Liver cell circuits and therapeutic discovery for advanced liver disease and cancer

AbstractChronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

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Serum CYFRA 21 – 1 levels are elevated in advanced liver disease and associate with poor survival

10.1055/s-0038-1677127 ◽

2019 ◽

Author(s):

K Hamesch ◽

N Guldiken ◽

M Aly ◽

N Hueser ◽

D Hartmann ◽

...

Keyword(s):

Liver Disease ◽

Poor Survival ◽

Advanced Liver Disease

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REAL WORLD IMPACT OF RIFAXIMIN-Α USE IN HEPATIC ENCEPHALOPATHY PATIENTS WITH ADVANCED LIVER DISEASE OR CONTINUED ALCOHOL MISUSE: A POST-HOC ANALYSIS OF THE IMPRESS STUDY

10.26226/morressier.59a6b341d462b80290b53ebd ◽

2017 ◽

Author(s):

Paola Di Maggio

Keyword(s):

Liver Disease ◽

Hepatic Encephalopathy ◽

Real World ◽

Alcohol Misuse ◽

Advanced Liver Disease ◽

Post Hoc Analysis ◽

Post Hoc

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Faculty Opinions recommendation of Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726172820.793515335 ◽

2016 ◽

Author(s):

Philip Rosenthal

Keyword(s):

Hepatitis C Virus ◽

Liver Disease ◽

Hepatitis C ◽

Virus Infection ◽

Phase 2 ◽

Hepatitis C Virus Infection ◽

Genotype 1 ◽

Open Label ◽

Advanced Liver Disease ◽

Phase 2 Trial

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Sarcopenia in Patients with Advanced Liver Disease

Current Protein and Peptide Science ◽

10.2174/1389203718666170428121647 ◽

2018 ◽

Vol 19 (7) ◽

pp. 681-691 ◽

Cited By ~ 11

Author(s):

Francesca Romana Ponziani ◽

Antonio Gasbarrini

Keyword(s):

Liver Disease ◽

Advanced Liver Disease

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Advance Care Planning and Goals of Care Discussions in Advanced Liver Disease

Current Hepatology Reports ◽

10.1007/s11901-021-00565-x ◽

2021 ◽

Author(s):

Nneka N. Ufere

Keyword(s):

Liver Disease ◽

Advance Care Planning ◽

Care Planning ◽

Advanced Liver Disease ◽

Goals Of Care ◽

Advance Care

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Patterns of dendritic cell and monocyte subsets are associated with disease severity and mortality in liver cirrhosis patients

Scientific Reports ◽

10.1038/s41598-021-85148-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chandra Chiappin Cardoso ◽

Camila Matiollo ◽

Carolina Hilgert Jacobsen Pereira ◽

Janaina Santana Fonseca ◽

Helder Emmanuel Leite Alves ◽

...

Keyword(s):

Dendritic Cells ◽

Liver Cirrhosis ◽

Liver Disease ◽

Dendritic Cell ◽

Disease Severity ◽

Advanced Liver Disease ◽

Hla Dr ◽

Acute Decompensation ◽

Cirrhotic Patients ◽

Classical Monocytes

AbstractLiver cirrhosis is often complicated by an immunological imbalance known as cirrhosis-associated immune dysfunction. This study aimed to investigate disturbances in circulating monocytes and dendritic cells in patients with acute decompensation (AD) of cirrhosis. The sample included 39 adult cirrhotic patients hospitalized for AD, 29 patients with stable cirrhosis (SC), and 30 healthy controls (CTR). Flow cytometry was used to analyze monocyte and dendritic cell subsets in whole blood and quantify cytokines in plasma samples. Cirrhotic groups showed higher frequencies of intermediate monocytes (iMo) than CTR. AD patients had lower percentages of nonclassical monocytes than CTR and SC. Cirrhotic patients had a profound reduction in absolute and relative dendritic cell numbers compared with CTR and showed higher plasmacytoid/classical dendritic cell ratios. Increased plasma levels of IL-6, IL-10, and IL-17A, elevated percentages of CD62L+ monocytes, and reduced HLA-DR expression on classical monocytes (cMo) were also observed in cirrhotic patients. Patients with more advanced liver disease showed increased cMo and reduced tissue macrophages (TiMas) frequencies. It was found that cMo percentages greater than 90.0% within the monocyte compartment and iMo and TiMas percentages lower than 5.7% and 8.6%, respectively, were associated with increased 90-day mortality. Monocytes and dendritic cells are deeply altered in cirrhotic patients, and subset profiles differ between stable and advanced liver disease. High cMo and low TiMas frequencies may be useful biomarkers of disease severity and mortality in liver cirrhosis.

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