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Shen, Q., Polom, K., Williams, C., de Oliveira, F. M., Guergova-Kuras, M., Lisacek, F., . . . Kamali-Moghaddam, M. (2019). A targeted proteomics approach reveals a serum protein signature as diagnostic biomarker for resectable gastric cancer. EBioMedicine, 44, 322-333
Open this publication in new window or tab >>A targeted proteomics approach reveals a serum protein signature as diagnostic biomarker for resectable gastric cancer
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 44, p. 322-333Article in journal (Refereed) Published
Abstract [en]

Background: Gastric cancer (GC) is the third leading cause of cancer death. Early detection is a key factor to reduce its mortality. Methods: We retrospectively collected pre- and postoperative serum samples as well as tumour tissues and adjacent normal tissues from 100 GC patients. Serum samples from non-cancerous patients were served as controls (n = 50). A high-throughput protein detection technology, multiplex proximity extension assays (PEA), was applied to measure levels of over 300 proteins. Alteration of each protein was analysed by univariate analysis. Elastic-net logistic regression was performed to select serum proteins into the diagnostic model. Findings: We identified 19 serum proteins (CEACAM5, CA9, MSLN, CCL20, SCF, TGF-alpha, MMP-1, MMP-10, IGF-1, CDCPI, PPIA, DDAH-1, HMOX-1, FLI1, IL-7, ZBTB-17, APBB1IP, KAZALD-1, and ADAMTS-15) that together distinguish GC cases from controls with a diagnostic sensitivity of 93%, specificity of 100%, and area under receiver operating characteristic curve (AUC) of 0.99 (95% CI: 0.98-1). Moreover, the 19-serum protein signature pro-vided an increased diagnostic capacity in patients at TNMI-II stage (sensitivity 89%, specificity 100%, AUC 0.99) and in patients with high miaosatellite instability (MSI) (91%. 98%, and 0.99) compared to individual proteins. These promising results will inspire a large-scale independent cohort study to be pursued for validating the proposed protein signature. Interpretation: Based on targeted proteomics and elastic-net logistic regression, we identified a 19-serum protein signature which could contribute to clinical GC diagnosis, especially for patients at early stage and those with high MSI. (C) 2019 The Authors. Published by Elsevier B.V.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Gastric cancer, Diagnosis, Biomarker, PEA, Proteomics
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-390592 (URN)10.1016/j.ebiom.2019.05.044 (DOI)000472768900038 ()31151932 (PubMedID)
Funder
EU, Horizon 2020, 316929
Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-13Bibliographically approved
Bhandage, A. K., Cunningham, J. L., Jin, Z., Shen, Q., Bongiovanni, S., Korol, S., . . . Birnir, B. (2019). Depression, GABA, and Age Correlate with Plasma Levels of Inflammatory Markers. International Journal of Molecular Sciences, 20(24), Article ID 6172.
Open this publication in new window or tab >>Depression, GABA, and Age Correlate with Plasma Levels of Inflammatory Markers
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2019 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, no 24, article id 6172Article in journal (Refereed) Published
Abstract [en]

Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined whether levels of immunological protein markers changed with depression, age, or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). An analysis of plasma samples from patients with a major depressive episode and control blood donors (CBD) revealed the expression of 67 inflammatory markers. Thirteen of these markers displayed augmented levels in patients compared to CBD. Twenty-one markers correlated with the age of the patients, whereas 10 markers correlated with the age of CBD. Interestingly, CST5 and CDCP1 showed the strongest correlation with age in the patients and CBD, respectively. IL-18 was the only marker that correlated with the MADRS-S scores of the patients. Neuronal growth factors (NGFs) were significantly enhanced in plasma from the patients, as was the average plasma GABA concentration. GABA modulated the release of seven cytokines in anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs) from the patients. The study reveals significant changes in the plasma composition of small molecules during depression and identifies potential peripheral biomarkers of the disease.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
GABAA receptor, inflammation, mental health
National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-401785 (URN)10.3390/ijms20246172 (DOI)000506840100066 ()31817800 (PubMedID)
Funder
Swedish Research CouncilSwedish Society of Medicine
Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-03-05Bibliographically approved
Dyhrfort, P., Shen, Q., Clausen, F., Eriksson, M., Enblad, P., Kamali-Moghaddam, M., . . . Hillered, L. (2019). Monitoring of Protein Biomarkers of Inflammation in Human Traumatic Brain Injury Using Microdialysis and Proximity Extension Assay Technology in Neurointensive Care. Journal of Neurotrauma, 36(20), 2872-2885
Open this publication in new window or tab >>Monitoring of Protein Biomarkers of Inflammation in Human Traumatic Brain Injury Using Microdialysis and Proximity Extension Assay Technology in Neurointensive Care
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2019 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 36, no 20, p. 2872-2885Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) is followed by secondary injury mechanisms strongly involving neuroinflammation. To monitor the complex inflammatory cascade in human TBI, we used cerebral microdialysis (MD) and multiplex proximity extension assay (PEA) technology and simultaneously measured levels of 92 protein biomarkers of inflammation in MD samples every three hours for five days in 10 patients with severe TBI under neurointensive care. One mu L MD samples were incubated with paired oligonucleotide-conjugated antibodies binding to each protein, allowing quantification by real-time quantitative polymerase chain reaction. Sixty-nine proteins were suitable for statistical analysis. We found five different patterns with either early (<48 h; e.g., CCL20, IL6, LIF, CCL3), mid (48-96 h; e.g., CCL19, CXCL5, CXCL10, MMP1), late (>96 h; e.g., CD40, MCP2, MCP3), biphasic peaks (e.g., CXCL1, CXCL5, IL8) or stable (e.g., CCL4, DNER, VEGFA)/low trends. High protein levels were observed for e.g., CXCL1, CXCL10, MCP1, MCP2, IL8, while e.g., CCL28 and MCP4 were detected at low levels. Several proteins (CCL8, -19, -20, -23, CXCL1, -5, -6, -9, -11, CST5, DNER, Flt3L, and SIRT2) have not been studied previously in human TBI. Cross-correlation analysis revealed that LIF and CXCL5 may play a central role in the inflammatory cascade. This study provides a unique data set with individual temporal trends for potential inflammatory biomarkers in patients with TBI. We conclude that the combination of MD and PEA is a powerful tool to map the complex inflammatory cascade in the injured human brain. The technique offers new possibilities of protein profiling of complex secondary injury pathways.

Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2019
Keywords
biomarkers, inflammation, microdialysis, molecular tools, neurointensive care, proteomics, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-396069 (URN)10.1089/neu.2018.6320 (DOI)000472621900001 ()31017044 (PubMedID)
Funder
Swedish Research CouncilVinnova
Available from: 2019-10-30 Created: 2019-10-30 Last updated: 2020-04-08Bibliographically approved
Wu, D., Yan, J., Shen, X., Sun, Y., Thulin, M., Cai, Y., . . . Kamali-Moghaddam, M. (2019). Profiling surface proteins on individual exosomes using a proximity barcoding assay. Nature Communications, 10, Article ID 3854.
Open this publication in new window or tab >>Profiling surface proteins on individual exosomes using a proximity barcoding assay
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 3854Article in journal (Refereed) Published
Abstract [en]

Exosomes have been implicated in numerous biological processes, and they may serve as important disease markers. Surface proteins on exosomes carry information about their tissues of origin. Because of the heterogeneity of exosomes it is desirable to investigate them individually, but this has so far remained impractical. Here, we demonstrate a proximity-dependent barcoding assay to profile surface proteins of individual exosomes using antibody-DNA conjugates and next-generation sequencing. We first validate the method using artificial streptavidin-oligonucleotide complexes, followed by analysis of the variable composition of surface proteins on individual exosomes, derived from human body fluids or cell culture media. Exosomes from different sources are characterized by the presence of specific combinations of surface proteins and their abundance, allowing exosomes to be separately quantified in mixed samples to serve as markers for tissue-specific engagement in disease.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-398851 (URN)10.1038/s41467-019-11486-1 (DOI)000482567200002 ()31451692 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationEU, FP7, Seventh Framework Programme, 294409
Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2019-12-18Bibliographically approved
Siart, B., de Oliveira, F. M., Shen, Q., Björkesten, J., Pekar, T., Steinborn, R., . . . Wallner, B. (2019). Protein measurements in venous plasma, earlobe capillary plasma and in plasma stored on filter paper. Analytical Biochemistry, 566, 146-150
Open this publication in new window or tab >>Protein measurements in venous plasma, earlobe capillary plasma and in plasma stored on filter paper
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2019 (English)In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 566, p. 146-150Article in journal (Refereed) Published
Abstract [en]

In this study, levels of inflammatory protein biomarkers in venous plasma, plasma derived from capillary blood from the earlobe, and capillary plasma stored as dried plasma spots (DPS) were compared. Samples from 12 male individuals were assessed with a panel of 92 inflammation-related proteins using multiplex proximity extension assay. Correlations between sample types varied greatly between analytes. A high correlation of rho > 0.8 was observed between capillary plasma and DPS for 32 analytes. At this level of correlation, 13 analytes correlated between venous and capillary plasma and 5 analytes in the comparison of venous blood with DPS.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2019
Keywords
Cytokines, Earlobe capillary, Dried plasma spots, Extension assay, Inflammation protein biomarkers
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-376729 (URN)10.1016/j.ab.2018.11.016 (DOI)000456354900024 ()30472219 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 316929
Available from: 2019-02-08 Created: 2019-02-08 Last updated: 2019-02-08Bibliographically approved
Acharya, S., Jin, C., Bylund, J., Shen, Q., Kamali-Moghaddam, M., Jontell, M., . . . Karlsson, N. G. (2019). Reduced sialyl-Lewis(x) on salivary MUC7 from patients with burning mouth syndrome. MOLECULAR OMICS, 15(5), 331-339
Open this publication in new window or tab >>Reduced sialyl-Lewis(x) on salivary MUC7 from patients with burning mouth syndrome
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2019 (English)In: MOLECULAR OMICS, ISSN 2515-4184, Vol. 15, no 5, p. 331-339Article in journal (Refereed) Published
Abstract [en]

We analysed and compared MUC7 O-glycosylation and inflammatory biomarkers in saliva from female patients with burning mouth syndrome (BMS) and gender/age-matched controls. Oligosaccharides from salivary MUC7 from BMS and controls were released. Inflammatory mediators were measured by multiplex proximity extension assay. Presence of sialyl-Lewis(x) (Si-Le(x)) epitope on MUC7 was confirmed using Western blot. MUC7 O-glycans and measured inflammatory biomarkers were found to be similar between BMS and controls. However, oligosaccharides sialyl-Lewis(x) (Si-Le(x)) was found to be reduced in samples from BMS patients. Positive correlation (combined patients and controls) was found between levels of C-C motif chemokine 19 (CCL-19) and the amount of core-2 oligosaccharides on MUC7 as well as fractalkine (CX3CL1) and level of sialylation. Patients with BMS were shown to represent a heterogeneous group in terms of inflammatory biomarkers. This indicates that BMS patients could be further stratified on the basis of low-level inflammation. The results furthermore indicate that reduced sialylation of MUC7, particularly Si-Le(x), may be an important feature in patients with BMS. However, the functional aspects and potential involvement in immune regulation of Si-Le(x) remains unclear. Our data suggests a chemokine driven alteration of MUC7 glycosylation.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-396661 (URN)10.1039/c9mo00061e (DOI)000489036100002 ()31414088 (PubMedID)
Funder
Swedish Research Council, 621-2013-5895
Available from: 2019-11-12 Created: 2019-11-12 Last updated: 2019-11-12Bibliographically approved
de Oliveira, F. M., Mereiter, S., Lönn, P., Siart, B., Shen, Q., Heldin, J., . . . Kamali-Moghaddam, M. (2018). Detection of post-translational modifications using solid-phase proximity ligation assay. New Biotechnology, 45, 51-59
Open this publication in new window or tab >>Detection of post-translational modifications using solid-phase proximity ligation assay
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2018 (English)In: New Biotechnology, ISSN 1871-6784, E-ISSN 1876-4347, Vol. 45, p. 51-59Article in journal (Refereed) Published
Abstract [en]

Post-translational modifications (PTMs) regulate protein activities to help orchestrate and fine-tune cellular processes. Dysregulation of PTMs is often related with disorders and malignancies, and may serve as a precise biomarker of disease. Developing sensitive tools to measure and monitor low-abundant PTMs in tissue lysates or serum will be instrumental for opening up new PTM-based diagnostic avenues. Here, we investigate the use of solid-phase proximity ligation assay (SP-PLA) for detection of different PTMs. The assay depends on the recognition of the target protein molecule and its modification by three affinity binders. Using antibodies and lectins, we applied the method for detection of glycosylated CD44 and E-Cadherin, and phosphorylated p53 and EGFR. The assay was found to have superior dynamic range and limit of detection compared to standard ELISAs. In summary, we have established the use of SP-PLA as an appropriate method for sensitive detection of PTMs in lysates and sera, which may provide a basis for future PTM-based diagnostic and prognostic biomarkers

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-334520 (URN)10.1016/j.nbt.2017.10.005 (DOI)000441913800008 ()29101055 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 316929
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-10-05Bibliographically approved
Bhandage, A. K., Jin, Z., Korol, S. V., Shen, Q., Pei, Y., Deng, Q., . . . Birnir, B. (2018). GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes. EBioMedicine, 30, 283-294
Open this publication in new window or tab >>GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes
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2018 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 30, p. 283-294Article in journal (Refereed) Published
Abstract [en]

The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.

Keywords
PBMCs, Immune cells, Proliferation, Cytokine, GABAA receptor, Diabetes, T1D, Autoimmune disease, T cell
National Category
Other Medical Sciences not elsewhere specified Endocrinology and Diabetes
Research subject
Biology; Physiology
Identifiers
urn:nbn:se:uu:diva-348232 (URN)10.1016/j.ebiom.2018.03.019 (DOI)000430303000033 ()
Funder
Swedish Research Council, 2015-02417Swedish Diabetes AssociationSwedish Child Diabetes FoundationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-06-19Bibliographically approved
Palma, M., Krstic, A., Perez, L. P., Bergloef, A., Meinke, S., Wang, Q., . . . Smith, C. I. (2018). Ibrutinib induces rapid down-regulation of inflammatory markers and altered transcription of chronic lymphocytic leukaemia-related genes in blood and lymph nodes. British Journal of Haematology, 183(2), 212-224
Open this publication in new window or tab >>Ibrutinib induces rapid down-regulation of inflammatory markers and altered transcription of chronic lymphocytic leukaemia-related genes in blood and lymph nodes
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2018 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 183, no 2, p. 212-224Article in journal (Refereed) Published
Abstract [en]

In chronic lymphocytic leukaemia (CLL) patients, treatment with the Bruton tyrosine kinase inhibitor ibrutinib induces a rapid shift of tumour cells from lymph nodes (LN) to peripheral blood (PB). Here, we characterized in depth the dynamics of ibrutinib-induced inflammatory, transcriptional and cellular changes in different compartments immediately after treatment initiation in seven relapsed/refractory CLL patients. Serial PB and LN samples were taken before start and during the first 29 days of treatment. Changes in plasma inflammation-related biomarkers, CLL cell RNA expression, B-cell activation and migration markers expression, and PB mononuclear cell populations were assessed. A significant reduction of 10 plasma inflammation markers, the majority of which were chemokines and not CLL-derived, was observed within hours, and was paralleled by very early increase of CD19(+) circulating cells. At the RNA level, significant and continuous changes in transcription factors and signalling molecules linked to B-cell receptor signalling and CLL biology was observed in both PB and LN CLL cells already after 2 days of treatment. In conclusion, ibrutinib seems to instantly shut off an ongoing inflammatory response and interfere with diverse sensitive pathways in the LN.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
chronic lymphocytic leukaemia, ibrutinib, chemokines, RNA sequencing, flow-cytometry
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-387259 (URN)10.1111/bjh.15516 (DOI)000449671500007 ()30125946 (PubMedID)
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2019-06-27Bibliographically approved
Lindblom, R. P., Shen, Q., Axén, S., Landegren, U., Kamali-Moghaddam, M. & Thelin, S. (2018). Protein Profiling in Serum and Cerebrospinal Fluid Following Complex Surgery on the Thoracic Aorta Identifies Biological Markers of Neurologic Injury.. Journal of Cardiovascular Translational Research, 11(6), 503-516
Open this publication in new window or tab >>Protein Profiling in Serum and Cerebrospinal Fluid Following Complex Surgery on the Thoracic Aorta Identifies Biological Markers of Neurologic Injury.
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2018 (English)In: Journal of Cardiovascular Translational Research, ISSN 1937-5387, E-ISSN 1937-5395, Vol. 11, no 6, p. 503-516Article in journal (Refereed) Published
Abstract [en]

Surgery on the arch or descending aorta is associated with significant risk of neurological complications. As a consequence of intubation and sedation, early neurologic injury may remain unnoticed. Biomarkers to aid in the initial diagnostics could prove of great value as immediate intervention is critical. Twenty-three patients operated in the thoracic aorta with significant risk of perioperative neurological injury were included. Cerebrospinal fluid (CSF) and serum were obtained preoperatively and in the first and second postoperative days and assessed with a panel of 92 neurological-related proteins. Three patients suffered spinal cord injury (SCI), eight delirium, and nine hallucinations. There were markers in both serum and CSF that differed between the affected and non-affected patients (SCI; IL6, GFAP, CSPG4, delirium; TR4, EZH2, hallucinations; NF1). The study identifies markers in serum and CSF that reflect the occurrence of neurologic insults following aortic surgery, which may aid in the care of these patients.

Keywords
Biomarkers, Cardiovascular surgery, Neurologic injury, Thoracic aortic disease
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-369702 (URN)10.1007/s12265-018-9835-8 (DOI)000453355000007 ()30367354 (PubMedID)
Available from: 2018-12-16 Created: 2018-12-16 Last updated: 2019-01-15Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2103-4253

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