| 1. |
- Chen, Dongfeng, et al.
(författare)
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Better Prognosis of Patients with Glioma Expressing FGF2-Dependent PDGFRA Irrespective of Morphological Diagnosis.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- Signaling of platelet derived growth factor receptor alpha (PDGFRA) is critically involved in the development of gliomas. However, the clinical relevance of PDGFRA expression in glioma subtypes and the mechanisms of PDGFRA expression in gliomas have been controversial. Under the supervision of morphological diagnosis, analysis of the GSE16011 and the Repository of Molecular Brain Neoplasia Data (Rembrandt) set revealed enriched PDGFRA expression in low-grade gliomas. However, gliomas with the top 25% of PDGFRA expression levels contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to those gliomas with lower levels of PDGFRA expression. SNP analysis in Rembrandt data set and FISH analysis in eleven low passage glioma cell lines showed infrequent amplification of PDGFRA. Using in vitro culture of these low passage glioma cells, we tested the hypothesis of gliogenic factor dependent expression of PDGFRA in glioma cells. Fibroblast growth factor 2 (FGF2) was able to maintain PDGFRA expression in glioma cells. FGF2 also induced PDGFRA expression in glioma cells with low or non-detectable PDGFRA expression. FGF2-dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Further, concordant expression patterns of FGF2 and PDGFRA were detected in glioma samples by immunohistochemical staining. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas with younger age at disease onset and longer patient survival regardless of their morphological diagnosis.
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| 2. |
- Chen, Dongfeng, et al.
(författare)
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Glioma Cell Proliferation Controlled by ERK Activity-Dependent Surface Expression of PDGFRA.
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Increased PDGFRA signaling is an essential pathogenic factor in many subtypes of gliomas. In this context the cell surface expression of PDGFRA is an important determinant of ligand sensing in the glioma microenvironment. However, the regulation of spatial distribution of PDGFRA in glioma cells remains poorly characterized. Here, we report that cell surface PDGFRA expression in gliomas is negatively regulated by an ERK-dependent mechanism, resulting in reduced proliferation of glioma cells. Glioma tumor tissues and their corresponding cell lines were isolated from 14 patients and analyzed by single-cell imaging and flow cytometry. In both cell lines and their corresponding tumor samples, glioma cell proliferation correlated with the extent of surface expression of PDGFRA. High levels of surface PDGFRA also correlated to high tubulin expression in glioma tumor tissue in vivo. In glioma cell lines, surface PDGFRA declined following treatment with inhibitors of tubulin, actin and dynamin. Screening of a panel of small molecule compounds identified the MEK inhibitor U0126 as a potent inhibitor of surface PDGFRA expression. Importantly, U0126 inhibited surface expression in a reversible, dose- and time-dependent manner, without affecting general PDGFRA expression. Treatment with U0126 resulted in reduced co-localization between PDGFRA and intracellular trafficking molecules e.g. clathrin, RAB11 and early endosomal antigen-1, in parallel with enhanced co-localization between PDGFRA and the Golgi cisternae maker, Giantin, suggesting a deviation of PDGFRA from the endosomal trafficking and recycling compartment, to the Golgi network. Furthermore, U0126 treatment in glioma cells induced an initial inhibition of ERK1/2 phosphorylation, followed by up-regulated ERK1/2 phosphorylation concomitant with diminished surface expression of PDGFRA. Finally, down-regulation of surface PDGFRA expression by U0126 is concordant with reduced glioma cell proliferation. These findings suggest that manipulation of spatial expression of PDGFRA can potentially be used to combat gliomas.
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| 3. |
- Chen, Dongfeng
(författare)
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Studies on the Roles of PDGFRA and EGFR in the Classification and Identification of Therapeutic Targets for Human Gliomas
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glioma is the most common type of primary tumor in the adult central nervous system (CNS). However, the current classification of gliomas is highly subjective and even inaccurate in some cases, which leads to clinical confusion and hinders the development of targeted therapies. EGFR and PDGFRA play crucial roles in glia development and glioma pathogenesis. In this thesis we aim to establish a glial genesis-guided molecular classification scheme for gliomas based on the genes co-expressed with EGFR or PDGFRA and to clarify the clinical relevance and the mechanism of PDGFRA expression in different glioma subtypes. We also aim to investigate the role of cell surface PDGFRA expression in regulating glioma cell proliferation. In order to establish a glial genesis-guided classification scheme, we identified 69 genes co-expressed with EGFR (EM) or PDGFRA (PM) as classifiers. Using these 69 classifiers, gliomas are clarified into EM (highly expressing EM genes), PM (highly expressing PM genes), and EMlowPMlow (lowly expressing both EM and PM genes) subtypes in a morphology-independent manner. Our results showed that besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, stronger expression of neural stem cell genes and astrogenesis genes, while PM and EMlowPMlow gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EMlowPMlow gliomas were enriched in the signatures of mature neurons and oligodendrocytes. These findings constitute a framework for improving molecular diagnosis and identifying therapeutic targets to combat gliomas. To investigate the clinical relevance of PDGFRA in gliomas, the clinical outcomes of gliomas with the top 25% of PDGFRA expression levels (PDGFRA-high) were compared with the gliomas with lowest 25% of PDGFRA expression levels (PDGFRA-low). We found that PDGFRA-high gliomas contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to PDGFRA-low gliomas. We also found that the PDGFRA expression can be induced and maintained by fibroblast growth factor 2 (FGF2) in primary glioma cells. FGF2-dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas. To investigate the role of cell surface expression of PDGFRA in regulating cell proliferation, we compared the growth rate of primary glioma cells having high cell surface PDGFRA expression level with the glioma cells having low cell surface PDGFRA expression level. We demonstrated that glioma cell proliferation correlated with the extent of surface expression of PDGFRA in both glioma cell lines and their corresponding tumor samples. We also found that MEK inhibitor U0126 treatment can decrease the surface PDGFRA expression and result in deviation of PDGFRA from endosomal trafficking and recycling compartment to the Golgi network in a reversible, dose- and time-dependent manner without affecting total PDGFRA expression. U0126 mediated down-regulation of PDGFRA surface expression correlated with diminished cell proliferation. Our findings suggested that the trafficking of PDGFRA in glioma cells is regulated by ERK activity and can potentially be manipulated to combat glioma growth.
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| 4. |
- Dang, Dongfeng, 1988, et al.
(författare)
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Enhanced Photovoltaic Performance of Indacenodithiophene-Quinoxaline Copolymers by Side- Chain Modulation
- 2014
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Ingår i: Advanced Energy Materials. - : Wiley. - 1614-6840 .- 1614-6832. ; 4:15, s. Art. no. 1400680-
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Tidskriftsartikel (refereegranskat)abstract
- Two pairs of indacenodithiophene (IDT) and quinoxaline-based copolymers with meta- or para-hexyl-phenyl side chains on the IDT unit are synthesized. The meta-substituted polymers offer better solubility, higher molecular weight for both fluorinated and non-fluorinated copolymers, and a superior photovoltaic performance with a power conversion efficiency of 7.8%. The side-chain design strategy presented is an efficient way to produce high performance conjugated polymers for organic electronics.
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| 5. |
- Dang, Dongfeng, 1988, et al.
(författare)
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Fluorine substitution enhanced photovoltaic performance of a D-A 1-D-A2 copolymer
- 2013
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Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1364-548X .- 1359-7345. ; 49:81, s. 9335-9337
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Tidskriftsartikel (refereegranskat)abstract
- A new alternating donor-acceptor (D-A1-D-A2) copolymer containing two electron-deficient moieties, isoindigo and quinoxaline, was synthesized. The photovoltaic performance of this polymer could be improved by incorporating fluorine atoms into the quinoxaline units, resulting in an efficiency of 6.32%. This result highlights the attractive promise of D-A 1-D-A2 copolymers for high-performance bulk heterojunction solar cells. © 2013 The Royal Society of Chemistry.
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| 6. |
- Na, Manli, et al.
(författare)
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Adenovirus assembly is impaired by BMI1-related histone deacetylase activity.
- 2014
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Ingår i: Virology. - : Elsevier BV. - 1096-0341 .- 0042-6822. ; 456:Apr 17, s. 227-237
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Tidskriftsartikel (refereegranskat)abstract
- Polycomb ring finger oncogene BMI1 (B cell-specific Moloney murine leukemia virus integration site 1) plays a critical role in development of several types of cancers. Here, we report an inverse relationship between levels of BMI1 expression and adenovirus (Ad) progeny production. Enforced BMI1 expression in A549 cells impaired Ad progeny production. In contrast, knocking-down of endogenous BMI1 expression enhanced progeny production of a conditionally replicating Ad and wild-type Ad5 and Ad11p. Ad vectors overexpressing BMI1 were not impaired in the replication of progeny genomes and in the expression of E1A and Ad structural proteins. However, 293 cells infected by Ad vector overexpressing BMI1 contained a large proportion of morphologically irregular Ad particles. This effect was reversed in 293 cells pre-treated with the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) in parallel with the production of infectious Ad particles. Our findings suggest an inhibitory role of BMI1 in Ad morphogenesis that can be implied in Ad tropism and Ad-mediated cancer therapy.
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| 7. |
- Sun, Yingyu, et al.
(författare)
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A glioma classification scheme based on coexpression modules of EGFR and PDGFRA
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 111:9, s. 3538-3543
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were identified. Based on EM and PM expression signatures, nonnegative matrix factorization reproducibly clustered 1,369 adult diffuse gliomas WHO grades II-IV from four independent databases generated in three continents, into the subtypes (EM, PM and EMlowPMlow gliomas) in a morphology-independent manner. Besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, and stronger expression of neural stem cell and astrogenesis genes. Both PM and EMlowPMlow gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EMlowPMlow gliomas were enriched in the signatures of mature neurons and oligodendrocytes. The EM/PM-based molecular classification scheme is applicable to adult low-grade and high-grade diffuse gliomas, and outperforms existing classification schemes in assigning diffuse gliomas to subtypes with distinct transcriptomic and genomic profiles. The majority of the EM/PM classifiers, including regulators of glial fate decisions, have not been extensively studied in glioma biology. Subsets of these classifiers were coexpressed in mouse glial precursor cells, and frequently amplified or lost in an EM/PM glioma subtypespecific manner, resulting in somatic copy number alteration-dependent gene expression that contributes to EM/PM signatures in glioma samples. EM/PM-based molecular classification provides a molecular diagnostic framework to expedite the search for new glioma therapeutic targets.
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