| 1. |
- Franklin, Oskar, 1985-, et al.
(författare)
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Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer
- 2019
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Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 5:2, s. 130-141
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Tidskriftsartikel (refereegranskat)abstract
- The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.
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| 2. |
- Hellman, Urban, 1966-, et al.
(författare)
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Genetic variants in cardiac calcification in Northern Sweden
- 2019
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Ingår i: Medicine. - : Wolters Kluwer. - 0025-7974 .- 1536-5964. ; 98:15
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Tidskriftsartikel (refereegranskat)abstract
- Extensive coronary calcification without significant stenosis, described as calcific coronary artery disease (CCAD) may cause abnormal myocardial perfusion and hence generalized ischemia. There is a discrepancy in the expression pattern of CCAD compared to the well-known atherosclerotic disease which raises questions about the exact pathophysiology of coronary calcification and whether there is a genetic etiology for it.In this pilot study we studied 3 candidate genes, ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), ATP Binding Cassette Subfamily C Member 6 (ABCC6), and 5'-Nucleotidase Ecto (NT5E) involved in pyrophosphate (PPi) and inorganic phosphate (Pi) metabolism, which may predispose to coronary arterial or valvular calcification. We studied 70 patients with calcific cardiac disease; 65 with CCAD (age 43-83 years) and 5 with calcific aortic valve disease (CAVD) (age 76-82 years).Five DNA variants potentially affecting protein function were found in 6 patients. One variant is a known disease-causing mutation in the ABCC6 gene. Our findings support that disturbances in the PPi and Pi metabolism might influence the development of CCAD and CAVD. However, segregation in the families must first be performed to ascertain any damaging effect of these variants we have found.We report 4 new genetic variants potentially related to coronary calcification, through the disturbed Pi and PPi metabolism. The search for direct causative genetic variants in coronary artery and aortic valve calcification must be broadened with other genes particularly those involved with Pi and PPi metabolism.
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| 3. |
- Hellman, Urban, 1966-, et al.
(författare)
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Hyaluronan concentration and molecular mass in psoriatic arthritis : biomarkers of disease severity, resistance to treatment, and outcome
- 2019
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Ingår i: Scandinavian Journal of Rheumatology. - : Taylor & Francis Group. - 0300-9742 .- 1502-7732. ; 48:4, s. 284-293
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Low molecular mass hyaluronan causes inflammatory processes and can act as a pro-inflammatory cytokine in skin and other sites of activity in psoriatic arthritis (PsA). This study investigated whether the molecular mass distribution of hyaluronan (HA) in skin and the quantity of circulating HA are related to the clinical inflammatory picture in PsA with active disease and to the effect of treatment with anti-tumour necrosis factor-α (anti-TNF-α) adalimumab.Methods: Twenty patients with TNF-α-naïve active polyarticular PsA were included in this prospective clinical trial of treatment with 40 mg s.c. adalimumab according to standard procedure. Clinical activity, patients’ assessments, and skin biopsies were captured at inclusion and at the 12 week follow-up. Ten healthy individuals were recruited for comparison of HA analyses. Histochemistry of skin inflammation, serum HA, and molecular mass of HA were determined.Results: Overall improvements in clinical parameters were observed. Eight of 18 patients reached minimum disease activity after 12 weeks and disease activity was significantly reduced (p < 0.0001). Patients with elevated serum HA values were significantly older, had later onset of arthritis and more deformed joints, still had swollen joints after treatment, and had more circulating inflammatory biomarkers. More severe disease pathology showed a wide spectrum of high-molecular-mass HA accompanied by low mass HA. The treatment appears partly to normalize the HA mass distribution.Conclusion: HA concentration and mass seem to be two possible factors in the inflammatory pathology of PsA acting as biomarkers for disease severity, resistance to treatment, and worse outcome.
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| 4. |
- Hellman, Urban, 1966-, et al.
(författare)
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Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type
- 2019
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Taylor & Francis. - 0036-5513 .- 1502-7686. ; 79:6, s. 372-376
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Tidskriftsartikel (refereegranskat)abstract
- For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.
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| 5. |
- Holm, Anna, et al.
(författare)
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Hyaluronan in vocal folds and false vocal folds in patients with recurrent respiratory papillomatosis
- 2018
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Ingår i: Acta Oto-Laryngologica. - : Taylor & Francis. - 0001-6489 .- 1651-2251. ; 138:11, s. 1020-1027
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hyaluronan (HA) is a glycosaminoglycan with viscoelastic properties necessary for vocal fold (VF) vibration and voice production. Changes in HAs molecular mass, possibly related to human papilloma virus, could affect formation/persistence of recurrent respiratory papillomatosis (RRP).Aims/Objective: Describing mass and localization of HA and localization of HA receptor CD44 in VF and false vocal folds (FVF) in RRP.Materials and Methods: Biopsies from VF and FVF from 24 RRP patients. Twelve were studied with histo-/immunohistochemistry for HA and CD44 in epithelium, stroma and RRP lesions. Twelve samples were analyzed for HA molecular mass distribution with gas-phase-electrophoretic-molecular-mobility-analyzer (GEMMA).Results: Three of 23 stains (VF and FVF combined) showed faint HA staining in the epithelium; there was more extensive staining in the stroma. CD44 was present throughout all areas in FVF and VF, it did not concur with HA. GEMMA analysis revealed very high mass HA (vHMHA) with more varying amounts in VF.Conclusions/Significance: HA was mainly distributed in the stroma. CD44 not binding to HA might explain the non-inflammatory response described in RRP. Possibly crosslinked vHMHA was seen in VF and FVF, with more variable amounts in VF samples. Counteracting HA crosslinking could become a treatment option in RRP.
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| 6. |
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| 7. |
- Kumar, Anjani, et al.
(författare)
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Overexpression of macrophage migration inhibitory factor in patients with ankylosing spondylitis and its relation to sex, inflammation and treatment
- 2018
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Ingår i: Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 36:4, s. 716-716
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Tidskriftsartikel (refereegranskat)abstract
- Background: Macrophage migration inhibitory factor (MIF) is a multipotent cytokine involved in the regulation of immune and inflammatory responses. The present study aimed to investigate the MIF expression in patients with ankylosing spondylitis (AS) compared with controls and to examine associations between MIF and demographic and inflammation related factors in AS overall and stratified by sex.Methods: MIF in plasma was measured in a cohort of patients with AS from Northern Sweden (n= 155) and age- & sex-matched controls (n=151) using Human MIF Quantikine ELISA Kit (R&D). The patients were assessed with laboratory markers of inflammation, ASDAS-CRP, BASDAI, BASMI and BASFI. Comparisons were analyzed by T-test and associations by bivariate Pearson correlations.Results: The expression of MIF was significantly augmented in the AS patients (Mean 65.1 ng/ml±2.0 SEM) compared with the controls (Mean 42.0 ng/ml±2.1 SEM) (p<0.001), the difference was also found in sex stratified analyses. MIF had a weak negative correlation with age in AS (-0.144, p=0.07) but not in controls (-0.037, p=0.66). Stratified by sex, the inverse correlation with age was shown in the AS men only (-0.28, p=0.004). When analyzing MIF in different age-groups it was revealed that MIF was significantly higher in the men ≤50 years compared to the women with AS ≤50 years. Moreover, MIF was positively correlated with inflammation related variables; swollen joint count, ESR, hsCRP, thrombocytes and leukocytes. The expression of MIF was significantly increased in AS patients on cDMARDs with or without a biological drug, while NSAIDs, glucocorticosteriods or single therapy with a biological drug did not influence the MIF levels.Conclusions: Our results suggest that MIF is overexpressed in AS patients. MIF was associated with inflammation and treatment and, in addition, sex seemed to have an impact on MIF plasma levels in the AS patients. MIF might be a potential biomarker for the development of new treatment-strategies in AS.
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| 8. |
- Lorén, Christina, et al.
(författare)
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Low Molecular Mass Myocardial Hyaluronan in Human Hypertrophic Cardiomyopathy
- 2019
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- During the development of hypertrophic cardiomyopathy, the heart returns to fetal energy metabolism where cells utilize more glucose instead of fatty acids as a source of energy. Metabolism of glucose can increase synthesis of the extracellular glycosaminoglycan hyaluronan, which has been shown to be involved in the development of cardiac hypertrophy and fibrosis. The aim of this study was to investigate hyaluronan metabolism in cardiac tissue from patients with hypertrophic cardiomyopathy in relation to cardiac growth. NMR and qRT-PCR analysis of human cardiac tissue from hypertrophic cardiomyopathy patients and healthy control hearts showed dysregulated glucose and hyaluronan metabolism in the patients. Gas phase electrophoresis revealed a higher amount of low molecular mass hyaluronan and larger cardiomyocytes in cardiac tissue from patients with hypertrophic cardiomyopathy. Histochemistry showed high concentrations of hyaluronan around individual cardiomyocytes in hearts from hypertrophic cardiomyopathy patients. Experimentally, we could also observe accumulation of low molecular mass hyaluronan in cardiac hypertrophy in a rat model. In conclusion, the development of hypertrophic cardiomyopathy with increased glucose metabolism affected both hyaluronan molecular mass and amount. The process of regulating cardiomyocyte size seems to involve fragmentation of hyaluronan.
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| 9. |
- Svennerholm, Kristina, 1981, et al.
(författare)
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Myocardial ischemic preconditioning in a porcine model leads to rapid changes in cardiac extracellular vesicle messenger RNA content
- 2015
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Ingår i: International Journal of Cardiology Heart and Vasculature. - : Elsevier. - 2352-9067. ; 8, s. 62-67
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Tidskriftsartikel (refereegranskat)abstract
- Background: Extracellular vesicles (EVs) are thought to exert protective effects after ischemic and remote ischemic preconditioning. It is not well understood which EV content factors are most relevant for protective effects. We hypothesize that ischemic preconditioning leads to qualitative changes in EV mRNA content and quantitative changes in EV size and number.Methods: Using an in vivo porcine ischemic preconditioning model, EVs were collected from coronary venous blood, and isolated by differential ultracentrifugations. The presence and purity of EV were verified by electron microscopy and Western blot, and EV number was assessed by nanoparticle tracking analysis. The mRNA EV was identified by microarray.Results: Gene ontology analysis showed enrichment of EV mRNA coding for proteins associated with regulation of transcription, translation, extracellular matrix, morphogenic development and feeding behavior. There were 11,678 different mRNA transcripts detected in EV, where a total of 1103 was significantly increased or decreased after preconditioning, of which 638 mRNA sequences were up-regulated and/or emerged due to preconditioning. Several of them have known association with ischemic preconditioning. There was no significant difference in EV quantity or size before and after preconditioning.Conclusions: These findings demonstrate in an in vivo model that myocardial ischemic preconditioning influences the composition of mRNA in EV, including gene transcripts for proteins associated with the protective effect of ischemic preconditioning. The finding that preconditioned parental cells release EV containing mRNA that is qualitatively different from those released by non-preconditioned cells shows the importance of the external milieu on parental cell EV production.
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