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Steven Dooley

About Steven Dooley:
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SEEK ID: https://seek.lisym.org/people/38

Location: Germany

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Related items

LiSyM-Krebs Partnering

This generic project is intended to be a forum for all LiSyM partner and external stakeholders interested in participating in the BMBF initiative LiSyM-Krebs.

Public web page: https://www.ptj.de/projektfoerderung/gesundheitsforschung/lisym-krebs

LiSyM network

This comprises the whole LiSyM network

Public web page: http://www.lisym.org

Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF - Pillar III)

The incidence of this life-threatening acute-on-chronic liver failure (ACLF) is increasing, and early detection and cure are urgent clinical needs. Pillar III applies a Systems Medicine approach to identify the critical mechanisms of acute-on-chronic liver failure (ACLF) and to foster liver regeneration and repair.

Public web page: Not specified

Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Chronic liver diseases (CLD) progression leads to cirrhosis, often cancer, and ultimately to organ failure and death. Because of the complexity of this scenario, a Systems Medicine approach is chosen to develop strategies to better characterize progression and resolution of fibrosis. Pillar II aims to define key molecular mechanisms and structural changes in tissue architecture during the progression of CLD by visualizing and quantifying at a cellular level, tissue and organ scale.

Public web page: Not specified

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Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance.
Early Metabolic Injury (LiSyM-EMI - Pillar I)

Abstract (Expand)

BACKGROUND: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways … are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed. METHODS: We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with (13)C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients. FINDINGS: In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues. INTERPRETATION: A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. FUND: DFG, BMBF and Sino-German Cooperation Project.

Authors: Z. C. Nwosu, W. Pioronska, N. Battello, A. D. Zimmer, B. Dewidar, M. Han, S. Pereira, B. Blagojevic, D. Castven, V. Charlestin, P. Holenya, J. Lochead, C. De La Torre, N. Gretz, P. Sajjakulnukit, L. Zhang, M. H. Ward, Jens Marquardt, M. P. di Magliano, C. A. Lyssiotis, J. Sleeman, S. Wolfl, M. P. Ebert, C. Meyer, Ute Hofmann, Steven Dooley

Date Published: 25th Apr 2020

Journal: EBioMedicine

TGF-β2 silencing to target biliary-derived liver diseases
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Abstract

Not specified

Authors: Anne Dropmann, Steven Dooley, Bedair Dewidar, Seddik Hammad, Tatjana Dediulia, Julia Werle, Vanessa Hartwig, Shahrouz Ghafoory, Stefan Woelfl, Hanna Korhonen, Michel Janicot, Katja Wosikowski, Timo Itzel, Andreas Teufel, Detlef Schuppan, Ana Stojanovic, Adelheid Cerwenka, Stefanie Nittka, Albrecht Piiper, Timo Gaiser, Naiara Beraza, Malgorzata Milkiewicz, Piotr Milkiewicz, John G Brain, David E J Jones, Thomas S Weiss, Ulrich M Zanger, Matthias Ebert, Nadja M Meindl-Beinker

Date Published: 28th Jan 2020

Journal: Gut

Adenovirusmediated overexpression of bone morphogenetic protein9 promotes methionine choline deficiencyinduced nonalcoholic steatohepatitis in nonobese mice.
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Abstract (Expand)

Liver inflammation and macrophage infiltration are critical steps in the progression of nonalcoholic fatty liver to the development of nonalcoholic steatohepatitis. Bone morphogenetic protein9 is a … cytokine involved in the regulation of chemokines and lipogenesis. However, the function of bone morphogenetic protein9 in nonalcoholic steatohepatitis is still unknown. The present study hypothesized that bone morphogenetic protein9 may contribute to steatohepatitis in mice fed a methionine choline deficiency diet (MCD). C57BL/6 mice overexpressing bone morphogenetic protein9 and control mice were fed the MCD diet for 4 weeks. Liver tissue and serum samples were obtained for subsequent measurements. Bone morphogenetic protein9 overexpression exacerbated steatohepatitis in mice on the MCD diet, as indicated by liver histopathology, increased serum alanine aminotransferase activity, aspartate transaminase activity, hepatic inflammatory gene expression and M1 macrophage recruitment. Although bone morphogenetic protein9 overexpression did not affect the expression of profibrogenic genes, including Collagen I (alpha)1 or matrix metalloproteinase (MMP) 9, it did upregulate the expression of transforming growth factorbeta and plasminogen activator inhibitor 1, and downregulated the expression of MMP2. The above results indicate that bone morphogenetic protein9 exerts a proinflammatory role in MCD dietinduced nonalcoholic steatohepatitis.

Authors: Q. Li, B. Liu, K. Breitkopf-Heinlein, H. Weng, Yixin Jiang, P. Dong, Steven Dooley, K. Xu, H. Ding

Date Published: 20th Jul 2019

Journal: Mol Med Rep

TGF-beta in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019.
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Abstract (Expand)

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment … is mainly the removal of the causative factor. Transforming growth factor (TGF)-beta is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-beta has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-beta and its upstream and downstream regulatory mechanisms will help to design better TGF-beta based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-beta signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-beta on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-beta. Finally, we discuss new approaches to target the TGF-beta pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

Authors: B. Dewidar, C. Meyer, Steven Dooley, A. N. Meindl-Beinker

Date Published: 11th Nov 2019

Journal: Cells

Editorial: Systems Biology and Bioinformatics in Gastroenterology and Hepatology
LiSyM network

Abstract

Not specified

Authors: Peter Jansen, Kai Breuhahn, Andreas Teufel, Steven Dooley

Date Published: 22nd Nov 2019

Journal: Front. Physiol.

P2-LiSyM Intro-v2-SD-0605
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Modified slides 6 and 7

Creator: Steven Dooley

Contributor: Steven Dooley

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P2 LiSyM Introduction-v1-SD-0305
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)
No description specified

Creator: Steven Dooley

Contributor: Steven Dooley

Focused Scores Enable Reliable Discrimination of Small Differences in Steatosis
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Poster presented at Hünfeld Retreat 2018

Creators: André Homeyer, Seddik Hammad, Lars Ole Schwen, Steven Dooley, Andrea Schenk, Uta Dahmen, Henning Höfener, Yan Gao

Contributor: Lars Ole Schwen

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Liver regeneration in ACLF patients
Chronic Liver Disease Progression (LiSyM-DP - Pillar II), Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF - Pillar III)

confidential, with unpublished data

Creator: Steven Dooley

Contributor: Steven Dooley

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