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- Reker, D., et al.
(author)
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Sprifermin (rhFGF18) versus vehicle induces a biphasic process of extracellular matrix remodeling in human knee OA articular cartilage ex vivo
- 2020
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Journal article (peer-reviewed)abstract
- Sprifermin, recombinant human fibroblast growth factor 18 (rhFGF18), induces cartilage regeneration in knees of patients with osteoarthritis (OA). We hypothesized that a temporal multiphasic process of extracellular matrix (ECM) degradation and formation underlie this effect. We aimed to characterize the temporal ECM remodeling of human knee OA articular cartilage in response to sprifermin treatment. Articular cartilage explants from patients with knee OA (npatients = 14) were cultured for 70 days, with permanent exposure to sprifermin (900, 450, 225 ng/mL), FGF18 (450 ng/mL), insulin-like growth factor-1 (100 ng/mL, positive control) or vehicle (nreplicates/treatment/patient = 2). Metabolic activity (AlamarBlue) and biomarkers of type IIB collagen (PIIBNP) formation (Pro-C2 enzyme-linked immunosorbent assay [ELISA]) and aggrecanase-mediated aggrecan neo-epitope NITEGE (AGNx1 ELISA) were quantified once a week. At end of culture (day 70), gene expression (quantitative reverse transcription polymerase chain reaction) and proteoglycan content (Safranin O/Fast green staining) were quantified. The cartilage had continuously increased metabolic activity, when treated with sprifermin/FGF18 compared to vehicle. During days 7–28 PIIBNP was decreased and NITEGE was increased, and during days 35–70 PIIBNP was increased. At end of culture, the cartilage had sustained proteoglycan content and relative expression of ACAN < COL2A1 < SOX9 < COL1A1, indicating that functional chondrocytes remained in the explants. Sprifermin induces a temporal biphasic cartilage remodeling in human knee OA articular cartilage explants, with early-phase increased aggrecanase activity and late-phase increased type II collagen formation.
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- Englund, E, et al.
(author)
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Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer
- 2016
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In: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 35:43, s. 5585-5596
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Journal article (peer-reviewed)abstract
- Cartilage oligomeric matrix protein (COMP) is a soluble pentameric protein expressed in cartilage and involved in collagen organization. Tissue microarrays derived from two cohorts of patients with breast cancer (n=122 and n=498) were immunostained, revealing varying expression of COMP, both in the tumor cells and surrounding stroma. High levels of COMP in tumor cells correlated, independently of other variables, with poor survival and decreased recurrence-free survival. Breast cancer cells, MDA-MB-231, stably expressing COMP were injected into the mammary fat pad of SCID (CB-17/Icr-Prkdc(scid)/Rj) mice. Tumors expressing COMP were significantly larger and were more prone to metastasize as compared with control, mock-transfected, tumors. In vitro experiments confirmed that COMP-expressing cells had a more invasive phenotype, which could in part be attributed to an upregulation of matrix metalloprotease-9. Furthermore, microarray analyses of gene expression in tumors formed in vivo showed that COMP expression induced higher expression of genes protecting against endoplasmic reticulum stress. This observation was confirmed in vitro as COMP-expressing cells showed better survival as well as a higher rate of protein synthesis when treated with brefeldin A, compared with control cells. Further, COMP-expressing cells appeared to undergo a metabolic switch, that is, a Warburg effect. Thus, in vitro measurement of cell respiration indicated decreased mitochondrial metabolism. In conclusion, COMP is a novel biomarker in breast cancer, which contributes to the severity of the disease by metabolic switching and increasing invasiveness and tumor cell viability, leading to reduced survival in animal models and human patients.
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- Eriksson, P, et al.
(author)
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Neonatal exposure to DDT and its fatty acid conjugate: effects on cholinergic and behavioural variables in the adult mouse
- 1990
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In: NeuroToxicology. - 1872-9711. ; 11:2, s. 345-354
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Journal article (peer-reviewed)abstract
- We have recently observed that DDT and a DDT metabolite, DDOH, conjugated to a fatty acid, palmitic acid, DDOH-PA, affects muscarinic cholinergic receptors (MAChR) in the neonatal mouse brain when given to suckling mice during rapid brain growth. This early exposure of the neonatal mouse also affects the behaviour of the animals as adults. When DDT and DDOH-PA was given as a single low oral dose of 1.4 mumol/kg body weight, DDT (0.5 mg), DDOH-PA (0.7 mg) and a 20% fat emulsion vehicle (10 ml) per kg body weight to 10-day-old NMRI mice, behavioural tests at adult age of four months, indicated disruption of a simple, non-associative learning process, i.e. habituation, in both DDT and DDOH-PA treated mice. There was also a significant increase in the potassium evoked release of ACh from slices of cerebral cortex and a tendency towards a decrease in the density of MAChR in mice receiving DDT. These effects in the adult mice could not be correlated to the concentration of DDT in the adult brain since DDT one month after its administration to the 10-day-old mouse no longer is present in the brain.
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- Rysinska, A., et al.
(author)
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Aseptic loosening after total hip arthroplasty and the risk of cardiovascular disease: A nested case-control study
- 2018
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:11
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Journal article (peer-reviewed)abstract
- Background Patients with surgically treated osteoarthritis of the hip have an increased risk of cardiovascular morbidity and mortality many years after the operation compared with controls. Our hypothesis is that this increased risk after total hip arthroplasty (THA) is mediated by development of periprosthetic osteolysis leading to aseptic loosening of the implant. Methods We conducted a nation-wide, nested, case-control study consisting of patients receiving a cemented THA due to osteoarthritis between the years 1992 and 2005. Our study population included a total of 14,430 subjects identified in the Swedish hip arthroplasty register and linked to the Swedish National Patient Register. The case group consisted of patients (n = 2,886) who underwent reoperation of the treated hip due to osteolysis or aseptic loosening at any time within five years after the index surgery. Each case was matched with four controls (n = 11,544) who had not undergone reoperation. The main outcomes were cardiovascular events i.e. myocardial infarction, heart failure and cerebral infarction according to ICD-codes and time to the first cardiovascular event during the exposure period. Outcomes were subgrouped into cardiac and cerebral events. We used regression models to calculate the incidence rates and adjusted our results for confounders. Findings Overall, 5.1% of patients had cardiac events, with slightly more overall cardiovascular events occurring in the control group (8.1% vs. 6.7%, odds ratio 0.8, 95% confidence interval (CI) 0.7 to 1.0). After adjusting for confounders, the case group had an increased relative risk of 1.3 (95% confidence interval (CI) 1.1 to 1.3) for total number of cardiovascular events. Similar effect sizes were observed for time to first event. Interpretation Patients with osteoarthritis who received THA and subsequently underwent a revision operation due to loosening had a higher relative risk of developing cardiovascular events than controls. Thus there is an association which could be explained by a common inflammatory disease pathway that requires further experimental research. Copyright: © 2018 Rysinska et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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- Thalin, C, et al.
(author)
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Trousseau's Syndrome, a Previously Unrecognized Condition in Acute Ischemic Stroke Associated With Myocardial Injury
- 2014
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In: Journal of investigative medicine high impact case reports. - : SAGE Publications. - 2324-7096. ; 2:2, s. 2324709614539283-
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Journal article (peer-reviewed)abstract
- Trousseau’s syndrome is a well-known malignancy associated hypercoagulative state leading to venous or arterial thrombosis. The pathophysiology is however poorly understood, although multiple mechanisms are believed to be involved. We report a case of Trousseau’s syndrome resulting in concomitant cerebral and myocardial microthrombosis, presenting with acute ischemic stroke and markedly elevated plasma troponin T levels suggesting myocardial injury. Without any previous medical history, the patient developed multiple cerebral infarctions and died within 11 days of admission. The patient was postmortem diagnosed with an advanced metastatic adenocarcinoma of the prostate with disseminated cerebral, pulmonary, and myocardial microthrombosis. Further analyses revealed, to the best of our knowledge for the first time in stroke patients, circulating microvesicles positive for the epithelial tumor marker CK18 and citrullinated histone H3 in thrombi, markers of the recently described cancer-associated procoagulant DNA-based neutrophil extracellular traps. We also found tissue factor, the main in vivo initiator of coagulation, both in thrombi and in metastases. Troponin elevation in acute ischemic stroke is common and has repeatedly been associated with an increased risk of mortality. The underlying pathophysiology is however not fully clarified, although a number of possible explanations have been proposed. We now suggest that unexplainable high levels of troponin in acute ischemic stroke deserve special attention in terms of possible occult malignancy.
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| 10. |
- Aspberg, A., et al.
(author)
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Cartilage oligomeric matrix protein forms protein complexes with synovial lubricin via non-covalent and covalent interactions
- 2017
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In: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 25:9, s. 1496-1504
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Journal article (peer-reviewed)abstract
- Objective: Understanding the cartilage surface structure, lost in arthritic disease, is essential for developing strategies to effectively restore it. Given that adherence of the lubricating protein, lubricin, to the cartilage surface is critical for boundary lubrication, an interaction with cartilage oligomeric matrix protein (COMP) was investigated. COMP, an abundant cartilage protein, is known to be important for matrix formation. Design: Synovial fluid (SF) from arthritic patients was used to detect possible COMP-lubricin complexes by immunological methods. Recombinant (RC) COMP and lubricin fragments were expressed to characterize this bonding and mass spectrometry employed to specifically identify the cysteines involved in inter-protein disulfide bonds. Results: COMP-lubricin complexes were identified in the SF of arthritic patients by Western blot, co-immunoprecipitation and sandwich ELISA. RC fragment solid-phase binding assays showed that the C-terminal (amino acids (AA) 518-757) of COMP bound non-covalently to the N-terminal of lubricin (AA 105-202). Mass spectrometry determined that although cysteines throughout COMP were involved in binding with lubricin, the cysteines in lubricin were primarily focused to an N-terminal region (AA 64-86). The close proximity of the non-covalent and disulfide binding domains on lubricin suggest a two-step mechanism to strongly bind lubricin to COMP. Conclusion: These data demonstrate that lubricin forms a complex network with COMP involving both non-covalent and covalent bonds. This complex between lubricin and the cartilage protein COMP can be identified in the SF of patients with arthritis conditions including osteoarthritis (OA) and rheumatoid arthritis (RA). (C) 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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