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  • 101.
    Just, David
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Månberg, Anna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Mitsios, Nicholas
    Stockmeier, Craig
    Rajkowska, Grazyna
    Mulder, Jan
    Feuk, Lars
    Cunningham, Janet
    Nilsson, Peter
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Lindholm Carlström, Eva
    Exploring autoantibody signatures in brain tissue lysates from patients with schizophreniaManuscript (preprint) (Other academic)
  • 102.
    Just, David
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Månberg, Anna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Sjöberg, Ronald
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Burman, Joachim
    Nilsson, Peter
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Cunningham, Janet
    Exploring the autoantibody repertoire in patients with obsessive compulsive disorderManuscript (preprint) (Other academic)
  • 103. Kato, Bernet S.
    et al.
    Nicholson, George
    Neiman, Maja
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Rantalainen, Mattias
    Holmes, Chris C.
    Barrett, Amy
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Spector, Tim D.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Variance decomposition of protein profiles from antibody arrays using a longitudinal twin model2011In: Proteome Science, ISSN 1477-5956, E-ISSN 1477-5956, Vol. 9, no 1, p. 73-Article in journal (Refereed)
    Abstract [en]

    The advent of affinity-based proteomics technologies for global protein profiling provides the prospect of finding new molecular biomarkers for common, multifactorial disorders. The molecular phenotypes obtained from studies on such platforms are driven by multiple sources, including genetic, environmental, and experimental. In characterizing the contribution of different sources of variation to the measured phenotypes, the aim is to facilitate the design and interpretation of future biomedical studies employing exploratory and multiplexed technologies. Thus, biometrical genetic modelling of twin or other family data can be used to decompose the variation underlying a phenotype into biological and experimental components. RESULTS: Using antibody suspension bead arrays and antibodies from the Human Protein Atlas, we study unfractionated serum from a longitudinal study on 154 twins. In this study, we provide a detailed description of how the variation in a molecular phenotype in terms of protein profile can be decomposed into familial i.e. genetic and common environmental; individual environmental, short-term biological and experimental components. The results show that across 69 antibodies analyzed in the study, the median proportion of the total variation explained by familial sources is 12% (IQR 1-22%), and the median proportion of the total variation attributable to experimental sources is 63% (IQR 53-72%). CONCLUSION: The variability analysis of antibody arrays highlights the importance to consider variability components and their relative contributions when designing and evaluating studies for biomarker discover with exploratory, high-throughput and multiplexed methods.

  • 104. Kemmer, D.
    et al.
    Faxen, M.
    Hodges, E.
    Lim, J.
    Herzog, E.
    Ljungstrom, E.
    Lundmark, A.
    Olsen, M. K.
    Podowski, R.
    Sonnhammer, E. L. L.
    Nilsson, Peter
    KTH, Superseded Departments, Biotechnology.
    Reimers, M.
    Lenhard, B.
    Roberds, S. L.
    Wahlestedt, C.
    Hoog, C.
    Agarwal, P.
    Wasserman, W. W.
    Exploring the foundation of genomics: a Northern blot reference set for the comparative analysis of transcript profiling technologies2004In: Comparative and functional genomics, ISSN 1531-6912, E-ISSN 1532-6268, Vol. 5, no 8, p. 584-595Article in journal (Refereed)
    Abstract [en]

    In this paper we aim to create a reference data collection of Northern blot results and demonstrate how such a collection can enable a quantitative comparison of modern expression profiling techniques, a central component of functional genomics studies. Historic ally, Northern blots were the de facto standard for determining RNA transcript levels. However, driven by the demand for analysis of large sets of genes in parallel, high-throughput methods, such as microarrays, dominate modern profiling efforts. To facilitate assessment of these methods, in comparison to Northern blots, we created a database of published Northern results obtained with a standardized commercial multiple tissue blot (dbMTN). In order to demonstrate the utility of the dbMTN collection for technology comparison, we also generated expression profiles for genes across a set of human tissues, using multiple profiling techniques. No method produced profiles that were strongly correlated with the Northern blot data. The highest correlations to the Northern blot data were determined with microarrays for the subset of genes observed to be specifically expressed in a single tissue in the Northern analyses. The database and expression profiling data are available via the project website (http://www.cisreg.ca). We believe that emphasis on multitechnique validation of expression profiles is justified, as the correlation results between platforms are not encouraging on the whole. Supplementary material for this article can be found at: http://www.interscience.wiley.com/jpages/1531-6912/suppmat

  • 105. Khoonsari, Payam Emami
    et al.
    Häggmark, Anna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lonnberg, Maria
    Mikus, Maria
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kilander, Lena
    Lannfelt, Lars
    Bergquist, Jonas
    Ingelsson, Martin
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kultima, Kim
    Shevchenko, Ganna
    Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0150672Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is a neurodegenerative disorder accounting for more than 50% of cases of dementia. Diagnosis of Alzheimer's disease relies on cognitive tests and analysis of amyloid beta, protein tau, and hyperphosphorylated tau in cerebrospinal fluid. Although these markers provide relatively high sensitivity and specificity for early disease detection, they are not suitable for monitor of disease progression. In the present study, we used label-free shotgun mass spectrometry to analyse the cerebrospinal fluid proteome of Alzheimer's disease patients and non-demented controls to identify potential biomarkers for Alzheimer's disease. We processed the data using five programs (DecyderMS, Maxquant, OpenMS, PEAKS, and Sieve) and compared their results by means of reproducibility and peptide identification, including three different normalization methods. After depletion of high abundant proteins we found that Alzheimer's disease patients had lower fraction of low-abundance proteins in cerebrospinal fluid compared to healthy controls (p<0.05). Consequently, global normalization was found to be less accurate compared to using spiked-in chicken ovalbumin for normalization. In addition, we determined that Sieve and OpenMS resulted in the highest reproducibility and PEAKS was the programs with the highest identification performance. Finally, we successfully verified significantly lower levels (p<0.05) of eight proteins (A2GL, APOM, C1QB, C1QC, C1S, FBLN3, PTPRZ, and SEZ6) in Alzheimer's disease compared to controls using an antibody-based detection method. These proteins are involved in different biological roles spanning from cell adhesion and migration, to regulation of the synapse and the immune system.

  • 106.
    Khoonsari, Payam Emami
    et al.
    Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Shevchenko, Ganna
    Uppsala Univ, Dept Chem BMC, Analyt Chem, Uppsala, Sweden..
    Herman, Stephanie
    Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Remnestål, Julia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Giedraitis, Vilmantas
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Brundin, RoseMarie
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Gunnarsson, Malin Degerman
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Kilander, Lena
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Zetterberge, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden.;UK Dementia Res Inst UCL, London, England.;UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lannfelt, Lars
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Ingelsson, Martin
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Kultima, Kim
    Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, no 2, p. 639-651Article in journal (Refereed)
    Abstract [en]

    Background: Alzheimer's disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: A beta(42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4-9 years and 21 of these converted to AD, whereas 53 remained stable. Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCl/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

  • 107. Kremer, A. N.
    et al.
    van der Griendt, J. C.
    van der Meijden, E. D.
    Honders, M. W.
    Ayoglu, Burcu
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Falkenburg, J. H. F.
    Griffioen, M.
    Development of a coordinated allo T cell and auto B cell response against autosomal PTK2B after allogeneic hematopoietic stem cell transplantation2014In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 2, p. 365-369Article in journal (Refereed)
    Abstract [en]

    It is well known that allo-reactive T cells play a crucial role in graft-versus-leukemia and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (alloSCT). Allo-reactive CD4+ T cells can mediate direct cytolysis, but may also stimulate production of IgG antibodies as helper cells. Immune complexes may subsequently be processed and presented by professional antigen presenting cells and stimulate induction of specific CD8+ T cells. As such, proteins targeted in coordinated T- and B-cell responses may represent a class of immunodominant antigens in clinical responses after alloSCT. We previously identified LB-PTK2B-1T as HLA class II restricted polymorphic antigen in a patient treated with donor lymphocyte infusion for relapsed chronic myeloid leukemia after HLA-matched alloSCT. Since PTK2B has also been described as antibody target, we here investigated whether a coordinated T- and B-cell response against PTK2B was induced. Patient serum before and after alloSCT and donor lymphocyte infusion (DLI) was screened for antibodies, and we indeed observed development of a humoral immune response against PTK2B. Antibodies against PTK2B were only found after DLI and, in contrast to the CD4+ T cells, recognized a monomorphic region of the protein. To our knowledge, this is the first description of a coordinated allo-reactive CD4+ T-cell and auto-reactive antibody response against an autosomal antigen.

  • 108.
    Larsson, Karin
    et al.
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101).
    Nilsson, Peter
    KTH, School of Biotechnology (BIO).
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO).
    Hober, Sophia
    KTH, School of Biotechnology (BIO).
    Wernérus, Henrik
    KTH, School of Biotechnology (BIO).
    Multiplexed PrEST immunization for high-throughput affinity proteomics2006In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 315, p. 110-120Article in journal (Refereed)
    Abstract [en]

    Monospecific antibodies dfdfdfdf (msAbs) generated through antigen specific purification of polyclonal antisera are valuable tools in proteome analyses. However, proteome wide generation of msAbs would require extensive immunization programs. Therefore, it would be desirable to develop efficient immunization and purification methods to reduce the number of animals needed for such antibody-based research. Here we describe a multiplex immunization strategy for generation of msAbs towards recombinantly produced human protein fragments, denoted PrESTs. Antisera from rabbits immunized with a mixture of two, three, five and up to ten different PrESTs have been purified by a two-step immunoaffinity-based protocol and the efficiency of the purification method was analyzed using a two-color protein array concept. The obtained results showed that almost 80% of the animals immunized with antigens composed of two or three different PrESTs yielded antibodies recognizing all the included PrESTs. Furthermore, the modified two-step purification method effectively eliminated all background binding and produced pure antibody pools against individual PrESTs. This indicates that the multiplexed PrEST immunization strategy described here could become useful for high-throughput antibody-based proteomics initiatives, thus significantly reducing the number of animals needed in addition to providing a more cost-efficient method for production of msAbs.

  • 109.
    Laurell, Cecilia
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Velázquez-Fernández, David
    Lindsten, Kristina
    Juhlin, Christoffer
    Enberg, Ulla
    Geli, Janos
    Höög, Anders
    Kjellman, Magnus
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Hamberger, Bertil
    Larsson, Catharina
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics.
    Bäckdahl, Martin
    Transcriptional profiling enables molecular classification of adrenocortical tumours2009In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 161, no 1, p. 141-152Article in journal (Refereed)
    Abstract [en]

    Objective: Tumours in the adrenocortex are common human tumours. Malignancy is however, rare, the yearly incidence being 0.5-2 per million inhabitants, but associated with a very aggressive behaviour. Adrenocortical tumours are often associated with altered hormone production with a variety of clinical symptoms. The aggressiveness of carcinomas together with the high frequency of adenomas calls for a deeper understanding of the underlying biological mechanisms and an improvement of the diagnostic possibilities. Methods: Microarray gene expression analysis was performed in tumours of adrenocortex with emphasis on malignancy as well as hormonal activity. The sample set consisted of 17 adenomas, 11 carcinomas and 4 histological normal adrenocortexes. RNA from these was hybridised according to a reference design on microarrays harbouring 29 760 human cDNA clones. Confirmation was performed with quantitative real time-PCR and western blot analysis. Results: Unsupervised clustering to reveal relationships between samples based on the entire gene expression profile resulted in two subclusters; carcinomas and non-cancer specimens. A large number of genes were accordingly found to be differentially expressed comparing carcinomas to adenomas. Among these were IGF2, FGFR1 and FGFR4 in growth factor signalling the most predominant and also the USP4, UBE2C and UFD1L in the ubiquitin-proteasome pathway. Moreover, two subgroups of carcinomas were identified with different survival outcome, suggesting that survival prediction can be made on the basis of gene expression profiles. Regarding adenomas with aldosterone overproduction, OSBP and VEGFB were among the most up-regulated genes compared with the other samples. Conclusions: Adrenocortical carcinomas are associated with a distinct molecular signature apparent in their gene expression profiles. Differentially expressed genes were identified associated with malignancy, survival as well as hormonal activity providing a resource of candidate genes for an exploration of possible drug targets and diagnostic and prognostic markers.

  • 110.
    Laurell, Cecilia
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Wirta, Valtteri
    KTH, School of Biotechnology (BIO), Gene Technology.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Comparative analysis of a 3' end tag PCR and a linear RNA amplification approach for microarray analysis2007In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 127, no 4, p. 638-646Article in journal (Refereed)
    Abstract [en]

     Background: Various types of amplification techniques have been developed in order to enable microarray gene expression analysis when the amount of starting material is limited. The two main strategies are linear amplification, using in vitro transcription, and exponential amplification, based on PCR. We have evaluated the performance of a linear and an in-house developed exponential amplification protocol that relies on 3' end tag sequences. We used 100 ng total RNA as starting material for amplification and compared the results with data from hybridizations with unamplified mRNA and total RNA.

    Results: Preservation of expression ratios after amplification was examined comparing 1092 ratios obtained with amplification protocols to those obtained with standard labelling of mRNA. The Pearson correlations were 0.61 and 0.84, respectively, for the two linear amplification replicates and 0.76 and 0.80 for the two exponential amplification replicates. The correlations between repeated amplifications was 0.82 with the exponential method and 0.63 with the linear, indicating a better reproducibility with the PCR-based approach.

    Conclusion: Both amplification methods generated results in agreement with unamplified material. In this study, the PCR-based method was more reproducible than in vitro transcription amplification. Advantages with the in-house developed method are the lower cost since it is non-commercial and that the PCR generated product offers compatibility with both sense and antisense arrays.

  • 111.
    Lindberg, Johan
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    af Klint, Erik
    Department of Medicine, Karolinska Institute, Karolinska University Hospital.
    Catrina, Anca Irinel
    Department of Medicine, Karolinska Institute, Karolinska University Hospital.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Gene Technology.
    Klareskog, Lars
    Department of Medicine, Karolinska Institute, Karolinska University Hospital.
    Ulfgren, Ann-Kristin
    Department of Medicine, Karolinska Institute, Karolinska University Hospital.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Effect of infliximab on mRNA expression profiles in synovial tissue of rheumatoid arthritis patients2006In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 8, no 6, p. R179-Article in journal (Refereed)
    Abstract [en]

    We examined the gene expression profiles in arthroscopic biopsies retrieved from 10 rheumatoid arthritis patients before and after anti-TNF treatment with infliximab to investigate whether such profiles can be used to predict responses to the therapy, and to study effects of the therapy on the profiles. Responses to treatment were assessed using European League Against Rheumatism response criteria. Three patients were found to be good responders, five patients to be moderate responders and two patients to be nonresponders. The TNF-alpha status of the biopsies from each of the patients before treatment was also investigated immunohistochemically, and it was detected in biopsies from four of the patients, including all three of the good responders. The gene expression data demonstrate that all patients had unique gene expression signatures, with low intrapatient variability between biopsies. The data also revealed significant differences between the good responding and nonresponding patients (279 differentially expressed genes were detected, with a false discovery rate < 0.025). Among the identified genes we found that MMP-3 was significantly upregulated in good responders (log(2) fold change, 2.95) compared with nonresponders, providing further support for the potential of MMP-3 as a marker for good responses to therapy. An even more extensive list of 685 significantly differentially expressed genes was found between patients in whom TNF-alpha was found and nonresponders, indicating that TNF-alpha could be an important biomarker for successful infliximab treatment. Significant differences were also observed between biopsies taken before and after anti-TNF treatment, including 115 differentially expressed genes in the good responding group. Interestingly, the effect was even stronger in the group in which TNF-a was immunohistochemically detected before therapy. Here, 1,058 genes were differentially expressed, including many that were novel in this context (for example, CXCL3 and CXCL14). Subsequent Gene Ontology analysis revealed that several 'themes' were significantly over-represented that are known to be affected by anti-TNF treatment in inflammatory tissue; for example, immune response (GO:0006955), cell communication (GO:0007154), signal transduction (GO:0007165) and chemotaxis (GO:0006935). No genes reached statistical significance in the moderately responding or nonresponding groups. In conclusion, this pilot study suggests that further investigation is warranted on the usefulness of gene expression profiling of synovial tissue to predict and monitor the outcome of rheumatoid arthritis therapies.

  • 112.
    Lindberg, Johan
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    af Klint, Erik
    Department of Rheumatology, Karolinska Institutet, Karolinska University Hospital.
    Ulfgren, Ann-Kristin
    Department of Rheumatology, Karolinska Institutet, Karolinska University Hospital.
    Stark, André
    Department of Orthopedics, Karolinska University Hospital.
    Andersson, Tove
    KTH, School of Biotechnology (BIO), Gene Technology.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Gene Technology.
    Klareskog, Lars
    Department of Rheumatology, Karolinska Institutet, Karolinska University Hospital.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Variability in synovial inflammation in rheumatoid arthritis investigated by microarray technology2006In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 8, no 2Article in journal (Refereed)
    Abstract [en]

    In recent years microarray technology has been used increasingly to acquire knowledge about the pathogenic processes involved in rheumatoid arthritis. The present study investigated variations in gene expression in synovial tissues within and between patients with rheumatoid arthritis. This was done by applying microarray technology on multiple synovial biopsies obtained from the same knee joints. In this way the relative levels of intra-patient and inter-patient variation could be assessed. The biopsies were obtained from 13 different patients: 7 by orthopedic surgery and 6 by rheumatic arthroscopy. The data show that levels of heterogeneity varied substantially between the biopsies, because the number of genes found to be differentially expressed between pairs of biopsies from the same knee ranged from 6 to 2,133. Both arthroscopic and orthopedic biopsies were examined, allowing us to compare the two sampling methods. We found that the average number of differentially expressed genes between biopsies from the same patient was about three times larger in orthopedic than in arthroscopic biopsies. Using a parallel analysis of the tissues by immunohistochemistry, we also identified orthopedic biopsies that were unsuitable for gene expression analysis of synovial inflammation due to sampling of non-inflamed parts of the tissue. Removing these biopsies reduced the average number of differentially expressed genes between the orthopedic biopsies from 455 to 171, in comparison with 143 for the arthroscopic biopsies. Hierarchical clustering analysis showed that the remaining orthopedic and arthroscopic biopsies had gene expression signatures that were unique for each patient, apparently reflecting patient variation rather than tissue heterogeneity. Subsets of genes found to vary between biopsies were investigated for overrepresentation of biological processes by using gene ontology. This revealed representative 'themes' likely to vary between synovial biopsies affected by inflammatory disease.

  • 113. Liu, Tao
    et al.
    Laurell, Cecilia
    KTH, School of Biotechnology (BIO), Gene Technology.
    Selivanova, Galina
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Gene Technology.
    Wiman, Klas
    Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis2007In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 14, no 3, p. 411-421Article in journal (Refereed)
    Abstract [en]

    p53 triggers apoptosis in response to cellular stress. We analyzed p53-dependent gene and protein expression in response to hypoxia using wild-type p53-carrying or p53 null HCT116 colon carcinoma cells. Hypoxia induced p53 protein levels and p53-dependent apoptosis in these cells. cDNA microarray analysis revealed that only a limited number of genes were regulated by p53 upon hypoxia. Most classical p53 target genes were not upregulated. However, we found that Fas/CD95 was significantly induced in response to hypoxia in a p53-dependent manner, along with several novel p53 target genes including ANXA1, DDIT3/ GADD153 (CHOP), SEL1L and SMURF1. Disruption of Fas/CD95 signalling using anti-Fas-blocking antibody or a caspase 8 inhibitor abrogated p53-induced apoptosis in response to hypoxia. We conclude that hypoxia triggers a p53-dependent gene expression pattern distinct from that induced by other stress agents and that Fas/CD95 is a critical regulator of p53-dependent apoptosis upon hypoxia.

  • 114. Lonnstedt, I.
    et al.
    Rimini, R.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics.
    Empirical Bayes microarray ANOVA and grouping cell lines by equal expression levels2005In: Statistical Applications in Genetics and Molecular Biology, ISSN 1544-6115, E-ISSN 1544-6115, Vol. 4Article in journal (Refereed)
    Abstract [en]

    In the exploding field of gene expression techniques such as DNA microarrays, there are still few general probabilistic methods for analysis of variance. Linear models and ANOVA are heavily used tools in many other disciplines of scientific research. The usual F-statistic is unsatisfactory for microarray data, which explore many thousand genes in parallel, with few replicates. We present three potential one-way ANOVA statistics in a parametric statistical framework. The aim is to separate genes that are differently regulated across several treatment conditions from those with equal regulation. The statistics have different features and are evaluated using both real and simulated data. Our statistic B-1 generally shows the best performance, and is extended for use in an algorithm that groups cell lines by equal expression levels for each gene. An extension is also outlined for more general ANOVA tests including several factors. The methods presented are implemented in the freely available statistical language R. They are available at http://www.math.uu.se/staff/pages/?uname=ingrid.

  • 115. Lourido, L.
    et al.
    Ayoglu, Burcu
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fernandez-Tajes, J.
    Henjes, Frauke
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, J. M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ruiz-Romero, C.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Blanco, F. J.
    IDENTIFICATION OF A SERUM PROTEIN BIOMARKER PANEL FOR THE DIAGNOSIS OF KNEE OSTEOARTHRITIS2016In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 24, p. S23-S23Article in journal (Other academic)
  • 116.
    Lourido, L.
    et al.
    Hosp Univ A Coruna, INIBIC, RIER RED Inflamac & Enfermedades Reumat, La Coruna, Spain.;Hosp Univ A Coruna, INIBIC, Rheumatol Div, ProteoRed ISCIII Prote Grp, La Coruna, Spain..
    Ayoglu, Burcu
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Henjes, Frauke
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Schwenk, Jochen M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Fuentes, M.
    Univ Salamanca, IBSAL, Prote Unit ProteoRed ISCIII, Canc Res Ctr CIC,Dept Med, Salamanca, Spain..
    Ruiz-Romero, C.
    Hosp Univ A Coruna, INIBIC, Rheumatol Div, ProteoRed ISCIII Prote Grp, La Coruna, Spain.;Hosp Univ A Coruna, INIBIC, Inst Salud Carlos 3, CIBER BBN, La Coruna, Spain..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Blanco, F. J.
    Hosp Univ A Coruna, INIBIC, RIER RED Inflamac & Enfermedades Reumat, La Coruna, Spain.;Hosp Univ A Coruna, INIBIC, Rheumatol Div, ProteoRed ISCIII Prote Grp, La Coruna, Spain..
    DISCOVERY OF POTENTIAL SERUM BIOMARKERS IN OSTEOARTHRITIS USING PROTEIN ARRAYS2015In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 74, p. 373-374Article in journal (Other academic)
  • 117.
    Lourido, L.
    et al.
    INIBIC Hosp Univ Rio A Coruna, ProteoRed ISCIII Prote Grp, Rheumatol Div, La Coruna, Spain.;RIER RED Inflamac & Enfermedades Reumat, Madrid, Spain..
    Ruiz-Romero, C.
    INIBIC Hosp Univ Rio A Coruna, ProteoRed ISCIII Prote Grp, Rheumatol Div, La Coruna, Spain.;INIBIC CHUAC, CIBER BBN Inst Salud Carlos III, La Coruna, Spain..
    Camacho, M.
    INIBIC Hosp Univ Rio A Coruna, ProteoRed ISCIII Prote Grp, Rheumatol Div, La Coruna, Spain..
    Rego-Perez, I.
    INIBIC Hosp Univ Rio A Coruna, ProteoRed ISCIII Prote Grp, Rheumatol Div, La Coruna, Spain..
    Oreiro, N.
    INIBIC Hosp Univ Rio A Coruna, ProteoRed ISCIII Prote Grp, Rheumatol Div, La Coruna, Spain..
    Fernandez-Lopez, C.
    INIBIC Hosp Univ Rio A Coruna, ProteoRed ISCIII Prote Grp, Rheumatol Div, La Coruna, Spain..
    Nilsson, Peter
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Blanco, F.
    INIBIC Hosp Univ Rio A Coruna, ProteoRed ISCIII Prote Grp, Rheumatol Div, La Coruna, Spain.;RIER RED Inflamac & Enfermedades Reumat, Madrid, Spain..
    ITIH1 (INTER-ALPHA TRYPSIN INHIBITOR HEAVY CHAIN 1) IS A POTENTIAL PROTEOMIC BIOMARKER TO PREDICT EARLY KNEE OSTEOARTHRITIS. A QUALIFICATION PHASE STUDY USING DATA FROM THE OSTEOARTHRITIS INICIATIVE (OAI)2019In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 27, p. S69-S70Article in journal (Other academic)
  • 118. Lourido, Lucia
    et al.
    Ayoglu, Burcu
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fernandez-Tajes, Juan
    Henjes, Frauke
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ruiz-Romero, Cristina
    Nilsson, Peter
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Blanco, Francisco J.
    Discovery of Novel Serum Biomarkers for Osteoarthritis Using Affinity Proteomics2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67Article in journal (Other academic)
  • 119. Lourido, Lucia
    et al.
    Ayoglu, Burcu
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fernandez-Tajes, Juan
    Oreiro, Natividad
    Henjes, Frauke
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hellström, Cecilia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Schwenk, Jochen M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Ruiz-Romero, Cristina
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Blanco, Francisco J.
    Discovery of circulating proteins associated to knee radiographic osteoarthritis2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 137Article in journal (Refereed)
    Abstract [en]

    Currently there are no sufficiently sensitive biomarkers able to reflect changes in joint remodelling during osteoarthritis (OA). In this work, we took an affinity proteomic approach to profile serum samples for proteins that could serve as indicators for the diagnosis of radiographic knee OA. Antibody suspension bead arrays were applied to analyze serum samples from patients with OA (n = 273), control subjects (n = 76) and patients with rheumatoid arthritis (RA, n = 244). For verification, a focused bead array was built and applied to an independent set of serum samples from patients with OA (n = 188), control individuals (n = 83) and RA (n = 168) patients. A linear regression analysis adjusting for sex, age and body mass index (BMI) revealed that three proteins were significantly elevated (P < 0.05) in serum from OA patients compared to controls: C3, ITIH1 and S100A6. A panel consisting of these three proteins had an area under the curve of 0.82 for the classification of OA and control samples. Moreover, C3 and ITIH1 levels were also found to be significantly elevated (P < 0.05) in OA patients compared to RA patients. Upon validation in additional study sets, the alterations of these three candidate serum biomarker proteins could support the diagnosis of radiographic knee OA.

  • 120.
    Lourido Salas, Lucia Maria
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ruiz-Romero, C.
    Hosp Univ A Coruna, INBIG, ProteoRed ISCIII Prote Grp, Div Rheumatol, La Coruna, Spain.;Inst Salud Carlos III, CIBER BBN, Madrid, Spain..
    Picchi, F.
    Hosp Univ A Coruna, INBIG, ProteoRed ISCIII Prote Grp, Div Rheumatol, La Coruna, Spain..
    Perez-Pampin, E.
    Hosp Clin Univ Santiago, Inst Invest Sanitaria, Lab Invest 10, Santiago De Compostela, Spain.;Hosp Clin Univ Santiago, Inst Invest Sanitaria, Rheumatol Unit, Santiago De Compostela, Spain..
    Regueiro, C.
    RIER RED Inflamac & Enfermedades Reumat, Madrid, Spain.;Hosp Clin Univ Santiago, Inst Invest Sanitaria, Lab Invest 10, Santiago De Compostela, Spain.;Hosp Clin Univ Santiago, Inst Invest Sanitaria, Rheumatol Unit, Santiago De Compostela, Spain..
    Mera-Varela, A.
    Hosp Clin Univ Santiago, Inst Invest Sanitaria, Lab Invest 10, Santiago De Compostela, Spain.;Hosp Clin Univ Santiago, Inst Invest Sanitaria, Rheumatol Unit, Santiago De Compostela, Spain..
    Gonzalez, A.
    RIER RED Inflamac & Enfermedades Reumat, Madrid, Spain.;Hosp Clin Univ Santiago, Inst Invest Sanitaria, Lab Invest 10, Santiago De Compostela, Spain.;Hosp Clin Univ Santiago, Inst Invest Sanitaria, Rheumatol Unit, Santiago De Compostela, Spain..
    Hambardzumyan, K.
    Karolinska Inst, Dept Med, Unit Rheumatol, Stockholm, Sweden.;Karolinska Univ Hosp, Rheumatol Clin, Stockholm, Sweden..
    Saevarsdottir, S.
    Karolinska Inst, Dept Med, Unit Rheumatol, Stockholm, Sweden.;Karolinska Univ Hosp, Rheumatol Clin, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Blanco, F. J.
    Hosp Univ A Coruna, INBIG, ProteoRed ISCIII Prote Grp, Div Rheumatol, La Coruna, Spain.;RIER RED Inflamac & Enfermedades Reumat, Madrid, Spain..
    CIRCULATING AUTOANTIBODIES AS INDICATORS TO PREDICT THE CLINICAL RESPONSE TO INFLIXIMAB IN RHEUMATOID ARTHRITIS2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 312-312Article in journal (Other academic)
  • 121.
    Lundgren, M.
    et al.
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University.
    Andersson, Anders
    KTH, Superseded Departments, Biotechnology.
    Chen, L. M.
    Danish Archaea Center, Institute of Molecular Biology, University of Copenhagen.
    Nilsson, Peter
    KTH, Superseded Departments, Biotechnology.
    Bernander, R.
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University.
    Three replication origins in Sulfolobus species: synchronous initiation of chromosome replication and asynchronous termination2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 18, p. 7046-7051Article in journal (Refereed)
    Abstract [en]

    Chromosome replication origins were mapped in vivo in the two hyperthermophilic archaea, Sulfolobus acidocaidarius and Sulfolobus solfataricus, by using microarray-based marker frequency analysis. Bidirectional replication was found to be initiated in near synchrony from three separate sites in both organisms. Two of the three replication origins in each species were located in the vicinity of a cdc6/orc1 replication initiation gene, whereas no known replication-associated gene could be identified near the third origin in either organism. In contrast to initiation, replication termination occurred asynchronously, such that certain replication forks continued to progress for >40 min after the others had terminated. In each species, all replication forks advanced at similar DNA polymerization rates; this was found to be an order of magnitude below that displayed by Escherichia coli and thus closer to eukaryotic elongation rates. In S. acidocaidarius, a region containing short regularly spaced repeats was found to hybridize aberrantly, as compared to the rest of the chromosome, raising the possibility of a centromere-like function.

  • 122. Lundin, A.
    et al.
    Bjorkholm, B.
    Kupershmidt, I.
    Unemo, M.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101).
    Andersson, D. I.
    Engstrand, L.
    Slow genetic divergence of Helicobacter pylori strains during long-term colonization2005In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 73, no 8, p. 4818-4822Article in journal (Refereed)
    Abstract [en]

    The genetic variability of Helicobacter pylori is known to be high compared to that of many other bacterial species. H. pylori is adapted to the human stomach, where it persists for decades, and adaptation to each host results in every individual harboring a distinctive bacterial population. Although clonal variants may exist within such a population, all isolates are generally genetically related and thus derived from a common ancestor. We sought to determine the rate of genetic change of H. pylori over 9 years in two asymptomatic adult patients. Arbitrary primed PCR confirmed the relatedness of individual subclones within a patient. Furthermore, sequencing of 10 loci (similar to 6,000 bp) in three subclones per time and patient revealed only two base pair changes among the subclones from patient I. All sequences were identical among the patient II subclones. However, PCR amplification of the highly divergent gene amiA revealed great variation in the size of the gene between the subclones within each patient. Thus, both patients harbored a single strain with clonal variants at both times. We also studied genetic changes in culture- and mouse-passaged strains, and under both conditions no genetic divergence was found. These results suggest that previous estimates of the rate of genetic change in H. pylori within an individual might be overestimates.

  • 123. Mantripragada, K. K.
    et al.
    Tapia-Paez, I.
    Blennow, E.
    Nilsson, Peter
    KTH, Superseded Departments, Biotechnology.
    Wedell, A.
    Dumanski, J. P.
    DNA copy-number analysis of the 22q11 deletion-syndrome region using array-CGH with genomic and PCR-based targets2004In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 13, no 2, p. 273-279Article in journal (Refereed)
    Abstract [en]

    Deletions and duplications of genomic segments commonly cause developmental disorders. The resolution and efficiency in diagnosing such gene-dosage alterations can be drastically increased using microarray-based comparative genomic hybridization (array-CGH). However, array-CGH currently relies on spotting genomic clones as targets, which confers severe limitations to the approach including resolution of analysis and reliable gene-dosage assessment of regions with high content of redundant sequences. To improve the methodology for analysis, we compared the use of genomic clones, repeat-free pools of amplified genomic DNA and cDNAs (single and pooled) as targets on the array. For this purpose, we chose q11.2 locus on chromosome 22 as a testing ground. Microdeletions at 22q11 cause birth defects collectively described as the DiGeorge/velocardiofacial syndrome. The majority of patients present 3 Mb typical deletions. Here, we report the construction of a gene-dosage array, covering 6 Mb of 22q11 and including the typically deleted region. We hybridized DNA from six DiGeorge syndrome patients to the array, and show that as little as 11.5 kb non-redundant, repeat-free PCR-generated sequence can be used for reliable detection of hemizygous deletions. By extrapolation, this would allow analysis of the genome with an average resolution of 25 kb. In the case of cDNAs our results indicate that 3.5 kb sequence is necessary for accurate identification of haploid/diploid dosage alterations. Thus, for regions rich in redundant sequences and repeats, such as 22q11, a specifically tailored array-CGH approach is good for gene copy number profiling.

  • 124. Meneghel, Lauro
    et al.
    Mattsson, Cecilia
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Meisgen, Sabrina
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wahren-Herlenius, Marie
    Identification of cross-reactive targets of anti-Ro52 antibodies in congenital heart block2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 321-321Article in journal (Other academic)
  • 125. Mersmann, Michael
    et al.
    Meier, Doris
    Mersmann, Jana
    Helmsing, Saskia
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Graslund, Susanne
    Colwill, Karen
    Hust, Michael
    Duebel, Stefan
    Towards proteome scale antibody selections using phage display2010In: NEW BIOTECHNOL, ISSN 1871-6784, Vol. 27, no 2, p. 118-128Article in journal (Refereed)
    Abstract [en]

    In vitro antibody generation by panning a large universal gene library with phage display was employed to generate antibodies to more than 60 different antigens. Of particular interest was a comparison of pannings on 20 different SH2 domains provided by the Structural Genomics Consortium (SGC). Streamlined methods for high throughput antibody generation developed within the 'Antibody Factory' of the German National Genome Research Network (NGFN) were demonstrated to minimise effort and provide a reliable and robust source for antibodies. For the SH2 domains, in two successive series of selections, 2668 clones were analysed, resulting in 347 primary hits in ELISA. Half of these hits were further analysed, and more than 90 different scFv antibodies to all antigens were identified. The validation of selected antibodies by cross-reactivity ELISA, western blot and on protein microarrays demonstrated the versatility of the in vitro antibody selection pipeline to generate a renewable resource of highly specific monoclonal binders in proteome scale numbers with substantially reduced effort and time.

  • 126.
    Mikus, Maria
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Drobin, Kimi
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Gry, Marcus
    KTH.
    Bachmann, J.
    Lindberg, J.
    Yimer, G.
    Aklillu, E.
    Makonnen, E.
    Aderaye, G.
    Roach, J.
    Fier, I.
    Kampf, C.
    Göpfert, J.
    Perazzo, H.
    Poynard, T.
    Stephens, C.
    Andrade, R. J.
    Lucena, M. I.
    Arber, N.
    Uhlén, Mattias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Watkins, P. B.
    Schwenk, Jochen M
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Nilsson, P. Anders
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Schuppe-Koistinen, I.
    Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury2016In: Liver international (Print), ISSN 1478-3223, E-ISSN 1478-3231, Vol. 37, no 1, p. 132-140Article in journal (Refereed)
    Abstract [en]

    Background & Aims: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. Methods: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. Results: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. Conclusions: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers. © 2016 John Wiley & Sons A/S.

  • 127.
    Mikus, Maria
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Johansson, C.
    Acevedo, N.
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Scheynius, A.
    The antimicrobial protein S100A12 identified as a potential autoantigen in a subgroup of atopic dermatitis patients2019In: Clinical and Translational Allergy, ISSN 2045-7022, E-ISSN 2045-7022, Vol. 9, no 1, article id 6Article in journal (Refereed)
    Abstract [en]

    Background: Atopic dermatitis (AD) is a complex heterogeneous chronic inflammatory skin disease. Specific IgE antibodies against autoantigens have been observed in a subgroup of AD patients, however, little is known about IgG-auto-reactivity in AD. To investigate the presence of autoreactive IgG antibodies, we performed autoantibody profiling of IgG in patients with AD of different severities and in healthy controls (HC). Methods: First, we performed an untargeted screening in plasma samples from 40 severe AD (sAD) patients and 40 HC towards 1152 protein fragments on planar antigen microarrays. Next, based on the findings and addition of more fragments, a targeted antigen suspension bead array was designed to profile a cohort of 50 sAD patients, 123 patients with moderate AD (mAD), and 84 HC against 148 protein fragments representing 96 unique proteins. Results: Forty-nine percent of the AD patients showed increased IgG-reactivity to any of the four antigens representing keratin associated protein 17-1 (KRTAP17-1), heat shock protein family A (Hsp70) member 4 (HSPA4), S100 calcium binding proteins A12 (S100A12), and Z (S100Z). The reactivity was more frequent in the sAD patients (66%) than in those with mAD (41%), whereas only present in 25% of the HC. IgG-reactivity to S100A12, a protein including an antimicrobial peptide, was only observed in AD patients (13/173). Conclusions: Autoantibody profiling of IgG-reactivity using microarray technology revealed an autoantibody-based subgroup in patients with AD. The four identified autoantigens and especially S100A12 could, if characterized further, increase the understanding of different pathogenic mechanisms behind AD and thereby enable better treatment.

  • 128.
    Mikus, Maria
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Johansson, Catharina
    Acevedo, Nathalie
    Nilsson, Peter
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Scheynius, Annika
    The antimicrobial protein S100A12 identified as a potential autoantigen in a subgroup of atopic dermatitis patientsManuscript (preprint) (Other academic)
  • 129.
    Mikus, Maria
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Kolmert, J.
    Karolinska Inst, Stockholm, Sweden..
    Andersson, L. I.
    Karolinska Inst, Stockholm, Sweden..
    James, A.
    Karolinska Inst, Stockholm, Sweden..
    Gomez, C.
    Karolinska Inst, Stockholm, Sweden..
    Dahlen, B. U.
    Karolinska Inst, Stockholm, Sweden..
    De Meulder, B.
    European Inst Syst Biol & Med, Lyon, France..
    Djukanovic, R.
    Univ Southampton, Southampton, Hants, England..
    Sterk, P. J.
    Amsterdam Med Univ, Amsterdam, Netherlands..
    Adcock, I. M.
    Imperial Coll, London, England..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Dahlen, S. K.
    Karolinska Inst, Stockholm, Sweden..
    Asthma Sub-Phenotyping in Plasma from U-BIOPRED and BIOAIR Using Array-Based Proteomics2019In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 199Article in journal (Other academic)
  • 130.
    Mikus, Maria
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kolmert, Johan
    James, Anna
    Andersson, Lars I
    Gomez, Cristina
    Ericsson, Magnus
    Thörngren, John-Olof
    Dahlén, Barbro
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Dahlén, Sven-Erik
    Identification of proteins associated with asthma severityManuscript (preprint) (Other academic)
  • 131. Mok, Bobo W.
    et al.
    Ribacke, Ulf
    Rasti, Niloofar
    Kironde, Fred
    Chen, Qijun
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Gene Technology.
    Wahlgren, Mats
    Default Pathway of var2csa Switching and Translational Repression in Plasmodium falciparum2008In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 3, no 4, p. e1982-Article in journal (Refereed)
    Abstract [en]

    Antigenic variation is a subtle process of fundamental importance to the survival of a microbial pathogen. In Plasmodium falciparum malaria, PfEMP1 is the major variable antigen and adhesin expressed at the surface of the infected erythrocyte, which is encoded for by members of a family of 60 var-genes. Peri-nuclear repositioning and epigenetic mechanisms control their mono-allelic expression. The switching of PfEMP1 depends in part on variable transition rates and short-lived immune responses to shared minor epitopes. Here we show var-genes to switch to a common gene that is highly transcribed, but sparsely translated into PfEMP1 and not expressed at the erythrocyte surface. Highly clonal and adhesive P. falciparum, which expressed distinct var-genes and the corresponding PfEMP1s at onset, were propagated without enrichment or panning. The parasites successively and spontaneously switched to transcribe a shared var-gene (var2csa) matched by the loss of PfEMP1 surface expression and host cell-binding. The var2csa gene repositioned in the peri-nuclear area upon activation, away from the telomeric clusters and heterochromatin to transcribe spliced, full-length RNA. Despite abundant transcripts, the level of intracellular PfEMP1 was low suggesting post-transcriptional mechanisms to partake in protein expression. In vivo, off-switching and translational repression may constitute one pathway, among others, coordinating PfEMP1 expression.

  • 132. Mok, Bobo W.
    et al.
    Ribacke, Ulf
    Winter, Gerhard
    Yip, Ben H.
    Tan, Cheun-Seng
    Fernandez, Victor
    Chen, Qijun
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics.
    Wahgren, Mats
    Comparative transcriptornal analysis of isogenic Plasmodium falciparum clones of distinct antigenic and adhesive phenotypes2007In: Molecular and biochemical parasitology (Print), ISSN 0166-6851, E-ISSN 1872-9428, Vol. 151, no 2, p. 184-192Article in journal (Refereed)
    Abstract [en]

    Antigenic variation is a survival mechanism developed by the malaria parasite Plasmodium falciparum in order to allow for the establishment of a chronic infection. Here we have studied clonal differences in the transcriptomes of two isogenic P. falciparum clones (3D7S8.4 and 3D7AH1S2) of distinct adhesive and antigenic phenotypes employing a P. falciparum 70-mer oligonucleolide microarray. Fifteen transcripts were highly differentially expressed (greater than a 5-fold change) with five transcripts upregulated in 3D7AH1S2 compared to 3D7S8.4, and ten downregulated. Identified genes encode apical organellar (Gbph2, GBP-related antigen), cell cycle and DNA/RNA processing (SERA-5, RNA-methylase), cell-rescue, defense/virulence (RESA-2, RIFIN, PfEMP1) and hypothetical proteins (PFB0115w, PFI1445w, MAL13P1.121). A number of short and full-length var transcripts were differentially expressed between the clones but one full-length transcript was dominant in both rings and trophozoites (PFD0630c versus PFF0845c). Distinct members of two other variant gene families (phist-a and rif-like), scattered over the subtelomeric areas of the 14 chromosomes, were also found to be clonally and developmentally expressed. Three sibling-clones of 3D7AH1S2 (3D7AH1S1, -S3, -S4) were further studied for the expression of transcripts upregulated in 3D7AH1S2 compared to 3D7S8.4. Individual var and phist-a genes were found expressed in all of the clones while the expression of a rif-like gene and gbph2 varied in-between the clones. The present data provides evidence for complex transcriptional differences between closely related isogenic R falciparum of distinct adhesive and antigenic characteristics.

  • 133. Moreau, C.
    et al.
    Aksenov, N.
    Lorenzo, M. G.
    Segerman, B.
    Funk, C.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics.
    Jansson, S.
    Tuominen, H.
    A genomic approach to investigate developmental cell death in woody tissues of Populus trees2005In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 6, no 4Article in journal (Refereed)
    Abstract [en]

    Background: Poplar ( Populus sp.) has emerged as the main model system for molecular and genetic studies of forest trees. A Populus expressed sequence tag ( EST) database (POPULUSDB) was previously created from 19 cDNA libraries each originating from different Populus tree tissues, and opened to the public in September 2004. We used this dataset for in silico transcript profiling of a particular process in the woody tissues of the Populus stem: the programmed death of xylem fibers. Results: One EST library in POPULUSDB originates from woody tissues of the Populus stem where xylem fibers undergo cell death. Analysis of EST abundances and library distribution within the POPULUSDB revealed a large number of previously uncharacterized transcripts that were unique in this library and possibly related to the death of xylem fibers. The in silico analysis was complemented by a microarray analysis utilizing a novel Populus cDNA array with a unigene set of 25,000 sequences. Conclusions: In silico analysis, combined with the microarray analysis, revealed the usefulness of non-normalized EST libraries in elucidating transcriptional regulation of previously uncharacterized physiological processes. The data suggested the involvement of two novel extracellular serine proteases, nodulin-like proteins and an Arabidopsis thaliana OPEN STOMATA 1 (AtOST1) homolog in signaling fiber-cell death, as well as mechanisms responsible for hormonal control, nutrient remobilization, regulation of vacuolar integrity and autolysis of the dying fibers.

  • 134. Musunuri, Sravani
    et al.
    Khoonsari, Payam Emami
    Mikus, Maria
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wetterhall, Magnus
    Häggmark-Mänberg, Anna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lannfelt, Lars
    Erlandsson, Anna
    Bergquist, Jonas
    Ingelsson, Martin
    Shevchenko, Ganna
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kultima, Kim
    Increased Levels of Extracellular Microvesicle Markers and Decreased Levels of Endocytic/Exocytic Proteins in the Alzheimer's Disease Brain2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 54, no 4, p. 1671-1686Article in journal (Refereed)
    Abstract [en]

    Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-beta and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins. Objective: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology. Methods: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays. Results: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation. Conclusions: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.

  • 135.
    Månberg, Anna
    et al.
    KTH Royal Inst Technol, Dept Prot Sci, SciLifeLab, Affin Prote, Stockholm, Sweden.
    Bradley, Frideborg
    Karolinska Univ Hosp, Ctr Mol Med, Karolinska Inst, Dept Med Solna,Unit Infect Dis, Stockholm, Sweden.
    Qundos, Ulrika
    KTH Royal Inst Technol, Dept Prot Sci, SciLifeLab, Affin Prote, Stockholm, Sweden.
    Guthrie, Brandon L.
    Univ Washington, Dept Global Hlth, Washington, DC USA;Univ Washington, Dept Epidemiol Hlth, Washington, DC USA.
    Birse, Kenzie
    Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada;Publ Hlth Agcy Canada, JC Wilt Infect Dis Ctr, Natl HIV & Retrovirol Labs, Winnipeg, MB, Canada.
    Noel-Romas, Laura
    Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada;Publ Hlth Agcy Canada, JC Wilt Infect Dis Ctr, Natl HIV & Retrovirol Labs, Winnipeg, MB, Canada.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Bosire, Rose
    Kenya Govt Med Res Ctr, Nairobi, Kenya.
    Kiarie, James
    Univ Nairobi, Dept Obstet & Gynecol, Nairobi, Kenya.
    Farquhar, Carey
    Univ Washington, Dept Med Global Hlth & Epidemiol, Seattle, WA 98195 USA.
    Burgener, Adam D.
    Karolinska Univ Hosp, Ctr Mol Med, Karolinska Inst, Dept Med Solna,Unit Infect Dis, Stockholm, Sweden;Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada;Publ Hlth Agcy Canada, JC Wilt Infect Dis Ctr, Natl HIV & Retrovirol Labs, Winnipeg, MB, Canada.
    Nilsson, Peter
    KTH Royal Inst Technol, Dept Prot Sci, SciLifeLab, Affin Prote, Stockholm, Sweden.
    Broliden, Kristina
    Karolinska Univ Hosp, Ctr Mol Med, Karolinska Inst, Dept Med Solna,Unit Infect Dis, Stockholm, Sweden.
    A High-throughput Bead-based Affinity Assay Enables Analysis of Genital Protein Signatures in Women At Risk of HIV Infection2019In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 3, p. 461-476Article in journal (Refereed)
    Abstract [en]

    Women at high risk of HIV infection, including sex workers and those with active genital inflammation, have molecular signatures of immune activation and epithelial barrier remodeling in samples of their genital mucosa. These alterations in the local immunological milieu are likely to impact HIV susceptibility. We here analyze host genital protein signatures in HIV uninfected women, with high frequency of condom use, living in HIV-serodiscordant relationships. Cervicovaginal secretions from women living in HIV-serodiscordant relationships (n = 62) were collected at three time points over 12 months. Women living in HIV-negative seroconcordant relationships (controls, n = 25) were sampled at one time point. All study subjects were examined for demographic parameters associated with susceptibility to HIV infection. The cervicovaginal samples were analyzed using a high-throughput bead-based affinity assay. Proteins involved in epithelial barrier function and inflammation were increased in HIV-serodiscordant women. By combining several methods of analysis, a total of five proteins (CAPG, KLK10, SPRR3, elafin/PI3, CSTB) were consistently associated with this study group. Proteins analyzed using the affinity set-up were further validated by label-free tandem mass spectrometry in a partially overlapping cohort with concordant results. Women living in HIV-serodiscordant relationships thus had elevated levels of proteins involved in epithelial barrier function and inflammation despite low prevalence of sexually transmitted infections and a high frequency of safe sex practices. The identified proteins are important markers to follow during assessment of mucosal HIV susceptibility factors and a high-throughput bead-based affinity set-up could be a suitable method for such evaluation.

  • 136.
    Neiman, Maja
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fredolini, Claudia
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Johansson, H.
    Lehtiö, Janne
    Karolinska Institutet, Solna, Sweden .
    Nygren, Per-Åke
    KTH, School of Biotechnology (BIO), Protein Technology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Selectivity analysis of single binder assays used in plasma protein profiling2013In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 13, no 23-24, p. 3406-3410Article in journal (Refereed)
    Abstract [en]

    The increasing availability of antibodies toward human proteins enables broad explorations of the proteomic landscape in cells, tissues, and body fluids. This includes assays with antibody suspension bead arrays that generate protein profiles of plasma samples by flow cytometer analysis. However, antibody selectivity is context dependent so it is necessary to corroborate on-target detection over off-target binding. To address this, we describe a concept to directly verify interactions from antibody-coupled beads by analysis of their eluates by Western blots and MS. We demonstrate selective antibody binding in complex samples with antibodies toward a set of chosen proteins with different abundance in plasma and serum, and illustrate the need to adjust sample and bead concentrations accordingly. The presented approach will serve as an important tool for resolving differential protein profiles from antibody arrays within plasma biomarker discoveries.

  • 137.
    Neiman, Maja
    et al.
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hedberg, Jesper J.
    Dönnes, Pierre R.
    Schuppe-Koistinen, Ina
    Hanschke, Stephan
    Schindler, Ralf
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Plasma Profiling Reveals Human Fibulin-1 as Candidate Marker for Renal Impairment2011In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 10, no 11, p. 4925-4934Article in journal (Refereed)
    Abstract [en]

    There is a need for reliable and sensitive biomarkers for renal impairments to detect early signs of kidney toxicity and to monitor progression of disease. Here, antibody suspension bead arrays were applied to profile plasma samples from patients with four types of kidney disorders: glomerulonephritis, diabetic nephropathy, obstructive uropathy, and analgesic abuse. In total, 200 clinical renal-associated cases and control plasma samples from different cohorts were profiled. Parallel plasma protein profiles were obtained using biotinylated and nonfractionated samples and a selected set of 94 proteins targeted by 129 antigen-purified polyclonal antibodies. Out of the analyzed target proteins, human fibulin-1 was detected at significantly higher levels in the glomerulonephritis patient group compared to the controls and with elevated levels in patient samples for all other renal disorders investigated. Two polyclonal antibodies and one monoclonal antibody directed toward separate, nonoverlapping epitopes showed the same trend in the discovery cohorts. A technical verification using Western blot analysis of selected patient plasma confirmed the trends toward higher abundance of the target protein in disease samples. Furthermore, a verification study was carried out in the context of glomerulonephritis using an independent case and control cohort, and this confirmed the results from the discovery cohort, suggesting that plasma levels of fibulin-1 could serve as a potential indicator to monitor kidney malfunction or kidney damage.

  • 138.
    Neiman, Maja
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Hellström, Cecilia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Just, David
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Mattsson, Cecilia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fagerberg, Linn
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Schuppe-Koistinen, Ina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gummesson, Anders
    Sahlgrens Univ Hosp, Dept Clin Pathol & Genet, Gothenburg, Sweden..
    Bergstrom, Goran
    Sahlgrens Univ Hosp, Dept Clin Physiol, Gothenburg, Sweden..
    Kallioniemi, Olli
    Univ Helsinki, Inst Mol Med Finland, FIMM, Helsinki, Finland.;Karolinska Inst, Dept Pathol & Oncol, SciLifeLab, Stockholm, Sweden..
    Achour, Adnane
    Karolinska Inst, SciLifeLab, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Div Infect Dis, Stockholm, Sweden..
    Sallinen, Riitta
    Univ Helsinki, Inst Mol Med Finland, FIMM, Helsinki, Finland.;Karolinska Inst, Dept Pathol & Oncol, SciLifeLab, Stockholm, Sweden..
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Individual and stable autoantibody repertoires in healthy individuals2019In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 52, no 1, p. 1-11Article in journal (Refereed)
    Abstract [en]

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

  • 139.
    Neiman, Maja
    et al.
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nygren, Per-Åke
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics (closed 20130101).
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Validating the selectivity of antibodies used in multiplexed serum profiling via parallel immunocapture analysisManuscript (preprint) (Other academic)
    Abstract [en]

    The increasing availability of antibodies towards human proteins drives the generation of new and exploratory data, which can be generated by profiling e.g. plasma samples using multiplexed arrays. However, antibody assays can lead to erroneous results due to cross-­‐reactivity to off-­‐targets. Here, we describe an approach in which an antibody-­‐based suspension bead array is combined with subsequent validation of on-­‐ target binding using a coupled affinity purification assay. Based on differential heat treatment of samples, antibody performance was investigated and the results for antibodies directed towards several complement factors provide insights on the detection of proteins in sera from patients with complement deficiency. In conclusion, the combined parallel flow and blot based immunocapture analysis serves an important, first line tool for resolving differently detected serum or plasma protein profiles proposed by antibody arrays. 

  • 140.
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Affinity proteomics for array based profiling of autoantibody repertoires.2018In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, p. 69-70Article in journal (Other academic)
  • 141.
    Nilsson, Peter
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Jonsson, L. T. I.
    Ersson, Mikael
    KTH, School of Industrial Engineering and Management (ITM), Materials Science and Engineering.
    Jönsson, Pär Göran
    KTH, School of Industrial Engineering and Management (ITM), Materials Science and Engineering.
    A New Tundish Design to Produce a Swirling Flow in the SEN During Continuous Casting of Steel2016In: Steel Research International, ISSN 1611-3683, E-ISSN 1869-344XArticle in journal (Refereed)
    Abstract [en]

    A new tundish is designed with the aim to produce a swirling flow in a tundish SEN by an economical way of using the steel flow potential as the required power. This design is easily obtained by adding a cylindrical part of the tundish onto a traditional tundish. The results show that a swirling flow in the SEN of the new tundish is successfully obtained, also, that the tangential velocity in the SEN can reach around 1.6ms-1. The installation of weirs in the cylindrical tundish can contribute to stabilize the steel flow at the top of the tundish. However, this reduces the swirling flow intensity in the SEN around 30%. In addition, the possibility of slag entrainment at the top of the tundish is analyzed. The calculated Weber Number is around 5.0 for no weir case and 2.8 for the weir case, which means that the risk of slag entrainment is small. A high value of shear stress is found on the SEN wall due to the swirling flow in SEN. A further investigation shows that a smooth transition of SEN inlet can reduce the maximum shear stress level in the SEN, without decreasing the swirling flow intensity.

  • 142.
    Nilsson, Peter
    et al.
    KTH, Superseded Departments, Biotechnology.
    Larsson, A
    Lundeberg, Joakim
    KTH, Superseded Departments, Biotechnology.
    Uhlen, Mathias
    KTH, Superseded Departments, Biotechnology.
    Nygren, Per-Åke
    KTH, Superseded Departments, Biotechnology.
    Mutational scanning of PCR products by subtractive oligonucleotide hybridization analysis1999In: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 26, no 2, p. 308-+Article in journal (Refereed)
    Abstract [en]

    Here, we describe a new approach for mutational scanning of PCR products through hybridization analysis between complementary oligonucleotides. Sets of overlapping probe oligonucleotides complementary to wild-type (WT) sequence are hybridized to microbead-immobilized PCR products under solution-like conditions. Mismatch-hybridization situations between a mutant sample and probe oligonucleotides result in higher remaining concentrations in solution of involved probe oligonucleotides. Post-hybridization supernatants are subsequently analyzed for their probe oligonucleotide compositions using surface plasmon resonance-based biosensor technology Relative remaining probe oligonucleotide concentrations are monitored in real-time through hybridization analysis between probe oligonucleotides and their corresponding sensor-chip immobilized complementary counterparts. This allows for the construction of composition diagrams revealing the existence and approximate location of a mutation within an investigated sample DNA sequence. Applied on PCR products derived from clinical samples of microdissected tumor biopsies, single mutations in exons 6 and 7 of the human p53 tumor-suppressor gene were successfully detected and approximately localized.

  • 143.
    Nilsson, Peter
    et al.
    KTH, School of Biotechnology (BIO), Proteomics.
    Larsson, Karin
    KTH, School of Biotechnology (BIO).
    Persson, Anja
    KTH, School of Biotechnology (BIO), Proteomics.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics.
    Wernérus, Henrik
    KTH, School of Biotechnology (BIO).
    Hober, Sophia
    KTH, School of Biotechnology (BIO), Proteomics.
    Björling, Erik
    KTH, School of Biotechnology (BIO).
    Ottoson, Jenny
    KTH, School of Biotechnology (BIO), Proteomics.
    Ödling, Jenny
    KTH, School of Biotechnology (BIO).
    Sundberg, Mårten
    KTH, School of Biotechnology (BIO), Proteomics.
    Al-Khalili Szigyarto, Cristina
    KTH, School of Biotechnology (BIO), Proteomics.
    Paavilainen, Linda
    Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Andersson, Ann-Catrin
    Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Kampf, Caroline
    Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Wester, Kenneth
    Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Towards a human proteome atlas: High-throughput generation of mono-specific antibodies for tissue profiling2005In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 5, p. 4327-4337Article in journal (Refereed)
    Abstract [en]

    A great need exists for the systematic generation of specific antibodies to explore the human proteome. Here, we show that antibodies specific to human proteins can be generated in a high-throughput manner involving stringent affinity purification using recombinant protein epitope signature tags (PrESTs) as immunogens and affinity-ligands. The specificity of the generated affinity reagents, here called mono-specific antibodies (msAb), were validated with a novel protein microarray assay. The success rate for 464 antibodies generated towards human proteins was more than 90% as judged by the protein array assay. The antibodies were used for parallel profiling of patient biopsies using tissue microarrays generated from 48 human tissues. Comparative analysis with well-characterized monoclonal antibodies showed identical or similar specificity and expression patterns. The results suggest that a comprehensive atlas containing extensive protein expression and subcellular localization data of the human proteome can be generated in an efficient manner with mono-specific antibodies.

  • 144.
    Nilsson, Peter
    et al.
    KTH, Superseded Departments, Biotechnology.
    O'Meara, Deirdre
    KTH, Superseded Departments, Biotechnology.
    Edebratt, Fredrik
    KTH, Superseded Departments, Biotechnology.
    Persson, Björn
    Uhlén, Mattias
    KTH, Superseded Departments, Biotechnology.
    Lundeberg, Joakim
    KTH, Superseded Departments, Biotechnology.
    Nygren, Per-Åke
    KTH, Superseded Departments, Biotechnology.
    Quantitative Investigation of the Modular Primer Effect for DNA and Peptide Nucleic Acid Hexamers1999In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 269, no 1, p. 155-161Article in journal (Refereed)
    Abstract [en]

    The effect on oligonucleotide–template duplex stability upon cohybridization of adjacently annealing oligonucleotides, the modular primer effect, was studied with biosensor technology. DNA and peptide nucleic acid (PNA) hexamer modules and sensor chip-immobilized template DNA strands were designed for analysis of nick, overlap, and gap modular hybridization situations. The fast hybridization kinetics for such hexamer modules allowed for the determination of apparent duplex affinities from equilibrium responses. The results showed that the hybridizational stability of modular hexamer pairs is strongly dependent on the positioning, concentration, and inherent affinity of the adjacently annealing hexamer module. Up to 80-fold increases in apparent affinities could be observed for adjacent modular oligonucleotide pairs compared to affinities determined for single hexamer oligonucleotide hybridizations. Interestingly, also for coinjections of different module combinations where DNA hexamer modules were replaced by their PNA counterparts, a modular primer effect was observed. The introduction of a single base gap between two hexamer modules significantly reduced the stabilization effect, whereas a gap of two bases resulted in a complete loss of the effect. The results suggest that the described biosensor-based methodology should be useful for the selection of appropriate modules and working concentrations for use in different modular hybridization applications.

  • 145.
    Nilsson, Peter
    et al.
    KTH, Superseded Departments, Biotechnology.
    Persson, B
    Larsson, A
    Uhlen, Mathias
    KTH, Superseded Departments, Biotechnology.
    Nygren, Per-Åke
    KTH, Superseded Departments, Biotechnology.
    Detection of mutations in PCR products from clinical samples by surface plasmon resonance1997In: Journal of Molecular Recognition, ISSN 0952-3499, E-ISSN 1099-1352, Vol. 10, no 1, p. 7-17Article in journal (Refereed)
    Abstract [en]

    Two different strategies for scanning and screening of mutations in polymerase chain reaction (PCR) products by hybridization analysis are described, employing real-time biospecific interaction analysis (BIA) for detection, Real-time BIA was used to detect differences in hybridization responses between PCR products and different 17-mer oligonucleotide probes, For the analysis using a biosensor instrument, two different experimental formats were investigated based on immobilization of either biotinylated PCR products or oligonucleotide probes onto a sensor chip, Applied on the human tumour suppressor p53 gene, differences in hybridization levels for full-match and mismatch situations employing both formals allowed the detection of point mutations in exon 6 PCR products, derived from a breast tumour biopsy sample, In addition, a mutant sample sequence could be detected in a 50/50 background of wild type exon 6 sequence, The suitability of the different formats for obtaining a regenerable system and a high throughput of samples is discussed.

  • 146.
    NILSSON, PETER
    et al.
    KTH, Superseded Departments, Biotechnology.
    PERSSON, BJÖRN
    UHLEN, MATHIAS
    KTH, Superseded Departments, Biotechnology.
    NYGREN, PER-ÅKE
    KTH, Superseded Departments, Biotechnology.
    REAL-TIME MONITORING OF DNA MANIPULATIONS USING BIOSENSOR TECHNOLOGY1995In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 224, no 1, p. 400-408Article in journal (Refereed)
    Abstract [en]

    The potential of real-time biospecific interaction analysis technology for applications in molecular biology is described. DNA fragments are immobilized onto a biosensor surface using the high-affinity streptavidin-biotin system and subsequently used to monitor different unit operations in molecular biology, e.g., DNA strand separation, DNA hybridization kinetics, and enzymatic modifications. A model system comprising six oligonucleotides was used, which can be assembled into a 69-bp double-stranded DNA fragment. Using this system, the biosensor approach was employed to analyze multistep solid-phase gene assembly and the performance of different enzymes routinely used for the synthesis and manipulation of DNA. In addition, a concept for the determination of single-point mutations in DNA samples is described.

  • 147.
    Nilsson, Peter
    et al.
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Biomarker of renal impairment2011Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    There is provided a method of determining whether a subject belongs to a first or a second group of subjects, wherein the risk of having or developing of a renal impairment is higher in the first group than in the second group, comprising the steps of: a) measuring an amount of fibulin 1 in a sample from the subject to obtain a sample value; b) comparing the sample value to a reference value; and if the sample value is higher than the reference value, c1) concluding that the subject belongs to the first group; and if the sample value is lower than the previous sample value, c2) concluding that the subject belongs to the second group. Associated means are also provided.

  • 148.
    Nilsson, Peter
    et al.
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Prostate cancer biomarkers2010Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    The present disclosure relates to a method of determining whether a mammalian subject belongs to a first or a second group of subjects, wherein the risk of having a prostate cancer, such as an aggressive prostate cancer, is higher in the first group than in the second group. The method comprises the steps of: a) evaluating an amount of unglycosylated CNDP1 protein in a sample derived from blood, semen or urine from the subject and determining a sample value corresponding to the evaluated amount; b) comparing the sample value with a predetermined reference value; and if the sample value is lower than or equal to the reference value, c1) concluding that the subject belongs to the first group; and if the sample value is higher than the reference value, c2) concluding that the subject belongs to the second group. Further, the present disclosure relates to a similar method based on the protein HCRTR1 as well as corresponding uses and means useful when carrying out the methods.

  • 149. Nordstrom, H.
    et al.
    Falk, K. I.
    Lindegren, G.
    Mouzavi-Jazi, M.
    Walden, A.
    Elgh, F.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics.
    Lundkvist, A.
    DNA microarray technique for detection and identification of seven Flaviviruses pathogenic for man2005In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 77, no 4, p. 528-540Article in journal (Refereed)
    Abstract [en]

    A flavivirus microarray was developed for detection and identification of yellow fever (YF), West Nile, Japanese encephalitis (JE), and the dengue 1-4 viruses, which are causing severe human disease all over the world. The microarray was based on 500-nucleotide probe fragments from five different parts of the seven viral genomes. A low-stringent amplification method targeting the corresponding regions of the viral genomic RNA was developed and combined with hybridization to the microarray for detection and identification. For distinction of the generated virus-specific fluorescence-patterns a fitting analysis procedure was adapted. The method was verified as functional for all seven flaviviruses and the strategy for the amplification, combined with the long probes, provided a high tolerance for smaller genetic variability, most suitable for these rapidly changing RNA viruses. A potentially high detection and identification capacity was proven on diverged strains of West Nile and dengue viruses. The lower limit for detection was equivalent, or better, when compared to routinely used RT-PCR methods. The performance of the method was verified on human patient samples containing dengue viruses, or normal human serum spiked with YF or JE viruses. The results demonstrated the ability of the flavivirus microarray to screen simultaneously a sample for several viruses in parallel, in combination with a good lower limit of detection.

  • 150. Nordstrom, H.
    et al.
    Johansson, P.
    Li, Q. G.
    Lundkvist, A.
    Nilsson, Peter
    KTH, Superseded Departments, Biotechnology.
    Elgh, F.
    Microarray technology for identification and distinction of hantaviruses2004In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 72, no 4, p. 646-655Article in journal (Refereed)
    Abstract [en]

    DNA microarrays combine high-precision technology with advanced molecular biology to achieve high-throughput screening of DNA fragments. In this study, we investigated the potential of the cDNA microarray technique to identify and discriminate PCR derived amplicons from genetically highly similar viruses. The wide range of sequence variation among hantaviruses makes them suitable as a model for this purpose. The hantaviruses, carried by rodents, cause several hundred thousand cases of severe human disease every year in many parts of the world. A hantavirus-specific microarray, including DNA fragments from 12 viral isolates of six different hantaviruses, was designed. The S and M genome segments were represented by 500-nucleotide overlapping and 250-nucleotide non-overlapping fragments. A considerable ability to distinguish between different hantaviruses was demonstrated using a novel analysis method. Even different isolates of a single virus, were identified correctly despite 90% sequence similarity. The distinction ability was accompanied by a tolerance for smaller sequence differences, which makes the microarray suitable for testing samples containing unknown viruses. Viral genetic material found in samples from the lungs of bank voles caught in the wild was identified precisely, which demonstrated further the potential for this technology.

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