Refine
Year of publication
Document Type
- Preprint (693)
- Article (591)
- Working Paper (10)
- Conference Proceeding (3)
- Part of Periodical (2)
- Part of a Book (1)
- Report (1)
Has Fulltext
- yes (1301)
Is part of the Bibliography
- no (1301)
Keywords
- Heavy Ion Experiments (20)
- Hadron-Hadron Scattering (11)
- Hadron-Hadron scattering (experiments) (11)
- LHC (9)
- Heavy-ion collision (6)
- ALICE experiment (4)
- Collective Flow (4)
- Hepatocellular carcinoma (4)
- Jets (4)
- Quark-Gluon Plasma (4)
- ALICE (3)
- COVID-19 (3)
- Cirrhosis (3)
- Gene expression (3)
- HIV (3)
- Heavy Ions (3)
- Immunology (3)
- Inflammation (3)
- Jets and Jet Substructure (3)
- Liver diseases (3)
- cancer (3)
- child (3)
- pp collisions (3)
- Antitrust (2)
- Beauty production (2)
- Bone density (2)
- Charm physics (2)
- Consumer Welfare (2)
- Diagnostic markers (2)
- Ewing sarcoma (2)
- Experimental nuclear physics (2)
- Experimental particle physics (2)
- HCC (2)
- Heavy Quark Production (2)
- Lepton-Nucleon Scattering (experiments) (2)
- Literaturtheorie (2)
- MLL (2)
- Mouse models (2)
- Oncology (2)
- Osteoporosis (2)
- Particle Correlations and Fluctuations (2)
- Particle and resonance production (2)
- Particle correlations and fluctuations (2)
- Pb–Pb collisions (2)
- Psychiatric disorders (2)
- QCD (2)
- Relativistic heavy-ion collisions (2)
- SARS-CoV-2 (2)
- Single electrons (2)
- Sustainability (2)
- aortic stenosis (2)
- biomarker (2)
- children (2)
- cirrhosis (2)
- habitat destruction (2)
- hematopoietic stem cell transplantation (2)
- hepatitis C virus (2)
- invasive fungal disease (2)
- lung cancer (2)
- proteomics (2)
- soft tissue sarcoma (2)
- sphingolipids (2)
- web archiving (2)
- 15-PGDH (1)
- 8 weeks (1)
- 900 GeV (1)
- ACURATE neo (1)
- AKI (1)
- ALICE detector (1)
- ALK-rearranged NSCLC (1)
- ALL (1)
- AML (1)
- APRI (1)
- Accelerators & Beams (1)
- Accelerators & storage rings (1)
- Actin (1)
- Active middle ear implants (1)
- Acute coronary syndrome (1)
- Acute myeloid leukemia (1)
- Adenylyl cyclase (1)
- Amino acid analysis (1)
- Anandamide (1)
- Angiogenesis (1)
- Animal models (1)
- Anti-nuclei (1)
- Antibiotic steward-ship (1)
- Antibiotic therapy (1)
- Antibiotics (1)
- Antiretroviral therapy (1)
- Antiretrovirals (1)
- Antiviral therapy (1)
- Apoptosis (1)
- Artificial Intelligence (1)
- Ataxia-telangiectasia (1)
- Atomic & molecular beams (1)
- Atomic, Molecular & Optical (1)
- Atoms (1)
- Atrial fibrillation (1)
- Auditory system (1)
- Autologous stem cell transplantation (1)
- Autorschaft (1)
- BFIS (1)
- BRAF (1)
- Backscattering (1)
- Beam loss (1)
- Biodiversity Data (1)
- Biomarker (1)
- Biomarkers (1)
- Biomass monitoring (1)
- Biomonitoring (1)
- Bioprocess automation (1)
- Bipolar disorder (1)
- Blood plasma (1)
- Bone conduction devices (1)
- Bone diseases, Metabolic (1)
- Boosted Jets (1)
- Botanical Collections (1)
- Breast cancer (1)
- Breast tumors (1)
- Buprestidae (1)
- C6 ceramide (1)
- CCL2 (1)
- CEP68 (1)
- COMT (1)
- COVID 19 (1)
- CRISPR/Cas (1)
- CT (1)
- CT dual-energy computed tomography (1)
- CVID (1)
- Cancer (1)
- Cancer chemotherapy (1)
- Cancer detection and diagnosis (1)
- Cancer treatment (1)
- Canopy height model (1)
- Cardiac hypertrophy (1)
- Cardiac surgery (1)
- Cardiac troponin (1)
- Cardiology (1)
- Cardiovascular biology (1)
- Cardiovascular disease risk (1)
- Cardiovascular diseases (1)
- Cell binding (1)
- Cell membranes (1)
- Cell staining (1)
- Centrality Class (1)
- Centrality Selection (1)
- Cerambycidae (1)
- Charge fluctuations (1)
- Charge-transfer collisions (1)
- Checkpoint inhibitor (1)
- Chronic hepatitis C (1)
- Circular accelerators (1)
- Cleanliness level (1)
- Clinical Trials and Observations (1)
- Clinical genetics (1)
- Collective Flow, (1)
- Colon capsule endoscopy (1)
- Colorectal cancer (1)
- Comparison with QCD (1)
- Complementation rate (1)
- Computer-aided drug design (1)
- Congenital anomalies (1)
- Consensus statement (1)
- Conservation (1)
- CuveWaters (1)
- C‐reactive protein (1)
- DNA sequence analysis (1)
- DST (1)
- Data sharing (1)
- Denervation (1)
- Diauxic effects (1)
- Differentiation (1)
- Digestive system procedures (1)
- Digitization (1)
- Dilated cardiomyopathy (1)
- Direct Acting Antivirals (DAA) (1)
- Drug susceptibility testing (1)
- Dual-energy computed tomography (1)
- ESBL (1)
- ESG (1)
- ETP-ALL (1)
- Early goal-directed therapy (1)
- Eicosanoids (1)
- Electroantennography (1)
- Electron-pion identification (1)
- Electronic transitions (1)
- Electroweak interaction (1)
- Elliptic flow (1)
- Embryos (1)
- Empirische Ästhetik (1)
- European Society for Immunodeficiencies (ESID) (1)
- Extended donor criteria (1)
- F508del homozygous (1)
- FDM (1)
- FGFR (1)
- FIB-4 (1)
- FLT3 (1)
- Fatty acids (1)
- Fatty liver (1)
- Femtoscopy (1)
- Fibre/foam sandwich radiator (1)
- Fibrosis (1)
- Fibrotest (1)
- Filovirus cell entry; attachment factors redundancy; SH-SY5Y cell line; host–pathogen interactions (1)
- Flow cytometry (1)
- Forschung (1)
- Forschungsdatenmanagement (1)
- Functional clustering (1)
- G-protein-coupled receptors (1)
- GWAS (1)
- Gastric cancer (1)
- Genetic causes of cancer (1)
- Genetic testing (1)
- Genetics (1)
- Genome editing (1)
- German PID-NET registry (1)
- Gomphus flavipes (1)
- Guanine nucleotide exchange factors (1)
- Guanosine triphosphatase (1)
- Gαq/11 (1)
- HBT (1)
- HBV (1)
- HCV (1)
- HDAC4 (1)
- HIF1α (1)
- HIPPO signalling (1)
- HIV-1 (1)
- HNO (1)
- Hadron production (1)
- Hadron-Hadron Scattering Heavy (1)
- Hadron-hadron interactions (1)
- Hals-Nasen-Ohren-Heilkunde (1)
- Haploidentical stem cell transplantation (1)
- Hard Scattering (1)
- Health policy (1)
- Heart (1)
- Heavy Ion Experiment (1)
- Heavy flavor production (1)
- Heavy flavour production (1)
- Heavy ions (1)
- Heavy-flavour decay muons (1)
- Heavy-flavour production (1)
- Heavy-ion collisions (1)
- Hepatitis B virus (1)
- Hepatitis C (1)
- Hepatitis C virus (1)
- Hepatotoxicity (1)
- Herbaria (1)
- High-dose chemotherapy (1)
- Histology (1)
- Homeostasis (1)
- Hsp70 (1)
- Human genetics (1)
- Hypertension (1)
- Hypoxic responses (1)
- IHC (1)
- IWRM (1)
- Icelandic Family Sagas (1)
- IgG substitution therapy (1)
- Immunogenetics (1)
- Inclusive spectra (1)
- Incomplete colonoscopy (1)
- Infection (1)
- Intensity interferometry (1)
- Intensive care unit (1)
- International Law (1)
- Internationales Recht (1)
- Interventional oncological treatment (1)
- Intravenous injections (1)
- Invariant Mass Distribution (1)
- Ionisation energy loss (1)
- Ions (1)
- Jet Physics (1)
- Jet Substructure (1)
- KDIGO (1)
- KIR (1)
- Konstitutionalismus (1)
- Kupffer cells (1)
- LCH (1)
- Landesinitiative (1)
- Landesinitiative für Forschungsdatenmanagement (1)
- Langerhans cell histiocytosis (1)
- Laser interstitial thermal therapy (1)
- Lehre (1)
- Lenalidomide (1)
- Libellen (1)
- Library screening (1)
- Literarischer Stil (1)
- Literaturwissenschaft (1)
- Liver (1)
- Liver cancer (1)
- Liver cirrhosis (1)
- Liver enzymes (1)
- Liver fibrosis (1)
- Liver transplantation (1)
- Long non-coding RNAs (1)
- Low & intermediate-energy accelerators (1)
- Low volume prep (1)
- Luciferase (1)
- Lymphoid Neoplasia (1)
- Lyrik (1)
- M. Intracellulare (1)
- M. avium (1)
- M. avium complex (1)
- M. chimaera (1)
- MALAT1 (1)
- MRP4 (1)
- Macrophages (1)
- Marker genes (1)
- Material budget (1)
- Mechanisms of disease (1)
- Mena/VASP (1)
- Mesenchymal stem cells (1)
- Metabolic shift (1)
- Metabolism (1)
- Microbiology and Infectious Disease (1)
- Microglial cells (1)
- Microwave ablation (1)
- Mid-rapidity (1)
- Minimal residual disease (1)
- Minimum Bias (1)
- Mixed hearing loss (1)
- Mongolia (1)
- Monochamus galloprovincialis (1)
- Monte Carlo (1)
- Mortality (1)
- Moviprep (1)
- Multi-Parton Interactions (1)
- Multi-nucleated cardiomyocytes (1)
- Multi-stakeholder approach (1)
- Multi-strange baryons (1)
- Multi-wire proportional drift chamber (1)
- Multidrug-resistant organisms (1)
- Multiple myeloma (1)
- Multivariate analysis (1)
- Muscle atrophy (1)
- Musikästhetik (1)
- Mutation databases (1)
- Myocardial infarction (1)
- NCoR1 (1)
- NFDI (1)
- NK cells (1)
- NMR spectroscopy (1)
- NOTCH1 (1)
- NTM (1)
- Nachhaltigkeit (1)
- Namibia (1)
- Nationale Forschungsdateninfrastruktur (1)
- Neural network (1)
- Neurons (1)
- Neuroästhetik (1)
- Non-tuberculous mycobacteria (1)
- Nuclear astrophysics (1)
- Nuclear modification factor (1)
- Nuclear physics of explosive environments (1)
- Nuclear reactions (1)
- Nucleus accumbens (1)
- ORL (1)
- Oncogenes (1)
- Online monitoring (1)
- Ophiogomphus cecilia (1)
- Optogenetics (1)
- Organ allocation (1)
- Orphan disease (1)
- Osteoporotic fractures (1)
- Otorhinolaryngology (1)
- Ovarian cancer (1)
- PD-L1 (1)
- PGE2 (1)
- PID prevalence (1)
- PKA (1)
- PKD (1)
- PKD/IC (1)
- PRRT2 (1)
- PYTHIA (1)
- Pancreas transplantation (1)
- Parallelisation (1)
- Particle and Resonance Production (1)
- Pb–Pb (1)
- Periodontal disease (1)
- Periodontal therapy (1)
- Perturbative methods (1)
- Phaenops cyanea (1)
- Phantoms (imaging) (1)
- Phospho-soda (1)
- Phosphorylation (1)
- Photon counting (1)
- PillCamColon2 (1)
- Plasminogen (1)
- Platelets (1)
- Polyps (1)
- Portal veins (1)
- Production Cross Section (1)
- Properties of Hadrons (1)
- Prostaglandin (1)
- Proton–proton (1)
- Pulsed SILAC (1)
- QGP (1)
- Quark Deconfinement (1)
- Quark Gluon Plasma (1)
- Quark Production (1)
- Quark gluon plasma (1)
- Quarkonium (1)
- RDM (1)
- RNA (1)
- RNA, long noncoding (1)
- RNA-binding proteins (1)
- Radiative capture (1)
- Random forest (1)
- Rapidity Range (1)
- Regression analysis (1)
- Rehabilitation (1)
- Rejection (1)
- Relapse (1)
- Relativistic heavy ion physics (1)
- Renal cell carcinoma (1)
- Research (1)
- Research Article (1)
- Research Data Management (1)
- Research Infrastructure (1)
- Residency (1)
- Resolution Parameter (1)
- Riftia pachyptila (1)
- S. cerevisiae (1)
- SARS CoV 2 (1)
- SARS-CoV‑2 pandemic (1)
- SARS-CoV‑2-Pandemie (1)
- SCCHN (1)
- SENP (1)
- SKI II (1)
- STED superresolution (1)
- SUMO (1)
- SVR (1)
- Safety (1)
- Sarcopenia (1)
- Scattering of atoms, molecules, clusters & ions (1)
- Scattering theory (1)
- Second-line treatment (1)
- Semantics (1)
- Sepsis-bundle (1)
- Sequence (1)
- Shake flask (1)
- Single muons (1)
- Single-cell RNA-sequencing (1)
- Small molecules (1)
- Specialist training (1)
- Spectrin (1)
- Sphingolipids (1)
- Stem cells (1)
- Surgery (1)
- Surgical and invasive medical procedures (1)
- Surgical oncology (1)
- Survival (1)
- Sustained virological response (SVR) (1)
- Systematic Uncertainty (1)
- Systemic treatment (1)
- T-ALL (1)
- TACE (1)
- TAVR (1)
- TGF-beta (1)
- TOR signalling (1)
- TP53 mutation status (1)
- TR (1)
- Targeted therapy (1)
- Taxonomy (1)
- Teaching (1)
- Technical data (1)
- Thrombosis (1)
- Thromboxane (1)
- Time Projection Chamber (1)
- Tomography (x-ray computed) (1)
- Tracking (1)
- Transarterial chemoembolization (1)
- Transcriptome analysis (1)
- Transferases (1)
- Transient elastography (1)
- Transition radiation detector (1)
- Transverse momentum (1)
- Trigger (1)
- Trousseau’s syndrome (1)
- Type 2 diabetes (1)
- Tyrosine kinase inhibitor mTOR inhibition (1)
- UAV (1)
- Ubiquitination (1)
- University hospitals (1)
- Universitätskliniken (1)
- VRE (1)
- Vector Boson Production (1)
- Veins (1)
- Vesicles (1)
- Viral load (1)
- Weiterbildung (1)
- Wettbewerbsrecht (1)
- X-ray crystallography (1)
- Xenon-based gas mixture (1)
- Yellow fluorescent protein (1)
- a-induced reactions (1)
- accessory proteins (1)
- acoustic radiation force impulse imaging (1)
- activation (1)
- acute coronary syndrome (1)
- acute leukemia (1)
- acute lymphoblastic leukemia (1)
- adenocarcinoma (1)
- adenosine receptors (1)
- aesthetic reward (1)
- age (1)
- agriculture (1)
- alcoholic hepatitis (1)
- allogeneic stem cell transplantation (1)
- amino acids (1)
- angiopoietin-like 3 (ANGPTL3) (1)
- anti-EGFR therapy (1)
- antibiotic therapy (1)
- antibodies (1)
- antiepileptic drugs (1)
- antifungal combination therapy (1)
- antifungal therapy (1)
- antimicrobial stewardship (1)
- antiviral therapy (1)
- arachidonate 12/15-lipoxygenase (Alox12/15) (1)
- architecture (1)
- ascites (1)
- atherosclerosis (1)
- atrial fibrillation (1)
- atrophy (1)
- autophagy (1)
- b-cell lymphomas (1)
- bacteremia (1)
- bendamustine (1)
- blood (1)
- bone marrow metastasis (1)
- bone metastasis (1)
- cAMP (1)
- cART (1)
- cancer surveillance (1)
- carbapenem resistance (1)
- cardiac I/R injury (1)
- cardiac remodeling (1)
- cell differentiation (1)
- cell heterogeneity (1)
- cell-free protein synthesis (1)
- centrosome (1)
- centrosome linker (1)
- ceramides (1)
- chemoembolization (1)
- chemorefractory metastatic colorectal cancer (1)
- chemotherapy regimen (1)
- children and adolescents (1)
- chills (1)
- chimeric antigen receptor t-cell therapy (1)
- chimeric antigen receptors (1)
- cholestasis (1)
- chromosomal translocations (1)
- chronic kidney disease (1)
- chronic viral hepatitis (1)
- co-infection (1)
- cohort study (1)
- computed tomography (1)
- confidence interval (1)
- confirmatory factor analysis (1)
- constitutionalisation (1)
- constitutionalism (1)
- coronary disease (1)
- critical care unit (1)
- critical ill patients (1)
- cutaneous T cell lymphoma (1)
- cystic fibrosis (1)
- dE/dx (1)
- damage detection (1)
- decision aids (1)
- demand-responsive approach (1)
- desmoplastic small round cell tumor (1)
- detector (1)
- dihydroceramide (1)
- dihydroceramides (1)
- direct-acting antivirals (1)
- disease progression (1)
- drone (1)
- eNPP2 (1)
- enrichment (1)
- entity and event extraction (1)
- epigenomics (1)
- experimental results (1)
- extraskeletal (1)
- familial infantile epilepsy (1)
- fatigue testing (1)
- fibrocytes (1)
- fibrosis (1)
- fibrotest (1)
- fine spatial resolution remote sensing (1)
- first-time shoulder dislocation (1)
- fixed-links modeling (1)
- fluid intelligence (1)
- fumonisin B1 (1)
- gap junction protein alpha 4-genotype (1)
- genetic generalized epilepsy (1)
- germ cell tumors (1)
- glass fiber reinforced materials (1)
- glecaprevir (1)
- glioblastoma (1)
- global change (1)
- graft rejection (1)
- head-and-neck cancer (1)
- heart failure (1)
- heavy ion experiments (1)
- hematopoietic cell transplantation (1)
- hemiplegic migraine (1)
- hepatic fibrosis (1)
- hepatic tumor (1)
- hepatitis C (1)
- hepatitis c (1)
- herbarium (1)
- high-dose chemotherapy (1)
- histology (1)
- homoarginine (1)
- host-microbe interaction (1)
- human knockout model (1)
- hypertension, pulmonary (1)
- idiopathic pulmonary fibrosis (1)
- immobilization in external rotation and abduction (1)
- immune checkpoint inhibitor (ICI) (1)
- immunohistochemistry (1)
- immunoprecipitation (1)
- immunotherapy (1)
- infection (1)
- infection control (1)
- infections (1)
- inflammatory markers (1)
- insulin resistance (1)
- interferon regulatory factor 9 (IRF9) (1)
- international legal theory (1)
- intraperitoneal therapy (1)
- intrinsically disordered region (1)
- ischemic type biliary lesions (1)
- knockout mouse (1)
- lamotrigine (1)
- land use (1)
- leukapheresis (1)
- leukemia (1)
- levetiracetam (1)
- lipoxin A4 (1)
- liver (1)
- liver abscess (1)
- liver cirrhosis (1)
- liver transplantation (1)
- long non-coding RNA (1)
- lung disease phenotype (1)
- lung function (1)
- lymphoma (1)
- l‐arginine:glycine amidinotransferase (1)
- maintenance therapy (1)
- malignancy (1)
- mass spectrometry (1)
- metastasis (1)
- methyltransferases (1)
- molecular characteristics (1)
- multi-resources mix (1)
- multidrug resistance (1)
- naturalization (1)
- neovascularization, physiologic (1)
- neuroaesthetics (1)
- neutralizing antibodies (1)
- neutropenia (1)
- nomadic lifestyles (1)
- non-ST-segment elevation acute coronary syndrome (1)
- non-invasive fibrosis assessment (1)
- non-neutropenic episode (1)
- nonstructural proteins (1)
- odds ratio (1)
- oral narratives (1)
- orthopic liver transplantation (1)
- outcome (1)
- ovary (1)
- p97 (1)
- parliament libraries (1)
- pediatric solid tumors (1)
- performativity (1)
- peritoneal carcinomatosis (1)
- pharmacoresistance (1)
- phenotype/genotype relation (1)
- phenotypic spectrum (1)
- pibrentasvir (1)
- piloerection (1)
- plant diversity (1)
- plant height (1)
- pneumonia (1)
- poetic language (1)
- point shear wave elastography (1)
- precision medicine (1)
- pressurized intraperitoneal aerosol chemotherapy (PIPAC) (1)
- primary biliary cirrhosis (1)
- primary immunodeficiency (1)
- primary immunodeficiency (PID) (1)
- primary sclerosing cholangitis (1)
- prognostic biomarker (1)
- quark gluon plasma (1)
- radar-based structural health monitoring (1)
- radio sensitivity (1)
- rain- and floodwater harvesting (1)
- rangeland ecosystems (1)
- rats (1)
- re-exposure (1)
- rechallenge (1)
- registry for primary immunodeficiency (1)
- reintroduction (1)
- resolution of inflammation (1)
- retrospective trial (1)
- risk assessment (1)
- rituximab (1)
- rootletin (1)
- rural-urban migration (1)
- sanitation (1)
- sarcoma (1)
- screening routine (1)
- semantic content analysis (1)
- sepsis (1)
- sequential ALK-inhibitor therapy (1)
- sex (1)
- short-chain ceramide (1)
- shortening of treatment (1)
- shoulder instability (1)
- shoulder stabilization (1)
- skeletal muscle (1)
- skin (1)
- social Web (1)
- solid tumor (1)
- sorafenib (1)
- specialized pro-resolving lipid mediators (SPMs) (1)
- spectra (1)
- sphinganine 1-phosphate (1)
- sphingolipid (1)
- sphingosine 1-phosphate (1)
- sphingosine kinase (1)
- sphingosine-1-phosphate (1)
- spike protein (1)
- steppe ecosystem (1)
- stopping rule (1)
- structural proteins (1)
- structure-from-motion photogrammetry (1)
- sulfur-oxidizing symbiont (1)
- symbiosis (1)
- tense switches (1)
- testis (1)
- text analysis (1)
- tomography (1)
- topic detection (1)
- transcatheter aortic valve replacement (1)
- transdisciplinarity (1)
- transfemoral (1)
- transient elastography (1)
- translocation partner genes (1)
- transmission (1)
- treatment (1)
- tumor microenvironment (TME) (1)
- type I interferons (IFNs) (1)
- tyrosine kinase inhibitor (TKI) (1)
- upper gastrointestinal cancer (1)
- valproic acid (1)
- variants of concern (1)
- vascular calcification (1)
- vemurafenib (1)
- versican (VCAN) (1)
- web crawler (1)
- whole-genome sequencing (1)
- wildlife mobility (1)
- wind turbine blades (1)
- working memory capacity (1)
- x-ray techniques (1)
- Ästhetik (1)
- γ-spectroscopy (1)
- гепатит С (1)
- правила прекращения лечения (1)
- противовирусные препараты прямого действия (ПППД) (1)
- сокращение лечения (1)
- устойчивый вирусологический ответ (УВО) (1)
- √sN N = 2.76 TeV (1)
Institute
- Physik (1086)
- Frankfurt Institute for Advanced Studies (FIAS) (961)
- Informatik (924)
- Medizin (160)
- Biowissenschaften (7)
- ELEMENTS (7)
- Biochemie, Chemie und Pharmazie (6)
- Sustainable Architecture for Finance in Europe (SAFE) (6)
- Wirtschaftswissenschaften (6)
- Geowissenschaften (5)
Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and micro-environmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) α/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67-positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCC model as revealed by magnetic resonance imaging. Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novel mechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
The 124Xe(p,γ) reaction has been measured for the first time at energies around the Gamow window by using stored ions at the ESR facility. The desired beam energies below 10 MeV/u introduce new experimental challenges like windowless ions detection under UHV conditions, extremely short beam lifetimes and efficient beam deceleration and cooling, all of which have been successfully met.
Filoviruses infect a wide range of cell types with the exception of lymphocytes. The intracellular proteins cathepsin B and L, two-pore channel 1 and 2, and bona fide receptor Niemann–Pick Disease C1 (NPC1) are essential for the endosomal phase of cell entry. However, earlier steps of filoviral infection remain poorly characterized. Numerous plasma membrane proteins have been implicated in attachment but it is still unclear which ones are sufficient for productive entry. To define a minimal set of host factors required for filoviral glycoprotein-driven cell entry, we screened twelve cell lines and identified the nonlymphocytic cell line SH-SY5Y to be specifically resistant to filovirus infection. Heterokaryons of SH-SY5Y cells fused to susceptible cells were susceptible to filoviruses, indicating that SH-SY5Y cells do not express a restriction factor but lack an enabling factor critical for filovirus entry. However, all tested cell lines expressed functional intracellular factors. Global gene expression profiling of known cell surface entry factors and protein expression levels of analyzed attachment factors did not reveal any correlation between susceptibility and expression of a specific host factor. Using binding assays with recombinant filovirus glycoprotein, we identified cell attachment as the step impaired in filovirus entry in SH-SY5Y cells. Individual overexpression of attachment factors T-cell immunoglobulin and mucin domain 1 (TIM-1), Axl, Mer, or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) rendered SH-SY5Y cells susceptible to filovirus glycoprotein-driven transduction. Our study reveals that a lack of attachment factors limits filovirus entry and provides direct experimental support for a model of filoviral cell attachment where host factor usage at the cell surface is highly promiscuous.
The electron-capture process was studied for Xe54+ colliding with H2 molecules at the internal gas target of the Experimental Storage Ring (ESR) at GSI, Darmstadt. Cross-section values for electron capture into excited projectile states were deduced from the observed emission cross section of Lyman radiation, being emitted by the hydrogenlike ions subsequent to the capture of a target electron. The ion beam energy range was varied between 5.5 and 30.9 MeV/u by applying the deceleration mode of the ESR. Thus, electron-capture data were recorded at the intermediate and, in particular, the low-collision-energy regime, well below the beam energy necessary to produce bare xenon ions. The obtained data are found to be in reasonable qualitative agreement with theoretical approaches, while a commonly applied empirical formula significantly overestimates the experimental findings.
Background and aims: Clinical trials of therapy against chronic hepatitis C virus (HCV) infection including boceprevir (BOC) or telaprevir (TVR) plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than those achieved with PR alone. This study sought to evaluate the efficacy and safety of triple therapy including BOC or TVR in combination with PR in HIV/HCV-coinfected patients under real-life conditions.
Methods: In a multicentre study conducted in 24 sites throughout five European countries, all HIV/HCV-coinfected patients who initiated a combination of BOC or TVR plus PR and who had at least 60 weeks of follow-up, were analyzed. Sustained virologic response 12 weeks after the scheduled end of therapy date (SVR12) and the rate of discontinuations due to adverse events (AE) were evaluated.
Results: Of the 159 subjects included, 127 (79.9%) were male, 45 (34.4%) were treatment-naïve for PR and 60 (45.4%) showed cirrhosis. SVR12 was observed in 31/46 (67.4%) patients treated with BOC and 69/113 (61.1%) patients treated with TVR. Overall discontinuations due to AE rates were 8.7% for BOC and 8% for TVR. Grade 3 or 4 hematological abnormalities were frequently observed; anemia 7%, thrombocytopenia 17.2% and neutropenia 16.4%.
Conclusion: The efficacy and safety of triple therapy including BOC or TVR plus PR under real-life conditions of use in the HIV/HCV-coinfected population was similar to what is observed in clinical trials. Hematological side effects are frequent but manageable.
The production of 77,79,85,85mKr and 77Br via the reaction Se(a, x) was investigated between Ea = 11 and 15 MeV using the activation technique. The irradiation of natural selenium targets on aluminum backings was conducted at the Physikalisch-Technische Bundesanstalt (PTB) in Braunschweig, Germany. The spectroscopic analysis of the reaction products was performed using a high-purity germanium detector located at PTB and a low energy photon spectrometer detector at the Goethe University Frankfurt, Germany. Thicktarget yields were determined. The corresponding energy-dependent production cross sections of 77,79,85,85mKr and 77Br were calculated from the thicktarget yields. Good agreement between experimental data and theoretical predictions using the TALYS-1.6 code was found.
Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer
(2022)
Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell–mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell–mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.
Malignant germ cell tumors (GCT) are the most common malignant tumors in young men between 18 and 40 years. The correct identification of histological subtypes, in difficult cases supported by immunohistochemistry, is essential for therapeutic management. Furthermore, biomarkers may help to understand pathophysiological processes in these tumor types. Two GCT cell lines, TCam-2 with seminoma-like characteristics, and NTERA-2, an embryonal carcinoma-like cell line, were compared by a quantitative proteomic approach using high-resolution mass spectrometry (MS) in combination with stable isotope labelling by amino acid in cell culture (SILAC). We were able to identify 4856 proteins and quantify the expression of 3936. 347 were significantly differentially expressed between the two cell lines. For further validation, CD81, CBX-3, PHF6, and ENSA were analyzed by western blot analysis. The results confirmed the MS results. Immunohistochemical analysis on 59 formalin-fixed and paraffin-embedded (FFPE) normal and GCT tissue samples (normal testis, GCNIS, seminomas, and embryonal carcinomas) of these proteins demonstrated the ability to distinguish different GCT subtypes, especially seminomas and embryonal carcinomas. In addition, siRNA-mediated knockdown of these proteins resulted in an antiproliferative effect in TCam-2, NTERA-2, and an additional embryonal carcinoma-like cell line, NCCIT. In summary, this study represents a proteomic resource for the discrimination of malignant germ cell tumor subtypes and the observed antiproliferative effect after knockdown of selected proteins paves the way for the identification of new potential drug targets.