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, Prestwich G, Panitch A, Paderi J, Karsdal MA
Abstract Introduction: Hepatic fibrosis is the excessive synthesis and deposition of extracellular matrix including collagen in the tissue. Chronic liver insult leads to progressive parenchymal damage, portal hypertension, and cirrhosis. Determination of hepatic collagen by invasive liver biopsy ...
September 24, 2020
Journal:
Expert Rev Mol Diagn
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
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
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
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
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
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
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, Oersnes-Leeming DJ, Kendrick, Anstee QM, Karsdal MA
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
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
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, Leeming DJ, Trebicka J, Karsdal MA
Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluatio...
January 2, 2019
Journal:
Nature Communications
Author:
Woodcock HV, Eley JD, Platé M, Manthakumar CB, Martufi M, Peace S, Joberty G, Poeckel D, Good RB, Taylor AR, Zinn N, Redding M, Forty EJ, Hynds RE, Santon C, Karsdal MA, Maher TM, Bergamini G, Marshall RP, Blanchard AD, Mercer PF, Chambers RC
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
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