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  1. Article ; Online: A serologically assessed neo-epitope biomarker of cellular fibronectin degradation is related to pulmonary fibrosis.

    Hansen, Annika Hummersgaard / Breisnes, Helene Wallem / Prior, Thomas Skovhus / Hilberg, Ole / Rasmussen, Daniel Guldager Kring / Genovese, Federica / Lukassen, Marie Vestergaard / Svensson, Birte / Langholm, Lasse Løcke / Manon-Jensen, Tina / Karsdal, Morten Asser / Leeming, Diana Julie / Bendstrup, Elisabeth / Sand, Jannie Marie Bülow

    Clinical biochemistry

    2023  Volume 118, Page(s) 110599

    Abstract: Background: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive extracellular matrix (ECM) remodeling, herein ECM degradation. Fibronectin (FN) is an important component of the ECM that is produced by multiple cell types, including ... ...

    Abstract Background: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive extracellular matrix (ECM) remodeling, herein ECM degradation. Fibronectin (FN) is an important component of the ECM that is produced by multiple cell types, including fibroblasts. Extra domain B (EDB) is specific for a cellular FN isoform which is found in the ECM. We sought to develop a non-invasive test to investigate whether matrix metalloproteinase 8 (MMP-8) degradation of EDB in cellular FN results in a specific protein fragment that can be assessed serologically and if levels relate to pulmonary fibrosis.
    Method: Cellular FN was cleaved in vitro by MMP-8 and a protein fragment was identified by mass spectrometry. A monoclonal antibody (mAb) was generated, targeting a neo-epitope originating from EDB in cellular FN. Utilizing this mAb, a neo-epitope specific enzyme-linked immunosorbent assay (FN-EDB) was developed and technically validated. Serum FN-EDB was assessed in an IPF cohort (n = 98), registered at clinicaltrials.gov (NCT02818712), and in healthy controls (n = 35).
    Results: The FN-EDB assay had high specificity for the MMP-8 degraded neo-epitope and was technically robust. FN-EDB serum levels were not influenced by age, sex, ethnicity, or BMI. Moreover, FN-EDB serum levels were significantly higher in IPF patients (median 31.38 [IQR 25.79-46.84] ng/mL) as compared to healthy controls (median 28.05 [IQR 21.58-33.88] ng/mL, p = 0.023).
    Conclusion: We developed the neo-epitope specific FN-EDB assay, a competitive ELISA, as a tool for serological assessment of MMP-8 mediated degradation of EDB in cellular FN. This study indicates that degradation of EDB in cellular FN is elevated in IPF and warrants further investigation.
    MeSH term(s) Humans ; Pulmonary Fibrosis ; Matrix Metalloproteinase 8 ; Fibronectins/chemistry ; Fibronectins/metabolism ; Epitopes ; Antibodies, Monoclonal ; Biomarkers
    Chemical Substances Matrix Metalloproteinase 8 (EC 3.4.24.34) ; Fibronectins ; Epitopes ; Antibodies, Monoclonal ; Biomarkers
    Language English
    Publishing date 2023-06-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 390372-2
    ISSN 1873-2933 ; 0009-9120
    ISSN (online) 1873-2933
    ISSN 0009-9120
    DOI 10.1016/j.clinbiochem.2023.110599
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 624: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Serologically assessed heat shock protein 47 is related to fibrosis stage in early compensated alcohol-related liver disease.

    Lønsmann, Ida / Gudmann, Natasja Stæhr / Manon-Jensen, Tina / Thiele, Maja / Moreno, Ydalina Maria / Langholm, Lasse Løcke / Nielsen, Mette Juul / Detlefsen, Sönke / Karsdal, Morten Asser / Krag, Aleksander Ahm / Leeming, Diana Julie

    Clinical biochemistry

    2021  Volume 104, Page(s) 36–43

    Abstract: Background and aims: Heat shock protein (HSP)47 is a collagen-specific chaperone, essential for the correct formation of fibrillar procollagens. Collagen accumulation in the extracellular matrix (ECM) is a hallmark of fibrogenesis. The expression of ... ...

    Abstract Background and aims: Heat shock protein (HSP)47 is a collagen-specific chaperone, essential for the correct formation of fibrillar procollagens. Collagen accumulation in the extracellular matrix (ECM) is a hallmark of fibrogenesis. The expression of HSP47 is proportional to the rate of collagen formation. Thus, HSP47 is a potential drug target for fibrotic diseases. We hypothesized that a C-terminal fragment of HSP47 (HSP47-C) could be quantified serologically and related to liver fibrosis stage. For this, a novel competitive enzyme-linked immunosorbent assay (ELISA) was developed.
    Method: An ELISA employing a monoclonal antibody targeting HSP47-C was developed and technically validated. The assay was evaluated in serum from a cross-sectional biopsy-controlled study of 281 patients with alcohol-related liver disease (ALD) and 50 gender, age and BMI matched healthy controls (HC). All liver biopsies from ALD patients were scored by one pathologist according to fibrosis stage (F0-4).
    Results: The HSP47-C assay was technically robust and specific for the target sequence. HSP47-C was 39% higher in ALD patients (median 17.7 ng/mL, IQR 12.4-24.0 ng/mL) compared to HC (median 12.7 ng/mL, IQR 9.4-15.7 ng/mL, p < 0.0001). In addition, HSP47-C was elevated in patients with severe fibrosis (F3-4, median 22.8 ng/mL, IQR 17.5-33.3 ng/mL) compared to none-to-moderate fibrosis (F0-2, median 16.5 ng/mL, IQR 11.8-22.5 ng/mL) with an AUROC of 0.72 (p < 0.0001). HSP47-C also correlated with other liver disease parameters, albumin, bilirubin and aspartate transaminase.
    Conclusion: We developed a competitive ELISA for serological detection of HSP47-C. The study supports HSP47 as a potential marker of liver fibrosis in ALD.
    MeSH term(s) Collagen/metabolism ; Cross-Sectional Studies ; Fibrosis ; HSP47 Heat-Shock Proteins/metabolism ; Humans ; Liver Cirrhosis
    Chemical Substances HSP47 Heat-Shock Proteins ; Collagen (9007-34-5)
    Language English
    Publishing date 2021-12-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 390372-2
    ISSN 1873-2933 ; 0009-9120
    ISSN (online) 1873-2933
    ISSN 0009-9120
    DOI 10.1016/j.clinbiochem.2021.12.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 624: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Type IV collagen turnover is predictive of mortality in COPD: a comparison to fibrinogen in a prospective analysis of the ECLIPSE cohort.

    Rønnow, Sarah Rank / Sand, Jannie Marie Bülow / Langholm, Lasse Løcke / Manon-Jensen, Tina / Karsdal, Morten Asser / Tal-Singer, Ruth / Miller, Bruce E / Vestbo, Jørgen / Leeming, Diana Julie

    Respiratory research

    2019  Volume 20, Issue 1, Page(s) 63

    Abstract: Background: Identifying subjects with chronic obstructive pulmonary disease (COPD) at high risk of exacerbation and mortality is key to aid individual management of COPD. The only FDA approved blood-based drug development biomarker for patients at high ... ...

    Abstract Background: Identifying subjects with chronic obstructive pulmonary disease (COPD) at high risk of exacerbation and mortality is key to aid individual management of COPD. The only FDA approved blood-based drug development biomarker for patients at high risk of mortality, is plasma fibrinogen. In this study, we benchmarked two biomarkers of basement membrane remodeling, a characteristic of COPD, against plasma fibrinogen alone and as a combination. The biomarkers of basement membrane remodeling are two neoepitopes from of the alpha 3 chain of type IV collagen (COL4A3).
    Materials and methods: COL4A3 degradation was assessed by the biomarkers C4Ma3 and tumstatin (TUM) in year 1 plasma samples in 984 COPD subjects, 95 non-smoking controls and 95 smoking controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. They were measured by competitive ELISA using monoclonal antibodies recognizing two specific MMP-generated cleavage site within COL4A3. The level of fibrinogen was previously assessed in year 1 plasma.
    Results: In COPD subjects, plasma C4Ma3 levels were significantly correlated with plasma fibrinogen levels (0.389 (P < 0.0001)). Cox proportional-hazards regression adjusted for relevant confounders showed that high levels of plasma C4Ma3, but not TUM, were related to a higher risk of mortality (hazard ratio 5.12 (95% CI 2.28-11.50), P < 0.0001). High levels of plasma fibrinogen were not associated with all-cause mortality in this subpopulation, contradictory to published results. Whereas plasma C4Ma3 multiplied by fibrinogen showed to be related to a higher risk of mortality (hazard ratio 5.74 (95% CI 2.65-12.41), P < 0.0001). Plasma C4Ma3 levels were related to the number of hospitalizations due to COPD exacerbations in the year before study start (P = 0.0375). Fibrinogen levels were related to hospitalized exacerbations prior to study start (P = 0.0058) and were also related to future exacerbations (P < 0.0001).
    Conclusion: We compared herein fibrinogen, C4Ma3 and TUM as biomarkers for COPD prognosis. Fibrinogen was related to future exacerbation, whereas C4Ma3 and the combination of C4Ma3 with fibrinogen were superior to fibrinogen alone in predicting mortality. This pilot study suggests that the assessment of plasma C4Ma3 could be important for identifying COPD patients with a poor prognosis.
    Trial registration: NCT00292552 , GSK Study No. SCO104960.
    MeSH term(s) Aged ; Autoantigens/blood ; Biomarkers/blood ; Cohort Studies ; Collagen Type IV/blood ; Female ; Fibrinogen/metabolism ; Hospitalization/trends ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Mortality/trends ; Pilot Projects ; Prognosis ; Prospective Studies ; Pulmonary Disease, Chronic Obstructive/blood ; Pulmonary Disease, Chronic Obstructive/diagnosis ; Pulmonary Disease, Chronic Obstructive/mortality
    Chemical Substances Autoantigens ; Biomarkers ; Collagen Type IV ; type IV collagen alpha3 chain ; Fibrinogen (9001-32-5)
    Language English
    Publishing date 2019-04-01
    Publishing country England
    Document type Clinical Trial ; Comparative Study ; Journal Article ; Observational Study
    ZDB-ID 2041675-1
    ISSN 1465-993X ; 1465-9921
    ISSN (online) 1465-993X
    ISSN 1465-9921
    DOI 10.1186/s12931-019-1026-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Specific elastin degradation products are associated with poor outcome in the ECLIPSE COPD cohort.

    Rønnow, Sarah Rank / Langholm, Lasse Løcke / Sand, Jannie Marie Bülow / Thorlacius-Ussing, Jeppe / Leeming, Diana Julie / Manon-Jensen, Tina / Tal-Singer, Ruth / Miller, Bruce E / Karsdal, Morten Asser / Vestbo, Jørgen

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 4064

    Abstract: Chronic obstructive pulmonary disease (COPD) is characterized by a slow heterogeneous progression. Therefore, improved biomarkers that can accurately identify patients with the highest likelihood of progression and therefore the ability to benefit from a ...

    Abstract Chronic obstructive pulmonary disease (COPD) is characterized by a slow heterogeneous progression. Therefore, improved biomarkers that can accurately identify patients with the highest likelihood of progression and therefore the ability to benefit from a given treatment, are needed. Elastin is an essential structural protein of the lungs. In this study, we investigated whether elastin degradation products generated by the enzymes proteinase 3, cathepsin G, neutrophil elastase, MMP7 or MMP9/12 were prognostic biomarkers for COPD-related outcomes. The elastin degradome was assessed in a subpopulation (n = 1307) of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort with 3 years of clinical follow-up. Elastin degraded by proteinase 3 could distinguish between COPD participants and non-smoking controls (p = 0.0006). A total of 30 participants (3%) died over the 3 years of observation. After adjusting for confounders, plasma levels of elastin degraded by proteinase 3 and cathepsin G were independently associated with mortality outcome with a hazard ratio per 1 SD of 1.49 (95%CI 1.24-1.80, p < 0.0001) and 1.31 (95%CI 1.10-1.57, p = 0.0029), respectively. Assessing the elastin degradome demonstrated that specific elastin degradation fragments have potential utility as biomarkers identifying subtypes of COPD patients at risk of poor prognosis and supports further exploration in confirmatory studies.
    MeSH term(s) Biomarkers/metabolism ; Cohort Studies ; Disease Progression ; Elastin/genetics ; Elastin/ultrastructure ; Female ; Humans ; Lung/metabolism ; Lung/pathology ; Male ; Matrix Metalloproteinase 12/genetics ; Matrix Metalloproteinase 7/genetics ; Matrix Metalloproteinase 9/genetics ; Middle Aged ; Myeloblastin/genetics ; Proportional Hazards Models ; Proteolysis ; Pulmonary Disease, Chronic Obstructive/genetics ; Pulmonary Disease, Chronic Obstructive/metabolism ; Pulmonary Disease, Chronic Obstructive/pathology
    Chemical Substances Biomarkers ; Elastin (9007-58-3) ; Myeloblastin (EC 3.4.21.76) ; Matrix Metalloproteinase 7 (EC 3.4.24.23) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Matrix Metalloproteinase 12 (EC 3.4.24.65)
    Language English
    Publishing date 2019-03-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-019-40785-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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