| 1. |
- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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Fluid-based proteomics targeted on pathophysiological processes and pathologies in neurodegenerative diseases.
- 2019
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 151:4, s. 417-434
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Tidskriftsartikel (refereegranskat)abstract
- Neurodegenerative dementias constitute a broad group of diseases in which abnormally folded proteins accumulate in specific brain regions and result in tissue reactions that eventually cause neuronal dysfunction and degeneration. Depending on where in the brain this happens, symptoms appear which may be used to classify the disorders on clinical grounds. However, brain changes in neurodegenerative dementias start to accumulate many years prior to symptom onset and there is a poor correlation between the clinical picture and what pathology that is the most likely to cause it. Thus, novel drug candidates having disease-modifying effects that is targeting the underlying pathology and changes the course of the disease needs to be defined using objective biomarker-based measures since the clinical symptoms are often non-specific and overlap between different disorders. Furthermore, the treatment should ideally be initiated as soon as symptoms are evident or when biomarkers confirm an underlying pathology (pre-clinical phase of the disease) to reduce irreversible damage to, for example, neurons, synapses and axons. Clinical trials in the pre-clinical phase bring a greater importance to biomarkers since by definition the clinical effects are difficult or slow to discern in a population that is not yet clinically affected. Here, we discuss neuropathological changes that may underlie neurodegenerative dementias, including how they can be detected and quantified using currently available biofluid-based biomarkers and how more of them could be identified using targeted proteomics approaches.
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| 2. |
- Dahlén, Rahil, et al.
(författare)
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Global mucosal and serum cytokine profile in patients with ulcerative colitis undergoing anti-TNF therapy
- 2015
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 50:9, s. 1118-1126
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective. The knowledge of the effects of anti-tumour necrosis factor (TNF) treatment on the global cytokine profile in patients with ulcerative colitis (UC) is limited. A better understanding of these mechanisms could improve the ability to select patients that should undergo the therapy. Therefore, the aim was to determine the global mucosal and serum cytokine profile before and during induction therapy with anti-TNF in UC patients. Materials and methods. In total, mucosal biopsies (n = 28) and serum samples (n = 42) were collected from UC patients (total n = 48) before anti-TNF therapy. At week 14 response to the therapy was evaluated and again mucosal biopsies (n = 14) and serum samples (n = 42) were collected. Quantitative real-time PCR was used to determine mucosal cytokine mRNA expression and the MSD MULTI-ARRAY assay system platform was used for analysis of cytokines in serum. The global cytokine profile was evaluated by multivariate factor analysis. Results. At baseline, the global profile of mucosal cytokine mRNA expression and serum cytokines discriminated therapy responders from non-responders. Responders had lower mucosal mRNA expression of interleukin 1 beta (IL-1 beta), IL-17A, IL-6 and interferon gamma (IFN-gamma) than non-responders. Fourteen weeks after therapy start mucosal IL-1 beta and IL-6 were down-regulated in therapy responders but not in non-responders. At week 14, serum levels of IL-6 were decreased in therapy responders whereas IFN-gamma and IL-12p70 were increased in non-responders. Conclusions. Our data suggest that patients with a therapy failure have a more severe pro-inflammatory cytokine profile before start of anti-TNF treatment, which is less well suppressed by the treatment as compared to therapy responders.
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| 3. |
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| 4. |
- Dahlén, Rahil, et al.
(författare)
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Infliximab Inhibits Activation and Effector Functions of Peripheral Blood T Cells in vitro from Patients with Clinically Active Ulcerative Colitis
- 2013
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475. ; 78:3, s. 275-284
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Tidskriftsartikel (refereegranskat)abstract
- Many patients with inflammatory bowel disease (IBD) are undergoing therapy with infliximab, an antibody specific for TNF. However, the exact mechanisms of action of infliximab are not completely understood. The aim of this study was to determine the in vitro effects of infliximab on blood T cells derived from anti-TNF therapy-naive ulcerative colitis (UC) patients with clinically active disease. Peripheral blood mononuclear cells were stimulated polyclonally or by antigen in the presence or absence of infliximab. The T cell phenotype was investigated by flow cytometry, cytokine secretion was determined by ELISA, and cell proliferation was determined by thymidine assay or CFSE dye. Presence of infliximab resulted in reduced expression of CD25 in CD4(+) and CD8(+) T cell populations and inhibited secretion of IFN-, IL-13, IL-17A, TNF as well as granzyme A. Infliximab also suppressed CD4(+) and CD8(+) T cell proliferation. These effects of infliximab were recorded both in T cells activated by polyclonal and antigen-specific stimulation. The effects of infliximab on T cell apoptosis and induction of FOXP3(+)CD4(+) T regulatory cells were ambiguous and depended on the originating cellular source and/or the stimulation mode and strength. In conclusion, infliximab is able to reduce T cell activation as measured by CD25, proliferation and cytokine secretion in vitro from UC patients with clinically active disease. These data suggest that suppression of T cell activity may be important for infliximab-mediated disease remission in patients with UC.
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| 5. |
- Hallen, Thomas, et al.
(författare)
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Genome-Wide DNA Methylation Differences in Nonfunctioning Pituitary Adenomas With and Without Postsurgical Progression
- 2022
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:8, s. 2318-2328
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Tidskriftsartikel (refereegranskat)abstract
- Context Tumor progression in surgically treated patients with nonfunctioning pituitary adenomas (NFPAs) is associated with excess mortality. Reliable biomarkers allowing early identification of tumor progression are missing. Objective To explore DNA methylation patterns associated with tumor progression in NFPA patients. Methods This case-controlled exploratory trial at a university hospital studied patients who underwent surgery for NFPA that had immunohistochemical characteristics of a gonadotropinoma. Cases included patients requiring reintervention due to tumor progression (reintervention group, n = 26) and controls who had a postoperative residual tumor without tumor progression for at least 5 years (radiologically stable group, n = 17). Genome-wide methylation data from each tumor sample were analyzed using the Infinium MethylationEPIC BeadChip platform. Results The analysis showed that 605 CpG positions were significantly differently methylated (differently methylated positions, DMPs) between the patient groups (false discovery rate adjusted P value < 0.05, beta value > 0.2), mapping to 389 genes. The largest number of DMPs were detected in the genes NUP93 and LGALS1. The 3 hypomethylated DMPs and the 3 hypermethylated DMPs with the lowest P values were all significantly (P < 0.05) and individually associated with reintervention-free survival. One of the hypermethylated DMPs with the lowest P value was located in the gene GABRA1. Conclusion In this exploratory study, DNA methylation patterns in NFPA patients were associated with postoperative tumor progression requiring reintervention. The DMPs included genes that have been previously associated with tumor development. Our study is a step toward finding epigenetic signatures to predict tumor progression in patients with NFPA.
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| 6. |
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| 7. |
- Hansson, Karl, 1985, et al.
(författare)
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Use of the tau protein-to-peptide ratio in CSF to improve diagnostic classification of Alzheimer's disease
- 2019
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Ingår i: Clinical Mass Spectrometry. - : Elsevier BV. - 2376-9998. ; 14, s. 74-82
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) tau and phospho-tau are well established biomarkers of Alzheimer's disease. While these measures are conventionally referred to as 'total tau' (T-tau) and 'phospho-tau' (P-tau), several truncated and modified tau forms exist that may relay additional diagnostic information. We evaluated the diagnostic performance of an endogenous tau peptide in CSF, tau 175-190, in the phosphorylated and non-phosphorylated state. A liquid chromatography-mass spectrometry (LC-MS) method was established to measure these peptides in CSF and was used to analyze two independent clinical cohorts; the first cohort included patients with Alzheimer's disease (AD, n = 15), Parkinson's disease (PD, n = 15), progressive supranuclear palsy (PSP, n = 15), and healthy controls (n = 15), the second cohort included AD patients (n = 16), and healthy controls (n = 24). In both cohorts T-tau and P-tau concentrations were determined by immunoassay. While tau 175-190 and P-tau 175-190 did not differentiate the study groups, the separation of AD and controls by T-tau (area under the ROC Curve (AUC) = 95%) and P-tau (AUC = 92%) was improved when normalizing the ELISA measurements to the concentrations of the endogenous peptides: T-tau/tau 175-190 (AUC = 100%), P-tau/P-tau 175-190 (AUC = 95%). The separation between patients and controls by T-tau (AUC = 88%) and P-tau (AUC = 82%) was similarly improved in the second cohort by taking the ratios of T-tau/tau 175-190 (AUC = 97%) and P-tau/P-tau 175-190 (AUC = 98%). In conclusion, our results suggest that the performance of the AD biomarkers T-tau and P-tau could be improved by normalizing their measurements to the endogenous peptides tau 175-190 and P-tau 175-190, possibly because these endogenous tau peptides serve to normalize for physiological, and disease-independent, secretion of tau from neurons to the extracellular space and the CSF. Finally, the observations made here add to the general applicability of mass spectrometry as a tool for rapid identification and accurate quantification of biomarker candidates. (C) 2019 The Association for Mass Spectrometry: Applications to the Clinical Lab (MSACL). Published by Elsevier B.V. All rights reserved.
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| 8. |
- Magnusson, Maria K, 1972, et al.
(författare)
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CD25 and TNF receptor II reflect early primary response to infliximab therapy in patients with ulcerative colitis
- 2013
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Ingår i: United European Gastroenterology Journal. - : Wiley. - 2050-6406 .- 2050-6414. ; 1:6, s. 467-476
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Tidskriftsartikel (refereegranskat)abstract
- Background Although infliximab treatment is an option for patients with ulcerative colitis (UC), not all patients do respond to therapy, and cellular mechanisms leading to therapy response are incompletely known. Objective The objective of this article is to determine early effects of infliximab therapy on T cells in the blood of UC patients and if effects differed in therapy responders and nonresponders. Methods: Blood samples were obtained before and two weeks post-treatment start from 34 anti-tumor necrosis factor (TNF) therapy-naïve UC patients undergoing infliximab therapy. Response to therapy was evaluated prior to the fourth treatment dose. Expression of T cell surface markers and levels of soluble receptors and cytokines in serum were determined. Results At baseline, there were no differences in cellular, biochemical or clinical parameters between therapy responders and nonresponders. Infliximab therapy reduced frequencies of CD25+ T cells and increased frequencies of annexin V+ T cells in patients responding to infliximab, but not in nonresponding patients, two weeks after therapy start. Only therapy responders had decreased serum levels of sCD25 and sTNFRII two weeks after treatment start. In contrast, clinical parameters did not reflect therapy outcome already two weeks after therapy start. Conclusion Soluble and membrane-bound T cell receptors may be early indicators of infliximab therapy response in UC, which can be of clinical importance for the decision when to continue or to stop the treatment.
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| 9. |
- Portelius, Erik, 1977, et al.
(författare)
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Proteomic studies of cerebrospinal fluid biomarkers of Alzheimer's disease: an update.
- 2017
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Ingår i: Expert review of proteomics. - : Informa UK Limited. - 1744-8387 .- 1478-9450. ; 14:11, s. 1007-1020
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Forskningsöversikt (refereegranskat)abstract
- Alzheimer's disease (AD) is a neurodegenerative disease affecting the brain. Today there are three cerebrospinal fluid (CSF) biomarkers, amyloid-β consisting of 42 amino acids (Aβ42), total-tau (t-tau) and phosphorylated-tau (p-tau), which combined have sensitivity and specificity figures around 80%. However, pathological studies have shown that comorbidity is a common feature in AD and that the three currently used CSF biomarkers do not optimally reflect the activity of the disease process. Thus, additional markers are needed. Areas covered: In the present review, we screened PubMed for articles published the last five years (2012-2017) for proteomic studies in CSF with the criteria that AD had to be included as one of the diagnostic groups. Based on inclusion criteria, 28 papers were included reporting in total 224 biomarker-data that were altered in AD compared to control. Both mass spectrometry and multi-panel immunoassays were considered as proteomic studies. Expert commentary: A large number of pilot studies have been reported but so far there is a lack of replicated findings and to date no CSF biomarker discovered in proteomic studies has reached the clinic to aid in the diagnostic work-up of patients with cognitive impairment.
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| 10. |
- Skillbäck, Tobias, et al.
(författare)
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A novel quantification-driven proteomic strategy identifies an endogenous peptide of pleiotrophin as a new biomarker of Alzheimer's disease
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- We present a new, quantification-driven proteomic approach to identifying biomarkers. In contrast to the identification-driven approach, limited in scope to peptides that are identified by database searching in the first step, all MS data are considered to select biomarker candidates. The endopeptidome of cerebrospinal fluid from 40 Alzheimer's disease (AD) patients, 40 subjects with mild cognitive impairment, and 40 controls with subjective cognitive decline was analyzed using multiplex isobaric labeling. Spectral clustering was used to match MS/MS spectra. The top biomarker candidate cluster (215% higher in AD compared to controls, area under ROC curve = 0.96) was identified as a fragment of pleiotrophin located near the protein's C-terminus. Analysis of another cohort (n = 60 over four clinical groups) verified that the biomarker was increased in AD patients while no change in controls, Parkinson's disease or progressive supranuclear palsy was observed. The identification of the novel biomarker pleiotrophin 151-166 demonstrates that our quantification-driven proteomic approach is a promising method for biomarker discovery, which may be universally applicable in clinical proteomics.
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