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Sökning: WFRF:(Vesterlund Mattias)

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1.
  • Yang, Minjun, et al. (författare)
  • Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia
  • 2019
  • Ingår i: Nature Communications. - Nature Publishing Group. - 2041-1723. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6/RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 2/4 cases displayed a clear loss of TAD boundary strength and 3/4 showed reduced insulation at TAD borders, with putative leukemogenic effects.
2.
  • Akhtar, Monira, et al. (författare)
  • Cell type and context-specific function of PLAG1 for IGF2 P3 promoter activity
  • 2012
  • Ingår i: International Journal of Oncology. - 1019-6439. ; 41:6, s. 1959-1966
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The fetal transcription factor PLAG1 is found to be overexpressed in cancers, and has been suggested to bind the insulin like growth factor 2 (IGF2) P3 promoter, and to activate the IGF2 gene. The expression of IGF2 has partly been linked to loss of CTCF-dependent chromatin insulator function at the H19 imprinting control region (ICR). We investigated the role of PLAG1 for IGF2 regulation in Hep3B and JEG-3 cell lines. Chromatin immunoprecipitation revealed cell type-specific binding of PLAG1 to the IGF2 P3 promoter, which was substantially insensitive to recombinant PLAG1 overexpression in the endogenous context. We hypothesized that the H19 chromatin insulator may be involved in the cell type-specific PLAG1 response. By using a GFP reporter gene/insulator assay plasmid construct with and without the H19 ICR and/or an SV40 enhancer, we confirm that the effect of the insulator is specifically associated with the activity of the IGF2 P3 promoter in the GFP reporter system, and furthermore, that the reporter insulator is functional in JEG-3 but not in Hep3B cells. FACS analysis was used to assess the function of PLAG1 in low endogenously expressing, but Zn-inducible stable PLAG1 expressing JEG-3 cell clones. Considerable increase in IGF2 expression upon PLAG1 induction with a partial insulator overriding activity was found using the reporter constructs. This is in contrast to the effect of the endogenous IGF2 gene which was insensitive to PLAG1 expression in JEG-3, while modestly induced the already highly expressed IGF2 gene in Hep3B cells. We suggest that the PLAG1 binding to the IGF2 P3 promoter and IGF2 expression is cell type-specific, and that the PLAG1 transcription factor acts as a transcriptional facilitator that partially overrides the insulation by the H19 ICR.</p>
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3.
  • Brännvall, Rickard, 1975-, et al. (författare)
  • Data Center Excess Heat Recovery : A Case Study of Apple Drying
  • 2020
  • Ingår i: ECOS 2020 : Proceedings of the 33rd International Conference on Efficiency, Cost, Optimization, Simulation and Enviromental Impact of Energy Systems. - ECOS 2020 Local Organizing Committee. ; s. 2165-2174
  • Konferensbidrag (refereegranskat)abstract
    • <p>Finding synergies between heat producing and heat consuming actors in an economy provides opportunity for more efficient energy utilization and reduction of overall power consumption. We propose to use low-grade heat recovered from data centers directly in food processing industries, for example for the drying of fruit and berries. This study analyses how the heat output of industrial IT-load on servers can dry apples in a small-scale experimental set up.To keep the temperatures of the server exhaust airflow near a desired set-point we use a model predictive controller (MPC) re-purposed to the drying experiment set-up from a previous work that used machine learning models for cluster thermal management. Thus, conditions with for example 37 C for 8 hours drying can be obtained with results very similar to conventional drying of apples.The proposed solution increases the value output of the electricity used in a data center by capturing and using the excess heat that would otherwise be exhausted. The results from our experiments show that drying foods with excess heat from data center is possible with potential of strengthening the food processing industry and contribute to food self-sufficiency in northern Sweden.</p>
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4.
  • Brännvall, Rickard, 1975-, et al. (författare)
  • EDGE Microgrid Data Center with Mixed Energy Storage
  • 2020
  • Ingår i: e-Energy '20 : Proceedings of the Eleventh ACM International Conference on Future Energy Systems. - Association for Computing Machinery (ACM). ; s. 466-473
  • Konferensbidrag (refereegranskat)abstract
    • <p>Low latency requirements are expected to increase with 5G telecommunications driving data and compute to EDGE data centers located in cities near to end users.</p><p>This article presents a testbed for such data centers that has been built at RISE ICE Datacenter in northern Sweden in order to perform full stack experiments on load balancing, cooling, micro-grid interactions and the use of renewable energy sources. This system is described with details on both hardware components and software implementations used for data collection and control. A use case for off-grid operation is presented to demonstrate how the test lab can be used for experiments on edge data center design, control and autonomous operation.</p>
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5.
  • Brännvall, Rickard, et al. (författare)
  • EDGE : Microgrid Data Center with Mixed Energy Storage
  • 2020
  • Ingår i: e-Energy 2020 - Proceedings of the 11th ACM International Conference on Future Energy Systems. - Association for Computing Machinery, Inc. - 9781450380096 ; s. 466-473
  • Konferensbidrag (refereegranskat)abstract
    • <p>Low latency requirements are expected to increase with 5G telecommunications driving data and compute to EDGE data centers located in cities near to end users. This article presents a testbed for such data centers that has been built at RISE ICE Datacenter in northern Sweden in order to perform full stack experiments on load balancing, cooling, micro-grid interactions and the use of renewable energy sources. This system is described with details on both hardware components and software implementations used for data collection and control. A use case for off-grid operation is presented to demonstrate how the test lab can be used for experiments on edge data center design, control and autonomous operation. © 2020 Author.</p>
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6.
  • Fotouhi, Omid, et al. (författare)
  • Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors
  • 2019
  • Ingår i: Oncogene. - NATURE PUBLISHING GROUP. - 0950-9232 .- 1476-5594. ; 38:43, s. 6881-6897
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.</p>
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7.
  • Fotouhi, Omid, et al. (författare)
  • Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors
  • 2019
  • Ingår i: Oncogene. - NATURE PUBLISHING GROUP. - 0950-9232 .- 1476-5594. ; 38:43, s. 6881-6897
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.</p>
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8.
  • Herr, Patrick, et al. (författare)
  • Cell Cycle Profiling Reveals Protein Oscillation, Phosphorylation, and Localization Dynamics
  • 2020
  • Ingår i: Molecular & Cellular Proteomics. - AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 1535-9476 .- 1535-9484. ; 19:4, s. 608-623
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The cell cycle is a highly conserved process involving the coordinated separation of a single cell into two daughter cells. To relate transcriptional regulation across the cell cycle with oscillatory changes in protein abundance and activity, we carried out a proteome- and phospho-proteome-wide mass spectrometry profiling. We compared protein dynamics with gene transcription, revealing many transcriptionally regulated G2 mRNAs that only produce a protein shift after mitosis. Integration of CRISPR/Cas9 survivability studies further highlighted proteins essential for cell viability. Analyzing the dynamics of phosphorylation events and protein solubility dynamics over the cell cycle, we characterize predicted phospho-peptide motif distributions and predict cell cycle-dependent translocating proteins, as exemplified by the S-adenosylmethionine synthase MAT2A. Our study implicates this enzyme in translocating to the nucleus after the G1/S-checkpoint, which enables epigenetic histone methylation maintenance during DNA replication. Taken together, this data set provides a unique integrated resource with novel insights on cell cycle dynamics.</p>
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9.
  • Johansson, Henrik J., et al. (författare)
  • Breast cancer quantitative proteome and proteogenomic landscape
  • 2019
  • Ingår i: Nature Communications. - NATURE PUBLISHING GROUP. - 2041-1723 .- 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.</p>
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10.
  • Johansson, Henrik J., et al. (författare)
  • Breast cancer quantitative proteome and proteogenomic landscape
  • 2019
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.</p>
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