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- Lind, Anne-Li, et al.
(författare)
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Affinity Proteomics Applied to Patient CSF Identifies Protein Profiles Associated with Neuropathic Pain and Fibromyalgia
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Today, there are no biological tests on which to base pain diagnoses, treatment choices or to understand the biological processes underlying and accompanying chronic pain for the individual pain patient. Relevant biological markers would greatly aid in diagnosis and treatment of patients with chronic pain. Our study aimed to find proteins in CSF associated with fibromyalgia and neuropathic pain, two common and poorly understood chronic pain conditions.Methods: We have performed CSF protein profiling of 55 proteins using a 100-plex antibody suspension bead array. We collected, analyzed and compared CSF samples from 25 patients with neuropathic pain (two independent sets, n=14 patients for discovery and n=11 for verification), 40 patients with fibromyalgia and 135 controls without neurological disease from two different populations.Results: We found significant differences in CSF protein levels between patients and controls (p<0.05). Among these proteins, Apolipoprotein C1 (APOC1) was found to be increased in CSF of neuropathic pain patients compared to controls and there was a non-significant trend for increased levels also in fibromyalgia patient CSF. Ectonucleotide pyrophosphatase (ENPP2, Autotaxin) was increased in the CSF of fibromyalgia patients compared to all other groups including neuropathic pain patients. Multivariate analysis revealed partially overlapping and partially distinct CSF profiles in neuropathic pain patients compared with fibromyalgia and controls for several other proteins including angiotensinogen (AGT), prostaglandin-H2 D-isomerase (PTGDS), neurexin-1 (NRXN1), superoxide dismutase 1 (SOD1) and superoxide dismutase 3 (SOD3).Conclusions: Our results, suggest that the CSF protein profiles of neuropathic pain and fibromyalgia patients may be different from each other and from those of controls. CSF levels of APOC1, ENPP2, AGT, PTGDS, NRXN1, SOD1 and SOD3 should be further investigated for their potential to serve as biomarkers of different kinds of pain pathophysiology.
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| 2. |
- Orru, Anna Maria, 1976, et al.
(författare)
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AHA! festival 2015
- 2015
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The AHA festival investigates the borders between art and science in a three-day event at the Chalmers University of Technology hosted by the Department of Architecture. An international festival intended to provide enlightening experiences, staging surprises, new thoughts and displaced perspectives that lead to alternative modes of thinking about the space between art and science. We invite scientists (physicists, historians, mathematicians, medical students), artists (dancers, musicians, painters, poets, chefs) and not least architects, who reside in these borderlands and wish to share their vision and work. The key intention is to celebrate both art and science as key knowledge building devices.
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| 3. |
- Garousi, Javad, et al.
(författare)
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Radionuclide Therapy Using ABD-fused ADAPT Scaffold Protein: Proof of Principle
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The molecular recognition characteristics of targeted therapeutics is typically attributed to immunoglobulins. However, recent development of engineered scaffold proteins (ESPs) has provided additional opportunities for the improvement of these targeted therapies. ESPs offer inexpensive production in prokaryotic hosts and high molecular stability as well as convenient approaches to modify the biodistribution. In this study, we have demonstrated successful modification of the biodistribution of a particular ESP known as ADAPT (Albumin-binding domain Derived Affinity ProTein). These ADAPTs are generated through screening of combinatorial libraries based on the rigid scaffold of ABD (Albumin Binding Domain) of protein G. As one of these ADAPTs, ADAPT6 binds to human epidermal growth factor type 2 (HER2) with high affinity. Preclinical and early clinical studies have demonstrated that radiolabeled ADAPT6 can image HER2-expression in tumors with high contrast. However, its rapid glomerular filtration and high renal re-absorption have prevented its use in radionuclide therapy. To modify the biodistribution of ADAPT6 and allow for a therapeutic use, we present here an ADAPT6 genetically fused to ABD. The non-covalent binding of this fusion protein to the host albumin resulted in a 14-fold reduction of renal uptake and appreciable increase of tumor uptake for the best variant, 177Lu-DOTA-ADAPT6-ABD035. Experimental therapy in mice bearing HER2-expressing xenografts demonstrated more than two-fold increase of median survival even after a single injection of 18 MBq 177Lu-DOTA-ADAPT6-ABD035. The injections were not associated with any observable toxicity. Thus, a fusion with ABD and optimization of the molecular design provides ADAPT derivatives with attractive targeting properties for radionuclide therapy.
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| 6. |
- Johansson, Camilla, et al.
(författare)
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Identification of Gene-Therapy Responsive Blood Biomarkers for Duchenne Muscular Dystrophy
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionAssessing muscle dystrophin expression systemically is important for understanding the effect of dystrophin-restoring therapies in Duchenne muscular dystrophy (DMD). Many potential blood biomarkers have been identified in DMD patients which are either more or less abundant in blood samples compared to healthy individuals and that have been shown to change with disease progression or respond to pharmacological treatment. In this study, it was suggested that a panel of such blood biomarker candidates could be used to monitor dystrophin rescue in microdystrophin therapies. MethodsPlasma samples from mdx mice treated with the microdystrophin therapy SGT-001 were analysed with an antibody suspension bead array consisting of 87 antibodies targeting 83 proteins previously identified as biomarker candidates for DMD. Each sample was assayed at two different plasma dilutions to cover a broader concentration range. Median fluorescent intensities (MFI) for each antibody were correlated to dystrophin expression in muscle tissue, as measured by immunohistochemistry and Western blot. 13 targets were selected and validated in a DMD and Becker muscular dystrophy (BMD) longitudinal natural history cohort using a suspension bead array. Results10 proteins were found significantly elevated in untreated mdx mice compared to C57 wild-type mice and 10 were found to correlate with dystrophin expression (Spearman’s correlation, FDR < 0.05) upon gene transfer. Abundance of TTN, ADSSL1, LONP1, OTUD5, MYL3 as well as DMD protein were associated with dystrophin expression in BMD patients. Of these, MYL3 and ADSSL1 had different abundance in DMD compared to healthy individuals, and MYL3 also displayed different age trajectories between DMD and BMD patients. DiscussionThe ten proteins identified in mouse plasma are related to muscle contraction (ADSSL1, ASAH1, CA3, MYL3, TTN), microtubule formation (TPI1), and protein degradation (PSMA2, OTUD4, LONP1). Of these, MYL3 and ADSSL1 showed the most promise as a dystrophin monitoring biomarker in patient samples.
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| 7. |
- Fredriksson, Ingemar, 1980-, et al.
(författare)
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Microcirculatory changes in type 2 diabetes assessed with velocity resolved quantitative laser Doppler flowmetry
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The response to local heating (44oC for 20 min) was evaluated in 28 type 2 diabetes patients (DM) and 29 non-diabetes controls (ND). Microcirculatory perfusion was assessed using conventional and quantitative Laser Doppler flowmetry (cLDF and qLDF), respectively. The qLDF estimates perfusion in a physiological relevant unit (g RBC / 100 g tissue × mm/s) in a fixed output volume, separated into three velocity regions, v < 1 mm/s, 1 - 10 mm/s, and v > 10 mm/s. Perfusion in cLDF is given in arbitrary units with unknown velocity distribution and measurement volume. A significantly lower response in DM than in ND was found after heat provocation both for the initial peak and the plateau response, while no significant differences were found at baseline. The qLDF showed increased perfusion for the velocity regions 1-10 mm/s and above 10 mm/s, while no significant increase was found for v < 1 mm/s. In conclusion, we found a lowered LDF response to local heating in DM. The new qLDF method showed that the increased blood flow occurs in vessels with a velocity above 1 mm/s. Baseline qLDF-data indicated that a redistribution of flow to higher velocity regions was associated with longer DM duration and for DM a negative correlation between perfusion and BMI.
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| 8. |
- Karén, Jakob, 1973-, et al.
(författare)
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Defining the pericyte to fibroblast lineage
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In the present study placental tissues were characterized in vivo with regards to markers expressed on pericytes, fibroblasts and collagen type I synthesis. Microvascular fragments (MVFs) isolated from human placentas had a phenotypical marker profile consistent with microvessels in situ. Cells emerging from MVFs from placenta express a marker profile consistent with a pericyte phenotype. Temporal studies identified three optimal time points (T0, T1 and T2) subsequent to the onset of cells emerging from MVFs for further analysis with regards to divergence in marker expression profiles. T0, T1 and T2 time points contained a population of cells with a cellular phenotype consistent with mesenchymal stem/progenitor cells, activated microvascular pericytes and mature connective tissue cells. Three discernable subpopulations of cells were identified i.e. Stro-1+/CD146+/podoplanin-, Stro-1-/CD146+/podoplanin- and Stro-1-/CD146-/podoplanin+ cells. Flow cytometry analysis allowed for the Stro-1-/CD146+/podoplanin- and Stro-1-/CD146-/podplanin+ cell populations to be further divided into 2 subgroups based on the expression of desmin, αSMA and TE-7. Five steps in the differentiation process from mesenchymal stem/progenitor cell to collagen type I producing fibroblast and the order by which they progressed could be defined by re-diversification studies i.e. ability of one population of cells to give rise to the other population of cells. Two in vivo experimental systems, TPA induced inflammation and excisional cutaneous wound healing were analyzed for the existence of slow cycling cells. The in vivo evidence shows that microvascular pericytes constitute a reservoir of stem/progenitor cells for pro-fibrotic connective tissue cells. This study presents novel evidence for a connective tissue cell lineage originating from a undifferentiated mesenchymal vessel associated cell population that via pericytes differentiate into pro-fibrotic fibroblasts.
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| 10. |
- Nowak, Christoph, et al.
(författare)
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Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivity
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Impaired insulin sensitivity (IS) is a major risk factor for cardiovascular disease and type 2 diabetes. Metabolomic profiling during an oral glucose tolerance test (OGTT) can reveal early pathogenic alterations in healthy individuals. Our aim was to identify IS biomarkers and gain new pathophysiologic insights by applying untargeted metabolomics to repeated OGTT plasma samples in association with a hyperinsulinemic-euglycemic clamp assessment. We studied 192 metabolites identified by non-targeted liquid chromatography/mass spectrometry in plasma samples taken at 0, 30, and 120 min during an OGTT in 470 non-diabetic 71-yr-old men. Insulin sensitivity was associated with 35 metabolites at one or more time points in multivariable-adjusted linear regression. The trajectories of nine metabolites during the OGTT were related to IS, six of which (oleic and palmitoleic acid, decanoyl- and dodecanoylcarnitine, deoxycholate-glycine and hexose) showed no associations with IS in the baseline fasting state. The strongest effects were detected for medium-chain acylcarnitines, which increased between 30-120 min in insulin-resistant individuals compared to those with normal IS. In this large community sample, we identified novel associations between clamp-measured IS and metabolite profiles that became apparent only after an oral glucose challenge. Associations of differential medium-chain acylcarnitine and monounsaturated fatty acid trajectories with IS provide new insights into the pathogenesis of insulin resistance.
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