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Publications (10 of 498) Show all publications
Wang, D., Eraslan, B., Wieland, T., Hallström, B. M., Hopf, T., Zolg, D. P., . . . Kuster, B. (2019). A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Molecular Systems Biology, 15(2), Article ID e8503.
Open this publication in new window or tab >>A deep proteome and transcriptome abundance atlas of 29 healthy human tissues
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2019 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 15, no 2, article id e8503Article in journal (Refereed) Published
Abstract [en]

Genome-, transcriptome- and proteome-wide measurements provide insights into how biological systems are regulated. However, fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully understood. Therefore, we generated a quantitative proteome and transcriptome abundance atlas of 29 paired healthy human tissues from the Human Protein Atlas project representing human genes by 18,072 transcripts and 13,640 proteins including 37 without prior protein-level evidence. The analysis revealed that hundreds of proteins, particularly in testis, could not be detected even for highly expressed mRNAs, that few proteins show tissue-specific expression, that strong differences between mRNA and protein quantities within and across tissues exist and that protein expression is often more stable across tissues than that of transcripts. Only 238 of 9,848 amino acid variants found by exome sequencing could be confidently detected at the protein level showing that proteogenomics remains challenging, needs better computational methods and requires rigorous validation. Many uses of this resource can be envisaged including the study of gene/protein expression regulation and biomarker specificity evaluation.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
human proteome, human transcriptome, proteogenomics, quantitative mass spectrometry, RNA-Seq
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-246279 (URN)10.15252/msb.20188503 (DOI)000459628300002 ()30777892 (PubMedID)2-s2.0-85061866375 (Scopus ID)
Note

QC 20190325

Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-04-04Bibliographically approved
Robinson, J. L., Feizi, A., Uhlén, M. & Nielsen, J. (2019). A Systematic Investigation of the Malignant Functions and Diagnostic Potential of the Cancer Secretome. Cell reports, 26(10), 2622-+
Open this publication in new window or tab >>A Systematic Investigation of the Malignant Functions and Diagnostic Potential of the Cancer Secretome
2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 26, no 10, p. 2622-+Article in journal (Refereed) Published
Abstract [en]

The collection of proteins secreted from a cell-the secretome-is of particular interest in cancer pathophysiology due to its diagnostic potential and role in tumorigenesis. However, cancer secretome studies are often limited to one tissue or cancer type or focus on biomarker prediction without exploring the associated functions. We therefore conducted a pan-cancer analysis of secretome gene expression changes to identify candidate diagnostic biomarkers and to investigate the underlying biological function of these changes. Using transcriptomic data spanning 32 cancer types and 30 healthy tissues, we quantified the relative diagnostic potential of secretome proteins for each cancer. Furthermore, we offer a potential mechanism by which cancer cells relieve secretory pathway stress by decreasing the expression of tissue-specific genes, thereby facilitating the secretion of proteins promoting invasion and proliferation. These results provide a more systematic understanding of the cancer secretome, facilitating its use in diagnostics and its targeting for therapeutic development.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:kth:diva-246230 (URN)10.1016/j.celrep.2019.02.025 (DOI)000460280800010 ()30840886 (PubMedID)2-s2.0-85061659881 (Scopus ID)
Note

QC 20190404

Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2019-04-04Bibliographically approved
Dusart, P., Hallström, B. M., Renne, T., Odeberg, J., Uhlén, M. & Butler, L. M. (2019). A Systems-Based Map of Human Brain Cell-Type Enriched Genes and Malignancy-Associated Endothelial Changes. Cell reports, 29(6), 1690-+
Open this publication in new window or tab >>A Systems-Based Map of Human Brain Cell-Type Enriched Genes and Malignancy-Associated Endothelial Changes
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 29, no 6, p. 1690-+Article in journal (Refereed) Published
Abstract [en]

Changes in the endothelium of the cerebral vasculature can contribute to inflammatory, thrombotic, and malignant disorders. The importance of defining cell-type-specific genes and their modification in disease is increasingly recognized. Here, we develop a bioinformatics-based approach to identify normal brain cell-enriched genes, using bulk RNA sequencing (RNA-seq) data from 238 normal human cortex samples from 2 independent cohorts. We compare endothelial cell-enriched gene profiles with astrocyte, oligodendrocyte, neuron, and microglial cell profiles. Endothelial changes in malignant disease are explored using RNA-seq data from 516 lower-grade gliomas and 401 glioblastomas. Lower-grade gliomas appear to be an "endothelial intermediate'' between normal brain and glioblastoma. We apply our method for the prediction of glioblastoma-specific endothelial biomarkers, providing potential diagnostic or therapeutic targets. In summary, we provide a roadmap of endothelial cell identity in normal and malignant brain, using a method developed to resolve bulk RNA-seq into constituent cell-type-enriched profiles.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Clinical Medicine
Identifiers
urn:nbn:se:kth:diva-264333 (URN)10.1016/j.celrep.2019.09.088 (DOI)000495045400024 ()31693905 (PubMedID)2-s2.0-85074281897 (Scopus ID)
Note

QC 20191126

Available from: 2019-11-26 Created: 2019-11-26 Last updated: 2019-11-26Bibliographically approved
Pineau, C., Hikmet, F., Zhang, C., Oksvold, P., Chen, S., Fagerberg, L., . . . Lindskog, C. (2019). Cell Type-Specific Expression of Testis Elevated Genes Based on Transcriptomics and Antibody-Based Proteomics. Journal of Proteome Research
Open this publication in new window or tab >>Cell Type-Specific Expression of Testis Elevated Genes Based on Transcriptomics and Antibody-Based Proteomics
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2019 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907Article in journal (Refereed) Published
Abstract [en]

One of the most complex organs in the human body is the testis, where spermatogenesis takes place. This physiological process involves thousands of genes and proteins that are activated and repressed, making testis the organ with the highest number of tissue-specific genes. However, the function of a large proportion of the corresponding proteins remains unknown and testis harbors many missing proteins (MPs), defined as products of protein-coding genes that lack experimental mass spectrometry evidence. Here, an integrated omics approach was used for exploring the cell type-specific protein expression of genes with an elevated expression in testis. By combining genome-wide transcriptomics analysis with immunohistochemistry, more than 500 proteins with distinct testicular protein expression patterns were identified, and these were selected for in-depth characterization of their in situ expression in eight different testicular cell types. The cell type-specific protein expression patterns allowed us to identify six distinct clusters of expression at different stages of spermatogenesis. The analysis highlighted numerous poorly characterized proteins in each of these clusters whose expression overlapped with that of known proteins involved in spermatogenesis, including 88 proteins with an unknown function and 60 proteins that previously have been classified as MPs. Furthermore, we were able to characterize the in situ distribution of several proteins that previously lacked spatial information and cell type-specific expression within the testis. The testis elevated expression levels both at the RNA and protein levels suggest that these proteins are related to testis-specific functions. In summary, the study demonstrates the power of combining genome-wide transcriptomics analysis with antibody-based protein profiling to explore the cell type-specific expression of both well-known proteins and MPs. The analyzed proteins constitute important targets for further testis-specific research in male reproductive disorders. Copyright

Place, publisher, year, edition, pages
American Chemical Society, 2019
Keywords
antibody-based proteomics, immunohistochemistry, missing proteins, protein evidence, reproduction, spermatogenesis, testis, transcriptomics
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-263250 (URN)10.1021/acs.jproteome.9b00351 (DOI)2-s2.0-85072574178 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20191106

Available from: 2019-11-06 Created: 2019-11-06 Last updated: 2019-11-06Bibliographically approved
Benfeitas, R., Bidkhori, G., Mukhopadhyay, B., Klevstig, M., Arif, M., Zhang, C., . . . Mardinoglu, A. (2019). Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis. EBioMedicine
Open this publication in new window or tab >>Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964Article in journal (Refereed) Published
National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:kth:diva-248702 (URN)
Note

QC 20190423

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-04-23Bibliographically approved
Lundqvist, M., Thalén, N., Volk, A.-L., Hansen, H. G., von Otter, E., Nygren, P.-Å., . . . Rockberg, J. (2019). Chromophore pre-maturation for improved speed and sensitivity of split-GFP monitoring of protein secretion. Scientific Reports, 9, Article ID 310.
Open this publication in new window or tab >>Chromophore pre-maturation for improved speed and sensitivity of split-GFP monitoring of protein secretion
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 310Article in journal (Refereed) Published
Abstract [en]

Complementation-dependent fluorescence is a powerful way to study co-localization or interactions between biomolecules. A split-GFP variant, involving the self-associating GFP 1-10 and GFP 11, has previously provided a convenient approach to measure recombinant protein titers in cell supernatants. A limitation of this approach is the slow chromophore formation after complementation. Here, we alleviate this lag in signal generation by allowing the GFP 1-10 chromophore to mature on a solid support containing GFP 11 before applying GFP 1-10 in analyses. The pre-maturated GFP 1-10 provided up to 150-fold faster signal generation compared to the non-maturated version. Moreover, pre-maturated GFP 1-10 significantly improved the ability of discriminating between Chinese hamster ovary (CHO) cell lines secreting GFP 11-tagged erythropoietin protein at varying rates. Its improved kinetics make the pre-maturated GFP 1-10 a suitable reporter molecule for cell biology research in general, especially for ranking individual cell lines based on secretion rates of recombinant proteins.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:kth:diva-243949 (URN)10.1038/s41598-018-36559-x (DOI)000456282100065 ()30670736 (PubMedID)2-s2.0-85060382656 (Scopus ID)
Note

QC 20190305

Available from: 2019-03-05 Created: 2019-03-05 Last updated: 2019-03-05Bibliographically approved
Andersson, A., Remnestål, J., Nellgård, B., Vunk, H., Kotol, D., Edfors, F., . . . Fredolini, C. (2019). Development of parallel reaction monitoring assays for cerebrospinal fluid proteins associated with Alzheimer's disease. Clinica Chimica Acta, 494, 79-93
Open this publication in new window or tab >>Development of parallel reaction monitoring assays for cerebrospinal fluid proteins associated with Alzheimer's disease
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2019 (English)In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 494, p. 79-93Article in journal (Refereed) Published
Abstract [en]

Detailed knowledge of protein changes in cerebrospinal fluid (CSF) across healthy and diseased individuals would provide a better understanding of the onset and progression of neurodegenerative disorders. In this study, we selected 20 brain-enriched proteins previously identified in CSF by antibody suspension bead arrays (SBA) to be potentially biomarkers for Alzheimer's disease (AD) and verified these using an orthogonal approach. We examined the same set of 94 CSF samples from patients affected by AD (including preclinical and prodromal), mild cognitive impairment (MCI), non-AD dementia and healthy individuals, which had previously been analyzed by SBA. Twenty-eight parallel reaction monitoring (PRM) assays were developed and 13 of them could be validated for protein quantification. Antibody profiles were verified by PRM. For seven proteins, the antibody profiles were highly correlated with the PRM results (r > 0.7) and GAP43, VCAM1 and PSAP were identified as potential markers of preclinical AD. In conclusion, we demonstrate the usefulness of targeted mass spectrometry as a tool for the orthogonal verification of antibody profiling data, suggesting that these complementary methods can be successfully applied for comprehensive exploration of CSF protein levels in neurodegenerative disorders.

Place, publisher, year, edition, pages
Elsevier B.V., 2019
Keywords
AD, Alzheimer's disease, Biomarkers, Cerebrospinal fluid, Parallel reaction monitoring (PRM), Suspension bead array (SBA), alpha 1 aantitrypsin, alpha 1 antichymotrypsin, apolipoprotein, biological marker, cathepsin D, cholecystokinin, creatine kinase B type, dickkopf related protein 3, fibrinogen alpha, fructose bisphosphate aldolase C, glucose regulated protein 94, inter alpha trypsin inhibitor heavy chain H1, leucine rich alpha 2 glycoprotein, neurobeachin, neurofilament medium polypeptide, neuromodulin, plasminogen, prosaposin, protein S100B, SPARC like protein 1, unclassified drug, vascular cell adhesion protein 1, adult, aged, Alzheimer disease, Article, clinical article, cohort analysis, controlled study, correlational study, disease course, female, human, male, mass spectrometry, middle aged, mild cognitive impairment, multiple reaction monitoring, priority journal, protein blood level, protein cerebrospinal fluid level, protein microarray, suspension bead array, very elderly
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-252444 (URN)10.1016/j.cca.2019.03.243 (DOI)000470950400013 ()2-s2.0-85063002689 (Scopus ID)
Note

QC 20190715

Available from: 2019-07-15 Created: 2019-07-15 Last updated: 2019-07-15Bibliographically approved
Lundgren, S., Fagerström-Vahman, H., Zhang, C., Ben-Dror, L., Mardinoglu, A., Uhlén, M., . . . Jirström, K. (2019). Discovery of KIRREL as a biomarker for prognostic stratification of patients within melanoma [Letter to the editor]. Biomarker Research
Open this publication in new window or tab >>Discovery of KIRREL as a biomarker for prognostic stratification of patients within melanoma
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2019 (English)In: Biomarker Research, ISSN 0961-088X, E-ISSN 1475-925XArticle in journal, Letter (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-248690 (URN)000455575200001 ()2-s2.0-85062927349 (Scopus ID)
Note

QC 20190425

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-08-01Bibliographically approved
Turanli, B., Zhang, C., Kim, W., Benfeitas, R., Uhlén, M., Yalcin Arga, K. & Mardinoglu, A. (2019). Discovery of therapeutic agents for prostate cancer using genome-scale metabolic modeling and drug repositioning. EBioMedicine, 42, 386-396
Open this publication in new window or tab >>Discovery of therapeutic agents for prostate cancer using genome-scale metabolic modeling and drug repositioning
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 42, p. 386-396Article in journal (Refereed) Published
Abstract [sv]

Background: Genome-scale metabolic models (GEMs)offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a time- and cost-effective method of drug discovery that can be applied together with GEMs for effective cancer treatment. Methods: In this study, we reconstruct a prostate cancer (PRAD)-specific GEM for exploring prostate cancer metabolism and also repurposing new therapeutic agents that can be used in development of effective cancer treatment. We integrate global gene expression profiling of cell lines with >1000 different drugs through the use of prostate cancer GEM and predict possible drug-gene interactions. Findings: We identify the key reactions with altered fluxes based on the gene expression changes and predict the potential drug effect in prostate cancer treatment. We find that sulfamethoxypyridazine, azlocillin, hydroflumethiazide, and ifenprodil can be repurposed for the treatment of prostate cancer based on an in silico cell viability assay. Finally, we validate the effect of ifenprodil using an in vitro cell assay and show its inhibitory effect on a prostate cancer cell line. Interpretation: Our approach demonstate how GEMs can be used to predict therapeutic agents for cancer treatment based on drug repositioning. Besides, it paved a way and shed a light on the applicability of computational models to real-world biomedical or pharmaceutical problems.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Medical and Health Sciences Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:kth:diva-248689 (URN)10.1016/j.ebiom.2019.03.009 (DOI)000466175100052 ()30905848 (PubMedID)2-s2.0-85063114920 (Scopus ID)
Note

QC 20190424

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-05-21Bibliographically approved
Svensson, M. C., Borg, D., Zhang, C., Hedner, C., Nodin, B., Uhlén, M., . . . Jirström, K. (2019). Expression of PD-L1 and PD-1 in Chemoradiotherapy-Naïve Esophageal and Gastric Adenocarcinoma: Relationship With Mismatch Repair Status and Survival. Frontiers in Oncology
Open this publication in new window or tab >>Expression of PD-L1 and PD-1 in Chemoradiotherapy-Naïve Esophageal and Gastric Adenocarcinoma: Relationship With Mismatch Repair Status and Survival
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2019 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943XArticle in journal (Refereed) Published
Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-248694 (URN)10.3389/fonc.2019.00136 (DOI)000461111200002 ()2-s2.0-85063302688 (Scopus ID)
Note

QC 20190424

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-08-06Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8993-048X

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