Publications by authors named "Andreas Teufel"

139 Publications

Identification of liver-derived bone morphogenetic protein (BMP)-9 as a potential new candidate for treatment of colorectal cancer.

J Cell Mol Med 2021 Nov 28. Epub 2021 Nov 28.

Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Colorectal cancer (CRC) is a high-incidence malignancy worldwide which still needs better therapy options. Therefore, the aim of the present study was to investigate the responses of normal or malignant human intestinal epithelium to bone morphogenetic protein (BMP)-9 and to find out whether the application of BMP-9 to patients with CRC or the enhancement of its synthesis in the liver could be useful strategies for new therapy approaches. In silico analyses of CRC patient cohorts (TCGA database) revealed that high expression of the BMP-target gene ID1, especially in combination with low expression of the BMP-inhibitor noggin, is significantly associated with better patient survival. Organoid lines were generated from human biopsies of colon cancer (T-Orgs) and corresponding non-malignant areas (N-Orgs) of three patients. The N-Orgs represented tumours belonging to three different consensus molecular subtypes (CMS) of CRC. Overall, BMP-9 stimulation of organoids promoted an enrichment of tumour-suppressive gene expression signatures, whereas the stimulation with noggin had the opposite effects. Furthermore, treatment of organoids with BMP-9 induced ID1 expression (independently of high noggin levels), while treatment with noggin reduced ID1. In summary, our data identify the ratio between ID1 and noggin as a new prognostic value for CRC patient outcome. We further show that by inducing ID1, BMP-9 enhances this ratio, even in the presence of noggin. Thus, BMP-9 is identified as a novel target for the development of improved anti-cancer therapies of patients with CRC.
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http://dx.doi.org/10.1111/jcmm.17084DOI Listing
November 2021

[Budd-Chiari syndrome, review and illustration].

Z Gastroenterol 2021 Nov 24. Epub 2021 Nov 24.

Allgemeine Innere Medizin (DAIM), Kliniken Beau Site, Salem und Permanence, Bern, Switzerland.

Budd-Chiari syndrome is a rare vascular disorder characterized by obstruction of the hepatic venous outflow. Various diseases causing coagulopathy play a role in aetiology, such as myeloproliferative disorders. Acute vascular occlusion may lead to acute phlebitis with fever. The classic triad of acute liver failure may be present with ascites, hepatomegaly, and abdominal pain. However, subacute courses of disease were also observed. Because of the variable symptoms and severity extent, depending on the acuity of the course and the extent of the affected vessels, diagnosis is often difficult. Sonography, as a ubiquitously available and cost-effective diagnostic tool, plays a leading role. Doppler ultrasonography can be used to visualize hemodynamics in particular. In acute thrombotic occlusion, the affected hepatic veins usually cannot or only partially be visualized. In non-occluding thrombi, turbulent flow patterns may develop in the area of venous outflow obstruction, and flow velocity is then increased in the area of stenosis. Contrast enhanced ultrasound offers even better specificity of diagnosis. Computed tomography and magnetic resonance imaging can directly visualize thrombi and the cause of obstruction. Once the diagnosis is confirmed, anticoagulation must be initiated, but therapy of the underlying disease must also be started. If symptom-controlling measures are not sufficient, angioplasty/stenting to reopen short-segment stenoses or implantation of a TIPSS device may be considered. Liver transplantation remains ultima ratio. As studies on the precision of diagnostic methods are controversial, the characteristics of imaging for BCS are therefore summarized in this review on the basis of several illustrating case reports.
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http://dx.doi.org/10.1055/a-1645-2760DOI Listing
November 2021

RASSF1A independence and early galectin-1 upregulation in PIK3CA-induced hepatocarcinogenesis: new therapeutic venues.

Mol Oncol 2021 Nov 8. Epub 2021 Nov 8.

Institute of Pathology, University of Regensburg, Germany.

Aberrant activation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR and Ras/mitogen-activated protein kinase (MAPK) pathways is a hallmark of hepatocarcinogenesis. In a subset of hepatocellular carcinomas (HCCs), PI3K/AKT/mTOR signaling dysregulation depends on phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, while RAS/MAPK activation is partly attributed to promoter methylation of the tumor suppressor Ras association domain-containing protein 1 (RASSF1A). To evaluate a possible cocarcinogenic effect of PIK3CA activation and RASSF1A knockout, plasmids expressing oncogenic forms of PIK3CA (E545K or H1047R mutants) were delivered to the liver of RASSF1A knockout and wild-type mice by hydrodynamic tail vein injection combined with sleeping beauty-mediated somatic integration. Transfection of either PIK3CA E545K or H1047R mutants sufficed to induce HCCs in mice irrespective of RASSF1A mutational background. The related tumors displayed a lipogenic phenotype with upregulation of fatty acid synthase and stearoyl-CoA desaturase-1 (SCD1). Galectin-1, which was commonly upregulated in preneoplastic lesions and tumors, emerged as a regulator of SCD1. Co-inhibitory treatment with PIK3CA inhibitors and the galectin-1 inhibitor OTX008 resulted in synergistic cytotoxicity in human HCC cell lines, suggesting novel therapeutic venues.
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http://dx.doi.org/10.1002/1878-0261.13135DOI Listing
November 2021

Severe dysbiosis and specific Haemophilus and Neisseria signatures as hallmarks of the oropharyngeal microbiome in critically ill COVID-19 patients.

Clin Infect Dis 2021 Oct 25. Epub 2021 Oct 25.

Department of Medicine II, Section of Hepatology, University Medical Center Mannheim, University of Heidelberg, Mannheim, and Center for Preventive Medicine and Digital Health Baden-Württemberg, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with Coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict COVID-19 illness. However, the results are not conclusive, as critical illness can drastically alter a patient's microbiome through multiple confounders.

Methods: To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multi-center, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate and severe COVID-19 (n=322 participants).

Results: In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features.

Conclusion: In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.
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http://dx.doi.org/10.1093/cid/ciab902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586732PMC
October 2021

Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression.

Cells 2021 09 23;10(10). Epub 2021 Sep 23.

Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty at Heinrich-Heine-University, University Hospital Duesseldorf, 40225 Dusseldorf, Germany.

Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of 'rest-and-jump genes' that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30-48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.
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http://dx.doi.org/10.3390/cells10102516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533774PMC
September 2021

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

J Hepatol 2021 Oct 11. Epub 2021 Oct 11.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Background: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). Prognostic biomarkers are an unmet need.

Methods: Patients with HCC put on PD-(L)1-based immunotherapy in 6 European centers (training set; n=190) and in 8 European centers (validation set; n=102) were included. We investigated the prognostic value of baseline variables on overall survival by using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n=204).

Results: Baseline serum alpha-fetoprotein ≥100 ng/ml (HR, 1.7; p=0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p=0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95%CI, 19.5-35.8) months), followed by those fulfilling one criterion (1 point; CRAFITY-intermediate; 11.3 (95%CI, 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95%CI, 4.8-8.1) months; p<0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low:9%/20%/52%/20% vs. CRAFITY-intermediate:3%/25%/36%/36% vs. CRAFITY-high:2%/15%/22%/61%; p=0.003). These results were confirmed in the independent validation set as well as in different subgroups including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response.

Conclusions: The CRAFITY score is associated with survival and radiological response. The score may help with patient counseling, but requires prospective validation.

Lay Summary: The immunotherapy based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.
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http://dx.doi.org/10.1016/j.jhep.2021.09.035DOI Listing
October 2021

Durable response with lenvatinib and pembrolizumab combination therapy in a patient with pre-treated metastatic cholangiocarcinoma.

J Gastrointestin Liver Dis 2021 09 21;30(3):409-410. Epub 2021 Sep 21.

Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

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http://dx.doi.org/10.15403/jgld-3730DOI Listing
September 2021

Evaluation und Notwendigkeit einer Anpassung des MELD Scores in der Eurotransplantregion.

Z Gastroenterol 2021 Sep 10;59(9):991-994. Epub 2021 Sep 10.

Klinische Kooperationseinheit Healthy Metabolism, Zentrum für Präventivmedizin und Digitale Gesundheit Baden-Württemberg, Medizinische Fakultät Mannheim Universität Heidelberg, Mannheim.

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http://dx.doi.org/10.1055/a-1484-1544DOI Listing
September 2021

[Prevention of gastrointestinal cancer].

Z Gastroenterol 2021 Sep 10;59(9):964-982. Epub 2021 Sep 10.

II. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Universitätsklinikum Mannheim, Mannheim.

Throughout the past decades, considerable progress has been made in the (early) diagnosis and treatment of gastrointestinal cancers. However, the prognosis for advanced stages of gastrointestinal tumors remains limited for many patients and approximately one third of all tumor patients die as a result of gastrointestinal tumors. The prevention and early detection of gastrointestinal tumors is therefore of great importance.For this reason, we summarize the current state of knowledge and recommendations for the primary, secondary and tertiary prevention of esophageal, stomach, pancreas, liver and colorectal cancer in the following.
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http://dx.doi.org/10.1055/a-1540-7539DOI Listing
September 2021

Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure.

Hepatology 2021 Aug 26. Epub 2021 Aug 26.

Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background & Aims: In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPC) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of HNF4α, its regulators and targets in LPC determines clinical outcome of ALF patients.

Approach & Results: Clinicopathological associations were scrutinized in 19 ALF patients (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 cirrhotic patients for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure (ACLF). Recovered ALF patients robustly express HNF4α in either LPC or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPC requires the FOXH1-SMAD2/3/4 transcription factor complex, which is promoted by the TGF-β superfamily member activin. Activin signaling in LPC is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated SMAD2 and HNF4α in LPC, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of ACLF.

Conclusions: These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggests a key role of the systemic metabolic state in ALF.
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http://dx.doi.org/10.1002/hep.32119DOI Listing
August 2021

Semiautomated quantification of the fibrous tissue response to complex three-dimensional filamentous scaffolds using digital image analysis.

J Biomed Mater Res A 2021 Aug 14. Epub 2021 Aug 14.

Institute of Pathology, University Regensburg, Regensburg, Germany.

Fibrosis represents a relevant response to the implantation of biomaterials, which occurs not only at the tissue-material interface (fibrotic encapsulation) but also within the void fraction of complex three-dimensional (3D) biomaterial constructions (fibrotic ingrowth). Usual evaluation of the biocompatibility mostly depicts fibrosis at the interface of the biomaterial using semiquantitative scores. Here, the relations between encapsulation and infiltrating fibrotic growth are poorly represented. Virtual pathology and digital image analysis provide new strategies to assess fibrosis in a more differentiated way. In this study, we adopted a method previously used to quantify fibrosis in visceral organs to the quantification of fibrosis to 3D biomaterials. In a proof-of-concept study, we transferred the "Collagen Proportionate Area" (CPA) analysis from hepatology to the field of biomaterials. As one task of an experimental animal study, we used CPA analysis to quantify the fibrotic ingrowth into a filamentous scaffold after subcutaneous implantation. We were able to demonstrate that the application of the CPA analysis is well suited as an additional fibrosis evaluation strategy for new biomaterial constructions. The CPA method can contribute to a better understanding of the fibrotic interactions between 3D scaffolds and the host tissue responses.
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http://dx.doi.org/10.1002/jbm.a.37293DOI Listing
August 2021

Presence of gustatory and olfactory dysfunction in the time of the COVID-19 pandemic.

BMC Infect Dis 2021 Jun 26;21(1):612. Epub 2021 Jun 26.

Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: The unexpected outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused more than 49 million cases and an estimated 2,000,000 associated deaths worldwide. In Germany, there are currently more than 2,000,000 laboratory-confirmed coronavirus disease 2019 (COVID-19) cases including 51,800 deaths. However, regional differences also became apparent and with the second wave of infections, the detailed characterization of COVID-19 patients is crucial to early diagnosis and disruption of chains of infections.

Methods: Handing out detailed questionnaires to all individuals tested for COVID-19, we evaluated the clinical characteristics of negative and positive tested individuals. Expression of symptoms, symptom duration and association between predictor variables (i.e. age, gender) and a binary outcome (olfactory and gustatory dysfunction) were assessed.

Results: Overall, the most common symptoms among individuals who tested positive for SARS-CoV-2 were fatigue, headache, and cough. Olfactory and gustatory dysfunction were also reported by many SARS-CoV-2 negative individuals, more than 20% of SARS-CoV-2 negative tested individuals in our study reported olfactory and gustatory dysfunction. Independent of SARS-CoV-2 status, more females displayed symptoms of gustatory (29.8%, p = 0.0041) and olfactory dysfunction (22.9%, p = 0.0174) compared to men.

Conclusions: Bringing early SARS-CoV-2 tests to the populations at risk must be a main focus for the upcoming months. The reliability of olfactory and gustatory dysfunction in COVID-19 negative tested individuals requires deeper investigation in the future.
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http://dx.doi.org/10.1186/s12879-021-06294-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234756PMC
June 2021

Conventional ultrasound for diagnosis of hepatic steatosis is better than believed.

Z Gastroenterol 2021 Jun 25. Epub 2021 Jun 25.

Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Background: Hepatic steatosis is a condition frequently encountered in clinical practice, with potential progression towards fibrosis, cirrhosis, and hepatocellular carcinoma. Detection and staging of hepatic steatosis are of most importance in nonalcoholic fatty liver disease (NAFLD), a disease with a high prevalence of more than 1 billion individuals affected. Ultrasound (US) is one of the most used noninvasive imaging techniques used in the diagnosis of hepatic steatosis. Detection of hepatic steatosis with US relies on several conventional US parameters, which will be described. US is the first-choice imaging in adults at risk for hepatic steatosis. The use of some scoring systems may add additional accuracy especially in assessing the severity of hepatic steatosis.

Summary: In the presented paper, we discuss screening and risk stratification, ultrasound features for diagnosing hepatic steatosis, B-mode criteria, focal fatty patterns and Doppler features of the hepatic vessels, and the value of the different US signs for the diagnosis of liver steatosis including classifying the severity of steatosis using different US scores. Limitations of conventional B-mode and Doppler features in the evaluation of hepatic steatosis are also discussed, including those in grading and assessing the complications of steatosis, namely fibrosis and nonalcoholic steatohepatitis.

Key Messages: Ultrasound is the first-line imaging examination for the screening and follow-up of patients with liver steatosis. The use of some scoring systems may add additional accuracy in assessing the severity of steatosis. Conventional B-mode and Doppler ultrasound have limitations in grading and assessing the complications of steatosis.
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http://dx.doi.org/10.1055/a-1491-1771DOI Listing
June 2021

Surrogate scores of advanced fibrosis in NAFLD/NASH do not predict mortality in patients with medium-to-high cardiovascular risk.

Am J Physiol Gastrointest Liver Physiol 2021 09 16;321(4):G252-G261. Epub 2021 Jun 16.

Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Untreated non-alcoholic fatty liver disease (NAFLD) may have significant consequences including an increase in mortality and cardiovascular injury. Thus, early detection of NAFLD is currently believed not only to prevent liver-related but also cardiovascular mortality. However, almost nothing is known about coexisting NAFLD in patients with coronary artery disease (CAD). We investigated the impact of surrogate scores of fibrosis in NAFLD in a large cohort of patients referred to coronary angiography. Modeling the common NALFD and fibrosis scores, fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), as splines revealed significant associations with all-cause and cardiovascular mortality when Cox regression models were only adjusted for cardiovascular risk factors that were not already included in the calculation of the scores. Stratifying the scores into quartiles yielded hazard ratios [95% confidence interval (CI)] for all-cause and cardiovascular mortality for the 4th quartile versus the 1st quartile of 2.28 (1.90-2.75) and 2.11 (1.67-2.67) for FIB-4 and of 3.21 (2.61-3.94) and 3.12 (2.41-4.04) for NFS. However, we did not observe an independent association of FIB-4 or NFS with overall or cardiovascular mortality in our prospective CAD cohort after full adjustment for all cardiovascular risk factors [all-cause mortality: HR 1.13 (0.904-1.41) and 1.17 (0.903-1.52); cardiovascular mortality: HR 1.06 (0.8-1.41) and 1.02 (0.738-1.41)]. Thus, neither FIB-4 nor NFS, as surrogate markers for NAFLD/NASH, were independent risk factors for overall or cardiovascular mortality in patients with CAD. Our data show that surrogate risk scores for NAFLD-related fibrosis do not add information in assessing the CVD events in patients with CAD proven by angiography. We investigated the impact of NAFLD surrogate markers in a large cohort of patients that had been referred to coronary angiography. In contrast to a repeatedly demonstrated increased link of cardiovascular events in patients with NALFD, we demonstrated that NAFLD surrogate markers were not independent risk factors for overall or cardiovascular mortality in patients with CAD. Thus, these markers may not be useful for primary prevention of cardiovascular events in patients with CAD.
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http://dx.doi.org/10.1152/ajpgi.00058.2021DOI Listing
September 2021

Prognostic Cancer Gene Expression Signatures: Current Status and Challenges.

Cells 2021 03 15;10(3). Epub 2021 Mar 15.

Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.

Current staging systems of cancer are mainly based on the anatomical extent of disease. They need refinement by biological parameters to improve stratification of patients for tumor therapy or surveillance strategies. Thanks to developments in genomic, transcriptomic, and big-data technologies, we are now able to explore molecular characteristics of tumors in detail and determine their clinical relevance. This has led to numerous prognostic and predictive gene expression signatures that have the potential to establish a classification of tumor subgroups by biological determinants. However, only a few gene signatures have reached the stage of clinical implementation so far. In this review article, we summarize the current status, and present and future challenges of prognostic gene signatures in three relevant cancer entities: breast cancer, colorectal cancer, and hepatocellular carcinoma.
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http://dx.doi.org/10.3390/cells10030648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000474PMC
March 2021

Obeticholic Acid Inhibits Anxiety via Alleviating Gut Microbiota-Mediated Microglia Accumulation in the Brain of High-Fat High-Sugar Diet Mice.

Nutrients 2021 Mar 15;13(3). Epub 2021 Mar 15.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.

Anxiety is one of the complications of metabolic disorders (MDs). Obeticholic acid (OCA), the bile acids (BAs) derivative, is a promising agent for improving MDs in association with gut dysbiosis. Yet, its protective effect on MDs-driven anxiety remains unknown. Here, we assessed the serum biochemical parameters and behavioral performance by open field and Morris water maze tests in HFHS diet-induced MDs mice after OCA intervention for nine and 18 weeks. Moreover, antibiotics intervention for microbial depletion was conducted simultaneously. We found that OCA treatment inhibited the initiation and progression of anxiety in HFHS diet-MDs mice via a microbiota-BAs-brain axis: OCA decreased the neuroinflammatory microglia and IL-1β expression in the hippocampus, reversed intestinal barrier dysfunction and serum proinflammatory LPS to a normal level, modified the microbial community, including the known anxiety-related Rikenellaceae and , and improved the microbial metabolites especially the increased BAs in feces and circulation. Moreover, the OCA-reversed bile acid taurocholate linked disordered serum lipid metabolites and indole derivatives to anxiety as assessed by network analysis. Additionally, microbial depletion with antibiotics also improved the anxiety, microgliosis and BAs enrichment in the experimental MDs mice. Together, these findings provide microbiota-BAs-brain axis as a novel therapeutic target for MDs-associated neuropsychiatric disorders.
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http://dx.doi.org/10.3390/nu13030940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999854PMC
March 2021

p53-Independent Induction of p21 Fails to Control Regeneration and Hepatocarcinogenesis in a Murine Liver Injury Model.

Cell Mol Gastroenterol Hepatol 2021 21;11(5):1387-1404. Epub 2021 Jan 21.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address:

Background & Aims: A coordinated stress and regenerative response is important after hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the checkpoint kinase 2/transformation-related protein 53 (p53)/cyclin-dependent kinase inhibitor 1A (p21) pathway in a murine model of metabolic liver injury.

Methods: Nitisinone was reduced or withdrawn in Fah mice lacking Chk2, p53, or p21, and survival, tumor development, liver injury, and regeneration were analyzed. Partial hepatectomies were performed and mice were challenged with the Fas antibody Jo2.

Results: In a model of metabolic liver injury, loss of p53, but not Chk2, impairs the oxidative stress response and aggravates liver damage, indicative of a direct p53-dependent protective effect on hepatocytes. Cell-cycle control during chronic liver injury critically depends on the presence of both p53 and its downstream effector p21. In p53-deficient hepatocytes, unchecked proliferation occurs despite a strong induction of p21, showing a complex interdependency between p21 and p53. The increased regenerative potential in the absence of p53 cannot fully compensate the surplus injury and is not sufficient to promote survival. Despite the distinct phenotypes associated with the loss of individual components of the DNA damage response, gene expression patterns are dominated by the severity of liver injury, but reflect distinct effects of p53 on proliferation and the anti-oxidative stress response.

Conclusions: Characteristic phenotypes result from the genetic abrogation of individual components of the DNA damage-response cascade in a liver injury model. The extent to which loss of gene function can be compensated, or affects injury and proliferation, is related to the level at which the cascade is interrupted. Accession numbers of repository for expression microarray data: GSE156983, GSE156263, GSE156852, and GSE156252.
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http://dx.doi.org/10.1016/j.jcmgh.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024980PMC
January 2021

Co-Medication and Nutrition in Hepatocellular Carcinoma: Potentially Preventative Strategies in Hepatocellular Carcinoma.

Dig Dis 2021 11;39(5):526-533. Epub 2021 Jan 11.

Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, with about 841,000 new cases and 782,000 deaths annually. Given the clearly defined population at risk, mostly patients with liver cirrhosis, prevention of HCC could be highly effective.

Summary: Besides regular ultrasound surveillance, numerous publications have suggested protective effects of diverse drugs and nutrients. However, none of those preventive options has made it into clinical routine or practice guidelines. We therefore summarize the current status of preventive effects of drugs such as statins, acetylsalicylic acid (ASA), and metformin, but also dietary aspects and nutrients such as coffee, tea, and vitamin D supplementation. A successful implementation of some of these strategies may potentially lead to improved prevention of HCC development in patients with liver cirrhosis. Key Messages: Accumulating data suggest that particularly ASA, antidiabetic therapies, and statins may substantially decrease HCC incidence in patients at risk.
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http://dx.doi.org/10.1159/000514277DOI Listing
November 2021

Digital Gastroenterology.

J Gastrointestin Liver Dis 2020 12 12;29(4):493-496. Epub 2020 Dec 12.

Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim; Preventive Medicine Baden- Württemberg (CPMBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

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http://dx.doi.org/10.15403/jgld-3099DOI Listing
December 2020

[Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality].

Z Gastroenterol 2020 10 9;58(10):1003-1005. Epub 2020 Oct 9.

Sektion Hepatologie, II. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg.

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http://dx.doi.org/10.1055/a-1162-1200DOI Listing
October 2020

Autoimmune Hepatitis: a Review of Established and Evolving Treatments.

J Gastrointestin Liver Dis 2020 Sep 9;29(3):429-443. Epub 2020 Sep 9.

Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Autoimmune hepatitis (AIH) is a necroinflammatory liver disease commonly presenting with a fluctuating course of activity, presence of circulating autoantibodies, hyperglobulinemia of IgG, and/or response to immunosuppressive drugs. However, the disease displays a considerable heterogeneity. No single clinical or biochemical test may establish diagnosis of AIH. Thus, diagnosis still requires extensive clinical evaluation and experience. Prednisolone and azathioprine are considered standard treatment leading to remission in most patients. However, this standard treatment may not be effective in some patients or not be feasible due to one of these drugs. Over the past two decades additional immunosuppressant drugs for the treatment of AIH have been evaluated and have significantly extended the therapeutic spectrum. Among those novel drugs are mycophenolate mofetil, tacrolimus, everolimus, 6-mercaptopurine, infliximab, rituximab and several others. In this review we summarize the current standard of therapy but also efforts of providing novel therapeutic strategies to AIH patients.
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http://dx.doi.org/10.15403/jgld-2667DOI Listing
September 2020

Long, relapsing, and atypical symptomatic course of COVID-19 in a B-cell-depleted patient after rituximab.

Semin Arthritis Rheum 2020 10 30;50(5):1087-1088. Epub 2020 Jun 30.

Department of Medicine II, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.semarthrit.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833880PMC
October 2020

Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure.

Z Gastroenterol 2020 Aug 12;58(8):773-777. Epub 2020 Aug 12.

Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy, and these drugs have already become essential for the treatment of various noncurable tumors. However, monotherapy in advanced hepatocellular carcinoma (aHCC) failed to show statistically significant improvement.Recently, the combination of atezolizumab and bevacizumab demonstrated efficacy of combining ICI and VEGF inhibition, further substantiating previous data on synergistic mechanisms among respective substance classes.As TKI treatment is currently standard of care for aHCC, and ICIs are approved by the FDA and available in many areas of the world, numerous patients may have been treated with monotherapy of those drugs. However, it remains unclear if failure to monotherapy has an impact on combination therapy. We therefore report a patient well responding to combination therapy despite previous failures to TKI and ICI monotherapy.
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http://dx.doi.org/10.1055/a-1190-5681DOI Listing
August 2020

Benefit of adjuvant chemotherapy in high-risk colon cancer: A 17-year population-based analysis of 6131 patients with Union for International Cancer Control stage II T4N0M0 colon cancer.

Eur J Cancer 2020 09 7;137:148-160. Epub 2020 Aug 7.

Regensburg Tumor Center, Institute for Quality Assurance and Health Services Research at the University of Regensburg, Regensburg, Germany; Association of German Tumor Centers ADT, Berlin, Germany.

Background: The benefit of adjuvant chemotherapy in Union for International Cancer Control (UICC) stage III colon cancer has been demonstrated in numerous studies. While adjuvant chemotherapy is generally not recommended in stage II patients, its role in high-risk UICC stage II disease (e.g. T4 tumours) remains controversial.

Methods: The present population-based multicenter cohort study investigated the influence of adjuvant chemotherapy on survival and recurrence rates in high-risk UICC stage II T4N0M0 tumours. Based on an anonymised nationwide ADT data set from 31 clinical cancer registries, we identified a total of 6651 patients with a T4 tumour of the colon, of whom 6131 were eligible for survival analysis. A matched-pair analysis based on propensity scores (PSM) was performed with a subset of 3986 patients.

Results: Multivariable analyses demonstrated a significant benefit of adjuvant chemotherapy for overall survival (OS) (hazard ratio [HR]: 0.711, 95% confidence interval [CI]: 0.643-0.785, p < 0.001), cumulative recurrence rate (HR: 0.780, 95% CI: 0.681-0.893, p < 0.001), and recurrence-free survival (HR: 0.715, 95% CI: 0.652-0.785, p < 0.001) further confirmed by the matched-pair cohort.

Conclusion: This large and representative study demonstrated a significant advantage of adjuvant chemotherapy for patients with T4 UICC stage II colon cancer in terms of OS, recurrence rate, and relapse-free survival. Based on these results, adjuvant chemotherapy should be recommended for these patients.
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http://dx.doi.org/10.1016/j.ejca.2020.06.036DOI Listing
September 2020

Current Opinion about Hepatocellular Carcinoma <10 mm.

Digestion 2021 9;102(3):335-341. Epub 2020 Jun 9.

Department Allgemeine Innere Medizin (DAIM), Kliniken Hirslanden Beau Site, Salem und Permanence, Bern, Switzerland,

Background: Early detection of hepatocellular carcinoma (HCC) is important. Advances in liver imaging techniques have facilitated the detection of HCC at an early stage. However, there is a controversial discussion on how to diagnose very small HCC by imaging. The aim of the current review is to present current published data on HCC ≤10 mm and discuss on how to best diagnose and treat such lesions.

Summary: It is still challenging, however, to accurately characterize HCC <10 mm. The accuracy of contrast-enhanced ultrasound may be critical for early treatment decisions for cancer patients, particularly when CECT and/or CEMRI are inconclusive. Key Messages: The characterization of focal liver lesions <10 mm is frequently delayed until a follow-up imaging procedure demonstrates growth or stability. A repetition of ultrasound examination after 3 months for new nodules <1 cm should be recommended.
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http://dx.doi.org/10.1159/000507923DOI Listing
August 2021

TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice.

Cell Death Dis 2020 03 31;11(3):212. Epub 2020 Mar 31.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Non-alcoholic fatty liver disease (NAFLD) shows an increasing prevalence and is associated with the development of liver fibrosis and cirrhosis as the major risk factors of liver-related mortality in this disease. The therapeutic possibilities are limited and restricted to life style intervention, since specific drugs for NAFLD are unavailable so far. TNFα has been implicated as a major pathogenic driver of NAFLD. TNFα-mediated liver injury occurs mainly via TNF-receptor-1 (TNFR1) signaling, whereas TNFR2 mediates protective pathways. In this study, we analyzed the therapeutic effects of a novel antibody, which selectively inhibits TNFR1 while retaining protective TNFR2 signaling in a high-fat diet (HFD) mouse model of NAFLD. Mice were fed with HFD for 32 weeks and treated with anti-TNFR1-antibody or control-antibody for the last 8 weeks. We then investigated the mechanisms of TNFR1 inhibition on liver steatosis, inflammatory liver injury, insulin resistance and fibrosis. Compared to control-antibody treatment, TNFR1 inhibition significantly reduced liver steatosis and triglyceride content, which was accompanied by reduced expression and activation of the transcription factor SREBP1 and downstream target genes of lipogenesis. Furthermore, inhibition of TNFR1 resulted in reduced activation of the MAP kinase MKK7 and its downstream target JNK, which was associated with significant improvement of insulin resistance. Apoptotic liver injury, NAFLD activity and alanine aminotransferase (ALT) levels, as well as liver fibrosis significantly decreased by anti-TNFR1 compared to control-antibody treatment. Thus, our results suggest selective TNFR1 inhibition as a promising approach for NAFLD treatment.
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http://dx.doi.org/10.1038/s41419-020-2411-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109108PMC
March 2020

Hepamine - A Liver Disease Microarray Database, Visualization Platform and Data-Mining Resource.

Sci Rep 2020 03 16;10(1):4760. Epub 2020 Mar 16.

Division of Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Numerous gene expression profiling data on liver diseases were generated and stored in public databases. Only few were used for additional analyses by the hepatology research community. This may mostly be due to limited bioinformatics knowledge of most biomedical research personnel. In order to support an easy translation of bioinformatics data into translational hepatology research, we created Hepamine, a liver disease gene expression, visualization platform and data-mining resource. Microarray data were obtained from the NCBI GEO database. Pre-analysis of expression data was performed using R statistical software and the limma microarray analysis package from the Bioconductor repository. We generated Hepamine, a web-based repository of pre-analyzed microarray data for various liver diseases. At its initial release Hepamine contains 13 gene expression datasets, 20 microarray experiments and approximately 400 000 gene expression measurements. A self-explanatory website offers open and easy access to gene expression profiles. Results are furthermore visualized in simple three-color tables indicating differential expression. All data were linked to common functional and genetic databases particularly through the DAVID bioinformatics suite. Hepamine provides comprehensive data and easy access to hepatologic gene expression data even without in depth bioinformatics or microarray profiling experience. http://www.hepamine.de.
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http://dx.doi.org/10.1038/s41598-020-61508-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075926PMC
March 2020

BMP-9 Modulates the Hepatic Responses to LPS.

Cells 2020 03 4;9(3). Epub 2020 Mar 4.

Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.

It was previously shown that Bone Morphogenetic Protein (BMP)-9 is constitutively produced and secreted by hepatic stellate cells (HSC). Upon acute liver damage, BMP-9 expression is transiently down-regulated and blocking BMP-9 under conditions of chronic damage ameliorated liver fibrogenesis in C57BL/6 mice. Thereby, BMP-9 acted as a pro-fibrogenic cytokine in the liver but without directly activating isolated HSC in vitro. Lipopolysaccharide (LPS), an endotoxin derived from the membrane of Gram-negative bacteria in the gut, is known to be essential in the pathogenesis of diverse kinds of liver diseases. The aim of the present project was therefore to investigate how high levels of BMP-9 in the context of LPS signalling might result in enhanced liver damage. For this purpose, we stimulated human liver sinusoidal endothelial cells (LSEC) with LPS and incubated primary human liver myofibroblasts (MF) with the conditioned medium of these cells. We found that LPS led to the secretion of factors from LSEC that upregulate BMP-9 expression in MF. At least one of these BMP-9 enhancing factors was defined to be IL-6. High BMP-9 in turn, especially in combination with LPS stimulation, induced the expression of certain capillarization markers in LSEC and enhanced the LPS-mediated induction of pro-inflammatory cytokines in primary human macrophages. In LSEC, pre-treatment with BMP-9 reduced the LPS-mediated activation of the NfkB pathway, whereas in macrophages, LPS partially inhibited the BMP-9/Smad-1 signaling cascade. In vivo, in mice, BMP-9 led to the enhanced presence of F4/80-positive cells in the liver and it modulated the LPS-mediated regulation of inflammatory mediators. In summary, our data point to BMP-9 being a complex and highly dynamic modulator of hepatic responses to LPS: Initial effects of LPS on LSEC led to the upregulation of BMP-9 in MF but sustained high levels of BMP-9 in turn promote pro-inflammatory reactions of macrophages. Thereby, the spatial and timely fine-tuned presence (or absence) of BMP-9 is needed for efficient wound-healing responses in the liver.
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http://dx.doi.org/10.3390/cells9030617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140468PMC
March 2020

Applicability of scoring systems predicting outcome of transarterial chemoembolization for hepatocellular carcinoma.

J Cancer Res Clin Oncol 2020 Apr 27;146(4):1033-1050. Epub 2020 Feb 27.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, INF 110, 69120, Heidelberg, Germany.

Purpose: Several scoring systems have been proposed to predict the outcome of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). However, the application of these scores to a bridging to transplant setting is poorly validated. Evaluation of the applicability of prognostic scores for patients undergoing TACE in palliative intention vs. bridging therapy to liver transplantation (LT) is necessary.

Methods: Between 2008 and 2017, 148 patients with HCC received 492 completed TACE procedures (158 for bridging to transplant; 334 TACE procedures in palliative treatment intention at our center and were analyzed retrospectively. Scores (ART, CLIP, ALBI, APRI, SNACOR, HAP, STATE score, Child-Pugh, MELD, Okuda and BCLC) were calculated and evaluated for prediction of overall survival. ROC analysis was performed to assess prediction of 3-year survival and treatment discontinuation.

Results: In patients receiving TACE in palliative intention most scores predicted OS in univariate analysis but only mSNACOR score (p = 0.006), State score (p < 0.001) and Child-Pugh score (p < 0.001) revealed statistical significance in the multivariate analysis. In the bridging to LT cohort only the BCLC score revealed statistical significance (p = 0.002).

Conclusions: Clinical usability of suggested scoring systems for TACE might be limited depending on the individual patient cohorts and the indication. Especially in patients receiving TACE as bridging to LT none of the scores showed sufficiently applicability. In our study Child-Pugh score, STATE score and mSNACOR score showed the best performance assessing OS in patients with TACE as palliative therapy.
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http://dx.doi.org/10.1007/s00432-020-03135-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085483PMC
April 2020
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