Refine
Year of publication
Document Type
- Article (839)
- Preprint (826)
- Conference Proceeding (7)
- Working Paper (2)
- Book (1)
- Doctoral Thesis (1)
- Other (1)
- Part of Periodical (1)
Has Fulltext
- yes (1678)
Is part of the Bibliography
- no (1678)
Keywords
- Heavy Ion Experiments (22)
- Hadron-Hadron Scattering (14)
- Hadron-Hadron scattering (experiments) (12)
- LHC (10)
- Heavy-ion collision (6)
- Heavy-ion collisions (6)
- Jets (6)
- Heavy Quark Production (5)
- immunotherapy (5)
- ALICE experiment (4)
- CIK cells (4)
- Collective Flow (4)
- HIV (4)
- Heavy Ions (4)
- Quark-Gluon Plasma (4)
- ALICE (3)
- Breast cancer (3)
- COVID-19 (3)
- Diffraction (3)
- Elastic scattering (3)
- Genetics (3)
- Jets and Jet Substructure (3)
- Machine learning (3)
- Predictive markers (3)
- Prostate cancer (3)
- Quarkonium (3)
- allogeneic stem cell transplantation (3)
- biomarker (3)
- children (3)
- cytokine-induced killer cells (3)
- global change (3)
- pp collisions (3)
- rhabdomyosarcoma (3)
- Acuris (2)
- Beam Energy Scan (2)
- Beauty production (2)
- Bipolar disorder (2)
- Charm physics (2)
- Chiral Magnetic Effect (2)
- Clinical Trials and Observations (2)
- Collectivity (2)
- Consensus (2)
- Correlation (2)
- Diagnostic markers (2)
- Diagnostik (2)
- Elliptic flow (2)
- EphB4 (2)
- Experimental nuclear physics (2)
- Experimental particle physics (2)
- Früherkennung (2)
- Heavy-Ion Collision (2)
- Lepton-Nucleon Scattering (experiments) (2)
- Mammakarzinom (2)
- Monte Carlo (2)
- NK cells (2)
- Nachsorge (2)
- Oncology (2)
- Particle Correlations and Fluctuations (2)
- Particle and resonance production (2)
- Particle correlations and fluctuations (2)
- Pb–Pb collisions (2)
- Polarization (2)
- Psychiatric disorders (2)
- Pulmonary embolism (2)
- QCD (2)
- Quark Gluon Plasma (2)
- RHIC (2)
- Radiotherapy (2)
- Relativistic heavy-ion collisions (2)
- Richtlinie (2)
- SARS-CoV-2 (2)
- STAR (2)
- Shear viscosity (2)
- Single electrons (2)
- Statistical analysis (2)
- Surgery (2)
- Systematic Uncertainty (2)
- Taxonomy (2)
- Time Projection Chamber (2)
- biodiversity protection (2)
- bone metastasis (2)
- breast cancer (2)
- cell therapy (2)
- chimeric antigen receptor (2)
- cirrhosis (2)
- conservation funding (2)
- conservation planning (2)
- decision making (2)
- diagnosis (2)
- ephrinB2 (2)
- flow cytometry (2)
- follow‑up (2)
- glioblastoma (2)
- glioma (2)
- guideline (2)
- hematopoietic stem cell transplantation (2)
- immune reconstitution (2)
- leukemia (2)
- lymphoma (2)
- meningioma (2)
- molecular machines (2)
- post-2020 biodiversity targets (2)
- reference values (2)
- screening (2)
- strategic site selection (2)
- 140Ce (1)
- 16S (1)
- 900 GeV (1)
- AB-serum (1)
- ABC proteins, ribosome recycling (1)
- ABC transporters (1)
- AKI (1)
- ALICE LHC (1)
- ALICE detector (1)
- AML (1)
- APRI (1)
- ARDS (1)
- ATPases (1)
- Actin (1)
- Active middle ear implants (1)
- Activities of daily living (1)
- Acute inflammation (1)
- Advanced biliary tract cancer (1)
- Allogeneic hematopoietic stem (1)
- Allogeneic stem cell transplantation (1)
- Analysis and statistical methods (1)
- Anandamide (1)
- Angiogenesis (1)
- Anti-nuclei (1)
- Antibiotics (1)
- Antibody isotypes (1)
- Antigen-presenting cells (1)
- Antiretroviral therapy (1)
- Antiretrovirals (1)
- Antirheumatic agents (1)
- Aortic valve competency (1)
- Apes (1)
- Artesunate (1)
- Artificial Intelligence (1)
- Artificial intelligence (1)
- Ataxia-telangiectasia (1)
- Auditory system (1)
- Autologous stem cell transplantation (1)
- Awareness campaign (1)
- B cell subpopulations (1)
- B-slope (1)
- BESIII (1)
- BRCA1 (1)
- BRCA2 (1)
- BTC (1)
- BV6 (1)
- Backpropagating action potential (1)
- Bacterial leakage (1)
- Bacterial pathogens (1)
- Balance function (1)
- Beam energy scan (1)
- Bidirectional genes (1)
- Big Data (1)
- Biodiversity Data (1)
- Biodiversity conservation (1)
- Biogeography (1)
- Bioinformatics (1)
- Biological (1)
- Biomonitoring (1)
- Blood (1)
- Bone conduction devices (1)
- Bone marrow (1)
- Bone metastases (1)
- Bone strength assessment (1)
- Boosted Jets (1)
- Borrelia burgdorferi (1)
- Botanical Collections (1)
- Buchbesprechung (1)
- Burns (1)
- Business strategy in drug development (1)
- C1-INH (C1 inhibitor, C1-esterase inhibitor) (1)
- CAD/ CAM crown (1)
- CAD/CAM crown (1)
- CAR (1)
- CCL2 (1)
- CD16 (1)
- CD3/19 depletion (1)
- CD3/CD19 depletion (1)
- CD34 selection (1)
- CD56 (1)
- CDI (1)
- COI (1)
- COMT (1)
- CTLA-4 (1)
- CVID (1)
- Calcium (1)
- Calcium gluconate (1)
- Calorimeters (1)
- Cancer (1)
- Cancer check up (1)
- Cancer detection and diagnosis (1)
- Canonical suppression (1)
- Cardiac surgery (1)
- Cardiomyopathy (1)
- Cell membranes (1)
- Cement gap (1)
- Centrality Class (1)
- Centrality Selection (1)
- Charge correlations (1)
- Charge fluctuations (1)
- Charged-particle density (1)
- Charged-particle multiplicity (1)
- Charm quark spatial diffusion coefficient (1)
- Charmonia (1)
- Chemoradiotherapy (1)
- Cherenkov counter: lead-glass (1)
- Child (1)
- Children (1)
- Chimerism (1)
- Chiral magnetic effect (1)
- Chronic hepatitis C (1)
- Circadian (1)
- Cirrhosis (1)
- Cleanliness level (1)
- Clinical study (1)
- Clinical variation (1)
- Closure (1)
- Coalescence (1)
- Cognitive impairment (1)
- Cold nuclear matter effects (1)
- Collective Flow, (1)
- Colon capsule endoscopy (1)
- Community dynamics (1)
- Comparative effectiveness research (1)
- Comparison with QCD (1)
- Compartmental modeling (1)
- Complement system (1)
- Complementation rate (1)
- Complex I (1)
- Computer simulation (1)
- Conometric connection (1)
- Consensus statement (1)
- Conservation (1)
- Coronary heart disease (1)
- Coronary perfusion (1)
- Critical care (1)
- Critical point (1)
- Culturomics (1)
- DST (1)
- Data processing methods (1)
- Data sharing (1)
- Dendritic spines (1)
- Depression (1)
- Dermatomyositis (1)
- Deuteron production (1)
- Di-hadron correlations (1)
- Diagnosis (1)
- Diagnostic differentiation (1)
- Digital humanities (1)
- Digital subtraction angiography (1)
- Digitization (1)
- Dilated cardiomyopathy (1)
- Dinarides (1)
- Direct Acting Antivirals (DAA) (1)
- Direct oral anticoagulation (1)
- Docetaxel (1)
- Drug susceptibility testing (1)
- Drug therapy (1)
- EGFR (1)
- EGFR inhibitor (1)
- ERBB2 (1)
- ERBB2 (HER2/neu) (1)
- Ecology (1)
- Ecophysiology (1)
- Elderly (1)
- Electromagnetic form factors (1)
- Electromagnetic transitions (1)
- Electron-pion identification (1)
- Electrotonic analysis (1)
- Electroweak interaction (1)
- Employment (1)
- Ena/VASP proteins (1)
- Enzyme-linked immunoassays (1)
- Ephrin-B2–EphB4 (1)
- Epigenetics (1)
- Epstein-Barr virus (1)
- Etanercept (1)
- Europe (1)
- European Society for Immunodeficiencies (ESID) (1)
- Ewing sarcoma (1)
- Exosomes (1)
- Extended donor criteria (1)
- FIB-4 (1)
- Falciparum (1)
- Fc receptor (1)
- Femoral neck (1)
- Femtoscopy (1)
- Fertility counseling (1)
- Fibre/foam sandwich radiator (1)
- Fibrotest (1)
- First-line combination antiretroviral therapy (1)
- Fistula (1)
- Flow (1)
- Flow cytometry (1)
- Forschung (1)
- Forward physics (1)
- Fracture risk (1)
- Frailty (1)
- GFAP (1)
- Gadobutrol (1)
- Gadopentate dimeglumine (1)
- Gene expression (1)
- General practitioners (1)
- Genetic causes of cancer (1)
- Genetic testing (1)
- Genetics research (1)
- Genome-wide association studies (1)
- German PID-NET registry (1)
- Glioblastoma (1)
- Glioblastoma survival (1)
- Granule cell (1)
- Groomed jet radius (1)
- Guanine nucleotide exchange factors (1)
- Guanosine triphosphatase (1)
- Guidelines (1)
- HADES (1)
- HBT (1)
- HBV (1)
- HCV (1)
- HDAC4 (1)
- HER2-positive (1)
- HER2/neu (1)
- HIPPO signalling (1)
- HIV-1 (1)
- HNO (1)
- Hadron production (1)
- Hadron-Hadron Scattering Heavy (1)
- Hadron-hadron interactions (1)
- Hadronization (1)
- Hals-Nasen-Ohren-Heilkunde (1)
- Hand-foot syndrome (1)
- Hard Scattering (1)
- Head and neck cancer (1)
- Health policy (1)
- Heart (1)
- Heart transplantation (1)
- Heavy Ion Experiment (1)
- Heavy flavor production (1)
- Heavy flavour production (1)
- Heavy ion collisions (1)
- Heavy ions (1)
- Heavy-flavor decay electron (1)
- Heavy-flavour decay muons (1)
- Heavy-flavour production (1)
- Heavy-ion (1)
- Heavy-ion detectors (1)
- Hepatitis C (1)
- Hepatitis C virus (1)
- Hepatotoxicity (1)
- Herbaria (1)
- Hereditary angioedema (1)
- Hereditary breast and ovarian cancer (1)
- Hif-1 alpha (1)
- Hif1α (1)
- High-dose chemotherapy (1)
- Higher moments (1)
- Histology (1)
- Homeostatic plasticity (1)
- Horses (1)
- Human behaviour (1)
- Human genetics (1)
- Hydrofluoric acid (1)
- Hypertension (1)
- IL-10 (1)
- IL-15 (1)
- IL-21 (1)
- IL-6 (1)
- IgG substitution therapy (1)
- Immunoassays (1)
- Immunogenetics (1)
- Immunology (1)
- Immunosuppressive therapy (1)
- Immunotherapy (1)
- Inclusive spectra (1)
- Incomplete colonoscopy (1)
- Indication for fertility preservation (1)
- Individual based modeling (1)
- Induction chemotherapy (1)
- Inflammation (1)
- Influenza (1)
- Initial state radiation (1)
- Intensity interferometry (1)
- Interference fragmentation function (1)
- Intra-abdominal infection (1)
- Invariant Mass Distribution (1)
- Inverse kinematics (1)
- Ionisation energy loss (1)
- Isoscalar giant resonances (1)
- J/ψ suppression (1)
- Jet Physics (1)
- Jet Substructure (1)
- Jet substructure (1)
- KDIGO (1)
- KPS (1)
- Knowledgebased analysis (1)
- Lactic acidosis (1)
- Landscape genetics (1)
- Laparostomy (1)
- Large Hadron Collider (1)
- Large detector systems for particle and astroparticle physics (1)
- Lehre (1)
- Lenalidomide (1)
- Library screening (1)
- Liver diseases (1)
- Liver enzymes (1)
- Liver transplantation (1)
- Load flow calculations (1)
- Long distance movement (1)
- Low volume prep (1)
- Low-molecular-weight heparin (1)
- Luciferase (1)
- Lumbar spine (1)
- Luzulo-Fagetum (1)
- Lymphoid Neoplasia (1)
- M. Intracellulare (1)
- M. avium (1)
- M. avium complex (1)
- M. chimaera (1)
- MACS (1)
- MALAT1 (1)
- MGMT (1)
- MMF (1)
- MPA (1)
- MRI (1)
- MSC-subsets (1)
- Maianthemo-Fagetum (1)
- Malaria (1)
- Marginal integrity (1)
- Marine chemistry (1)
- Material budget (1)
- Medical imaging (1)
- Medical research (1)
- Mena/VASP (1)
- Meriç River (1)
- Mesenchymal stem cells (1)
- Mesh (1)
- Metabolism (1)
- Methylene blue perfusion (1)
- MicroRNAs (1)
- Microbiome (1)
- Microgap (1)
- Mid-rapidity (1)
- Minimal residual disease (1)
- Minimum Bias (1)
- Mitochondrial disorder (1)
- Mixed hearing loss (1)
- Mobile links (1)
- Models & methods for nuclear reactions (1)
- Molecular neuroscience (1)
- Morphological modeling (1)
- Moviprep (1)
- Multi-Parton Interactions (1)
- Multi-stakeholder approach (1)
- Multi-strange baryons (1)
- Multi-wire proportional drift chamber (1)
- Multiomics (1)
- Multiparametric MRI (1)
- Multiple myeloma (1)
- Multiple parton interactions (1)
- Myeloid Neoplasia (1)
- NADPH oxidase (1)
- NCoR1 (1)
- NK-92 (1)
- NMDA IgA/IgM antibodies (1)
- NMDA antibody (1)
- NSE (1)
- NSG mice (1)
- NTM (1)
- Natural language processing (1)
- Neoadjuvant radiochemotherapy (1)
- Neoadjuvant therapy (1)
- Neolithic (1)
- Neonatal (1)
- Net-charge correlations (1)
- Net-charge fluctuations (1)
- Network analysis (1)
- Neural network (1)
- Neuroscience (1)
- Neutron physics (1)
- Next-generation sequencing (1)
- Nf2 (1)
- Non-trauma (1)
- Non-tuberculous mycobacteria (1)
- Nonflow (1)
- Noninferiority (1)
- Nox1 (1)
- NoxO1 (1)
- Nuclear modification factor (1)
- Nuclear reactions (1)
- Nutrition (1)
- Nymphs (1)
- ORL (1)
- Obesity (1)
- Oesophagogastric cancer oxaliplatin (1)
- Oldest-old (1)
- Omics (1)
- Open abdomen (1)
- Optical clearing (1)
- Organ allocation (1)
- Osteoporosis (1)
- Osteoporosis diagnosis (1)
- Otorhinolaryngology (1)
- Outcome (1)
- Ovarian cancer (1)
- PD-1 (1)
- PDGFRβ (1)
- PID prevalence (1)
- PRG5 (1)
- PSA screening (1)
- PSA-Screening (1)
- PTEN (1)
- PTSD (1)
- PYTHIA (1)
- Paediatric research (1)
- Palaeoceanography (1)
- Palaeoclimate (1)
- Pancreas transplantation (1)
- Pancreatitis (1)
- Parainfluenza (1)
- Parkinson disease (1)
- Parkinson's disease (1)
- Particle and Resonance Production (1)
- Particle production (1)
- Pathological complete response (1)
- Pathology (1)
- Patterns of care (1)
- Pb–Pb (1)
- Pediatric (1)
- Pediatric oncology (1)
- Pediatric stem cell transplantation (1)
- Performance of High Energy Physics Detectors (1)
- Periclymeno-Fagetum (1)
- Periodontitis (1)
- Peritoneal macrophages (1)
- Peritonitis (1)
- Personalized medicine (1)
- Phospho-soda (1)
- Phosphorylation (1)
- Physics (1)
- PillCamColon2 (1)
- Plasmodium (1)
- Pneumonia (1)
- Polyps (1)
- Posttraumatic stress disorder (1)
- Power system simulations (1)
- Pre-emptive immunotherapy (1)
- Pre-treatment drug resistance mutations (1)
- Preclinical research (1)
- Prediction (1)
- Preventive medicine (1)
- Production Cross Section (1)
- Prognosis (1)
- Prognostic markers (1)
- Prognostic models (1)
- Properties of Hadrons (1)
- Prostata-specific antigen (1)
- Prostataspezifisches Antigen (1)
- Proton (1)
- Proton-proton collisions (1)
- Proton–proton (1)
- Proton–proton collisions (1)
- Prävention (1)
- Psychiatry (1)
- Pyogenic spondylodiscitis (1)
- QGP (1)
- Quantitative features (1)
- Quark Deconfinement (1)
- Quark Production (1)
- Quark gluon plasma (1)
- Quark–gluon plasma (1)
- Quinine (1)
- RD cells (1)
- REMS (1)
- RH30 cells (1)
- RMS (1)
- RSL curve (1)
- Radiative capture (1)
- Radiomics (1)
- Rapidity Range (1)
- Re-exploration (1)
- Reactive oxygen species (1)
- Real world (1)
- Red blood cell transfusion (1)
- Rehabilitation (1)
- Reintervention (1)
- Rejection (1)
- Relapse (1)
- Relativistic heavy ion physics (1)
- Remission (1)
- Renal lesions (1)
- Research (1)
- Research Infrastructure (1)
- Residency (1)
- Resolution Parameter (1)
- Resonance reactions (1)
- Resonances (1)
- Respiratory syncytial virus (1)
- Rheumatoid arthritis (1)
- Risk factor (1)
- Rpo4/7 (1)
- Ryanodine (1)
- S100b (1)
- SARS-CoV‑2 pandemic (1)
- SARS-CoV‑2-Pandemie (1)
- SKALE score (1)
- STAMPE2 (1)
- SVR (1)
- Safety (1)
- Salivary gland carcinoma (1)
- Seasonal variation (1)
- Second-line treatment (1)
- Semantics (1)
- Sensory systems (1)
- Serine proteases (1)
- Severe malaria (1)
- Shannon index (1)
- Single muons (1)
- Single-cell RNA-seq (1)
- Small molecules (1)
- SoftDrop (1)
- Solar insolation (1)
- Sorafenib (1)
- Specialist training (1)
- Species coexistence (1)
- Spectrin (1)
- Spin alignment (1)
- Spirochetes (1)
- Splitting function (1)
- Stentoplasty (1)
- Storage ring (1)
- Strangeness enhancement (1)
- Structural plasticity (1)
- Sudden cardiac death (1)
- Suicide (1)
- Sunlight (1)
- Superinfection (1)
- Superoxide (1)
- Surgical oncology (1)
- Sustained virological response (SVR) (1)
- Synaptopodin (1)
- Synthetic (1)
- TGFB-induced factor homeobox 1 (1)
- TGIF (1)
- TOR signalling (1)
- TR (1)
- Tailored medicine (1)
- Teaching (1)
- Technical data (1)
- Technique (1)
- Teeth (1)
- Temozolomide (1)
- Temporal text analysis (1)
- Therapeutic anticoagulation (1)
- Thermal model (1)
- Timing (1)
- Tracking (1)
- Transient elastography (1)
- Transition radiation detector (1)
- Translational research (1)
- Transverse Momentum (1)
- Transverse momentum (1)
- Transversity (1)
- Trastorno de estrés postraumático (1)
- Trauma (1)
- Treatment (1)
- Trigger (1)
- Triple negative (1)
- Triple-negative breast cancer (1)
- U2-OS (1)
- Ultrasound (1)
- University hospitals (1)
- Universitätskliniken (1)
- Upper respiratory tract infection (1)
- VEGF receptor 2 internalization and signaling (1)
- VEGFR (1)
- VEGFR-2 (1)
- VEGFR-3 (1)
- Vasa vasorum (1)
- Vascular emergencies (1)
- Vasospasm (1)
- Vector Boson Production (1)
- Vertebral augmentation (1)
- Vertebral body stenting (1)
- Vertebral fracture (1)
- Vesicles (1)
- Viral infection (1)
- Virological failure (1)
- Vitamin (1)
- Voltage attenuation (1)
- Vorsorgeuntersuchung (1)
- WAF (1)
- Weiterbildung (1)
- Wide rapidity coverage (1)
- WoMo score (1)
- Wound healing potential (1)
- X-ray crystallography (1)
- Xenon-based gas mixture (1)
- ZF-L (1)
- acneiform skin toxicity (1)
- acoustic radiation force impulse imaging (1)
- acute lymphoblastic leukemia (1)
- adjuvant chemotherapy (1)
- aegean (1)
- age (1)
- age-related macular degeneration (1)
- alleles (1)
- allogeneic hematological stem cell transplantation (1)
- allogeneic transplantation (1)
- ames fluctuation assay (1)
- amoxicillin/metronidazole (1)
- amphiregulin (1)
- anaemia (1)
- anaesthesia in orthopaedics (1)
- anaesthetics (1)
- anchialine cave (1)
- angiogenesis (1)
- angiopoietin-2 (1)
- angiopoietin-like 3 (ANGPTL3) (1)
- antiangiogenic therapy (1)
- antiangiogenic therapy resistance (1)
- antibiotic prophylactic therapy (1)
- antibodies (1)
- anticonvulsants (1)
- antiviral therapy (1)
- archeological sea-level limiting points (1)
- attachment loss (1)
- autism spectrum disorder (1)
- autistic disorder (1)
- autoantibodies (1)
- autoimmunity (1)
- axions (1)
- azacitidine (1)
- b-cell lymphomas (1)
- bacterial leakage (1)
- bendamustine (1)
- bioactivity testing (1)
- biobank (1)
- biodiversity change (1)
- biogeographic legaciese (1)
- bone (1)
- bone marrow metastasis (1)
- brain metastasis (1)
- c-kit (1)
- cART (1)
- calorimeter: electromagnetic (1)
- cancer immunotherapy (1)
- cancer surveillance (1)
- cancer therapy (1)
- capture (1)
- carbon and proton assignments (1)
- cardiocerebral resuscitation (1)
- cardiopulmonary resuscitation (1)
- cell transplantation (1)
- cellular heterogeneity (1)
- cellular therapy (1)
- cerium (1)
- chemotherapy regimen (1)
- child (1)
- children and adolescents (1)
- chimeric antigen receptor (CAR) (1)
- chimeric antigen receptor t-cell therapy (1)
- chimeric antigen receptors (1)
- chromosomal aberrations (1)
- chronic viral hepatitis (1)
- clinical relevance (1)
- cluster analysis (1)
- co-infection (1)
- coastal geomorphology (1)
- cognitive-behavioral therapy (1)
- common genetic variation (1)
- conical coupling (1)
- conometric connection (1)
- copy number polymorphism (1)
- cross-section (1)
- crude oil (1)
- cryo-EM (1)
- cryopreservation (1)
- cytotoxic T cells (1)
- dE/dx (1)
- dark matter experiments (1)
- data science (1)
- debridement (1)
- detector (1)
- dexamethasone (1)
- diabetes mellitus (1)
- disease prevalence (1)
- domestication (1)
- eInfrastructure (1)
- eScience (1)
- easyPACId (1)
- ectosomes (1)
- elderly (1)
- elderly patients (1)
- electrical resistivity tomography (1)
- electronics: readout (1)
- endothelial cells (1)
- energy system simulations (1)
- ensayo controlado aleatorizado (1)
- epilepsy (1)
- epiregulin (1)
- evolution (1)
- ex vivo expansion (1)
- exosomes (1)
- experimental results (1)
- exponential model (1)
- extracellular vesicles (1)
- fibre: optical (1)
- fibrotest (1)
- follow-up (1)
- foraminifera (1)
- foraminifers (1)
- forest classification (1)
- forest functional similarity (1)
- fresh frozen plasma (1)
- gene flow (1)
- genes (1)
- genetic distance (1)
- genetic diversity (1)
- genetics (1)
- genome (1)
- genome-wide association study (1)
- genotype (1)
- genotype determination (1)
- geophysical prospections (1)
- geriatric medicine (1)
- germ cell tumors (1)
- glioblastoma survival (1)
- glioma microenvironment (1)
- global biodiversity framework (1)
- graft-versus host (1)
- guidelines (1)
- habitat destruction (1)
- heavy ion experiments (1)
- heavy-ion collisions (1)
- hepatitis C (1)
- hepatitis c (1)
- hepatocellular carcinoma (1)
- high-dose chemotherapy (1)
- histology (1)
- hospital exemption (1)
- human knockout model (1)
- human olfaction (1)
- imagery rescripting (1)
- immune checkpoint blockade (1)
- immune infiltration (1)
- immune monitoring (1)
- immune profiling (1)
- implementation (1)
- infection precaution (1)
- inflammation (1)
- juvenile myelomonocytic leukemia (1)
- kidney function (1)
- knockout mouse (1)
- land use (1)
- lectotype (1)
- leukapheresis (1)
- liver metastasis (1)
- long non-coding RNA (1)
- long-term protection (1)
- long36 term protection (1)
- lppr5 (1)
- mRNA surveillance (1)
- machine-learning (1)
- magnetic gradiometry (1)
- mainstreaming (1)
- malignancy (1)
- marginal fit (1)
- membrane proteins (1)
- mesenchymal stromal cell (1)
- mesenchymal stromal cells (1)
- metabolic syndrome (1)
- metastasis (1)
- micronucleus assay (1)
- micropalaeontology (1)
- microparticles (1)
- microvesicles (1)
- minimal information requirements (1)
- monitoring (1)
- multiple trauma (1)
- mutation (1)
- n_TOF (1)
- natural killer cells (1)
- natural products (1)
- neuroblastoma (1)
- neurooncology (1)
- neutralizing antibodies (1)
- neutron (1)
- non-invasive fibrosis assessment (1)
- non-malignant hematological diseases (1)
- nucleosynthesis (1)
- obesity (1)
- optimal power flow (1)
- outcome parameter (1)
- ovary (1)
- oxidative stress (1)
- p+p collisions (1)
- p47phox (1)
- patients (1)
- pediatric cancer (1)
- periodontitis (1)
- peritumoral edema (1)
- peritumoral edema zone (1)
- pharmacokinetics (1)
- phenotype (1)
- phylogenetic community distance (1)
- phylogeny (1)
- platelet lysate (1)
- plppr5 (1)
- point shear wave elastography (1)
- portal hypertension (1)
- post-transplantation lymphoproliferative disease (1)
- posttraumatic inflammation (1)
- preclinical (1)
- predictive biomarkers (1)
- primary active transporters (1)
- primary biliary cholangitis (1)
- primary immunodeficiency (1)
- primary immunodeficiency (PID) (1)
- principal component analysis (1)
- prognosis (1)
- prostate cancer (1)
- proteobacteria (1)
- psoriasis (1)
- pulmonary embolism (1)
- quark gluon plasma (1)
- radio sensitivity (1)
- randomised controlled trial (1)
- randomized-controlled trial (1)
- recurrence pattern (1)
- reescritura de imágenes (1)
- refined fuels (1)
- refractory aGvHD (1)
- refugees (1)
- refugiados (1)
- registry for primary immunodeficiency (1)
- remote responsibility (1)
- renewable energy (1)
- renin-angiotensin system (1)
- reproducibility (1)
- restoration (1)
- ribosome-associated quality control (1)
- rigor (1)
- risk prediction (1)
- rituximab (1)
- s-process (1)
- scenario (1)
- schizophrenia (1)
- sea-level indicator (1)
- second line therapy (1)
- second mitochondria-derived activator of caspases mimetic (1)
- secondary chemical shifts (1)
- secukinumab (1)
- security-constrained optimal power flow (1)
- seed and soil (1)
- seizures (1)
- sequence alignment (1)
- severe congenital neutropenia (1)
- sex (1)
- shell morphology (1)
- shortening of treatment (1)
- sickle cell anemia (1)
- simplified production (1)
- single nucleotide polymorphism (1)
- single subject classification (1)
- single-cell proteomics (1)
- soft tissue sarcoma (1)
- solar physics (1)
- solid-state NMR (1)
- spectra (1)
- sphingolipid (1)
- spike protein (1)
- spinal bone metastasis (1)
- spinal metastasis (1)
- sprouting angiogenesis (1)
- ssFLYA (1)
- stability (1)
- stage II/III colorectal cancer (1)
- standardization (1)
- steroid-resistant aGvHD (1)
- stopping rule (1)
- stroke (1)
- structural biology (1)
- subterranean ecology (1)
- sunitinib (1)
- surgery (1)
- syntaxonomy (1)
- systemic antibiotics (1)
- temporal classification (1)
- testis (1)
- thalassemia (1)
- therapeutic anticoagulation (1)
- tip cell filopodia formation (1)
- transarterial chemoembolization (1)
- transient elastography (1)
- transplantation (1)
- trauma (1)
- traumatic brain injury (TBI) (1)
- treatment resistance (1)
- treatment response (1)
- troglobitic microsnails (1)
- tropical forests (1)
- unit commitment; (1)
- ursodeoxycholic acid (1)
- uveal melanoma (1)
- vaccination (1)
- values (1)
- variants of concern (1)
- vascular endothelial growth factor (1)
- white and brown dwarfs (1)
- women (1)
- Öffentlichkeit (1)
- Υ suppression (1)
- гепатит С (1)
- правила прекращения лечения (1)
- противовирусные препараты прямого действия (ПППД) (1)
- сокращение лечения (1)
- устойчивый вирусологический ответ (УВО) (1)
- √sN N = 2.76 TeV (1)
- 创伤后应激障碍 (1)
- 意向重构 (1)
- 随机对照试验 (1)
- 难民 (1)
Institute
- Physik (1304)
- Frankfurt Institute for Advanced Studies (FIAS) (1171)
- Informatik (1024)
- Medizin (186)
- Geowissenschaften (24)
- Biowissenschaften (7)
- Senckenbergische Naturforschende Gesellschaft (7)
- Informatik und Mathematik (6)
- Biochemie und Chemie (5)
- Institut für Ökologie, Evolution und Diversität (5)
The metastasis-associated lung adenocarcinoma transcript 1, MALAT1, is a long non-coding RNA (lncRNA) that has been discovered as a marker for lung cancer metastasis. It is highly abundant, its expression is strongly regulated in many tumor entities including lung adenocarcinoma and hepatocellular carcinoma as well as physiological processes, and it is associated with many RNA binding proteins and highly conserved throughout evolution. The nuclear transcript MALAT-1 has been functionally associated with gene regulation and alternative splicing and its regulation has been shown to impact proliferation, apoptosis, migration and invasion.
Here, we have developed a human and a mouse knockout system to study the loss-of-function phenotypes of this important ncRNA. In human tumor cells, MALAT1 expression was abrogated using Zinc Finger Nucleases. Unexpectedly, the quantitative loss of MALAT1 did neither affect proliferation nor cell cycle progression nor nuclear architecture in human lung or liver cancer cells. Moreover, genetic loss of Malat1 in a knockout mouse model did not give rise to any obvious phenotype or histological abnormalities in Malat1-null compared with wild-type animals. Thus, loss of the abundant nuclear long ncRNA MALAT1 is compatible with cell viability and normal development.
Background: Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated.
Methods: Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history.
Results: In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for BRCA1/2 would miss in our series more than 5% of the patients with a deleterious variant in established risk genes.
Conclusions: 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to BRCA1/2 seems to be not sufficient.
Members of the ATP‐binding cassette (ABC) transporter superfamily translocate a broad spectrum of chemically diverse substrates. While their eponymous ATP‐binding cassette in the nucleotide‐binding domains (NBDs) is highly conserved, their transmembrane domains (TMDs) forming the translocation pathway exhibit distinct folds and topologies, suggesting that during evolution the ancient motor domains were combined with different transmembrane mechanical systems to orchestrate a variety of cellular processes. In recent years, it has become increasingly evident that the distinct TMD folds are best suited to categorize the multitude of ABC transporters. We therefore propose a new ABC transporter classification that is based on structural homology in the TMDs:
BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks.
RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired.
CONCLUSIONS: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
Objectives: Multidrug-resistant organisms (MDRO) are considered an emerging threat worldwide. Data covering the clinical impact of MDRO colonization in patients with solid malignancies, however, is widely missing. We sought to determine the impact of MDRO colonization in patients who have been diagnosed with Non-small cell lung cancer (NSCLC) who are at known high-risk for invasive infections.
Materials and methods: Patients who were screened for MDRO colonization within a 90-day period after NSCLC diagnosis of all stages were included in this single-center retrospective study.
Results: Two hundred and ninety-five patients were included of whom 24 patients (8.1%) were screened positive for MDRO colonization (MDROpos) at first diagnosis. Enterobacterales were by far the most frequent MDRO detected with a proportion of 79.2% (19/24). MDRO colonization was present across all disease stages and more present in patients with concomitant diabetes mellitus. Median overall survival was significantly inferior in the MDROpos study group with a median OS of 7.8 months (95% CI, 0.0–19.9 months) compared to a median OS of 23.9 months (95% CI, 17.6–30.1 months) in the MDROneg group in univariate (p = 0.036) and multivariate analysis (P = 0.02). Exploratory analyses suggest a higher rate of non-cancer-related-mortality in MDROpos patients compared to MDROneg patients (p = 0.002) with an increased rate of fatal infections in MDROpos patients (p = 0.0002).
Conclusions: MDRO colonization is an independent risk factor for inferior OS in patients diagnosed with NSCLC due to a higher rate of fatal infections. Empirical antibiotic treatment approaches should cover formerly detected MDR commensals in cases of (suspected) invasive infections.
The Gleason grading system remains the most powerful prognostic predictor for patients with prostate cancer since the 1960s. Its application requires highly-trained pathologists, is tedious and yet suffers from limited inter-pathologist reproducibility, especially for the intermediate Gleason score 7. Automated annotation procedures constitute a viable solution to remedy these limitations. In this study, we present a deep learning approach for automated Gleason grading of prostate cancer tissue microarrays with Hematoxylin and Eosin (H&E) staining. Our system was trained using detailed Gleason annotations on a discovery cohort of 641 patients and was then evaluated on an independent test cohort of 245 patients annotated by two pathologists. On the test cohort, the inter-annotator agreements between the model and each pathologist, quantified via Cohen’s quadratic kappa statistic, were 0.75 and 0.71 respectively, comparable with the inter-pathologist agreement (kappa = 0.71). Furthermore, the model’s Gleason score assignments achieved pathology expert-level stratification of patients into prognostically distinct groups, on the basis of disease-specific survival data available for the test cohort. Overall, our study shows promising results regarding the applicability of deep learning-based solutions towards more objective and reproducible prostate cancer grading, especially for cases with heterogeneous Gleason patterns.
Background: Few studies have evaluated the impact of pre-treatment drug resistance (PDR) on response to combination antiretroviral treatment (cART) in children. The objective of this joint EuroCoord-CHAIN-EPPICC/PENTA project was to assess the prevalence of PDR mutations and their association with virological outcome in the first year of cART in children.
Methods: HIV-infected children <18 years initiating cART between 1998 and 2008 were included if having at least one genotypic resistance test prior to cART initiation. We used the World Health Organization 2009 resistance mutation list and Stanford algorithm to infer resistance to prescribed drugs. Time to virological failure (VF) was defined as the first of two consecutive HIV-RNA > 500 copies/mL after 6 months cART and was assessed by Cox proportional hazards models. All models were adjusted for baseline demographic, clinical, immunology and virology characteristics and calendar period of cART start and initial cART regimen.
Results: Of 476 children, 88 % were vertically infected. At cART initiation, median (interquartile range) age was 6.6 years (2.1–10.1), CD4 cell count 297 cells/mm3 (98–639), and HIV-RNA 5.2 log10copies/mL (4.7–5.7). Of 37 children (7.8 %, 95 % confidence interval (CI), 5.5–10.6) harboring a virus with ≥1 PDR mutations, 30 children had a virus resistant to ≥1 of the prescribed drugs. Overall, the cumulative Kaplan-Meier estimate for virological failure was 19.8 % (95 %CI, 16.4–23.9). Cumulative risk for VF tended to be higher among children harboring a virus with PDR and resistant to ≥1 drug prescribed than among those receiving fully active cART: 32.1 % (17.2–54.8) versus 19.4 % (15.9–23.6) (P = 0.095). In multivariable analysis, age was associated with a higher risk of VF with a 12 % reduced risk per additional year (HR 0.88; 95 %CI, 0.82–0.95; P < 0.001).
Conclusions: PDR was not significantly associated with a higher risk of VF in children in the first year of cART. The risk of VF decreased by 12 % per additional year at treatment initiation which may be due to fading of PDR mutations over time. Lack of appropriate formulations, in particular for the younger age group, may be an important determinant of virological failure.
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: 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.
The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS.
High-risk rhabdomyosarcoma (RMS) occurring in childhood to young adulthood is associated with a poor prognosis; especially children above the age of 10 with advanced stage alveolar RMS still succumb to the disease within a median of 2 years. The advent of chimeric antigen receptor (CAR)-engineered T cells marked significant progress in the treatment of refractory B cell malignancies, but experience for solid tumors has proven challenging. We speculate that this is at least in part due to the poor quality of the patient's own T cells and therefore propose using CAR-modified cytokine-induced killer (CIK) cells as effector cells. CIK cells are a heterogeneous population of polyclonal T cells that acquire phenotypic and cytotoxic properties of natural killer (NK) cells through the cultivation process, becoming so-called T-NK cells. CIK cells can be genetically modified to express CARs. They are minimally alloreactive and can therefore be acquired from haploidentical first-degree relatives. Here, we explored the potential of ERBB2-CAR-modified random-donor CIK cells as a treatment for RMS in xenotolerant mice bearing disseminated high-risk RMS tumors. In otherwise untreated mice, RMS tumors engrafted 13–35 days after intravenous tumor cell injection, as shown by in vivo bioluminescence imaging, immunohistochemistry, and polymerase chain reaction for human gDNA, and mice died shortly thereafter (median/range: 62/56–66 days, n = 5). Wild-type (WT) CIK cells given at an early stage delayed and eliminated RMS engraftment in 4 of 6 (67%) mice, while ERBB2-CAR CIK cells inhibited initial tumor load in 8 of 8 (100%) mice. WT CIK cells were detectable but not as active as CAR CIK cells at distant tumor sites. CIK cell therapies during advanced RMS delayed but did not inhibit tumor progression compared to untreated controls. ERBB2-CAR CIK cell therapy also supported innate immunity as evidenced by selective accumulation of NK and T-NK cell subpopulations in disseminated RMS tumors, which was not observed for WT CIK cells. Our data underscore the power of heterogenous immune cell populations (T, NK, and T-NK cells) to control solid tumors, which can be further enhanced with CARs, suggesting ERBB2-CAR CIK cells as a potential treatment for high-risk RMS.
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.
Glioblastoma (GBM) is a cancer type with high thrombogenic potential and GBM patients are therefore at a particularly high risk for thrombotic events. To date, only limited data on anticoagulation management after pulmonary embolism (PE) in GBM is available and the sporadic use of DOACs remains off-label. A retrospective cohort analysis of patients with GBM and postoperative, thoracic CT scan confirmed PE was performed. Clinical course, follow-up at 6 and 12 months and the overall survival (OS) were evaluated using medical charts and neuroradiological data. Out of 584 GBM patients, 8% suffered from postoperative PE. Out of these, 30% received direct oral anticoagulants (DOACs) and 70% low-molecular-weight heparin (LMWH) for therapeutic anticoagulation. There was no significant difference in major intracranial hemorrhage (ICH), re-thrombosis, or re-embolism between the two cohorts. Although statistically non-significant, a tendency to reduced mRS at 6 and 12 months was observed in the LMWH cohort. Furthermore, patients receiving DOACs had a statistical benefit in OS. In our analysis, DOACs showed a satisfactory safety profile in terms of major ICH, re-thrombosis, and re-embolism compared to LMWH in GBM patients with postoperative PE. Prospective, randomized trials are urgent to evaluate DOACs for therapeutic anticoagulation in GBM patients with PE.
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
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.
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.
Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females.
Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score.
Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
Acne‐like skin reactions frequently occur in patients undergoing treatment with drugs inhibiting the epidermal growth factor receptor. Recently, the effects of vitamin K1 containing cream (Reconval K1) as prophylactic skin treatment in addition to doxycycline were explored in a double‐blind randomized phase II trial (EVITA) in patients with metastatic colorectal cancer receiving cetuximab. EVITA demonstrated a trend towards less severe skin rash in Reconval K1‐treated patients using the tripartite WoMo skin reaction grading score as a thorough tool for quantification of drug related skin reactions. This gender‐specific analysis of the EVITA trial evaluated the application of the WoMo score for assessment of epidermal growth factor receptor (EGFR)‐related skin toxicities according to treatment arm and gender. To show the robustness of results parametric and non‐parametric statistical analyses were conducted. All three parts of the WoMo score independently demonstrated the superiority of the treatment arm (Reconval K1) regarding a significant reduction in acneiform skin reactions in women. Men did not benefit from Reconval K1 cream at any time point in none of the WoMo score analyses. The treatment effect in women was confirmed by the use of skin rash categories based on the final WoMo overall score and mixed effect longitudinal multiple linear regression analysis. The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne‐like skin rash. Part C of the WoMo score seems to be sufficient for quantification of drug related skin toxicities in further studies. Standard WoMo skin reaction score values for future studies are provided.
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.
Radiographic and safety details of vertebral body stenting : results from a multicenter chart review
(2013)
Background: Up to one third of BKP treated cases shows no appreciable height restoration due to loss of both restored height and kyphotic realignment after balloon deflation. This shortcoming has called for an improved method that maintains the height and realignment reached by the fully inflated balloon until stabilization of the vertebral body by PMMA-based cementation. Restoration of the physiological vertebral body height for pain relief and for preventing further fractures of adjacent and distant vertebral bodies must be the main aim for such a method. A new vertebral body stenting system (VBS) stabilizes the vertebral body after balloon deflation until cementation. The radiographic and safety results of the first 100 cases where VBS was applied are presented.
Methods: During the planning phase of an ongoing international multicenter RCT, radiographic, procedural and followup details were retrospectively transcribed from charts and xrays for developing and testing the case report forms. Radiographs were centrally assessed at the institution of the first/senior author.
Results: 100 patients (62 with osteoporosis) with a total of 103 fractured vertebral bodies were treated with the VBS system. 49 were females with a mean age of 73.2 years; males were 66.7 years old. The mean preoperative anterior-middle-posterior heights were 20.3-17.6-28.0 mm, respectively. The mean local kyphotic angle was 13.1°. The mean preoperative Beck Index (anterior edge height/posterior edge height) was 0.73, the mean alternative Beck Index (middle height/posterior edge height) was 0.63. The mean postoperative heights were restored to 24.5-24.6-30.4 mm, respectively. The mean local kyphotic angle was reduced to 8.9°. The mean postoperative Beck Index was 0.81, the mean alternative one was 0.82. The overall extrusion rate was 29.1%, the symptomatic one was 1%. In the osteoporosis subgroup there were 23.8% extrusions. Within the three months followup interval there were 9% of adjacent and 4% of remote new fractures, all in the osteoporotic group.
Conclusions: VBS showed its strengths especially in realignment of crush and biconcave fractures. Given that fracture mobility is present, the realignment potential is sound and increases with the severity of preoperative vertebral body deformation.
This study included 30 patients with diagnosed rheumatoid arthritis (RA) and 30 test subjects without RA (control group). The objective of the study was to examine both groups for the presence of temporomandibular disorders (TMD) and morphological changes of the temporomandibular joint (TMJ). All individuals were examined using a systematic detailed clinical TMD examination as well as magnetic resonance imaging (MRI). The clinical TMD examination yielded significant differences between the RA patients and the control group concerning crepitus of the TMJ, and palpation tenderness of the masticatory muscles as well as the unassisted mandibular opening. The evaluation of the MRI images for the RA group showed significantly more frequent deformations of the condyle, osteophyte formations and erosions in the condylar compacta, and degenerative changes in the spongiosa. Increased intra-articular accumulation of synovial liquid and signs of inflammatory changes of the spongiosa were only found in the RA group. Statistical analysis showed a significant correlation between crepitus and specific osteoarthrotic changes (MRI), respectively, and between crepitus and a complete anterior disk displacement without reduction (MRI). The duration of the RA disease correlated neither with the anamnestic and clinical dysfunction index by Helkimo nor with RA-specific MRI findings.
The seasonality of transport and mixing of air into the lowermost stratosphere (LMS) is studied using distributions of mean age of air and a~mass balance approach, based on in-situ observations of SF6 and CO2 during the SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) aircraft campaigns. Combining the information of the mean age of air and the water vapour distributions we demonstrate that the tropospheric air transported into the LMS above the extratropical tropopause layer (ExTL) originates predominantly from the tropical tropopause layer (TTL). The concept of our mass balance is based on simultaneous measurements of the two passive tracers and the assumption that transport into the LMS can be described by age spectra which are superposition of two different modes. Based on this concept we conclude that the stratospheric influence on LMS composition is strongest in April with tropospheric fractions (α1) below 20% and that the strongest tropospheric signatures are found in October with (α1 greater than 80%. Beyond the fractions, our mass balance concept allows to calculate the associated transit times for transport of tropospheric air from the tropics into the LMS. The shortest transit times (<0.3 years) are derived for the summer, continuously increasing up to 0.8 years by the end of spring. These findings suggest that strong quasi-horizontal mixing across the weak subtropical jet from summer to mid of autumn and the considerably shorter residual transport time-scales within the lower branch of the Brewer-Dobson circulation in summer than in winter dominates the tropospheric influence in the LMS until the beginning of next year's summer.
The seasonality of transport and mixing of air into the lowermost stratosphere (LMS) is studied using distributions of mean age of air and a mass balance approach, based on in-situ observations of SF6 and CO2 during the SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) aircraft campaigns. Combining the information of the mean age of air and the water vapour distributions we demonstrate that the tropospheric air transported into the LMS above the extratropical tropopause layer (ExTL) originates predominantly from the tropical tropopause layer (TTL). The concept of our mass balance is based on simultaneous measurements of the two passive tracers and the assumption that transport into the LMS can be described by age spectra which are superposition of two different modes. Based on this concept we conclude that the stratospheric influence on LMS composition is strongest in April with extreme values of the tropospheric fractions (alpha1) below 20% and that the strongest tropospheric signatures are found in October with alpha1 greater than 80%. Beyond the fractions, our mass balance concept allows us to calculate the associated transit times for transport of tropospheric air from the tropics into the LMS. The shortest transit times (<0.3 years) are derived for the summer, continuously increasing up to 0.8 years by the end of spring. These findings suggest that strong quasi-horizontal mixing across the weak subtropical jet from summer to mid of autumn and the considerably shorter residual transport time-scales within the lower branch of the Brewer-Dobson circulation in summer than in winter dominates the tropospheric influence in the LMS until the beginning of next year's summer.
Background: Pythium ultimum (P. ultimum) is a ubiquitous oomycete plant pathogen responsible for a variety of diseases on a broad range of crop and ornamental species. Results: The P. ultimum genome (42.8 Mb) encodes 15,290 genes and has extensive sequence similarity and synteny with related Phytophthora species, including the potato blight pathogen Phytophthora infestans. Whole transcriptome sequencing revealed expression of 86% of genes, with detectable differential expression of suites of genes under abiotic stress and in the presence of a host. The predicted proteome includes a large repertoire of proteins involved in plant pathogen interactions although surprisingly, the P. ultimum genome does not encode any classical RXLR effectors and relatively few Crinkler genes in comparison to related phytopathogenic oomycetes. A lower number of enzymes involved in carbohydrate metabolism were present compared to Phytophthora species, with the notable absence of cutinases, suggesting a significant difference in virulence mechanisms between P. ultimum and more host specific oomycete species. Although we observed a high degree of orthology with Phytophthora genomes, there were novel features of the P. ultimum proteome including an expansion of genes involved in proteolysis and genes unique to Pythium. We identified a small gene family of cadherins, proteins involved in cell adhesion, the first report in a genome outside the metazoans. Conclusions: Access to the P. ultimum genome has revealed not only core pathogenic mechanisms within the oomycetes but also lineage specific genes associated with the alternative virulence and lifestyles found within the pythiaceous lineages compared to the Peronosporaceae.
Background: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study.
Patients and methods: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0–2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA).
Results: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS.
Conclusion: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.
Purpose: The purpose of this paper was to review the available approaches for bone strength assessment, osteoporosis diagnosis and fracture risk prediction, and to provide insights into radiofrequency echographic multi spectrometry (REMS), a non-ionizing axial skeleton technique.
Methods: A working group convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis met to review the current image-based methods for bone strength assessment and fracture risk estimation, and to discuss the clinical perspectives of REMS.
Results: Areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is the consolidated indicator for osteoporosis diagnosis and fracture risk assessment. A more reliable fracture risk estimation would actually require an improved assessment of bone strength, integrating also bone quality information. Several different approaches have been proposed, including additional DXA-based parameters, quantitative computed tomography, and quantitative ultrasound. Although each of them showed a somewhat improved clinical performance, none satisfied all the requirements for a widespread routine employment, which was typically hindered by unclear clinical usefulness, radiation doses, limited accessibility, or inapplicability to spine and hip, therefore leaving several clinical needs still unmet. REMS is a clinically available technology for osteoporosis diagnosis and fracture risk assessment through the estimation of BMD on the axial skeleton reference sites. Its automatic processing of unfiltered ultrasound signals provides accurate BMD values in view of fracture risk assessment.
Conclusions: New approaches for improved bone strength and fracture risk estimations are needed for a better management of osteoporotic patients. In this context, REMS represents a valuable approach for osteoporosis diagnosis and fracture risk prediction.
Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001). Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability
(2023)
Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.
Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed.
Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome.
Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response.
Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.
No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors
(2019)
Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.
Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.
Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.
Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
Background: High-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) is a treatment option for pediatric patients with relapsed nephroblastoma. We present long term results of 9 patients treated between 1993 and 2013 at our center.
Procedure: Reinduction therapy was carried out according to GPOH and SIOP recommendations. The conditioning regimen consisted of carboplatin (1 200 mg/m²), etoposide (800 mg/m² or 40 mg/kg) and melphalan (180 mg/m²). Purging of the grafts with immunomagnetic CD34 positive selection was performed in 5 patients.
Results: 8 of 9 Patients (90%) are alive without evidence of disease after a median follow-up of 8.5 years. Leukocyte engraftment occurred after a median of 10 days (range 8-12). Median numbers of 667/µl CD3+, 329/µl CD4+, 369/µl CD8+T cells and 949/µl B cells were reached after 180 days. No negative impact of CD34 selection was observed. No transplantation-related death occurred. Acute toxicity comprised mucositis III°-IV° in all and veno-occlusive disease in one patient. Long term effects probably related to treatment occurred in 3/7 evaluable patients and comprised hearing impairment, reduced renal phosphate reabsorption, mild creatinine elevation and hypothyroidism (n=1, each).
Conclusion: Thus, in our experience HDC with ASCR is an effective treatment of recurrent or refractory nephroblastoma with acceptable side effects. However, a randomized trial proving its efficiency with a high level of evidence is needed.
In non-hadronic axion models, which have a tree-level axion-electron interaction, the Sun produces a strong axion flux by bremsstrahlung, Compton scattering, and axiorecombination, the "BCA processes." Based on a new calculation of this flux, including for the first time axio-recombination, we derive limits on the axion-electron Yukawa coupling gae and axion-photon interaction strength ga using the CAST phase-I data (vacuum phase). For ma <~ 10 meV/c2 we find ga gae < 8.1 × 10−23 GeV−1 at 95% CL. We stress that a next-generation axion helioscope such as the proposed IAXO could push this sensitivity into a range beyond stellar energy-loss limits and test the hypothesis that white-dwarf cooling is dominated by axion emission.
Background: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM.
Methods: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements.
Results: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease.
Conclusion: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.
Reducing neuronal size results in less cell membrane and therefore lower input conductance. Smaller neurons are thus more excitable as seen in their voltage responses to current injections in the soma. However, the impact of a neuron’s size and shape on its voltage responses to synaptic activation in dendrites is much less understood. Here we use analytical cable theory to predict voltage responses to distributed synaptic inputs and show that these are entirely independent of dendritic length. For a given synaptic density, a neuron’s response depends only on the average dendritic diameter and its intrinsic conductivity. These results remain true for the entire range of possible dendritic morphologies irrespective of any particular arborisation complexity. Also, spiking models result in morphology invariant numbers of action potentials that encode the percentage of active synapses. Interestingly, in contrast to spike rate, spike times do depend on dendrite morphology. In summary, a neuron’s excitability in response to synaptic inputs is not affected by total dendrite length. It rather provides a homeostatic input-output relation that specialised synapse distributions, local non-linearities in the dendrites and synaptic plasticity can modulate. Our work reveals a new fundamental principle of dendritic constancy that has consequences for the overall computation in neural circuits.
Our purpose was to analyze the robustness and reproducibility of magnetic resonance imaging (MRI) radiomic features. We constructed a multi-object fruit phantom to perform MRI acquisition as scan-rescan using a 3 Tesla MRI scanner. We applied T2-weighted (T2w) half-Fourier acquisition single-shot turbo spin-echo (HASTE), T2w turbo spin-echo (TSE), T2w fluid-attenuated inversion recovery (FLAIR), T2 map and T1-weighted (T1w) TSE. Images were resampled to isotropic voxels. Fruits were segmented. The workflow was repeated by a second reader and the first reader after a pause of one month. We applied PyRadiomics to extract 107 radiomic features per fruit and sequence from seven feature classes. We calculated concordance correlation coefficients (CCC) and dynamic range (DR) to obtain measurements of feature robustness. Intraclass correlation coefficient (ICC) was calculated to assess intra- and inter-observer reproducibility. We calculated Gini scores to test the pairwise discriminative power specific for the features and MRI sequences. We depict Bland Altmann plots of features with top discriminative power (Mann–Whitney U test). Shape features were the most robust feature class. T2 map was the most robust imaging technique (robust features (rf), n = 84). HASTE sequence led to the least amount of rf (n = 20). Intra-observer ICC was excellent (≥ 0.75) for nearly all features (max–min; 99.1–97.2%). Deterioration of ICC values was seen in the inter-observer analyses (max–min; 88.7–81.1%). Complete robustness across all sequences was found for 8 features. Shape features and T2 map yielded the highest pairwise discriminative performance. Radiomics validity depends on the MRI sequence and feature class. T2 map seems to be the most promising imaging technique with the highest feature robustness, high intra-/inter-observer reproducibility and most promising discriminative power.
A new technique developed for measuring nuclear reactions at low momentum transfer with stored beams in inverse kinematics was successfully used to study isoscalar giant resonances. The experiment was carried out at the experimental heavy-ion storage ring (ESR) at the GSI facility using a stored 58Ni beam at 100 MeV/u and an internal helium gas-jet target. In these measurements, inelastically scattered α-recoils at very forward center-of-mass angles (θcm ≤ 1.5°) were detected with a dedicated setup, including ultra-high vacuum compatible detectors. Experimental results indicate a dominant contribution of the isoscalar giant monopole resonance at this very forward angular range. It was found that the monopole contribution exhausts 79+12−11% of the energy-weighted sum rule (EWSR), which agrees with measurements performed in normal kinematics. This opens up the opportunity to investigate the giant resonances in a large domain of unstable and exotic nuclei in the near future. It is a fundamental milestone towards new nuclear reaction studies with stored ion beams.
The three-dimensional quantification of small scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe and TACTS/ESMVal aircraft campaigns. The focus of this work is on the so-called dynamics mode data characterized by a medium spectral and a very high spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3 and CFC-12) and their spatial resolution are discussed. During ESSenCe, high resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in-situ data indicate a good agreement between the data sets. During TACTS/ESMVal a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere has been performed. This filament could be reconstructed with an unprecedented spatial resolution of better than 500 m vertically and 20 km × 20 km horizontally.
Objectives: To analyze the performance of radiological assessment categories and quantitative computational analysis of apparent diffusion coefficient (ADC) maps using variant machine learning algorithms to differentiate clinically significant versus insignificant prostate cancer (PCa). Methods: Retrospectively, 73 patients were included in the study. The patients (mean age, 66.3 ± 7.6 years) were examined with multiparametric MRI (mpMRI) prior to radical prostatectomy (n = 33) or targeted biopsy (n = 40). The index lesion was annotated in MRI ADC and the equivalent histologic slides according to the highest Gleason Grade Group (GrG). Volumes of interest (VOIs) were determined for each lesion and normal-appearing peripheral zone. VOIs were processed by radiomic analysis. For the classification of lesions according to their clinical significance (GrG ≥ 3), principal component (PC) analysis, univariate analysis (UA) with consecutive support vector machines, neural networks, and random forest analysis were performed. Results: PC analysis discriminated between benign and malignant prostate tissue. PC evaluation yielded no stratification of PCa lesions according to their clinical significance, but UA revealed differences in clinical assessment categories and radiomic features. We trained three classification models with fifteen feature subsets. We identified a subset of shape features which improved the diagnostic accuracy of the clinical assessment categories (maximum increase in diagnostic accuracy ΔAUC = + 0.05, p < 0.001) while also identifying combinations of features and models which reduced overall accuracy. Conclusions: The impact of radiomic features to differentiate PCa lesions according to their clinical significance remains controversial. It depends on feature selection and the employed machine learning algorithms. It can result in improvement or reduction of diagnostic performance.
Profiles of CFC-11 (CCl3F) and CFC-12 (CCl2F2) of the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) aboard the European satellite Envisat have been retrieved from versions MIPAS/4.61 to MIPAS/4.62 and MIPAS/5.02 to MIPAS/5.06 level-1b data using the scientific level-2 processor run by Karlsruhe Institute of Technology (KIT), Institute of Meteorology and Climate Research (IMK) and Consejo Superior de Investigaciones Científicas (CSIC), Instituto de Astrofísica de Andalucía (IAA). These profiles have been compared to measurements taken by the balloon-borne cryosampler, Mark IV (MkIV) and MIPAS-Balloon (MIPAS-B), the airborne MIPAS-STRatospheric aircraft (MIPAS-STR), the satellite-borne Atmospheric Chemistry Experiment Fourier transform spectrometer (ACE-FTS) and the High Resolution Dynamic Limb Sounder (HIRDLS), as well as the ground-based Halocarbon and other Atmospheric Trace Species (HATS) network for the reduced spectral resolution period (RR: January 2005–April 2012) of MIPAS. ACE-FTS, MkIV and HATS also provide measurements during the high spectral resolution period (full resolution, FR: July 2002–March 2004) and were used to validate MIPAS CFC-11 and CFC-12 products during that time, as well as profiles from the Improved Limb Atmospheric Spectrometer, ILAS-II. In general, we find that MIPAS shows slightly higher values for CFC-11 at the lower end of the profiles (below ∼ 15 km) and in a comparison of HATS ground-based data and MIPAS measurements at 3 km below the tropopause. Differences range from approximately 10 to 50 pptv ( ∼ 5–20 %) during the RR period. In general, differences are slightly smaller for the FR period. An indication of a slight high bias at the lower end of the profile exists for CFC-12 as well, but this bias is far less pronounced than for CFC-11 and is not as obvious in the relative differences between MIPAS and any of the comparison instruments. Differences at the lower end of the profile (below ∼ 15 km) and in the comparison of HATS and MIPAS measurements taken at 3 km below the tropopause mainly stay within 10–50 pptv (corresponding to ∼ 2–10 % for CFC-12) for the RR and the FR period. Between ∼ 15 and 30 km, most comparisons agree within 10–20 pptv (10–20 %), apart from ILAS-II, which shows large differences above ∼ 17 km. Overall, relative differences are usually smaller for CFC-12 than for CFC-11. For both species – CFC-11 and CFC-12 – we find that differences at the lower end of the profile tend to be larger at higher latitudes than in tropical and subtropical regions. In addition, MIPAS profiles have a maximum in their mixing ratio around the tropopause, which is most obvious in tropical mean profiles. Comparisons of the standard deviation in a quiescent atmosphere (polar summer) show that only the CFC-12 FR error budget can fully explain the observed variability, while for the other products (CFC-11 FR and RR and CFC-12 RR) only two-thirds to three-quarters can be explained. Investigations regarding the temporal stability show very small negative drifts in MIPAS CFC-11 measurements. These instrument drifts vary between ∼ 1 and 3 % decade−1. For CFC-12, the drifts are also negative and close to zero up to ∼ 30 km. Above that altitude, larger drifts of up to ∼ 50 % decade−1 appear which are negative up to ∼ 35 km and positive, but of a similar magnitude, above.
The three-dimensional quantification of small-scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents the first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe (ESa Sounder Campaign) and TACTS/ESMVal (TACTS: Transport and composition in the upper troposphere/lowermost stratosphere, ESMVal: Earth System Model Validation) aircraft campaigns. The focus of this work is on the so-called dynamics-mode data characterized by a medium-spectral and a very-high-spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3, and CFC-12) and their spatial resolution are discussed. During ESSenCe, high-resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in situ data indicate a good agreement between the data sets. During TACTS/ESMVal, a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere was performed. It was possible to reconstruct this filament at an unprecedented spatial resolution of better than 500 m vertically and 20 × 20 km horizontally.
Profiles of CFC-11 (CCl3F) and CFC-12 (CCl2F2) of the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) aboard the European satellite Envisat have been retrieved from versions MIPAS/4.61 to MIPAS/4.62 and MIPAS/5.02 to MIPAS/5.06 level-1b data using the scientific level-2 processor run by Karlsruhe Institute of Technology (KIT), Institute of Meteorology and Climate Research (IMK) and Consejo Superior de Investigaciones Científicas (CSIC), Instituto de Astrofísica de Andalucía (IAA). These profiles have been compared to measurements taken by the balloon-borne cryosampler, Mark IV (MkIV) and MIPAS-Balloon (MIPAS-B), the airborne MIPAS-STRatospheric aircraft (MIPAS-STR), the satellite-borne Atmospheric Chemistry Experiment Fourier transform spectrometer (ACE-FTS) and the High Resolution Dynamic Limb Sounder (HIRDLS), as well as the ground-based Halocarbon and other Atmospheric Trace Species (HATS) network for the reduced spectral resolution period (RR: January 2005–April 2012) of MIPAS. ACE-FTS, MkIV and HATS also provide measurements during the high spectral resolution period (full resolution, FR: July 2002–March 2004) and were used to validate MIPAS CFC-11 and CFC-12 products during that time, as well as profiles from the Improved Limb Atmospheric Spectrometer, ILAS-II. In general, we find that MIPAS shows slightly higher values for CFC-11 at the lower end of the profiles (below ∼ 15 km) and in a comparison of HATS ground-based data and MIPAS measurements at 3 km below the tropopause. Differences range from approximately 10 to 50 pptv ( ∼ 5–20 %) during the RR period. In general, differences are slightly smaller for the FR period. An indication of a slight high bias at the lower end of the profile exists for CFC-12 as well, but this bias is far less pronounced than for CFC-11 and is not as obvious in the relative differences between MIPAS and any of the comparison instruments. Differences at the lower end of the profile (below ∼ 15 km) and in the comparison of HATS and MIPAS measurements taken at 3 km below the tropopause mainly stay within 10–50 pptv (corresponding to ∼ 2–10 % for CFC-12) for the RR and the FR period. Between ∼ 15 and 30 km, most comparisons agree within 10–20 pptv (10–20 %), apart from ILAS-II, which shows large differences above ∼ 17 km. Overall, relative differences are usually smaller for CFC-12 than for CFC-11. For both species – CFC-11 and CFC-12 – we find that differences at the lower end of the profile tend to be larger at higher latitudes than in tropical and subtropical regions. In addition, MIPAS profiles have a maximum in their mixing ratio around the tropopause, which is most obvious in tropical mean profiles. Comparisons of the standard deviation in a quiescent atmosphere (polar summer) show that only the CFC-12 FR error budget can fully explain the observed variability, while for the other products (CFC-11 FR and RR and CFC-12 RR) only two-thirds to three-quarters can be explained. Investigations regarding the temporal stability show very small negative drifts in MIPAS CFC-11 measurements. These instrument drifts vary between ∼ 1 and 3 % decade−1. For CFC-12, the drifts are also negative and close to zero up to ∼ 30 km. Above that altitude, larger drifts of up to ∼ 50 % decade−1 appear which are negative up to ∼ 35 km and positive, but of a similar magnitude, above.
Movement of organisms is one of the key mechanisms shaping biodiversity, e.g. the distribution of genes, individuals and species in space and time. Recent technological and conceptual advances have improved our ability to assess the causes and consequences of individual movement, and led to the emergence of the new field of ‘movement ecology’. Here, we outline how movement ecology can contribute to the broad field of biodiversity research, i.e. the study of processes and patterns of life among and across different scales, from genes to ecosystems, and we propose a conceptual framework linking these hitherto largely separated fields of research. Our framework builds on the concept of movement ecology for individuals, and demonstrates its importance for linking individual organismal movement with biodiversity. First, organismal movements can provide ‘mobile links’ between habitats or ecosystems, thereby connecting resources, genes, and processes among otherwise separate locations. Understanding these mobile links and their impact on biodiversity will be facilitated by movement ecology, because mobile links can be created by different modes of movement (i.e., foraging, dispersal, migration) that relate to different spatiotemporal scales and have differential effects on biodiversity. Second, organismal movements can also mediate coexistence in communities, through ‘equalizing’ and ‘stabilizing’ mechanisms. This novel integrated framework provides a conceptual starting point for a better understanding of biodiversity dynamics in light of individual movement and space-use behavior across spatiotemporal scales. By illustrating this framework with examples, we argue that the integration of movement ecology and biodiversity research will also enhance our ability to conserve diversity at the genetic, species, and ecosystem levels.
Vascular guidance is critical in developmental vasculogenesis and pathological angiogenesis. Brain tumors are strongly vascularized, and antiangiogenic therapy was anticipated to exhibit a strong anti-tumor effect in this tumor type. However, vascular endothelial growth factor A (VEGFA) specific inhibition had no significant impact in clinical practice of gliomas. More research is needed to understand the failure of this therapeutic approach. EphrinB2 has been found to directly interact with vascular endothelial growth factor receptor 2 (VEGFR2) and regulate its activity. Here we analyzed the expression of ephrinB2 and EphB4 in human glioma, we observed vascular localization of ephrinB2 in physiology and pathology and found a significant survival reduction in patients with elevated ephrinB2 tumor expression. Induced endothelial specific depletion of ephrinB2 in the adult mouse (efnb2i∆EC) had no effect on the quiescent vascular system of the brain. However, we found glioma growth and perfusion altered in efnb2i∆EC animals similar to the effects observed with antiangiogenic therapy. No additional anti-tumor effect was observed in efnb2i∆EC animals treated with antiangiogenic therapy. Our data indicate that ephrinB2 and VEGFR2 converge on the same pathway and intervention with either molecule results in a reduction in angiogenesis.