechanism for receptor activation by SCF and biological properties of the activated c-kit product, we transfected the wild-type human c-kit cDNA into porcine aortic endothelial cells. We found that the receptor was down-regulated and transmitted a mitogenic signal in response to stimulation with soluble SCF. We also demonstrate that SCF induces dimerization of the c-kit product in intact cells, and that dimerization of the receptor is correlated with activation of its kinase. Activation of the c-kit product by SCF was found to induce circular actin reorganization indistinguishable from that mediated by the PDGF beta-receptor in response to PDGF-BB. Furthermore, soluble SCF was a potent chemotactic agent for cells expressing the c-kit product, a property which might be of importance during embryonic development.
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| 20. |
- Boije, Maria
(författare)
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Investigations of Proneural Glioblastoma to Identify Novel Therapeutic Targets
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malignant glioma is a highly lethal and destructive disease with no proper cure. We have investigated some of the hallmarks of cancer in connection to glioma and found ways to disrupt these and prevent tumor growth. The work is done within the context of a glioma subtype distinguished by activation of PDGF signaling termed the proneural subtype. In two of the studies we have investigated mechanisms regulating the glioma cells themselves, and in the other two we have focused on the tumor stroma. In the first study, glioma-initiating cells were isolated in defined serum free culture medium from PDGF-B driven murine glioma and shown to be independent of EGF and FGF2 for self-renewal and proliferation. When cultured in serum the GICs displayed an aberrant differentiation pattern that was reversible. Specific depletion of the transduced PDGF-B caused a loss of self-renewal and tumorigenicity and induced oligodendrocyte differentiation. The transcription factor S-SOX5 has previously been shown to have a tumor suppressive effect on PDGF-B induced murine glioma, and to induce cellular senescence in PDGF-B stimulated cells in vitro. We found that S-SOX5 had a negative effect on proliferation of newly established human glioma cells cultured under stem cell conditions. We also revealed a connection between alterations causing up-regulation of SOX5 with the proneural subgroup and a tendency towards co-occurrence with PDGFRA alterations. Angiogenesis, the formation of new blood vessels from existing ones, is an important hallmark for glioma malignancy. We found that the anti-angiogenic protein HRG had a negative effect on glioma progression in PDGF-B induced experimental tumors and that HRG was able to completely prevent formation of glioblastomas. Subsequently it was shown that HRG could skew pro-tumorigenic tumor associated macrophages into an anti-tumorigenic phenotype. Stromal cells had not previously been fully investigated in gliomas. We observed a correlation between tumor malignancy and increased numbers of tumor-associated macrophages as well as pericytes in PDGF-B induced gliomas. There was also a correlation between tumor grade and vessel functionality that had not previously been shown. Our results offer further understanding of gliomagenesis and present possible future therapies.
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| 21. |
- Caglayan, Demet, et al.
(författare)
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Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma Multiforme (GBM), the most malignant and common neoplasm of the central nervous system (CNS), has been classified into subgroups with gene-expression profile as the basis for categorization. Among these the mesenchymal subgroup is most greatly associated with inflammatory infiltrates and increased expression of inflammatory associated genes. GBMs exhibit T cell infiltration to a varying degree and today the degree of infiltration is not used in prognostics. The Sleeping Beauty (SB) system was used to introduce AKT, a mutant variant of NRAS and a shp53 coupled to green fluorescent protein (GFP) into mice that are fully immunocomptetent, lack mature T cells or have reduced regulatory T (Treg) cell function respectively. We report, for the first time, the induction of Gliomatosis Cerebri with the SB system. Tumors that originated were either GBM or Gliomatosis Cerebri with a similar incidence. There was no difference in survival, grade or incidence of induced tumors in wild type mice and mice that lack mature T cells.
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| 22. |
- Çağlayan, Demet
(författare)
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Molecular and Cellular Complexity of Glioma : Highlights on the Double-Edged-Sword of Infiltration Versus Proliferation and the Involvement of T Cells
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma multiforme (GBM), the most common and malignant brain tumor, is characterized by high molecular and cellular heterogeneity within and among tumors. Parameters such as invasive growth, infiltration of immune cells and endothelial proliferation contribute in a systemic manner to maintain the malignancy.Studies in this thesis show that the expression of Sox2 is correlated with Sox21 in human gliomas. We demonstrate that an upregulation of Sox21 induces loss of proliferation, apoptosis and differentiation in glioma cells in vitro and in vivo and seems to correlate with decreased Sox2 expression. Induced expression of Sox21 in vivo significantly reduces the tumor size and increase the survival extensively, suggesting that Sox21 can act as a tumor suppressor Our studies indicate that the balance of Sox21-Sox2 in glioma cells is decisive of either a proliferative or a non-proliferative state.Several TGFß family members have an important role in glioma development. TGFß promotes proliferation and tumorigenicity whereas BMPs mostly inhibit proliferation. We demonstrate that BMP7 can induce the transcription factor Snail in glioma cells and that this reduces the tumorigenicity with a concomitant increase in invasiveness. Thus, we have identified a mechanism to the double-edged sword of proliferation versus invasiveness in GBM, the latter contributing to relapse in patients.Experimental gliomas were induced with the Sleeping Beauty (SB) model in mice with different immunological status of their T cells. The tumors that developed were either GBMs or highly diffuse in their growth, reminiscent of gliomatosis cerebri (GC). GC is a highly uncommon form of glioma characterized by extensive infiltrative growth in large parts of the brain. It is an orphan disease and today there is practically a total lack of relevant experimental models. The SB system would constitute a novel experimental model to study the mechanisms behind the development of diffusely growing tumors like GC. The presence or absence of T cells did not affect tumor development.The work in this thesis demonstrates that the proliferative and the invasive capacities of glioma cells can be dissociated and that the SB model constitutes an excellent model to study the highly proliferative cells in GBMs versus the highly invasive cells in diffuse tumors like .GC.
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| 23. |
- Caglayan, Demet, et al.
(författare)
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Sox21 inhibits glioma progression in vivo by forming complexes with Sox2 and stimulating aberrant differentiation
- 2013
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 133:6, s. 1345-1356
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Tidskriftsartikel (refereegranskat)abstract
- Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas. What's new? Glioma formation is driven by brain tumor-initiating cells with stem cell-like properties. Here the authors show for the first time that the transcription factor Sox21 can act as a suppressor gene in gliomagenesis. Induced expression of Sox21 in human glioma cells results in reduced tumor growth and prolonged survival of xenotranplanted mice. Sox21 reduces the stem-cell like properties of the tumor cells, leading to abnormal differentiation, induced apoptosis, and decreased proliferation. The results point to a shift in balance between the counteracting and widely distributed Sox2 and Sox21, revealing the Sox2/Sox21 axis as a target for novel therapy of gliomas.
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| 24. |
- Caglayan, Demet, et al.
(författare)
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Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation
- 2013
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 133:6, s. 1345-1356
-
Tidskriftsartikel (refereegranskat)abstract
- Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100β, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas.
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| 25. |
- Cancer, Matko, et al.
(författare)
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BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells
- 2019
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Ingår i: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.
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| 26. |
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| 27. |
- Carlsson, Jonas, et al.
(författare)
-
A folding study on IAPP (Islet Amyloid Polypeptide) using molecular dynamics simulations
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Amyloidosis is the largest group among the protein misfolding diseases, and includes well known diseases such as Alzheimer’s disease and type 2 diabetes. In the latter, islet amyloid is present in the pancreas in almost all individuals. Today, more than 25 different proteins have been isolated from amyloid deposits in human. Even though these proteins differ in size, charge and sequence they all have the capacity to assemble in to fibrillar structures with inseparable morphological appearance. Therefore, it can be assumed that the fibril process is based upon principles that are general for all proteins and knowledge derived from one protein can be used for other amyloid proteins. In this paper, we study the process of amyloid formation in parts of islet amyloid polypeptide (residues 18-29 and 11-37) by analyzing mutations using three different in silico methods. Finally, we use the methods to predict the amyloidogenic properties of the native IAPP and 16 variants thereof and compare the result with in vitro measurements. Using a consensus prediction of the three methods we managed to correctly classify all but two peptides. We have also given further evidence to the importance of S28P for inhibiting amyloid fibre formation, found evidence for antiparallel stacking, and identified important regions for beta sheet stability.
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| 28. |
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| 29. |
- Dalmo, Erika
(författare)
-
Glioblastoma heterogeneity and plasticity : Investigating the roles of BMP4 and SOX2
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The malignant primary brain tumor glioblastoma has a dismal prognosis and is distinguished by its heterogeneous character. Current treatment with surgical resection, radiotherapy and adjuvant chemotherapy with the alkylating agent temozolomide does not provide a cure, but simply prolongs survival by a few months. Since the tumors recur, cells remaining after treatment can act as cancer stem cells and are able to reform the tumor. This thesis provides insights into glioblastoma heterogeneity and how dominant transcriptional programs have a substantial impact on glioblastoma cell responses to altered levels of the intrinsic proteins BMP4 and SOX2. SOX2 has a role as a stem cell transcription factor in the normal nervous system and in glioblastoma, while BMP4 acts as a cue for astrocytic differentiation during normal nervous system development. As a response to BMP4, we find a wide spectrum of growth-inhibition across 40 human glioblastoma cell lines and correlate the extent of the response with baseline gene expression in the cells. We discover a connection between high SOX2 expression and a more pronounced growth-inhibitory response and establish a causative relationship between SOX2 downregulation and reduced proliferation in BMP4-responsive cell lines. We also find how BMP4 can induce a senescence-like phenotype in glioblastoma and connect it to a mesenchymal phenotype on a proneural-mesenchymal scale by investigating clonally derived cultures from the same tumor. Through elimination of senescent cells by senolytic treatment and generation p21-knockout cells we also establish a p21-dependence for BMP4-induced senescence.Studies on cellular organization identify a hierarchical cell-state pattern which the cells move through during culture and show that external perturbations (here by BMP4 and temozolomide) alter this hierarchy, demonstrating a substantial cellular plasticity.Also, we establish a strategy to eradicate endogenous SOX2 with the inducible exogenous SOX2-system present, demonstrating that SOX2 is not an essential transcription factor in all glioblastomas. In summary, this thesis highlights several aspects of inter- and intratumoral heterogeneity as well as cellular plasticity, providing valuable insights that could help guide the glioblastoma community in the pursuit of more effective therapies against glioblastoma.
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| 30. |
- 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
-
Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:7, s. 981-991
-
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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| 31. |
- Dalmo, Erika, et al.
(författare)
-
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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| 32. |
- Darmanis, Spyros, et al.
(författare)
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Simultaneous Multiplexed Measurement of RNA and Proteins in Single Cells
- 2016
-
Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 14:2, s. 380-389
-
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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| 33. |
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| 34. |
- El-Obeid, A., et al.
(författare)
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TGF-alpha-driven tumor growth is inhibited by an EGF receptor tyrosine kinase inhibitor
- 2002
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 290:1, s. 349-58
-
Tidskriftsartikel (refereegranskat)abstract
- The simultaneous presence of the EGFR and its ligand TGF-alpha in human tumor tissues suggests that autocrine TGF-alpha stimulation drives tumor growth. Here we show that autocrine TGF-alpha stimulation does cause increased tumor growth in vivo, an effect that was proven to be mediated via EGFR activation, and that this TGF-alpha/EGFR autocrine loop was accessible to an EGFR specific tyrosine kinase inhibitor. Clones of the EGFR expressing glioma cell line U-1242 MG were transfected with TGF-alpha cDNA using a tetracycline-inhibitory system for gene expression. TGF-alpha expression was inhibited by the presence of tetracycline, and subcutaneous tumors forming from cell lines injected into nude mice could be inhibited by feeding mice tetracycline. We confirmed that TGF-alpha mRNA and protein were present in these tumors and that, subsequently, the endogenous EGFR was activated. Tumor growth could be inhibited by an EGFR specific tyrosine kinase inhibitor of the type 4-(3-chloroanilino)-6,7-dimethoxy-quinazoline, administered daily by intraperitoneal injection, thereby interrupting the autocrine loop.
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| 35. |
- Enarsson, Mia, 1974-
(författare)
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Roles of PDGF for Neural Stem Cells
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Stem cells are endowed with unique qualities: they can both self-renew and give rise to new mature cell types. Central nervous system (CNS) stem cells can give rise to neurons and glia. What factors regulate stem cell fate decisions? Identifying signals that are involved in the regulation of CNS stem cell proliferation, survival, differentiation and migration is fundamental to the understanding of CNS development. In addition, this knowledge hopefully will contribute to more efficient therapies of CNS damages and diseases.The focus of this thesis was to investigate mechanisms of CNS stem cell proliferation and differentiation. We have studied the role for platelet-derived growth factor (PDGF) in these cellular events both in vitro and in vivo. Previous reports have shown that PDGF are implicated in brain tumorigenesis and also supports neuronal differentiation of CNS stem cells. We have found that PDGF promotes survival and proliferation of immature neurons, thereby supporting neuronal differentiation. The intracellular Ras/ERK signaling pathway probably mediates the mitogenic activity of PDGF. In contrast, neuronal differentiation is not dependent on the Ras/ERK pathway. A genetic expression profile of stem cells during their differentiation was obtained. This microarray analysis suggests that PDGF-treated stem cells are at an intermediate stage between proliferation and differentiation. Furthermore, we generated transgenic mice that overexpress Pdgf-b in neural stem cells. Preliminary data indicate no signs of enhanced proliferation of immature neurons. Instead, increased apoptosis was detected in the developing striatum.The results presented in this thesis show how CNS stem cells are regulated by PDGF. PDGFs are widely expressed in the developing CNS and also in some brain tumors, which are thought to arise from CNS stem cells. Thus, this knowledge may contribute to an increased understanding of brain tumorigenesis in addition to normal CNS development.
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| 36. |
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| 37. |
- Erlandsson, Anna, et al.
(författare)
-
Autocrine/Paracrine platelet-derived growth factor regulates proliferation of neural progenitor cells
- 2006
-
Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 66:16, s. 8042-8048
-
Tidskriftsartikel (refereegranskat)abstract
- Growth factors play an important role in regulating neural stem cell proliferation and differentiation. This study shows that platelet-derived growth factor (PDGF) induces a partial differentiation of neural stem/progenitor cells (NSPCs) in the absence of other mitogens in vitro. NSPCs thus acquire an immature morphology and display markers for both neurons and glia. In addition, these cells do not readily mature in the absence of further stimuli. When NSPC cultures treated with PDGF were exposed to additional differentiation factors, however, the differentiation proceeded into neurons, astrocytes, and oligodendrocytes. We find that NSPC cultures are endowed with an endogenous PDGF-BB production. The PDGF-BB expression peaks during early differentiation and is present both in cell lysates and in conditioned medium, allowing for autocrine as well as paracrine signaling. When the NSPC-derived PDGF was inhibited, progenitor cell numbers decreased, showing that PDGF is involved in NSPC expansion. Addition of a PDGF receptor (PDGFR) inhibitor resulted in a more rapid differentiation. Neurons and oligodendrocytes appeared earlier and had more elaborate processes than in control cultures where endogenous PDGFR signaling was not blocked. Our observations point to PDGF as an inducer of partial differentiation of NSPC that also sustains progenitor cell division. Such an intermediate stage in stem cell differentiation is of relevance for the understanding of brain tumor development because autocrine PDGF stimulation is believed to drive malignant conversion of central nervous system progenitor cells.
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| 38. |
- Erlandsson, Anna, 1973-
(författare)
-
Neural Stem Cell Differentiation and Migration
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neural stem cells are the precursors of neurons, astrocytes and oligodendrocytes. During neural development, the division of stem cells takes place close to the lumen of the neural tube, after which they migrate to their final positions within the central nervous system (CNS). Soluble factors, including growth factors, regulate neural stem cell proliferation, survival, migration and differentiation towards specific cell lineages.This thesis describes the function of platelet-derived growth factor (PDGF) and stem cell factor (SCF) in neural stem cell regulation. PDGF was previously suggested to stimulate neuronal differentiation, but the mechanisms were not defined. This study shows that PDGF is a mitogen and a survival factor that expands a pool of immature cells from neural stem cells. The PDGF-treated cells can be stained by neuronal markers, but need further stimuli to continue their maturation. They can become either neurons or glia depending on the secondary instructive cues. Moreover, neural stem cells produce PDGF. Inhibition of this endogenous PDGF negatively affects the cell number in stem cell cultures. We find that SCF stimulates migration and supports the survival of neural stem cells, but that it has no effect on their proliferation or differentiation into neurons and glia. Intracellular signaling downstream from the receptors for PDGF and SCF includes activation of extracellular signal-regulated kinase (ERK). This investigation shows that active ERK is not needed for the differentiation of stem cells into neurons, at least not during early stages.Neural stem cells have a future potential in the treatment of CNS disorders. To be able to use neural stem cells clinically we need to understand how their proliferation, differentiation, survival and migration are controlled. The results presented in this thesis increase our knowledge of how neural stem cells are regulated by growth factors.
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| 39. |
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| 40. |
- Ferletta, Maria, 1973-, et al.
(författare)
-
Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells
- 2011
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 129:1, s. 45-60
-
Tidskriftsartikel (refereegranskat)abstract
- Numerous studies support a role for Sox2 to keep stem cells and progenitor cells in an immature and proliferative state. Coexpression of Sox2 and GFAP has been found in regions of the adult brain where neural stem cells are present and in human glioma cells. In our study, we have investigated the roles of Sox2 and its counteracting partner Sox21 in human glioma cells. We show for the first time that Sox21 is expressed in both primary glioblastoma and in human glioma cell lines. We found that coexpression of Sox2, GFAP and Sox21 was mutually exclusive with expression of fibronectin. Our result suggests that glioma consists of at least two different cell populations: Sox2+/GFAP+/Sox21+/FN- and Sox2-/GFAP-/Sox21-/FN1+. Reduction of Sox2 expression by using siRNA against Sox2 or by overexpressing Sox21 using a tetracyclineregulated expression system (Tet-on) caused decreased GFAP expression and a reduction in cell number due to induction of apoptosis. We suggest that Sox21 can negatively regulate Sox2 in glioma. Our findings imply that Sox2 and Sox21 may be interesting targets for the development of novel glioma therapy.
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| 41. |
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| 42. |
- Ferletta, Maria, et al.
(författare)
-
Sox10 Has a Broad Expression Pattern in Gliomas and Enhances Platelet-Derived Growth Factor-B–Induced Gliomagenesis
- 2007
-
Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 5:9, s. 891-897
-
Tidskriftsartikel (refereegranskat)abstract
- In a previously published insertional mutagenesis screen for candidate brain tumor genes in the mouse using a Moloney mouse leukemia virus encoding platelet-derived growth factor (PDGF)-B, the Sox10 gene was tagged in five independent tumors. The proviral integrations suggest an enhancer effect on Sox10. All Moloney murine leukemia virus/PDGFB tumors had a high protein expression of Sox10 independently of malignant grade or tumor type. To investigate the role of Sox10 in gliomagenesis, we used the RCAS/tv-a mouse model in which the expression of retroviral-encoded genes can be directed to glial progenitor cells (Ntv-a mice). Both Ntv-a transgenic mice, wild-type, and Ntv-a p19Arf null mice were injected with RCAS-SOX10 alone or in combination with RCAS-PDGFB. Infection with RCAS-SOX10 alone did not induce any gliomas. Combined infection of RCAS-SOX10 and RCAS-PDGFB in wild-type Ntv-a mice yielded a tumor frequency of 12%, and in Ntv-a Arf−/− mice the tumor frequency was 30%. This indicates that Sox10 alone is not sufficient to induce gliomagenesis but acts synergistically with PDGFB in glioma development. All induced tumors displayed characteristics of PNET-like structures and oligodendroglioma. The tumors had a strong and widely distributed expression of Sox10 and PDGFR-α. We investigated the expression of Sox10 in other human tumors and in a number of gliomas. The Sox10 expression was restricted to gliomas and melanomas. All glioma types expressed Sox10, and tumors of low-grade glioma had a much broader distribution of Sox10 compared with high-grade gliomas.
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| 43. |
- Forsberg-Nilsson, Karin, et al.
(författare)
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Oligodendrocyte precursor hypercellularity and abnormal retina development in mice overexpressing PDGF-B in myelinating tracts
- 2003
-
Ingår i: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 41:3, s. 276-89
-
Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) influences the generation of neurons and glia during embryogenesis and in early postnatal life. In an attempt to determine the consequences of an overexpression of PDGF-B during the first weeks of life, we targeted transgenic expression of a human PDGF-B cDNA to myelinating tracts using the promoter region of the myelin basic protein (MBP) gene. Transgenic mRNA and protein were expressed in the brain and the expression profile of the human PDGF-B during early postnatal development closely paralleled that of the endogenous mouse MBP gene. The gross morphological appearance of transgenic brains was normal but at the cellular level several phenotypic alterations could be identified. In white matter tracts such as the corpus callosum and cerebellar medulla, there was a marked hypercellularity. The number of oligodendrocyte precursors was increased and astrocytes were more abundant. In adult mice carrying the MBP-PDGF-B transgene, however, myelination appeared normal and the amount of oligodendrocytes was similar to that of control littermates. In addition to the phenotypic alterations in the brain, investigation of eye structure revealed a striking disorganization of retinal architecture. The retina was folded with cells collected in papillar or follicular-like structures. Retinal whole mount preparations after India ink perfusion revealed capillary disorganization with large-caliber vessels supporting only a few fine branches. Our observations strengthen the notion that PDGF is an important effector molecule in postnatal CNS development.
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| 44. |
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| 45. |
- Gupta, Rajesh Kumar, et al.
(författare)
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Tumor-specific migration routes of xenotransplanted human glioblastoma cells in mouse brain
- 2024
-
Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14
-
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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| 46. |
- Görling, Martin, 1984-
(författare)
-
Turbomachinery in Biofuel Production
- 2011
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim for this study has been to evaluate the integration potential of turbo-machinery into the production processes of biofuels. The focus has been on bio-fuel produced via biomass gasification; mainly methanol and synthetic natural gas. The research has been divided into two parts; gas and steam turbine applications. Steam power generation has a given role within the fuel production process due to the large amounts of excess chemical reaction heat. However, large amounts of the steam produced are used within the production process and is thus not available for power production. Therefore, this study has been focused on lowering the steam demand in the production process, in order to increase the power production. One possibility that has been evaluated is humidification of the gasification agent in order to lower the demand for high quality steam in the gasifier and replace it with waste heat. The results show that the power penalty for the gasification process could be lowered by 18-25%, in the specific cases that have been studied. Another step in the process that requires a significant amount of steam is the CO2-removal. This step can be avoided by adding hydrogen in order to convert all carbon into biofuel. This is also a way to store hydrogen (e.g. from wind energy) together with green carbon. The results imply that a larger amount of sustainable fuels can be produced from the same quantity of biomass. The applications for gas turbines within the biofuel production process are less obvious. There are large differences between the bio-syngas and natural gas in energy content and combustion properties which are technical problems when using high efficient modern gas turbines. This study therefore proposes the integration of a natural gas fired gas turbine; a hybrid plant. The heat from the fuel production and the heat recovery from the gas turbine flue gas are used in a joint steam cycle. Simulations of the hybrid cycle in methanol production have shown good improvements. The total electrical efficiency is increased by 1.4-2.4 percentage points, depending on the fuel mix. The electrical efficiency for the natural gas used in the hybrid plant is 56-58%, which is in the same range as in large-scale combined cycle plants. A bio-methanol plant with a hybrid power cycle is consequently a competitive production route for both biomass and natural gas.
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| 47. |
- Hede, Sanna-Maria, et al.
(författare)
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GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background
- 2009
-
Ingår i: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 57:11, s. 1143-1153
-
Tidskriftsartikel (refereegranskat)abstract
- Glioblastomas are the most common and malignant astrocytic brain tumors in human adults. The tumor suppressor gene TP53 is commonly mutated and/or lost in astrocytic brain tumors and the TP53 alterations are often found in combination with excessive growth factor signaling via PDGF/PDGFRalpha. Here, we have generated transgenic mice over-expressing human PDGFB in brain, under control of the human GFAP promoter. These mice showed no phenotype, but on a Trp53 null background a majority of them developed brain tumors. This occurred at 2-6 months of age and tumors displayed human glioblastoma-like features with integrated development of Pdgfralpha+ tumor cells and Pdgfrbeta+/Nestin+ vasculature. The transgene was expressed in subependymal astrocytic cells, in glia limitans, and in astrocytes throughout the brain substance, and subsequently, microscopic tumor lesions were initiated equally in all these areas. With tumor size, there was an increase in Nestin positivity and variability in lineage markers. These results indicate an unexpected plasticity of all astrocytic cells in the adult brain, not only of SVZ cells. The results also indicate a contribution of widely distributed Pdgfralpha+ precursor cells in the tumorigenic process.
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| 48. |
- Heldin, Carl-Henrik, 1952-, et al.
(författare)
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Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis
- 2018
-
Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 283:1, s. 16-44
-
Forskningsöversikt (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins ofthe receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours.
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| 49. |
- Heldin, Carl-Henrik, 1952-, et al.
(författare)
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Mechanism of action and in vivo role of platelet-derived growth factor
- 1999
-
Ingår i: Physiological Reviews. - 0031-9333 .- 1522-1210. ; 79:4, s. 1283-1316
-
Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) is a major mitogen for connective tissue cells and certain other cell types. It is a dimeric molecule consisting of disulfide-bonded, structurally similar A- and B-polypeptide chains, which combine to homo- and heterodimers. The PDGF isoforms exert their cellular effects by binding to and activating two structurally related protein tyrosine kinase receptors, denoted the alpha-receptor and the beta-receptor. Activation of PDGF receptors leads to stimulation of cell growth, but also to changes in cell shape and motility; PDGF induces reorganization of the actin filament system and stimulates chemotaxis, i.e., a directed cell movement toward a gradient of PDGF. In vivo, PDGF has important roles during the embryonic development as well as during wound healing. Moreover, overactivity of PDGF has been implicated in several pathological conditions. The sis oncogene of simian sarcoma virus (SSV) is related to the B-chain of PDGF, and SSV transformation involves autocrine stimulation by a PDGF-like molecule. Similarly, overproduction of PDGF may be involved in autocrine and paracrine growth stimulation of human tumors. Overactivity of PDGF has, in addition, been implicated in nonmalignant conditions characterized by an increased cell proliferation, such as atherosclerosis and fibrotic conditions. This review discusses structural and functional properties of PDGF and PDGF receptors, the mechanism whereby PDGF exerts its cellular effects, and the role of PDGF in normal and diseased tissues.
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| 50. |
- Heldin, Carl-Henrik, et al.
(författare)
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Platelet-derived growth factor : isoform-specific signalling via heterodimeric or homodimeric receptor complexes
- 1992
-
Ingår i: Kidney International. - : Elsevier BV. - 0085-2538 .- 1523-1755. ; 41:3, s. 571-574
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Growth factors are polypeptides that are involved in the regulation of cell growth and differentiation, such as, during the embryonal development, in wound healing, in hematopoiesis, in the immune response, as well as in several adverse reactions including malignancies. Several families of structurally-related growth factors are known; new members of these families continue to be discovered and occasionally new families are found. One of the best characterized growth factor family is the platelet-derived growth factor (PDGF) family. PDGF was originally found to be present in the alpha-granules of platelets and to have growth promoting activity for fibroblasts and smooth muscle cells; subsequent studies have shown that PDGF is synthesized by a large number of different normal as well as transformed cell types, and that it acts not only on connective tissue cells but also on other types of cells [reviewed in 1, 2]. The present review summarizes some recent developments in the elucidation of the structural and functional properties of PDGF and PDGF receptors, the mechanism for PDGF signalling at the cellular level and the possible in vivo effects of PDGF.
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