Introduction: Metabolic-associated fatty liver disease is common, with fibrosis the major determinant of adverse outcomes. Population-based screening tools with high diagnostic accuracy for the staging of fibrosis are lacking. Methods: Three independent cohorts, 2 with both liver biopsy and liver s...
November 26, 2020
Journal:
Am J Physiol Gastrointest Liver Physiol
Author:
Eslam M, Wong GL, Hashem AM, Chan HL, Nielsen MJ, Leeming DJ, Chan AW, Chen Y, Duffin KL, Karsdal M, Schattenberg JM, George J, Wong VW
New therapeutic strategies are needed for the growing unmet clinical needs in liver disease and fibrosis. Platelet activation and PDGF activity are recognized as important therapeutic targets; however, no therapeutic approach has yet addressed these two upstream drivers of liver fibrosis. We therefo...
November 20, 2020
Journal:
Biomaterials
Author:
Kabra H, Walimbe T, Stuart K, Indey C, Jalgaonkar S, Ikwa E, Skurnac T, Chen J, Woolley A, Snead NM, Bachtell N, Leeming DJ, Karsdal M, Prestwich G, Panitch A, Paderi J
Purpose: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis is present in 80-90% of HCC patients. Cirrhosis is characterized by deposition and cross-linking of collagens that have crucial roles in HCC initiation and progression. We eva...
November 20, 2020
Journal:
J Hepatocell Carcinoma
Author:
Jensen C, Holm Nielsen S, Eslam M, Genovese F, Nielsen MJ, Vongsuvanh R, Uchila R, van der Poorten D, George J, Karsdal MA, Leeming DJ, Willumsen N.
Purpose: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis is present in 80-90% of HCC patients. Cirrhosis is characterized by deposition and cross-linking of collagens that have crucial roles in HCC initiation and progression. We eva...
November 20, 2020
Journal:
J Hepatocell Carcinoma
Author:
Jensen C, Holm Nielsen S, Eslam M, Genovese F, Nielsen MJ, Vongsuvanh R, Uchila R, van der Poorten D, George J, Karsdal MA, Leeming DJ, Willumsen N.
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 bi...
November 19, 2020
Journal:
Lancet Respir Med
Author:
Sand JMB, Rønnow SR, Langholm LL, Karsdal MA, Manon-Jensen T, Tal-Singer R, Miller BE, Vestbo J, Leeming DJ
The effect of direct-acting antiviral (DAA) therapy on extracellular matrix (ECM) turnover, a prominent feature of chronic hepatitis C (CHC), is unknown. ECM protein degradation and formation generate fragments reflecting the tissue turnover balance when quantified in the blood. PRO-C3 and PRO-C4 re...
October 15, 2020
Journal:
J Viral Hepat
Author:
Laursen TL, Villesen IF, Leeming DJ, Karsdal MA, Sølund C, Tarp B, Kristensen LH, Holmboe CH, Leuthcher P, Laursen AL, Gudmann NS, Grønbaek H
Background & aims: Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are phenotypically distinct autoimmune liver diseases that progress to cirrhosis and liver failure; however, their histological fibrosis distribution differs. We investigated...
September 3, 2020
Journal:
JHEP Rep
Author:
Vesterhus M, Nielsen MJ, Hov JR, Saffioti F, Manon-Jensen T, Leeming DJ, Moum B, Boberg KM, Pinzani M, Karlsen TH, Karsdal MA, Thorburn D
There is an unmet need for high-quality liquid biomarkers that can safely and reproducibly predict the stage of fibrosis and the outcomes of chronic liver disease (CLD). The requirement for such markers has intensified because of the high global prevalence of diseases such as non-alcoholic fatty liv...
April 9, 2020
Journal:
Liver Int
Author:
Karsdal MA, Daniels SJ, Nielsen SH, Bager CL, Rasmussen DGK, Loomba R, Surabattula R, Villesen IF, Luo Y, Shevell D, Gudmann NS, Nielsen MJ, George J, Christian R, Leeming DJ, Schuppan D
Extracellular matrix (ECM) remodeling is a hallmark of the pathology of gastrointestinal disorders. Collagen type VI (COL6) is produced by fibroblasts, and the COL6 α3-chain has shown to be elevated in patients with ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC). Measuring...
April 3, 2020
Journal:
Sci Rep
Author:
Nielsen SH, Mortensen JH, Willumsen N, guldager Kring Rasmussen D, Mogensen DJ, Di Sabatino A, Mazza G, Jørgensen LN, giuffrida P, Pinzani M, Klinge LG, Kjeldsen J, Leeming DJ, Karsdal MA, Genovese F
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 es...
March 11, 2020
Journal:
Sci Rep
Author:
Rønnow S, Langholm LL, Sand JMB, Thoracius-Using J, Leeming DJ, Manon-Jensen T, Tal-Singer R, Miller BE, Karsdal MA, Vestbo J
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,...
March 9, 2020
Journal:
Int J Chron Obstruct Pulmon
Author:
Langholm LL, Rønnow S, bülow Sand JM, Leeming DJ, Talsinger R, Miller BE, Vestbo J, Karsdal MA, Manon-Jensen T
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essenti...
January 6, 2020
Journal:
Am J Physiol Gastrointest Liver Physiol
Author:
Daniels SJ, Leeming DJ, Detlefsen S, Bruun MF, Hjuler ST, Henriksen K, Hein P, Krag A, Karsdal MA, Nielsen MJ, Brockbank S, Cruwys S
An altered liver microenvironment characterized by a dysregulated extracellular matrix (ECM) supports the development and progression of hepatocellular carcinoma (HCC). The development of experimental platforms able to reproduce these physio-pathological conditions is essential in order to identify ...
December 28, 2019
Journal:
Cells
Author:
Mazza G, Telese A, Al-Akkad W, Frenguelli L, Levi A, Marrali M, Longato L, Thanapirom K, Vilia MG, Lombardi B, Crowley C, Crawford M, Karsdal MA, Leeming DJ, Marrone G, Bottcher K, Robinson B, Del Rio Hernandez A, Tamburrino D, Spoletini G, Malago M, Hall AR, Godovac-Zimmermann J, Luong TV, De Coppi P, Pinzani M, Rombouts K
Background: Chronic obstructive pulmonary disease (COPD) is characterized by abnormal epithelial repair process that may result in intra-airway accumulation of fibrin. Given that plasma fibrinogen is the only FDA approved biomarker that predicts mortality and COPD exacerbations, we hypothesized that...
December 2, 2019
Journal:
Lancet Respir Med
Author:
Manon-Jensen T, Langholm LL, Ronnow SR, Karsdal MA, Tal-Singer R, Vestbo J, Leeming DJ, Miller BE, bülow Sand JM
Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups...
October 25, 2019
Journal:
Nat Med
Author:
Moroni F, Dwyer BJ, Graham C, Pass C, Bailey L, Ritchie L, Mitchell D, Glover A, Lauire A, Doig S, Hargreaves E, Fraser AR, Turner ML, Cambpell JDM, McGowan NWA, Barry J, Moore JK, Hayes PC, Leeming DJ, Nielsen MJ, Musa K, Fallowfield JA, Forbes SJ
BACKGROUND: Lifestyle modifications remain the cornerstone of treatment in non-alcoholic fatty liver disease (NAFLD). However, they requently fail related to the inability of patients to implement lasting changes. AIMS: To evaluate the effects of a short, web-based, individualised exercise program ...
October 16, 2019
Journal:
Aliment Pharmacol Ther.
Author:
Huber Y, Pfirrmann D, Gebhardt I, Labenz C, Gehrke N, Straub C, Ruckes C, Bantel H, Belda E, Clément K, Leeming DJ, Karsdal MA, Galle PR, Simon P, Schattenberg JM
Following liver transplantation (LT), 10-30% of patients develop recurrent cirrhosis (RC). There is an urgent need for predictive non-invasive markers for improved monitoring of these patients. Here we studied extracellular matrix biomarkers as predictors of RC after LT. Forty-seven LT patients were...
October 16, 2019
Journal:
Sci Rep
Author:
Nielsen MJ, Villesen IF, Gudmann NS, Leeming DJ, Krag A, Karsdal MA, Zimmermann T, Schuppan D
Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was ass...
July 12, 2019
Journal:
Respir Res.
Author:
Orlan LA, Duggan AR, Oballa E, Taggart SC, Simpson JK, Kangombe AR, Braybrooke R, Molyneaux PL, North B, Karkera Y, Leeming DJ, Karsdal MA, Nanthakumar CB, Fahy WA, Marshall RP, Jenkins RG, Maher TM
Background and aims: Although combined antiretroviral treatment (cART) has improved overall survival of HIV infected patients, liver fibrosis and liver related-mortality still constitute major challenges in HIV positive patients. Collagen accumulates in the liver during fibrogenesis. Recent studies ...
July 11, 2019
Journal:
PLoS One
Author:
Dold L, Nielsen MJ, Praktiknjo M, Schwarzer-Zander C, Boesecke C, Schierwagen R, Mohr R, Wasmuth JC, Jansen C, Bischoff J, Rockstroh J, Karsdal MA, Trebicka J, Leeming DJ
OBJECTIVE: This study assessed the utility of plasma fragments of propeptides of type III (PRO-C3), V (PRO-C5), and VI (PRO-C6) procollagen for the detection of liver fibrosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Patients with T2DM (n = 191) underwent an or...
July 1, 2019
Journal:
Diabetes Care
Author:
Bril F, Leeming DJ, Karsdal MA, Kalavalapalli S, Darb D, Lai J, Rabe M, Cusi K
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 es...
March 9, 2019
Journal:
Sci Rep
Author:
Ronnow SR, Langholm LL, Sand JMB, Thoracius-Ussing J, Leeming DJ, Manon-Jensen T, Tal-Singer R, Miller BE, Karsdal MA, Vestbo J
BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a prevalent disease that is highly associated with the metabolic syndrome and type II diabetes. The development of in vivo models that reflect all nuances of the human NASH pathology is essential for drug discovery and development. We aimed to furt...
March 1, 2019
Journal:
biomed pharmacother
Author:
Daniels SJ, Leeming DJ, Detlefsen S, Bruun MF, Hjuler ST, Henriksen K, Hein P, Karsdal MA, Brockbank S, Cruwys S
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...
February 12, 2019
Journal:
Eur J Gastroenterol Hepatol
Author:
Langholm LL, Manon-Jensen T, Karsdal MA, Bendtsen F, Leeming DJ, Møller S
OBJECTIVES: Remodeling of the extracellular matrix (ECM) is a key event in different lung disorders, such as fibrosis and cancer. The most common cell type in the connective tissue is fibroblasts, which transdifferentiate into myofibroblasts upon activation. All myofibroblasts express α-SMA, which h...
February 12, 2019
Journal:
Transl Oncol
Author:
Holm Nielsen S, Willumsen N, Leeming DJ, Daniels SJ, brix s, Karsdal MA, Genovese F, Nielsen MJ
BACKGROUND AIMS: Remodelling of extracellular matrix is crucial in progressive liver fibrosis. Collagen type III desposition has been shown in acute decompensation. Extratracellular matrix is compiled of deposition of various components. The role of basement membrane collagen type IV in advanced cir...
February 9, 2019
Journal:
Liver Int
Author:
Lehmann J, Praktiknjo M, Nielsen MJ, Schierwagen R, Meyer C, Thomas D, Violi F, Strassburg CP, Bendtsen F, Møller S, Krag A, Karsdal M, Leeming DJ, Trebicka J
OBJECTIVES: Lysyl oxidase like 2 (LOXL2) is associated with poor prognosis in idiopathic pulmonary disease (IPF) and cancer. We developed an Enzyme-linked immunosorbent assay (ELISA) targeting the LOXL2 neo-epitope generated through the release of the signal peptide during LOXL2 maturation. DESIGN ...
November 30, 2018
Journal:
Biochem Biophys Rep
Author:
Leeming DJ, Willumsen N, Sand JM, Holm Nielsen S, Dasgupta B, Brodmerkel C, Bager CL, Karsdal MA
Background: Patients with atherosclerosis have a high risk of cardiovascular events and death. Atherosclerosis is characterized by accumulation of lipids, cells and extracellular matrix proteins in the intima. We hypothesized that dysregulated remodeling of the basement membrane proteins may be asso...
November 6, 2018
Journal:
J am heart assoc
Author:
Nielsen SH, Tengryd C, Edsfeldt A, Brix S, Genovese F, Bengtsson E, Karsdal MA, Leeming DJ, Nilsson J, Goncalves I
Chronic obstructive pulmonary disease (COPD) is characterized by high levels of protease activity leading to degradation of elastin followed by loss of elasticity of the lung and the development of emphysema. Elastin is an essential structural component of the lung parenchyma to support the expansio...
September 10, 2018
Journal:
Biochem Biophys Res Commun
Author:
Gudmann NS, Manon-Jensen T, Sand JMB, Diefenbach C, Sun S, Danielsen A, Karsdal MA, Leeming DJ
Chronic obstructive pulmonary disease (COPD) is characterized by high levels of protease activity leading to degradation of elastin followed by loss of elasticity of the lung and the development of emphysema. Elastin is an essential structural component of the lung parenchyma to support the expansio...
September 10, 2018
Journal:
Biochem Biophys Res Commun
Author:
Gudmann NS, Manon-Jensen T, Sand JM, Diefenbach C, Sun S, Danielsen A, Karsdal MA, Leeming DJ
BACKGROUND AND AIMS: Macrophages play a significant role in chronic liver disease as reflected by elevated soluble (s)CD163 and mannose receptor (sMR) levels and associated with liver disease severity and prognosis. Extracellular matrix remodelling associated with fibrogenesis may be affected by sys...
September 5, 2018
Journal:
PLoS One
Author:
kimer N, Gudmann NS, Pedersen JS, Møller S, Nielsen MJ, Leeming DJ, Karsdal MA, Møller HJ, Bedtsen F, Grønbæk H
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