Amylin treatment improves body weight and glucose control, although it is limited by a short action and need for high doses. Dual amylin and calcitonin receptor agonists (DACRAs) are dual amylin and calcitonin receptor agonists with beneficial effects beyond those of amylin. However, to what extent ...
April 21, 2020
Journal:
J Pharmacol Exp Ther
Author:
Larsen AT, Sonne N, Andreassen KV, Karsdal MA, Henriksen K
Pharmacological treatment with dual amylin and calcitonin receptor agonists (DACRAs) cause significant weight loss and improvement of glucose homeostasis. In this study, the maximally efficacious dose of the novel DACRA, KeyBiosciencePeptide (KBP)-066, was investigated. Two different rat models were...
April 14, 2020
Journal:
J Pharmacol Exp Ther
Author:
Sonne N, Larsen AT, Andreassen KV, Karsdal MA, Henriksen K
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
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
Is liver fibrosis just liver fibrosis? Or do the subtype of collagen, its spatial localization in the liver, its cell of origin, and the time point at which it is synthesized also matter? It is important, since the various collagen subtypes hold different informative values regarding reparative proc...
December 18, 2019
Journal:
Hepatology
Author:
Karsdal MA, Detlefsen S, Daniels SJ, Nielsen MJ, Krag A, Schuppan D
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
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
There is an unmet need for non-invasive biomarkers in non-alcoholic fatty liver disease (NAFLD) that can diagnose advanced disease and identify patients suitable for clinical trials. The PRO-C3 collagen neo-epitope is a putative direct marker of fibrogenesis. We assessed the performance of PRO-C3 in...
July 4, 2019
Journal:
JHEP Rep
Author:
Boyle M, tiniakos D, Schattenberg JM, Ratziu V, Bugianessi E, Petta S, Oliveira CP, Govaere O, Yournes R, McPherson S, Bedossa P, Nielsen MJ, Karsdal M, Oersnes-Leeming DJ, Kendrick, Anstee QM
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
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, Bendtsen F, Grønbæk H
BACKGROUND: Host genetic modifiers of the natural history of chronic hepatitis B (CHB) remain poorly understood. Recently, a genome-wide association study (GWAS)-identified polymorphism in the STAT4 gene that contributes to the risk for hepatocellular carcinoma (HCC) was shown to be associated with ...
September 3, 2018
Journal:
Aliment Pharmacol Ther
Author:
El Sharkawy R, Thabet K, Lampertico P, Petta S, Mangia A, Berg T, Netwally M, Bayoumi A, Boonstra A, Brouwer WP, Smedile A, Abate ML, Loglio A, Douglas MW, Khan A, Santoro R, Fischer J, Leeming DJ, Liddle C, George J, Eslam M
OBJECTIVE: There is a need for non-invasive biomarkers that can identify patients with progressive liver fibrosis and monitor response to anti-fibrotic therapy. An equally important need is identification of patients with spontaneous fibrosis regression, since they may not need treatment nor be incl...
August 30, 2018
Journal:
Am J Physiol Gastrointest Liver Physiol
Author:
Karsdal MA, Hjuler ST, Luo Y, Rasmussen DG, Nielsen MJ, Nielsen SH, Leeming DJ, Goodman ZD, Arch RH, Patel K, Schuppan D
OBJECTIVE: There is a need for non-invasive biomarkers that can identify patients with progressive liver fibrosis and monitor response to anti-fibrotic therapy. An equally important need is identification of patients with spontaneous fibrosis regression, since they may not need treatment nor be incl...
August 30, 2018
Journal:
Am J Physiol Gastrointest Liver Physiol.
Author:
Karsdal MA, Hjuler ST, Luo Y, Rasmussen DG, Nielsen MJ, Holm Nielsen S, Leeming DJ, goodman Z, Arch RH, Patel K, Schuppan D
BACKGROUND AND AIM: Given the high global prevalence of non-alcoholic fatty liver disease (NAFLD), the need for relevant non-invasive biomarkers and algorithms to accurately stage disease severity is a critical unmet medical need. Identifying those with advanced fibrosis (≥F3) is the most crucial, a...
July 16, 2018
Journal:
Hepagology
Author:
Daniels SJ, Leeming DJ, Eslam M, Hashem AM, Nielsen MJ, Krag A, Karsdal MA, Grove JI, Guha IN, Kawaguchi T, Torimura T, McLeod D, Akiba J, Kaye P, de Boer B, Aithal GP, Adams LA, George J
BACKGROUND: Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Biomarkers of disease activity or prognostic models predicting outcome at an individual level are currently not established. AIM: To evaluate the prognostic utility of four biomarkers of bas...
July 16, 2018
Journal:
Alimentary pharmacology therapeutics
Author:
Nielsen MJ, Thorburn D, Leeming DJ, Hov JR, Nygård S, Moum B, Saffioti F, Gilja OH, Boberg KM, Mazza G, Røsjø H, Pinzani M, Karlsen TH, Karsdal MA, Vesterhus M
Patients with end-stage liver disease develop acute decompensation (AD) episodes, which become more frequent and might develop into acute-on-chronic liver failure (ACLF). However, it remains unknown how AD induces acceleration of liver disease. We hypothesized that remodeling of collagen type III pl...
January 18, 2018
Journal:
Hepatol Commun
Author:
Praktiknjo M, Lehmann J, Nielsen MJ, Schierwagen R, Uschner FE, Meyer C, Thomas D, Strassburg CP, Bendtsen F, Møller S, Krag A, Karsdal MA, Leeming DJ, Trebicka J
Organ fibrosis is characterized by a chronic wound-healing response, with excess deposition of extracellular matrix components. Here, collagen type I represents the most abundant scar component and a primary target for antifibrotic therapies. Liver fibrosis can progress to cirrhosis and primary live...
November 6, 2017
Journal:
Matrix Biol.
Author:
Molokanova O, Schönig K, Weng SY, Wang X, Bros M, Diken M, Ohngemach S, Karsdal MA, Strand D, Nikolaev A, Eshkind L, Schuppan D
OBJECTIVE:Detecting significant fibrosis and cirrhosis remains important in treatment and follow-up of patients with chronic hepatitis C Infection (CHC). The aim of this study was to assess the ability of PRO-C3 to identify significant fibrosis (Ishak score ≥3) and cirrhosis (Ishak score ≥5) both as...
October 25, 2017
Journal:
Scand J Gastroenterol
Author:
Hansen JF, Juul Nielsen M, Nyström K, Leeming DJ, Lagging M, Norkrans G, Brehm Christensen P, Karsdal MA
There are no approved treatments for liver fibrosis. To aid development of antifibrotic therapies, noninvasive biomarkers that can identify patients with progressive fibrosis and that permit monitoring of the response to antifibrotic therapy are much needed. Samples from a phase II antifibrotic tria...
October 20, 2016
Journal:
Am J Physiol Gastrointest Liver Physiol
Author:
Karsdal MA, Henriksen K, Nielsen MJ, Byrjalsen I, Leeming DJ, Gardner SD, Goodman ZD, Patel K, Krag A, Christiansen C, Schuppan D
BACKGROUND: While morphological patterns differ, the molecular phenotype of liver fibrosis is considered a stereotypical response to chronic liver injury. However, with different cellular triggers and networks regulating fibrosis, the molecular responses of the injured liver may not be identical. A...
October 3, 2016
Journal:
Aliment Pharmacol Ther.
Author:
Nielsen MJ, Karsdal MA, Kazankov K, Krag A, Grønbæk H, Leeming DJ, Schuppan D, George J
Background and aims: Progressive fibrosis increases hepatic resistance and causes portal hypertension with complications. During progressive fibrosis remodeling and deposition of collagens and elastin occur. Elastin remodeling is crucially involved in fibrosis progression in animal models and human ...
July 3, 2015
Journal:
Dig Dis Sci
Author:
Nielsen MJ, Lehmann J, Leeming DJ, Schierwagen R, Klein S, Jansen C, Strassburg CP, Bendtsen F, Møller S, Sauerbruch T, Karsdal MA, Krag A, Trebicka J
Background and aims: The hepatic venous pressure gradient (HVPG) is an important but invasive diagnostic and prognostic marker in cirrhotic patients. The aim of the study was to evaluate a novel biochemical plasma marker of true type V collagen formation (Pro-C5) for describing HVPG. Methods: Ninet...
May 1, 2015
Journal:
Scand J Gastroenterol
Author:
Leeming DJ, Veidal SS, Karsdal MA, Nielsen MJ, Trebicka J, Busk T, Bendtsen F, Krag A, Møller S
Fibrogenesis results in release of certain extracellular matrix protein fragments into the circulation. We evaluated the diagnostic and prognostic performance of two novel serological markers, the precisely cleaved N-terminal propeptide of type III collagen (Pro-C3) and a peptide of helical collagen...
February 1, 2015
Journal:
Liver Int
Author:
Nielsen MJ, Veidal SS, Karsdal MA, Leeming DJ, Vainer B, Gardner SD, Hamatake R, Goodman ZD, Schuppan D, Patel K
Background: Liver-related deaths represent the leading cause of mortality among patients with HIV/HCV-co-infection, and are mainly related to complications of fibrosis and portal hypertension. In this study, we aimed to evaluate the structural changes by the assessment of extracellular matrix (ECM) ...
September 29, 2014
Journal:
PLoS One
Author:
Christian Jansen, Diana J Leeming, Mattias Mandorfer, Inger Byrjalsen, Robert Schierwagen, Philipp Schwabl, Morten A Karsdal, Evrim Anadol, Christian P Strassburg, Jürgen Rockstroh, Markus Peck-Radosavljevic, Søren Møller, Flemming Bendtsen, Aleksander Krag, Thomas Reiberger, Jonel Trebicka
Objectives: Combined antiretroviral therapy (cART) attenuates hepatic fibrosis in hepatitis C virus and HIV coinfected patients. However, the role of HIV or cART on hepatic fibrosis in HIV monoinfection is discussed controversially. During liver fibrosis, matrix metalloproteinases (MMPs) degrade ext...
September 1, 2014
Journal:
AIDS
Author:
Leeming DJ, Anadol E, Schierwagen R, Karsdal MA, Byrjalsen I, Nielsen MJ, Schwarzer-Zander C, Boesecke C, Bendtsen F, Møller S, Strassburg CP, Spengler U, Krag A, Rockstroh J, Trebicka JK
Background: Nearly 45% of all deaths are associated with chronic fibroproliferative diseases, of which the primary characteristic is altered remodelling of the extracellular matrix. A major difficulty in developing anti-fibrotic therapies is the lack of accurate and established techniques to estimat...
August 5, 2014
Journal:
Aliment Pharmacol Ther.
Author:
Karsdal MA, Krarup H, Sand JM, Christensen PB, Gerstoft J, Leeming DJ, Weis N, Schaffalitzky de Muckadell OB, Krag A
Background: The hepatic venous pressure gradient (HVPG) is an invasive, but important diagnostic and prognostic marker in cirrhosis with portal hypertension (PHT). During cirrhosis, remodelling of fibrotic tissue by matrix metalloproteinases (MMPs) is a permanent process generating small fragments o...
November 5, 2013
Journal:
Aliment Pharmacol Ther.
Author:
Leeming DJ, Karsdal MA, Bendtsen F, Trebicka J, Nielsen MJ, Christiansen C, Møller S, Krag A
BACKGROUND:Progression of liver fibrosis is characterized by synthesis and degradation of extracellular matrix (ECM). Matrix-metalloproteinases (MMP) cleave collagen fibers at a specific site and thereby generate soluble fragments of ECM (neo-epitopes). The levels of these neo-epitopes might reflect...
July 30, 2013
Journal:
Front Physiol
Author:
Schierwagen R, Leeming DJ, Klein S, Granzow M, Nielsen MJ, Sauerbruch T, Krag A, Karsdal MA, Trebicka J
Having previously shown that levels of the citrullinated vimentin peptide VICM are raised in liver fibrosis in rats, we aimed to investigate whether inhibition of citrullination as measured by VICM levels could affect fibrogenesis. Methods: Fibrogenesis was evaluated by quantitative histology and ci...
May 24, 2013
Journal:
Am J Transl Res
Author:
Vassiliadis E, Veidal SS, Kristiansen MN, Hansen C, Jorgensen M, Leeming DJ, Karsdal MA
Background: The proteoglycan biglycan (BGN) is involved in collagen fibril assembly and its fragmentation is likely to be associated with collagen turnover during the pathogenesis of diseases which involve dysregulated extracellular matrix remodeling (ECMR), such as rheumatoid arthritis (RA) and liv...
May 15, 2013
Journal:
Fibrogenesis Tissue Repair
Author:
Genovese F, Barascuk N, Larsen L, Nawrocki A, Li Y, Zheng Q, Wang J, Veidal SS, Leeming DJ, Karsdal MA
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