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Article: Fibroblast Activation Protein (FAP)-Mediated Cleavage of Type III Collagen Reveals Serum Biomarker Potential in Non-Small Cell Lung Cancer and Spondyloarthritis.

Pedersen, Rasmus S / Thorlacius-Ussing, Jeppe / Raimondo, Maria G / Langholm, Lasse L / Schett, Georg / Ramming, Andreas / Karsdal, Morten / Willumsen, Nicholas

Biomedicines

2024 Volume 12, Issue 3

Abstract: Fibroblast activation protein (FAP) is a known promoter of tumor development and is associated with poor clinical outcome for various cancer types. Being specifically expressed in pathological conditions including multiple types of fibrosis and cancers, ... ...

Abstract	Fibroblast activation protein (FAP) is a known promoter of tumor development and is associated with poor clinical outcome for various cancer types. Being specifically expressed in pathological conditions including multiple types of fibrosis and cancers, FAP is an optimal target for diagnostics and treatment. Treatment strategies utilizing the unique proteolytic activity of FAP are emerging, thus emphasizing the importance of biomarkers to directly assess FAP activity. FAP is a type II transmembrane serine protease that has been shown to cleave collagens and other ECM components. In this study, we developed an ELISA assay (C3F) targeting a circulating type III collagen fragment derived from FAP cleavage to reflect FAP activity. We demonstrated that C3F was specific to the neoepitope of the cleavage site and that the fragment was generated through FAP cleavage of type III collagen. We measured C3F in serum from a cohort of patients with non-small cell lung cancer (NSCLC) (
Language	English
Publishing date	2024-02-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines12030545
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Article: Lot-to-Lot Variance in Immunoassays-Causes, Consequences, and Solutions.

Luo, Yunyun / Pehrsson, Martin / Langholm, Lasse / Karsdal, Morten / Bay-Jensen, Anne-Christine / Sun, Shu

Diagnostics (Basel, Switzerland)

2023 Volume 13, Issue 11

Abstract: Immunoassays, which have gained popularity in clinical practice and modern biomedical research, play an increasingly important role in quantifying various analytes in biological samples. Despite their high sensitivity and specificity, as well as their ... ...

Abstract	Immunoassays, which have gained popularity in clinical practice and modern biomedical research, play an increasingly important role in quantifying various analytes in biological samples. Despite their high sensitivity and specificity, as well as their ability to analyze multiple samples in a single run, immunoassays are plagued by the problem of lot-to-lot variance (LTLV). LTLV negatively affects assay accuracy, precision, and specificity, leading to considerable uncertainty in reported results. Therefore, maintaining consistency in technical performance over time presents a challenge in reproducing immunoassays. In this article, we share our two-decade-long experience and delve into the reasons for and locations of LTLV, as well as explore methods to mitigate its effects. Our investigation identifies potential contributing factors, including quality fluctuation in critical raw materials and deviations in manufacturing processes. These findings offer valuable insights to developers and researchers working with immunoassays, emphasizing the importance of considering lot-to-lot variance in assay development and application.
Language	English
Publishing date	2023-05-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics13111835
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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
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Article ; Online: Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis.

Pedersen, Rasmus S / Nissen, Neel I / Jensen, Christina / Thorlacius-Ussing, Jeppe / Manon-Jensen, Tina / Olesen, Majken L / Langholm, Lasse L / Diab, Hadi M H / Jorgensen, Lars N / Hansen, Carsten P / Chen, Inna M / Johansen, Julia S / Karsdal, Morten A / Willumsen, Nicholas

Biomolecules

2022 Volume 12, Issue 9

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a hard-to-treat cancer due to the collagen-rich (fibrotic) and immune-suppressed microenvironment. A major driver of this phenomenon is transforming growth factor beta (TGF-β). TGF-β is produced in an inactive ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is a hard-to-treat cancer due to the collagen-rich (fibrotic) and immune-suppressed microenvironment. A major driver of this phenomenon is transforming growth factor beta (TGF-β). TGF-β is produced in an inactive complex with a latency-associated protein (LAP) that can be cleaved by plasma kallikrein (PLK), hereby releasing active TGF-β. The aim of this study was to evaluate LAP cleaved by PLK as a non-invasive biomarker for PDAC and tumor fibrosis. An ELISA was developed for the quantification of PLK-cleaved LAP-TGF-β in the serum of 34 patients with PDAC (stage 1−4) and 20 healthy individuals. Biomarker levels were correlated with overall survival (OS) and compared to serum type III collagen (PRO-C3) and type VI collagen (PRO-C6) pro-peptides. PLK-cleaved LAP-TGF-β was higher in patients with PDAC compared to healthy individuals (p < 0.0001). High levels (>median) of PLK-cleaved LAP-TGF-β were associated with poor OS in patients with PDAC independent of age and stage (HR 2.57, 95% CI: 1.22−5.44, p = 0.0135). High levels of PLK-cleaved LAP-TGF-β were associated with high PRO-C3 and PRO-C6, indicating a relationship between the PLK-cleaved LAP-TGF-β fragment, TGF-β activity, and tumor fibrosis. If these preliminary results are validated, circulating PLK-cleaved LAP-TGF-β may be a biomarker for future clinical trials.
MeSH term(s)	Biomarkers/metabolism ; Carcinoma, Pancreatic Ductal/metabolism ; Collagen Type III ; Collagen Type VI ; Complement C3 ; Fibrosis ; Humans ; Pancreatic Neoplasms/metabolism ; Plasma Kallikrein ; Prognosis ; Transforming Growth Factor beta/metabolism ; Tumor Microenvironment ; Pancreatic Neoplasms
Chemical Substances	Biomarkers ; Collagen Type III ; Collagen Type VI ; Complement C3 ; Transforming Growth Factor beta ; Plasma Kallikrein (EC 3.4.21.34)
Language	English
Publishing date	2022-09-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12091315
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Article ; Online: Enhanced processing of von Willebrand factor reflects disease severity and discriminates severe portal hypertension in cirrhosis.

Langholm, Lasse L / Manon-Jensen, Tina / Karsdal, Morten A / Bendtsen, Flemming / Leeming, Diana J / Møller, Søren

European journal of gastroenterology & hepatology

2019 Volume 31, Issue 8, Page(s) 1040–1048

Abstract: Objectives: Portal hypertension in cirrhosis is associated with endothelial dysfunction, impaired wound healing, and decreased platelet count. Increased von Willebrand factor (VWF) formation has been suggested as a compensatory mechanism, but the role ... ...

Abstract	Objectives: Portal hypertension in cirrhosis is associated with endothelial dysfunction, impaired wound healing, and decreased platelet count. Increased von Willebrand factor (VWF) formation has been suggested as a compensatory mechanism, but the role of VWF processing has not been directly assessed. The aim was to measure the processing of activated VWF (VWF-A) in addition to VWF release (VWF-N) to investigate the association of primary hemostasis with disease activity and portal hypertension in liver cirrhosis. Participants and methods: Plasma samples from 105 participants undergoing liver vein catheterization and with liver cirrhosis of varying severity were included in the study together with 20 controls without liver disease. Competitive enzyme-linked immunosorbent assay format was used to estimate biomarkers of VWF turnover using neo-epitope-specific monoclonal antibodies. Results: VWF-N levels and VWF-A levels were significantly elevated in cirrhotic patients compared with controls (P<0.0001), and both markers could discriminate mild from severe cirrhosis (VWF-N, P<0.0001; VWF-A, P<0.05). Both markers correlated well with increasing portal hypertension and could identify patients with clinically significant portal hypertension (VWF-N, area under the curve: 0.78; VWF-A, area under the curve: 0.67). Only VWF-A significantly separated compensated from decompensated patients (P<0.05). Conclusion: The data indicate that both VWF release and processing of active VWF are increased in cirrhosis, reflecting ongoing wound healing initiation. VWF-N and VWF-A may specifically contain information to assess the presence and severity of PHT as an early indicator of cirrhosis, and for acute damage in decompensated cirrhosis. Whether the increased wound healing affects long-term outcome needs to be addressed in future studies.
MeSH term(s)	Aged ; Aged, 80 and over ; Biomarkers/blood ; Blood Pressure/physiology ; Enzyme-Linked Immunosorbent Assay ; Female ; Follow-Up Studies ; Hemostasis/physiology ; Humans ; Hypertension, Portal/blood ; Hypertension, Portal/etiology ; Hypertension, Portal/physiopathology ; Liver/diagnostic imaging ; Liver Cirrhosis/blood ; Liver Cirrhosis/complications ; Liver Cirrhosis/diagnosis ; Male ; Middle Aged ; Retrospective Studies ; Severity of Illness Index ; von Willebrand Factor/metabolism
Chemical Substances	Biomarkers ; von Willebrand Factor
Language	English
Publishing date	2019-02-12
Publishing country	England
Document type	Journal Article
ZDB-ID	1034239-4
ISSN	1473-5687 ; 0954-691X
ISSN (online)	1473-5687
ISSN	0954-691X
DOI	10.1097/MEG.0000000000001380
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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
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Article ; Online: Noninvasive prognostic biomarker potential of quantifying the propeptides of Type XI collagen alpha-1 chain (PRO-C11) in patients with pancreatic ductal adenocarcinoma.

Nissen, Neel Ingemann / Kehlet, Stephanie / Johansen, Astrid Z / Chen, Inna M / Karsdal, Morten / Johansen, Julia S / Diab, Hadi M H / Jørgensen, Lars N / Sun, Shu / Manon-Jensen, Tina / He, Yi / Langholm, Lasse / Willumsen, Nicholas

International journal of cancer

2021 Volume 149, Issue 1, Page(s) 228–238

Abstract: Type XI collagen has been associated with tumor fibrosis and aggressiveness in patients with pancreatic ductal adenocarcinoma (PDAC). The propeptide on Type XI collagen is released into the circulation after proteolytic processing at either amino acid ... ...

Abstract	Type XI collagen has been associated with tumor fibrosis and aggressiveness in patients with pancreatic ductal adenocarcinoma (PDAC). The propeptide on Type XI collagen is released into the circulation after proteolytic processing at either amino acid 253 or 511. This allows for a noninvasive biomarker approach to quantify Type XI collagen production. We developed two ELISA-based biomarkers, targeting the two enzymatic cleavage sites (PRO-C11-253 and PRO-C11-511). In a discovery cohort including serum from patients with PDAC (n = 39, Stages 1-4), chronic pancreatitis (CP, n = 12) and healthy controls (n = 20), PRO-C11-511, but not PRO-C11-253, was significantly upregulated in patients with PDAC and CP compared to healthy controls. Furthermore, PRO-C11-511 levels >75th percentile were associated with poor overall survival (OS) (HR, 95% CI: 3.40, 1.48-7.83). The PRO-C11-511 biomarker potential was validated in serum from 686 patients with PDAC. Again, high levels of PRO-C11-511 (>75th percentile) were associated with poor OS (HR, 95% CI: 1.68, 1.40-2.02). Furthermore, PRO-C11-511 remained significant after adjusting for clinical risk factors (HR, 95% CI: 1.50, 1.22-1.86). In conclusion, quantifying serum levels of Type XI collagen with PRO-C11-511 predicts poor OS in patients with PDAC. This supports that Type XI collagen is important for PDAC biology and that PRO-C11-511 has prognostic noninvasive biomarker potential for patients with PDAC.
MeSH term(s)	Aged ; Biomarkers, Tumor/blood ; Carcinoma, Pancreatic Ductal/blood ; Carcinoma, Pancreatic Ductal/diagnosis ; Case-Control Studies ; Collagen Type XI/metabolism ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Pancreatic Neoplasms/blood ; Pancreatic Neoplasms/diagnosis ; Peptide Fragments/blood ; Prognosis ; Retrospective Studies ; Survival Rate ; Pancreatic Neoplasms
Chemical Substances	Biomarkers, Tumor ; Collagen Type XI ; Peptide Fragments
Language	English
Publishing date	2021-03-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.33551
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Zs.A 478: 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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Article ; Online: Increased von Willebrand Factor Processing in COPD, Reflecting Lung Epithelium Damage, Is Associated with Emphysema, Exacerbations and Elevated Mortality Risk.

Langholm, Lasse L / Rønnow, Sarah Rank / Sand, Jannie M B / Leeming, Diana Julie / Tal-Singer, Ruth / Miller, Bruce E / Vestbo, Jørgen / Karsdal, Morten A / Manon-Jensen, Tina

International journal of chronic obstructive pulmonary disease

2020 Volume 15, Page(s) 543–552

Abstract: Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and lung tissue deterioration. Given the high vascularity of the lung, von Willebrand factor (VWF), a central component of wound healing initiation, has ... ...

Abstract	Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and lung tissue deterioration. Given the high vascularity of the lung, von Willebrand factor (VWF), a central component of wound healing initiation, has previously been assessed in COPD. VWF processing, which is crucial for regulating the primary response of wound healing, has not been assessed directly. Therefore, this study aimed to characterize wound healing initiation in COPD using dynamic VWF-processing biomarkers and to evaluate how these relate to disease severity and mortality. Methods: A cross-sectional analysis of plasma samples from the ECLIPSE study collected at year 1 from moderate to very severe COPD subjects (GOLD 2-4, n=984) was performed. We applied competitive neo-epitope ELISAs specifically targeting the formation of and ADAMTS13-processed form of VWF, VWF-N and VWF-A, respectively. Results: VWF-A and VWF-N were significantly increased (VWF-N, p=0.01; VWF-A, p=0.0001) in plasma of symptomatic (mMRC score ≥2) compared to asymptomatic/mild symptomatic COPD subjects. Increased VWF-N and VWF-A levels were specifically associated with emphysema (VWF-N, p<0.0001) or prior exacerbations (VWF-A, p=0.01). When dichotomized, high levels of both biomarkers were associated with increased risk of all-cause mortality (VWF-N, HR 3.5; VWF-A, HR 2.64). Conclusion: We demonstrate that changes in VWF processing were related to different pathophysiological aspects of COPD. VWF-N relates to the chronic condition of emphysema, while VWF-A was associated with the more acute events of exacerbations. This study indicates that VWF-A and VWF-N may be relevant markers for characterization of disease phenotype and are associated with mortality in COPD. Study identifier: NCT00292552; GSK study code SCO104960.
MeSH term(s)	Adult ; Aged ; Biomarkers/blood ; Case-Control Studies ; Cross-Sectional Studies ; Disease Progression ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/pathology ; Female ; Humans ; Lung/blood supply ; Male ; Middle Aged ; Predictive Value of Tests ; Prognosis ; Pulmonary Disease, Chronic Obstructive/blood ; Pulmonary Disease, Chronic Obstructive/diagnosis ; Pulmonary Disease, Chronic Obstructive/mortality ; Pulmonary Emphysema/blood ; Pulmonary Emphysema/diagnosis ; Pulmonary Emphysema/mortality ; Risk Assessment ; Risk Factors ; Severity of Illness Index ; Up-Regulation ; Wound Healing ; von Willebrand Factor/metabolism
Chemical Substances	Biomarkers ; von Willebrand Factor
Language	English
Publishing date	2020-03-09
Publishing country	New Zealand
Document type	Comparative Study ; Journal Article ; Multicenter Study ; Observational Study
ISSN	1178-2005
ISSN (online)	1178-2005
DOI	10.2147/COPD.S235673
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Article ; Online: Endotrophin, an extracellular hormone, in combination with neoepitope markers of von Willebrand factor improves prediction of mortality in the ECLIPSE COPD cohort.

Rønnow, Sarah R / Langholm, Lasse L / Karsdal, Morten A / Manon-Jensen, Tina / Tal-Singer, Ruth / Miller, Bruce E / Vestbo, Jørgen / Leeming, Diana J / Sand, Jannie M B

Respiratory research

2020 Volume 21, Issue 1, Page(s) 202

Abstract: Background: Lung epithelial damage, activation of the wound healing cascade, and remodeling of the extracellular matrix (ECM) play a major role in chronic obstructive pulmonary disease (COPD). The pro-peptide of type VI collagen has been identified as ... ...

Abstract	Background: Lung epithelial damage, activation of the wound healing cascade, and remodeling of the extracellular matrix (ECM) play a major role in chronic obstructive pulmonary disease (COPD). The pro-peptide of type VI collagen has been identified as the hormone endotrophin. Endotrophin has been shown to promote fibrosis and inflammation, whereas von Willebrand factor (VWF) is a crucial part of wound healing initiation. Here, we assessed the released and activated form of VWF and endotrophin, the pro-peptide of type VI collagen, serologically to investigate their association with mortality in COPD subjects alone or in combination. Methods: One thousand COPD patients with 3 years of clinical follow-up from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort were included. Serum and heparin plasma were collected at 6 months and 1 year, respectively. Competitive ELISA utilizing specific monoclonal antibodies assessed endotrophin/type VI collagen formation (PRO-C6), VWF release (VWF-N), and activated VWF (VWF-A). Biomarker levels were dichotomized into high and low as defined by receiver operating characteristic (ROC) curves based on mortality data. Kaplan-Meier analysis was used to determine hazard ratios for all-cause mortality for biomarkers alone or in combination. Results: High levels of PRO-C6, VWF-A, and VWF-N have previously been shown to be individually associated with a higher risk of mortality with hazard ratios of 5.6 (95% CI 2.4-13.1), 3.7 (1.8-7.6), and 4.6 (2.2-9.6), respectively. The hazard ratios increased when combining the biomarkers: PRO-C6VWFA 8.8 (2.8-27.7) and PRO-C6VWFN 13.3 (5.6-32.0). Notably, PRO-C6VWF-N increased more than 2-fold. Conclusion:* We demonstrated that by combining two pathological relevant aspects of COPD, tissue remodeling, and wound healing, the predictive value of biomarkers for mortality increased notably.
MeSH term(s)	Aged ; Biomarkers/blood ; Cohort Studies ; Collagen Type VI/blood ; Collagen Type VI/genetics ; Epitopes/blood ; Epitopes/genetics ; Extracellular Matrix/genetics ; Extracellular Matrix/metabolism ; Female ; Follow-Up Studies ; Genetic Markers/genetics ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Mortality/trends ; Peptide Fragments/blood ; Peptide Fragments/genetics ; Predictive Value of Tests ; Pulmonary Disease, Chronic Obstructive/blood ; Pulmonary Disease, Chronic Obstructive/genetics ; Pulmonary Disease, Chronic Obstructive/mortality ; von Willebrand Factor/genetics ; von Willebrand Factor/metabolism
Chemical Substances	Biomarkers ; Collagen Type VI ; Epitopes ; Genetic Markers ; Peptide Fragments ; endotrophin ; von Willebrand Factor
Language	English
Publishing date	2020-07-30
Publishing country	England
Document type	Clinical Trial ; Letter
ZDB-ID	2041675-1
ISSN	1465-993X ; 1465-9921
ISSN (online)	1465-993X
ISSN	1465-9921
DOI	10.1186/s12931-020-01461-6
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Article ; Online: Combining biomarkers of clot resolution and alveolar basement membrane destruction predicts mortality in the ECLIPSE COPD cohort.

Sand, Jannie M B / Rønnow, Sarah R / Langholm, Lasse L / Karsdal, Morten A / Manon-Jensen, Tina / Tal-Singer, Ruth / Miller, Bruce E / Vestbo, Jørgen / Leeming, Diana J

Respiratory medicine

2020 Volume 173, Page(s) 106185

Abstract: Background: Chronic obstructive pulmonary disease (COPD) is characterized by abnormal epithelial repair resulting in a hypercoagulable state with intra-alveolar accumulation of fibrin and alveolar basement membrane destruction. This study aimed to ... ...

Abstract	Background: Chronic obstructive pulmonary disease (COPD) is characterized by abnormal epithelial repair resulting in a hypercoagulable state with intra-alveolar accumulation of fibrin and alveolar basement membrane destruction. This study aimed to investigate if the combination of two serological biomarkers evaluating these pathological processes could improve the prediction of mortality risk compared to single biomarkers. Methods: Matrix metalloproteinase-mediated degradation of the type IV collagen α3 chain (C4Ma3), located in the alveolar basement membrane, and plasmin-mediated degradation of crosslinked fibrin (X-FIB), an end-product of fibrinogen, were assessed serologically in a subset of the ECLIPSE cohort (n = 982). Biomarker data were dichotomized into high versus low at the median. Cox regression and Kaplan-Meier curves were used to analyze the predictive value of having one or two high biomarkers for all-cause mortality over two years. Results: COPD participants with high levels of two biomarkers were at significantly higher risk of all-cause mortality with a hazard ratio of 7.66 (95% CI 1.75-33.48; p = 0.007) while participants with one high biomarker were not at significantly higher risk (HR 3.79 [95% CI 0.85-16.94]; p = 0.08). Conclusions: A combination of serological biomarkers of alveolar basement membrane destruction and clot resolution was predictive of all-cause mortality in COPD. The combination of two different pathological aspects may strengthen prognostic accuracy and could be used in conjunction with clinical assessment to guide treatment decisions.
MeSH term(s)	Aged ; Autoantigens/blood ; Basement Membrane/pathology ; Biomarkers/blood ; Cause of Death ; Cohort Studies ; Collagen Type IV/blood ; Female ; Forecasting ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Prognosis ; Pulmonary Alveoli/pathology ; Pulmonary Disease, Chronic Obstructive/complications ; Pulmonary Disease, Chronic Obstructive/mortality ; Pulmonary Disease, Chronic Obstructive/pathology ; Risk ; Thrombophilia/diagnosis ; Thrombophilia/etiology ; Thrombosis/diagnosis ; Thrombosis/etiology
Chemical Substances	Autoantigens ; Biomarkers ; Collagen Type IV ; type IV collagen alpha3 chain
Keywords	covid19
Language	English
Publishing date	2020-10-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1003348-8
ISSN	1532-3064 ; 0954-6111
ISSN (online)	1532-3064
ISSN	0954-6111
DOI	10.1016/j.rmed.2020.106185
Database	MEDical Literature Analysis and Retrieval System OnLINE

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