Refine
Year of publication
Document Type
- Article (779)
- Preprint (723)
- Conference Proceeding (6)
- Working Paper (5)
- Report (3)
- Doctoral Thesis (1)
Has Fulltext
- yes (1517)
Is part of the Bibliography
- no (1517)
Keywords
- Heavy Ion Experiments (21)
- Hadron-Hadron Scattering (14)
- Hadron-Hadron scattering (experiments) (11)
- LHC (10)
- Heavy-ion collision (6)
- Jets (6)
- immunotherapy (6)
- COVID-19 (5)
- ALICE experiment (4)
- Breast cancer (4)
- Collective Flow (4)
- Diagnostic markers (4)
- Heavy Ions (4)
- Heavy Quark Production (4)
- Quark-Gluon Plasma (4)
- cancer (4)
- child (4)
- children (4)
- lung cancer (4)
- ALICE (3)
- Bipolar disorder (3)
- Jets and Jet Substructure (3)
- Psychiatric disorders (3)
- biomarker (3)
- hematopoietic stem cell transplantation (3)
- pp collisions (3)
- radical prostatectomy (3)
- 140Ce (2)
- ADHD (2)
- Aspergillus fumigatus (2)
- Atrial fibrillation (2)
- Beauty production (2)
- COVID-19 surveillance (2)
- Cancer (2)
- Charm physics (2)
- Depression (2)
- Diagnostik (2)
- Drug therapy (2)
- Experimental nuclear physics (2)
- Experimental particle physics (2)
- Früherkennung (2)
- Genetics (2)
- Heart failure (2)
- Heavy-ion collisions (2)
- Hypertension (2)
- Immunology (2)
- Lepton-Nucleon Scattering (experiments) (2)
- Mammakarzinom (2)
- NIRS (2)
- Nachsorge (2)
- Nuclear reactions (2)
- Omicron (2)
- Oncology (2)
- Outcome (2)
- Particle Correlations and Fluctuations (2)
- Particle and resonance production (2)
- Particle correlations and fluctuations (2)
- Pb–Pb collisions (2)
- QCD (2)
- Quark Gluon Plasma (2)
- Quarkonium (2)
- Rehabilitation (2)
- Richtlinie (2)
- SARS-CoV-2 monitoring (2)
- Shell model (2)
- Single electrons (2)
- Structural plasticity (2)
- Suicide (2)
- Superficial vein thrombosis (2)
- Surgery (2)
- Treatment (2)
- Ursus arctos (2)
- bipolar disorder (2)
- breast cancer (2)
- data science (2)
- diagnosis (2)
- follow‑up (2)
- functional outcome (2)
- guideline (2)
- inflammation (2)
- invasive fungal disease (2)
- leukemia (2)
- outcome (2)
- prostate cancer (2)
- psoriasis (2)
- screening (2)
- 16 segment AHA model (1)
- 19F (1)
- 900 GeV (1)
- ACL (1)
- AIS (1)
- AKI (1)
- AKT (1)
- ALICE detector (1)
- ARDS (1)
- Actin (1)
- Active middle ear implants (1)
- Acute coronary syndrome (1)
- Acute inflammation (1)
- Adjustment of dosage at steady state (1)
- Adult neurogenesis (1)
- Adverse events (1)
- Age groups (1)
- Amino acid analysis (1)
- Analysis and statistical methods (1)
- Anlegerschutz (1)
- Annual General Meeting (1)
- Annual general meeting (1)
- Anti-nuclei (1)
- Anti-seizure medication (1)
- Antibody isotypes (1)
- Antifungal agents (1)
- Antigen-presenting cells (1)
- Antirheumatic agents (1)
- Aortic valve (1)
- Aortic valve replacement (1)
- Apes (1)
- Artesunate (1)
- Artificial Intelligence (1)
- Artificial intelligence (1)
- Aspergillosis (1)
- Aspergillus (1)
- Atomic and Molecular Physics (1)
- Auditory system (1)
- Autorschaft (1)
- Awareness campaign (1)
- B cell receptor (1)
- B.1.1.529 (1)
- BA.4 (1)
- BA.5 (1)
- BFIS (1)
- BI1361849 (1)
- Bacteria (1)
- Bankberatung (1)
- Behavior (1)
- Biliary tree (1)
- Biodiversity (1)
- Biodiversity Data (1)
- Biological (1)
- Biological heart valves (1)
- Biomarker (1)
- Biomarkers (1)
- Biomonitoring (1)
- Bioprosthesis (1)
- Blood pressure (1)
- Body mass index (1)
- Bone conduction devices (1)
- Bone metastases (1)
- Bone metastasis (1)
- Bone strength assessment (1)
- Boosted Jets (1)
- Botanical Collections (1)
- Brain DNA methylation (1)
- Brain injury (1)
- Breast neoplasms (1)
- Breast tumors (1)
- Business strategy in drug development (1)
- CD3/19 depletion (1)
- CD34 selection (1)
- CD36 (1)
- CEO Speeches (1)
- CEO speeches (1)
- CHRNA10 (1)
- CHRNA7 (1)
- CHRNA9 (1)
- CIK cells (1)
- COMT (1)
- COVID 19 (1)
- CRPC (1)
- CT pulmonary angiography (1)
- CT radiation exposure (1)
- CTLA-4 (1)
- CV9202 (1)
- CVID (1)
- CWS Studiengruppe (1)
- Calcium (1)
- Calorimeters (1)
- Cancer check up (1)
- Cancer detection (1)
- Cancer detection and diagnosis (1)
- Candida spp (1)
- Cardiac implantable electronic devices (1)
- Cardiac rehabilitation (1)
- Cardiac resynchronization therapy (1)
- Cardiac surgery (1)
- Cardiac troponin (1)
- Cardiovascular biology (1)
- Cardiovascular disease risk (1)
- Cardiovascular diseases (1)
- Cardiovascular magnetic resonance (1)
- Catheter ablation (1)
- Cell binding (1)
- Cell membranes (1)
- Cell staining (1)
- Cellular imaging (1)
- Centrality Class (1)
- Centrality Selection (1)
- Charged-particle density (1)
- Cherenkov counter: lead-glass (1)
- Child (1)
- Child abuse (1)
- Children (1)
- Chronic obstructive pulmonary disease (1)
- Circadian (1)
- Clinical Trials and Observations (1)
- Clinical genetics (1)
- Clinical study (1)
- Clinical trial (1)
- Clinical variation (1)
- Closure (1)
- Cohort studies (1)
- Coincidence measurement (1)
- Collective Flow, (1)
- Combo® DTS (1)
- Community ecology (1)
- Comparative effectiveness research (1)
- Comparison with QCD (1)
- Complexity (1)
- Computational models (1)
- Computational science (1)
- Computed tomography pulmonary angiography (CTPA) (1)
- Computer-aided drug design (1)
- Congenital anomalies (1)
- Consensus (1)
- Consensus document (1)
- Consensus statement (1)
- Conservation (1)
- Conservation biology (1)
- Critical care (1)
- Cryoballoon (1)
- Cryoelectron microscopy (1)
- Cryoelectron tomography (1)
- DNA sequence analysis (1)
- DNA-PAINT (1)
- DYT1 (1)
- Data processing methods (1)
- Death rates (1)
- Dendritic spines (1)
- Denosumab (1)
- Dermatomyositis (1)
- Detection workflow (1)
- Developmental programming (1)
- Diagnosis (1)
- Digital breast tomosynthesis (DBT) (1)
- Digital mammography (1)
- Digitization (1)
- Dilated cardiomyopathy (1)
- Diphosphonates (1)
- Direct reactions (1)
- Dopamine (1)
- Drug screens (1)
- Dynamical systems (1)
- Early (prenatal and postnatal) life experiences (1)
- Ecological networks (1)
- Ecology (1)
- Ecosystem ecology (1)
- Ejection fraction (1)
- Elderly (1)
- Electromagnetic transitions (1)
- Electron-pion identification (1)
- Electroweak interaction (1)
- Elliptic flow (1)
- Embryos (1)
- Employment (1)
- Ena/VASP proteins (1)
- Endothelium (1)
- Entorhinal cortex lesion (1)
- Environmental enrichment (1)
- Environmental impact (1)
- Enzyme-linked immunoassays (1)
- Epilepsy (1)
- Etanercept (1)
- Europe (1)
- European Society for Immunodeficiencies (ESID) (1)
- Everolimus (1)
- Excitability (1)
- Exercise training (1)
- Exosomes (1)
- Experimental Finance (1)
- Extended donor criteria (1)
- FBS (1)
- FFLU (1)
- FGFR (1)
- Falciparum (1)
- Femoral neck (1)
- Femtoscopy (1)
- Fibre/foam sandwich radiator (1)
- Financial Advice (1)
- Finanzbildung (1)
- Fistula (1)
- Flow cytometry (1)
- Follow-up (1)
- Fondaparinux (1)
- Forschung (1)
- Fracture risk (1)
- Frailty (1)
- Functional outcome (1)
- Functional outcomes (1)
- FungiScope® registry (1)
- GPS collar (1)
- Gene expression (1)
- General practitioners (1)
- Genetic causes of cancer (1)
- Genetic testing (1)
- German PID-NET registry (1)
- Global positioning system (1)
- Guanine nucleotide exchange factors (1)
- Guanosine triphosphatase (1)
- Guidelines (1)
- HADES (1)
- HBT (1)
- HER2-positive (1)
- HNO (1)
- HPV-positive OPSCC (1)
- Hadron production (1)
- Hadron-Hadron Scattering Heavy (1)
- Hadron-hadron interactions (1)
- Hals-Nasen-Ohren-Heilkunde (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-Ion Collision (1)
- Heavy-flavour decay muons (1)
- Heavy-flavour production (1)
- Heavy-ion detectors (1)
- Hematologic malignancies (1)
- Hematology (1)
- Hepatocellular carcinoma (1)
- Herafill (1)
- Herbaria (1)
- High-energy neutron detection (1)
- Histology (1)
- Household Finance (1)
- Human behaviour (1)
- Human genetics (1)
- Hypofractionated radiotherapy (1)
- ICU (1)
- IFN-β (1)
- ISS (1)
- IgG substitution therapy (1)
- Immune response (1)
- Immunity (1)
- Immunoassays (1)
- Immunogenetics (1)
- Immunology and Microbiology Section (1)
- Immunomonitoring (1)
- Implantable cardioverter-defibrillator (1)
- Inclusive spectra (1)
- Inflammation (1)
- Intensity interferometry (1)
- Interleukin-17A (1)
- Intra-abdominal infection (1)
- Invariant Mass Distribution (1)
- Invasive candidiasis (1)
- Invasive fungal infections (1)
- Inverse kinematics (1)
- Ionisation energy loss (1)
- Isoproterenol (1)
- Jet Physics (1)
- Jet Substructure (1)
- Jurkat (1)
- K48-linked (1)
- K63-linked (1)
- KDIGO (1)
- KOOS IV (1)
- Kidney (1)
- Knochendefektheilung (1)
- Kupffer cells (1)
- Köcherfliegen (1)
- LASS (1)
- LFP (1)
- Laparostomy (1)
- Large detector systems for particle and astroparticle physics (1)
- Lee-type (1)
- Lehre (1)
- Leukemias (1)
- Library screening (1)
- Lipid signaling (1)
- Literarischer Stil (1)
- Literaturwissenschaft (1)
- Lomentospora prolificans (1)
- Low-molecular-weight heparin (1)
- Luciferase (1)
- Lumbar spine (1)
- Lymphoid Neoplasia (1)
- MACS (1)
- Machine learning (1)
- Macrophages (1)
- Malaria (1)
- Malignancy (1)
- Market Efficiency (1)
- Market efficiency (1)
- Masquelet (1)
- Masquelet technique (1)
- Material budget (1)
- Maternal separation (1)
- Mena/VASP (1)
- Mental health and psychiatry (1)
- Mesh (1)
- Metagenomics (1)
- MicroRNAs (1)
- Mid-rapidity (1)
- Minimum Bias (1)
- Mittelhessen (1)
- Mixed hearing loss (1)
- Models & methods for nuclear reactions (1)
- Molecular neuroscience (1)
- Monitoring (1)
- Monte Carlo (1)
- Motor control (1)
- Mouse models (1)
- Multi-Parton Interactions (1)
- Multi-neutron detection (1)
- Multi-stakeholder approach (1)
- Multi-strange baryons (1)
- Multi-wire proportional drift chamber (1)
- Multimodal imaging (1)
- Multiparametric MRI (1)
- Multiple sclerosis (1)
- Multivariate analysis (1)
- Mutation databases (1)
- Mycoses (1)
- Myocardial infarction (1)
- Myocardial perfusion (1)
- Myocardial segmentation (1)
- NADPH oxidase (1)
- NMR spectroscopy (1)
- NSG mice (1)
- NVBP (1)
- Neoadjuvant therapy (1)
- Neural network (1)
- Neuroinflammation (1)
- Neuroscience (1)
- Neutron physics (1)
- Neutropenia (1)
- Non-small cell lung cancer (1)
- Non-trauma (1)
- Nordhessen (1)
- Nox1 (1)
- NoxO1 (1)
- Nuclear modification factor (1)
- Nuclear resonance fluorescence (1)
- Nuclear structure & decays (1)
- Nucleon induced nuclear reactions (1)
- Nutrition (1)
- ORL (1)
- Observational (1)
- Oldest-old (1)
- Open abdomen (1)
- Organ allocation (1)
- Osteoporosis diagnosis (1)
- Otorhinolaryngology (1)
- Outcome assessment (1)
- Outpatients (1)
- Ovarian cancer (1)
- P2X7 receptor (1)
- PD-1 (1)
- PD-L1 (1)
- PID prevalence (1)
- PKD (1)
- PKD/IC (1)
- PRRT2 (1)
- PSA screening (1)
- PSA-Screening (1)
- PYTHIA (1)
- Pacemaker (1)
- Paediatric research (1)
- Pancreas transplantation (1)
- Pancreatitis (1)
- Pandemic (1)
- Particle and Resonance Production (1)
- Pathological complete response (1)
- Pb–Pb (1)
- Pediatric infections (1)
- Pediatric patients (1)
- Pediatrics (1)
- Performance of High Energy Physics Detectors (1)
- Peritoneal macrophages (1)
- Peritonitis (1)
- Personalized medicine (1)
- Phosphorylation (1)
- Physical activity (1)
- Plasmodium (1)
- Plastic scintillator array (1)
- Pneumonia (1)
- Population-based screening (1)
- Post treatment (1)
- Post-traumatic stress disorder (1)
- Predictive markers (1)
- Prevention (1)
- Preventive medicine (1)
- Production Cross Section (1)
- Prognosis (1)
- Prognostic models (1)
- Properties of Hadrons (1)
- Prostata-specific antigen (1)
- Prostataspezifisches Antigen (1)
- Prostate cancer (1)
- Proteinkinase (1)
- Proton–proton (1)
- Prävention (1)
- Pseudo HE-images (1)
- Psychiatry (1)
- Psychological and psychosocial issues (1)
- Pygmy Dipole Resonance (1)
- Quality of life (1)
- Quark Deconfinement (1)
- Quark Production (1)
- Quark gluon plasma (1)
- Quasi-free scattering (1)
- Quasi-particle phonon model (1)
- Quinine (1)
- REMS (1)
- RNA (1)
- RTS (1)
- Radiative capture (1)
- Radical prostatectomy (1)
- Radiofrequency (1)
- Radiomics (1)
- Raman spectroscopy (1)
- Rapidity Range (1)
- Re-exploration (1)
- Re-injury (1)
- Reactions with relativistic radioactive beams (1)
- Reactive oxygen species (1)
- Real world (1)
- Recall rate (1)
- Recurrence (1)
- Registries (1)
- Rehospitalization (1)
- Reintervention (1)
- Rejection (1)
- Relativistic heavy ion physics (1)
- Relativistic heavy-ion collisions (1)
- Remission (1)
- Renal replacement therapy (1)
- Research (1)
- Research Infrastructure (1)
- Residency (1)
- Resolution Parameter (1)
- Resonance reactions (1)
- Return to play (1)
- Return to sports (1)
- Rhabdomyoma (1)
- Rhabdomyosarcoma (1)
- Rheumatoid arthritis (1)
- Risk assessment (1)
- Ryanodine (1)
- SARS CoV 2 (1)
- SARS-CoV-2 (1)
- SARS-CoV‑2 pandemic (1)
- SARS-CoV‑2-Pandemie (1)
- SMAD (1)
- Saarland (1)
- Scedosporium spp. (1)
- Seasonal variation (1)
- Secondary prevention (1)
- Seizure (1)
- Semantics (1)
- Sensory systems (1)
- Serine proteases (1)
- Severe malaria (1)
- Single muons (1)
- Small molecules (1)
- Solar insolation (1)
- South West Germany (1)
- Specialist training (1)
- Spectrin (1)
- Spectroscopic factors (1)
- Spectroscopic factors & electromagnetic moments (1)
- Stress vulnerability/resilience genes (1)
- Sub-segmentation (1)
- Sunlight (1)
- Superoxide (1)
- Survival analysis (1)
- Sustainable Finance (1)
- Synaptic plasticity (1)
- Synaptopodin (1)
- Synthetic (1)
- Systematic Uncertainty (1)
- T-cell (1)
- TAVI (1)
- TGF-beta (1)
- TGFB-induced factor homeobox 1 (1)
- TGFβ (1)
- TGIF (1)
- TOR1A (1)
- TR (1)
- Taxonomy (1)
- Tea (1)
- Teaching (1)
- Technical data (1)
- Technique (1)
- Textual Analysis (1)
- Textual Sentiment (1)
- Textual analysis (1)
- Textual sentiment (1)
- Therapeutics (1)
- Therapy (1)
- Thoracic trauma (1)
- Time Projection Chamber (1)
- Timing (1)
- Tracking (1)
- Transcriptome analysis (1)
- Transition radiation detector (1)
- Translation (1)
- Transverse momentum (1)
- Trauma (1)
- Trigger (1)
- Triple negative (1)
- Two-hit hypothesis (1)
- Ultrasound (1)
- University hospitals (1)
- Universitätskliniken (1)
- Urinary continence (1)
- Urinary incontinence (1)
- VASP (1)
- VEGF receptor 2 internalization and signaling (1)
- Variant of concern (1)
- Vascular emergencies (1)
- Vector Boson Production (1)
- Venous thrombosis (1)
- Vesicles (1)
- Voriconazole (1)
- Vorsorgeuntersuchung (1)
- Wastewater-based epidemiology (WBE) (1)
- Weiterbildung (1)
- Wide rapidity coverage (1)
- X-ray crystallography (1)
- Xenon-based gas mixture (1)
- Z-inspection (1)
- accessory proteins (1)
- activity sensors (1)
- acute lymphoblastic leukemia (1)
- adenocarcinoma (1)
- alcoholic hepatitis (1)
- allogeneic stem cell transplant (1)
- allogeneic stem cell transplantation (1)
- anaesthesia in orthopaedics (1)
- anaesthetics (1)
- animal personality (1)
- anti-EGFR therapy (1)
- antibiotic resistance (1)
- antibodies (1)
- antifungal combination therapy (1)
- antifungal therapy (1)
- aortic stenosis (1)
- apex (1)
- arachidonate 12/15-lipoxygenase (Alox12/15) (1)
- artifacts (1)
- artificial intelligence (1)
- astrocytes (1)
- atherosclerosis (1)
- attention deficit hyperactivity disorder (1)
- attention-deficit/hyperactivity disorder (ADHD) (1)
- autoantibodies (1)
- b-cell lymphomas (1)
- bacteremia (1)
- behavioural syndrome (1)
- bendamustine (1)
- bioactivity testing (1)
- biodiversity (1)
- biogeographic legaciese (1)
- bloodstream infections (1)
- bone marrow derived mononuclear cells (1)
- bone marrow mononuclear cells (1)
- brain injury (1)
- brown bear (1)
- cAMP (1)
- cGMP (1)
- calcium-independent phospholipase A2β (1)
- calorimeter: electromagnetic (1)
- calretinin (1)
- candidemia (1)
- capture (1)
- cardiac magnetic resonance (1)
- castration resistance (1)
- cell lines (1)
- cell stress (1)
- cell-free protein synthesis (1)
- central nervous system (1)
- ceramide synthase (1)
- ceramides (1)
- cerium (1)
- chemorefractory metastatic colorectal cancer (1)
- chemotherapy (1)
- chemotherapy regimen (1)
- chimeric antigen receptor (CAR) (1)
- chimeric antigen receptor t-cell therapy (1)
- chimeric antigen receptors (1)
- cholestasis (1)
- chronic kidney disease (1)
- chronic total occlusion (1)
- cisplatin (1)
- clinical research (1)
- cohort study (1)
- colon (1)
- combined modality therapy (1)
- component study (1)
- coronary disease (1)
- critical size defect (1)
- cross-section (1)
- cytokine (1)
- dE/dx (1)
- damage detection (1)
- data quality (1)
- decision aids (1)
- delirium (1)
- dementia (1)
- dentate gyrus (1)
- depression (1)
- detector (1)
- diagnostics (1)
- disease prevalence (1)
- disease progression (1)
- double hierarchical model (1)
- double immune checkpoint inhibition (1)
- early recognition (1)
- easyPACId (1)
- ecological and phytosociological classification (1)
- ectosomes (1)
- electroencephalography (EEG) (1)
- electronics: readout (1)
- endocannabinoids (1)
- endothelial cells (1)
- entorhinal cortex lesion (1)
- ethical co-design (1)
- ethics (1)
- excitation transport (1)
- exosomes (1)
- experimental results (1)
- extracellular vesicles (1)
- facial nerve functional outcome (1)
- familial infantile epilepsy (1)
- fatigue testing (1)
- fibre: optical (1)
- fibrosis (1)
- flow cytometry (1)
- fluorine (1)
- fondaparinux (1)
- forest classification (1)
- forest functional similarity (1)
- fragment-based screening (1)
- galactomannan (1)
- gene expression (1)
- genetic phenotypes (1)
- geriatric medicine (1)
- glass fiber reinforced materials (1)
- guidelines (1)
- head and neck neoplasms (1)
- head-and-neck cancer (1)
- healthcare (1)
- hearing nerve (1)
- heavy ion experiments (1)
- hematopoietic cell transplantation (1)
- hemiplegic migraine (1)
- homeostatic synaptic scaling (1)
- human natural killer cell (1)
- human subjects (1)
- hypertension and anti-hypertensive treatment (1)
- imaging (1)
- immune checkpoint blockade (1)
- immune checkpoint inhibitor (ICI) (1)
- immune monitoring (1)
- immune reconstitution (1)
- immunohistochemistry (1)
- impulsivity (1)
- incontinence (1)
- induced membrane (1)
- induction therapy (1)
- infants (1)
- infection (1)
- infections (1)
- inflammasome (1)
- intensive care admission and mortality (1)
- interferon regulatory factor 9 (IRF9) (1)
- interleukin-1β (1)
- interoperability (1)
- intratumoral (1)
- intrinsically disordered region (1)
- invasive mold infection (1)
- layer-specificity (1)
- learning loss (1)
- leukapheresis (1)
- light harvesting networks (1)
- light–energy conversion (1)
- lipids (1)
- lipiodol (1)
- lipoxin A4 (1)
- liver metastasis (1)
- low molecular weight heparin (1)
- low-dose imaging (1)
- lymphoma (1)
- mRNA active cancer immunotherapy (1)
- mTOR (1)
- mTOR inhibitor (1)
- machine learning (1)
- magnetic resonance imaging of the brain (1)
- major depression (1)
- malignant melanoma (1)
- mast cells (1)
- mechanical accuracy (1)
- membranous urethra (1)
- mesenchymal stromal cells (1)
- metabolic syndrome (1)
- metastasis (1)
- metastatic prostate cancer (1)
- microparticles (1)
- microsurgical treatment (1)
- microvesicles (1)
- microwave ablation (1)
- mid-term urinary continence (1)
- mindfulness (1)
- minimal information requirements (1)
- misallocation rate (1)
- misinterpretation rate (1)
- mitral regurgitation (1)
- mitral valve surgery (1)
- mortality (1)
- movement (1)
- multicenter study (1)
- multiparametric magnetic resonance imaging (1)
- multivariate mixed model (1)
- myocardial fibrosis (1)
- n_TOF (1)
- natural products (1)
- neonates (1)
- nerve-sparing surgery (1)
- neurofeedback (1)
- neutron (1)
- neutropenia (1)
- non-ST-segment elevation acute coronary syndrome (1)
- non-neutropenic episode (1)
- nonstructural proteins (1)
- nucleosynthesis (1)
- obesity (1)
- olfaction (1)
- open quantum systems (1)
- optical coherence tomography (1)
- organ preservation (1)
- organotypic slice cultures (1)
- overlooking rate (1)
- p47phox (1)
- pad-test (1)
- patients (1)
- pediatric patients (1)
- penile cancer (1)
- perforant path transection (1)
- perforin (1)
- personality (1)
- phagocytosis (1)
- phantom study (1)
- phenotypic spectrum (1)
- phylogenetic community distance (1)
- pneumonia (1)
- polygenic risk score (1)
- polymerase chain reaction (1)
- polyubiquitin (1)
- preclinical (1)
- primary biliary cholangitis (1)
- primary biliary cirrhosis (1)
- primary immunodeficiency (PID) (1)
- primary sclerosing cholangitis (1)
- proteins (1)
- proteobacteria (1)
- proteomics (1)
- psychotherapy process (1)
- quantum transport (1)
- quark gluon plasma (1)
- radar-based structural health monitoring (1)
- randomized controlled trial (RCT) (1)
- re-exposure (1)
- rechallenge (1)
- registry for primary immunodeficiency (1)
- reintroduction (1)
- repeatability (1)
- reproducibility (1)
- residual intra‐individual variability (1)
- resolution (1)
- resolution of inflammation (1)
- rhabdomyosarcoma (1)
- rigor (1)
- risk assessment (1)
- rituximab (1)
- robot-guided stereotaxy (1)
- s-process (1)
- sarcoma (1)
- scaffold size (1)
- scar (1)
- schizophrenia (1)
- school closure (1)
- second line therapy (1)
- secukinumab (1)
- semiconductors (1)
- simplified production (1)
- single subject classification (1)
- sleep disordered breathing (1)
- smart home (1)
- smart living (1)
- solid tumor (1)
- specialized pro-resolving lipid mediators (SPMs) (1)
- species differences (1)
- spectra (1)
- sprouting angiogenesis (1)
- stability (1)
- standardization (1)
- stereotactic frame (1)
- stereotactic neurosurgery (1)
- stroke (1)
- structural proteins (1)
- student achievement (1)
- survival (1)
- systematic review (1)
- tandem mass spectrometry (1)
- targeted therapy (1)
- telmisartan (1)
- temporal classification (1)
- therapeutic alliance (1)
- tip cell filopodia formation (1)
- toll-like receptor (1)
- tomography (1)
- treatment (1)
- treatment resistance (1)
- treatment response (1)
- tropical forests (1)
- trustworthy AI (1)
- trustworthy AI Co-design (1)
- tumor (1)
- tumor microenvironment (1)
- tumor microenvironment (TME) (1)
- type I interferons (IFNs) (1)
- tyrosine kinase inhibitor (TKI) (1)
- ubiquitin-conjugating enzymes (1)
- urinary incontinence (1)
- ursodeoxycholic acid (1)
- uveal melanoma (1)
- variant of concern (1)
- vascular calcification (1)
- vascular dysfunction and inflammation (1)
- vegetation monitoring (1)
- venous thrombosis (1)
- versican (VCAN) (1)
- vestibular schwannoma (1)
- viral tracing (1)
- virtual reality (1)
- wastewater-based epidemiology (WBE) (1)
- web of things (1)
- weed communities (1)
- wind turbine blades (1)
- Öffentlichkeit (1)
- ß-D-glucan (1)
- γ-ray spectroscopy (1)
- √sN N = 2.76 TeV (1)
Institute
- Physik (1208)
- Frankfurt Institute for Advanced Studies (FIAS) (1040)
- Informatik (1007)
- Medizin (192)
- Geowissenschaften (48)
- Biowissenschaften (9)
- ELEMENTS (8)
- Biochemie, Chemie und Pharmazie (7)
- Georg-Speyer-Haus (6)
- Institut für Ökologie, Evolution und Diversität (6)
Background: Common ECG criteria such as ST-segment changes are of limited value in patients with suspected acute myocardial infarction (AMI) and bundle branch block or wide QRS complex. A large proportion of these patients do not suffer from an AMI, whereas those with ST-elevation myocardial infarction (STEMI) equivalent AMI benefit from an aggressive treatment. Aim of the present study was to evaluate the diagnostic information of cardiac troponin I (cTnI) in hemodynamically stable patients with wide QRS complex and suspected AMI.
Methods: In 417 out of 1818 patients presenting consecutively between 01/2007 and 12/2008 in a prospective multicenter observational study with suspected AMI a prolonged QRS duration was observed. Of these, n = 117 showed significant obstructive coronary artery disease (CAD) used as diagnostic outcome variable. cTnI was determined at admission.
Results: Patients with significant CAD had higher cTnI levels compared to individuals without (median 250ng/L vs. 11ng/L; p<0.01). To identify patients needing a coronary intervention, cTnI yielded an area under the receiver operator characteristics curve of 0.849. Optimized cut-offs with respect to a sensitivity driven rule-out and specificity driven rule-in strategy were established (40ng/L/96ng/L). Application of the specificity optimized cut-off value led to a positive predictive value of 71% compared to 59% if using the 99th percentile cut-off. The sensitivity optimized cut-off value was associated with a negative predictive value of 93% compared to 89% provided by application of the 99th percentile threshold.
Conclusion: cTnI determined in hemodynamically stable patients with suspected AMI and wide QRS complex using optimized diagnostic thresholds improves rule-in and rule-out with respect to presence of a significant obstructive CAD.
Background: The introduction of modern troponin assays has facilitated diagnosis of acute myocardial infarction due to improved sensitivity with corresponding loss of specificity. Atrial fibrillation (AF) is associated with elevated levels of troponin. The aim of the present study was to evaluate the diagnostic performance of troponin I in patients with suspected acute coronary syndrome and chronic AF.
Methods: Contemporary sensitive troponin I was assayed in a derivation cohort of 90 patients with suspected acute coronary syndrome and chronic AF to establish diagnostic cut-offs. These thresholds were validated in an independent cohort of 314 patients with suspected myocardial infarction and AF upon presentation. Additionally, changes in troponin I concentration within 3 hours were used.
Results: In the derivation cohort, optimized thresholds with respect to a rule-out strategy with high sensitivity and a rule-in strategy with high specificity were established. In the validation cohort, application of the rule-out cut-off led to a negative predictive value of 97 %. The rule-in cut-off was associated with a positive predictive value of 88 % compared with 71 % if using the 99th percentile cut-off. In patients with troponin I levels above the specificity-optimized threshold, additional use of the 3-hour change in absolute/relative concentration resulted in a further improved positive predictive value of 96 %/100 %.
Conclusions: Troponin I concentration and the 3-hour change in its concentration provide valid diagnostic information in patients with suspected myocardial infarction and chronic AF. With regard to AF-associated elevation of troponin levels, application of diagnostic cut-offs other than the 99th percentile might be beneficial.
Aims: Patients with aortic stenosis (AS) may have concomitant heart failure (HF) that determines prognosis despite successful transcatheter aortic valve implantation (TAVI). We compared outcomes of TAVI patients with low stroke volume index (SVI) ≤35 ml/m2 body surface area in different HF classes.
Methods and results: Patients treated by transfemoral TAVI at our center (n = 1822) were classified as 1) ‘HF with preserved ejection fraction (EF)’ (HFpEF, EF ≥50%), 2) ‘HF with mid-range EF’ (HFmrEF, EF 40–49%), or 3) ‘HF with reduced EF’ (HFrEF, EF <40%). Patients with SVI >35 ml/m2 served as controls. The prevalence of cardiovascular disease and symptoms increased stepwise from controls (n = 968) to patients with HFpEF (n = 591), HFmrEF (n = 97), and HFrEF (n = 166). Mortality tended to be highest in HFrEF patients 30 days post-procedure, and it became significant after one year: 10.2% (controls), 13.5% (HFpEF), 13.4% (HFmrEF), and 23.5% (HFrEF). However, symptomatic improvement in survivors of all groups was achieved in the majority of patients without differences among groups.
Conclusions: Patients with AS and HF benefit from TAVI with respect to symptom alleviation. TAVI in patients with HFpEF and HFmrEF led to an identical, favorable post-procedural prognosis that was significantly better than that of patients with HFrEF, which remains a high-risk population.
Die Universität Frankfurt will Stiftungsuniversität mit einem hohen Maß an Autonomie werden. Die Vortragsreihe „Die Universität der Zukunft“ begleitet diesen Prozess des Wandels. Profilierte Hochschulpioniere, Hochschulreformer und Stifter geben Auskunft über ihre Visionen einer Universität der Zukunft und über die Projekte, an denen sie arbeiten. Thomas Oppermann und Dr. Konrad Schily machten im Sommersemester 2007 den Auftakt. Im Wintersemester wurde die Vortragsreihe von Dr. Arend Oetker eröffnet, Prof. Matthias Kleiner folgte und Prof. Andreas Pinkwart schloss sie am 28. November ab. Die Johann Wolfgang Goethe-Universität steht mit der geplanten Umwandlung in eine Stiftungsuniversität mit weitgehender Autonomie vor den größten Veränderungen der letzten 50 Jahre. Solche grundlegenden Veränderungsprozesse bieten Gelegenheit, auch einen Blick auf andere Reform-Modelle zu werfen mit dem Ziel, die eigene Urteilsfähigkeit zu stärken. Die neue, hochkarätig besetzte Vortragsreihe „Die Universität der Zukunft“ sollte den Prozess der Veränderung der Universität Frankfurt in diesem und im kommenden Jahr inhaltlich begleiten. Zu Wort kamen Frauen und Männer, die als politische Pioniere Hochschulen den Weg der Veränderung geebnet, als Geldgeber ermöglicht oder gar eine neue Hochschule gegründet und mit aufgebaut haben. Was hat sie bewegt, diese Schritte zu unternehmen? Wo sahen und sehen sie die Chancen? Mit welchen Widerständen waren sie konfrontiert? Darüber werden sie Auskunft geben und sich auch den Fragen des Publikums stellen. Den Auftakt machten im Sommersemester zwei Männer, die in Deutschland viel bewegt haben: Der ehemalige niedersächsische Wissenschaftsminister Thomas Oppermann gilt als „Vater“ der deutschen Stiftungsuniversität. Während seiner Amtszeit in Hannover hat er die Landesuniversitäten einem grundlegenden Veränderungsprozess unterzogen: Sie wurden Stiftungshochschule mit einem höheren Maß an Autonomie als davor. Wie sehen die Erfahrungen mit diesem Modell im Rückblick mehrerer Jahre Praxis heute aus? Der Arzt und Gründer der Privaten Universität Witten/Herdecke, Dr. Konrad Schily, hat sich als deutscher Hochschulpionier einen Namen gemacht: Witten/Herdecke, 1982 gegründet, ist die erste private Volluniversität in Deutschland. Mit ihrem ambitionierten und bis heute einzigartigen Bildungskonzept hat die kleine Universität an der Ruhr deutsche Bildungsgeschichte geschrieben, war aber auch oft von Finanznöten geplagt. Bedeutet „privat“ eine zu starke Abhängigkeit von Geldgebern aus der Wirtschaft. Oder hat die Universität ihren Freiheitskurs über die Jahre erfolgreich verteidigen können? Im Wintersemester 2007/08 wurde die Reihe fortgesetzt. Dann standen auf dem Programm Dr. Arend Oetker (23.10.), Präsident des Stifterverbandes und Unternehmer, Prof. Matthias Kleiner (13.11.), Präsident der Deutschen Forschungsgemeinschaft (DFG) sowie der nordrhein-westfälische Minister für Innovation, Wissenschaft, Forschung und Technologie, Prof. Andreas Pinkwart (28.11.). Dr. Arend Oetker ist einer der herausragenden Mäzene und Unternehmer unseres Landes. Als Präsident des Stifterverbandes für die deutsche Wissenschaft in Essen sitzt er mit über 350 Einzelstiftungen und einem Gesamtvermögen von 1,4 Mrd. Euro dem wichtigsten Fördernetzwerk privater Stiftungen in Deutschland vor. Damit ist er in der BRD der bedeutendste Experte im Bereich der privaten Förderung von Wissenschaft. Daneben trägt er Verantwortung für die "Dr. Arend Oetker Holding", zu der rund 5.500 Mitarbeiter gehören und die sich mit Rohstoffhandel ebenso beschäftigt wie mit Schifffahrt. Sein Vortrag wird u.a. Auskunft darüber geben, wie man Stiftungs-Potenziale für universitäre Zwecke besser nutzen kann. Prof. Matthias Kleiner ist seit Januar 2007 DFG-Präsident. Bei seinem Vortrag im Universitätsklinikum wird er berichten über die Arbeit der wichtigsten und größten Förderorganisation für die Forschung in Deutschland. Ihre Kernaufgabe besteht in der Finanzierung von Forschungsvorhaben von Wissenschaftlerinnen und Wissenschaftlern in Universitäten und Forschungsinstituten und in der Auswahl der besten Projekte im Wettbewerb. Prof. Andreas Pinkwart ist seit 2005 Minister für Innovation, Wissenschaft, Forschung und Technologie sowie stellvertretender Ministerpräsident in Nordrhein-Westfalen. Das Hochschulfreiheitsgesetz gilt als eines der wichtigsten Reform-Projekte in der deutschen Bildungspolitik. Ermöglicht es doch allen Landes-Hochschulen ein Ausmaß an Freiheit und Selbstverantwortung, das bisher nicht denkbar war. Pinkwarts Vortrag reflektiert die Erfahrungen, die er und sein Haus in der Phase der Umsetzung mit den Hochschulen gemacht haben.
Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34+-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3+, CD3+CD4+, and CD3+CD8+ T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34+-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3+CD4+ helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34+-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.
Background: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. Results: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective.
We report here the nuclear magnetic resonance 19F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter-screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow-up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low-micromolar binding affinity without losing binding specificity between two different terminator structures.
Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
Protein signatures of oxidative stress response in a patient specific cell line model for autism
(2014)
Background: Known genetic variants can account for 10% to 20% of all cases with autism spectrum disorders (ASD). Overlapping cellular pathomechanisms common to neurons of the central nervous system (CNS) and in tissues of peripheral organs, such as immune dysregulation, oxidative stress and dysfunctions in mitochondrial and protein synthesis metabolism, were suggested to support the wide spectrum of ASD on unifying disease phenotype. Here, we studied in patient-derived lymphoblastoid cell lines (LCLs) how an ASD-specific mutation in ribosomal protein RPL10 (RPL10[H213Q]) generates a distinct protein signature. We compared the RPL10[H213Q] expression pattern to expression patterns derived from unrelated ASD patients without RPL10[H213Q] mutation. In addition, a yeast rpl10 deficiency model served in a proof-of-principle study to test for alterations in protein patterns in response to oxidative stress.
Methods: Protein extracts of LCLs from patients, relatives and controls, as well as diploid yeast cells hemizygous for rpl10, were subjected to two-dimensional gel electrophoresis and differentially regulated spots were identified by mass spectrometry. Subsequently, Gene Ontology database (GO)-term enrichment and network analysis was performed to map the identified proteins into cellular pathways.
Results: The protein signature generated by RPL10[H213Q] is a functionally related subset of the ASD-specific protein signature, sharing redox-sensitive elements in energy-, protein- and redox-metabolism. In yeast, rpl10 deficiency generates a specific protein signature, harboring components of pathways identified in both the RPL10[H213Q] subjects' and the ASD patients' set. Importantly, the rpl10 deficiency signature is a subset of the signature resulting from response of wild-type yeast to oxidative stress.
Conclusions: Redox-sensitive protein signatures mapping into cellular pathways with pathophysiology in ASD have been identified in both LCLs carrying the ASD-specific mutation RPL10[H213Q] and LCLs from ASD patients without this mutation. At pathway levels, this redox-sensitive protein signature has also been identified in a yeast rpl10 deficiency and an oxidative stress model. These observations point to a common molecular pathomechanism in ASD, characterized in our study by dysregulation of redox balance. Importantly, this can be triggered by the known ASD-RPL10[H213Q] mutation or by yet unknown mutations of the ASD cohort that act upstream of RPL10 in differential expression of redox-sensitive proteins.
Endothelium-dependent vasodilation is thought to be mediated primarily by the NO/cGMP signaling pathway whereas cAMP-elevating vasodilators are considered to act independent of the endothelial cell layer. However, recent functional data suggest that cAMP-elevating vasodilators such as β-receptor agonists, adenosine or forskolin may also be endothelium-dependent. Here we used functional and biochemical assays to analyze endothelium-dependent, cGMP- and cAMP-mediated signaling in rat aorta. Acetylcholine and sodium nitroprusside (SNP) induced a concentration-dependent relaxation of phenylephrine-precontracted aorta. This response was reflected by the phosphorylation of the vasodilator-stimulated phosphoprotein (VASP), a validated substrate of cGMP- and cAMP-dependent protein kinases (cGK, cAK), on Ser157 and Ser239. As expected, the effects of acetylcholine were endothelium-dependent. However, relaxation induced by the β-receptor agonist isoproterenol was also almost completely impaired after endothelial denudation. At the biochemical level, acetylcholine- and isoproterenol-evoked cGK and cAK activation, respectively, as measured by VASP Ser239 and Ser157 phosphorylation, was strongly diminished. Furthermore, the effects of isoproterenol were repressed by eNOS inhibition when endothelium was present. We also observed that the relaxing and biochemical effects of forskolin were at least partially endothelium-dependent. We conclude that cAMP-elevating vasodilators, i.e. isoproterenol and to a lesser extent also forskolin, induce vasodilation and concomitant cyclic nucleotide protein kinase activation in the vessel wall in an endothelium-dependent way.
Crista junctions (CJs) are important for mitochondrial organization and function, but the molecular basis of their formation and architecture is obscure. We have identified and characterized a mitochondrial membrane protein in yeast, Fcj1 (formation of CJ protein 1), which is specifically enriched in CJs. Cells lacking Fcj1 lack CJs, exhibit concentric stacks of inner membrane in the mitochondrial matrix, and show increased levels of F1FO–ATP synthase (F1FO) supercomplexes. Overexpression of Fcj1 leads to increased CJ formation, branching of cristae, enlargement of CJ diameter, and reduced levels of F1FO supercomplexes. Impairment of F1FO oligomer formation by deletion of its subunits e/g (Su e/g) causes CJ diameter enlargement and reduction of cristae tip numbers and promotes cristae branching. Fcj1 and Su e/g genetically interact. We propose a model in which the antagonism between Fcj1 and Su e/g locally modulates the F1FO oligomeric state, thereby controlling membrane curvature of cristae to generate CJs and cristae tips.
Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool.
Background: Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest. Methods: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue samples from BC patients treated in the GAIN (German Adjuvant Intergroup Node-Positive) study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining. Endpoints were disease-free survival (DFS), overall survival (OS) and time to primary bone metastasis as first site of relapse (TTPBM). Results: We found associations of higher TGIF protein expression with smaller tumor size (p= 0.015), well differentiated phenotype (p< 0.001) and estrogen receptor (ER)-positive BC (p< 0.001). Patients with higher TGIF expression levels showed a significantly longer disease-free (DFS: HR 0.75 [95%CI 0.59–0.95], log-rank p=0.019) and overall survival (OS: HR 0.69 [95%CI 0.50–0.94], log-rank p= 0.019), but no association with TTPBM (HR 0.77 [95%CI 0.51–1.16]; p= 0.213). Univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: HR 0.68 [95%CI 0.51–0.91]; log-rank p= 0.009, interaction p= 0.130; OS: HR 0.60 [95%CI 0.41–0.88], log-rank p= 0.008, interaction p= 0.107) and in the HER2-negative subgroup (DFS:HR 0.67 [95%CI 0.50–0.88], log-rank p= 0.004, interaction p= 0.034; OS: HR 0.57 [95%CI 0.40–0.81], log-rank p= 0.002, interaction p= 0.015). Conclusions: Our results suggest that moderate to high TGIF expression is a common feature of breast cancer cells and that this is not associated with bone metastases as first site of relapse. However, a reduced expression is linked to tumor progression, especially in HER2-negative breast cancer.
Following publication of the original article, the authors noticed an incorrect affiliation for Christine Stürken and Udo Schumacher. The correct affiliations are as follows: Christine Stürken: Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Udo Schumacher: Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. The affiliations have been correctly published in this correction and the original article has been updated.
Don't poke the bear : using tracking data to quantify behavioural syndromes in elusive wildlife
(2018)
Animal personality traits and the emergence of behavioural syndromes, i.e. between-individual correlation of behaviours, are commonly quantified from behavioural observations in controlled environments. Subjecting large and elusive wildlife to controlled test situations is, however, rarely possible, suggesting that ecologists should exploit alternative measures of behaviours for quantifying differences between individuals. Our goal was to test whether movement and space use data can be used to quantify behavioural syndromes in the wild. We quantified six behaviours from GPS and dual motion sensor tracking devices of 46 adult female brown bears followed in southcentral Sweden over the summer and early autumn. As well as daily travel distance, an indicator for activity, and daily displacement, an indicator for exploration, we quantified four behaviours that increase a bear's likelihood of encountering humans and could thus serve as indicators for boldness: diurnality, selection for roads and selection for two open habitat types, bogs and clearcuts, with low lateral cover. We tested (1) whether behaviours showed repeatable between-individual variation (animal personality) and (2) whether behaviours were correlated between individuals and thus formed a behavioural syndrome. Repeatability of behaviours ranged from 0.16 to 0.61 confirming between-individual variation in movement, activity and space use. A multivariate mixed model revealed significant positive correlations between travel distance, displacement and diurnality, suggesting the existence of an activity–exploration and potentially partial boldness syndrome in our bear population. Selection for exposed or human-frequented habitats were uncorrelated with the activity–exploration syndrome and with each other, albeit there was a trend for stronger road avoidance by bears that readily used clearcuts. We show that large tracking data sets can be used to quantify between-individual correlation in spatial behaviours. We suggest that delineating behavioural types from wildlife tracking data will be of increasing interest because of the importance of animal personality for ecological processes, wildlife conservation and human–wildlife coexistence.
The 2[4Fe-4S] ferredoxin from Chromatium vinosum arises as one prominent member of a recently defined family of proteins found in very diverse bacteria. The potentiometric circular dichroism titrations of the protein and of several molecular variants generated by site-directed mutagenesis have established that the reduction potentials of the two clusters differ widely by almost 200 mV. This large difference has been confirmed by electrochemical methods, and each redox transition has been assigned to one of the clusters. The unusually low potential center is surprisingly the one that displays a conventional CX1X2CX3X4C (Xn, variable amino acid) binding motif and a structural environment similar to that of clusters having less negative potentials. A comparison with other ferredoxins has highlighted factors contributing to the reduction potential of [4Fe-4S] clusters in proteins. (i) The loop between the coordinating cysteines 40 and 49 and the C terminus alpha-helix of C. vinosum ferredoxin cause a negative, but relatively moderate, shift of approximately 60 mV for the nearby cluster. (ii) Very negative potentials, below -600 mV, correlate with the presence of a bulky side chain in position X4 of the coordinating triad of cysteines. These findings set the framework in which previous observations on ferredoxins can be better understood. They also shed light onto the possible occurrence and properties of very low potential [4Fe-4S] clusters in less well characterized proteins.
The crystal structure of the bovine Rieske iron-sulfur protein indicates a sulfur atom (S-1) of the iron-sulfur cluster and the sulfur atom (Sgamma) of a cysteine residue that coordinates one of the iron atoms form hydrogen bonds with the hydroxyl groups of Ser-163 and Tyr-165, respectively. We have altered the equivalent Ser-183 and Tyr-185 in the Saccharomyces cerevisiae Rieske iron-sulfur protein by site-directed mutagenesis of the iron-sulfur protein gene to examine how these hydrogen bonds affect the midpoint potential of the iron-sulfur cluster and how changes in the midpoint potential affect the activity of the enzyme. Eliminating the hydrogen bond from the hydroxyl group of Ser-183 to S-1 of the cluster lowers the midpoint potential of the cluster by 130 mV, and eliminating the hydrogen bond from the hydroxyl group of Tyr-185 to Sgamma of Cys-159 lowers the midpoint potential by 65 mV. Eliminating both hydrogen bonds has an approximately additive effect, lowering the midpoint potential by 180 mV. Thus, these hydrogen bonds contribute significantly to the positive midpoint potential of the cluster but are not essential for its assembly. The activity of the bc1 complex decreases with the decrease in midpoint potential, confirming that oxidation of ubiquinol by the iron-sulfur protein is the rate-limiting partial reaction in the bc1 complex, and that the rate of this reaction is extensively influenced by the midpoint potential of the iron-sulfur cluster.
Background: Predicted increases in suicide were not generally observed in the early months of the COVID-19 pandemic. However, the picture may be changing and patterns might vary across demographic groups. We aimed to provide a timely, granular picture of the pandemic's impact on suicides globally.
Methods: We identified suicide data from official public-sector sources for countries/areas-within-countries, searching websites and academic literature and contacting data custodians and authors as necessary. We sent our first data request on 22nd June 2021 and stopped collecting data on 31st October 2021. We used interrupted time series (ITS) analyses to model the association between the pandemic's emergence and total suicides and suicides by sex-, age- and sex-by-age in each country/area-within-country. We compared the observed and expected numbers of suicides in the pandemic's first nine and first 10-15 months and used meta-regression to explore sources of variation.
Findings: We sourced data from 33 countries (24 high-income, six upper-middle-income, three lower-middle-income; 25 with whole-country data, 12 with data for area(s)-within-the-country, four with both). There was no evidence of greater-than-expected numbers of suicides in the majority of countries/areas-within-countries in any analysis; more commonly, there was evidence of lower-than-expected numbers. Certain sex, age and sex-by-age groups stood out as potentially concerning, but these were not consistent across countries/areas-within-countries. In the meta-regression, different patterns were not explained by countries’ COVID-19 mortality rate, stringency of public health response, economic support level, or presence of a national suicide prevention strategy. Nor were they explained by countries’ income level, although the meta-regression only included data from high-income and upper-middle-income countries, and there were suggestions from the ITS analyses that lower-middle-income countries fared less well.
Interpretation: Although there are some countries/areas-within-countries where overall suicide numbers and numbers for certain sex- and age-based groups are greater-than-expected, these countries/areas-within-countries are in the minority. Any upward movement in suicide numbers in any place or group is concerning, and we need to remain alert to and respond to changes as the pandemic and its mental health and economic consequences continue.
Background: Aortic valve stenosis has gained increasingly more importance due to its high prevalence in elderly people. More than two decades ago, transcatheter aortic valve replacement emerged for patients who were denied surgery, and its noninferiority has been demonstrated in numerous studies. Oxidative stress has generated great interest because of its sensitivity to cell damage and the possibility of offering early hints of clinical outcomes. The aim of the present study was to investigate whether there is a significant difference between transcatheter (TAVR) or surgical aortic valve replacement (SAVR) in terms of the changes in oxidation-reduction potential (ORP) and antioxidant capacity. Therefore, we investigated perioperative oxidative stress levels and their influence on clinical outcomes.
Methods: A total of 72 patients (50% TAVR versus 50% SAVR) were included in the present study. Static oxidation-reduction potential (sORP) and antioxidant capacity were measured using the RedoxSys™ Diagnostic System (Luoxis Diagnostics, USA) in serum samples drawn before and after surgery, as well as on the first postoperative day. In addition, clinical data were obtained to evaluate the clinical outcome of each case.
Results: TAVR patients had higher preoperative sORP levels compared to the SAVR patients and more severe comorbidities. Unlike the TAVR cohort, patients in the SAVR group showed a significant difference in sORP from the pre- to postoperative levels. Capacity demonstrated higher preoperative levels in the SAVR cohort and also a greater difference postoperatively compared to the TAVR cohort. Regression analysis revealed a significant correlation between pre- and postoperative capacity levels (r = -0.9931, p < 0.0001), providing a method of predicting postoperative capacity levels by knowing the preoperative levels. According to the multivariable analysis, both sORP and antioxidant capacity are dependent on time point, baseline value, and type of surgery, with the largest variations observed for time effect and surgery method.
Conclusion: A high preoperative sORP level correlated to more severe illness in the TAVR patients. As the TAVR patients did not show significant differences in their preoperative levels, we assume that there was a smaller production of oxidative agents during TAVR due to the less invasive nature of the procedure. Baseline values and development of antioxidant capacity values strengthen this hypothesis. The significant correlation of pre- and postoperative capacity levels might allow high risk patients to be detected more easily and might provide more adequate and individualized therapy preoperatively. This trial is registered with clinicaltrials.gov, identifier: NCT 02488876.
Aim: NADPH oxidases are important sources of reactive oxygen species (ROS). Several Nox homologues are present together in the vascular system but whether they exhibit crosstalk at the activity level is unknown. To address this, vessel function of knockout mice for the cytosolic Nox organizer proteins p47phox, NoxO1 and a p47phox-NoxO1-double knockout were studied under normal condition and during streptozotocin-induced diabetes.
Results: In the mouse aorta, mRNA expression for NoxO1 was predominant in smooth muscle and endothelial cells, whereas p47phox was markedly expressed in adventitial cells comprising leukocytes and tissue resident macrophages. Knockout of either NoxO1 or p47phox resulted in lower basal blood pressure. Deletion of any of the two subunits also prevented diabetes-induced vascular dysfunction. mRNA expression analysis by MACE (Massive Analysis of cDNA ends) identified substantial gene expression differences between the mouse lines and in response to diabetes. Deletion of p47phox induced inflammatory activation with increased markers of myeloid cells and cytokine and chemokine induction. In contrast, deletion of NoxO1 resulted in an attenuated interferon gamma signature and reduced expression of genes related to antigen presentation. This aspect was also reflected by a reduced number of circulating lymphocytes in NoxO1-/- mice.
Innovation and conclusion: ROS production stimulated by NoxO1 and p47phox limit endothelium-dependent relaxation and maintain blood pressure in mice. However, NoxO1 and p47phox cannot substitute each other despite their similar effect on vascular function. Deletion of NoxO1 induced an anti-inflammatory phenotype, whereas p47phox deletion rather elicited a hyper-inflammatory response.
Endothelial tip cells are essential for VEGF-induced angiogenesis, but underlying mechanisms are elusive. The Ena/VASP protein family, consisting of EVL, VASP, and Mena, plays a pivotal role in axon guidance. Given that axonal growth cones and endothelial tip cells share many common features, from the morphological to the molecular level, we investigated the role of Ena/VASP proteins in angiogenesis. EVL and VASP, but not Mena, are expressed in endothelial cells of the postnatal mouse retina. Global deletion of EVL (but not VASP) compromises the radial sprouting of the vascular plexus in mice. Similarly, endothelial-specific EVL deletion compromises the radial sprouting of the vascular plexus and reduces the endothelial tip cell density and filopodia formation. Gene sets involved in blood vessel development and angiogenesis are down-regulated in EVL-deficient P5-retinal endothelial cells. Consistently, EVL deletion impairs VEGF-induced endothelial cell proliferation and sprouting, and reduces the internalization and phosphorylation of VEGF receptor 2 and its downstream signaling via the MAPK/ERK pathway. Together, we show that endothelial EVL regulates sprouting angiogenesis via VEGF receptor-2 internalization and signaling.
We analyze the market reaction to the sentiment of the CEO speech at the Annual General Meeting (AGM). As the AGM is typically preceded by several information disclosures, the CEO speech may be expected to contribute only marginally to investors’ decision-making. Surprisingly, however, we observe from the transcripts of 338 CEO speeches of German corporates between 2008 and 2016 that their sentiment is significantly related to abnormal stock returns and trading volumes following the AGM. Using a novel business-specific German dictionary based on Loughran and McDonald (2011), we find a negative association of the post-AGM returns with the speeches’ negativity and a positive association with the speeches’ relative positivity (i.e. positivity relative to negativity). Relative positivity moreover corresponds with a lower trading volume in a short time window surrounding the AGM. Investors hence seem to perceive the sentiment of CEO speeches at AGMs as a valuable indicator of future firm performance.
We analyze the market reaction to the sentiment of the CEO speech at the Annual General Meeting (AGM). As the AGM is typically preceded by several information disclosures, the CEO speech may be expected to contribute only marginally to investors’ decision making. Surprisingly, however, we observe from the transcripts of 338 CEO speeches of German corporates between 2008 and 2016 that their sentiment is significantly related to abnormal stock returns and trading volume around the AGM. By adapting a finance-specific German dictionary based on Loughran and McDonald (2011), we find a negative association of the post-AGM returns with the speeches’ negativity and a positive association with the speeches’ relative positivity (i.e. positivity relative to negativity). Relative positivity moreover corresponds with a lower trading volume around the AGM. Investors hence seem to perceive the sentiment of CEO speeches at AGMs as a valuable indicator of future firm performance. Our results are robust against different weighting schemes and our dictionary appears to be better suited to grasp the sentiment of German business documents compared to general dictionaries.
We report measurements of the deuterium content of molecular hydrogen (H2) obtained from a suite of air samples that were collected during a stratospheric balloon flight between 12 and 33 km at 40º N in October 2002. Strong deuterium enrichments of up to 400 permil versus Vienna Standard Mean Ocean Water (VSMOW) are observed, while the H2 mixing ratio remains virtually constant. Thus, as hydrogen is processed through the H2 reservoir in the stratosphere, deuterium is accumulated in H2 . Using box model calculations we investigated the effects of H2 sources and sinks on the stratospheric enrichments. Results show that considerable isotope enrichments in the production of H2 from CH4 must take place, i.e., deuterium is transferred preferentially to H2 during the CH4 oxidation sequence. This supports recent conclusions from tropospheric H2 isotope measurements which show that H2 produced photochemically from CH4 and non-methane hydrocarbons must be enriched in deuterium to balance the tropospheric hydrogen isotope budget. In the absence of further data on isotope fractionations in the individual reaction steps of the CH4 oxidation sequence, this effect cannot be investigated further at present. Our measurements imply that molecular hydrogen has to be taken into account when the hydrogen isotope budget in the stratosphere is investigated.
Background: Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).
Methodology/Principal Findings: Associations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99–1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12–2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13–1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (P>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis.
Conclusions/Significance: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.
Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
Serial quantification of BCR–ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR–ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 106, 1.08±0.11 × 105, 1.03±0.10 × 104, 1.02±0.09 × 103, 1.04±0.10 × 102 and 10.0±1.5 copies/μl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR–ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR–ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).
Comparative proteomics reveals a diagnostic signature for pulmonary head‐and‐neck cancer metastasis
(2018)
Patients with head‐and‐neck cancer can develop both lung metastasis and primary lung cancer during the course of their disease. Despite the clinical importance of discrimination, reliable diagnostic biomarkers are still lacking. Here, we have characterised a cohort of squamous cell lung (SQCLC) and head‐and‐neck (HNSCC) carcinomas by quantitative proteomics. In a training cohort, we quantified 4,957 proteins in 44 SQCLC and 30 HNSCC tumours. A total of 518 proteins were found to be differentially expressed between SQCLC and HNSCC, and some of these were identified as genetic dependencies in either of the two tumour types. Using supervised machine learning, we inferred a proteomic signature for the classification of squamous cell carcinomas as either SQCLC or HNSCC, with diagnostic accuracies of 90.5% and 86.8% in cross‐ and independent validations, respectively. Furthermore, application of this signature to a cohort of pulmonary squamous cell carcinomas of unknown origin leads to a significant prognostic separation. This study not only provides a diagnostic proteomic signature for classification of secondary lung tumours in HNSCC patients, but also represents a proteomic resource for HNSCC and SQCLC.
Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.
Clinical outcomes of cancer-associated isolated superficial vein thrombosis in daily practice
(2022)
Highlights
• In acute isolated SVT, the prevalence of cancer is almost 7 %.
• Cancer increases the SVT-associated VTE risk at 3 and 12 months.
• Cancer patients with isolated SVT may benefit from prolonged anticoagulation.
Abstract
Background: Despite significant progress in the understanding of paraneoplastic deep vein thrombosis (DVT) and pulmonary embolism (PE), little is known about the outcomes of cancer-associated superficial vein thrombosis (SVT) in daily practice.
Methods: INSIGHTS-SVT was a prospective observational study on patients with acute isolated SVT. Primary outcome measure was symptomatic venous thromboembolism (VTE), a composite of DVT, PE, and SVT extension/recurrence, at 3 months. Clinically relevant bleeding was also assessed.
Results: Of 1151 patients included, 6.7 % either had active cancer at baseline or were diagnosed with cancer during 12 months of follow-up. At 3 months, symptomatic VTE had occurred in 13.0 % and 5.4 % of cancer and non-cancer patients, respectively (HR 2.6, 95 % CI 1.3–5.0). Regarding secondary outcomes, cancer patients had increased risks of DVT and PE (HR 3.9, 95 % CI 1.3–11.8) and hospitalization due to VTE (HR 11.0, 95 % CI 2.5–49.0). The rate of clinically relevant bleeding was numerically higher in the cancer cohort (3.9 % vs 1.3 %, HR 3.1, 95 % CI 0.9–10.7). At 12 months, the primary composite outcome had occurred in 15.6 % and 11.9 % of cancer and non-cancer patients, respectively (HR 1.9, 95 % CI 1.0–3.5). After adjusting for additional risk factors, including age, history of DVT/PE and cardiovascular risk factors/diseases, the association of cancer with the primary outcome remained statistically significant.
Conclusion: Cancer patients with isolated SVT are at significant risk of symptomatic VTE. While most events occur within 3 months, the VTE risk remains elevated up to one year of follow-up.
ClinicalTrials.gov identifier: NCT02699151.
Objective: TGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.
Design: As we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.
Results: TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.
Conclusions: Taken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.
Background and aims: Individualization of treatment with peginterferon alfa and ribavirin in patients with chronic hepatitis C showed benefit in controlled trials and was implemented in treatment guidelines to increase response rates and to reduce side effects and costs. However, it is unknown whether individualization was adopted in routine daily practice and whether it translated into improved outcomes.
Methods: From a large noninterventional cohort study, clinical and virologic response data of 10,262 HCV patients who received peginterferon alfa-2a and ribavirin between 2003-2007 and 2008-2011 were analyzed. To account for treatment individualization, a matched-pair analysis (2,997 matched pairs) was performed. Variation in treatment duration and dosing of ribavirin were analyzed as indicators for individualization.
Results: Sustained virological response (SVR) rates were similar between 2003-2007 and 2008-2011 (62.0% vs. 63.7%). Patients with comorbidities were more abundant in the later period, (44.3% vs. 57.1%). The subsequent matched-pair analysis demonstrated higher SVR rates in the 2008-2011 period (64.3%) than in the 2003-2007 period (61.2%, p=0.008). More patients received abbreviated or extended treatment regimens in the later than the earlier period as an indicator of treatment individualization. To the same end, ribavirin doses were higher in the later period (12.6 versus 11.6 mg/kg/day). Factors independently associated with SVR included HCV genotype, low baseline viral load, younger age, route of infection, absence of concomitant diseases, lower APRI score, normal gamma-GT, higher ribavirin doses, no substitution for drug abuse, treatment duration, and treatment in the 2008-2011 period.
Conclusions: Treatment individualization with peginterferon alfa and ribavirin was implemented in daily routine between 2003-2007 and 2008-2011, SVR rates improved in the same period. These findings may be most relevant in resource-limited settings.
Background: Intestinal perforation or leakage increases morbidity and mortality of surgical and endoscopic interventions. We identified criteria for use of full-covered, extractable self-expanding metal stents (cSEMS) vs. "Over the scope"-clips (OTSC) for leak closure.
Methods: Patients who underwent endoscopic treatment for postoperative leakage, endoscopic perforation, or spontaneous rupture of the upper gastrointestinal tract between 2006 and 2013 were identified at four tertiary endoscopic centers. Technical success, outcome (e.g. duration of hospitalization, in-hospital mortality), and complications were assessed and analyzed with respect to etiology, size and location of leakage.
Results: Of 106 patients (male: 75 (71%), female: 31 (29%); age (mean ± SD): 62.5 ± 1.3 years, 72 (69%) were treated by cSEMS and 34 (31%) by OTSC. For cSEMS vs. OTSC, mean treatment duration was 41.1 vs. 25 days, p<0.001, leakage size 10 (1-50) vs. 5 (1-30) mm (median (range)), and complications were observed in 68% vs. 8.8%, p<0.001, respectively. Clinical success for primary interventional treatment was observed in 29/72 (40%) vs. 24/34 (70%, p = 0.006), and clinical success at the end of follow-up was 46/72 (64%) vs. 29/34 (85%) for patients treated by cSEMS vs. OTSC; p = 0.04.
Conclusion: OTSC is preferred in small-sized lesions and in perforation caused by endoscopic interventions, cSEMS in patients with concomitant local infection or abscess. cSEMS is associated with a higher frequency of complications. Therefore, OTSC might be preferred if technically feasible. Indication criteria for cSEMS vs. OTSC vary and might impede design of randomized studies.
Background: Due to the steadily increasing number of cancer patients worldwide the early diagnosis and treatment of cancer is a major field of research. The diagnosis of cancer is mostly performed by an experienced pathologist via the visual inspection of histo-pathological stained tissue sections. To save valuable time, low quality cryosections are frequently analyzed with diagnostic accuracies that are below those of high quality embedded tissue sections. Thus, alternative means have to be found that enable for fast and accurate diagnosis as the basis of following clinical decision making.
Methods: In this contribution we will show that the combination of the three label-free non-linear imaging modalities CARS (coherent anti-Stokes Raman-scattering), TPEF (two-photon excited autofluorescence) and SHG (second harmonic generation) yields information that can be translated into computational hematoxylin and eosin (HE) images by multivariate statistics. Thereby, a computational HE stain is generated resulting in pseudo-HE overview images that allow for identification of suspicious regions. The latter are analyzed further by Raman-spectroscopy retrieving the tissue’s molecular fingerprint.
Results: The results suggest that the combination of non-linear multimodal imaging and Raman-spectroscopy possesses the potential as a precise and fast tool in routine histopathology.
Conclusions: As the key advantage, both optical methods are non-invasive enabling for further pathological investigations of the same tissue section, e.g. a direct comparison with the current pathological gold-standard.
Betrachtet man die Anzahl der in Hessen ausgestorbenen Pflanzenarten über den gesamten Zeitraum ab Beginn der floristischen Erforschung, so scheint ein Zusammenhang zwischen der geringeren Anzahl ausgestorbener Arten in den letzten Dekaden und den gleichzeitig vermehrt ausgewiesenen Naturschutzgebieten zu bestehen. Es stellt sich daher die Frage, ob es auch einen kausalen Zusammenhang gibt, oder ob andere Faktoren einen Einfluss auf das Ausmaß an ausgestorbenen Pflanzenarten haben. Für die Entwicklung der Aussterberate in den kommenden Jahrzehnten wird es nötig werden, alle Vorkommen der derzeit vom Aussterben bedrohten Pflanzenarten dahingehend zu überprüfen, ob ihr Bestand gesichert und erhalten werden kann. So kann dann die Frage beantwortet werden, ob es gelungen ist, das Aussterben von Pflanzenarten in Hessen zu stoppen oder lediglich zu verlangsamen.
Buchbesprechungen
(2023)
Early experiences of childhood sexual or physical abuse are often associated with functional impairments, reduced well-being and interpersonal problems in adulthood. Prior studies have addressed whether the traumatic experience itself or adult psychopathology is linked to these limitations. To approach this question, individuals with posttraumatic stress disorder (PTSD) and healthy individuals with and without a history of child abuse were investigated. We used global positioning system (GPS) tracking to study temporal and spatial limitations in the participants’ real-life activity space over the course of one week. The sample consisted of 228 female participants: 150 women with PTSD and emotional instability with a history of child abuse, 35 mentally healthy women with a history of child abuse (healthy trauma controls, HTC) and 43 mentally healthy women without any traumatic experiences in their past (healthy controls, HC). Both traumatized groups—i.e. the PTSD and the HTC group—had smaller movement radii than the HC group on the weekends, but neither spent significantly less time away from home than HC. Some differences between PTSD and HC in movement radius seem to be related to correlates of PTSD psychopathology, like depression and physical health. Yet group differences between HTC and HC in movement radius remained even when contextual and individual health variables were included in the model, indicating specific effects of traumatic experiences on activity space. Experiences of child abuse could limit activity space later in life, regardless of whether PTSD develops.
Folgende Publikationen werden rezensiert: Garve & al.: Verbreitungsatlas Niedersachsen, Hölzel & al.: Stromtalwiesen, Lübcke & Frede: Naturschutzgebiete in Hessen Band 4, Notizbuch 68 der Kasseler Schule, Riecken & al.: Rote Liste Biotoptypen, Schulz & Dengler: Verbreitungsatlas Moose Schleswig-Holstein, Szabo: Wandern – Erkennen – Heilen
Buchbesprechungen
(2016)
Es werden folgende Publikation rezensiert: Ackermann & Sachteleben: Identifizierung der Hotspots der Biologischen Vielfalt in Deutschland; Bellin-Harder: In der Schwebe. Vegetationsdynamik und Pflegeprognostik. Ein vegetationskundlicher Beitrag zur Gartendenkmalpflege am Beispiel der Löwenburg im Bergpark Wilhelmshöhe, Kassel; Düll & Kutzelnigg: Taschenlexikon der Pflanzen Deutschlands und angrenzender Länder. Die wichtigsten mitteleuropäischen Arten im Porträt; Nassauischer Verein für Naturkunde: Zwischen Mittelrhein und Taunus. Naturschätze in Lorch am Rhein; Parolly & Rohwer: Schmeil-Fitschen. Die Flora Deutschlands und der angrenzenden Länder; Pusch et al: Die Botaniker Thüringens.
2011 wurden Gräben der Oberrheinebene auf ihren Makrophytenbestand untersucht. Die Mehrzahl der Gräben wies keine bemerkenswerten Pflanzenvorkommen auf. Callitriche obtusangula gehört allerdings zu den im Gebiet offenbar relativ weit verbreiteten Arten. Bemerkenswert ist der Bereich innerhalb einer Altrheinschlinge zwischen Geinsheim, Leeheim und Wallerstädten, wo in kleinen Gräben, deren Umgebung intensiv ackerbaulich genutzt wird, bemerkenswerte Arten wie Nitella capillaris, Ranunculus lingua, Samolus valerandi und Utricularia vulgaris vorkommen. Die Neuanlage von Gräben in diesem Bereich wird empfohlen.
Im Rahmen einer hessenweiten Untersuchung wurden etwa 70 künstliche Stillgewässer – Kiesgruben, Tagebaurestseen, Fischteiche – auf das Vorkommen von Wasserpflanzen untersucht.
Die Untersuchung erbrachte den Nachweis von 78 Taxa, darunter 59 Arten Höherer Pflanzen und 19 Arten Characeen. Rund 25 % der nachgewiesnen Arten sind in der Roten Liste des Landes Hessen aufgeführt. Einige der nachgewiesenen Arten galten als verschollen. Von herausragender Bedeutung sind Kiesgruben in der Untermain- und Oberrhein-ebene, wo bis zu 10 Characeen-Arten in einem Gewässer nachgewiesen werden konnten. Von bundesweiter Bedeutung sind Funde von Nitella confervacea, N. tenuissima, Tolypella glomerata, T. intricata und T. prolifera. Als weit häufiger als erwartet erwies sich Potamogeton trichoides, die in allen Untersuchungsbereichen festgestellt wurde. Elodea nuttallii ist in den untersuchten Gewässern deutlich häufiger als E. canadensis. Sehr stark als Vogelrastplatz genutzte Teiche in der Wetterau zeigen, offenbar bedingt durch den Nährstoffeintrag durch Wasservögel, eine deutliche Eutrophierung.
Zur Schließung von Kenntnislücken zur Flora der Gewässer Hessens wurden 2009 von der BVNH neun Altarme von Rhein und Main untersucht. Die Ergeb-nisse zeigen, dass viele als sehr selten oder verschollen geltende Gewässermakrophyten noch oder wieder in den Altarmen des hessischen Oberrheinabschnitts zu finden sind. Insgesamt wurden 51 Arten nachgewiesen, darunter fünf Armleuchteralgen.
Bacterial and fungal toll-like receptor activation elicits type I IFN responses in mast cells
(2021)
Next to their role in IgE-mediated allergic diseases and in promoting inflammation, mast cells also have antiinflammatory functions. They release pro- as well as antiinflammatory mediators, depending on the biological setting. Here we aimed to better understand the role of mast cells during the resolution phase of a local inflammation induced with the Toll-like receptor (TLR)-2 agonist zymosan. Multiple sequential immunohistology combined with a statistical neighborhood analysis showed that mast cells are located in a predominantly antiinflammatory microenvironment during resolution of inflammation and that mast cell-deficiency causes decreased efferocytosis in the resolution phase. Accordingly, FACS analysis showed decreased phagocytosis of zymosan and neutrophils by macrophages in mast cell-deficient mice. mRNA sequencing using zymosan-induced bone marrow-derived mast cells (BMMC) revealed a strong type I interferon (IFN) response, which is known to enhance phagocytosis by macrophages. Both, zymosan and lipopolysaccharides (LPS) induced IFN-β synthesis in BMMCs in similar amounts as in bone marrow derived macrophages. IFN-β was expressed by mast cells in paws from naïve mice and during zymosan-induced inflammation. As described for macrophages the release of type I IFNs from mast cells depended on TLR internalization and endosome acidification. In conclusion, mast cells are able to produce several mediators including IFN-β, which are alone or in combination with each other able to regulate the phagocytotic activity of macrophages during resolution of inflammation.
Background Vasoplegic syndrome is frequently observed during cardiac surgery and resembles a complication of high mortality and morbidity. There is a clinical need for therapy and prevention of vasoplegic syndrome during complex cardiac surgical procedures. Therefore, we investigated different strategies in a porcine model of vasoplegia.
Methods We evaluated new medical therapies and prophylaxis to avoid vasoplegic syndrome in a porcine model. After induction of anesthesia, cardiopulmonary bypass was established through median sternotomy and central cannulation. Prolonged aortic cross-clamping (120 min) simulated a complex surgical procedure. The influence of sevoflurane-guided anesthesia (sevoflurane group) and the administration of glibenclamide (glibenclamide group) were compared to a control group, which received standard anesthesia using propofol. Online hemodynamic assessment was performed using PiCCO® measurements. In addition, blood and tissue samples were taken to evaluate hemodynamic effects and the degree of inflammatory response.
Results Glibenclamide was able to break through early vasoplegic syndrome by raising the blood pressure and systemic vascular resistance as well as less need of norepinephrine doses. Sevoflurane reduced the occurrence of the vasoplegic syndrome in the mean of stable blood pressure and less need of norepinephrine doses.
Conclusion Glibenclamide could serve as a potent drug to reduce effects of vasoplegic syndrome. Sevoflurane anesthesia during cardiopulmonary bypass shows less occurrence of vasoplegic syndrome and therefore could be used to prevent it in high-risk patients.
Clinical Perspective; what is new?
* to our knowledge, this is the first randomized in vivo study evaluating the hemodynamic effects of glibenclamide after the onset of vasoplegic syndrome
* furthermore according to literature research, there is no study showing the effect of sevoflurane-guided anesthesia on the occurrence of a vasoplegic syndrome
Clinical Perspective; clinical implications?
to achieve better outcomes after complex cardiac surgery there is a need for optimized drug therapy and prevention of the vasoplegic syndrome
The Heidelberg Ion-Beam Therapy Centre (HIT) provides proton, helium, and carbon-ion beams with different energies and intensities for cancer treatment and oxygen-ion beams for experiments. For several experiments and possible future applications, such as helium ion beam radiography, a low-intensity ion beam monitor integrated into the dose delivery feedback system for the accelerator control is a necessary pre-requisite. The updated 2D prototype for this purpose consists of scintillating fibres with enhanced radiation hardness, silicon photomultipliers (SiPMs) to amplify the emitted light, and a dedicated front-end readout system (FERS) to process and record the generated signals. This setup was tested successfully on monitoring ion-beam position and profile horizontally and vertically, as well as the beam intensity, for all four ion types with energies from 50 to 430 MeV/u and intensities from 1E2 to 1E7 ions/s. Additionally, time-of-arrival (ToA) measurements on single ions have been successfully performed for a limited intensity range, allowing for ion tracking in a further update. This will reduce noise, and will also improve the accuracy and usability of ion radiography.