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  • 51.
    Ayoglu, Burcu
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Gundberg, Anna
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Khademi, Mohsen
    Karolinska Hosp, Dept Clin Neurosci, Stockholm, Sweden..
    Olsson, Tomas
    Karolinska Hosp, Dept Clin Neurosci, Stockholm, Sweden..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Proteomic profiling of the autoimmunity repertoire in multiple sclerosis2012Ingår i: New Biotechnology, ISSN 1871-6784, E-ISSN 1876-4347, Vol. 29, s. S20-S20Artikel i tidskrift (Övrigt vetenskapligt)
  • 52.
    Ayoglu, Burcu
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Häggmark, Anna
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Khademi, M.
    Olsson, T.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Autoantibody profiling in multiple sclerosis using arrays of human protein fragments2013Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 12, nr 9, s. 2657-2672Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Profiling the autoantibody repertoire with large antigen collections is emerging as a powerful tool for the identification of biomarkers for autoimmune diseases. Here, a systematic and undirected approach was taken to screen for profiles of IgG in human plasma from 90 individuals with multiple sclerosis related diagnoses. Reactivity pattern of 11,520 protein fragments (representing ̃38% of all human protein encoding genes) were generated on planar protein microarrays built within the Human Protein Atlas. For more than 2,000 antigens IgG reactivity was observed, among which 64% were found only in single individuals. We used reactivity distributions among multiple sclerosis subgroups to select 384 antigens, which were then reevaluated on planar microarrays, corroborated with suspension bead arrays in a larger cohort (n = 376) and confirmed for specificity in inhibition assays. Among the heterogeneous pattern within and across multiple sclerosis subtypes, differences in recognition frequencies were found for 51 antigens, which were enriched for proteins of transcriptional regulation. In conclusion, using protein fragments and complementary high-throughput protein array platforms facilitated an alternative route to discovery and verification of potentially disease-associated autoimmunity signatures, that are now proposed as additional antigens for large-scale validation studies across multiple sclerosis biobanks.

  • 53.
    Ayoglu, Burcu
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Häggmark, Anna
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Neiman, Maja
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Igel, Ulrika
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Schwenk, Jochen
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Systematic antibody and antigen-based proteomic profiling with microarrays2011Ingår i: EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, ISSN 1473-7159, Vol. 11, nr 2, s. 219-234Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Current approaches within affinity-based proteomics are driven both by the accessibility and availability of antigens and capture reagents, and by suitable multiplexed technologies onto which these are implemented. By combining planar microarrays and other multiparallel systems with sets of reagents, possibilities to discover new and unpredicted protein disease associations, either via directed hypothesis-driven or via undirected hypothesis-generating target selection, can be created. In the following stages, the discoveries made during these screening phases have to be verified for potential clinical relevance based on both technical and biological aspects. The use of affinity tools throughout discovery and verification has the potential to streamline the introduction of new markers, as transition into clinically required assay formats appears straightforward. In this article, we summarize some of the current building blocks within array-and affinity-based proteomic profiling with a focus on body fluids, by giving a perspective on how current and upcoming developments in this bioscience could enable a path of pursuit for biomarker discovery.

  • 54.
    Ayoglu, Burcu
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mitsios, N.
    Khademi, M.
    Alfredsson, L.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mulder, J.
    Olsson, T.
    Schwenk, Jochen
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Anoctamin 2, a novel autoimmune target candidate in multiple sclerosis2014Ingår i: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 20, s. 49-50Artikel i tidskrift (Övrigt vetenskapligt)
  • 55.
    Ayoglu, Burcu
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Mitsios, Nicholas
    Kockum, Ingrid
    Khademi, Mohsen
    Zandian, Arash
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sjoberg, Ronald
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Forsstrom, Bjorn
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bredenberg, Johan
    Bomfim, Izaura Lima
    Holmgren, Erik
    Gronlund, Hans
    Guerreiro-Cacais, Andre Ortlieb
    Abdelmagid, Nada
    Uhlen, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Waterboer, Tim
    Alfredsson, Lars
    Mulder, Jan
    Schwenk, Jochen M.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Olsson, Tomas
    Nilsson, Peter
    Anoctamin 2 identified as an autoimmune target in multiple sclerosis2016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 8, s. 2188-2193Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.

  • 56.
    Ayoglu, Burcu
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sjöberg, Ronald
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    et al.,
    The calcium-activated chloride channel anoctamine 2 as an autoimmune component of multiple sclerosisManuskript (preprint) (Övrigt vetenskapligt)
  • 57. Azimi, A.
    et al.
    Caramuta, S.
    Seashore-Ludlow, B.
    Boström, J.
    Robinson, J. L.
    Edfors, Fredrik
    KTH, Skolan för bioteknologi (BIO). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Tuominen, R.
    Kemper, K.
    Krijgsman, O.
    Peeper, D. S.
    Nielsen, J.
    Hansson, J.
    Egyhazi Brage, S.
    Altun, M.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO).
    Maddalo, G.
    Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors2018Ingår i: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 14, nr 3, artikel-id e7858Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy-resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX-derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL888 treatment. The CDK2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK2 upregulation in patients; thus, dinaciclib would warrant consideration for treatment of patients unresponsive to BRAF-MEK and/or Hsp90 inhibitors and/or harboring MITF amplification/overexpression. 

  • 58.
    Bachmann, Julie
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Burte, Florence
    Pramana, Setia
    Conte, Ianina
    Brown, Biobele J.
    Orimadegun, Adebola E.
    Ajetunmobi, Wasiu A.
    Afolabi, Nathaniel K.
    Akinkunmi, Francis
    Omokhodion, Samuel
    Akinbami, Felix O.
    Shokunbi, Wuraola A.
    Kampf, Caroline
    Pawitan, Yudi
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sodeinde, Olugbemiro
    Schwenk, Jochen M.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Wahlgren, Mats
    Fernandez-Reyes, Delmiro
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Affinity Proteomics Reveals Elevated Muscle Proteins in Plasma of Children with Cerebral Malaria2014Ingår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 10, nr 4, s. e1004038-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Systemic inflammation and sequestration of parasitized erythrocytes are central processes in the pathophysiology of severe Plasmodium falciparum childhood malaria. However, it is still not understood why some children are more at risks to develop malaria complications than others. To identify human proteins in plasma related to childhood malaria syndromes, multiplex antibody suspension bead arrays were employed. Out of the 1,015 proteins analyzed in plasma from more than 700 children, 41 differed between malaria infected children and community controls, whereas 13 discriminated uncomplicated malaria from severe malaria syndromes. Markers of oxidative stress were found related to severe malaria anemia while markers of endothelial activation, platelet adhesion and muscular damage were identified in relation to children with cerebral malaria. These findings suggest the presence of generalized vascular inflammation, vascular wall modulations, activation of endothelium and unbalanced glucose metabolism in severe malaria. The increased levels of specific muscle proteins in plasma implicate potential muscle damage and microvasculature lesions during the course of cerebral malaria.

  • 59.
    Barbe, L.
    et al.
    KTH.
    Lundberg, E.
    KTH.
    Brismar, H.
    KTH.
    Uhlén, Mathias
    KTH.
    Andersson, H.
    KTH.
    High-throughput confocal subcellular mapping for antibody-based proteomics2006Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 5, nr 10, s. S240-S240Artikel i tidskrift (Övrigt vetenskapligt)
  • 60.
    Barbe, Laurent
    et al.
    KTH, Skolan för bioteknologi (BIO).
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Oksvold, Per
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Stenius, Anna
    KTH, Skolan för bioteknologi (BIO).
    Lewin, Erland
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik.
    Björling, Erik
    KTH, Skolan för bioteknologi (BIO).
    Asplund, Anna
    Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University.
    Pontén, Fredrik
    Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University.
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Andersson-Svahn, Helene
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Toward a confocal subcellular atlas of the human proteome2008Ingår i: Molecular and cellular proteomics, ISSN 1535-9476, Vol. 7, nr 3, s. 499-508Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Information on protein localization on the subcellular level is important to map and characterize the proteome and to better understand cellular functions of proteins. Here we report on a pilot study of 466 proteins in three human cell lines aimed to allow large scale confocal microscopy analysis using protein-specific antibodies. Approximately 3000 high resolution images were generated, and more than 80% of the analyzed proteins could be classified in one or multiple subcellular compartment(s). The localizations of the proteins showed, in many cases, good agreement with the Gene Ontology localization prediction model. This is the first large scale antibody-based study to localize proteins into subcellular compartments using antibodies and confocal microscopy. The results suggest that this approach might be a valuable tool in conjunction with predictive models for protein localization.

  • 61. Battisti, U. M.
    et al.
    Gao, C.
    Nilsson, O.
    Akladios, F.
    Lulla, A.
    Bogucka, A.
    Nain-Perez, A.
    Håversen, L.
    Kim, Woonghee
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, J.
    Hyvönen, M.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, A.
    Grøtli, M.
    Serendipitous Identification of a Covalent Activator of Liver Pyruvate Kinase2023Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 24, nr 1, artikel-id e202200339Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Enzymes are effective biological catalysts that accelerate almost all metabolic reactions in living organisms. Synthetic modulators of enzymes are useful tools for the study of enzymatic reactions and can provide starting points for the design of new drugs. Here, we report on the discovery of a class of biologically active compounds that covalently modifies lysine residues in human liver pyruvate kinase (PKL), leading to allosteric activation of the enzyme (EC50=0.29 μM). Surprisingly, the allosteric activation control point resides on the lysine residue K282 present in the catalytic site of PKL. These findings were confirmed by structural data, MS/MS experiments, and molecular modelling studies. Altogether, our study provides a molecular basis for the activation mechanism and establishes a framework for further development of human liver pyruvate kinase covalent activators. 

  • 62.
    Battisti, Umberto Maria
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Scilifelab Univ Gothenburg, Dept Chem & Mol Biol.
    Gao, Chunxia
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Univ Gothenburg, Dept Chem & Mol Biol, S-41296 Gothenburg, Sweden.;KTH Royal Inst Technol, Sci Life Lab, S-10450 Stockholm, Sweden..
    Akladios, Fady
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Nanobioteknologi. Univ Gothenburg, Dept Chem & Mol Biol, S-41296 Gothenburg, Sweden.;KTH Royal Inst Technol, Sci Life Lab, S-10450 Stockholm, Sweden..
    Kim, Woonghee
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Yang, Hong
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Bayram, Cemil
    Ataturk Univ, Fac Med, Dept Med Pharmacol, TR-25240 Erzurum, Turkiye..
    Bolat, Ismail
    Ataturk Univ, Fac Vet, Dept Pathol, TR-25240 Erzurum, Turkiye..
    Kiliclioglu, Metin
    Ataturk Univ, Fac Vet, Dept Pathol, TR-25240 Erzurum, Turkiye..
    Yuksel, Nursena
    Erzurum Tech Univ, Fac Sci, Dept Mol Biol & Genet, TR-25050 Erzurum, Turkiye..
    Tozlu, Ozlem Ozdemir
    Erzurum Tech Univ, Fac Sci, Dept Mol Biol & Genet, TR-25050 Erzurum, Turkiye..
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China..
    Sebhaoui, Jihad
    Trustlife Labs, Drug Res & Dev Ctr, TR-34774 Istanbul, Turkiye..
    Iqbal, Shazia
    Trustlife Labs, Drug Res & Dev Ctr, TR-34774 Istanbul, Turkiye..
    Shoaie, Saeed
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Hacimuftuoglu, Ahmet
    Ataturk Univ, Fac Med, Dept Med Pharmacol, TR-25240 Erzurum, Turkiye..
    Yildirim, Serkan
    Ataturk Univ, Fac Vet, Dept Pathol, TR-25240 Erzurum, Turkiye..
    Turkez, Hasan
    Ataturk Univ, Fac Med, Dept Med Biol, TR-25240 Erzurum, Turkiye..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Boren, Jan
    Univ Gothenburg, Dept Mol & Clin Med, S-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, S-40530 Gothenburg, Sweden..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Grotli, Morten
    Univ Gothenburg, Dept Chem & Mol Biol, S-41296 Gothenburg, Sweden..
    Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase2023Ingår i: Nutrients, E-ISSN 2072-6643, Vol. 15, nr 3, s. 577-, artikel-id 577Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Liver pyruvate kinase (PKL) has recently emerged as a new target for non-alcoholic fatty liver disease (NAFLD), and inhibitors of this enzyme could represent a new therapeutic option. However, this breakthrough is complicated by selectivity issues since pyruvate kinase exists in four different isoforms. In this work, we report that ellagic acid (EA) and its derivatives, present in numerous fruits and vegetables, can inhibit PKL potently and selectively. Several polyphenolic analogues of EA were synthesized and tested to identify the chemical features responsible for the desired activity. Molecular modelling studies suggested that this inhibition is related to the stabilization of the PKL inactive state. This unique inhibition mechanism could potentially herald the development of new therapeutics for NAFLD.

  • 63.
    Battisti, Umberto Maria
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Monjas, Leticia
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Akladios, Fady
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Matic, Josipa
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH). Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Andresen, Eric
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Nagel, Carolin H.
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Hagkvist, Malin
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Haversen, Liliana
    Univ Gothenburg, Dept Mol & Clin Med, SE-41345 Gothenburg, Sweden.;Sahlgrens Univ Hosp, SE-41345 Gothenburg, Sweden..
    Kim, Woonghee
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Boren, Jan
    Univ Gothenburg, Dept Mol & Clin Med, SE-41345 Gothenburg, Sweden.;Sahlgrens Univ Hosp, SE-41345 Gothenburg, Sweden..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Grotli, Morten
    Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden..
    Exploration of Novel Urolithin C Derivatives as Non-Competitive Inhibitors of Liver Pyruvate Kinase2023Ingår i: Pharmaceuticals, E-ISSN 1424-8247, Vol. 16, nr 5, artikel-id 668Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The inhibition of liver pyruvate kinase could be beneficial to halt or reverse non-alcoholic fatty liver disease (NAFLD), a progressive accumulation of fat in the liver that can lead eventually to cirrhosis. Recently, urolithin C has been reported as a new scaffold for the development of allosteric inhibitors of liver pyruvate kinase (PKL). In this work, a comprehensive structure-activity analysis of urolithin C was carried out. More than 50 analogues were synthesized and tested regarding the chemical features responsible for the desired activity. These data could pave the way to the development of more potent and selective PKL allosteric inhibitors.

  • 64.
    Bayraktar, Abdulahad
    et al.
    Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England..
    Lam, Simon
    Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England..
    Altay, Özlem
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Li, Xiangyu
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Yuan, Meng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Arif, Muhammad
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Turkez, Hasan
    Ataturk Univ, Dept Med Biol, Fac Med, TR-25240 Erzurum, Turkey..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Shoaie, Saeed
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England.
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England.
    Revealing the Molecular Mechanisms of Alzheimer's Disease Based on Network Analysis2021Ingår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, nr 21, artikel-id 11556Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The complex pathology of Alzheimer's disease (AD) emphasises the need for comprehensive modelling of the disease, which may lead to the development of efficient treatment strategies. To address this challenge, we analysed transcriptome data of post-mortem human brain samples of healthy elders and individuals with late-onset AD from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and Mayo Clinic (MayoRNAseq) studies in the AMP-AD consortium. In this context, we conducted several bioinformatics and systems medicine analyses including the construction of AD-specific co-expression networks and genome-scale metabolic modelling of the brain in AD patients to identify key genes, metabolites and pathways involved in the progression of AD. We identified AMIGO1 and GRPRASP2 as examples of commonly altered marker genes in AD patients. Moreover, we found alterations in energy metabolism, represented by reduced oxidative phosphorylation and ATPase activity, as well as the depletion of hexanoyl-CoA, pentanoyl-CoA, (2E)-hexenoyl-CoA and numerous other unsaturated fatty acids in the brain. We also observed that neuroprotective metabolites (e.g., vitamins, retinoids and unsaturated fatty acids) tend to be depleted in the AD brain, while neurotoxic metabolites (e.g., beta-alanine, bilirubin) were more abundant. In summary, we systematically revealed the key genes and pathways related to the progression of AD, gained insight into the crucial mechanisms of AD and identified some possible targets that could be used in the treatment of AD.

  • 65.
    Begum, Neelu
    et al.
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Harzandi, Azadeh
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Lee, Sunjae
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Moyes, David L.
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Shoaie, Saeed
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Host-mycobiome metabolic interactions in health and disease2022Ingår i: Gut microbes, ISSN 1949-0976, E-ISSN 1949-0984, Vol. 14, nr 1, artikel-id e2121576Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Fungal communities (mycobiome) have an important role in sustaining the resilience of complex microbial communities and maintenance of homeostasis. The mycobiome remains relatively unexplored compared to the bacteriome despite increasing evidence highlighting their contribution to host-microbiome interactions in health and disease. Despite being a small proportion of the total species, fungi constitute a large proportion of the biomass within the human microbiome and thus serve as a potential target for metabolic reprogramming in pathogenesis and disease mechanism. Metabolites produced by fungi shape host niches, induce immune tolerance and changes in their levels prelude changes associated with metabolic diseases and cancer. Given the complexity of microbial interactions, studying the metabolic interplay of the mycobiome with both host and microbiome is a demanding but crucial task. However, genome-scale modelling and synthetic biology can provide an integrative platform that allows elucidation of the multifaceted interactions between mycobiome, microbiome and host. The inferences gained from understanding mycobiome interplay with other organisms can delineate the key role of the mycobiome in pathophysiology and reveal its role in human disease.

  • 66.
    Begum, Neelu
    et al.
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Lee, Sunjae
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Pellon, Aize
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Nasab, Shervin Sadeghi
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Nieslen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41296 Gothenburg, Sweden.;Biolnnovat Inst, Ole Maaloes Vej 3, DK-2200 Copenhagen N, Denmark..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Moyes, David
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Shoaie, Saeed
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Portlock, Theo John
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Integrative functional analysis uncovers metabolic differences between Candida species2022Ingår i: Communications Biology, E-ISSN 2399-3642, Vol. 5, nr 1, artikel-id 1013Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Metabolic differences between Candida species are uncovered using the BioFung database alongside genomic and metabolic analysis. Candida species are a dominant constituent of the human mycobiome and associated with the development of several diseases. Understanding the Candida species metabolism could provide key insights into their ability to cause pathogenesis. Here, we have developed the BioFung database, providing an efficient annotation of protein-encoding genes. Along, with BioFung, using carbohydrate-active enzyme (CAZymes) analysis, we have uncovered core and accessory features across Candida species demonstrating plasticity, adaption to the environment and acquired features. We show a greater importance of amino acid metabolism, as functional analysis revealed that all Candida species can employ amino acid metabolism. However, metabolomics revealed that only a specific cluster of species (AGAu species-C. albicans, C. glabrata and C. auris) utilised amino acid metabolism including arginine, cysteine, and methionine metabolism potentially improving their competitive fitness in pathogenesis. We further identified critical metabolic pathways in the AGAu cluster with biomarkers and anti-fungal target potential in the CAZyme profile, polyamine, choline and fatty acid biosynthesis pathways. This study, combining genomic analysis, and validation with gene expression and metabolomics, highlights the metabolic diversity with AGAu species that underlies their remarkable ability to dominate they mycobiome and cause disease.

  • 67.
    Benfeitas, Rui
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bidkhori, Gholamreza
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mukhopadhyay, Bani
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA..
    Klevstig, Martina
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Mol & Clin Med, Gothenburg, Sweden..
    Arif, Muhammad
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Lee, Sunjae
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Cinar, Resat
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA..
    Nielsen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Uhlén, Mathias
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Boren, Jan
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Mol & Clin Med, Gothenburg, Sweden..
    Kunos, George
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis2019Ingår i: EBioMedicine, E-ISSN 2352-3964, Vol. 40, s. 471-487Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Redox metabolism is often considered a potential target for cancer treatment, but a systematic examination of redox responses in hepatocellular carcinoma (HCC) is missing. Methods: Here, we employed systems biology and biological network analyses to reveal key roles of genes associated with redox metabolism in HCC by integrating multi-omics data. Findings: We found that several redox genes, including 25 novel potential prognostic genes, are significantly co-expressed with liver-specific genes and genes associated with immunity and inflammation. Based on an integrative analysis, we found that HCC tumors display antagonistic behaviors in redox responses. The two HCC groups are associated with altered fatty acid, amino acid, drug and hormone metabolism, differentiation, proliferation, and NADPH-independent vs - dependent antioxidant defenses. Redox behavior varies with known tumor subtypes and progression, affecting patient survival. These antagonistic responses are also displayed at the protein and metabolite level and were validated in several independent cohorts. We finally showed the differential redox behavior using mice transcriptomics in HCC and noncancerous tissues and associated with hypoxic features of the two redox gene groups. Interpretation: Our integrative approaches highlighted mechanistic differences among tumors and allowed the identification of a survival signature and several potential therapeutic targets for the treatment of HCC. (C) 2018 Published by Elsevier B.V.

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  • 68.
    Benfeitas, Rui
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, A.
    New challenges to study heterogeneity in cancer redox metabolism2017Ingår i: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 5, nr JUL, artikel-id 65Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Reactive oxygen species (ROS) are important pathophysiological molecules involved in vital cellular processes. They are extremely harmful at high concentrations because they promote the generation of radicals and the oxidation of lipids, proteins, and nucleic acids, which can result in apoptosis. An imbalance of ROS and a disturbance of redox homeostasis are now recognized as a hallmark of complex diseases. Considering that ROS levels are significantly increased in cancer cells due to mitochondrial dysfunction, ROS metabolism has been targeted for the development of efficient treatment strategies, and antioxidants are used as potential chemotherapeutic drugs. However, initial ROS-focused clinical trials in which antioxidants were supplemented to patients provided inconsistent results, i.e., improved treatment or increased malignancy. These different outcomes may result from the highly heterogeneous redox responses of tumors in different patients. Hence, population-based treatment strategies are unsuitable and patient-tailored therapeutic approaches are required for the effective treatment of patients. Moreover, due to the crosstalk between ROS, reducing equivalents [e.g., NAD(P)H] and central metabolism, which is heterogeneous in cancer, finding the best therapeutic target requires the consideration of system-wide approaches that are capable of capturing the complex alterations observed in all of the associated pathways. Systems biology and engineering approaches may be employed to overcome these challenges, together with tools developed in personalized medicine. However, ROS- and redox-based therapies have yet to be addressed by these methodologies in the context of disease treatment. Here, we review the role of ROS and their coupled redox partners in tumorigenesis. Specifically, we highlight some of the challenges in understanding the role of hydrogen peroxide (H2O2), one of the most important ROS in pathophysiology in the progression of cancer. We also discuss its interplay with antioxidant defenses, such as the coupled peroxiredoxin/thioredoxin and glutathione/glutathione peroxidase systems, and its reducing equivalent metabolism. Finally, we highlight the need for system-level and patient-tailored approaches to clarify the roles of these systems and identify therapeutic targets through the use of the tools developed in personalized medicine.

  • 69. Bengtsson, Erik
    et al.
    Nerjovaj, Pashtrik
    Wangefjord, Sakarias
    Nodin, Björn
    Eberhard, Jakob
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Borgquist, Signe
    Jirström, Karin
    HMG-CoA reductase expression in primary colorectal cancer correlates with favourable clinicopathological characteristics and an improved clinical outcome2014Ingår i: Diagnostic Pathology, E-ISSN 1746-1596, Vol. 9, nr 1, s. 78-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: An association between tumor-specific HMG-CoA reductase (HMGCR) expression and good prognosis has previously been demonstrated in breast and ovarian cancer. In this study, the expression, clinicopathological correlates and prognostic value of HMGCR expression in colorectal cancer was examined. Findings: Immunohistochemical expression of HMGCR was assessed in tissue microarrays with primary tumours from 557 incident cases of colorectal cancer in the Malmo Diet and Cancer Study. Pearson's Chi Square test was applied to explore the associations between HMGCR expression and clinicopathological factors and other investigative biomarkers. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the relationship between HMGCR expression and cancer-specific survival (CSS) according to negative vs positive HMGCR expression. A total number of 535 (96.0%) tumours were suitable for analysis, of which 61 (11.4%) were HMGCR negative. Positive cytoplasmic HMGCR expression was associated with distant metastasis-free disease at diagnosis (p = 0.002), lack of vascular invasion (p = 0.043), microsatellite-instability (p = 0.033), expression of cyclin D1 (p = <0.001) and p21 (p = <0.001). Positive HMGCR expression was significantly associated with a prolonged CSS in unadjusted Cox regression analysis in the entire cohort (HR = 1.79; 95% CI 1.20-2.66) and in Stage III-IV disease (HR = 1.71; 95% CI 1.09-2.68), but not after adjustment for established clinicopathological parameters. Conclusions: Findings from this prospective cohort study demonstrate that HMGCR is differentially expressed in colorectal cancer and that positive expression is associated with favourable tumour characteristics and a prolonged survival in unadjusted analysis. The utility of HMGCR as a predictor of response to neoadjuvant or adjuvant statin treatment in colorectal cancer merits further study. Virtual slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2115647072103464.

  • 70. Bengtsson, Sofia
    et al.
    Krogh, Morten
    Al-Khalili Szigyarto, Cristina
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Schedvins, Kjell
    Silfversward, Claes
    Linder, Stig
    Auer, Gert
    Alaiya, Ayodele
    James, Peter
    Large-scale proteomics analysis of human ovarian cancer for biomarkers2007Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 6, nr 4, s. 1440-1450Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ovarian cancer is usually found at a late stage when the prognosis is often bad. Relative survival rates decrease with tumor stage or grade, and the 5-year survival rate for women with carcinoma is only 38%. Thus, there is a great need to find biomarkers that can be used to carry out routine screening, especially in high-risk patient groups. Here, we present a large-scale study of 64 tissue samples taken from patients at all stages and show that we can identify statistically valid markers using nonsupervised methods that distinguish between normal, benign, borderline, and malignant tissue. We have identified 217 of the significantly changing protein spots. We are expressing and raising antibodies to 35 of these. Currently, we have validated 5 of these antibodies for use in immunohistochemical analysis using tissue microarrays of healthy and diseased ovarian, as well as other, human tissues.

  • 71.
    Berglund, Lars
    et al.
    KTH, Skolan för bioteknologi (BIO).
    Jonasson, K.
    KTH, Skolan för bioteknologi (BIO).
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO). Royal Inst Technol, Sch Biotechnol, Stockholm, Sweden..
    Antibodypedia-towards a user community for antibody validation data2009Ingår i: New Biotechnology, ISSN 1871-6784, E-ISSN 1876-4347, Vol. 25, s. S360-S361Artikel i tidskrift (Övrigt vetenskapligt)
  • 72.
    Berglund, Lisa
    et al.
    KTH, Skolan för bioteknologi (BIO).
    Andrade, Jorge
    KTH, Skolan för bioteknologi (BIO).
    Odeberg, Jacob
    KTH, Skolan för bioteknologi (BIO).
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO).
    The epitope space of the human proteome2008Ingår i: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 17, nr 4, s. 606-613Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the post-genome era, there is a great need for protein-specific affinity reagents to explore the human proteome. Antibodies are suitable as reagents, but generation of antibodies with low cross-reactivity to other human proteins requires careful selection of antigens. Here we show the results from a proteomewide effort to map linear epitopes based on uniqueness relative to the entire human proteome. The analysis was based on a sliding window sequence similarity search using short windows (8, 10, and 12 amino acid residues). A comparison of exact string matching (Hamming distance) and a heuristic method (BLAST) was performed, showing that the heuristic method combined with a grid strategy allows for whole proteome analysis with high accuracy and feasible run times. The analysis shows that it is possible to find unique antigens for a majority of the human proteins, with relatively strict rules involving low sequence identity of the possible linear epitopes. The implications for human antibody-based proteomics efforts are discussed.

  • 73.
    Berglund, Lisa
    et al.
    KTH, Skolan för bioteknologi (BIO).
    Björling, Erik
    KTH, Skolan för bioteknologi (BIO).
    Gry, Marcus
    KTH, Skolan för bioteknologi (BIO).
    Asplund, Anna
    Uppsala Univ, Rudbeck laboratory.
    Al-Khalili Szigyarto, Cristina
    KTH, Skolan för bioteknologi (BIO).
    Persson, Anja
    KTH, Skolan för bioteknologi (BIO).
    Ottoson, Jenny
    KTH, Skolan för bioteknologi (BIO).
    Wernérus, Henrik
    KTH, Skolan för bioteknologi (BIO).
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO).
    Sivertsson, Åsa
    KTH, Skolan för bioteknologi (BIO).
    Wester, Kenneth
    Uppsala Univ, Rudbeck laboratory.
    Kampf, Caroline
    Uppsala Univ, Rudbeck laboratory.
    Hober, Sophia
    KTH, Skolan för bioteknologi (BIO).
    Pontén, Fredrik
    Uppsala Univ, Rudbeck laboratory.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO).
    Generation of validated antibodies towards the human proteomeArtikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Here we show the results from a large effort to generate antibodies towards the human proteome. A high-throughput strategy was developed based on cloning and expression of antigens as recombitant protein epitope signature tags (PrESTs) Affinity purified polyclonal antibodies were generated, followed by validation by protein microarrays, Western blotting and microarray-based immunohistochemistry. PrESTs were selected based on sequence uniqueness relative the proteome and a bioinformatics analysis showed that unique antigens can be found for at least 85% of the proteome using this general strategy. The success rate from antigen selection to validated antibodies was 31%, and from protein to antibody 55%. Interestingly, membrane-bound and soluble proteins performed equally and PrEST lengths between 75 and 125 amino acids were found to give the highest yield of validated antibodies. Multiple antigens were selected for many genes and the results suggest that specific antibodies can be systematically generated to most human proteibs.

  • 74.
    Berglund, Lisa
    et al.
    KTH, Skolan för bioteknologi (BIO).
    Björling, Erik
    KTH, Skolan för bioteknologi (BIO).
    Jonasson, Kalle
    KTH, Skolan för bioteknologi (BIO).
    Rockberg, Johan
    KTH, Skolan för bioteknologi (BIO).
    Fagerberg, Linn
    KTH, Skolan för bioteknologi (BIO).
    Al-Khalili Szigyarto, Cristina
    KTH, Skolan för bioteknologi (BIO).
    Sivertsson, Åsa
    KTH, Skolan för bioteknologi (BIO).
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO).
    A whole-genome bioinformatics approach to selection of antigens for systematic antibody generation2008Ingår i: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 8, nr 14, s. 2832-2839Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Here, we present an antigen selection strategy based on a whole-genome bioinformatics approach, which is facilitated by an interactive visualization tool displaying protein features from both public resources and in-house generated data. The web-based bioinformatics platform has been designed for selection of multiple, non-overlapping recombinant protein epitope signature tags by display of predicted information relevant for antigens, including domain- and epitope sized sequence similarities to other proteins, transmembrane regions and signal peptides. The visualization tool also displays shared and exclusive protein regions for genes with multiple splice variants. A genome-wide analysis demonstrates that antigens for approximately 80% of the human protein-coding genes can be selected with this strategy.

  • 75.
    Berglund, Lisa
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Björling, Erik
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Oksvold, Per
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Fagerberg, Linn
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Al-Khalili Szigyarto, Cristina
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Persson, Anja
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Ottosson, Jenny
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Wernérus, Henrik
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Sivertsson, Åsa
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Hober, Sophia
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    et al.,
    A genecentric human protein atlas for expression profiles based on antibodies2008Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, Vol. 7, nr 10, s. 2019-2027Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An attractive path forward in proteomics is to experimentally annotate the human protein complement of the genome in a genecentric manner. Using antibodies, it might be possible to design protein-specific probes for a representative protein from every protein-coding gene and to subsequently use the antibodies for systematical analysis of cellular distribution and subcellular localization of proteins in normal and disease tissues. A new version (4.0) of the Human Protein Atlas has been developed in a genecentric manner with the inclusion of all human genes and splice variants predicted from genome efforts together with a visualization of each protein with characteristics such as predicted membrane regions, signal peptide, and protein domains and new plots showing the uniqueness (sequence similarity) of every fraction of each protein toward all other human proteins. The new version is based on tissue profiles generated from 6120 antibodies with more than five million immunohistochemistry-based images covering 5067 human genes, corresponding to similar to 25% of the human genome. Version 4.0 includes a putative list of members in various protein classes, both functional classes, such as kinases, transcription factors, G-protein-coupled receptors, etc., and project-related classes, such as candidate genes for cancer or cardiovascular diseases. The exact antigen sequence for the internally generated antibodies has also been released together with a visualization of the application-specific validation performed for each antibody, including a protein array assay, Western blot analysis, immunohistochemistry, and, for a large fraction, immunofluorescence-based confocal microscopy. New search functionalities have been added to allow complex queries regarding protein expression profiles, protein classes, and chromosome location. The new version of the protein atlas thus is a resource for many areas of biomedical research, including protein science and biomarker discovery.

  • 76.
    Berglund, Lisa
    et al.
    KTH, Skolan för bioteknologi (BIO).
    Persson, Anja
    KTH, Skolan för bioteknologi (BIO).
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO).
    Primer design for high-throughput PCR cloningArtikel i tidskrift (Övrigt vetenskapligt)
  • 77.
    Bergman, Julia
    et al.
    Uppsala University.
    Botling, Johan
    Uppsala University.
    Fagerberg, Linn
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    M Hallström, Björn
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Djureinovic, Dijana
    Uppsala University.
    Pontén, Fredrik
    Uppsala University.
    Mathias, Uhlén
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    The human adrenal gland proteome defined by transcriptomics and antibody-based profiling.2017Ingår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 158, nr 2, s. 239-251Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The adrenal gland is a composite endocrine organ with vital functions that include the synthesis and release of glucocorticoids and catecholamines. To define the molecular landscape that underlies the specific functions of the adrenal gland, we combined a genome-wide transcriptomics approach using messenger RNA sequencing of human tissues with immunohistochemistry-based protein profiling on tissue microarrays. Approximately two-thirds of all putative protein coding genes were expressed in the adrenal gland, and the analysis identified 253 genes with an elevated pattern of expression in the adrenal gland, with only 37 genes showing a markedly greater expression level (more than fivefold) in the adrenal gland compared with 31 other normal human tissue types analyzed. The analyses allowed for an assessment of the relative expression levels for well-known proteins involved in adrenal gland function but also identified previously poorly characterized proteins in the adrenal cortex, such as the FERM (4.1 protein, ezrin, radixin, moesin) domain containing 5 and the nephroblastoma overexpressed (NOV) protein homolog. We have provided a global analysis of the adrenal gland transcriptome and proteome, with a comprehensive list of genes with elevated expression in the adrenal gland and spatial information with examples of protein expression patterns for corresponding proteins. These genes and proteins constitute important starting points for an improved understanding of the normal function and pathophysiology of the adrenal glands.

  • 78. Berntsson, Jonna
    et al.
    Lundgren, Sebastian
    Nodin, Björn
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Gaber, Alexander
    Jirström, Karin
    Expression and prognostic significance of the polymeric immunoglobulin receptor in epithelial ovarian cancer2014Ingår i: Journal of Ovarian Research, E-ISSN 1757-2215, Vol. 7, nr 1, s. 26-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: High expression of the polymeric immunoglobulin receptor (PIGR) has previously been associated with a favourable prognosis in a few cancer forms, but its expression and relationship with clinical outcome in epithelial ovarian cancer (EOC) has not yet been reported. The aim of this study was therefore to examine the clinicopathological correlates and prognostic significance of PIGR expression in EOC. Methods: After an initial screening in the Human Protein Atlas portal, a validated antibody was selected for extended analysis of immunohistochemical PIGR expression in tissue microarrays with tumours from 154 incident cases of EOC from two pooled prospective population-based cohorts. Subsets of corresponding benign-appearing fallopian tubes (n = 38) and omental metastases (n = 33) were also analysed. Kaplan-Meier analysis and Cox regression analysis were applied to examine the impact of PIGR expression on overall survival (OS) and ovarian cancer-specific survival (OCSS). Results: PIGR expression was significantly higher in fallopian tubes compared to primary tumours and metastases (p < 0.001) and lower in carcinoma of the serous subtype compared to other carcinomas (p < 0.001). PIGR expression was significantly associated with lower grade (p = 0.001), mucinous histological subtype (p = 0.002), positive progesterone receptor expression (p = 0.009) and negative or low Ki-67 expression (p = 0.003). Kaplan-Meier analysis revealed a significantly improved OS (p = 0.013) and OCSS (p = 0.009) for patients with tumours displaying high expression of PIGR. These associations were confirmed in unadjusted Cox regression analysis (HR = 0.48; 95% CI 0.26-0.87; p = 0.015 for OS and HR = 0.43, 95% CI 0.22-0.82; p = 0.011 for OCSS) but did not remain significant after adjustment for age, grade and clinical stage. Conclusions: This study provides a first demonstration of PIGR expression in human fallopian tubes, primary EOC tumours and metastases. High tumour-specific expression of PIGR was found to be associated with a favourable prognosis in unadjusted, but not in adjusted, analysis. These findings are novel and merit further investigation.

  • 79.
    Bidkhori, Gholamreza
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Elmas, Ezgi
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kararoudi, Meisam Naeimi
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Arif, Muhammad
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Metabolic Network-Based Identification and Prioritization o f Anticancer Targets Based on Expression Data in Hepatocellular Carcinoma2018Ingår i: Frontiers in Physiology, E-ISSN 1664-042X, Vol. 9, artikel-id 916Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is a deadly form of liver cancer with high mortality worldwide. Unfortunately, the large heterogeneity of this disease makes it difficult to develop effective treatment strategies. Cellular network analyses have been employed to study heterogeneity in cancer, and to identify potential therapeutic targets. However, the existing approaches do not consider metabolic growth requirements, i.e., biological network functionality, to rank candidate targets while preventing toxicity to non-cancerous tissues. Here, we developed an algorithm to overcome these issues based on integration of gene expression data, genome-scale metabolic models, network controllability, and dispensability, as well as toxicity analysis. This method thus predicts and ranks potential anticancer non-toxic controlling metabolite and gene targets. Our algorithm encompasses both objective-driven and-independent tasks, and uses network topology to finally rank the predicted therapeutic targets. We employed this algorithm to the analysis of transcriptomic data for 50 HCC patients with both cancerous and non-cancerous samples. We identified several potential targets that would prevent cell growth, including 74 anticancer metabolites, and 3 gene targets (PRKACA, PGS1, and CRLS1). The predicted anticancer metabolites showed good agreement with existing FDA-approved cancer drugs, and the 3 genes were experimentally validated by performing experiments in HepG2 and Hep3B liver cancer cell lines. Our observations indicate that our novel approach successfully identifies therapeutic targets for effective treatment of cancer. This approach may also be applied to any cancer type that has tumor and non-tumor gene or protein expression data.

  • 80.
    Bidkhori, Gholamreza
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Klevstig, Martina
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is one of the most frequent forms of liver cancer, and effective treatment methods are limited due to tumor heterogeneity. There is a great need for comprehensive approaches to stratify HCC patients, gain biological insights into subtypes, and ultimately identify effective therapeutic targets. We stratified HCC patients and characterized each subtype using transcriptomics data, genome-scale metabolic networks and network topology/controllability analysis. This comprehensive systems-level analysis identified three distinct subtypes with substantial differences in metabolic and signaling pathways reflecting at genomic, transcriptomic, and proteomic levels. These subtypes showed large differences in clinical survival associated with altered kynurenine metabolism, WNT/beta-catenin-associated lipid metabolism, and PI3K/AKT/mTOR signaling. Integrative analyses indicated that the three subtypes rely on alternative enzymes (e.g., ACSS1/ACSS2/ACSS3, PKM/PKLR, ALDOB/ALDOA, MTHFD1L/MTHFD2/MTHFD1) to catalyze the same reactions. Based on systems-level analysis, we identified 8 to 28 subtype-specific genes with pivotal roles in controlling the metabolic network and predicted that these genes may be targeted for development of treatment strategies for HCC subtypes by performing in silico analysis. To validate our predictions, we performed experiments using HepG2 cells under normoxic and hypoxic conditions and observed opposite expression patterns between genes expressed in high/moderate/low-survival tumor groups in response to hypoxia, reflecting activated hypoxic behavior in patients with poor survival. In conclusion, our analyses showed that the heterogeneous HCC tumors can be stratified using a metabolic network-driven approach, which may also be applied to other cancer types, and this stratification may have clinical implications to drive the development of precision medicine.

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  • 81. Binz, Hans
    et al.
    Ngoc, Thien Nguyen
    Ståhl, Stefan
    Uhlén, Mathias
    Nygren, Per-Åke
    Respiratory syncytial virus protein g expressed on bacterial membrane1994Patent (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    A method for preparing a peptide or protein, wherein (a) a DNA sequence coding for a heterologous polypeptide on a peptide sequence between amino acid residues 130 and 230 of respiratory syncytial virus protein G, sub-groups A and B, or a peptide sequence at least 80 % homologous thereto, and (b) means enabling the expression of the polypeptide on the bacterial membrane surface, are inserted into a bacterium which is not pathogenic for mammals. The resulting conjugate polypeptide and a live bacterium expressing same, pharmaceutical compositions containing them and their use for preparing a vaccine, as well as a DNA sequence coding for said polypeptide, are also disclosed.

  • 82. Binz, Hans
    et al.
    Nguyen, Thien Ngoc
    Andreoni, Christine
    Nygren, Per-Åke
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Ståhl, Stefan
    Uhlén, Mathias
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Method for enhancing the immunogenicity of an immunogenic compound or hapten, and use thereof for preparing vaccines1994Patent (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    The present invention relates to a process for improving the immunogenicity of an immunogen, an antigen or a hapten, when it is administered to a host, independently of the mode of administration, characterized in that the said antigen or hapten is coupled covalently to a support molecule in order to form a complex, and in that this support molecule is a polypeptide fragment which is able to bind specifically to mammalian serum albumin. The invention also relates to the use, as a medicament, of the product which can be obtained in this way.

  • 83. Bjarnadottir, O.
    et al.
    Romero, Q.
    Bendahl, P-O
    Ryden, L.
    Rose, C.
    Loman, N.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Jirstrom, K.
    Grabau, D.
    Borgquist, S.
    Statin-induced decrease in proliferation depends on HMG-CoA reductase expression in breast cancer2012Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 72Artikel i tidskrift (Övrigt vetenskapligt)
  • 84. Bjarnadottir, Olof
    et al.
    Romero, Quinci
    Bendahl, Pär-Ola
    Jirström, Karin
    Rydén, Lisa
    Loman, Niklas
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Johannesson, Henrik
    Atlas Antibodies AB, AlbaNova University Center, Stockholm, Sweden.
    Rose, Carsten
    Grabau, Dorthe
    Borgquist, Signe
    Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial2013Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 138, nr 2, s. 499-508Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lipophilic statins purportedly exert anti-tumoral effects on breast cancer by decreasing proliferation and increasing apoptosis. HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, is the target of statins. However, data on statin-induced effects on HMGCR activity in cancer are limited. Thus, this pre-operative study investigated statin-induced effects on tumor proliferation and HMGCR expression while analyzing HMGCR as a predictive marker for statin response in breast cancer treatment. The study was designed as a window-of-opportunity trial and included 50 patients with primary invasive breast cancer. High-dose atorvastatin (i.e., 80 mg/day) was prescribed to patients for 2 weeks before surgery. Pre- and post-statin paired tumor samples were analyzed for Ki67 and HMGCR immunohistochemical expression. Changes in the Ki67 expression and HMGCR activity following statin treatment were the primary and secondary endpoints, respectively. Up-regulation of HMGCR following atorvastatin treatment was observed in 68 % of the paired samples with evaluable HMGCR expression (P = 0.0005). The average relative decrease in Ki67 expression following atorvastatin treatment was 7.6 % (P = 0.39) in all paired samples, whereas the corresponding decrease in Ki67 expression in tumors expressing HMGCR in the pre-treatment sample was 24 % (P = 0.02). Furthermore, post-treatment Ki67 expression was inversely correlated to post-treatment HMGCR expression (rs = -0.42; P = 0.03). Findings from this study suggest that HMGCR is targeted by statins in breast cancer cells in vivo, and that statins may have an anti-proliferative effect in HMGCR-positive tumors. Future studies are needed to evaluate HMGCR as a predictive marker for the selection of breast cancer patients who may benefit from statin treatment.

  • 85. Bjork, L.
    et al.
    Ait Blal, C.
    Alm, Tove L.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Bäckström, Anna
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Gnann, C.
    Hjelmare, Martin
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Schutten, Rutger
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Skogs, Marie
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Stadler, Charlotte
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Application specific antibody validation. The Human Protein Atlas validation scheme and how to confirm subcellular protein localization.2016Ingår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Artikel i tidskrift (Refereegranskat)
  • 86. Bjorling, E.
    et al.
    Oksvold, P.
    KTH.
    Forsberg, M.
    Lund, J.
    Ponten, F.
    Uhlén, Mathias
    KTH.
    Human protein atlas, version 22006Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 5, nr 10, s. S328-S328Artikel i tidskrift (Övrigt vetenskapligt)
  • 87.
    Bjorling, E.
    et al.
    KTH.
    Oksvold, P.
    KTH.
    Forsberg, M.
    KTH.
    Lund, J.
    KTH.
    Ponten, F.
    Uppsala Univ, Uppsala, Sweden..
    Uhlén, Mathias
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    The creation and usage of a human protein atlas database2005Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 4, nr 8, s. S18-S18Artikel i tidskrift (Övrigt vetenskapligt)
  • 88. Bjornson, Elias
    et al.
    Mukhopadhyay, Bani
    Asplund, Anna
    Pristovsek, Nusa
    Cinar, Resat
    Romeo, Stefano
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kunos, George
    Nielsen, Jens
    Mardinoglu, Adil
    Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization2015Ingår i: Cell Reports, E-ISSN 2211-1247, Vol. 13, nr 9, s. 2014-2026Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC.

  • 89.
    Björling, Erik
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Lindskog, Cecilia
    Uppsala Univ, Rudbeck Lab.
    Oksvold, Per
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Linné, Jerker
    Uppsala Univ, Rudbeck Lab.
    Kampf, Caroline
    Uppsala Univ, Rudbeck Lab.
    Hober, Sophia
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO).
    Pontén, Fredrik
    Uppsala Univ, Rudbeck Lab.
    A web-based tool for in silico biomarker discovery based on tissue-specific protein profiles in normal and cancer tissues2008Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, Vol. 7, nr 5, s. 825-844Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Here we report the development of a publicly available Web-based analysis tool for exploring proteins expressed in a tissue- or cancer-specific manner. The search queries are based on the human tissue profiles in normal and cancer cells in the Human Protein Atlas portal and rely on the individual annotation performed by pathologists of images representing immunohistochemically stained tissue sections. Approximately 1.8 million images representing more than 3000 antibodies directed toward human proteins were used in the study. The search tool allows for the systematic exploration of the protein atlas to discover potential protein biomarkers. Such biomarkers include tissue-specific markers, cell type-specific markers, tumor type-specific markers, markers of malignancy, and prognostic or predictive markers of cancers. Here we show examples of database queries to generate sets of candidate biomarker proteins for several of these different categories. Expression profiles of candidate proteins can then subsequently be validated by examination of the underlying high resolution images. The present study shows examples of search strategies revealing several potential protein biomarkers, including proteins specifically expressed in normal cells and in cancer cells from specified tumor types. The lists of candidate proteins can be used as a starting point for further validation in larger patient cohorts using both immunological approaches and technologies utilizing more classical proteomics tools.

  • 90.
    Björling, Erik
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Antibodypedia: a portal for sharing antibody and antigen validation data2008Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, Vol. 7, nr 10, s. 2028-2037Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antibodies are useful tools to characterize the components of the human proteome and to validate potential protein biomarkers discovered through various clinical proteomics efforts. The lack of validation results across various applications for most antibodies often makes it necessary to perform cumbersome investigations to ensure specificity of a particular antibody in a certain application. A need therefore exists for a standardized system for sharing validation data about publicly available antibodies and to allow antibody providers as well as users to contribute and edit experimental evidence data, including data also on the antigen. Here we describe a new publicly available portal called Antibodypedia, which has been developed to allow sharing of information regarding validation of antibodies in which providers can submit their own validation results and reliability scores. We report standardized validation criteria and submission rules for applications such as Western blots, protein arrays, immunohistochemistry, and immunofluorescence. The contributor is expected to provide experimental evidence and a validation score for each antibody, and the users can subsequently provide feedback and comments on the use of the antibody. The database thus provides a virtual resource of publicly available antibodies toward human proteins with accompanying experimental evidence supporting an individual validation score for each antibody in an application-specific manner.

  • 91. Blomstergren, A.
    et al.
    O'Meara, D.
    Lukacs, M.
    Uhlén, Mathias
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Lundeberg, Joakim
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Cooperative oligonucleotides in purification of cycle sequencing products2000Ingår i: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 29, nr 2, s. 352-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nucleic acid hybridization is an essential component in many of today's standard molecular biology techniques. In a recent study, we investigated whether nucleic acid capture could be improved by taking advantage of stacking hybridization, which refers to the stabilizing effect that exists between oligonucleotides when they hybridize in a contiguous tandem fashion. Here, we describe a specific approach for purification of sequencing products using cooperative probes that hybridize to single-strand targets where one of the probes has been coupled to a magnetic bead. This approach has been developed for standard sequencing primers and has been applied to shotgun plasmid libraries. The cooperative probes have been designed to anneal within the common vector sequence and to avoid copurification of non extended sequencing primers and misprimed sequencing products. The reuse of magnetic beads, together with salt independent elution, makes the approach suitable for high-capacity capillary electrophoresis instruments.

  • 92. Bock, Thomas
    et al.
    Moest, Hansjoerg
    Omasits, Ulrich
    Dolski, Silvia
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Frei, Andreas
    Hofmann, Andreas
    Bausch-Fluck, Damaris
    Jacobs, Andrea
    Krayenbuehl, Niklaus
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Aebersold, Ruedi
    Frei, Karl
    Wollscheid, Bernd
    Proteomic Analysis Reveals Drug Accessible Cell Surface N-Glycoproteins of Primary and Established Glioblastoma Cell Lines2012Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 11, nr 10, s. 4885-4893Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glioblastoma is the most common primary Glioblastoma Cell Surface Capturing brain tumor in adults with low average survival time after diagnosis. In order to improve glioblastoma treatment, new drug-accessible targets need to be identified. Cell surface glycoproteins are prime drug targets due to their accessibility at the surface of cancer cells. To overcome the limited availability of suitable antibodies for cell surface protein detection, we performed a comprehensive mass spectrometric investigation of the glioblastoma surfaceome. Our combined cell surface capturing analysis of primary ex vivo glioblastoma cell lines in combination with established glioblastoma cell lines revealed 633 N-glycoproteins, which vastly extends the known data of surfaceome drug targets at subcellular resolution. We provide direct evidence of common glioblastoma cell surface glycoproteins and an approximate estimate of their abundances, information that could not be derived from genomic and/or transcriptomic glioblastoma studies. Apart from our pharmaceutically valuable repertoire of already and potentially drug-accessible cell surface glycoproteins, we built a mass-spectrometry-based toolbox enabling directed, sensitive, and repetitive glycoprotein measurements for clinical follow-up studies. The included Skyline Glioblastoma SRM assay library provides an elevated starting point for parallel testing of the abundance level of the detected glioblastoma surfaceome members in future drug perturbation experiments.

  • 93. Bolander, Å.
    et al.
    Agnarsdóttir, M.
    Strömberg, S.
    Ponten, F.
    Hesselius, P.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Bergqvist, M.
    The protein expression of TRP-1 and galectin-1 in cutaneous malignant melanomas2008Ingår i: Cancer Genomics & Proteomics, ISSN 1109-6535, E-ISSN 1790-6245, Vol. 5, nr 6, s. 293-300Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Patients with metastazing malignant melanoma have a poor outcome and determination of thickness of the primary tumor remains as the most important prognostic predictor. The aim of this study was to use an antibody-based proteomics strategy to search for new molecular markers associated with melanoma progression. Two proteins, TRP-1 and galectin-1, were identified as proteins with enhanced expression in cells from the melanocytic lineage. Patients and Methods: Protein profiling of TRP-1 and galectin-1 together with proliferation marker Ki-67 and melanocyte marker Melan-A was performed in normal tissues from 144 individuals and in 216 different tumors using tissue microarrays and immunohistochemistry. The protein expression pattern was further analyzed in a defined cohort of 157 patients diagnosed with invasive cutaneous malignant melanoma. Results: Both TRP-1 and galectin-1 were highly expressed in normal melanocytes and melanoma. The expression of TRP-1 was inversely correlated with tumor stage (p=0.002, (R=-0.28)). Neither TRP-1 or galectin-1 was associated with overall or disease free survival (p>0.14, p>0.46 respectively). Ki-67 was associated with tumor stage and survival (p<0.001). Conclusion: TRP-1 and galectin-1 protein expression patterns were determined in normal and cancer tissues and both proteins were expressed in the majority of the malignant melanomas. There was no correlation between TRP-1 or galectin-1 expression and survival.

  • 94. Boman, K.
    et al.
    Larsson, A. H.
    Segersten, U.
    Kuteeva, E.
    Johannesson, H.
    Nodin, B.
    Eberhard, J.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Malmström, P-U
    Jirström, K.
    Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer2013Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, nr 11, s. 2321-2328Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Membranous expression of the anti-adhesive glycoprotein podocalyxin-like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer. Methods: Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n = 100 (Cohort I) and n = 343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression-free survival (PFS; Cohort II) was assessed. Results: Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR = 2.25 in Cohort I and 3.10 in Cohort II, adjusted HR = 2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR = 4.36, adjusted HR = 2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR = 6.19, adjusted HR = 4.60) and DSS (unadjusted HR = 8.34, adjusted HR = 7.16). Conclusion: Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer.

  • 95. Boman, Karolina
    et al.
    Segersten, Ulrika
    Ahlgren, Göran
    Eberhard, Jakob
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Jirström, Karin
    Malmström, Per-Uno
    Decreased expression of RNA-binding motif protein 3 correlates with tumour progression and poor prognosis in urothelial bladder cancer2013Ingår i: BMC Urology, E-ISSN 1471-2490, Vol. 13, s. 17-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Low nuclear expression of the RNA-binding motif protein 3 (RBM3) has previously been found to be associated with poor prognosis in several cancer forms e. g. breast, ovarian, colorectal, prostate cancer and malignant melanoma. The aim of this study was to examine the prognostic impact of RBM3 expression in urinary bladder cancer. Methods: Immunohistochemical RBM3 expression was examined in tumours from 343 patients with urothelial bladder cancer. Chi-square and Spearman's correlation tests were applied to explore associations between RBM3 expression and clinicopathological characteristics. The impact of RBM3 expression on disease-specific survival (DSS), 5-year overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan-Meier analysis and Cox proportional hazards modelling. Results: Reduced nuclear RBM3 expression was significantly associated with more advanced tumour (T) stage (p < 0.001) and high grade tumours (p= 0.004). Negative RBM3 expression was associated with a significantly shorter DSS (HR= 2.55; 95% CI 1.68-3.86)) and 5-year OS (HR= 2.10; 95% CI 1.56-2.82), also in multivariable analysis (HR= 1.65; 95% CI 1.07-2.53 for DSS and HR= 1.54; 95% CI 1.13-2.10 for 5-year OS). In patients with Ta and T1 tumours expressing reduced RBM3 levels, Kaplan-Meier analysis revealed a significantly shorter PFS (p= 0.048) and 5-year OS (p= 0.006). Conclusion: Loss of RBM3 expression is associated with clinically more aggressive tumours and an independent factor of poor prognosis in patients with urothelial bladder cancer and a potentially useful biomarker for treatment stratification and surveillance of disease progression.

  • 96.
    Bosley, J. R.
    et al.
    Clermont Bosley LLC, Philadelphia, PA 19348 USA..
    Björnson, Elias
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden.;Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Turkez, Hasan
    Ataturk Univ, Fac Med, Dept Med Biol, Erzurum, Turkey..
    Nielsen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Boren, Jan
    Ataturk Univ, Fac Med, Dept Med Biol, Erzurum, Turkey..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London, England..
    Informing Pharmacokinetic Models With Physiological Data: Oral Population Modeling of L-Serine in Humans2021Ingår i: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 12, artikel-id 643179Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To determine how to set optimal oral L-serine (serine) dose levels for a clinical trial, existing literature was surveyed. Data sufficient to set the dose was inadequate, and so an (n = 10) phase I-A calibration trial was performed, administering serine with and without other oral agents. We analyzed the trial and the literature data using pharmacokinetic (PK) modeling and statistical analysis. The therapeutic goal is to modulate specific serine-related metabolic pathways in the liver using the lowest possible dose which gives the desired effect since the upper bound was expected to be limited by toxicity. A standard PK approach, in which a common model structure was selected using a fit to data, yielded a model with a single central compartment corresponding to plasma, clearance from that compartment, and an endogenous source of serine. To improve conditioning, a parametric structure was changed to estimate ratios (bioavailability over volume, for example). Model fit quality was improved and the uncertainty in estimated parameters was reduced. Because of the particular interest in the fate of serine, the model was used to estimate whether serine is consumed in the gut, absorbed by the liver, or entered the blood in either a free state, or in a protein- or tissue-bound state that is not measured by our assay. The PK model structure was set up to represent relevant physiology, and this quantitative systems biology approach allowed a broader set of physiological data to be used to narrow parameter and prediction confidence intervals, and to better understand the biological meaning of the data. The model results allowed us to determine the optimal human dose for future trials, including a trial design component including IV and tracer studies. A key contribution is that we were able to use human physiological data from the literature to inform the PK model and to set reasonable bounds on parameters, and to improve model conditioning. Leveraging literature data produced a more predictive, useful model.

  • 97. Bosley, Jim
    et al.
    Borén, Christofer
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lee, Sunjae
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Grotli, Morten
    Nielsen, Jens
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Mardinoglu, Adil
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Improving the economics of NASH/NAFLD treatment through the use of systems biology2017Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 22, nr 10, s. 1532-1538Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD). We surveyed NASH therapies currently in development, and found a significant variety of targets and approaches. Evaluation and clinical testing of these targets is an expensive and time-consuming process. Systems biology approaches could enable the quantitative evaluation of the likely efficacy and safety of different targets. This motivated our review of recent systems biology studies that focus on the identification of targets and development of effective treatments for NASH. We discuss the potential broader use of genome-scale metabolic models and integrated networks in the validation of drug targets, which could facilitate more productive and efficient drug development decisions for the treatment of NASH.

  • 98.
    Boström, Tove
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Danielsson, Frida
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Johansson, Henrik J.
    Karlinska Institute, Cancer Proteomics Mass Spectrometry, Dep. of Oncology-Pathology.
    Tegel, Hanna
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Lehtiö, Janne
    Karolinska Institute, Cancer Proteomics Mass Spectrometry, Dep. of Oncology-Pathology.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Hober, Sophia
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Ottosson Takanen, Jenny
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Investigating the correlation of protein and mRNA levels in human cell lines using quantitative proteomics and transcriptomicsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    An important topic of discussion in proteomics is the degree of correlation of RNA and protein levels in cells, tissues and organs. In this study, the difference in protein and mRNA levels for a number of selected gene targets were investigated across six human cell lines using quantitative proteomics and next generation sequencing-based transcriptomics. The copy numbers of 32 proteins were determined using an absolute quantitative proteomics approach (PrEST-SILAC), where heavy isotope-labeled protein fragments were used as internal standards. A cross evaluation of protein copy numbers determined by mass spectrometry and staining profiles using immunohistochemistry showed good correlation. The mRNA levels were determined using RNA sequencing based on digital counting of sequencing reads and the levels determined as FPKM values. Comparison of the relative variations in mRNA and protein levels for individual genes across the six cell lines showed correlation between protein and mRNA levels, including six genes with high variability in expression levels in the six cell lines resulting in an average correlation of 0.9 (Spearman's rank coefficient). In summary, the analysis of the selected protein targets supports the conclusion that the translation rate across cell lines correlates for a particular gene, suggesting that individual protein levels can be predicted from the respective mRNA levels by defining the relation between protein and mRNA, specific for each human gene.

  • 99.
    Boström, Tove
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Johansson, Henrik J.
    Karolinska Institute.
    Lehtiö, Janne
    Karolinska Institute.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Hober, Sophia
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Investigating the Applicability of Antibodies Generated within the Human Protein Atlas as Capture Agents in Immunoenrichment Coupled to Mass Spectrometry2014Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, nr 10, s. 4424-4435Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    For identification and characterization of proteins in complex samples, immunoenrichment coupled to mass spectrometry is a good alternative due to the sensitivity of the affinity enrichment and the specificity of mass spectrometry analysis. Antibodies are commonly used affinity agents; however, for high-throughput analysis, antibody availability is usually a bottleneck. Here we present a protocol for immunoenrichment coupled to mass spectrometry in a high-throughput setup, where all steps from bead coupling to mass spectrometry sample preparation are performed in parallel in a 96-well format. Antibodies generated within the Human Protein Atlas project were tested for applicability as capture agents. The antibodies were covalently attached to protein A beads, making it possible to reuse the coupled beads at least three times without destroying the antibody binding efficiency. Target proteins were captured from a U251 MG cell lysate, eluted, digested, and analyzed using mass spectrometry. Of 30 investigated antibodies, around 50% could successfully capture the corresponding native target protein, making the available library of more than 21 000 antibodies a valuable resource for immunoenrichment assays. Due to the diversity of different antibodies regarding affinity and specificity, analyzing antibodies in a high-throughput format is challenging. Even though protocol optimization for individual antibodies can be advantageous for future studies, our method enables a fast screening strategy to determine the usefulness of antibodies in immunoenrichment setups. In addition, we show that the specificity of the antibodies can be investigated by using label-free quantification.

  • 100. Bourbeillon, Julie
    et al.
    Orchard, Sandra
    Benhar, Itai
    Borrebaeck, Carl
    de Daruvar, Antoine
    Duebel, Stefan
    Frank, Ronald
    Gibson, Frank
    Gloriam, David
    Haslam, Niall
    Hiltker, Tara
    Humphrey-Smith, Ian
    Hust, Michael
    Juncker, David
    Koegl, Manfred
    Konthur, Zoltan
    Korn, Bernhard
    Krobitsch, Sylvia
    Muyldermans, Serge
    Nygren, Per-Åke
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi. KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Palcy, Sandrine
    Polic, Bojan
    Rodriguez, Henry
    Sawyer, Alan
    Schlapshy, Martin
    Snyder, Michael
    Stoevesandt, Oda
    Taussig, Michael J.
    Templin, Markus
    Uhlén, Matthias
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    van der Maarel, Silvere
    Wingren, Christer
    Hermjakob, Henning
    Sherman, David
    Minimum information about a protein affinity reagent (MIAPAR)2010Ingår i: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 28, nr 7, s. 650-653Artikel i tidskrift (Övrigt vetenskapligt)
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