| 1. |
- Andersson, Mattias K, 1979, et al.
(författare)
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Nuclear expression of FLT1 and its ligand PGF in FUS-DDIT3 carrying myxoid liposarcomas suggests the existence of an intracrine signaling loop.
- 2010
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: The FUS-DDIT3 fusion oncogene encodes an abnormal transcription factor that has a causative role in the development of myxoid/round-cell liposarcomas (MLS/RCLS). We have previously identified FLT1 (VEGFR1) as a candidate downstream target gene of FUS-DDIT3. The aim of this study was to investigate expression of FLT1 and its ligands in MLS cells. Methods: HT1080 human fibrosarcoma cells were transiently transfected with FUS-DDIT3-GFP variant constructs and FLT1 expression was measured by quantitative real-time PCR. In addition, FLT1, PGF, VEGFA and VEGFB expression was measured in MLS/RCLS cell lines, MLS/RCLS tumors and in normal adiopocytes. We analyzed nine cases of MLS/RCLS and one cell line xenografted in mice for FLT1 protein expression using immunohistochemistry. MLS/RCLS cell lines were also analyzed for FLT1 by immunofluorescence and western blot. MLS/RCLS cell lines were additionally treated with FLT1 tyrosine kinase inhibitors and assayed for alterations in proliferation rate. Results: FLT1 expression was dramatically increased in transfected cells stably expressing FUS-DDIT3 and present at high levels in cell lines derived from MLS. The FLT1 protein showed a strong nuclear expression in cells of MLS tissue as well as in cultured MLS cells, which was confirmed by cellular fractionation. Tissue array analysis showed a nuclear expression of the FLT1 protein also in several other tumor and normal cell types including normal adipocytes. The FLT1 ligand coding gene PGF was highly expressed in cultured MLS cells compared to normal adipocytes while the other ligand genes VEGFA and VEGFB were expressed to lower levels. A more heterogeneous expression pattern of these genes were observed in tumor samples. No changes in proliferation rate of MLS cells were detected at concentrations for which the kinase inhibitors have shown specific inhibition of FLT1. Conclusions: Our results imply that FLT1 is induced as an indirect downstream effect of FUS-DDIT3 expression in MLS. This could be a consequence of the ability of FUS-DDIT3 to hijack parts of normal adipose tissue development and reprogram primary cells to a liposarcoma-like phenotype. The findings of nuclear FLT1 protein and expression of corresponding ligands in MLS and normal tissues may have implications for tissue homeostasis and tumor development through auto- or intracrine signaling.
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| 2. |
- Göransson, Melker, 1974, et al.
(författare)
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The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-kappaB target genes by interaction with NFKBIZ.
- 2009
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 28:2, s. 270-8
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Tidskriftsartikel (refereegranskat)abstract
- FUS (also called TLS), EWSR1 and TAF15 (also called TAF2N) are related genes involved in tumor type-specific fusion oncogenes in human malignancies. The FUS-DDIT3 fusion oncogene results from a t(12;16)(q13;p11) chromosome translocation and has a causative role in the initiation of myxoid/round cell liposarcomas (MLS/RCLS). The FUS-DDIT3 protein induces increased expression of the CAAT/enhancer-binding protein (C/EBP) and nuclear factor-kappaB (NF-kappaB)-controlled gene IL8, and the N-terminal FUS part is required for this activation. Chromatin immunoprecipitation analysis showed that FUS-DDIT3 binds the IL8 promoter. Expression studies of the IL8 promoter harboring a C/EBP-NF-kappaB composite site pinpointed the importance of NF-kappaB for IL8 expression in FUS-DDIT3-expressing cells. We therefore probed for possible interaction of FUS-DDIT3 with members of the NF-kappaB family. The nuclear factor NFKBIZ colocalizes with FUS-DDIT3 in nuclear structures, and immunoprecipitation experiments showed that FUS-DDIT3 binds the C-terminal of NFKBIZ. We also report that additional NF-kappaB-controlled genes are upregulated at the mRNA level in FUS-DDIT3-expressing cell lines and they can be induced by NFKBIZ. Taken together, the results indicate that FUS-DDIT3 deregulates some NF-kappaB-controlled genes through interactions with NFKBIZ. Similar mechanisms may be a part of the transformation process in other tumor types carrying FUS, EWSR1 and TAF15 containing fusion oncogenes.
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| 3. |
- Jauhiainen, Alexandra, 1981, et al.
(författare)
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Distinct cytoplasmic and nuclear functions of the stress induced protein DDIT3/CHOP/GADD153
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- DDIT3, also known as GADD153 or CHOP, encodes a basic leucine zipper transcription factor of the dimer forming C/EBP family. DDIT3 is known as a key regulator of cellular stress response, but its target genes and functions are not well characterized. Here, we applied a genome wide microarray based expression analysis to identify DDIT3 target genes and functions. By analyzing cells carrying tamoxifen inducible DDIT3 expression constructs we show distinct gene expression profiles for cells with cytoplasmic and nuclear localized DDIT3. Of 175 target genes identified only 3 were regulated by DDIT3 in both cellular localizations. More than two thirds of the genes were downregulated, supporting a role for DDIT3 as a dominant negative factor that could act by either cytoplasmic or nuclear sequestration of dimer forming transcription factor partners. Functional annotation of target genes showed cell migration, proliferation and apoptosis/survival as the most affected categories. Cytoplasmic DDIT3 affected more migration associated genes, while nuclear DDIT3 regulated more cell cycle controlling genes. Cell culture experiments confirmed that cytoplasmic DDIT3 inhibited migration, while nuclear DDIT3 caused a G1 cell cycle arrest. Promoters of target genes showed no common sequence motifs, reflecting that DDIT3 forms heterodimers with several alternative transcription factors that bind to different motifs. We conclude that expression of cytoplasmic DDIT3 regulated 94 genes. Nuclear translocation of DDIT3 regulated 81 additional genes linked to functions already affected by cytoplasmic DDIT3. Characterization of DDIT3 regulated functions helps understanding its role in stress response and involvement in cancer and degenerative disorders.
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| 4. |
- Engström, Katarina, 1956, et al.
(författare)
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The myxoid/round cell liposarcoma fusion oncogene FUS-DDIT3 and the normal DDIT3 induce a liposarcoma phenotype in transfected human fibrosarcoma cells.
- 2006
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Ingår i: The American journal of pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 168:5, s. 1642-53
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid/round cell liposarcoma (MLS/RCLS) is the most common subtype of liposarcoma. Most MLS/RCLS carry a t(12;16) translocation, resulting in a FUS-DDIT3 fusion gene. We investigated the role of the FUS-DDIT3 fusion in the development of MLS/RCLS in FUS-DDIT3- and DDIT3-transfected human HT1080 sarcoma cells. Cells expressing FUS-DDIT3 and DDIT3 grew as liposarcomas in severe combined immunodeficient mice and exhibited a capillary network morphology that was similar to networks of MLS/RCLS. Microarray-based comparison of HT1080, the transfected cells, and an MLS/RCLS-derived cell line showed that the FUS-DDIT3- and DDIT3-transfected variants shifted toward an MLS/RCLS-like expression pattern. DDIT3-transfected cells responded in vitro to adipogenic factors by accumulation of fat and transformation to a lipoblast-like morphology. In conclusion, because the fusion oncogene FUS-DDIT3 and the normal DDIT3 induce a liposarcoma phenotype when expressed in a primitive sarcoma cell line, MLS/RCLS may develop from cell types other than preadipocytes. This may explain the preferential occurrence of MLS/RCLS in nonadipose tissues. In addition, development of lipoblasts and the typical MLS/RCLS capillary network could be an effect of the DDIT3 transcription factor partner of the fusion oncogene.
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| 5. |
- Göransson, Melker, 1974, et al.
(författare)
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Myxoid liposarcoma FUS-DDIT3 fusion oncogene induces C/EBP β-mediated interleukin 6 expression
- 2005
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 115:4, s. 556-560
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Tidskriftsartikel (refereegranskat)abstract
- The myxoid/round cell liposarcoma oncogene FUS-DDIT3 is the result of a translocation derived gene fusion between the splicing factor FUS and DDIT3. In order to investigate the downstream targets of DDIT3, and the transforming effects of the FUS-DDIT3 fusion protein, we have introduced DDIT3-GFP and FUS-DDIT3-GFP constructs into a human flbrosarcoma cell line. The gene expression profiles of stable transfectants were compared to the original fibrosarcoma cell line by microarray analysis. We here report that the NFκB and C/EBP β controlled gene IL6 is upregulated in DDIT3- and FUS-DDIT3-expressing fibrosarcoma cell lines and in myxoid liposarcoma cell lines. Strong expression of the tumor associated multifunctional cytokine interleukin 6 was confirmed both at mRNA and protein level. Knockdown experiments using siRNA against CEBPB transcripts showed that the effect of FUS-DDIT3 on IL6 expression is C/EBP β dependent. Chromatin immunoprecipitation revealed direct interaction between the IL6 promoter and the C/EBP β protein. In addition, the effect of DDIT3 and FUS-DDIT3 on the expression of other acute phase genes was examined using real-time PCR. We demonstrate for the first time that DDIT3 and FUS-DDIT3 show opposite transcriptional regulation of IL8 and suggest that FUS-DDIT3 may affect the synergistic activation of promoters regulated by C/EBP β and NFκB.
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| 6. |
- Jonsson, Bert, Professor, 1961-, et al.
(författare)
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A learning method for all : The testing effect is independent of cognitive ability
- 2021
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Ingår i: Journal of Educational Psychology. - : American Psychological Association (APA). - 0022-0663 .- 1939-2176. ; 113:5, s. 972-985
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Tidskriftsartikel (refereegranskat)abstract
- The testing effect, defined as the positive effect of retrieval practice (i.e., self-testing) on long-term memory retention relative to other ways to support learning, is a robust empirical phenomenon. Despite substantial scientific evidence for the testing effect, less is known about its effectiveness in relation to individual differences in cognitive ability. In the present study, we examine whether the effect of retrieval practice is beneficial independent of cognitive ability using behavioral and brain imaging data. In a within-subject design, upper-secondary students learned Swahili–Swedish word pairs through retrieval practice and study. The testing effects were assessed at a direct test and for a subsample after 1- and 4-weeks retention intervals, respectively. Another subsample performed the 1-week retention test during functional MRI (fMRI). Memory retention was analyzed in relation to an educationally relevant composite score dividing participants into low, intermediate, and high cognitive-ability groups. We provide behavioral evidence that the testing effect is independent of cognitive ability. The fMRI findings confirmed a general effectiveness of retrieval practice by showing that brain regions associated with successful retrieval of conceptual representations and semantic processing were more strongly engaged after retrieval practice in all cognitive-ability groups. It is argued that the advantages of retrieval practice should be conveyed to all teachers and students.
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| 7. |
- Karlsson Wirebring, Linnea, 1979-, et al.
(författare)
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An fMRI intervention study of creative mathematical reasoning : behavioral and brain effects across different levels of cognitive ability
- 2022
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Ingår i: Trends in Neuroscience and Education. - : Elsevier. - 2452-0837 .- 2211-9493. ; 29
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many learning methods of mathematical reasoning encourage imitative procedures (algorithmic reasoning, AR) instead of more constructive reasoning processes (creative mathematical reasoning, CMR). Recent research suggest that learning with CMR compared to AR leads to better performance and differential brain activity during a subsequent test. Here, we considered the role of individual differences in cognitive ability in relation to effects of CMR.Methods: We employed a within-subject intervention (N=72, MAge=18.0) followed by a brain-imaging session (fMRI) one week later. A battery of cognitive tests preceded the intervention. Participants were divided into three cognitive ability groups based on their cognitive score (low, intermediate and high).Results: On mathematical tasks previously practiced with CMR compared to AR we observed better performance, and higher brain activity in key regions for mathematical cognition such as left angular gyrus and left inferior/middle frontal gyrus. The CMR-effects did not interact with cognitive ability, albeit the effects on performance were driven by the intermediate and high cognitive ability groups.Conclusions: Encouraging pupils to engage in constructive processes when learning mathematical reasoning confers lasting learning effects on brain activation, independent of cognitive ability. However, the lack of a CMR-effect on performance for the low cognitive ability group suggest future studies should focus on individualized learning interventions, allowing more opportunities for effortful struggle with CMR.
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| 8. |
- Stillesjö, Sara, 1989-, et al.
(författare)
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Active math and grammar learning engages overlapping brain networks
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:46
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Tidskriftsartikel (refereegranskat)abstract
- We here demonstrate common neurocognitive long-term memory effects of active learning that generalize over course subjects (mathematics and vocabulary) by the use of fMRI. One week after active learning, relative to more passive learning, performance and fronto-parietal brain activity was significantly higher during retesting, possibly related to the formation and reactivation of semantic representations. These observations indicate that active learning conditions stimulate common processes that become part of the representations and can be reactivated during retrieval to support performance. Our findings are of broad interest and educational significance related to the emerging consensus of active learning as critical in promoting good long-term retention.
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| 9. |
- Thulin, Anna, 1978, et al.
(författare)
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Clinical outcome of patients with brain metastases from breast cancer - A population based study over 21 years.
- 2020
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Ingår i: Breast. - : Elsevier BV. - 1532-3080. ; 50, s. 113-124
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Tidskriftsartikel (refereegranskat)abstract
- Brain metastases (BM) are a feared progression of breast cancer (BC) with impact on quality of life and survival. Despite improved treatments, it is believed patients suffering from BM are increasing.To study potential changes in the number of BM, the possible links between BC subgroup and extent of BM with prognosis. To investigate the interval between primary BC/extra cranial recurrence, and diagnosis of BM in the years 1994-2014.Clinical data from 191 patients with BM diagnosed 1994-2014, was retrieved from charts. Primary tumours where re-evaluated histologically.There was an increase of BM in 5 years cohorts (1994-99 (n=9); 2000-04 (n=36); 2005-09 (n=60); 2010-14 (n=86)). We found no difference in the time interval from primary BC to BM but an insignificant increase in time from extra cranial relapse to development of BM in the time periods 1994-2004 and 2005-2014 of 15.5 and 25.0 months (p=0.0612). Survival after BM was 7 months (95% CI 6-10) with a statistically significant difference between HER2 positive and TNBC with an inferior outcome for the latter (p=0.018) whilst no differences were present when Luminal BC were compared with HER2 positive BC (p=0.073).We show an increase of BM over time whilst the time span from primary BC to BM is unchanged supports earlier findings that adjuvant treatments have little preventive function. Time from extra cranial recurrence to BM was prolonged with one year. Patients with TNBC or more advance extent of BM had the shortest survival with BM.
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| 10. |
- Thulin, Anna, 1978, et al.
(författare)
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Discordance of PIK3CA and TP53 mutations between breast cancer brain metastases and matched primary tumors.
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- There is limited knowledge of the biology of breast cancer (BC) brain metastasis (BM). We primarily aimed to determine the mutations in BCBM and to compare the mutational pattern with the matched primary breast cancer (BC). Secondary aims were to determine mutations in each subgroup (Luminal A-/B-like, HER2+and TNBC) of BCBM, and to determine survival according to specific mutations. We investigated 57 BCBMs, including 46 cases with matched primary tumors (PT) by targeted Next Generation Sequencing (NGS) using the Cancer Hotspot Panel v2 (ThermoFisher Scientific) covering 207 targeted regions in 50 cancer related genes. Subtype according to immunohistochemistry was re-evaluated. NGS results fulfilling sequencing quality criteria were obtained from 52 BM and 41 PT, out of which 37 were matched pairs. Pathogenic mutations were detected in 66% of PTs (27/41), and 62% of BMs (32/52). TP53 mutations were most frequent; 49% (20/41) of PTs and 48% (25/52) in BMs, followed by PIK3CA mutations; 22% (9/42) in PTs and 25% (13/52) in BMs. Mutations in CDH1, EGFR, HRAS, RB1 CDKN2A and PTEN were detected in single pairs or single samples. Mutational pattern was discordant in 24% of matched pairs. We show a discordance of PIK3CA and TP53 mutations of roughly 25% indicating the need to develop methods to assess mutational status in brain metastasis where analysis of cell-free DNA from cerebrospinal fluid (CSF) has shown promising results.
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