| 1. |
- Trac, Quang Thinh, et al.
(författare)
-
Prediction model for drug response of acute myeloid leukemia patients
- 2023
-
Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Despite some encouraging successes, predicting the therapy response of acute myeloid leukemia (AML) patients remains highly challenging due to tumor heterogeneity. Here we aim to develop and validate MDREAM, a robust ensemble-based prediction model for drug response in AML based on an integration of omics data, including mutations and gene expression, and large-scale drug testing. Briefly, MDREAM is first trained in the BeatAML cohort (n = 278), and then validated in the BeatAML (n = 183) and two external cohorts, including a Swedish AML cohort (n = 45) and a relapsed/refractory acute leukemia cohort (n = 12). The final prediction is based on 122 ensemble models, each corresponding to a drug. A confidence score metric is used to convey the uncertainty of predictions; among predictions with a confidence score >0.75, the validated proportion of good responders is 77%. The Spearman correlations between the predicted and the observed drug response are 0.68 (95% CI: [0.64, 0.68]) in the BeatAML validation set, -0.49 (95% CI: [-0.53, -0.44]) in the Swedish cohort and 0.59 (95% CI: [0.51, 0.67]) in the relapsed/refractory cohort. A web-based implementation of MDREAM is publicly available at https://www.meb.ki.se/shiny/truvu/MDREAM/.
|
|
| 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. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 41:6, s. 1959-1966
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 3. |
- Chan, Sherwin, et al.
(författare)
-
Regulation of PfEMP1-VAR2CSA translation by a Plasmodium translation-enhancing factor
- 2017
-
Ingår i: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 2:7
-
Tidskriftsartikel (refereegranskat)abstract
- Pregnancy-associated malaria commonly involves the binding of Plasmodium falciparum-infected erythrocytes to placental chondroitin sulfate A (CSA) through the PfEMP1-VAR2CSA protein. VAR2CSA is translationally repressed by an upstream open reading frame. In this study, we report that the P. falciparum translation enhancing factor (PTEF) relieves upstream open reading frame repression and thereby facilitates VAR2CSA translation. VAR2CSA protein levels in var2csa-transcribing parasites are dependent on the expression level of PTEF, and the alleviation of upstream open reading frame repression requires the proteolytic processing of PTEF by PfCalpain. Cleavage generates a C-terminal domain that contains a sterile-alpha-motif-like domain. The C-terminal domain is permissive to cytoplasmic shuttling and interacts with ribosomes to facilitate translational derepression of the var2csa coding sequence. It also enhances translation in a heterologous translation system and thus represents the first non-canonical translation enhancing factor to be found in a protozoan. Our results implicate PTEF in regulating placental CSA binding of infected erythrocytes.
|
|
| 4. |
- 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
- 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.
|
|
| 5. |
- Galkin, Nikolai, et al.
(författare)
-
On Modelling of Edge Datacentre Microgrid for Participation in Smart Energy Infrastructures
- 2022
-
Ingår i: IEEE Open Journal of the Industrial Electronics Society. - : Institute of Electrical and Electronics Engineers Inc.. - 2644-1284. ; 3, s. 50-64
-
Tidskriftsartikel (refereegranskat)abstract
- Datacentres are becoming a sizable part of the energy system and are one of the biggest consumers of the energy grid. The so-called “Green Datacentre” is capable of not only consuming but also producing power, thus becoming an important kind of prosumers in the electric grid. Green datacentres consist of a microgrid with a backup uninterrupted power supply and renewable generation, e.g., using photovoltaic panels. As such, datacentres could realistically be important participants in demand/response applications. However, this requires reconsidering their currently rigid control and automation systems and the use of simulation models for online estimation of the control actions impact. This paper presents such a microgrid simulation model modelled after a real edge datacentre. A case study consumption scenario is presented for the purpose of validating the developed microgrid model against data traces collected from the green edge datacentre. Both simulation and real-time validation tests are performed to validate the accuracy of the datacentre model. Then the model is connected to the automation environment to be used for the online impact estimation and virtual commissioning purposes.
|
|
| 6. |
- Gao, Yu, et al.
(författare)
-
SOCS3 Expression by Thymic Stromal Cells Is Required for Normal T Cell Development
- 2021
-
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- The suppressor of cytokine signaling 3 (SOCS3) is a major regulator of immune responses and inflammation as it negatively regulates cytokine signaling. Here, the role of SOCS3 in thymic T cell formation was studied in Socs3fl/fl Actin-creER mice (Δsocs3) with a tamoxifen inducible and ubiquitous Socs3 deficiency. Δsocs3 thymi showed a 90% loss of cellularity and altered cortico-medullary organization. Thymocyte differentiation and proliferation was impaired at the early double negative (CD4-CD8-) cell stage and apoptosis was increased during the double positive (CD4+CD8+) cell stage, resulting in the reduction of recent thymic emigrants in peripheral organs. Using bone marrow chimeras, transplanting thymic organoids and using mice deficient of SOCS3 in thymocytes we found that expression in thymic stromal cells rather than in thymocytes was critical for T cell development. We found that SOCS3 in thymic epithelial cells (TECs) binds to the E3 ubiquitin ligase TRIM 21 and that Trim21−/− mice showed increased thymic cellularity. Δsocs3 TECs showed alterations in the expression of genes involved in positive and negative selection and lympho-stromal interactions. SOCS3-dependent signal inhibition of the common gp130 subunit of the IL-6 receptor family was redundant for T cell formation. Together, SOCS3 expression in thymic stroma cells is critical for T cell development and for maintenance of thymus architecture.
|
|
| 7. |
- Herr, Patrick, et al.
(författare)
-
Cell Cycle Profiling Reveals Protein Oscillation, Phosphorylation, and Localization Dynamics
- 2020
-
Ingår i: Molecular & Cellular Proteomics. - : Elsevier BV. - 1535-9476 .- 1535-9484. ; 19:4, s. 608-623
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 8. |
- Johansson, Henrik J., et al.
(författare)
-
Breast cancer quantitative proteome and proteogenomic landscape
- 2019
-
Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 9. |
- Johansson, Tim, et al.
(författare)
-
Energy performance certificates and 3-dimensional city models as a means to reach national targets : A case study of the city of Kiruna
- 2016
-
Ingår i: Energy Conversion and Management. - : Elsevier BV. - 0196-8904 .- 1879-2227. ; 116, s. 42-57
-
Tidskriftsartikel (refereegranskat)abstract
- Enhanced dissemination of information regarding energy saving and climate change targeted toward property owners is considered to be an important strategy in order to reach the Swedish national target of energy efficiency in the building sector by 2050. Here the municipality energy advisors and the national register for energy performance certificates can facilitate the mitigation of energy use in the building stock. So far few studies have focused on the practical road map to the national target of energy use on the city/district level and to the communication aspects with stakeholders in the creation of energy city models.In this paper a city energy model is developed based on the requests and need for visualization from a group of energy advisors. Six different scenarios are studied in order to analyze the possibility of reaching the energy targets specified by the government in the town of Kiruna. The results show that: (1) it is possible to automatically create city energy models using extract, transform and load tools based on spatial and non-spatial data from national registers and databases; (2) city energy models improve the understanding of energy use in buildings and can therefore be a valuable tool for energy advisors, real estate companies and urban planners. The case study of Kiruna showed that the proposed energy saving measures in the energy performance certificates need to be implemented and new buildings in the urban transformation must be of high energy standard in order to reach the national target in Kiruna.
|
|
| 10. |
- Joshi, Rubin Narayan, et al.
(författare)
-
TcellSubC : An Atlas of the Subcellular Proteome of Human T Cells
- 2019
-
Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- We have curated an in-depth subcellular proteomic map of primary human CD4+ T cells, divided into cytosolic, nuclear and membrane fractions generated by an optimized fractionation and HiRIEF-LC-MS/MS workflow for limited amounts of primary cells. The subcellular proteome of T cells was mapped under steady state conditions, as well as upon 15 min and 1 h of T cell receptor (TCR) stimulation, respectively. We quantified the subcellular distribution of 6,572 proteins and identified a subset of 237 potentially translocating proteins, including both well-known examples and novel ones. Microscopic validation confirmed the localization of selected proteins with previously known and unknown localization, respectively. We further provide the data in an easy-to-use web platform to facilitate re-use, as the data can be relevant for basic research as well as for clinical exploitation of T cells as therapeutic targets.
|
|
