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Publications (10 of 489) 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
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
Neiman, M., Hellström, C., Just, D., Mattsson, C., Fagerberg, L., Schuppe-Koistinen, I., . . . Nilsson, P. (2019). Individual and stable autoantibody repertoires in healthy individuals. Autoimmunity, 52(1), 1-11
Open this publication in new window or tab >>Individual and stable autoantibody repertoires in healthy individuals
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2019 (English)In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 52, no 1, p. 1-11Article in journal (Refereed) Published
Abstract [en]

In the era towards precision medicine, we here present the individual specific autoantibody signatures of 193 healthy individuals. The self-reactive IgG signatures are stable over time in a way that each individual profile is recognized in longitudinal sampling. The IgG autoantibody reactivity towards an antigen array comprising 335 protein fragments, representing 204 human proteins with potential relevance to autoimmune disorders, was measured in longitudinal plasma samples from 193 healthy individuals. This analysis resulted in unique autoantibody barcodes for each individual that were maintained over one year's time. The reactivity profiles, or signatures, are person specific in regards to the number of reactivities and antigen specificity. Two independent data sets were consistent in that each healthy individual displayed reactivity towards 0-16 antigens, with a median of six. Subsequently, four selected individuals were profiled on in-house produced high-density protein arrays containing 23,000 protein fragments representing 14,000 unique protein coding genes. Based on a unique, broad and deep longitudinal profiling of autoantibody reactivities, our results demonstrate a unique autoreactive profile in each analyzed healthy individual. The need and interest for broad-ranged and high-resolution molecular profiling of healthy individuals is rising. We have here generated and assessed an initial perspective on the global distribution of the self-reactive IgG repertoire in healthy individuals, by investigating 193 well-characterized healthy individuals.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2019
Keywords
Autoantibody repertoire, autoantibody profile, protein array, affinity proteomics, precision medicine
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-249825 (URN)10.1080/08916934.2019.1581774 (DOI)000462921100001 ()30835561 (PubMedID)2-s2.0-85062520789 (Scopus ID)
Note

QC 20190423

Available from: 2019-04-23 Created: 2019-04-23 Last updated: 2019-06-11Bibliographically approved
Turanli, B., Karagoz, K., Bidkhori, G., Sinha, R., Gatza, M. L., Uhlén, M., . . . Arga, K. Y. (2019). Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer. Frontiers in Genetics, 10, Article ID 420.
Open this publication in new window or tab >>Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer
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2019 (English)In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 10, article id 420Article in journal (Refereed) Published
Abstract [en]

Triple-negative breast cancer (TNBC), which is largely synonymous with the basal-like molecular subtype, is the 5th leading cause of cancer deaths for women in the United States. The overall prognosis for TNBC patients remains poor given that few treatment options exist; including targeted therapies (not FDA approved), and multi-agent chemotherapy as standard-of-care treatment. TNBC like other complex diseases is governed by the perturbations of the complex interaction networks thereby elucidating the underlying molecular mechanisms of this disease in the context of network principles, which have the potential to identify targets for drug development. Here, we present an integrated "omics" approach based on the use of transcriptome and interactome data to identify dynamic/active protein-protein interaction networks (PPINs) in TNBC patients. We have identified three highly connected modules, EED, DHX9, and AURKA, which are extremely activated in TNBC tumors compared to both normal tissues and other breast cancer subtypes. Based on the functional analyses, we propose that these modules are potential drivers of proliferation and, as such, should be considered candidate molecular targets for drug development or drug repositioning in TNBC. Consistent with this argument, we repurposed steroids, anti-inflammatory agents, anti-infective agents, cardiovascular agents for patients with basal-like breast cancer. Finally, we have performed essential metabolite analysis on personalized genome-scale metabolic models and found that metabolites such as sphingosine-1-phosphate and cholesterol-sulfate have utmost importance in TNBC tumor growth.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
breast cancer, drug repositioning, non-cancer therapeutics, repurposing, basal subtype, personalized metabolic models
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-252378 (URN)10.3389/fgene.2019.00420 (DOI)000467463700001 ()2-s2.0-85067884608 (Scopus ID)
Note

QC 20190718

Available from: 2019-07-18 Created: 2019-07-18 Last updated: 2019-07-18Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8993-048X

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