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Häggmark, A., Bradley, F., Qundos, U., Guthrie, B. L., Birse, K., Noel-Romas, L., . . . Broliden, K. (2019). A High-throughput Bead-based Affinity Assay Enables Analysis of Genital Protein Signatures in Women At Risk of HIV Infection. Molecular & Cellular Proteomics, 18(3), 461-476
Open this publication in new window or tab >>A High-throughput Bead-based Affinity Assay Enables Analysis of Genital Protein Signatures in Women At Risk of HIV Infection
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2019 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 3, p. 461-476Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2019
National Category
Basic Medicine
Identifiers
urn:nbn:se:kth:diva-252660 (URN)10.1074/mcp.RA118.000757 (DOI)000467885100006 ()30504243 (PubMedID)2-s2.0-85062943299 (Scopus ID)
Note

QC 20190610

Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Mikus, M., Kolmert, J., Andersson, L. I., James, A., Gomez, C., Dahlen, B. U., . . . Dahlen, S. K. (2019). Asthma Sub-Phenotyping in Plasma from U-BIOPRED and BIOAIR Using Array-Based Proteomics. Paper presented at International Conference of the American-Thoracic-Society, MAY 17-22, 2019, Dallas, TX. American Journal of Respiratory and Critical Care Medicine, 199
Open this publication in new window or tab >>Asthma Sub-Phenotyping in Plasma from U-BIOPRED and BIOAIR Using Array-Based Proteomics
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2019 (English)In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 199Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
AMER THORACIC SOC, 2019
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-252416 (URN)000466776705218 ()
Conference
International Conference of the American-Thoracic-Society, MAY 17-22, 2019, Dallas, TX
Note

QC 20190716

Available from: 2019-07-16 Created: 2019-07-16 Last updated: 2019-07-16Bibliographically approved
Idborg, H., Zandian, A., Ossipova, E., Wigren, E., Preger, C., Mobarrez, F., . . . Jakobsson, P.-J. (2019). Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients. Frontiers in Immunology, 10, Article ID 1029.
Open this publication in new window or tab >>Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1029Article in journal (Refereed) Published
Abstract [en]

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann-Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (p(adjusted) = 3 x 10(-9), 3 x 10(-6), and 5 x 10(-6) respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
Interferon regulating factor 5 (IRF5), antibody suspension bead arrays, subgroups, biomarker discovery, plasma proteomics, unsupervised clustering, hierarchical clustering, SLE - Systemic Lupus Erythematous, LONG ER, 1988, BIOMETRICS, V44, P837
National Category
Basic Medicine
Identifiers
urn:nbn:se:kth:diva-252598 (URN)10.3389/fimmu.2019.01029 (DOI)000468162000001 ()
Note

QC 20190610

Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Andersson, A., Remnestål, J., Nellgård, B., Vunk, H., Kotol, D., Edfors, F., . . . Fredolini, C. (2019). Development of parallel reaction monitoring assays for cerebrospinal fluid proteins associated with Alzheimer's disease. Clinica Chimica Acta, 494, 79-93
Open this publication in new window or tab >>Development of parallel reaction monitoring assays for cerebrospinal fluid proteins associated with Alzheimer's disease
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2019 (English)In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 494, p. 79-93Article in journal (Refereed) Published
Abstract [en]

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

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

QC 20190715

Available from: 2019-07-15 Created: 2019-07-15 Last updated: 2019-07-15Bibliographically approved
Papiol, S., Just, D., Kannaiyan, N., Anderson-Schmidt, H., Budde, M., Gade, K., . . . Schulze, T. (2019). HIGH-THROUGHPUT ANTIBODY-BASED PROFILING OF SERUM IN SCHIZOPHRENIA AND BIPOLAR DISORDER PATIENTS: AN INTEGRATIVE GENOMICS-PROTEOMICS PILOT STUDY. Paper presented at 25th World Congress of Psychiatric Genetics (WCPG), OCT 13-17, 2017, Orlando, FL. European Neuropsychopharmacology, 29, S993-S994
Open this publication in new window or tab >>HIGH-THROUGHPUT ANTIBODY-BASED PROFILING OF SERUM IN SCHIZOPHRENIA AND BIPOLAR DISORDER PATIENTS: AN INTEGRATIVE GENOMICS-PROTEOMICS PILOT STUDY
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2019 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, p. S993-S994Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-249901 (URN)10.1016/j.euroneuro.2017.08.378 (DOI)000462156400507 ()
Conference
25th World Congress of Psychiatric Genetics (WCPG), OCT 13-17, 2017, Orlando, FL
Note

QC 20190503

Available from: 2019-05-03 Created: 2019-05-03 Last updated: 2019-06-11Bibliographically approved
Khoonsari, P. E., Shevchenko, G., Herman, S., Remnestål, J., Giedraitis, V., Brundin, R., . . . Kultima, K. (2019). Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers. Journal of Alzheimer's Disease, 67(2), 639-651
Open this publication in new window or tab >>Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, no 2, p. 639-651Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Alzheimer's disease, cerebrospinal fluid, ELISA, mass spectrometry, mild cognitive impairment, proteomics
National Category
Neurology
Identifiers
urn:nbn:se:kth:diva-244560 (URN)10.3233/JAD-180855 (DOI)000457779300016 ()30614806 (PubMedID)2-s2.0-85060607932 (Scopus ID)
Note

QC 20190312

Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-12Bibliographically approved
Neiman, M., Hellström, C., Just, D., Mattsson, C., Fagerberg, L., Schuppe-Koistinen, I., . . . Nilsson, P. (2019). Individual and stable autoantibody repertoires in healthy individuals. Autoimmunity, 52(1), 1-11
Open this publication in new window or tab >>Individual and stable autoantibody repertoires in healthy individuals
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2019 (English)In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 52, no 1, p. 1-11Article in journal (Refereed) Published
Abstract [en]

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

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

QC 20190423

Available from: 2019-04-23 Created: 2019-04-23 Last updated: 2019-06-11Bibliographically approved
Lourido, L., Ruiz-Romero, C., Camacho, M., Rego-Perez, I., Oreiro, N., Fernandez-Lopez, C., . . . Blanco, F. (2019). 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). Paper presented at OARSI World Congress on Osteoarthritis - Promoting Clinical and Basic Research in Osteoarthritis, MAY 02-05, 2019, Toronto, Canada. Osteoarthritis and Cartilage, 27, S69-S70
Open this publication in new window or tab >>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)
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2019 (English)In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 27, p. S69-S70Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:kth:diva-251717 (URN)10.1016/j.joca.2019.02.098 (DOI)000466779300093 ()
Conference
OARSI World Congress on Osteoarthritis - Promoting Clinical and Basic Research in Osteoarthritis, MAY 02-05, 2019, Toronto, Canada
Note

QC 20190521

Available from: 2019-05-21 Created: 2019-05-21 Last updated: 2019-05-29Bibliographically approved
Bedri, S. K., Nilsson, O. B., Fink, K., Månberg, A., Hamsten, C., Ayoglu, B., . . . Glaser, A. (2019). Plasma protein profiling reveals candidate biomarkers for multiple sclerosis treatment. PLoS ONE, 14(5), Article ID e0217208.
Open this publication in new window or tab >>Plasma protein profiling reveals candidate biomarkers for multiple sclerosis treatment
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0217208Article in journal (Refereed) Published
Abstract [en]

Multiple sclerosis (MS) treatment options have improved significantly over the past decades, but the consequences of MS can still be devastating and the needs for monitoring treatment surveillance are considerable. In the current study we used affinity proteomics technology to identify potential biomarkers which could ultimately be used to as facilitate treatment decisions. We profiled the intra-individual changes in the levels of 59 target proteins using an antibody suspension bead array in serial plasma samples from 44 MS patients during treatment with natalizumab followed by fingolimod. Nine proteins showed decreasing plasma levels during natalizumab treatment, with PEBP1 and RTN3 displaying the most significant changes. Protein levels remained stable during fingolimod treatment for both proteins. The decreasing PEBP1 levels during natalizumab treatment could be validated using ELISA and replicated in an independent cohort. These results support the use of this technology as a high throughput method of identifying potentially useful biomarkers of MS treatment.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2019
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:kth:diva-254015 (URN)10.1371/journal.pone.0217208 (DOI)000469323000044 ()31141529 (PubMedID)2-s2.0-85066453037 (Scopus ID)
Note

QC 20190814

Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-08-14Bibliographically approved
Edfors, F., Forsström, B., Vunk, H., Kotol, D., Fredolini, C., Maddalo, G., . . . Uhlén, M. (2019). Screening a Resource of Recombinant Protein Fragments for Targeted Proteomics. Journal of Proteome Research, 18(7), 2706-2718
Open this publication in new window or tab >>Screening a Resource of Recombinant Protein Fragments for Targeted Proteomics
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2019 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 18, no 7, p. 2706-2718Article in journal (Refereed) Published
Abstract [en]

The availability of proteomics resources hosting protein and peptide standards, as well as the data describing their analytical performances, will continue to enhance our current capabilities to develop targeted proteomics methods for quantitative biology. This study describes the analysis of a resource of 26,840 individually purified recombinant protein fragments corresponding to more than 16,000 human protein-coding genes. The resource was screened to identify proteotypic peptides suitable for targeted proteomics efforts, and we report LC-MS/MS assay coordinates for more than 25,000 proteotypic peptides, corresponding to more than 10,000 unique proteins. Additionally, peptide formation and digestion kinetics were, for a subset of the standards, monitored using a time-course protocol involving parallel digestion of isotope-labeled recombinant protein standards and endogenous human plasma proteins. We show that the strategy by adding isotope-labeled recombinant proteins before trypsin digestion enables short digestion protocols (<= 60 min) with robust quantitative precision. In a proof-of-concept study, we quantified 23 proteins in human plasma using assay parameters defined in our study and used the standards to describe distinct clusters of individuals linked to different levels of LPA, APOE, SERPINAS, and TFRC. In summary, we describe the use and utility of a resource of recombinant proteins to identify proteotypic peptides useful for targeted proteomics assay development.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
Keywords
targeted proteomics, stable isotope standards, mass spectrometry, protein quantification, recombinant proteins, protein fragment, trypsin digestion, spectral library, assay generation, peptide formation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-255390 (URN)10.1021/acs.jproteome.8b00924 (DOI)000474795500003 ()31094526 (PubMedID)2-s2.0-85067403932 (Scopus ID)
Note

QC 20190730

Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2019-07-30Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-4657-8532

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