Refine
Year of publication
Document Type
- Article (144)
- Conference Proceeding (2)
Language
- English (146) (remove)
Has Fulltext
- yes (146)
Is part of the Bibliography
- no (146)
Keywords
- Cirrhosis (7)
- cirrhosis (7)
- Antiviral therapy (6)
- Hepatocellular carcinoma (6)
- Liver diseases (6)
- hepatitis C virus (6)
- Hepatitis C virus (4)
- liver transplantation (4)
- ACLF (3)
- Chronic hepatitis C (3)
- HCC (3)
- acute-on-chronic liver failure (3)
- direct-acting antivirals (3)
- hepatitis C (3)
- liver cirrhosis (3)
- portal hypertension (3)
- Cancer treatment (2)
- Cytoskeletal proteins (2)
- DAA (2)
- Diabetes mellitus (2)
- Directly acting antiviral agent (2)
- Endoscopy (2)
- HBV (2)
- HIV (2)
- Hepatitis (2)
- Immunology (2)
- Inflammation (2)
- Liver cirrhosis (2)
- Liver fibrosis (2)
- Liver transplantation (2)
- Mortality (2)
- NASH (2)
- Ribavirin (2)
- SPTAN1 (2)
- Viral load (2)
- ascites (2)
- biliary stricture (2)
- biomarker (2)
- chemotherapy (2)
- co-infection (2)
- fatigue (2)
- hepatocellular carcinoma (2)
- inflammation (2)
- insulin resistance (2)
- molecular dynamics (2)
- multidrug resistance (2)
- overall survival (2)
- resistance mutation (2)
- serine protease (NS3-4A) (2)
- transient elastography (2)
- 8 weeks (1)
- AGC kinase (1)
- APRI (1)
- ARA (1)
- Adeno associated virus (1)
- Adenylyl cyclase (1)
- Alcoholic liver disease (1)
- All oral (1)
- All-oral therapy (1)
- Antibiotic steward-ship (1)
- Antibiotics (1)
- Ascites (1)
- Aurora (1)
- B-cell (1)
- BNT162b2 (1)
- Bacterial abundance (1)
- Biliary physiology (1)
- Biochemistry (1)
- Blood (1)
- Blood plasma (1)
- Breast tumors (1)
- Burden of disease (1)
- CLIF-C ACLF score (1)
- CLIF-C ACLF-R score (1)
- COVID-19 vaccination (1)
- CT (1)
- Caco-2 cells (1)
- Cancer (1)
- Cancer chemotherapy (1)
- Capnography (1)
- Cardiovascular disease (1)
- Case report (1)
- Cell binding (1)
- Cell motility (1)
- Cell staining (1)
- Cellular (1)
- Chronic Hepatitis C (1)
- Chronic hepatitis (1)
- Clinical efficacy (1)
- Colorectal cancer (1)
- Computed axial tomography (1)
- DNA methylation (1)
- DNA mismatch repair (1)
- Death rates (1)
- Digestive system (1)
- Digestive system procedures (1)
- Direct-acting antiviral agents (DAAs) (1)
- Direct-acting antivirals (1)
- Discovery (1)
- Drug (1)
- EQ-5D (1)
- ESBL (1)
- Early goal-directed therapy (1)
- Eicosanoids (1)
- Endocrine cancer (1)
- Enterobacteriaceae (1)
- Etiology (1)
- FIB-4 (1)
- FSS (1)
- Fatty acids (1)
- Fatty liver (1)
- Fibrosis (1)
- Fibrotest (1)
- Flow cytometry (1)
- GSK2334470 (1)
- GSK3α (1)
- GSK3β (1)
- Gastric cancer (1)
- Gastroenterology (1)
- Gastrointestinal tract (1)
- Gene therapy (1)
- Genetics (1)
- Genome-wide association study (1)
- Genomic medicine (1)
- HBV reactivation (1)
- HCV (1)
- HCV treatment (1)
- Health care resource utilization (1)
- Hepatitis B virus (1)
- Hepatitis C (1)
- Hepatotoxicity (1)
- Hispanic people (1)
- Host-targeting agents (HTAs) (1)
- Hypoxia (1)
- IgG4-related disease (1)
- Immune complex vasculitis (1)
- Immune suppression (1)
- Immunohistochemistry techniques (1)
- Indeterminate biliary stricture (1)
- Individualized therapy (1)
- Infection (1)
- Infections (1)
- Infectious disease (1)
- Infectious disease epidemiology (1)
- Integrated Pulmonary Index (1)
- Intensive care unit (1)
- Interferon (1)
- Interferon-free HCV treatment (1)
- Interferon-α (1)
- Interferon-λ, (1)
- Interleukin-22 (1)
- Interventional oncological treatment (1)
- Intestinal neoplasms (1)
- Kupffer cells (1)
- Laser interstitial thermal therapy (1)
- Liver (1)
- Liver cancer (1)
- Liver enzymes (1)
- Liver-related complications (1)
- Lymphoma (1)
- MELD (1)
- MLH1 (1)
- MRP4 (1)
- Macrophages (1)
- Medical education (1)
- Membrane staining (1)
- Metabolic syndrome (1)
- Metastasis (1)
- Metastatic tumors (1)
- Methicillin-resistant Staphylococcus aureus (1)
- Microwave ablation (1)
- Molecular biology (1)
- Monitoring (1)
- Mouse models (1)
- Multidrug resistance (1)
- Multidrug-resistance (1)
- Multidrug-resistant organisms (1)
- NAFLD (1)
- NS3-4A protease inhibitor (1)
- NS3/4A protease inhibitors (PI) (1)
- NS5A inhibitors (1)
- NS5B polymerase inhibitor (1)
- Negative staining (1)
- Neuroendocrine cancer (1)
- Next-generation sequencing (1)
- Non-Hodgkin lymphoma (1)
- Non-nucleoside polymerase inhibitors (NNI) (1)
- Null responder (1)
- Obesity (1)
- PCR (1)
- PDK1 (1)
- PIF pocket (1)
- PKA (1)
- PROMISE (1)
- Pathogenesis (1)
- Percutaneous endoscopic gastrostomy (1)
- Personal medicine (1)
- Platelets (1)
- Portal hypertension (1)
- Portal veins (1)
- Primary sclerosing cholangitis (1)
- Prostaglandin (1)
- Protease inhibitor therapy (1)
- Quinolones (1)
- Radiation exposure (1)
- Regression analysis (1)
- SKI II (1)
- SVR (1)
- SW480 cells (1)
- Safety (1)
- Salmonella choleraesuis (1)
- Sarcopenia (1)
- Self-expandable metal stents (1)
- Self-expandable metal stents complications (1)
- Sepsis-bundle (1)
- Single nucleotide polymorphism (1)
- Specimen preparation and treatment (1)
- Sphingolipids (1)
- Surgical and invasive medical procedures (1)
- Surgical oncology (1)
- Survival (1)
- Sustained virological response (1)
- TACE (1)
- TMC435 (1)
- Thrombosis (1)
- Thromboxane (1)
- Transarterial chemoembolization (1)
- Transferases (1)
- Transient elastography (1)
- Tumor obstruction (1)
- Type three hypersensitivity (1)
- VRE (1)
- Veins (1)
- Vitamin D (1)
- Vitamin D deficiency (1)
- acoustic radiation force impulse (1)
- acoustic radiation force impulse imaging (1)
- acute decompensation (1)
- adaptation (1)
- adenosine (1)
- adenosine receptors (1)
- alcoholic hepatitis (1)
- allosteric regulation (1)
- angiopoietin-like 3 (ANGPTL3) (1)
- anti-EGFR therapy (1)
- antibiotic therapy (1)
- antimicrobial stewardship (1)
- antiviral therapy (1)
- arachidonate 12/15-lipoxygenase (Alox12/15) (1)
- arachidonic acid (1)
- bacterial translocation (1)
- bevacizumab (1)
- bile duct stenosis (1)
- cAMP (1)
- cART (1)
- carbapenem resistance (1)
- chemorefractory metastatic colorectal cancer (1)
- cholangiocarcinoma (1)
- chronic hepatitis C (1)
- chronic viral hepatitis (1)
- colorectal cancer (1)
- combination (1)
- computed tomography (1)
- core expression (1)
- critical care unit (1)
- critical ill patients (1)
- cytokines (1)
- cytoskeleton (1)
- death rates (1)
- decompensated liver cirrhosis (1)
- dihydroceramide (1)
- direct antiviral (1)
- direct antiviral agents (1)
- direct-acting antiviral (DAA) treatment (1)
- direct-acting antivirals (DAAs) (1)
- directly acting antiviral agents (1)
- double-pigtail stents (1)
- drug interaction (1)
- drug resistance (1)
- eNPP2 (1)
- elderly (1)
- endoscopic retrograde cholangiography (1)
- endoscopic retrograde cholangiopancreatography (1)
- endoscopy (1)
- enterobacter infections; pseudomonas aeruginosa; epidemiology (1)
- eosinophilic cholangitis (1)
- epidemiology (1)
- evolution (1)
- exosomes (1)
- fibrosis (1)
- fibrotest (1)
- first-line chemotherapy (1)
- fumonisin B1 (1)
- genotype G (1)
- glecaprevir (1)
- graft rejection (1)
- health related quality of life (1)
- hemophilia (1)
- hepatic fibrosis (1)
- hepatitis (1)
- hepatitis B (1)
- hepatitis B virus (1)
- hepatitis C virus (HCV) (1)
- hepatitis E virus (1)
- hepatitis c (1)
- hospital admission (1)
- host-targeting antivirals (1)
- immune escape (1)
- immune profiling (1)
- immunity (1)
- immunohistochemistry (1)
- infection control (1)
- innate immunity (1)
- interferon (1)
- interferon-free (1)
- interferon-free antiviral treatment (1)
- interferons (1)
- intrahepatic cholangiocarcinoma (1)
- in vivo (1)
- ischemic type biliary lesions (1)
- lipoxin A4 (1)
- liver (1)
- liver fibrosis (1)
- liver immunology (1)
- long-term follow-up (1)
- macrophages (1)
- male (1)
- mechanical ventilation (1)
- medical risk factors (1)
- metastasis (1)
- metastatic colorectal cancer (1)
- miR-122 (1)
- microsatellite instability (1)
- mitochondrial antiviral signaling protein (MAVS) (1)
- molecular adaptation (1)
- molecular biology (1)
- mortality (1)
- non-invasive fibrosis assessment (1)
- omega-3 fatty acids (1)
- organ dysfunction (1)
- organ failure (1)
- orthopic liver transplantation (1)
- patient-reported outcomes (1)
- peg-interferon lambda (1)
- peginterferon (1)
- peginterferon-α (1)
- perioperative mortality (1)
- phylogenetic analysis (1)
- pibrentasvir (1)
- platelet count (1)
- point shear wave elastography (1)
- prevalence (1)
- primary sclerosing cholangitis (1)
- protease inhibitor (1)
- protein evolution (1)
- protein folding (1)
- protein kinase (1)
- pseudomonas aeruginosa (1)
- pulmonary failure (1)
- re-exposure (1)
- rechallenge (1)
- recurrent cholangitis (1)
- reintroduction (1)
- replicative fitness (1)
- resistance-associated substitutions (RAS) (1)
- resolution of inflammation (1)
- respiratory failure (1)
- ribavirin (1)
- screening routine (1)
- sepsis (1)
- short-course antibiotic therapy (1)
- signature (1)
- simeprevir (1)
- small compounds (1)
- sofosbuvir (1)
- sorafenib (1)
- specialized pro-resolving lipid mediators (SPMs) (1)
- spectrin (1)
- sphingolipid (1)
- sphingolipids (1)
- stent patency (1)
- structure constraints (1)
- thrombocytopenia (1)
- thrombocytosis (1)
- transarterial chemoembolization (1)
- transmission (1)
- treatment (1)
- triple therapy (1)
- velpatasvir (1)
- viral fitness (1)
- voxilaprevir (1)
- whole-genome sequencing (1)
- work productivity (1)
Institute
- Medizin (146) (remove)
Distinct immune patterns of hepatocellular carcinoma (HCC) may have prognostic implications in the response to transarterial chemoembolization (TACE). Thus, we aimed to exploratively analyze tumor tissue of HCC patients who do or do not respond to TACE, and to identify novel prognostic biomarkers predictive of response to TACE. We retrospectively included 15 HCC patients who had three consecutive TACE between January 2019 and November 2019. Eight patients had a response while seven patients had no response to TACE. All patients had measurable disease according to mRECIST. Corresponding tumor tissue samples were processed for differential expression profiling using NanoString nCounter® PanCancer immune profiling panel. Immune-related pathways were broadly upregulated in TACE responders. The top differentially regulated genes were the upregulated CXCL1 (log2fc 4.98, Benjamini–Hochberg (BH)-p < 0.001), CXCL6 (log2fc 4.43, BH-p = 0.016) and the downregulated MME (log2fc −4.33, BH-p 0.001). CD8/T-regs was highly increased in responders, whereas the relative number of T-regs to tumor-infiltrating lymphocytes (TIL) was highly decreased. We preliminary identified CXCL1 and CXCL6 as candidate genes that might have the potential to serve as therapeutically relevant biomarkers in HCC patients. This might pave the way to improve patient selection for TACE in HCC patients beyond expert consensus.
Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.
Design: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.
Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.
Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.
Glecaprevir/pibrentasvir, a pangenotypic, direct-acting antiviral combination approved for chronic hepatitis C virus treatment, has limited real-world evidence supporting 8-week therapy in compensated cirrhosis. We investigated effectiveness and safety of 187 hepatitis C virus-infected, treatment-naïve, patients with compensated cirrhosis receiving 8-week glecaprevir/pibrentasvir therapy in the German Hepatitis C-Registry between 2 August 2017 and 1 January 2020. Sustained virologic response was 98.4% (127/129) in the per-protocol analysis (excluding patients lost to follow-up or who discontinued treatment due to compliance) and was 85.8% (127/148) in patients with data available in an intention-to-treat analysis. Nineteen patients were lost to follow-up; nine genotype 3 patients, nine nongenotype 3 patients and one mixed genotype patient. One patient relapsed, and one died, unrelated to treatment. Adverse events (>5%) were fatigue and headache. Two serious adverse events occurred; no adverse events resulted in drug discontinuation. An 8-week glecaprevir/pibrentasvir therapy was effective and well-tolerated in this real-world analysis.
Background and Aims: In patients with Rat sarcoma proto-oncogene (RAS) wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) antibodies have been established in first- and further therapy lines. Due to limited treatment options upon disease progression, anti-EGFR re-exposure is increasingly employed in real-world oncology. The aim of this study was to assess clinical implementation and utility of anti-EGFR retreatment strategies in real-world mCRC patients. Methods: In this monocentric retrospective study, we included 524 patients with CRC and identified patients who received an anti-EGFR-based treatment as well as anti-EGFR rechallenge (progression on first-line anti-EGFR therapy) or reintroduction (discontinuation due to intolerance/toxicity/other). Results: In total, 143 patients received an anti-EGFR-based first- or second-line treatment, showing a similar overall survival (OS) compared to the non-anti-EGFR treatment group (38.3 vs. 39.6 months, p = 0.88). Thirty-three patients met the inclusion criteria for anti-EGFR re-exposure and were either assigned to rechallenge (n = 21) or reintroduction (n = 12) subgroups. The median FU after re-exposure was 45.8 months. Cetuximab and Panitumumab were used in 21 and 12 patients, respectively, and the main chemotherapy at re-exposure was FOLFIRI in 39.4%. Anti-EGFR re-exposure was associated with a distinct trend towards a better outcome (median OS 56.0 vs. 35.4 months, p = 0.06). In a subgroup comparison, reintroduction was associated with a higher OS and PFS in trend compared to the rechallenge (mOS 66 vs. 52.4, n.s., mPFS 7.33 vs. 3.68 months, n.s.). Conclusions: This retrospective study provides real-world evidence underscoring that anti-EGFR re-exposure strategies might benefit patients independently of the reason for prior discontinuation.
The Q80K polymorphism in the NS3-4A protease of the hepatitis C virus is associated with treatment failure of direct-acting antiviral agents. This polymorphism is highly prevalent in genotype 1a infections and stably transmitted between hosts. Here, we investigated the underlying molecular mechanisms of evolutionarily conserved coevolving amino acids in NS3-Q80K and revealed potential implications of epistatic interactions in immune escape and variants persistence. Using purified protein, we characterized the impact of epistatic amino acid substitutions on the physicochemical properties and peptide cleavage kinetics of the NS3-Q80K protease. We found that Q80K destabilized the protease protein fold (p < 0.0001). Although NS3-Q80K showed reduced peptide substrate turnover (p < 0.0002), replicative fitness in an H77S.3 cell culture model of infection was not significantly inferior to the WT virus. Epistatic substitutions at residues 91 and 174 in NS3-Q80K stabilized the protein fold (p < 0.0001) and leveraged the WT protease stability. However, changes in protease stability inversely correlated with enzymatic activity. In infectious cell culture, these secondary substitutions were not associated with a gain of replicative fitness in NS3-Q80K variants. Using molecular dynamics, we observed that the total number of residue contacts in NS3-Q80K mutants correlated with protein folding stability. Changes in the number of contacts reflected the compensatory effect on protein folding instability by epistatic substitutions. In summary, epistatic substitutions in NS3-Q80K contribute to viral fitness by mechanisms not directly related to RNA replication. By compensating for protein-folding instability, epistatic interactions likely protect NS3-Q80K variants from immune cell recognition.
Inhibitors against the NS3-4A protease of hepatitis C virus (HCV) have proven to be useful drugs in the treatment of HCV infection. Although variants have been identified with mutations that confer resistance to these inhibitors, the mutations do not restore replicative fitness and no secondary mutations that rescue fitness have been found. To gain insight into the molecular mechanisms underlying the lack of fitness compensation, we screened known resistance mutations in infectious HCV cell culture with different genomic backgrounds. We observed that the Q41R mutation of NS3-4A efficiently rescues the replicative fitness in cell culture for virus variants containing mutations at NS3-Asp168. To understand how the Q41R mutation rescues activity, we performed protease activity assays complemented by molecular dynamics simulations, which showed that protease-peptide interactions far outside the targeted peptide cleavage sites mediate substrate recognition by NS3-4A and support protease cleavage kinetics. These interactions shed new light on the mechanisms by which NS3-4A cleaves its substrates, viral polyproteins and a prime cellular antiviral adaptor protein, the mitochondrial antiviral signaling protein MAVS. Peptide binding is mediated by an extended hydrogen-bond network in NS3-4A that was effectively optimized for protease-MAVS binding in Asp168 variants with rescued replicative fitness from NS3-Q41R. In the protease harboring NS3-Q41R, the N-terminal cleavage products of MAVS retained high affinity to the active site, rendering the protease susceptible for potential product inhibition. Our findings reveal delicately balanced protease-peptide interactions in viral replication and immune escape that likely restrict the protease adaptive capability and narrow the virus evolutionary space.
Gene therapy has garnered increasing interest over recent decades. Several therapies employing gene transfer mechanisms have been developed, and, of these, adeno-associated virus (AAV) vectors have demonstrated viability for use with in vivo gene therapy. Several AAV-based therapeutics have received regulatory approval in the last few years including those for retinal disease, spinal muscular atrophy or aromatic L-amino acid decarboxylase deficiency. Lately, with the introduction of novel liver-directed AAV vector-based therapeutics for the treatment of haemophilia A and B, gene therapy has attracted significant attention in the hepatology community, with the liver increasingly recognised as a target for gene therapy. However, the introduction of foreign DNA into hepatocytes is associated with a risk of hepatic reactions, with raised ALT (alanine aminotransferase) and AST (aspartate aminotransferase) being – so far – the most commonly reported side effects. The complete mechanisms underlying the ALT flairs remain to be determined and the long-term risks associated with these new treatments is not yet known. The liver community is increasingly being asked to support liver-directed gene therapy to mitigate potential liver associated harm. In this review, we focus on AAV vector-based gene therapy, shedding light on this promising technique and its remarkable success in haemophilia, with a special focus on hepatic complications and their management in daily clinical practice.