610 Medizin und Gesundheit
Refine
Year of publication
- 2020 (867) (remove)
Document Type
- Article (678)
- Doctoral Thesis (103)
- Preprint (66)
- Contribution to a Periodical (10)
- Part of Periodical (6)
- Book (3)
- Master's Thesis (1)
Has Fulltext
- yes (867)
Keywords
- COVID-19 (20)
- inflammation (17)
- SARS-CoV-2 (11)
- quality of life (8)
- Quality of life (7)
- biomarker (7)
- cancer (7)
- macrophage (7)
- obesity (7)
- ADHD (6)
- depression (6)
- MRI (5)
- Machine learning (5)
- immunotherapy (5)
- pain (5)
- polytrauma (5)
- stroke (5)
- ACLF (4)
- EEG (4)
- Epilepsy (4)
- HIV (4)
- Inflammation (4)
- Rare diseases (4)
- Stroke (4)
- TAVI (4)
- aortic stenosis (4)
- autophagy (4)
- bipolar disorder (4)
- bladder cancer (4)
- breast cancer (4)
- cognition (4)
- coronavirus (4)
- cytokines (4)
- drug resistance (4)
- exercise (4)
- portal hypertension (4)
- schizophrenia (4)
- tumor microenvironment (4)
- Abdominal aortic aneurysm (3)
- Aortic stenosis (3)
- Biomarkers (3)
- Cardiovascular magnetic resonance (3)
- Cirrhosis (3)
- DNA methylation (3)
- Diagnostics (3)
- Diagnostik (3)
- Endovascular repair (3)
- Gesundheitsökonomie (3)
- Health economics (3)
- Heart failure (3)
- Human behaviour (3)
- Hypoxia (3)
- Infections (3)
- Macrophages (3)
- Magnetic resonance imaging (3)
- Mortality (3)
- NASH (3)
- Offene Versorgung (3)
- Open repair (3)
- Peri-implantitis (3)
- Postural control (3)
- Register (3)
- Registries (3)
- Registry (3)
- Strength training (3)
- Treatment (3)
- acute-on-chronic liver failure (3)
- apoptosis (3)
- attention (3)
- child (3)
- chimeric antigen receptor (3)
- complications (3)
- cytotoxicity (3)
- epilepsy (3)
- glioblastoma (3)
- glioma (3)
- hippocampus (3)
- integrins (3)
- iron (3)
- machine learning (3)
- macrophages (3)
- mesenchymal stromal cells (3)
- miRNA (3)
- microRNA (3)
- microbiome (3)
- migration (3)
- neuroblastoma (3)
- neurodegeneration (3)
- outcome (3)
- ovarian cancer (3)
- physical activity (3)
- precision medicine (3)
- prevalence (3)
- prevention (3)
- proliferation (3)
- prostate cancer (3)
- proteostasis (3)
- psoriasis (3)
- reactive oxygen species (3)
- sulforaphane (3)
- toxicity (3)
- 3D printing (2)
- 3D rapid prototyping (2)
- AML (2)
- ATP (2)
- Abdominelles Aortenaneurysma (2)
- Alzheimer’s disease (2)
- Artificial intelligence (2)
- Ascites (2)
- Ataxia telangiectasia (2)
- Autism spectrum disorder (2)
- BMI (2)
- Bibliometrics (2)
- Bladder cancer (2)
- Borrelia (2)
- CD19 (2)
- CD44 (2)
- CNN (2)
- Cancer (2)
- Cardiology (2)
- Cerebrospinal fluid (2)
- Children (2)
- Clinical decision support systems (2)
- Cohort studies (2)
- Computer-assisted diagnosis (2)
- Critical care (2)
- DTI (2)
- Database searching (2)
- Datenschutz (2)
- Dementia (2)
- Depression (2)
- Emergency room (2)
- Endoscopy (2)
- Endovaskuläre Behandlung (2)
- Epidemiology (2)
- Erweiterter Suizid (2)
- Europe (2)
- Extended suicide (2)
- Gemeinschaftliche Selbsttötung (2)
- Gene expression (2)
- Gene regulation (2)
- General practice (2)
- Genetics (2)
- Germany (2)
- Glioma (2)
- HIV-1 (2)
- Healthy adults (2)
- Hepatocellular carcinoma (2)
- IDH mutation (2)
- IL-10 (2)
- Immunohistochemistry (2)
- Immunological methods (2)
- Immunologische Methoden (2)
- Immunology (2)
- In vitro (2)
- Klebsiella pneumoniae (2)
- Klinische Ergebnisse (2)
- Knochenersatzmaterial (2)
- Krankheit (2)
- Language (2)
- Lebensqualität (2)
- Liver diseases (2)
- Liver transplantation (2)
- Long-term potentiation (2)
- MSD (2)
- Medical research (2)
- Metaanalysis (2)
- Morbidity (2)
- Morphology (2)
- Multiple sclerosis (2)
- Myocardial perfusion (2)
- NADPH oxidase (2)
- NAFLD (2)
- Neurology (2)
- Neurons (2)
- Notaufnahme (2)
- Object vision (2)
- Outcome (2)
- PCR (2)
- Patient blood management (2)
- Patients (2)
- Pneumonia (2)
- Preventive medicine (2)
- Public health (2)
- Radiomics (2)
- Remuneration (2)
- Seizure (2)
- Suicide pact (2)
- Survey (2)
- Transfusion (2)
- Treatment outcome (2)
- Validation (2)
- Vergütung (2)
- Wearable cardioverter-defibrillator (2)
- Women (2)
- acute lymphoblastic leukemia (2)
- adaptation (2)
- adolescents (2)
- adult (2)
- aging (2)
- alveolar ridge augmentation (2)
- animal experiment (2)
- antiepileptic drugs (2)
- augmentation (2)
- bibliometrics (2)
- biomarkers (2)
- body mass index (2)
- cardiac surgery (2)
- cerebral hemorrhage (2)
- cerebral venous thrombosis (2)
- chemoresistance (2)
- children (2)
- cirrhosis (2)
- cleaning (2)
- clinical studies (2)
- coagulopathy (2)
- combination therapy (2)
- complement (2)
- connective tissue (2)
- continuous performance test (2)
- curcumin (2)
- cystic fibrosis (2)
- cytomegalovirus (2)
- data science (2)
- decompensated liver cirrhosis (2)
- delirium (2)
- dental education (2)
- dental implants (2)
- dental profession (2)
- dentoalveolar surgery (2)
- diabetes mellitus (2)
- direct-acting antivirals (2)
- drug discovery (2)
- elderly (2)
- electroencephalography (2)
- environmental tobacco smoke (2)
- evolution (2)
- fascia (2)
- fibroblasts (2)
- fibrosis (2)
- flow cytometry (2)
- gait analysis (2)
- growth (2)
- hepatic encephalopathy (2)
- hepatocellular carcinoma (2)
- histology (2)
- hyperactivity (2)
- hypoxia (2)
- immunity (2)
- immunosuppression (2)
- impulsivity (2)
- infection (2)
- innate immunity (2)
- integrin (2)
- joint contact forces (2)
- kidney (2)
- liver (2)
- liver cirrhosis (2)
- lung cancer (2)
- lung function (2)
- lymphocytes (2)
- mTOR (2)
- mass spectrometry (2)
- metformin (2)
- mitochondria (2)
- multiple sclerosis (2)
- musculoskeletal disorders (2)
- musculoskeletal modeling (2)
- natural killer cells (2)
- neural oscillations (2)
- neurocognition (2)
- oncology (2)
- oral and maxillofacial surgery (2)
- pancreatic cancer (2)
- patient blood management (2)
- periodontitis (2)
- polygenic risk score (2)
- post-translational modifications (2)
- prognosis (2)
- protein degradation (2)
- protein synthesis (2)
- proteome (2)
- proteomics (2)
- public health (2)
- renal cell carcinoma (2)
- resistance training (2)
- risk factors (2)
- risk prediction (2)
- screening (2)
- sepsis (2)
- severe acute respiratory syndrome coronavirus 2 (2)
- simulation training (2)
- sphingosine 1-phosphate (2)
- sphingosine 1-phosphate receptor (2)
- spinal dural leaks (2)
- stress (2)
- superficial siderosis (2)
- surgery (2)
- survival (2)
- survivin (2)
- thrombosis (2)
- thymus (2)
- transcriptome (2)
- transplantation (2)
- tumor growth (2)
- tumor progression (2)
- von Willebrand factor (2)
- (cardiac) surgery (1)
- 14-3-3 gene family (1)
- 16 segment AHA model (1)
- 16S rRNA sequencing (1)
- 19F MR spectroscopy (1)
- 1H MR spectroscopy (1)
- 2'-deoxyguanosine riboswitch (1)
- 2-hydroxyglutarate (1)
- 2019-nCoV (1)
- 3,4-DCA; biotransformation (1)
- 3-hydroxyanthranilic acid (1)
- 3D printed cell-free scaffold (1)
- 3D-Druck (1)
- 4-fluoroamphetamine (1)
- 9-HODE (1)
- A-FFIP (1)
- A2BP1 (1)
- AAA+ disaggregase (1)
- ABC transporters (1)
- ABCB1 (1)
- ABCC1 (1)
- ACE-Bestimmung (1)
- ADAMTS-13 (1)
- ADAMTS13 (1)
- ADGRE1 (1)
- ADHD differential diagnosis (1)
- ADHS (1)
- AKI (1)
- ALL (1)
- AMH (1)
- AML – acute myeloid leukemia (1)
- ARDS (1)
- ASD-specific (1)
- ASPECTS (1)
- ATP binding (1)
- Abductor pollicis longus (1)
- Ablation (1)
- Abrasion (1)
- Absenteeism (1)
- Absorption modeling (1)
- Abusive head trauma (AHT) (1)
- Access (1)
- Accumulated degree days (1)
- Acellular dermis (1)
- Acoustics (1)
- Action potentials (1)
- Acute HIV infection (1)
- Acute appendicitis (1)
- Acute elbow dislocation (1)
- Acute hospital (1)
- Acute lymphoblastic leukemia (1)
- Acute lymphocytic leukaemia (1)
- Acute-on-chronic subdural hematoma (1)
- Addison’s disease (1)
- Adenosine (1)
- Adherence (1)
- Adipose tissue (1)
- Administrative claims data (1)
- Advanced breast cancer (1)
- Adverse drug reaction (1)
- Afrikanische Schlafkrankheit (1)
- Age determination (1)
- Age determination by skeleton (1)
- Age groups (1)
- Aging (1)
- Albumin ratio (1)
- Algorithms (1)
- Alkaloid (1)
- Allergic rhinitis (1)
- Allgemeinmedizin (1)
- Allogeneic (1)
- Alpha oscillations (1)
- Alzheimer's disease (1)
- Amino acid analysis (1)
- Amisulpride (1)
- Amitriptyline (1)
- Anal cancer (1)
- Anandamide (1)
- Anatomy (1)
- Anderson–Fabry (1)
- Andropogon virginicus (1)
- Angiogenesis (1)
- Angiotensin Converting Enzyme (1)
- Angiotensin-converting enzyme (1)
- Animal model (1)
- Anterior cruciate ligament reconstruction (1)
- Anti-CMV IgG (1)
- Anti-inflammatory (1)
- Anti-rheumatic agents (1)
- Anticholinergic (1)
- Anticoagulant (1)
- Anticoagulant therapy (1)
- Anticoagulants (1)
- Anticoagulation (1)
- Antidepressiva (1)
- Antigens/Peptides/Epitopes (1)
- Antihormone therapy (1)
- Antiviral immune response (1)
- Aortic input function (1)
- Apoptosis (1)
- Appendectomy (1)
- Aquilegia (1)
- Arbeitsgedächtnis (1)
- Arrhythmia syndromes (1)
- Arthroplasty (1)
- Ataxia score (1)
- Athletes (1)
- Atm (1)
- Atrial fibrillation (1)
- Attention deficit (1)
- Auditory cortex (1)
- Auditory midbrain (1)
- Auditory system (1)
- Aufmerksamkeit (1)
- Aufmerksamkeitsleistung (1)
- Autoimmune vasculopathy (1)
- Autologous biomaterial (1)
- Autopsy (1)
- Awareness campaign (1)
- Axiography (1)
- B cells (1)
- B-cell lymphoma (1)
- B-cell receptor (1)
- BAG3 (1)
- BCL6 (1)
- BCX7353 (1)
- BDNF (1)
- BET inhibitor (1)
- BEZ235 (1)
- BFIS (1)
- BG-index (1)
- BIRC5 (1)
- BK channel (1)
- BMC (1)
- BRD4 (1)
- Bacterial abundance (1)
- Bagatelltrauma (1)
- Bakterien (1)
- Bakterientest (1)
- Balloon-expandable TAVI (1)
- Bauchaortenaneurysma (1)
- Bee venom allergy (1)
- Begriffsbestimmung (1)
- Belastung (1)
- Benign enlargement of the subarachnoid spaces (BESS) (1)
- Benign pulmonary diseases (1)
- Benigne Lungenerkrankungen (1)
- Bestimmungsmethoden (1)
- Bestrahlung (1)
- Betriebliche Gesundheitsförderung (1)
- Bewegungsanalyse mit Inertialsensoren (1)
- Bewegungsstörung (1)
- Bildgebung (1)
- BioID (1)
- Bioavailability prediction (1)
- Biomarker (1)
- Biopsy (1)
- Bleeding (1)
- Blocked occlusion (1)
- Blood flow (1)
- Body limbs (1)
- Body measurements (1)
- Body modification (1)
- Body temperature (1)
- Bone defect (1)
- Bone regeneration (1)
- Bone remodelling (1)
- Bone substitute (1)
- Bone tissue engineering (1)
- Brain asymmetry (1)
- Brain injuries (1)
- Brain size I (1)
- Brain structure (1)
- Brain tumor surgery (1)
- Brain tumors (1)
- Brain-stimulus synchrony (1)
- Breast cancer survivers (1)
- Breathing (1)
- Brustkrebs (1)
- Burden (1)
- Burden of illness (1)
- Büroangestellte (1)
- C1 inhibitor (1)
- C2 domain (1)
- CAD/CAM (1)
- CAKUT (1)
- CAR (1)
- CCL2 (1)
- CD107-Assay (1)
- CD3 (1)
- CD34 + cells (1)
- CD4 binding site (1)
- CD41 (1)
- CD49d (1)
- CD62P (1)
- CD8+ T cell (1)
- CDI (1)
- CDK9 (1)
- CEBPD (1)
- CIRS (1)
- CLP (1)
- CMVepidemiology (1)
- COINS (1)
- COMP (1)
- COVID 19 pandemic (1)
- CPT1A (1)
- CRE-dependent transcription (1)
- CRISPR/Cas9 (1)
- CUELA system (1)
- CXCL10 (1)
- CXCR3 (1)
- Callous-unemotional traits (1)
- Calpain (1)
- Cancer check up (1)
- Cancer treatment (1)
- Candida spp (1)
- Cannabidiol (1)
- Capnography (1)
- Cardiac acoustic biomarkers (1)
- Cardiac arrest (1)
- Cardiac masses (1)
- CardioMEMS™ HF system (1)
- Careers (1)
- Caspase-8 (1)
- Cell death and immune response (1)
- Cell staining (1)
- Cell-based therapies (1)
- Cellular neuroscience (1)
- Central nervous system (1)
- Cerebellum (1)
- Cerebral hypoperfusion (1)
- Cerebrovascular disorders (1)
- Checkpoint inhibitor (1)
- Chemoradiation (1)
- Chemoradiotherapy (1)
- Chemotherapie (1)
- Chemotherapy (1)
- Child (1)
- Child abuse (1)
- Child health (1)
- Children and adolescents (1)
- Chimiothérapie (1)
- Chirurgie (1)
- Chromatin accessibility (1)
- Chromatin conformation (1)
- Chronic conditions (1)
- Chronic depression (1)
- Chronic inflammation (1)
- Chronology of disease (1)
- Classification (1)
- Clavien–Dindo classification (1)
- Climate inequity (1)
- Clinical genetics (1)
- Clinical trial (1)
- Clinical trials (1)
- Clostridium (1)
- Clustering coefficients (1)
- Coagulation (1)
- Coagulopathy management (1)
- Cognition (1)
- Cognitive behavioral therapy (1)
- Cognitive impairment (1)
- Cognitive neurology (1)
- Cold hardiness (1)
- Cold tolerance (1)
- Collagen-based biomaterial (1)
- Colonic neoplasms (1)
- Combo® DTS (1)
- Comparators (1)
- Complications (1)
- Compression stocking (1)
- Computed axial tomography (1)
- Computer hardware (1)
- Computer science (1)
- Computer software (1)
- Computer-aided drug design (1)
- Computers (1)
- Concept paper (1)
- Conduct disorder (1)
- Conduct problems (1)
- Confinement (1)
- Congenital CMVinfection (1)
- Congenital anomalies (1)
- Congenital diaphragmatic hernia (1)
- Connectivity (1)
- Conservative treatment (1)
- Constitution (1)
- Continuous Process Verification (1)
- Control (1)
- Cooperation (1)
- Copy number (1)
- Coronary artery disease (1)
- Coronavirus (1)
- Cortical degeneration (1)
- Cortical thickness (1)
- Cp (1)
- Cpk (1)
- Craniomaxillofacial injuries (1)
- Critical Online Reasoning Assessment (1)
- Critical size (1)
- Croatia (1)
- Crohn's disease (1)
- Crohn’s disease (1)
- CspA (1)
- CspZ (1)
- Curriculum (1)
- Cyp46a1 (1)
- CysLTR1 (1)
- Cysteine‐Rich Domain (CRD) (1)
- Cystic fibrosis (1)
- Cytokines (1)
- Cytomegalovirus (CMV) (1)
- DAMPs (1)
- DBS (1)
- DFNB9 (1)
- DILI (1)
- DNA damage (1)
- DNA damage response (1)
- DNA sequence analysis (1)
- DNase1-seq (1)
- DRG (1)
- DST (1)
- DYRK1A (1)
- Darunavir (1)
- Data processing (1)
- Data protection (1)
- Data science (1)
- Datenverarbeitung (1)
- Decision making (1)
- Decontamination (1)
- Deep vein thrombosis (1)
- Defibrillation (1)
- Dehnen (1)
- Delegation (1)
- Demenz (1)
- Density equalizing mapping (1)
- Density-equalizing mapping (1)
- Dental air (1)
- Dental casts (1)
- Dental implant (1)
- Dental implants (1)
- Dental practice (1)
- Dental students (1)
- Determination method (1)
- Developmental disorders (1)
- Diabetes mellitus (1)
- Diagnosis (1)
- Diagnosis related groups (1)
- Diagnostic algorithm (1)
- Diagnostic error (1)
- Diagnostic markers (1)
- Differential diagnosis (1)
- Diffuse large B-cell lymphoma (1)
- Disabilities (1)
- Disaster victim identification (1)
- Disc herniation (1)
- Diseases (1)
- Disintegration (1)
- Distress screening (1)
- Distribution limits (1)
- Dopamine (1)
- Double suicide (1)
- Double-blind placebo-controlled trial (1)
- Douleur (1)
- Downy mildew (1)
- Dravet syndrome (1)
- Drug permeability (1)
- Drug susceptibility testing (1)
- Dural onlays (1)
- Dysphagia (1)
- Désir d’enfant (1)
- E-NTPDase (1)
- E3 ligase (1)
- EBM (1)
- EEG reference choices (1)
- EGFR (1)
- EGFR pathway (1)
- EGFRvIII mutation (1)
- EGR1-dependent transcription (1)
- ELISA (1)
- EMR1 (1)
- EMT (1)
- EQIP (1)
- ERBB2 (HER2/neu) (1)
- ERK3 (1)
- ES (1)
- ESMO-MCBS (1)
- Early intervention (1)
- Ebola virus (1)
- Echovirus-30 (1)
- Ecto-5'-nucleotidase (1)
- Edoxaban (1)
- Education (1)
- Einstellungen (1)
- Einwilligungsfähigkeit (1)
- Eisenmangel (1)
- Ejection fraction (1)
- Elderly (1)
- Electrical stimulation (1)
- Embryos (1)
- Emergency treatment (1)
- Emotions (1)
- End-of-life decisions (1)
- Endocrinology (1)
- Endometrial carcinoma (1)
- Endometriome (1)
- Endométriomes (1)
- Endothelial cells (1)
- Endothelial protein C receptor (1)
- Endovaskuläre Versorgung (1)
- Endpoints (1)
- Enterobacteriaceae (1)
- Entscheidungsassistenz (1)
- Epidemiological data (1)
- Epidural abscess (1)
- Epigenetics (1)
- Epilepsie (1)
- Episodic memory (1)
- Epstein-Barr virus (1)
- Erdnussallergie (1)
- Ergonomic analysis (1)
- Ergonomie am Arbeitsplatz (1)
- Ergonomische Analyse (1)
- Erregerspektrum der Tonsillitis (1)
- Erwachsene (1)
- Evaluation (1)
- Evidence based medicine (1)
- Evidence-based dentistry (1)
- Evidence-based medicine (1)
- Evidenzbasierte Medizin (1)
- Ewing sarcoma (1)
- Exercise challenge (1)
- Exercise therapy (1)
- Exercise-induced asthma (1)
- Exhaled nitric oxide (1)
- External-/self-assessment (1)
- Eye movements (1)
- Eye tracking (1)
- F4/80 (1)
- F508del homozygous (1)
- FBK-R23 (1)
- FDM (1)
- FET (1)
- FEV1 (1)
- FFF (1)
- FHIR (1)
- FLT3-ITD (1)
- FTMT (1)
- Factor H (1)
- Fasting (1)
- Feedback (1)
- Female subjects (1)
- Ferritinophagy (1)
- Ferroptose (1)
- Ferroptosis (1)
- Fertilität (1)
- Fertilité (1)
- Fibromyalgia (1)
- Finevo (1)
- Fingolimod (1)
- First-line regimen (1)
- Five-Konzept (1)
- Fluid therapy (1)
- Forced expiratory volume in 1 s (1)
- Forensic entomology (1)
- Forensic examination (1)
- Fourier analysis (1)
- Fracture (1)
- Fracture type (1)
- Fragebogenentwicklung (1)
- Fresh frozen plasma (1)
- Functional characterization (1)
- Functional clustering (1)
- Functional mitral regurgitation (1)
- G-CSF (1)
- G-protein-coupled receptors (1)
- G2A receptor (1)
- GABA (1)
- GCN (1)
- GFAP (1)
- GHQ-28 (1)
- GIRD (1)
- GLA deficiency (1)
- GPCR (1)
- GWAS (1)
- Gait analysis (1)
- Gas gangrene (1)
- Gastrocnemius muscles (1)
- Gastroschisis (1)
- Gene expression prediction (1)
- Genetic heart disease (1)
- Genetic syndromes (1)
- Geoffrey Burnstock (1)
- Geographical disparities (1)
- Gerontologie (1)
- Geschichte 1663-1748 (1)
- Geschlecht (1)
- Gesundheit (1)
- Gesundheitsamt (1)
- Gesundheitsberichterstattung (1)
- Gesundheitsbildung (1)
- Gesundheitserziehung (1)
- Gesundheitsförderung (1)
- Gesundheitswissenschaften (1)
- Glioblastom (1)
- Global warming (1)
- Graph theory (1)
- Gray matter volume (1)
- Green Tobacco Sickness (GTS) (1)
- Greenhouse effect (1)
- Guided bone regeneration (GBR) (1)
- Guided tissue regeneration (GTR) (1)
- HADS (1)
- HAE (1)
- HBV filaments (1)
- HBV genotypes (1)
- HBV surface protein (1)
- HCC (1)
- HCC recurrence (1)
- HCV (1)
- HDAC (1)
- HDAC and BET inhibitor (1)
- HDAC inhibitor (1)
- HDAC4 (1)
- HEUS (1)
- HEV (1)
- HFrEF (1)
- HHUSD (1)
- HIBCPP cells (1)
- HIFT (1)
- HILI (1)
- HIV-1 escape restriction (1)
- HLA DQ haplotypes (1)
- HLA class I (1)
- HNSCC (1)
- HOSO (1)
- HRM (1)
- Haematocrit (1)
- Haemodynamic monitoring (1)
- Hausarztmangel (1)
- HbA1c (1)
- HeLa cells (1)
- Health care (1)
- Health care sector (1)
- Health education and awareness (1)
- Health literacy (1)
- Health policy (1)
- Health services (1)
- Healthcare costs (1)
- Healthcare resource utilization (1)
- Health‐related quality of life (1)
- Heat shock protein 27 (1)
- Hematologic malignancies (1)
- Hematoxylin staining (1)
- Hemispheric specialization (1)
- Hemodynamics (1)
- Hepatic encephalopathy (1)
- Hepatitis C virus (1)
- Heregulin (1)
- Heterogeneity (1)
- HiC (1)
- HiChIP (1)
- High oblique sagittal osteotomy (1)
- Hippocampal excitability (1)
- Hippocampus (1)
- Histological analysis (1)
- Histology (1)
- Histoplasma qPCR (1)
- History (1)
- Hmox1 (1)
- HoLEP (1)
- Hodgkin lymphoma (1)
- Hodgkin’s lymphoma (1)
- Homicide-suicide (1)
- Homizid-Suizid (1)
- Hospital case volume (1)
- Hospitalization (1)
- House dust mite allergy (1)
- Human (1)
- Human immunodeficiency virus (HIV) (1)
- Hymenoptera venom immunotherapy (1)
- Hyperactivity (1)
- Hyperscanning (1)
- Hyponatremia (1)
- Hypoxia-inducible factor-1α (HIF-1α) (1)
- Höchstrichterliche Rechtsprechung (1)
- ICAM-1 (1)
- ICD (1)
- IDH1 inhibitor (1)
- IDO1 (1)
- IFA (1)
- IFN-γ expression (1)
- IKKε (1)
- IL-1β (1)
- IL-6 (1)
- ISR (1)
- IV iron (1)
- IVD degeneration (IVDD) (1)
- Iatrochemie (1)
- Iatrochemistry (1)
- Identification (1)
- Identifikation (1)
- Identifizierung von Katastrophenopfern (1)
- Idiopathische Dystonie (1)
- IgG (1)
- Image processing (1)
- Image processing (computer-assisted) (1)
- Immune suppression (1)
- Immune system (1)
- Immunomodulatory agents (1)
- Immunotherapy (1)
- Implant osseointegration (1)
- Implementación (1)
- Implementation (1)
- Imrt (1)
- In vivo (1)
- Induced membrane technique (1)
- Inducible nitric oxide synthase (iNOS) (1)
- Induction chemotherapy (1)
- Inertial motion capture (1)
- Infektionen (1)
- Inferior colliculus (1)
- Inflammatory bowel disease (1)
- Inflammatory pattern (1)
- Injury (1)
- Injury Severity Score (ISS) (1)
- Innate immunity (1)
- Integrated Pulmonary Index (1)
- Integration (1)
- IntelliCage (1)
- Intelligence (1)
- Intensive care (1)
- Interferons (1)
- Internet (1)
- Interoperability (1)
- Interposition (1)
- Interstitial pneumonia (1)
- Interview (1)
- Intoxication (1)
- Intoxikation (1)
- Intravenous antibiotic therapy (1)
- Intravenous injections (1)
- Invasive species (1)
- Ireb2 (1)
- Iron (1)
- Isocitrate dehydrogenase (1)
- JNK (1)
- Joint actions (1)
- Joint loading (1)
- Jumping (1)
- K-homology RNA-binding domain (1)
- KOOS IV (1)
- Ki-67/MIB1 (1)
- Ki67 transgenic c‐myc/TGFα mice (1)
- Kidney diseases (1)
- Kidney neoplasm (1)
- Kinder (1)
- Kinderwunsch (1)
- Kinds of diseases (1)
- Kinematic analysis (1)
- Knees (1)
- Kognitive Beeinträchtigungen (1)
- Konzeptpapier (1)
- Krankenhausfallaufkommen (1)
- Krankheitskosten (1)
- Körpermaße (1)
- Körpermodifizierung (1)
- L-DOPA (1)
- LBP (1)
- LIR interaction, (1)
- LPS (1)
- Lactobacillus (1)
- Landarztprogramm (1)
- Langstreckige Knochendefekte (1)
- Language delay (1)
- Late gadolinium enhancement (1)
- Left hemisphere (1)
- Legal considerations (1)
- Legs (1)
- Lennox-Gastaut syndrome (1)
- Leukemia (1)
- Leukämie (1)
- Lipodystrophy (1)
- Liver transplant (1)
- Local IgE (1)
- Local allergic rhinitis (1)
- Locally advanced (1)
- Lockdown (1)
- Loco-regional control (1)
- Long non-coding RNAs (1)
- Longchain polyunsaturated fatty acids (1)
- Loving kindness meditation (1)
- Low-dose ionizing radiation (1)
- Low-dose radiation therapy (1)
- Lower back pain (1)
- Lung cancer (1)
- Lung development (1)
- Lung function (1)
- Lung ultrasound (1)
- Lungenerkrankungen (1)
- Lymph nodes (1)
- Lymphocytes (1)
- Lymphoma (1)
- Lysophosphatidic acids (1)
- M. Intracellulare (1)
- M. avium (1)
- M. avium complex (1)
- M. chimaera (1)
- MAGGIC score (1)
- MAPK6 (1)
- MCAO (1)
- MHC (1)
- MICA (1)
- MM-121 (1)
- MMP14 (1)
- MODY (1)
- MR-spectroscopy (1)
- MS (1)
- MYC (1)
- Machine learning algorithms (1)
- Machine-learning (1)
- Macroautophagy (1)
- Macrophage polarization (1)
- Malaria (1)
- Mammakarzinom (1)
- Management (1)
- Marker genes (1)
- Market Access (1)
- Masquelet technique (1)
- Mass disaster (1)
- Massenkatastrophe (1)
- Massenspektrometrie (1)
- Master Plan 2020 (1)
- Masterplan 2020 (1)
- Maxillofacial surgery (1)
- Mean erythrocyte volume (1)
- Medical education (1)
- Medical implants (1)
- Medical law (1)
- Medical risk factors (1)
- Medical studies (1)
- Medicinal chemistry (1)
- Medizin (1)
- Medizinrecht (1)
- Medizinstudierende (1)
- Medizinstudium (1)
- Meldepflicht (1)
- Membrane potential (1)
- Memory consolidation (1)
- Memory quality (1)
- Mesenchymal stromal cells (MSC) (1)
- Mesh (1)
- Meta-analysis (1)
- Metabolic diseases (1)
- Metastatic (1)
- Metta (1)
- Michael acceptor (1)
- MicroRNA-181a (1)
- Microbiology (1)
- Microfluidics (1)
- Microglial cells (1)
- Microparticles (1)
- Microphysiological models (1)
- Microstates (1)
- Midwifery (1)
- Mindfulness (1)
- Minimally invasive surgical procedures (1)
- Minor injury (1)
- Mitochondrial dysfunction (1)
- MitraClip (1)
- Mobilization (1)
- Molecular autopsy (1)
- Molecular diagnostic testing (1)
- Molecular neuroscience (1)
- Monetary incentive delay (1)
- Mongolian spot (1)
- Monitoring (1)
- Monocytes (1)
- Morphologie (1)
- Motivational situation (1)
- Motivationslage (1)
- Motor control (1)
- Motor cortex (1)
- Mouse models (1)
- Mucomaix® matrix (1)
- Multidrug-resistance (1)
- Multimedication (1)
- Multimorbidity (1)
- Multiparametric MRI (1)
- Multiplate (1)
- Multiple Sklerose (1)
- Multiple-indication review (1)
- Mundhöhlenkarzinome (1)
- Muscle functions (1)
- Musculoskeletal diseases (1)
- Muskuloskelettale Erkrankungen (1)
- Mutation databases (1)
- Muttermilch (1)
- Mutual information (1)
- Myocardial infarction (MI) (1)
- Myocardial injury (1)
- Myocardial segmentation (1)
- Myonecrosis (1)
- Mφs (1)
- N-glycoproteome (1)
- N2 (1)
- NAFL (1)
- NCOA4 (1)
- NCoR1 (1)
- NDBI (1)
- NF-κB (1)
- NF-κB pathway (1)
- NF-кB (1)
- NIRS (1)
- NK-ZELL-BASIERTER IMMUNTHERAPIE (1)
- NK-ZELLEN (1)
- NKG2D (1)
- NLRP3 inflammasomes (1)
- NMES (1)
- NMR spectroscopy (1)
- NOTCH (1)
- NPH insulin (1)
- NREM sleep (1)
- NS1608 (1)
- NSE (1)
- NTM (1)
- Nachtschattengewächs (1)
- Natural sounds (1)
- Necrotizing fasciitis (1)
- Negative appendectomy rate (1)
- Nek1 (1)
- Neonatal brain damage (1)
- Neonatal surgery outcome (1)
- Nephrectomy (1)
- Nesplora Aquarium (1)
- Network models (1)
- Network motifs (1)
- Neural circuits (1)
- Neural networks (1)
- Neurocognition (1)
- Neurodegeneration (1)
- Neurodevelopmental disorders (1)
- Neuron (1)
- Neuronal plasticity (1)
- Neuropathic pain (1)
- Neurophysiology (1)
- Neuropsychological testing (1)
- Neuropsychology (1)
- Neuroscience (1)
- Neurosurgery (1)
- Neurotransmitter (1)
- Nevus of Ito (1)
- Nevus of Ota (1)
- Next-generation sequencing (1)
- Nicotine (Nicotiana tabacum/ Nicotiana rustica) (1)
- Nicotinic acetylcholine receptors (1)
- Nikotin (Nicotiana tabacum/ Nicotiana rustica) (1)
- Nikotinerge Acetylcholinrezeptoren (1)
- Nivolumab (1)
- Non-abusive head trauma (NAHT) (1)
- Non-allergic-rhinitis (1)
- Non-apoptotic functions (1)
- Non-clear cell renal cell cancer (1)
- Non-small cell lung cancer (1)
- Non-tuberculous mycobacteria (1)
- Non-vitamin K antagonist oral anticoagulants (1)
- Nordic questionnaire (1)
- Normal distribution (1)
- Normative modeling (1)
- NoxO1 (1)
- Number of platelets (1)
- OGTT (1)
- OR time (1)
- OSA (1)
- OTSC Proctology (1)
- Obduktion (1)
- Obstetrics (1)
- Omphalocele (1)
- Oncology (1)
- Open Access (1)
- Opioids (1)
- Oppositional defant disorder (1)
- Optogenetics (1)
- Oral anticoagulation (1)
- Oral cancer (1)
- Organoids (1)
- Orphan nuclear receptor (1)
- Orthognathic surgery (1)
- Oryctolagus cuniculus (1)
- OspE (1)
- Osteoarthritis (1)
- Osteonecrosis (1)
- Outcomes (1)
- Ovarian cancer treatment (1)
- Ovarielle Reserve (1)
- Ovartoxizität (1)
- Overwintering (1)
- Oxygen (1)
- PARK2 (1)
- PBMC (peripheral blood mononuclear cells) (1)
- PBPK (1)
- PD-1 inhibitor (1)
- PDE inhibition (1)
- PDE‐5‐inhibitor (1)
- PEA-15 (1)
- PHGDH (1)
- PI3K/mTor inhibition (1)
- PKD (1)
- PKD/IC (1)
- PLSC (1)
- PRNT (1)
- PROM (1)
- PRRT2 (1)
- PSA screening (1)
- PSA-Screening (1)
- PV loop (1)
- PWI (1)
- PYGL (1)
- Paediatric trauma patients (1)
- Pain (1)
- Pain sensation (1)
- Palliative care (1)
- Parasympathetic (1)
- Parkinson's disease (1)
- Pathogenesis (1)
- Pathologists (1)
- Patient information materials (1)
- Patient outcome assessment (1)
- Patient reported outcomes (1)
- Patient safety (1)
- Patterns of care (1)
- Peanut allergy (1)
- Pediatric patients (1)
- Peer review (1)
- Pelvic (1)
- Percutaneous endoscopic gastrostomy (1)
- Performance Metrics (1)
- Pericardial effusion (1)
- Pericarditis (1)
- Periodontitis grades B and C (1)
- Periprocedural anticoagulation (1)
- Perrault syndrome (1)
- Persistent depressive disorder (1)
- Pgrmc1 (1)
- Phalangeal fractures (1)
- Pharma Management (1)
- Pharmaceutical (1)
- Pharmacology (1)
- Phase I clinical trial (1)
- Phase II trial (1)
- Phase rotors (1)
- Phenotypic plasticity (1)
- Philemon and Baucis (1)
- Philemon und Baucis (1)
- Phosphoproteome (1)
- Phylogeny (1)
- Physical activity (1)
- Physician-assisted suicide (1)
- Physicians (1)
- Pim-1 (1)
- Plantagearbeiter (1)
- Plantation workers (1)
- Plasma transfusion (1)
- Plasma usage (1)
- Platelet-rich fibrin (1)
- Polygenic risk score (1)
- Polypharmacy (1)
- Polysomnography (1)
- Polytrauma (1)
- Portal hypertension (1)
- Portal veins (1)
- Post mortem interval (1)
- Posture (1)
- Pp (1)
- Ppk (1)
- Praktisches Jahr (1)
- PreS1 deletion (1)
- Preclinical drug development (1)
- Prediction (1)
- Premotor cortex (1)
- Pressure distribution (1)
- Pressure measuring plate (1)
- Prevalence (1)
- Prevention (1)
- Pre‐Ligand Assembly Domain (PLAD) (1)
- Primary breast lymphoma (1)
- Primary care (1)
- Primary health care (1)
- Probability density (1)
- Probability distribution (1)
- Procalcitonin (1)
- Procedural skills (1)
- Process Capability (1)
- Process Performance (1)
- Process Validation (1)
- Professions (1)
- Progestatifs synthétiques (1)
- Prostata-specific antigen (1)
- Prostataspezifisches Antigen (1)
- Prostate cancer (1)
- Protease inhibitor therapy (1)
- Proteasome inhibitor (1)
- Protestantism (1)
- Prototypes (1)
- Präanalytik (1)
- Prävention (1)
- Pseudoprogression (1)
- Psycho-oncology (1)
- Psychological stress (1)
- Psychologische Beeinträchtigung (1)
- Psychology (1)
- Psychopharmaka (1)
- Psychosocial impact (1)
- Pteridine (1)
- Pulmonary edema (1)
- Pulmonary embolism (1)
- Pulmonary hypertension (1)
- Pulmonary hypoplasia (1)
- QOL (1)
- Qb-Test (1)
- QbTest® (1)
- Qualitative research (1)
- Quality Control (1)
- Quality indicators (1)
- Qualitätsindikatoren (1)
- Quantitative (q)T2 mapping (1)
- Quantitative magnetic resonance imaging (1)
- Quantitative research (1)
- Quantra (1)
- Quarantine (1)
- Questionnaire (1)
- Questionnaires (1)
- Quinolones (1)
- R406 (1)
- RAS (1)
- RBC (1)
- RBFOX1 (1)
- RDoC (1)
- RIPK1 (1)
- RNA chaperone (1)
- RNA structures (1)
- RNA therapeutics (1)
- RNAseq analysis (1)
- RRMS (1)
- RUCAM (1)
- RULA (1)
- Radiation exposure (1)
- Radical cystectomy (1)
- Radiotherapy (1)
- Radiothérapie (1)
- Ramadan (1)
- Randomised trial (1)
- Randomized controlled trial (1)
- Randomized controlled trials (1)
- Randomized trial (1)
- Rapid diagnostic test (1)
- Ratgeber (1)
- Real-time phase contrast (1)
- Rechtliche Würdigung (1)
- Rectal cancer (1)
- Reference values (1)
- Referenzwerte (1)
- Refractory ALL (1)
- Refractory AML (1)
- RegJoint™ (1)
- Regeneration (1)
- Regret (1)
- Regulatory Affairs (1)
- Relaxometrie (1)
- Reliability (1)
- Renal replacement therapy (1)
- Rescue medication (1)
- Research & Development (1)
- Research investment (1)
- Respiration (1)
- Respiratory distress syndrome (1)
- Resting-state (1)
- Retinal diseases (1)
- Retinoic acid (1)
- Retrospective studies (1)
- Return to work (1)
- Review (1)
- Reward (1)
- Rezidiv (1)
- Rhabdomyosarkom (1)
- Rheumatoid arthritis (1)
- Right hemisphere (1)
- Risk factors (1)
- Risk-stratification (1)
- Robotik (1)
- Roussel Uclaf Causality Assessment Method (1)
- Roux-en-Y gastric bypass (1)
- Running (1)
- Rush protocol (1)
- Récidive (1)
- Réserve ovarienne (1)
- S100b (1)
- S1P lyase (1)
- S1P receptors (1)
- S1P1–5 (1)
- S1PR4 (1)
- SARS‐CoV‐2 (1)
- SCA2 (1)
- SCN5A (1)
- SEAP (1)
- SENP (1)
- SF-36 (1)
- SIDS (1)
- SIRS (1)
- SKI II (1)
- SLC20A1 (1)
- SLUG (1)
- SMAD (1)
- SNORD95 (1)
- SPC (1)
- SPSS (1)
- STAT3 (1)
- SUMO (1)
- Safety (1)
- Sarcoidosis (1)
- Sarcomas (1)
- Sarkoidose (1)
- Saudi Arabia (1)
- Scaffold (1)
- Schlaganfall (1)
- Schmerz (1)
- Schädel-MRT (1)
- Seattle heart failure model (1)
- Second donation (1)
- Secular trend (1)
- Selbstmordpakt (1)
- Self-expandable TAVI (1)
- Seltene Erkrankungen (1)
- Semitendinosus tendon autograft (1)
- Senescence (1)
- Sensorimotor processing (1)
- Sepsis (1)
- Seribantumab (1)
- Serin (1)
- Serious injured children (1)
- Seroconverter (1)
- Seroprevalence (1)
- Serum biomarker (1)
- Sex (1)
- Sharp injuries (1)
- Shoulder injury (1)
- Shoulder luxation (1)
- Sialic acid (1)
- Sialinsäure (1)
- Side effects (1)
- Signal intensity (1)
- Signs and symptoms (1)
- Single-Molecule Localization Microscopy (SMLM) (1)
- Slc11a2 (1)
- Slc25a37 (1)
- Sleep (1)
- Sleep deprivation (1)
- Smac mimetic (1)
- Small molecules (1)
- Social brain (1)
- Social differences (1)
- Social information processing (1)
- Social participation (1)
- Socio-economic analysis (1)
- Socioeconomic analysis (1)
- Socioeconomic indices (1)
- Soft tissue infection (1)
- Software tools (1)
- Solanaceae (1)
- Sozialwissenschaften (1)
- Speech (1)
- Spine fractures (1)
- Spinocerebellar ataxia type 2 (1)
- Sports and exercise medicine (1)
- Stage at presentation (1)
- Standard dataset (1)
- Standard reference values (1)
- Standard value (1)
- State of Control (1)
- Statisitcal Control (1)
- Statisitcal Process Control Chart (1)
- Statistical data (1)
- Status epilepticus (1)
- Stem cell (1)
- Stereoelektroenzephalographie (1)
- Stereotaxie (1)
- Sterols (1)
- Stiffness (1)
- Streptokokken (1)
- Striatum (1)
- Stroke genetics (1)
- Störfaktoren (1)
- Sub-segmentation (1)
- Sub-zero exposure (1)
- Sudden death (1)
- Sudden infant death syndrome (1)
- Sunitinib (1)
- Supported Decision-making (1)
- Supreme court ruling (1)
- Surgeons (1)
- Surgery (1)
- Surgical and invasive medical procedures (1)
- Surgical therapy (1)
- Surveys (1)
- Suspension (1)
- Swallowing (1)
- Syllables (1)
- Sympathetic (1)
- Symptome (1)
- Synaptic plasticity (1)
- Synaptic transmission (1)
- Synthetische Gestagene (1)
- Systematic reviews (1)
- Szientometrie (1)
- Säkularer Trend (1)
- T cell receptor (1)
- T cells (1)
- T-Zellen (1)
- T-cell receptor (1)
- T-tubule system (1)
- T1 and T2 mapping (1)
- T2 (1)
- TAMs (1)
- TAPSE (1)
- TBK1 (1)
- TBSS (1)
- TDM (1)
- TGF-beta (1)
- TGF-β (1)
- TGFβ (1)
- TGR(mREN2)27 (1)
- THV (1)
- TLR2/6 (1)
- TRIMs (1)
- TRPA1 (1)
- TSC22D3 (1)
- TVT (1)
- Tabakkonsum (1)
- Tagging (1)
- Tamponade (1)
- Target validation (1)
- Targeted sequencing (1)
- Temsirolimus (1)
- Tendon incontinence repair (1)
- Tendon transplantation (1)
- Tendons (1)
- Tennis player (1)
- Terminology (1)
- Test assay (1)
- Tfrc (1)
- Therapie (1)
- Therapies (1)
- Therapy (1)
- Thrombotic thrombocytopenic purpura (1)
- Thrombozytenkonzentrat (1)
- Thrombozytentransfusion (1)
- Thumb carpometacarpal joint osteoarthritis (1)
- Tissue engineering (1)
- Tocilizumab (1)
- Todesart (1)
- Toll-like receptor (1)
- Tonsillitis (1)
- Torque (1)
- Total hip arthroplasty (1)
- Touchscreen (1)
- Toxicité ovarienne (1)
- Training history (1)
- Transcatheter Aortic Valve Implantation (1)
- Transcription regulation (1)
- Transcriptional regulatory elements (1)
- Transcriptome analysis (1)
- Transfusion practice (1)
- Transfusionszwischenfall (1)
- Transgenic mice (1)
- Transitional cell carcinoma (1)
- Translation proteomics (1)
- Transportation (1)
- TraumaRegister DGU® (TR-DGU) (1)
- Treatment costs (1)
- Treatment effectiveness (1)
- Treatment modification (1)
- Treatment rates (1)
- Treg (1)
- Treg cell (1)
- Trend Analysis (1)
- Trypanosoma brucei (1)
- Tumor marker (1)
- Tumor microenvironment (1)
- Tumormarker (1)
- Tumormikromilieu (1)
- Type 2 diabetes (1)
- Type of death (1)
- ULK4 (1)
- UPPS (1)
- USP28 (1)
- UV/Vis spectroscopy (1)
- Ubiquitin (1)
- Ubiquitin ligase (1)
- Ubiquitinome (1)
- Ulcerative colitis (1)
- Ultra-rush protocol (1)
- Umfrage (1)
- Unc-51-like kinase (1)
- Uncertainty (1)
- Undergraduate education (1)
- Undergraduates (1)
- Unfälle (1)
- Upper body posture (1)
- Urothelial cancer (1)
- VHH (1)
- VIGALL (1)
- VIM (1)
- VLA4 (1)
- Vascular endothelial growth factor (VEGF) (1)
- Veins (1)
- Venous thromboembolism (1)
- Ventricular arrhythmia (1)
- Ventricular arrhythmias (1)
- Vespid venom allergy (1)
- Videorasterstereography (1)
- Viral infection (1)
- Vmem (1)
- Volume therapy (1)
- Volumetrie (1)
- Volunteer donor (1)
- Vorsorgeuntersuchung (1)
- Voxel-based morphometry (VBM) (1)
- Watertight Dural closure (1)
- Wearable cardioverter‐defibrillator (1)
- Western diet (1)
- Winter survival (1)
- Wissenschaftstheorie (1)
- Workplace ergonomics (1)
- Wound care (1)
- Wound healing (1)
- Wounds (1)
- Wundversorgung (1)
- YM155 (1)
- YWHAE (1)
- YWHAZ (1)
- Year of practical training (1)
- Yellow fluorescent protein (1)
- Zink (1)
- [18F]FET PET (1)
- abnormality detection (1)
- abuse (1)
- abuso (1)
- academic medicine (1)
- acetylation (1)
- acetylcholine (1)
- acetylcholinesterase (1)
- acid dentine lysate (1)
- acidosis (1)
- acoustic emission (1)
- acquired drug resistance (1)
- actin dynamics (1)
- action sounds (1)
- action-effect association (1)
- activated clotting time measurement (1)
- activities of daily life (1)
- activity-based benefits (1)
- acupuncture (1)
- acute coronary syndromes (1)
- acute decompensation (1)
- acute decompensation of cirrhosis (1)
- acute kidney injury (1)
- acute myeloid leukaemia (1)
- acute respiratory distress syndrome (1)
- acute-on-chronic liver failure (ACLF) (1)
- acute‐on‐chronic liver failure (1)
- adaptive cardiac remodelling (1)
- adaptive immunity (1)
- adenovirus (1)
- adhesion (1)
- adiabatic saturation (1)
- adipose-derived mesenchymal stem/stromal cells (1)
- adjuvante Krebstherapie (1)
- adolescentes (1)
- adoptive cancer immunotherapy (1)
- adrenoceptors (1)
- adult and elderly patients (1)
- advanced care planning (1)
- adverse events (1)
- aerobic exercise (1)
- affective disorder (1)
- affective disorders (1)
- affinity purification (1)
- aftercare structures (1)
- age (1)
- aggressiveness (1)
- air flow (1)
- alcohol use disorder (1)
- alcoholic hepatitis (1)
- algorithm (1)
- alirocumab (1)
- alkaloid (1)
- allergy (1)
- allocation (1)
- allogeneic donor (1)
- allogeneic hematopoietic stem cell transplantation (1)
- alpha power (1)
- alpha-galactosidase A deficiency (1)
- alpharetroviral vector (1)
- alternative matrices (1)
- alternative oxidase (1)
- amblyopia (1)
- amino acid PET (1)
- amlexanox (1)
- amyloid beta-peptides (1)
- amyotrophic lateral sclerosis (ALS) (1)
- anaemia walk-in clinic (1)
- anal cancer (1)
- anemia (1)
- angiography (1)
- angiokeratoma diffuse (1)
- animal (1)
- animal model (1)
- annual bleeding rate (1)
- anti-chronic myeloid leukemia (1)
- anti-diabetes (1)
- anti-inflammatory agents (1)
- anti-inflammatory drug (1)
- anti-inflammatory effects (1)
- anti-skin aging (1)
- anti-tumor activity (1)
- antibiotic treatment (1)
- antibody tests (1)
- anticoagulation (1)
- antigen (1)
- antigen processing and presentation (1)
- antigenic variation (1)
- antigens of infectious origin (1)
- antioxidant defense (1)
- antioxidants (1)
- antireflux surgery (1)
- antiresorptive agents (1)
- antiseizure (1)
- antiviral (1)
- antiviral peptide (1)
- anxiety disorder (1)
- aprotinin (1)
- aptamers (1)
- arachidonate 12/15-lipoxygenase (Alox12/15) (1)
- arousal (1)
- artesunate (ART) (1)
- artificial intelligence (1)
- ascites (1)
- aspiration (1)
- aspirin (1)
- asthma (1)
- asthma phenotypes (1)
- astrogliosis (1)
- asymptomatic (1)
- ataxia telangiectasia (1)
- athletes (1)
- atopy (1)
- attention module (1)
- attention-deficit/hyperactivity disorder (1)
- atypical MAPK kinase (1)
- auditory cortex (1)
- auditory fMRI (1)
- auditory prediction (1)
- auditory processing (1)
- autism (1)
- autism spectrum disorder (1)
- autograft (1)
- autoimmune diabetes (1)
- autoimmune polyglandular syndrome type 2 (1)
- autoimmune thyroiditis (1)
- autoreactivity (1)
- back pain diagnosis (1)
- bacteria (1)
- bacterial translocation (1)
- balloon pulmonary angioplasty (1)
- barbell training (1)
- basal insulin (1)
- behavioral adverse events (1)
- benchmark standards (1)
- berotralstat (1)
- biglycan (1)
- bio imaging (1)
- bio-enabling formulations (1)
- bioactive lipids (1)
- bioavailability (1)
- biobank (1)
- biological maturation (1)
- bioluminescence (1)
- biomarker study (1)
- biopsy naïve (1)
- bipolare Störung (1)
- bladder cancer (BCa) (1)
- bladder exstrophy-epispadias complex (1)
- blinatumomab (1)
- blood (1)
- blood flow recovery (1)
- blood flow restriction (1)
- blood loss (1)
- blood pressure (1)
- blood transfusion (1)
- blood-brain barrier (1)
- blood-cerebrospinal fluid barrier (1)
- body dysmorphic disorder (1)
- body plethysmography (1)
- bone healing (1)
- bone marrow (1)
- bone marrow mononuclear cells (1)
- bone tissue regeneration (1)
- brain (1)
- brain anatomy (1)
- brain function (1)
- brain metastases (1)
- brain shift (1)
- brain tumor (1)
- brain-derived neurotrophic factor (1)
- brainstem (1)
- broad-range qPCR (1)
- broadly neutralizing antibodies (1)
- bronchiolitis obliterans syndrome (1)
- buccal mucosal graft urethroplasty (1)
- bundle (1)
- butyrylcholinesterase (1)
- bypass (1)
- cART (1)
- cBioPortal (1)
- cHL (1)
- caesarean scar (1)
- caesarean section (1)
- calcium handling (1)
- calcium-sensor (1)
- cancer associated fibroblasts (1)
- cancer immunobiology (1)
- cancer information (1)
- cancer specific survival (1)
- candidemia (1)
- canine cancer (1)
- cannabidiol (1)
- cannabinoids (1)
- cannabis (1)
- capsaicin (1)
- carbapenem resistance (1)
- carbapenemase (1)
- carcinoma (1)
- cardiac (1)
- cardiac I/R injury (1)
- cardiac ischaemia‐reperfusion (1)
- cardiac magnetic (1)
- cardiac rehabilitation (1)
- cardiomyopathy (1)
- cardiothoracic surgery (1)
- career promotion (1)
- cartilage oligomeric matrix protein (1)
- catheter (1)
- cell and focal adhesion (1)
- cell death (1)
- cell motility (1)
- cell proliferation (1)
- cell survival (1)
- cell-free expression (1)
- cells (1)
- cellular immunology (1)
- cellular reaction (1)
- cellular therapy (1)
- central nervous system (1)
- ceramides (1)
- cerebellum (1)
- cerumen (1)
- cervical cancer (1)
- cetuximab-bevacizumab therapy sequence (1)
- changes immune activation (1)
- chaperones (1)
- chelation therapy (1)
- chemokine receptor 4 (1)
- chemokines (1)
- chemoprotection (1)
- chemotaxis (1)
- chemotherapeutics-treated (1)
- chemotherapy (1)
- chest trauma (1)
- children and adolescents (1)
- chloroplasts (1)
- cholestasis (1)
- cholesterol (1)
- cholinesterase (1)
- chronic coronary artery disease (1)
- chronic illness (1)
- chronic inflammation (1)
- chronic kidney disease (1)
- chronic liver disease (1)
- chronic low back pain (1)
- chronic metabolic acidosis (1)
- chronic myeloid leukemia (1)
- chronic thromboembolic pulmonary hypertension (1)
- chronic total occlusion (1)
- chronische Niereninsuffizienz (1)
- chronische metabolische Azidose (1)
- circulation (1)
- cisplatin resistance (1)
- cisplatin sensitivity (1)
- classical Hodgkin lymphoma (1)
- clinical (1)
- clinical benefit (1)
- clinical history (1)
- clinical immunology (1)
- clinical pathways (1)
- clinical study (1)
- clinically important restrictions and symptoms (1)
- cloacal malformation (1)
- clock genes (1)
- clopidogrel (1)
- clustering (1)
- co-crystallization (1)
- coagulation (1)
- cochlear implant (1)
- coffee (1)
- cognitive aging (1)
- cognitive decline (1)
- coherence (1)
- collagen type I (1)
- collagen-based matrix (1)
- collateral growth (1)
- colon carcinoma (1)
- colorectal cancer (1)
- colorectal cancer (CRC) (1)
- combined therapy (1)
- common genetic variation (1)
- common variants (1)
- comparative oncology (1)
- comparative pathology (1)
- competition fear (1)
- complement; patients (1)
- complex IV (1)
- computational biology (1)
- computational neuroimaging (1)
- computed tomography (1)
- computer vision (1)
- computer-aided diagnosis (1)
- computer-assisted (1)
- conduct disorder (1)
- confidence (1)
- consolidation treatment (1)
- contact heat evoked potentials (CHEPS) (1)
- contamination (1)
- contralateral delay activity (1)
- coping (1)
- coronary artery bypass surgery (1)
- coronary artery disease (1)
- coronavirus disease 2019 (1)
- cortex (1)
- cortex, gray matter (1)
- cortical folding (1)
- cortisol (1)
- cost-of-illness (1)
- covalent drugs (1)
- covalent inhibitors (1)
- cranberry (1)
- crepitation (1)
- crepitus (1)
- critical care (1)
- cross fitness (1)
- cryogenic electron microscopy (1)
- cyclin Y (1)
- cyclooxygenase 2 (1)
- cyclophosphamide (1)
- cytarabin (1)
- cytokine gene expression (1)
- cytokine storm (1)
- cytokine-induced killer cells (1)
- cytotoxic lymphocytes (1)
- dapagliflozin (1)
- data projection (1)
- day clinic (1)
- debris (1)
- decision making (1)
- decision support systems (1)
- decision-making (1)
- declaration of tobacco ingredients (1)
- decorin (1)
- deep fascia (1)
- deep mutational scanning (1)
- deep sedation (1)
- deferred treatment (1)
- delayed auditory feedback (1)
- delayed treatment (1)
- demineralized bone matrix (1)
- dendritic cells (1)
- dental assistants (1)
- dental emergency treatment (1)
- dentin adhesives (1)
- dentist (1)
- dentistry (1)
- dentists (1)
- depressive symptoms clusters (1)
- detoxification (1)
- deubiquitinating enzyme (1)
- development (1)
- diabetes (1)
- diabetes therapy (1)
- diagnosis (1)
- diagnostic algorithm (1)
- diagnostic test (1)
- diet (1)
- differential scanning fluorimetry (1)
- differentiation (1)
- diffusion tensor imaging (1)
- digital pathology (1)
- dihydroceramide (1)
- disease modelling (1)
- disease models (1)
- dislocation (1)
- distress (1)
- diuretics (1)
- docking studies (1)
- dog study (1)
- donor safety (1)
- drug abstinence (1)
- drug delivery (1)
- drug‐resistant epilepsy (1)
- drug–drug interaction (DDI) (1)
- dual BET/HDAC inhibitor (1)
- dual antiplatelet therapy (1)
- dysbiosis (1)
- dysferlin (1)
- dysferlinopathy (1)
- dysphagia (1)
- e-Health (1)
- e-health (1)
- e-scooter (1)
- eHealth (1)
- early detection (1)
- early myocardial damage (EMD) (1)
- early recognition (1)
- economic burden (1)
- effect mechanism (1)
- effectiveness (1)
- efficacy (1)
- effort (1)
- eight disorders (1)
- elderly patients (1)
- electric scooter (1)
- electroencephalography (EEG), EEG reference choices, event-related potentials (ERP), independent component analysis (ICA), pain research, contact heat evoked potentials (CHEPS) (1)
- electrolytic cleaning (1)
- electromyostimulation (1)
- electron transport chain (1)
- electronic adherence measurement (1)
- electrophilic fatty acids (1)
- elimination rate constant (1)
- embolization (1)
- emergence (1)
- empagliflozin (1)
- encoding (1)
- end of life care (1)
- endocannabinoids (1)
- endolysosomal system (1)
- endometrial cancer (1)
- endothelial cells (1)
- engagement (1)
- enterovirus (1)
- eph receptor tyrosin kinase family (1)
- ephrins (1)
- epidemics (1)
- epidemiology (1)
- epidermal growth factor receptor (1)
- epididymitis (1)
- epigenetic (1)
- epigenetics (1)
- epileptic encephalopathy (1)
- episodic memory (1)
- epithelial cells (1)
- epithelial-to-mesenchymal transition (EMT) (1)
- epithelial‐mesenchymal transition (1)
- epitope mapping (1)
- erectile dysfunction (1)
- ergonomics (1)
- erythropoietin (EPO) (1)
- escape mutations (1)
- essential tremor (1)
- ethyl pyruvate (1)
- euthymic (1)
- event logs (1)
- event-related potentials (1)
- event-related potentials (ERP) (1)
- everolimus (1)
- ex vivo model (1)
- ex-Gaussian analysis (1)
- executive function (1)
- exercise on prescription (1)
- exercise therapy (1)
- exercise treatment (1)
- exertion (1)
- experimental human pain models (1)
- experimental pain models (1)
- expertise (1)
- exposure (1)
- extensively drug-resistant (1)
- external fixation (1)
- external joint moments (1)
- extracellular matrix (1)
- extraction socket healing (1)
- extraversion (1)
- extremity (1)
- eye-tracking (1)
- fMRI (1)
- fMRT (1)
- face inversion effect (1)
- facial nerve functional outcome (1)
- factor VIII (FVIII) (1)
- familial infantile epilepsy (1)
- fasting (1)
- fatigue (1)
- feeder cells (1)
- femoral artery ligation (1)
- fenfluramine (1)
- ferric carboxymaltose (1)
- fibromodulin (1)
- fingolimod (1)
- fixation (1)
- focal cortical dysplasia (1)
- focal seizures (1)
- force transmission (1)
- formalin-fixed paraffin-embedded (FFPE) samples (1)
- fourth (1)
- fractional anisotropy (1)
- fractionation (1)
- fracture (1)
- fragile-X-associated tremor-ataxia syndrome (1)
- fragment-based design (1)
- fragment-based drug design (1)
- free gingival graft (1)
- frontal cortex (1)
- fronto-temporal lobar dementia (1)
- fronto-temporal-lobar-dementia (1)
- fully human (1)
- fumonisin B1 (1)
- functional connectivity (1)
- functional coupling (1)
- functional genetics (1)
- functional imaging (1)
- fundoplication (1)
- furcation involvement (1)
- further education (1)
- fusion (1)
- gap junction protein alpha 4-genotype (1)
- gas chromatography-mass spectrometry (1)
- gastric surgery (1)
- gastrocnemius (1)
- gastroesophageal reflux (1)
- gender (1)
- gender difference (1)
- gene regulation (1)
- gene therapy (1)
- genetic diversity (1)
- genetic generalized epilepsy (1)
- genetic phenotypes (1)
- genetic polymorphisms (1)
- genetic predisposition (1)
- genome-wide association study (1)
- geriatric patients (1)
- geriatrischer Ultraschall (1)
- germ cell tumors (1)
- glioblastoma cells (1)
- glucose (1)
- glucose metabolism (1)
- glycosaminoglycan (1)
- graft (1)
- graph theory (1)
- grey matter volume (1)
- growth inhibition (1)
- gyrification (1)
- haematologic malignancies (1)
- haemophilia A (1)
- haemophilic arthropathy (1)
- haemostasis (1)
- harmine (1)
- health care (1)
- health-related quality of life (1)
- healthcare workers (1)
- healthy subjects (1)
- hearing nerve (1)
- heat stress (1)
- hemadsorption (1)
- hematoma (1)
- hematopoietic stem and progenitor cells (1)
- heme-regulated inhibitory kinase (1)
- hemiplegic migraine (1)
- hemispherotomy (1)
- hemodynamic (1)
- hemodynamic instability (1)
- hemophilia A (1)
- hemorrhage (1)
- hemorrhagic transformation (1)
- hepatic fibrosis (1)
- hepatic stellate cells (1)
- hepatitis C virus (1)
- hepatitis C virus (HCV) (1)
- hepatitis E (1)
- hepatocellular cancer (1)
- hepatocyte nuclear factor 4α (1)
- herb induced liver injury (1)
- hereditary angioedema (1)
- hereditary dystopic lipidosis (1)
- herpes simplex virus (1)
- hiPSC (1)
- high dimensional complex data (1)
- high surgical risk (1)
- high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (1)
- high-throughput nucleotide sequencing (1)
- high-throughput screening (1)
- higher education (1)
- high‐mobility group box‐1 (HMGB1) (1)
- hip joint (1)
- histological outcomes (1)
- histological technic (1)
- histomorphometry (1)
- histone modifications (1)
- histoplasmosis (1)
- home-based (1)
- homeostasis (1)
- hospitalization (1)
- host-pathogen interaction (1)
- huCAR19 (1)
- human decellularized dermis (1)
- human genomics (1)
- human lymph node (1)
- human sera (1)
- humanized mice (1)
- humanized mouse model (1)
- hybrid abutment (1)
- hyperarousal (1)
- hyperexcitability (1)
- hyperglycemia (1)
- hyperhomocysteinemia (1)
- hyperkalemia (1)
- hypertension (1)
- hypoglycaemia (1)
- hypophosphataemia (1)
- iDILI (1)
- iDrug induced liver injury (1)
- image-based risk modelling (1)
- imaging (1)
- immun (1)
- immune checkpoint (1)
- immune checkpoint inhibitors (1)
- immune defense (1)
- immune evasion (1)
- immune response (1)
- immuno-oncotherapy (1)
- immunoprecipitation (1)
- improvement in quality of life (1)
- in vitro (1)
- in vitro in vivo extrapolation (IVIVE) (1)
- in vitro models (1)
- in vivo model of critical size defects (1)
- independent component analysis (ICA) (1)
- indoor air pollution (1)
- induced membrane (1)
- induction chemotherapy (1)
- inertial motion capture (1)
- infant (1)
- infants (1)
- infectious diseases (1)
- inferior frontal gyrus (1)
- inflammatory bowel disease (1)
- inflammatory cytokines (1)
- inflammatory markers (1)
- inhibitors (1)
- injury (1)
- innate and adaptive immune response (1)
- inner ear therapy (1)
- inositol signaling (1)
- insomnia (1)
- instructional interventions (1)
- insulin resistance (1)
- insulitis (1)
- integrated stress response (1)
- inter-individual variability (1)
- interaction partners (1)
- interactome (1)
- interferon type III (1)
- interleukin-6 (1)
- interleukins (1)
- intervertebral disc (IVD) (1)
- intrinsic drug resistance (1)
- invasion (1)
- invasive mold infection (1)
- inverse dynamics (1)
- investigational (1)
- inflammation (1)
- iron deficiency (1)
- iron overload versus deprivation (1)
- iron supplements (1)
- irradiation (1)
- ischaemia (1)
- isolation (1)
- joint bleeding (1)
- joint loading (1)
- joint moments (1)
- juvenile brain lesion (1)
- kaatsu training (1)
- kallikrein inhibitor (1)
- keratinized mucosa (1)
- ketogenic (1)
- ketone body (1)
- kidney formation (1)
- kidney function (1)
- kinase inhibitors (1)
- kinetic fingerprint (1)
- knee adduction moment (1)
- knee joint (1)
- knee noise (1)
- knee sound (1)
- knockout (1)
- kynureninase (1)
- kynurenine (1)
- lacosamide (1)
- lactate (1)
- lamotrigine (1)
- latent class analysis (1)
- left ventricular non-compaction (1)
- left ventricular trabeculation (1)
- leg alignment (1)
- lentiviral vector (1)
- leukocytes (1)
- leukopenia (1)
- levetiracetam (1)
- lichen extracts (1)
- light microscopy (1)
- limb girdle muscular dystrophy type 2B (LGMD2B) (1)
- lipid (1)
- lipid raft (1)
- lipidomic analysis (1)
- lipocalin-2 (1)
- lipoxin A4 (1)
- liquid PRF (1)
- liquid chromatography–mass spectrometry (1)
- liver fibrosis (1)
- liver transplantation (1)
- liver transplantation center (1)
- local inflammation (1)
- local-field potentials (1)
- locus coeruleus (1)
- long reads (1)
- long-term outcome (1)
- long-term potentiation (1)
- long-term prophylaxis (1)
- long-term success (1)
- long-term survival (1)
- longevity (1)
- longitudinal follow-up after epilepsy surgery (1)
- loss (1)
- low doses (1)
- low-density lipoprotein cholesterol (1)
- low-risk (1)
- lower extremity arterial disease (1)
- lumbago (1)
- lumbalgia (1)
- lumbar spinal canal stenosis (1)
- lumican (1)
- lung disease phenotype (1)
- lymphoma (1)
- lysosomes (1)
- mHealth (1)
- mRNA and protein expression (1)
- macrophage polarization (1)
- magentoencephalography (MEG) (1)
- magnetic resonance imaging (1)
- magnetic resonance imaging of the brain (1)
- maintenance (1)
- major adverse cardiovascular events (1)
- major depression (MD) (1)
- major depressive disorder (MDD) (1)
- mammary carcinomas (1)
- management (1)
- mandatory reporting (1)
- maternal tobacco smoke (1)
- mathematical modeling (1)
- matrikine (1)
- matrix metalloproteinases (1)
- mean diffusivity (1)
- measurement properties (1)
- mechanism of action (1)
- mechanistic oral absorption modeling (1)
- medical training (1)
- medication adherence rate (1)
- melanoma (1)
- membrane potential (1)
- membrane repair (1)
- memory (1)
- memory and learning tests (1)
- mental distress (1)
- mesenchymal stem cell (1)
- mesenchymal stromal/stem cells (1)
- meta-analysis (1)
- metabolic reprogramming (1)
- metabolic syndrome (1)
- metabolism (1)
- miR-142-3p (1)
- miR-181 (1)
- miR-6862-5p (1)
- mice (1)
- micro CT (1)
- microdialysis (1)
- microlesions (1)
- microsurgical treatment (1)
- mid-IR spectroscopy (1)
- migration and invasion (1)
- mini gastric bypass (1)
- minimal clinically important difference (1)
- minimal residual disease (1)
- mir-148a (1)
- mitochondrial antiviral signaling protein (MAVS) (1)
- mitochondrial dysfunction (1)
- mitochondrial metabolism (1)
- mitochondrial morphology (1)
- mitochondrial respiration (1)
- mixed lineage kinase domain-like (1)
- model psychosis (1)
- molecular adaptation (1)
- molecular biology (1)
- molecular dynamics (1)
- molecular switch (1)
- molecular tumor board (1)
- molecular typing (1)
- monoamine oxidase A (1)
- monocyte chemotactic protein 1 (MCP-1) (1)
- mononuclear cell (1)
- monotype abutment (1)
- monsoon (1)
- morphogenesis (1)
- morphological filtering (1)
- morphometry (1)
- mortality (1)
- mortality analysis (1)
- mortality risk (1)
- motivation (1)
- motor control exercise (1)
- mouse (1)
- mouse model (1)
- mouse models (1)
- movement pattern (1)
- movement profile (1)
- multi-network (1)
- multi-task learning (1)
- multimodal complex treatment (1)
- multimorbidity (1)
- multiple trauma (1)
- multitarget drugs (1)
- murine model (1)
- muscle (1)
- muscle disease (1)
- muscular dystrophy (1)
- musculoskeletal (1)
- musculoskeletal inflammation (1)
- musculoskeletal pain (1)
- musculoskeletal radiographs (1)
- mutational antigenic profiling (1)
- myocardial perfusion (1)
- myofascial (1)
- myofascial chains (1)
- myofascial force transmission (1)
- myoferlin (1)
- myotonia congenita (1)
- nanobodies (1)
- nanodiscs (1)
- narrative content analysis (1)
- narrative economics (1)
- narrative medicine (1)
- natriuretic peptide (1)
- natural cytotoxicity (1)
- natural killer cell (1)
- naturalistic sample (1)
- necrosis (1)
- neglect (1)
- negligencia (1)
- neonate (1)
- neonates (1)
- neonatology (1)
- neoplasms (1)
- nerve (1)
- nerve injury (1)
- networks (1)
- neurexin (1)
- neurogenesis (1)
- neurological impairment (1)
- neuronal maturation (1)
- neuropathic pain (1)
- neuropathy (1)
- neurophysiology (1)
- neuropsychology (1)
- neuroticism (1)
- neurovascular bundle preservation (1)
- neutralization (1)
- neutralizing antibodies (1)
- newborn (1)
- newborn screening (1)
- next-generation sequencing (1)
- nitroalkylation (1)
- niños (1)
- non-coding RNAs (1)
- non-malignant hematological diseases (1)
- noninterventional (1)
- noninvasive blood glucose analysis (1)
- nonspecific (1)
- non‐selective beta‐blocker (1)
- nuclear receptor (1)
- nucleotide analogue (1)
- nucleotide metabolism (1)
- nutrient endocytosis (1)
- observational study (1)
- occupational health (1)
- off-pump surgery (1)
- oncogenic signaling (1)
- oncological gastrectomy (1)
- oncological outcome (1)
- one anastomosis gastric bypass (1)
- online information processing (1)
- online reasoning patterns (1)
- online survey (1)
- operative (1)
- optical coherence tomography (1)
- orientation (1)
- orthopaedic patients (1)
- oscillations (1)
- osteoarthritis (1)
- osteogenic sarcoma cells (1)
- osteoimmunological changes (1)
- otoferlin (1)
- ouabain (1)
- outcomes (1)
- outside-in signaling (1)
- ovary (1)
- overweight (1)
- own-face perception (1)
- oxidised lipids (1)
- pacemaker implantation (1)
- pain research (1)
- pain screening (1)
- pancreatic ductal adenocarcinoma (1)
- pancreatic surgery (1)
- parkinson’s disease (1)
- passive immunization (1)
- passive smoke (1)
- patient centered care (1)
- patient preferences (1)
- patient questionnaire (1)
- patient triage (1)
- patient-reported outcome measure (1)
- patient’s decree (1)
- patient’s perspective (1)
- paxilline (1)
- peanut allergy (1)
- pediatric (1)
- pediatric epilepsy (1)
- pediatric eye screening (1)
- pediatrics (1)
- pelvic packing (1)
- pelvic ring fracture (1)
- peptide antibiotics (1)
- peptide transport (1)
- perceptual closure (1)
- performance assessment (1)
- performance tests (1)
- peri-implantitis (1)
- pericytes (1)
- periimplantitis (1)
- perineurium (1)
- periodontal disease progression (1)
- periodontal risk assessment (1)
- periodontal risk calculator (1)
- periodontal risk factors (1)
- perioperative outcome (1)
- perioperative period (1)
- peripheral arterial disease (1)
- peri‐implantitis (1)
- peri‐implantitis therapy (1)
- person-oriented approach (1)
- personalised therapy (1)
- pet rabbit (1)
- phage (1)
- phage display (1)
- phage lysis proteins (1)
- phage therapy (1)
- pharmacogenetics (1)
- pharmacokinetics/pharmacodynamics (PK/PD) (1)
- pharmacoresistance (1)
- phenotype/genotype relation (1)
- phenotypic spectrum (1)
- phosphate (1)
- phosphorus (1)
- photothermal detection (1)
- physical activity counseling (1)
- physical training (1)
- physiologically based pharmacokinetic (PBPK) modeling (1)
- pigs (1)
- placenta (1)
- planimetric measurement (1)
- plasma (1)
- plasma-derived factor VIII concentrate, prophylaxis (1)
- plasmid (1)
- plasticity (1)
- pneumocystis (1)
- point of care (1)
- polo-like kinase 1 (1)
- poly(A)-tail (1)
- polylactide (1)
- polyomavirus (1)
- polypharmacology (1)
- polysomnography (1)
- population dynamics (1)
- portosystemic shunt (1)
- positive organizational e-interventions (1)
- post-caesarean uterus (1)
- post-exercise hypotension (1)
- post-liver transplantation management (1)
- post-traumatic (1)
- posterior fossa tumor (1)
- postmonsoon (1)
- postoperative complications (1)
- postoperative delirium (1)
- posttransnational modification (1)
- posttraumatic inflammation (1)
- posttraumatic stress disorder (1)
- ppi1 (1)
- pre-school asthma (1)
- precision weighting (1)
- prediabetes (1)
- predictive coding (1)
- preschool health examination (1)
- primary biliary cirrhosis (1)
- primary sclerosing cholangitis (1)
- proanthocyanidin (1)
- process mining (1)
- prognostic marker (1)
- prognostic value (1)
- proinflammatory microenvironment (1)
- promotion index (1)
- prophylactic vaccine (1)
- prophylaxis (1)
- proprotein convertase subtilisin/kexin type 9 inhibition (1)
- prostate volume (1)
- protease inhibitor (1)
- protein quality control (1)
- protein turnover (1)
- proteoglycan (1)
- proximal tubule (1)
- pseudokinase (1)
- psoriatic arthritis (1)
- psychischer Stress (1)
- psycho-oncology (1)
- psychology (1)
- psychosocial adjustment (1)
- public health department (1)
- public mental health (1)
- pupillometry (1)
- qRT-PCR (1)
- qRT-PCR detection (1)
- quality (1)
- quality of care (1)
- quantitative MRT (1)
- quantitative proteomics (1)
- quantitative sensory testing (1)
- quantum cascade laser (QCL) (1)
- questionnaire (1)
- radiation oncology (1)
- radical prostatectomy (1)
- radioimmunotherapy (1)
- radiomic (1)
- radiosensitization (1)
- radiotherapy (1)
- radon therapy (1)
- range of motion (1)
- rare disease (1)
- rare diseases (1)
- rare variants (1)
- rat femur critical size defect (1)
- rct (1)
- re-osseointegration (1)
- re-transplantation (1)
- reaction (1)
- reaction time (1)
- readmission rates (1)
- receptor for advanced glycation end product (RAGE) (1)
- recombinant vesicular stomatitis virus‐Zaire ebolavirus (1)
- regioisomers (1)
- regulatory T cell (1)
- regulatory T cells (1)
- regulatory T helper cells (1)
- rehabilitation (1)
- relapsing fever (1)
- relaxometry (1)
- reliable change index (1)
- remodelling (1)
- renal cell cancer (1)
- renal transplantation (1)
- renal tubular cells (1)
- renal tubular epithelial cells (1)
- repeat biopsy (1)
- repeated (1)
- reperfusion injury (1)
- repetition suppression (RS) (1)
- repetitive firing (1)
- replicative fitness (1)
- repsonse process patterns (1)
- requirements analysis (1)
- resective surgery (1)
- resistance (1)
- resistance mutation (1)
- resolution (1)
- resolution of inflammation (1)
- resonance (1)
- resting EEG (1)
- reticulocyte haemoglobin (1)
- retinal (1)
- retinoid X receptor (1)
- rhabdomyosarcoma (1)
- rheumatoid arthritis (1)
- rhodopsin (1)
- ridge preservation (1)
- right heart catheter (1)
- risk factor (1)
- risk score (1)
- rotational thromboelastometry (1)
- sCD163 (1)
- sCD206 (1)
- safety (1)
- sarcoma (1)
- sarcopenia (1)
- scanner noise (1)
- scavenger receptor (1)
- sciatic nerve (1)
- second-hand smoke (1)
- seizures (1)
- selection (1)
- selective autophagy receptor (1)
- self‐expanding (1)
- sensorimotor (1)
- sensory coding (1)
- sensory neuropathy (1)
- serine protease (NS3-4A) (1)
- serology (1)
- serum (1)
- severe acute respiratory syndrome coronavirus (1)
- severe asthma (1)
- severe congenital neutropenia (1)
- severely injured (1)
- sex (1)
- shock filter (1)
- short linear motifs (SLiMs) (1)
- shrinkage (1)
- shunt (1)
- sialitis (1)
- sickle cell anemia (1)
- signaling (1)
- skeletal muscle (1)
- sleepiness (1)
- small molecule inhibitor (1)
- smoking in pregnancy (1)
- social determinants (1)
- social isolation (1)
- socioeconomic status (1)
- soft drinks (1)
- soluble MICA (1)
- sonography (1)
- sparse imaging (1)
- spatial learning (1)
- specialized pro-resolving lipid mediators (SPMs) (1)
- specific learning disorder (1)
- sphingosine 1-phoshate (1)
- sphingosine 1-phosphate antagonistst/inhibitors (1)
- sphingosine 1-phosphate metabolism (1)
- sphingosine 1-phosphate signaling (1)
- sphingosine kinase (1)
- sphingosine-1-phosphate (1)
- spiral ganglion cells (1)
- spirochetes (1)
- spirometry (1)
- spontaneous portosystemic shunt (1)
- sports (1)
- sports performance (1)
- spreading (1)
- squamous cell carcinoma (1)
- stabilization (1)
- standardization (1)
- standardized regression-based change norms (1)
- starvation (1)
- steady-state condition (1)
- stearic acid (1)
- steatosis (1)
- stem cell transplantation (1)
- stem cells (1)
- steroid control of aging (1)
- stiripentol (1)
- strength training (1)
- streptozotocin (1)
- stress response (1)
- stretching (1)
- stromal-derived factor 1 (1)
- structural biology (1)
- structure constraints (1)
- structure–activity relationships (1)
- substance abuse disorder (1)
- suicidality (1)
- suicide (1)
- supervision (1)
- supervisión (1)
- supplementary motor area (1)
- supportive periodontal therapy (1)
- suprapubic catheter (1)
- surfactant (1)
- surgical margin (1)
- surgical procedures (1)
- swallowing (1)
- sympathicus (1)
- symptoms (1)
- synaesthesia (1)
- synaptic plasticity (1)
- synaptic scaling (1)
- synergistic interaction (1)
- synovium (1)
- synuclein (1)
- systematic biopsy (1)
- systematic scoping review (1)
- tailored treatment schedule (1)
- talent development (1)
- talent identification (1)
- targeted biopsy (1)
- targeted therapy (1)
- targeting (1)
- tauopathies (1)
- tauopathy (1)
- tea (1)
- telemedicine (1)
- tension type headache (1)
- terapia cognitivo conductual enfocada en trauma (1)
- test protocol (1)
- testis (1)
- tetrahydrocannabinol (1)
- thalassemia (1)
- therapy monitoring (1)
- therapy resistance (1)
- thiazolidine and perhydrothiazine derivatives of aldophosphamide and I-aldophosphamide (1)
- third (1)
- three-dimensional analysis (1)
- three‐dimensional analysis (1)
- thrombopenia (1)
- thrombotic microangiopathy (1)
- thrombotic thrombocytopenic purpura (1)
- tick (1)
- time-lapse imaging (1)
- tissue slice co-cultures (1)
- tobacco control (1)
- tobacco products (1)
- toc64 (1)
- tooth (1)
- tooth autotransplantation (1)
- tooth loss (1)
- tooth transplantation (1)
- total hip replacement (1)
- tracking (1)
- traditional Chinese medicine (1)
- traffic accident (1)
- trafficking (1)
- training effects (1)
- transcatheter aortic valve replacement (TAVR) (1)
- transcatheter aortic valve replacement (TAVR), aortic valve stenosis (AS) (1)
- transcriptomics (1)
- transferrin (1)
- transforming growth factor-β (1)
- transfusion (1)
- transgenically augmented CAR NK cell (1)
- transjugular intrahepatic portosystemic shunt (TIPS) (1)
- transjugular portosystemic intrahepatic (1)
- translational medical research (1)
- translational medicine (1)
- translational reseach (1)
- translatome (1)
- translocon (1)
- transmission routes (1)
- transportation (1)
- transrectal prostate biopsy (1)
- transurethral catheter (1)
- transverse axis (1)
- trauma (1)
- trauma registry (1)
- traumafocused cognitive behavioural therapy (1)
- traumatic brain injury (1)
- traumatic brain injury (TBI) (1)
- traumaticbraininjury(TBI) (1)
- treatment-related changes (1)
- trigeminal pain (1)
- trophoblast (1)
- tryptophan (1)
- tumor adhesion (1)
- tumor angiogenesis (1)
- tumor hypoxia (1)
- tumor infiltrating lymphocytes (1)
- tumor invasion (1)
- tumor migration (1)
- tumor pain (1)
- tumor perfusion (1)
- tumor stroma (1)
- tumor xenograft (1)
- tumor-associated macrophages (1)
- type 1 diabetes (1)
- type 2 diabetes (1)
- type-1-diabetes (1)
- tyrosinase inhibitor (1)
- tyrosine kinase inhibitor (1)
- tyrosine kinase inhibitors (1)
- tyrosine kinase inhibitors. (1)
- tyrosine kinase receptor signaling (1)
- ubiquitin (1)
- ubiquitin hydrolase (1)
- ubiquitin receptor (1)
- ultrasonic cleaning (1)
- ultrasound (1)
- unanticipated (1)
- unconventional T cell (1)
- unilateral hip osteoarthritis (1)
- unspecific low back pain (1)
- urethral stricture (1)
- urethroplasty (1)
- urinary tract development (1)
- uterine wall (1)
- vaccination (1)
- vacuuming (1)
- valproic acid (1)
- value frameworks (1)
- variability (1)
- variable silent delay (1)
- vascular endothelial growth factor receptor (1)
- vascular surgery (1)
- vector (1)
- venous occlusion (1)
- ventralis intermedius nucleus (1)
- venturesomeness (1)
- vertical transmission (1)
- vestibular schwannoma (1)
- vibroarthrographic (1)
- vigilance (1)
- vincristine (1)
- viral infection (1)
- viruses (1)
- vision (1)
- visual attention (1)
- visual priming (1)
- vitamin B deficiency (1)
- vitamin B12 (1)
- vitamin D (1)
- vitamin D deficiency (1)
- vitamin D metabolites (1)
- vitamin k antagonists (1)
- volatile sedation (1)
- von Willebrand diseases (1)
- waiting time (1)
- walking (1)
- weakly supervised learning (1)
- weight loss (1)
- wheezing (1)
- white matter hyperintensity (1)
- whole abdominal radiotherapy (1)
- whole genome sequencing (1)
- whole slide image (1)
- working memory (1)
- workplace health promotion (1)
- xenograft (1)
- yellow flags (1)
- youth football (1)
- zebrafish development (1)
- Öffentlichkeit (1)
- Übertragungswege (1)
- ΔNp63 (1)
- α-amylase inhibitor (1)
- α-particles (1)
- γ‐H2AX (1)
- fibrogenesis (1)
- fingolimod (1)
Institute
- Medizin (732)
- Biochemie, Chemie und Pharmazie (41)
- Biowissenschaften (22)
- Frankfurt Institute for Advanced Studies (FIAS) (21)
- Sportwissenschaften (21)
- MPI für Hirnforschung (14)
- Präsidium (14)
- Biochemie und Chemie (11)
- Psychologie und Sportwissenschaften (11)
- Ernst Strüngmann Institut (9)
Introduction: In patients with severe pelvic ring injuries, exsanguination still is the leading cause of death in the early post-injury phase. While mechanical pelvic ring stabilization and pre-peritoneal pelvic packing are mainly addressing venous bleeding, angio-embolization aims to control arterial bleeding. The goal of the present study was to evaluate the rate of postoperative angio-embolization after mechanical pelvic ring injury stabilization and pre-peritoneal pelvic packing. Bleeding sources detected in the angiography and the patient's outcome were investigated. Patients and Methods: Retrospective observational cohort study at a single academic level I trauma center, reviewing all patients with pelvic ring injuries admitted from 01/2010 to 12/2019. Patients with emergent mechanical pelvic ring stabilization (supraacetabular external fixator and/or pelvic C-clamp) and direct pre-peritoneal pelvic packing were further analyzed. Patients that underwent postoperative angio-embolization were compared with those that did not. All postoperative angio-embolizations were evaluated with regards to bleeding sources and type of embolization. Results: During the study period, a total of 39 patients required immediate mechanical pelvic stabilization and direct pre-peritoneal pelvic packing. Of these, 12 patients (30.8%) underwent a postoperative angio-embolization. The following vessels were identified as bleeding sources: superior gluteal artery (n = 6), obturator artery (n = 2), internal pudendal artery (n = 2), unnamed branches of the internal iliac artery (n = 3). A selective embolization was successful in 11 patients; in 1 patient, an unilateral complete occlusion of the internal iliac artery was performed to control the bleeding. Mean time from hospital admission to the surgical procedure was 52.8 ± 14.7 min and the mean time from admission to angio-embolization was 189.1 ± 55.5 min. The in-hospital mortality rate of patients with angio-embolization was 25.0% (n = 3). Of these, 2 patients died due to multiple organ failure and 1 patient due to severe head injury. Conclusion: Secondary angio-embolization after external pelvic fixation and pre-peritoneal pelvic packing was effective in controlling ongoing bleeding. The most frequently detected bleeding vessel was the superior gluteal artery, which is difficult to surgically address, further highlighting the importance of angio-embolization in the management algorithm.
New innovative neuropsychological tests in attention deficit hyperactivity disorder ADHD have been proposed as objective measures for diagnosis and therapy. The current study aims to investigate two different commercial continuous performance tests (CPT) in a head-to-head comparison regarding their comparability and their link with clinical parameters. The CPTs were evaluated in a clinical sample of 29 adult patients presenting in an ADHD outpatient clinic. Correlational analyses were performed between neuropsychological data, clinical rating scales, and a personality-based measure. Though inattention was found to positively correlate between the two tests (r = 0.49, p = 0.01), no association with clinical measures and inattention was found for both tests. While hyperactivity did not correlate between both tests, current ADHD symptoms were positively associated with Nesplora Aquarium’s motor activity (r = 0.52 to 0.61, p < 0.05) and the Qb-Test’s hyperactivity (r = 0.52 to 0.71, p < 0.05). Conclusively, the overall comparability of the tests was limited and correlation with clinical parameters was low. While our study shows some interesting correlation between clinical symptoms and sub-scales of these tests, usage in clinical practice is not recommended.
Tumor-associated macrophages (TAMs) influence lung tumor development by inducing immunosuppression. Transcriptome analysis of TAMs isolated from human lung tumor tissues revealed an up-regulation of the Wnt/β-catenin pathway. These findings were reproduced in a newly developed in vitro “trained” TAM model. Pharmacological and macrophage-specific genetic ablation of β-catenin reprogrammed M2-like TAMs to M1-like TAMs both in vitro and in various in vivo models, which was linked with the suppression of primary and metastatic lung tumor growth. An in-depth analysis of the underlying signaling events revealed that β-catenin–mediated transcriptional activation of FOS-like antigen 2 (FOSL2) and repression of the AT-rich interaction domain 5A (ARID5A) drive gene regulatory switch from M1-like TAMs to M2-like TAMs. Moreover, we found that high expressions of β-catenin and FOSL2 correlated with poor prognosis in patients with lung cancer. In conclusion, β-catenin drives a transcriptional switch in the lung tumor microenvironment, thereby promoting tumor progression and metastasis.
Background: Since January 2018 performance of urethroplasties is done on regular basis at the University Hospital Frankfurt (UKF). We aimed to implement and transfer an institutional standardized perioperative algorithm for urethral surgery (established at the University Hospital Hamburg-Eppendorf—UKE) using a validated Urethral Stricture Surgery Patient-Reported Outcome Measure (USS-PROM) in patients undergoing urethroplasty at UKF. Materials and Methods: We retrospectively analyzed all patients who underwent urethroplasty for urethral stricture disease between January 2018 and January 2020 at UKF. All patients were offered to revisit for clinical follow-up (FU) and completion of USS-PROM. Primary end point was stricture recurrence-free survival (RFS). Secondary endpoints were functional outcomes, quality of life (QoL), and patient satisfaction. Results: In total, 50 patients underwent urethroplasty and 74 and 24% had a history of previous urethrotomy or urethroplasty, respectively. A buccal mucosal graft urethroplasty was performed in 86% (n = 43). After patient's exclusion due to lost of FU, FU <3 months, and/or a pending second stage procedure, 40 patients were eligible for final analysis. At median FU of 10 months (interquartile-range 5.0–18.0), RFS was 83%. After successful voiding trial, the postoperative median Qmax significantly improved (24.0 vs. 7.0 mL/s; p < 0.01). Conversely, median residual urine decreased significantly (78 vs. 10 mL; p < 0.01). Overall, 95% of patients stated that QoL improved and 90% were satisfied by the surgical outcome. Conclusions: We demonstrated a successful implementation and transfer of an institutional standardized perioperative algorithm for urethral surgery from one location (UKE) to another (UKF). In our short-term FU, urethroplasty showed excellent RFS, low complication rates, good functional results, improvement of QoL and high patient satisfaction. PROMs allow an objective comparison between different centers.
While impulsivity is a basic feature of attention-deficit / hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive–neurotic type, an adventurous–hyperactive type with a stronger genetic component, and an anxious–inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background.
Purpose: Medically recommended training often faces the dilemma that necessary mechanical intensities for muscle adaptations exceed patients' physical capacity. In this regard, blood flow restriction (BFR) training is becoming increasingly popular because it enables gains in muscle mass and strength despite using low-mechanical loads combined with external venous occlusion. Since the underlying mechanisms are still unknown, we applied invasive measurements during exercise with and without BFR to promote physiological understanding and safety of this popular training technique. Methods: In a randomized cross-over design, ten healthy men (28.1 ± 6.5 years) underwent two trials of unilateral biceps curls either with (BFR) and without BFR (CON). For analysis of changes in intravascular pressures, blood gases, oximetry and electrolytes, an arterial and a venous catheter were placed at the exercising arm before exercise. Arterial and venous blood gases and intravascular pressures were analyzed before, during and 5 min after exercise. Results: Intravascular pressures in the arterial and venous system were more increased during exercise with BFR compared to CON (p < 0.001). Furthermore, arterial and venous blood gas analyses revealed a BFR-induced metabolic acidosis (p < 0.05) with increased lactate production (p < 0.05) and associated elevations in [K+], [Ca2+] and [Na+] (p < 0.001). Conclusion: The present study describes for the first time the local physiological changes during BFR training. While BFR causes greater hypertension in the arterial and venous system of the exercising extremity, observed electrolyte shifts corroborate a local metabolic acidosis with concurrent rises in [K+] and [Na+]. Although BFR could be a promising new training concept for medical application, its execution is associated with comprehensive physiological challenges.
Purpose: To develop and validate a CT-based radiomics signature for the prognosis of loco-regional tumour control (LRC) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated by primary radiochemotherapy (RCTx) based on retrospective data from 6 partner sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG).
Material and methods: Pre-treatment CT images of 318 patients with locally advanced HNSCC were collected. Four-hundred forty-six features were extracted from each primary tumour volume and then filtered through stability analysis and clustering. First, a baseline signature was developed from demographic and tumour-associated clinical parameters. This signature was then supplemented by CT imaging features. A final signature was derived using repeated 3-fold cross-validation on the discovery cohort. Performance in external validation was assessed by the concordance index (C-Index). Furthermore, calibration and patient stratification in groups with low and high risk for loco-regional recurrence were analysed.
Results: For the clinical baseline signature, only the primary tumour volume was selected. The final signature combined the tumour volume with two independent radiomics features. It achieved moderately good discriminatory performance (C-Index [95% confidence interval]: 0.66 [0.55–0.75]) on the validation cohort along with significant patient stratification (p = 0.005) and good calibration.
Conclusion: We identified and validated a clinical-radiomics signature for LRC of locally advanced HNSCC using a multi-centric retrospective dataset. Prospective validation will be performed on the primary cohort of the HNprädBio trial of the DKTK-ROG once follow-up is completed.
The β-carboline alkaloid harmine is a potent DYRK1A inhibitor, but suffers from undesired potent inhibition of MAO-A, which strongly limits its application. We synthesized more than 60 analogues of harmine, either by direct modification of the alkaloid or by de novo synthesis of β-carboline and related scaffolds aimed at learning about structure-activity relationships for inhibition of both DYRK1A and MAO-A, with the ultimate goal of separating desired DYRK1A inhibition from undesired MAO-A inhibition. Based on evidence from published crystal structures of harmine bound to each of these enzymes, we performed systematic structure modifications of harmine yielding DYRK1A-selective inhibitors characterized by small polar substituents at N-9 (which preserve DYRK1A inhibition and eliminate MAO-A inhibition) and beneficial residues at C-1 (methyl or chlorine). The top compound AnnH75 remains a potent DYRK1A inhibitor, and it is devoid of MAO-A inhibition. Its binding mode to DYRK1A was elucidated by crystal structure analysis, and docking experiments provided additional insights for this attractive series of DYRK1A and MAO-A inhibitors.
Ataxia-Telangiectasia (A-T), a pleiotropic chromosomal breakage syndrome, is caused by the loss of the kinase Ataxia-telangiectasia mutated (ATM). ATM is not only involved in the response to DNA damage, but also in sensing and counteracting oxidative stress. Since a disturbed redox balance has been implicated in the pathophysiology of A-T lung disease, we aimed to further explore the interplay between ATM and oxidative stress in lung cells. Using a kinetic trapping approach, we could demonstrate an interaction between the trapping mutant TRX1-CS and ATM upon oxidative stress. We could further show that combined inhibition of thioredoxin reductase (TrxR) and ATM kinase activity, using Auranofin and KU55933 respectively, induced an increase in cellular reactive oxygen species (ROS) levels and protein oxidation in lung cells. Furthermore, ATM inhibition sensitized lung cells to Auranofin-induced cell death that could be rescued by ROS scavengers. As a consequence, targeted reduction of ATM by TRX1 could serve as a regulator of oxidative ATM activation and contribute to the maintenance of the cellular redox homeostasis. These results highlight the importance of the redox-active function of ATM in preventing ROS accumulation and cell death in lung cells.
Characterization of neonates born to mothers with SARS-CoV-2 infection: review and meta-analysis
(2020)
Characterization of neonates born to mothers with SARS-CoV-2 infection has been partially carried out. There has been no systematic review providing a holistic neonatal presentation including possible vertical transmission. A systematic literature search was performed using PubMed, Google Scholar and Web of Science up to June, 6 2020. Studies on neonates born to mothers with SARS-CoV-2 infection were included. A binary random effect model was used for prevalence and 95% confidence interval. 32 studies involving 261 neonates were included in meta-analysis. Most neonates born to infected mothers did not show any clinical abnormalities (80.4%). Clinical features were dyspnea in 11 (42.3%) and fever in 9 newborns (19.1%). Of 261 neonates, 120 neonates were tested for infection, of whom 12 (10.0%) tested positive. Swabs from placenta, cord blood and vaginal secretion were negative. Neonates are mostly non affected by the mother's SARS-CoV-2 infection. The risk of vertical transmission is low.
The B-cell receptor (BCR) signaling pathway is a crucial pathway of B cells, both for their survival and for antigen-mediated activation, proliferation and differentiation. Its activation is also critical for the genesis of many lymphoma types. BCR-mediated lymphoma proliferation may be caused by activating BCR-pathway mutations and/or by active or tonic stimulation of the BCR. BCRs of lymphomas have frequently been described as polyreactive. In this review, the role of specific target antigens of the BCRs of lymphomas is highlighted. These antigens have been found to be restricted to specific lymphoma entities. The antigens can be of infectious origin, such as H. pylori in gastric MALT lymphoma or RpoC of M. catarrhalis in nodular lymphocyte predominant Hodgkin lymphoma, or they are autoantigens. Examples of such autoantigens are the BCR itself in chronic lymphocytic leukemia, LRPAP1 in mantle cell lymphoma, hyper-N-glycosylated SAMD14/neurabin-I in primary central nervous system lymphoma, hypo-phosphorylated ARS2 in diffuse large B-cell lymphoma, and hyper-phosphorylated SLP2, sumoylated HSP90 or saposin C in plasma cell dyscrasia. Notably, atypical posttranslational modifications are often responsible for the immunogenicity of many autoantigens. Possible therapeutic approaches evolving from these specific antigens are discussed.
Background: Musculoskeletal disorders (MSD) are common among dental professionals. The most common areas affected are the trunk, neck, shoulders and wrists. Current evidence suggests that the causes of MSD can be found in the physical demands of the profession. Posture and movement during treatment is influenced by the arrangement of the treatment concept (patient chair, equipment and cabinets). It has not been investigated whether the ergonomic risk differs between the treatment concepts.
Methods: To evaluate the prevalence of MSD in dental professionals, 1000 responses will be collected from a nationwide (Germany) online questionnaire (mod. Nordic Questionnaire and mod. Meyer questionnaire). In order to assess the ergonomic risk of the treatment techniques used in the four treatment concepts, 3D movement analyses are carried out with inertial sensors. For this purpose, 20 teams of dentists and dental assistants from four dental fields of specializations (generalists, orthodontists, endodontists and oral surgeons) and a student control group will be recruited. Each team will execute field specific standardized treatments at a dummy head. Measurements are carried out in each of the four treatment concepts. The data will be analyzed using the Rapid Upper Limb Assessment (RULA) which will be modified for the evaluation of objective data.
Conclusions: On the basis of these investigations, a substantial gain of knowledge regarding work-related MSD in the field of dentistry and its potential biomechanical causes is possible. For the first time, objective and differentiated comparisons between the four treatment concepts are possible for different fields of dental specialization. Up to now, statically held positions of the trunk and proximal upper extremities, but also the repetitive movements of the hands have been considered a risk for MSD. Since both are included in the RULA, dental activities can be assessed in a detailed but also global manner with regard to ergonomic risks.
Background: The aim of this pilot study was to analyze postures during the work of neurologists with respect to their occupational activities.
Methods: A total data material of 64.8 h (3885.74 min) of nine (three m/six f) neurologists (assistant physicians) was collected. Kinematic data were collected using the CUELA system (electro-goniometry). In addition, the occupational tasks performed on-site were subject to a detailed objective activity analysis. All activities were assigned to the categories "Office activities" (I), "Measures on patients" (II) and "Other activities" (III). The angle values of each body region (evaluation parameters) were evaluated according to ergonomic ISO standards.
Results: Only 3.4% of the working hours were spent with (II), while 50.8% of time was spent with (I) and 45.8% with (III). All tasks of category (II) revealed an increased ergonomic risk to the head, neck, trunk and back areas. During category (I) especially neck and back movements in the sagittal plane showed higher ergonomic risk levels.
Conclusion: Despite frequently performed awkward body positions in (II), the ergonomic risk is considered as rather low, since the percentage time share totaled only 3.4%. As a result, "Office activities" have been detected as high predictor to cause stress load on the musculoskeletal system in the daily work of neurologists.
Sarcomas are rare cancers with high heterogeneity in terms of type, location, and treatment. The health-related quality of life (HRQoL) of sarcoma patients has rarely been investigated and is the subject of this analysis. Adult sarcoma patients and survivors were assessed between September 2017 and February 2019 in 39 study centers in Germany using standardized, validated questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)). Associated factors were analyzed exploratively using multivariable linear regressions. Among 1113 patients, clinically important limitations and symptoms were most pronounced in emotional (63%, 95% CI 60–66%), physical (60%, 95% CI 57–62%), role functioning (51%, 95% CI 48–54%), and pain (56%, 95% CI 53–59%) and fatigue (51%, 95% CI 48–54%). HRQoL differed between tumor locations with lower extremities performing the worst and sarcoma types with bone sarcoma types being most affected. Additionally, female gender, higher age, lower socioeconomic status, recurrent disease, not being in retirement, comorbidities, and being in treatment were associated with lower HRQoL. Sarcoma patients are severely restricted in their HRQoL, especially in functioning scales. The heterogeneity of sarcomas with regard to type and location is reflected in HRQoL outcomes. During treatment and follow-up, close attention has to be paid to the reintegration of the patients into daily life as well as to their physical abilities and emotional distress.
Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML.
The multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3) represents a key player in the quality control of the cellular proteostasis network. In response to stress, BAG3 specifically targets aggregation-prone proteins to the perinuclear aggresome and promotes their degradation via BAG3-mediated selective macroautophagy. To adapt cellular homeostasis to stress, BAG3 modulates and functions in various cellular processes and signaling pathways. Noteworthy, dysfunction and deregulation of BAG3 and its pathway are pathophysiologically linked to myopathies, cancer, and neurodegenerative disorders. Here, we report a BAG3 proteomic signature under proteostasis stress. To elucidate the dynamic and multifunctional action of BAG3 in response to stress, we established BAG3 interactomes under basal and proteostasis stress conditions by employing affinity purification combined with quantitative mass spectrometry. In addition to the identification of novel potential BAG3 interactors, we defined proteins whose interaction with BAG3 was altered upon stress. By functional annotation and protein-protein interaction enrichment analysis of the identified potential BAG3 interactors, we confirmed the multifunctionality of BAG3 and highlighted its crucial role in diverse cellular signaling pathways and processes, ensuring cellular proteostasis and cell viability. These include protein folding and degradation, gene expression, cytoskeleton dynamics (including cell cycle and transport), as well as granulostasis, in particular.
Ferric carboxymaltose (FCM) has been shown to achieve rapid replenishment of iron stores and correction of anaemia in various populations with iron deficiency. A decrease in serum phosphate (PO43−) levels, which in most cases is asymptomatic, has been reported with IV iron preparations. Hypophosphataemia (HP) is a known adverse drug reaction with FCM. This post hoc pooled analysis investigates the frequency, duration, risk factors, and clinical signs of HP as reported in interventional clinical trials with FCM. Pooled data from subjects enrolled across 45 clinical trials in different therapy areas were included. A three-step adjudication process was utilised to identify adverse events of HP. Stratified analyses by therapy group and stepwise logistic regression analysis were used to identify predictors of HP. This pooled analysis confirms that FCM is associated with increased rates of serum PO43− lowering, but mean serum PO43− values were seen to recover at Week 4 and further recover at Week 8. Among all subjects receiving FCM therapy (n = 6879), 41.4% (n = 2847) reached a PO43− nadir value <2.5 mg/dL at any point on study and 0.7% (n = 49) reached a nadir <1 mg/dL. Although gastroenterology and women’s health subjects were identified to be at higher risk, occurrence of severe HP (<1 mg/dL [0.3 mmol/L]) following FCM administration was not observed to be common among subjects in these studies. Furthermore, there was no correlation between laboratory serum PO43− values and the occurrence of reported adverse events related to low PO43− levels.
Improving long-term patient and graft survival after liver transplantation (LT) remains a major challenge. Compared to the early phase after LT, long-term morbidity and mortality of the recipients not only depends on complications immediately related to the graft function, infections, or rejection, but also on medical factors such as de novo malignancies, metabolic disorders (e.g., new-onset diabetes, osteoporosis), psychiatric conditions (e.g., anxiety, depression), renal failure, and cardiovascular diseases. While a comprehensive post-transplant care at the LT center and the connected regional networks may improve outcome, there is currently no generally accepted standard to the post-transplant management of LT recipients in Germany. We therefore described the structure and standards of post-LT care by conducting a survey at 12 German LT centers including transplant hepatologists and surgeons. Aftercare structures and form of cost reimbursement considerably varied between LT centers across Germany. Further discussions and studies are required to define optimal structure and content of post-LT care systems, aiming at improving the long-term outcomes of LT recipients.
Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment tool in decompensated liver cirrhosis that has been shown to prolong transplant-free survival. Hepatic encephalopathy (HE) is a frequent complication of decompensated cirrhosis, eventually induced and/or aggravated by TIPS, that remains a clinical challenge especially in these patients. Therefore, patient selection for TIPS requires careful assessment of risk factors for HE. TIPS procedural parameters regarding stent size and invasive portosystemic pressure gradient measurements thereby have an important role. Endovascular shunt modification, in combination with a conservative medical approach, often results in a significant reduction of symptoms. This review summarizes HE molecular mechanisms and pathophysiology as well as diagnostic and therapeutic approaches targeting shunt-induced HE.
Lack of sensitive diagnostic tests impairs the understanding of the epidemiology of histoplasmosis, a disease whose burden is estimated to be largely underrated. Broad-range PCRs have been applied to identify fungal agents from pathology blocks, but sensitivity is variable. In this study, we compared the results of a specific Histoplasma qPCR (H. qPCR) with the results of a broad-range qPCR (28S qPCR) on formalin-fixed, paraffin-embedded (FFPE) tissue specimens from patients with proven fungal infections (n = 67), histologically suggestive of histoplasmosis (n = 36) and other mycoses (n = 31). The clinical sensitivity for histoplasmosis of the H. qPCR and the 28S qPCR was 94% and 48.5%, respectively. Samples suggestive for other fungal infections were negative with the H. qPCR. The 28S qPCR did not amplify DNA of Histoplasma in FFPE in these samples, but could amplify DNA of Emergomyces (n = 1) and Paracoccidioides (n = 2) in three samples suggestive for histoplasmosis but negative in the H. qPCR. In conclusion, amplification of Histoplasma DNA from FFPE samples is more sensitive with the H. qPCR than with the 28S qPCR. However, the 28S qPCR identified DNA of other fungi in H. qPCR-negative samples presenting like histoplasmosis, suggesting that the combination of both assays may improve the diagnosis.
Central nervous hyperarousal is as a key component of current pathophysiological concepts of chronic insomnia disorder. However, there are still open questions regarding its exact nature and the mechanisms linking hyperarousal to sleep disturbance. Here, we aimed at studying waking state hyperarousal in insomnia by the perspective of resting-state vigilance dynamics. The VIGALL (Vigilance Algorithm Leipzig) algorithm has been developed to investigate resting-state vigilance dynamics, and it revealed, for example, enhanced vigilance stability in depressive patients. We hypothesized that patients with insomnia also show a more stable vigilance regulation. Thirty-four unmedicated patients with chronic insomnia and 25 healthy controls participated in a twenty-minute resting-state electroencephalography (EEG) measurement following a night of polysomnography. Insomnia patients showed enhanced EEG vigilance stability as compared to controls. The pattern of vigilance hyperstability differed from that reported previously in depressive patients. Vigilance hyperstability was also present in insomnia patients showing only mildly reduced sleep efficiency. In this subgroup, vigilance hyperstability correlated with measures of disturbed sleep continuity and arousal. Our data indicate that insomnia disorder is characterized by hyperarousal at night as well as during daytime.
The present study considered the entire leg alignment and links static parameters to the external joint moments during gait in patients with hip osteoarthritis. Eighteen patients with unilateral hip osteoarthritis were measured using the EOS® system. Clinical leg alignment and femoral parameters were extracted from the 3D reconstruction of the EOS images. A 3D gait analysis was performed and external knee and hip adduction moments were computed and compared to 18 healthy controls in the same age group. The knee adduction moments of the involved leg were strongly correlated to the femoral offset and the varus/valgus alignment. These parameters alone explained over 50% of the variance in the knee adduction moments. Adding the pelvic drop of the contralateral side increased the model of femoral offset and varus/valgus alignment and explained 78% of the knee adduction moment during the first half of the stance phase. The hip adduction moments were best associated with the hip kinematics and not the leg alignment.
In a previous study, EphB4 was demonstrated to be a positive regulator of A375-melanoma growth but a negative regulator of tumor vascularization and perfusion. To distinguish between EphB4 forward and ephrinB2 reverse signaling, we used the commercially available EphB4 kinase inhibitor NVP-BHG712 (NVP), which was later identified as its regioisomer NVPiso. Since there have been reported significant differences between the inhibition profiles of NVP and NVPiso, we compared the influence of NVP and NVPiso on tumor characteristics under the same experimental conditions. Despite the different inhibitory profiles of NVP and NVPiso, the comparative study conducted here showed the same EphB4-induced effects in vivo as in the previous investigation. This confirmed the conclusion that EphB4-ephrinB2 reverse signaling is responsible for increased tumor growth as well as decreased tumor vascularization and perfusion. These results are further substantiated by microarrays showing differences between mock-transfected and EphB4-transfected (A375-EphB4) cells with respect to at least 9 angiogenesis-related proteins. Decreased expression of vascular endothelial growth factor (VEGF), angiotensin 1 (Ang-1), and protein kinase B (Akt/PKB), together with the increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and transforming growth factor beta-2 (TGF-β2), is consistent with the impaired vascularization of A375-EphB4 xenografts. Functional overexpression of EphB4 in A375-EphB4 cells was confirmed by activation of a variety of signaling pathways, including the Janus kinase/signal transducers and activators of transcription (JAK/STAT), rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen activated protein kinase kinase (Ras/Raf/MEK), and nuclear factor kappa-B (NFkB) pathways.
Background: The ERGO2 (Ernaehrungsumstellung bei Patienten mit Rezidiv eines Glioblastoms) MR-spectroscopic imaging (MRSI) subtrial investigated metabolism in patients randomized to calorically restricted ketogenic diet/intermittent fasting (crKD-IF) versus standard diet (SD) in addition to re-irradiation (RT) for recurrent malignant glioma. Intracerebral concentrations of ketone bodies (KB), intracellular pH (pHi), and adenosine triphosphate (ATP) were non-invasively determined. Methods: 50 patients were randomized (1:1): Group A keeping a crKD-IF for nine days, and Group B a SD. RT was performed on day 4-8. Twenty-three patients received an extended MRSI-protocol (1H decoupled 31P MRSI with 3D chemical shift imaging (CSI) and 2D 1H point-resolved spectroscopy (PRESS)) at a 3T scanner at baseline and on day 6. Voxels were selected from the area of recurrent tumor and contralateral hemisphere. Spectra were analyzed with LCModel, adding simulated signals of 3-hydroxybutyrate (βOHB), acetone (Acn) and acetoacetate (AcAc) to the standard basis set. Results: Acn was the only reliably MRSI-detectable KB within tumor tissue and/or normal appearing white matter (NAWM). It was detected in 4/11 patients in Group A and in 0/8 patients in Group B. MRSI results showed no significant depletion of ATP in tumor tissue of patients at day 6 during crKD-IF, even though there were a significant difference in ketone serum levels between Group A and B at day 6 and a decline in fasting glucose in Group A from baseline to day 6. The tumor specific alkaline pHi was maintained. Conclusions: Our metabolic findings suggest that tumor cells maintain energy homeostasis even with reduced serum glucose levels and may generate additional ATP through other sources.r sources.
kurz und kn@pp news : Nr. 50
(2020)
Inhibitoren der Apoptose (IAP, inhibitor of apoptosis) Proteine spielen eine wichtige Rolle in Bezug auf Zelltodregulation und es ist anzunehmen, dass eine Dysregulation dieser Proteine zu einer Tumorentwicklung und Tumorprogression beiträgt. Erhöhte Expressionslevel von IAP Proteinen verhindern die Aktivierbarkeit des Zelltodprogrammes von Tumorzellen und eine Reihe von Studien konnte bereits erhöhte IAP Level in Tumorzelllinien sowie in primären Tumorproben nachweisen. Des Weiteren korrelieren erhöhte Expressionslevel von IAPs in Tumoren mit Behandlungsresistenzen und schlechten Prognosen für die Patienten.
Das diffuse großzellige B-Zell Lymphom (DLBCL, diffuse large B-cell lymphoma) zählt zu den häufigsten Subtypen der Non-Hodgkin Lymphome (NHL) mit 40 % aller neu diagnostizierten NHL Fälle. DLBCL ist eine sehr heterogene Erkrankung die in drei verschiedene Gruppen klassifiziert wurde: aktivierter B-Zell Typ (ABC, activated B-cell), Keimzentrum B-Zell Typ (GCB, germinal center B-Cell) und Mediastinaler großzelliger B-Zell Typ (PMBL, primary mediastinal B-cell lymphoma). Erhöhte Expressionslevel von zellulärem IAP1 (cIAP, cellular IAP) und cIAP2 wurden ebenfalls in primären Tumorproben von DLBCL Patienten nachgewiesen. Smac mimetics wurden entwickelt, um IAPs zu antagonisieren und stellen damit eine Behandlungsstrategie für DLBCL Patienten dar, denn ca. 40 % aller DLBCL Patienten entwickeln ein Rezidiv oder erreichen gar keine Remission unter Standardtherapie. Jedoch ist der Effekt von Smac mimetics in einer Einzelbehandlung limitiert, weswegen Kombinationstherapien mit Smac mimetics eine vielversprechende Strategie für ihren klinischen Einsatz darstellen. Aus diesem Grund haben wir in dieser Arbeit den Effekt von Smac mimetic in Kombination mit Proteasom-Inhibitoren analysiert und einen speziellen Fokus auf den molekularen Mechanismus des ausgelösten Zelltodsignalweges gelegt.
Die Kombination verschiedener Konzentrationen des Smac mimetics BV6 mit dem Proteasom-Inhibitor carfilzomib (CFZ) löst in allen drei getesteten DLBCL Subtypen (ABC, GCB und PMBL) Zelltod aus. Die Kalkulation des Kombinationsindexes (CI, combination index) sowie des Bliss Scores, zwei quantitative Parameter zur Bestimmung eines Synergismus, zeigen, dass fast alle getesteten Kombinationen einen Synergismus aufweisen. Dies verdeutlicht, dass eine Co-Behandlung von BV6 und CFZ eine wirksame Kombination ist um Zelltod in DLBCL Zelllinien auszulösen. Außerdem zeigt eine Kombination von BV6 mit anderen Proteasom-Inhibitoren wie ixazomib (IXA) oder oprozomib (OPR), ebenfalls eine synergistische Reduktion der Zellviabilität. Diese Ergebnisse deuten darauf hin, dass der detektierte Effekt nicht auf eine Substanz limitiert ist, sondern, dass ein genereller Effekt von Smac mimetic und Proteasom-Inhibitoren vorliegt, um Zellviabilität in DLBCL zu reduzieren. BV6 und CFZ induzieren einen apoptotischen Zelltod, da sie die Spaltung und Aktivierung von Initiator- und Effektorcaspasen (Caspasen-3, -7, -8 und -9) initiieren und sich der induzierte Zelltod mit Hilfe des Caspasen-Inhibitors zVAD.fmk verhindern lässt. Die Behandlung mit BV6 und CFZ führt zu einer Akkumulation von NIK, ein Protein welches zur Aktivierung des non-kanonischen NF-kB Signalweges benötigt wird. Weitere Untersuchungen zeigen jedoch, dass NIK nicht an der Zelltodinduktion beteiligt ist, da eine siRNA-basierte Herunterregulierung des NIK Proteins keinen Einfluss auf die Zelltodinduktion nimmt. Ebenfalls ist der Zelltod unabhängig von dem TNFa Signalweg, da weder eine Behandlung mit dem TNFa Inhibitor Enbrel den Zelltod verringern kann noch eine zusätzliche Gabe von TNFa den Zelltod erhöht. Weitere mechanistische Studien zeigen eine kritische Rolle der mitochondrialen Apoptose für den BV6/CFZ-vermittelten Zelltod. Unter Behandlung mit BV6/CFZ wurde eine Aktivierung von BAX und BAK nachgewiesen, welche beide mit verantwortlich für die Porenbildung in der mitochondrialen Membran sind. Eine Herunterregulation dieser beiden Proteine mittels siRNA reduziert signifikant den durch BV6/CFZ-induzierten Zelltod auf ein Minimum. Gleichzeitig löst eine Co-Behandlung mit BV6/CFZ einen Verlust des mitochondrialen Membranpotentials (LOMMP, loss of mitochondrial membrane potential) aus. In Übereinstimmung mit den vorherigen Experimenten, zeigen wir eine Akkumulation von mitochondrialen reaktiven Sauerstoffspezies (ROS; reactive oxygen species), sowie einen generellen Anstieg des allgemeinen ROS Levels. Eine Behandlung mit BV6/CFZ zeigt eine deutliche Akkumulation des pro-apoptotischen Proteins NOXA. Um dessen funktionelle Relevanz zu überprüfen, wurde die Proteinmenge von NOXA mittels siRNA stark reduziert. Eine Behandlung mit der Kombination aus BV6 und CFZ zeigt daraufhin eine signifikant reduzierte Zelltodinduktion, was die funktionelle Relevanz von NOXA für den BV6/CFZ-vermittelten Zelltod unterstreicht. Immunopräzipitationsstudien zeigen, dass in RIVA und U2932 Zellen NOXA konstitutiv an seinen anti-apoptotischen Bindungspartner MCL-1 gebunden ist, was die Zellen bereits darauf vorbereitet Apoptose zu durchlaufen. Dieses sogenannte „primen“ für Apoptose wird durch die Behandlung mit BV6 und CFZ weiter verstärkt, da es die Bindung zwischen NOXA und MCL-1 weiter erhöht. Dadurch wird die Balance zwischen pro- und anti-apoptotischen Proteinen zu Gunsten der pro-apoptotischen Proteine verschoben und die Induktion von Apoptose begünstigt.
Insgesamt zeigen die Ergebnisse, dass DLBCL Zelllinien sensitiv auf eine Behandlung mit Smac mimetic und Proteasom-Inhibitor reagieren und damit eine mögliche neue Behandlungsstrategie für diese heterogene Tumorerkrankung darstellt.
Context: Autoimmune polyglandular syndrome (APS-2: autoimmune Addison’s disease or type 1 diabetes) is conferred by predisposing HLA molecules, vitamin D deficiency, and heritable susceptibility. Organ destruction is accompanied by cytokine alterations. We addressed the monocytic cytokines of two distinct APS-2 cohorts, effects of vitamin D and HLA DQ risk.
Methods: APS-2 patients (n = 30) and healthy controls (n = 30) were genotyped for HLA DQA1/DQB1 and their CD14+ monocytes stimulated with IL1β and/or 1,25(OH)2D3 for 24 h. Immune regulatory molecules (IL-6, IL-10, IL-23A, IL-15, CCL-2, PD-L1), vitamin D pathway gene transcripts (CYP24A1, CYP27B1, VDR), and CD14 were analyzed by enzyme-linked immunosorbent assay and RTqPCR. Results: Pro-inflammatory CCL-2 was higher in APS-2 patients than in controls (p = 0.001), whereas IL-6 showed a trend – (p = 0.1). In vitro treatment with 1,25(OH)2D3 reduced proinflammatory cytokines (IL-6, CCL-2, IL-23A, IL-15) whereas anti-inflammatory cytokines (IL-10 and PD-L1) rose both in APS-type 1 diabetes and APS-Addison´s disease. Patients with adrenal autoimmunity showed a stronger response to vitamin D. Expression of IL-23A and vitamin D pathway genes VDR and CYP27B1 varied by HLA genotype and was lower in healthy individuals with high-risk HLA (p = 0.0025; p = 0.04), while healthy controls with low-risk HLA showed a stronger IL-10 and CD14 expression (p = 0.01; p = 0.03). Conclusion: 1,25(OH)2D3 regulates the monocytic response in APS-2 disorders type 1 diabetes or Addison´s disease. The monocytic cytokine profile of individuals carrying HLA high-risk alleles is proinflammatory, enhances polyglandular autoimmunity and can be targeted by vitamin D.
Background: Vacuum cleaning, which is associated with musculoskeletal complaints, is frequently carried out in private households and by professional cleaners. The aim of this pilot study was to quantify the movements during habitual vacuuming and to characterize the movement profile with regard to its variability. Methods: The data were collected from 31 subjects (21 f/10 m) using a 3D motion analysis system (XSens). Eight vacuum cleaners were used to vacuum polyvinyl chloride (PVC) and carpet floors. In 15 joints of the right upper extremity, the trunk and the lower extremities, Principal Component Analysis was used to determine the predominantly varying joints during vacuuming. Results: The movements of the trunk and the lower extremities were relatively constant and, therefore, had less influence. The shoulder, elbow and wrist joints were identified as joints that can be decisive for the movement profile and that can be influenced. These joints were represented in the course of the vacuuming cycle by the mean movement with its standard deviation. Conclusion: In summary, the generalization of a movement profile is possible for the trunk and the lower extremities due to the relative homogeneity. In future it will be necessary to identify factors influencing variability in order to draw conclusions about movement ergonomics.
The assessment of knee or hip joint loading by external joint moments is mainly used to draw conclusions on clinical decision making. However, the correlation between internal and external loads has not been systematically analyzed. This systematic review aims, therefore, to clarify the relationship between external and internal joint loading measures during gait. A systematic database search was performed to identify appropriate studies for inclusion. In total, 4,554 articles were identified, while 17 articles were finally included in data extraction. External joint loading parameters were calculated using the inverse dynamics approach and internal joint loading parameters by musculoskeletal modeling or instrumented prosthesis. It was found that the medial and total knee joint contact forces as well as hip joint contact forces in the first half of stance can be well predicted using external joint moments in the frontal plane, which is further improved by including the sagittal joint moment. Worse correlations were found for the peak in the second half of stance as well as for internal lateral knee joint contact forces. The estimation of external joint moments is useful for a general statement about the peak in the first half of stance or for the maximal loading. Nevertheless, when investigating diseases as valgus malalignment, the estimation of lateral knee joint contact forces is necessary for clinical decision making because external joint moments could not predict the lateral knee joint loading sufficient enough. Dependent on the clinical question, either estimating the external joint moments by inverse dynamics or internal joint contact forces by musculoskeletal modeling should be used.
SUMOylation is a reversible posttranslational modification pathway catalyzing the conjugation of small ubiquitin-related modifier (SUMO) proteins to lysine residues of distinct target proteins. SUMOylation modifies a wide variety of cellular regulators thereby affecting a multitude of key processes in a highly dynamic manner. The SUMOylation pathway displays a hallmark in cellular stress-adaption, such as heat or redox stress. It has been proposed that enhanced cellular SUMOylation protects the brain during ischemia, however, little is known about the specific regulation of the SUMO system and the potential target proteins during cardiac ischemia and reperfusion injury (I/R). By applying left anterior descending (LAD) coronary artery ligation and reperfusion in mice, we detect dynamic changes in the overall cellular SUMOylation pattern correlating with decreased SUMO deconjugase activity during I/R injury. Further, unbiased system-wide quantitative SUMO-proteomics identified a sub-group of SUMO targets exhibiting significant alterations in response to cardiac I/R. Notably, transcription factors that control hypoxia- and angiogenesis-related gene expression programs, exhibit altered SUMOylation during ischemic stress adaptation. Moreover, several components of the ubiquitin proteasome system undergo dynamic changes in SUMO conjugation during cardiac I/R suggesting an involvement of SUMO signaling in protein quality control and proteostasis in the ischemic heart. Altogether, our study reveals regulated candidate SUMO target proteins in the mouse heart, which might be important in coping with hypoxic/proteotoxic stress during cardiac I/R injury.
Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can serve as a powerful framework for predicting the influence as well as the interaction of formulation, genetic polymorphism and co-medication on the pharmacokinetics and pharmacodynamics of drug substances. In this study, flurbiprofen, a potent non-steroid anti-inflammatory drug, was chosen as a model drug. Flurbiprofen has absolute bioavailability of ~95% and linear pharmacokinetics in the dose range of 50–300 mg. Its absorption is considered variable and complex, often associated with double peak phenomena, and its pharmacokinetics are characterized by high inter-subject variability, mainly due to its metabolism by the polymorphic CYP2C9 (fmCYP2C9 ≥ 0.71). In this study, by leveraging in vitro, in silico and in vivo data, an integrated PBPK/PD model with mechanistic absorption was developed and evaluated against clinical data from PK, PD, drug-drug and gene-drug interaction studies. The PBPK model successfully predicted (within 2-fold) 36 out of 38 observed concentration-time profiles of flurbiprofen as well as the CYP2C9 genetic effects after administration of different intravenous and oral dosage forms over a dose range of 40–300 mg in both Caucasian and Chinese healthy volunteers. All model predictions for Cmax, AUCinf and CL/F were within two-fold of their respective mean or geometric mean values, while 90% of the predictions of Cmax, 81% of the predictions of AUCinf and 74% of the predictions of Cl/F were within 1.25 fold. In addition, the drug-drug and drug-gene interactions were predicted within 1.5-fold of the observed interaction ratios (AUC, Cmax ratios). The validated PBPK model was further expanded by linking it to an inhibitory Emax model describing the analgesic efficacy of flurbiprofen and applying it to explore the effect of formulation and genetic polymorphisms on the onset and duration of pain relief. This comprehensive PBPK/PD analysis, along with a detailed translational biopharmaceutic framework including appropriately designed biorelevant in vitro experiments and in vitro-in vivo extrapolation, provided mechanistic insight on the impact of formulation and genetic variations, two major determinants of the population variability, on the PK/PD of flurbiprofen. Clinically relevant specifications and potential dose adjustments were also proposed. Overall, the present work highlights the value of a translational PBPK/PD approach, tailored to target populations and genotypes, as an approach towards achieving personalized medicine.
To successfully learn using open Internet resources, students must be able to critically search, evaluate and select online information, and verify sources. Defined as critical online reasoning (COR), this construct is operationalized on two levels in our study: (1) the student level using the newly developed Critical Online Reasoning Assessment (CORA), and (2) the online information processing level using event log data, including gaze durations and fixations. The written responses of 32 students for one CORA task were scored by three independent raters. The resulting score was operationalized as “task performance,” whereas the gaze fixations and durations were defined as indicators of “process performance.” Following a person-oriented approach, we conducted a process mining (PM) analysis, as well as a latent class analysis (LCA) to test whether—following the dual-process theory—the undergraduates could be distinguished into two groups based on both their process and task performance. Using PM, the process performance of all 32 students was visualized and compared, indicating two distinct response process patterns. One group of students (11), defined as “strategic information processers,” processed online information more comprehensively, as well as more efficiently, which was also reflected in their higher task scores. In contrast, the distributions of the process performance variables for the other group (21), defined as “avoidance information processers,” indicated a poorer process performance, which was also reflected in their lower task scores. In the LCA, where two student groups were empirically distinguished by combining the process performance indicators and the task score as a joint discriminant criterion, we confirmed these two COR profiles, which were reflected in high vs. low process and task performances. The estimated parameters indicated that high-performing students were significantly more efficient at conducting strategic information processing, as reflected in their higher process performance. These findings are so far based on quantitative analyses using event log data. To enable a more differentiated analysis of students’ visual attention dynamics, more in-depth qualitative research of the identified student profiles in terms of COR will be required.
Background: Both EPO levels and anemia have shown prognostic value in several cardiac disorders. An observational study with a prospective follow-up was performed to investigate their independent prognostic roles in severe aortic stenosis. Methods: An up to 36-month follow-up of consecutive patients with severe aortic stenosis undergoing TAVR in a high-volume center was performed. Patients with eGRF <30 mL/min/1.73 m2 were excluded. EPO levels and/or anemia status and its association with mid-term mortality were assessed. Results: Out of 407, 360 met eligibility criteria. Median age was 83 years, with 71.4% having a NYHA class III/IV. Anemia was present in 51.9%, and iron deficiency in 52.8%. Median (IQR) EPO levels were 14.4 (9.30–24.30) mIU/mL. Median follow-up was 566 days. Anemia was associated with overall mortality (HR 2.40, 95% CI 1.51–3.80, p < 0.001). Higher logEPO levels were associated with mid-term mortality (HR 4.05, 95% CI 2.29–7.16, p < 0.001), even after adjusting for clinically and/or statistically relevant factors (multivariate HR 2.25, 95 CI 1.09–4.66, p = 0.029). Kaplan-Meier analyses showed early diverging curves for anemia vs. non-anemia, whereas curves for patients in various EPO level quartiles started to diverge at about 100 days, with differences consistently increasing during the subsequent entire follow-up period. Conclusions: Differently from anemia, which was a strong predictor for both early and late mortality in severe aortic stenosis after TAVR, independent prognostic value of EPO only emerged after post-TAVR recovery. EPO prognostic value was independent from anemia and mild-to-moderate renal dysfunction. High EPO levels could be useful to identify patients with severe aortic stenosis showing a compromised mid-term survival in spite of TAVR use and independently from early TAVR results.
Objective: This study aims to evaluate catheter management in acute epididymitis (AE) patients requiring inpatient treatment and risk factors predicting severity of disease.
Material and Methods: Patients with diagnosed AE and inpatient treatment between 2004 and 2019 at the University Hospital Frankfurt were analyzed. A risk score, rating severity of AE, including residual urine > 100 ml, fever > 38.0°C, C-reactive protein (CRP) > 5 mg/dl, and white blood count (WBC) > 10/nl was introduced.
Results: Of 334 patients, 107 (32%) received a catheter (transurethral (TC): n = 53, 16%, suprapubic (SPC): n = 54, 16%). Catheter patients were older, exhibited more comorbidities, and had higher CRP and WBC compared with the non-catheter group (NC). Median length of stay (LOS) was longer in the catheter group (7 vs. 6 days, p < 0.001), whereas necessity of abscess surgery and recurrent epididymitis did not differ. No differences in those parameters were recorded between TC and SPC. According to our established risk score, 147 (44%) patients exhibited 0–1 (low-risk) and 187 (56%) 2–4 risk factors (high-risk). In the high-risk group, patients received a catheter significantly more often than with low-risk (TC: 22 vs. 9%; SPC: 19 vs. 12%, both p ≤ 0.01). Catheter or high-risk patients exhibited positive urine cultures more frequently than NC or low-risk patients. LOS was comparable between high-risk patients with catheter and low-risk NC patients.
Conclusion: Patients with AE who received a catheter at admission were older, multimorbid, and exhibited more severe symptoms of disease compared with the NC patients. A protective effect of catheters might be attributable to patients with adverse risk constellations or high burden of comorbidities. The introduced risk score indicates a possibility for risk stratification.
Evoked potentials in the amplitude-time spectrum of the electroencephalogram are commonly used to assess the extent of brain responses to stimulation with noxious contact heat. The magnitude of the N- and P-waves are used as a semi-objective measure of the response to the painful stimulus: the higher the magnitude, the more painful the stimulus has been perceived. The strength of the N-P-wave response is also largely dependent on the chosen reference electrode site. The goal of this study was to examine which reference technique excels both in practical and theoretical terms when analyzing noxious contact heat evoked potentials (CHEPS) in the amplitude-time spectrum. We recruited 21 subjects (10 male, 11 female, mean age of 55.79 years). We applied seven noxious contact heat stimuli using two temperatures, 51°C, and 54°C, to each subject. During EEG analysis, we aimed to identify the referencing technique which produces the highest N-wave and P-wave amplitudes with as little artifactual influence as possible. For this purpose, we applied the following six referencing techniques: mathematically linked A1/A2 (earlobes), average reference, REST, AFz, Pz, and mathematically linked PO7/PO8. We evaluated how these techniques impact the N-P amplitudes of CHEPS based on our data from healthy subjects. Considering all factors, we found that mathematically linked earlobes to be the ideal referencing site to use when displaying and evaluating CHEPS in the amplitude-time spectrum.
Alzheimer’s disease (AD) is the major cause of dementia. It is characterized by the accumulation of abnormal proteins (amyloid-β plaque and neurofibrillary tangles) leading to loss of synapses, dendrites, neurons, memory and cognition. Sporadic late-onset AD is the major type of AD characterized by unclear etiology and a lack of disease-modifying therapy. To understand this disease, an alternative AD hypothesis has been proposed: AD may resemble diabetes in the brain or “diabetes type 3”. This hypothesis is supported by the fact that (1) brain glucose hypometabolism precedes AD clinical symptoms and (2) diabetes increases the risk of AD. To test this hypothesis, wild-type rats receiving intracerebroventricular administration of streptozotocin (icv-STZ) were used as a model. Streptozotocin (STZ) is a glucosamine-nitrosourea compound commonly used to induce experimental diabetes by peripheral administration. A similar pathological mechanism to peripheral STZ is then proposed to explain icv-STZ toxicity: insulin receptor signaling impairment results in glucose hypometabolism leading to cognitive deficits.
Objective: Icv-STZ model seems promising as a toxin-induced, non-transgenic AD model with the possibility to connect AD and diabetes mellitus (DM), one of the risk factors for AD. However, the mechanisms of how icv-STZ induced AD-like symptoms are unclear. Therefore, using microdialysis as the main technique, we tested 2 AD hypotheses in this model: (1) the glucose hypometabolism as an alternative AD hypothesis and (2) the cholinergic deficit as an important characteristic of AD pathology. Hippocampus was chosen because cholinergic function in this region is severely affected in AD. In comparison, the striatum was chosen because it contains cholinergic interneurons and is less affected in AD.
Methods: In this study, we used male Wistar rats of 190-220 g body weight (5 weeks of age). The rats were injected intracerebrally with STZ at a dose of 3 mg/kg (2x1.5 mg/kg; „high dose“) and 0.6 mg/kg („low dose“) with saline as control. After 21 days, samples were collected to investigate cholinergic and metabolic changes using histology, biochemistry, and neurochemistry. Brain injury was confirmed using GFAP staining and Fluoro jade staining in the hippocampus. Mitochondrial toxicity was investigated by measurement of mitochondrial
respiratory function in both hippocampus and striatum. Cholinergic markers such as acetylcholinesterase (AChE) activity, choline acetyltransferase (ChAT) activity, and choline transporter (CHT-1) activity, commonly known as high-affinity choline uptake (HACU), were measured in both hippocampus and striatum using a spectrophotometer and a scintillator.
Microdialysis is the main technique in our study. It was done in awake animals under behavioral or pharmacological stimulation. We used a self-built probe with a semi-permeable membrane (pore size of 30 kDa) that was implanted in either hippocampus or striatum. The probes were then perfused with artificial cerebrospinal fluid (aCSF) supplemented with 0.1 μM neostigmine for extracellular acetylcholine level measurement. During the perfusion, small hydrophilic compounds from brain extracellular space diffuse into the dialysates. Dialysates of 15 minutes intervals were collected for 90 minutes and used for analysis. After collection of dialysates for the first 90 minutes (basal data), rats were moved to an open field box (35x32x20 cm) for behavioral stimulation. After collection of the second 90 minute dialysates, the rats were transferred back to the microdialysis cage and dialysates were collected for another 90 minutes. On day 2, after collection of dialysates under basal conditions, 1 μM scopolamine was added to the perfusion solution for stimulation of acetylcholine release. The dialysates were also collected for 90 min followed by another 90 min of dialysis without scopolamine. The microdialysate samples were then analyzed as follows. ACh level was measured by HPLC-ECD. Glucose metabolites (glucose, lactate, pyruvate) were measured by a CMA-600 microanalyzer. An alternative energy metabolite (beta-hydroxybutyrate/BHB) was measured by GC-MS. Choline and glycerol as membrane breakdown markers were also measured by HPLC-ECD and CMA-600 microanalyzer, respectively. Markers of oxidative stress (isoprostanes) were measured using a commercially available ELISA kit.
...
An overexpression of the E3 ubiquitin ligase TRIM25 is implicated in several human cancers and frequently correlates with a poor prognosis and occurrence of therapy resistance in patients. Previous studies of our group have identified the mRNA encoding the pro-apoptotic caspase-2 as a direct target of the ubiquitous RNA binding protein human antigen R (HuR). The constitutive HuR binding observed in colon carcinoma cells negatively interferes with the translation of caspase-2 mainly through binding to the 5' untranslated region (UTR) of caspase-2 and thereby confers an increased survival of tumor cells. The main objective of this thesis was to unravel novel regulatory proteins critically involved in the control of caspase-2 translation and their impact on therapeutic drug resistance of human colon carcinoma cells. By employing RNA affinity chromatography in combination with mass-spectrometry, among several putative caspase-2 mRNA binding proteins, we have identified the tripartite motif-containing protein 25 (TRIM25) as novel caspase-2 translation regulatory protein in colon carcinoma cells. The constitutive TRIM25 binding to caspase-2 mRNA in two different human colorectal carcinoma cell lines was validated by ribonucleoprotein (RNP)-immunoprecipitation (RIP)-RT-PCR assay and by means of biotin-labeled RNA-pull-down assay. Since caspase-2 is a caspase which is particularly involved in the DNA-damage-induced apoptosis, I tested the functional relevance of negative caspase-2 regulation by TRIM25 for chemotherapeutic drug-induced cell death of different adenocarcinoma cells by RNA interference (RNAi)- mediated loss-of-function and gain-of-function approaches. In the first part of the thesis, I could demonstrate that transient silencing of TRIM25 caused a significant increase in caspase-2 protein levels without affecting the amount of corresponding mRNAs. Mechanistically, the TRIM25 silencing-triggered increase in caspase-2 was totally impaired by cycloheximide, indicating that the stimulatory effects on caspase-2 levels depend on protein synthesis. This finding was corroborated by RNP/polysomal fractionation, which revealed that the transient knockdown of TRIM25 caused a significant redistribution of caspase-2 transcripts from the fraction of RNP particles to that from translationally active polyribosomes.
The second part of my thesis aimed at the elucidation of the functional consequences of the negative caspase-2 regulation by TRIM25 for enhanced tumor cell survival. Thereby, I found that the siRNA-mediated knockdown of TRIM25 caused a significant increase in the chemotherapeutic drug-induced cleavage of caspase-3 and to elevations in cytoplasmic cytochrome c levels implicating that TRIM25 depletion did mainly affect the intrinsic apoptotic pathway. Concordantly, the ectopic expression of TRIM25 caused a reduction in caspase-2 protein levels, concomitant with an attenuated sensitivity of tumor cells to doxorubicin.
To test the functional impact of caspase-2 in the TRIM25 depletion-dependent sensitization to drug-induced apoptosis, I employed a siRNA-mediated knockdown of caspase-2. Interestingly, the strong induction of caspase-3 and -7 cleavage after doxorubicin treatment was fully impaired after the additional knockdown of caspase-2, indicating the sensitizing effects by TRIM25 knockdown depend on caspase-2.
Data from this thesis identified the TRIM25 as a novel RNA-binding protein of caspase-2 mRNA, which negatively interferes with the translation of caspase-2 and which functionally contributes to chemotherapeutic drug resistance of colon carcinoma cells. Interfering with the negative TRIM25-caspase-2 axis may represent a promising therapeutic avenue for sensitizing colorectal cancers to conventional anti-tumor therapies.
Bipolar disorder (BD) and major depressive disorder (MDD) are severe mood disorders that belong to the most debilitating diseases worldwide. Differentiating both mood disorders often poses a major clinical challenge, leading to frequent misdiagnoses. Objective biomarkers able to differentiate individuals with BD and MDD therefore represent a psychiatric research field of utmost importance. Recent studies have applied resting-state fMRI paradigms and found promising results differentiating both disorders based on the acquired data. However, most of these studies have focused their efforts on acutely depressed patients. Thus, it remains unclear whether the aberrations remain in a symptomless disease state.
The here presented study addresses these issues by evaluating the ability to differentiate both disorders from one another by conducting a between-group comparison of functional brain network connectivity (FNC) obtained from resting-state fMRI data. Data were collected from 20 BD, 15 MDD patients and 30 age- and gender-matched healthy controls (HC). Graph theoretical analyses were applied to detect differences in functional network organization between the groups on a global and regional network level.
Network analysis detected frontal, temporal and subcortical nodes in emotion regulation areas such as the limbic system and associated regions exhibiting significant differences in network integration and segregation in BD compared to MDD patients and HC. Participants with MDD and HC only differed in frontal and insular network centrality.
These results indicate that a significantly altered brain network topology in the limbic system might be a trait marker specific to BD. Brain network analysis in these regions may therefore be used to differentiate euthymic BD not only from HC but also from patients with MDD.
Aim: Left ventricular non-compaction (LVNC) is perceived as a rare high-risk cardiomyopathy characterized by excess left ventricular (LV) trabeculation. However, there is increasing evidence contesting the clinical significance of LV hyper-trabeculation and the existence of LVNC as a distinct cardiomyopathy. The aim of this study is to assess the association of LV trabeculation extent with cardiovascular morbidity and all-cause mortality in patients undergoing clinical cardiac magnetic resonance (CMR) scans across 57 European centers from the EuroCMR registry.
Methods and Results: We studied 822 randomly selected cases from the EuroCMR registry. Image acquisition was according to international guidelines. We manually segmented images for LV chamber quantification and measurement of LV trabeculation (as per Petersen criteria). We report the association between LV trabeculation extent and important cardiovascular morbidities (stroke, atrial fibrillation, heart failure) and all-cause mortality prospectively recorded over 404 ± 82 days of follow-up. Maximal non-compaction to compaction ratio (NC/C) was mean (standard deviation) 1.81 ± 0.67, from these, 17% were above the threshold for hyper-trabeculation (NC/C > 2.3). LV trabeculation extent was not associated with increased risk of the defined outcomes (morbidities, mortality, LV CMR indices) in the whole cohort, or in sub-analyses of individuals without ischaemic heart disease, or those with NC/C > 2.3.
Conclusion: Among 882 patients undergoing clinical CMR, excess LV trabeculation was not associated with a range of important cardiovascular morbidities or all-cause mortality over ~12 months of prospective follow-up. These findings suggest that LV hyper-trabeculation alone is not an indicator for worse cardiovascular prognosis.
Signature of consciousness in brain-wide synchronization patterns of monkey and human fMRI signals
(2020)
During the sleep-wake cycle, the brain undergoes profound dynamical changes, which manifest subjectively as transitions between conscious experience and unconsciousness. Yet, neurophysiological signatures that can objectively distinguish different consciousness states based are scarce. Here, we show that differences in the level of brain-wide signals can reliably distinguish different stages of sleep and anesthesia from the awake state in human and monkey fMRI resting state data. Moreover, a whole-brain computational model can faithfully reproduce changes in global synchronization and other metrics such as functional connectivity, structure-function relationship, integration and segregation across vigilance states. We demonstrate that the awake brain is close to a Hopf bifurcation, which naturally coincides with the emergence of globally correlated fMRI signals. Furthermore, simulating lesions of individual brain areas highlights the importance of connectivity hubs in the posterior brain and subcortical nuclei for maintaining the model in the awake state, as predicted by graph-theoretical analyses of structural data.
Background and Objective: Macrophages’ cytokine expression and polarization play a substantial role in the host's “destructive” inflammatory response to periodontal and peri‐implant pathogens. This study aimed to evaluate cell viability, anti‐inflammatory activity, and macrophage polarization properties of different cranberry concentrates.
Methods: THP‐1 cells (monocytic line) were treated with phorbol myristic acid to induce macrophage differentiation. Human gingival fibroblasts (HFIB‐G cell line), osteosarcoma‐derived osteoblasts (SAOS‐2 cell line), and induced macrophages were treated with cranberry concentrates at 25, 50, and 100 µg/mL for 120 seconds, 1 hour and 24 hours. Untreated cells at the same time points served as controls. For anti‐inflammatory analysis, induced macrophages exposed to cranberry concentrates (A‐type PACs) were stimulated with lipopolysaccharides (LPS) derived from E coli for 24 hours. Cell viability, interleukin (IL)‐8, IL‐1 ß, IL‐6, and IL‐10 expression of LPS‐stimulated macrophages, and macrophage polarization markers were evaluated through determination of live‐cell protease activity, enzyme‐linked immunosorbent assay, and immunofluorescence staining semi‐quantification.
Results: Cranberry concentrates (A‐type PACs) did not reduce HGF, SAOS‐2, and macrophage viability after 24 hours of exposure. Pro‐inflammatory cytokine expression (ie IL‐8 and IL‐6) was downregulated in LPS‐stimulated macrophages by cranberry concentrates at 50 and 100 µg/mL. Anti‐inflammatory IL‐10 expression was significantly upregulated in LPS‐stimulated macrophages by cranberry concentrates at 100 µg/mL after 24 hours of exposure. M1 polarization significantly decreased when LPS‐stimulated macrophages were exposed to cranberry concentrates. High levels of positive M1 macrophages were present in all untreated control groups. M2 polarization significantly increased at all LPS‐stimulated macrophages exposed to cranberry concentrates for 1 and 24 hours.
Conclusion: Cranberry‐derived proanthocyanidins may have the potential to act as an anti‐inflammatory component in the therapy of periodontal and peri‐implant diseases.
Consensus on definition and severity grading of lymphatic complications after kidney transplantation
(2020)
Background: The incidence of lymphatic complications after kidney transplantation varies considerably in the literature. This is partly because a universally accepted definition has not been established. This study aimed to propose an acceptable definition and severity grading system for lymphatic complications based on their management strategy.
Methods: Relevant literature published in MEDLINE and Web of Science was searched systematically. A consensus for definition and a severity grading was then sought between 20 high-volume transplant centres.
Results: Lymphorrhoea/lymphocele was defined in 32 of 87 included studies. Sixty-three articles explained how lymphatic complications were managed, but none graded their severity. The proposed definition of lymphorrhoea was leakage of more than 50 ml fluid (not urine, blood or pus) per day from the drain, or the drain site after removal of the drain, for more than 1 week after kidney transplantation. The proposed definition of lymphocele was a fluid collection of any size near to the transplanted kidney, after urinoma, haematoma and abscess have been excluded. Grade A lymphatic complications have a minor and/or non-invasive impact on the clinical management of the patient; grade B complications require non-surgical intervention; and grade C complications require invasive surgical intervention.
Conclusion: A clear definition and severity grading for lymphatic complications after kidney transplantation was agreed. The proposed definitions should allow better comparisons between studies.
Reduced Cl− conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca2+- and voltage-activated K+ channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK−/−) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotonia in-vitro. Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T90/10) were monitored. Compared to wild type, fast-twitch muscle specimen of BK−/− mice resulted in a significantly decreased T90/10 in presence of 9-AC. Paxilline significantly shortened T90/10 of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T90/10. The currently used standard therapy for myotonia is, in some individuals, not very effective. This in vitro study demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC).
Background: Cognitive dysfunctions represent a core feature of schizophrenia and a predictor for clinical outcomes. One possible mechanism for cognitive impairments could involve an impairment in the experience-dependent modifications of cortical networks.
Methods: To address this issue, we employed magnetoencephalography (MEG) during a visual priming paradigm in a sample of chronic patients with schizophrenia (n = 14), and in a group of healthy controls (n = 14). We obtained MEG-recordings during the presentation of visual stimuli that were presented three times either consecutively or with intervening stimuli. MEG-data were analyzed for event-related fields as well as spectral power in the 1–200 Hz range to examine repetition suppression and repetition enhancement. We defined regions of interest in occipital and thalamic regions and obtained virtual-channel data.
Results: Behavioral priming did not differ between groups. However, patients with schizophrenia showed prominently reduced oscillatory response to novel stimuli in the gamma-frequency band as well as significantly reduced repetition suppression of gamma-band activity and reduced repetition enhancement of beta-band power in occipital cortex to both consecutive repetitions as well as repetitions with intervening stimuli. Moreover, schizophrenia patients were characterized by a significant deficit in suppression of the C1m component in occipital cortex and thalamus as well as of the late positive component (LPC) in occipital cortex.
Conclusions: These data provide novel evidence for impaired repetition suppression in cortical and subcortical circuits in schizophrenia. Although behavioral priming was preserved, patients with schizophrenia showed deficits in repetition suppression as well as repetition enhancement in thalamic and occipital regions, suggesting that experience-dependent modification of neural circuits is impaired in the disorder.
Chronic viral hepatitis is associated with substantial morbidity and mortality worldwide. The aim of our study was to assess the ability of point shear‐wave elastography (pSWE) using acoustic radiation force impulse imaging for the prediction of the following liver‐related events (LREs): new diagnosis of HCC, liver transplantation, or liver‐related death (hepatic decompensation was not included as an LRE). pSWE was performed at study inclusion and compared with liver histology, transient elastography (TE), and serologic biomarkers (aspartate aminotransferase to platelet ratio index, Fibrosis‐4, FibroTest). The performance of pSWE and TE to predict LREs was assessed by calculating the area under the receiver operating characteristic curve and a Cox proportional‐hazards regression model. A total of 254 patients with a median follow‐up of 78 months were included in the study. LRE occurred in 28 patients (11%) during follow‐up. In both patients with hepatitis B virus and hepatitis C virus (HCV), pSWE showed significant correlations with noninvasive tests and TE, and median pSWE and TE values were significantly different between patients with LREs and patients without LREs (both P < 0.0001). In patients with HCV, the area under the receiver operating characteristic curve for pSWE and TE to predict LREs were comparable: 0.859 (95% confidence interval [CI], 0.747‐0.969) and 0.852 (95% CI, 0.737‐0.967) (P = 0.93). In Cox regression analysis, pSWE independently predicted LREs in all patients with HCV (hazard ratio, 17.9; 95% CI, 5.21‐61‐17; P < 0.0001) and those who later received direct‐acting antiviral therapy (hazard ratio, 17.11; 95% CI, 3.88‐75.55; P = 0.0002). Conclusion: Our study shows good comparability between pSWE and TE. pSWE is a promising tool for the prediction of LREs in patients with viral hepatitis, particularly those with chronic HCV. Further studies are needed to confirm our data and assess their prognostic value in other liver diseases.
Background: Recently, RBFOX1, a gene encoding an RNA binding protein, has consistently been associated with aggressive and antisocial behavior. Several loci in the gene have been nominally associated with aggression in genome-wide association studies, the risk alleles being more frequent in the general population. We have hence examined the association of four RBFOX1 single nucleotide polymorphisms, previously found related to aggressive traits, with aggressiveness, personality, and alcohol use disorder in birth cohort representative samples.
Methods: We used both birth cohorts of the Estonian Children Personality Behavior and Health Study (ECPBHS; original n = 1,238). Aggressiveness was assessed using the Buss–Perry Aggression Questionnaire and the Lifetime History of Aggressiveness structured interview at age 25 (younger cohort) or 33 (older cohort). Big Five personality at age 25 was measured with self-reports and the lifetime occurrence of alcohol use disorder assessed with the MINI interview. RBFOX1 polymorphisms rs809682, rs8062784, rs12921846, and rs6500744 were genotyped in all participants. Given the restricted size of the sample, correction for multiple comparisons was not applied.
Results: Aggressiveness was not significantly associated with the RBFOX1 genotype. RBFOX1 rs8062784 was associated with neuroticism and rs809682 with extraversion. Two out of four analyzed RBFOX1 variants, rs8062784 and rs12921846, were associated with the occurrence of alcohol use disorder.
Conclusions: In the birth cohort representative sample of the ECPBHS, no association of RBFOX1 with aggressiveness was found, but RBFOX1 variants affected basic personality traits and the prevalence of alcohol use disorder. Future studies on RBFOX1 should consider the moderating role of personality and alcohol use patterns in aggressiveness.
Objective: The establishment of patient-centered measures capable of empirically determining meaningful cognitive change after surgery can significantly improve the medical care of epilepsy patients. Thus, this study aimed to develop reliable change indices (RCIs) and standardized regression-based (SRB) change norms for a comprehensive neuropsychological test battery in the German language.
Methods: Forty-seven consecutive patients with temporal lobe epilepsy underwent neuropsychological assessments, both before and 12 months after surgery. Practice-effect-adjusted RCIs and SRB change norms for each test score were computed. To assess their usefulness, the presented methods were applied to a clinical sample, and binary logistic regression analyses were conducted to model the odds of achieving improvement in quality of life (QOL) after surgery.
Results: The determined RCIs at 90% confidence intervals and the SRB equations for each test score included in the test battery are provided. Cohen’s kappa analyses revealed a moderate mean agreement between the two measures, varying from slight to almost perfect agreement across test scores. Using these measures, a negative association between improvement in QOL and decline in verbal memory functions after surgery was detected (adjusted odds ratio = 0.09, p = 0.006).
Significance: To the best of our knowledge, this study is the first to develop RCIs and SRB change norms necessary for the objective determination of neuropsychological change in a comprehensive test battery in the German language, facilitating the individual monitoring of improvement and decline in each patients’ cognitive functioning and psychosocial situations after epilepsy surgery. The application of the described measures revealed a strong negative association between improvement in QOL and decline in verbal memory functions after surgery.
APPEAL‐1: A pan‐European survey of patient/caregiver perceptions of peanut allergy management
(2020)
Background: Peanut allergy (PA) is associated with marked quality‐of‐life (QoL) impairment. However, data are lacking on the experience and impact of living with PA from the perspectives of persons with PA (PwPA) and their caregivers. Allergy to Peanuts imPacting Emotions And Life study 1 (APPEAL‐1) was a pan‐European survey investigating these perspectives. This first of two articles reports clinical characteristics of PwPA and PA management practices.
Methods: APPEAL‐1 was a quantitative, online survey conducted in eight European countries, developed by eight representatives of patient advocacy groups and five healthcare professionals and researchers. Eligible participants included adults with PA and parents/caregivers of PwPA who responded by self‐report and provided proxy‐report for the PwPA under their care. Data were summarized using nonweighted descriptive statistics.
Results: Of 1846 completed/analysed questionnaires, 528 were from adults with PA (self‐report); 437 by proxy for children with PA (34 aged 0‐3 years, 287 aged 4‐12 years, 116 aged 13‐17 years) and 881 from parents/caregivers (self‐report). Of PwPA (N = 965), 95% reported diagnosis by healthcare professionals, mostly by clinical history and peanut‐specific allergy testing. Rates of allergic rhinitis, asthma and other food allergies in PwPA were 50%, 42% and 79%, respectively. Only 31% of PwPA received HCP advice/support following their worst allergic reaction, and 28% had not been prescribed an adrenaline auto‐injector. Results were similar by country but varied by age group.
Conclusions: The APPEAL‐1 findings contribute to greater understanding of PA impact on PwPA, caregivers and family members and the need for improved PA management across Europe.
Objectives: To assess the short‐term clinical outcomes of lateral augmentation of deficient extraction sockets and two‐stage implant placement using autogenous tooth roots (TR).
Material and methods: A total of n = 13 patients (13 implants) were available for the analysis. At the time of tooth extraction, each subject had received lateral augmentation using the respective non‐retainable but non‐infected tooth root where the thickness of the buccal bone was <0.5 mm or where a buccal dehiscence‐type defect was present. Titanium implants were placed after a submerged healing period of 6 months and loaded after 20 ± 2 weeks (V8). Clinical parameters (e.g., bleeding on probing—BOP, probing pocket depth—PD, mucosal recession—MR, clinical attachment level—CAL) were recorded at V8 and after 26 ± 4 weeks (V9) of implant loading.
Results: At V9, all patients investigated revealed non‐significant changes in mean BOP (−19.23 ± 35.32%), PD (0.24 ± 0.49 mm), MR (0.0 ± 0.0 mm) and CAL (0.24 ± 0.49 mm) values, respectively. There was no significant correlation between the initial gain in ridge width and changes in BOP and PD values.
Conclusions: The surgical procedure was associated with stable peri‐implant tissues on the short‐term.
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.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a subtype of Hodgkin lymphoma with a preserved B‐cell phenotype and follicular T helper (TFH) cells rosetting around the tumor cells, the lymphocyte‐predominant (LP) cells. As we recently described reactivity of the B‐cell receptors of LP cells of some NLPHL cases with Moraxella spp. proteins, we hypothesized that LP cells could present peptides to rosetting T cells in a major histocompatibility complex class II (MHCII)‐bound manner. Rosetting PD1+ T cells were present in the majority of NLPHL cases, both in typical (17/20) and variant patterns (16/19). In most cases, T‐cell rosettes were CD69+ (typical NLPHL, 17/20; NLPHL variant, 14/19). Furthermore, both MHCII alpha and beta chains were expressed in the LP cells in 23/39 NLPHL. Proximity ligation assay and confocal laser imaging demonstrated interaction of the MHCII beta chain expressed by the LP cells and the T‐cell receptor alpha chain expressed by rosetting T cells. We thus conclude that rosetting T cells in NLPHL express markers that are encountered after antigenic exposure, that MHCII is expressed by the LP cells, and that LP cells interact with rosetting T cells in an immunological synapse in a subset of cases. As they likely receive growth stimulatory signals in this way, blockade of this interaction, for example, by PD1‐directed checkpoint inhibitors, could be a treatment option in a subset of cases in the future.
Objective: To evaluate the benefit of resective surgical periodontal therapy (root amputation or resection, root separation, tunnelling) in periodontitis patients exhibiting class II and III furcation involvement (FI) compared with non‐surgical treatment (SRP) or open flap debridement (OFD).
Material: Outcomes were tooth survival (primary), vertical probing attachment gain, and reduction in probing pocket depth (secondary) evidenced by randomized clinical trials, prospective and retrospective cohort studies and case series with ≥ 12 months of follow‐up. Search was performed on 3 electronic databases from January 1998 to December 2018.
Results: From a total of 683 articles, 66 studies were identified for full‐text analysis and 7 studies finally included. Six hundred sixty‐seven patients contributed 2,021 teeth with class II or III FI. Data were very heterogeneous regarding follow‐up and distribution of FI. A total of 1,515 teeth survived 4 to 30.8 years after therapy. Survival ranged from 38%–94.4% (root amputation or resection, root separation), 62%–67% (tunnelling), 63%–85% (OFD) and 68%–80% (SRP). Overall, treatment provided better results for class II FI than class III.
Conclusion: Within their limits, the data indicate that in class II and III FI, SRP and OFD may result in similar survival rates as root amputation/resection, root separation or tunnelling.
An important measure in pain research is the intensity of nociceptive stimuli and their cortical representation. However, there is evidence of different cerebral representations of nociceptive stimuli, including the fact that cortical areas recruited during processing of intranasal nociceptive chemical stimuli included those outside the traditional trigeminal areas. Therefore, the aim of this study was to investigate the major cerebral representations of stimulus intensity associated with intranasal chemical trigeminal stimulation. Trigeminal stimulation was achieved with carbon dioxide presented to the nasal mucosa. Using a single‐blinded, randomized crossover design, 24 subjects received nociceptive stimuli with two different stimulation paradigms, depending on the just noticeable differences in the stimulus strengths applied. Stimulus‐related brain activations were recorded using functional magnetic resonance imaging with event‐related design. Brain activations increased significantly with increasing stimulus intensity, with the largest cluster at the right Rolandic operculum and a global maximum in a smaller cluster at the left lower frontal orbital lobe. Region of interest analyses additionally supported an activation pattern correlated with the stimulus intensity at the piriform cortex as an area of special interest with the trigeminal input. The results support the piriform cortex, in addition to the secondary somatosensory cortex, as a major area of interest for stimulus strength‐related brain activation in pain models using trigeminal stimuli. This makes both areas a primary objective to be observed in human experimental pain settings where trigeminal input is used to study effects of analgesics.
Background: Enhancers play a fundamental role in orchestrating cell state and development. Although several methods have been developed to identify enhancers, linking them to their target genes is still an open problem. Several theories have been proposed on the functional mechanisms of enhancers, which triggered the development of various methods to infer promoter–enhancer interactions (PEIs). The advancement of high-throughput techniques describing the three-dimensional organization of the chromatin, paved the way to pinpoint long-range PEIs. Here we investigated whether including PEIs in computational models for the prediction of gene expression improves performance and interpretability.
Results: We have extended our TEPIC framework to include DNA contacts deduced from chromatin conformation capture experiments and compared various methods to determine PEIs using predictive modelling of gene expression from chromatin accessibility data and predicted transcription factor (TF) motif data. We designed a novel machine learning approach that allows the prioritization of TFs binding to distal loop and promoter regions with respect to their importance for gene expression regulation. Our analysis revealed a set of core TFs that are part of enhancer–promoter loops involving YY1 in different cell lines.
Conclusion: We present a novel approach that can be used to prioritize TFs involved in distal and promoter-proximal regulatory events by integrating chromatin accessibility, conformation, and gene expression data. We show that the integration of chromatin conformation data can improve gene expression prediction and aids model interpretability.
The aging process is characterized by a chronic, low‐grade inflammatory state, termed “inflammaging.” It has been suggested that macrophage activation plays a key role in the induction and maintenance of this state. In the present study, we aimed to elucidate the mechanisms responsible for aging‐associated changes in the myeloid compartment of mice. The aging phenotype, characterized by elevated cytokine production, was associated with a dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis and diminished serum corticosteroid levels. In particular, the concentration of corticosterone, the major active glucocorticoid in rodents, was decreased. This could be explained by an impaired expression and activity of 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), an enzyme that determines the extent of cellular glucocorticoid responses by reducing the corticosteroids cortisone/11‐dehydrocorticosterone to their active forms cortisol/corticosterone, in aged macrophages and peripheral leukocytes. These changes were accompanied by a downregulation of the glucocorticoid receptor target gene glucocorticoid‐induced leucine zipper (GILZ) in vitro and in vivo. Since GILZ plays a central role in macrophage activation, we hypothesized that the loss of GILZ contributed to the process of macroph‐aging. The phenotype of macrophages from aged mice was indeed mimicked in young GILZ knockout mice. In summary, the current study provides insight into the role of glucocorticoid metabolism and GILZ regulation during aging.
Investigating the inhibition of anti-apoptotic BCL-2 family proteins in pediatric cancer cells
(2020)
Cancer is amongst the leading causes of death in childhood. Rhabdomyosarcoma (RMS) is the most frequently occurring soft tissue sarcoma in children and adolescents. It presumably arises from mesenchymal progenitors of skeletal muscle cells and presents with different subtypes that differ both histologically and genetically. Osteosarcoma (OS) and Ewing sarcoma (ES) are the most frequently diagnosed pediatric bone tumors. Even though the prognosis of these cancer entities improved significantly during recent decades, the survival rates are currently stagnating. Especially, dismal prognosis of relapsed and metastasizing cases of these malignancies urgently call for novel treatment options. BCL-2 proteins are vital guardians that control intrinsic apoptosis. Furthermore, it was shown that BCL-2 proteins critically regulate apoptosis in pediatric solid tumors. BH3 mimetics are small molecules that bind and inhibit anti-apoptotic BCL-2 proteins. They have already been investigated as cancer therapeutics for several years and show first encouraging clinical results. Therefore, we hypothesized that targeting BCL-2, MCL-1 and BCL-XL might be a promising approach to treat RMS, OS and ES.
In this study, we aimed to comprehensively evaluate the potential of anti-apoptotic BCL-2 family proteins as therapeutic targets for pediatric solid tumors such as RMS, OS and ES.
Notably, RMS, OS and ES cells largely expressed the most relevant BCL-2 family protein members. However, cells were widely insensitive to single pharmacological inhibition of either BCL-XL, BCL-2 or MCL-1 by A-1331852, ABT-199 and S63845, respectively. This finding was independent of their BCL-2 family protein expression levels. Significantly, co-administration of A-1331852 and S63845 induced cell death in RMS, OS and ES cell lines in a highly synergistic manner. Transient silencing of MCL-1 and/or BCL-XL verified the co-dependency of RMS cells on these proteins for survival. Importantly, A-1331852/S63845 co-treatment was more efficient in causing cell death in RMS, OS and ES cells than either inhibitor combined with ABT-199. Efficacy of A-1331852/S63845 co-treatment could be additionally demonstrated in a primary sample of pediatric malignant epithelioid mesothelioma.
Mechanistically, concomitant A-1331852/S63845 treatment mediated rapid intrinsic apoptosis involving swift loss of the mitochondrial outer membrane potential as well as activation of caspases-3, -8 and -9. An observed caspase dependent loss of MCL-1 might further amplify the A-1331852/S63845 triggered pro-death signaling. Furthermore, we identified BAX and BAK as key mediators of apoptosis caused by dual inhibition of MCL-1 and BCL-XL. A-1331852/S63845 induced cell death was relying on BAX and/or BAK in a cell line dependent manner. Interestingly, treatment with A-1331852 and S63845 liberated BAK from its interaction with MCL-1 and BCL-XL. Moreover, BAX and BAK were activated and interacted with each other to form a pore in the outer mitochondrial membrane. Further, in RD cells BIM and NOXA partially contributed to A-1331852/S63845 mediated cell death. Consistently, in this cell line BIM and NOXA were disrupted from their binding to BCL-XL and MCL-1 by A-1331852 and S63845, respectively. However, BH3 only proteins were not involved in A-1331852/S63845 induced cell death in Kym-1 cells. Therefore, we concluded that BH3 only proteins played only a marginal and cell line dependent role in mediating cell death caused by MCL-1 and BCL-XL co-repression.
Notably, A-1331852/S63845 co-treatment spared non-malignant fibroblasts, myoblasts and peripheral blood mononuclear cells, which suggests a therapeutic window for its application in vivo. Besides, we could demonstrate that sequential BH3 mimetic treatment still significantly induced cell death, albeit to minor extents compared to its dual administration. Importantly, we successfully evaluated concomitant treatment with A-1331852 and S63845 in multicellular RMS spheroids and in an in vivo embryonic chicken model of RMS. These findings stress the high transcriptional relevance of A-1331852/S63845 as an emerging novel cancer regimen.
Collectively, the thesis at hand explored the great potential of co-treatment with A-1331852 and S63845 in pediatric solid tumors and unveiled the underlying molecular mechanisms of cell death in RMS. Together, the current investigations support further preclinical and clinical studies to evaluate the effect of dual MCL-1 and BCL-XL targeting in pediatric solid tumors.
Aim: Our aim was to analyse the diagnostic workup of hospitalised infants with symptoms of congenital cytomegalovirus (CMV) infections.
Methods: This retrospective study was carried out at the University Hospital Frankfurt, Germany, from 2008 to 2017 on infants aged 4 weeks to 12 months presenting with neurological symptoms consistent with congenital CMV infections.
Results: We studied 117 infants, and workup data for CMV infections were available for 84%. Of these, 54% were immunoglobulin G‐ and immunoglobulin M‐seronegative for CMV or immunoglobulin G‐seropositive with no viral shedding. Congenital CMV infection was excluded in these cases. In 16%, the CMV workup was incomplete, precluding a definitive diagnosis. Dried blood spots (DBS) were requested from 30%. CMV polymerase chain reaction was negative in 19 of these 29 infants, and CMV deoxyribonucleic acid detection confirmed congenital CMV infections in six patients. DBS had been destroyed in line with German law in four cases. Congenital CMV infections were diagnosed (5%) or excluded (62%) in 67% of patients and unanswered in the remaining 33%.
Conclusion: Diagnoses of congenital CMV infections were widely considered and found in 5%. CMV was not stringently investigated in all patients or remained elusive due to German law on destroying DBS.
Aims: Heart failure (HF) leads to repeat hospitalisations and reduces the duration and quality of life. Pulmonary artery pressure (PAP)‐guided HF management using the CardioMEMS™ HF system was shown to be safe and reduce HF hospitalisation (HFH) rates in New York Heart Association (NYHA) class III patients. However, these findings have not been replicated in health systems outside the United States. Therefore, the CardioMEMS European Monitoring Study for Heart Failure (MEMS‐HF) evaluated the safety, feasibility, and performance of this device in Germany, The Netherlands, and Ireland.
Methods and results: A total of 234 NYHA class III patients (68 ± 11 years, 22% female, ≥1 HFH in the preceding year) from 31 centres were implanted with a CardioMEMS sensor and underwent PAP‐guided HF management. One‐year rates of freedom from device‐ or system‐related complications and from sensor failure (co‐primary outcomes) were 98.3% [95% confidence interval (CI) 95.8–100.0] and 99.6% (95% CI 97.6–100.0), respectively. Survival rate was 86.2%. For the 12 months post‐ vs. pre‐implant, HFHs decreased by 62% (0.60 vs. 1.55 events/patient‐year; hazard ratio 0.38, 95% CI 0.31–0.48; P < 0.0001). After 12 months, mean PAP decreased by 5.1 ± 7.4 mmHg, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall/clinical summary scores increased from 47.0 ± 24.0/51.2 ± 24.8 to 60.5 ± 24.3/62.4 ± 24.1 (P < 0.0001), and the 9‐item Patient Health Questionnaire sum score improved from 8.7 ± 5.9 to 6.3 ± 5.1 (P < 0.0001).
Conclusion: Haemodynamic‐guided HF management proved feasible and safe in the health systems of Germany, The Netherlands, and Ireland. Physician‐directed treatment modifications based on remotely obtained PAP values were associated with fewer HFH, sustainable PAP decreases, marked KCCQ improvements, and remission of depressive symptoms.
Background and Objectives: Red blood cell (RBC) transfusions are needed by almost every acute myeloid leukaemia (AML) patient undergoing induction chemotherapy and constitute a cornerstone in supportive measures for cancer patients in general. Randomized controlled trials have shown non‐inferiority or even superiority of restrictive transfusion guidelines over liberal transfusion guidelines in specific clinical situations outside of medical oncology. In this study, we analysed whether more restrictive RBC transfusion reduces blood use without affecting hard outcomes.
Materials and Methods: A total of 352 AML patients diagnosed between 2007 and 2018 and undergoing intensive induction chemotherapy were included in this retrospective analysis. In the less restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 8 g/dl (2007–2014). In the restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 7 g/dl (2016–2018). Liberal transfusion triggers were never endorsed.
Results: A total of 268 (76·1%) and 84 (23·9%) AML patients fell into the less restrictive and restrictive transfusion groups, respectively. The less restrictive transfusion group had 1 g/dl higher mean haemoglobin levels, received their first RBC transfusions earlier and needed 1·5 more units of RBC during the hospital stay of induction chemotherapy. Febrile episodes, C‐reactive protein levels, admission to the intensive care unit, length of hospital stay as well as response and survival rates did not differ between the two cohorts.
Conclusion: From our retrospective analysis, we conclude that a more restrictive transfusion trigger does not affect important outcomes of AML patients. The opportunity to test possible effects of the more severe anaemia in the restrictive transfusion group on quality of life was missed.
Overconsumption of carbohydrates and lipids are well known to cause nonalcoholic fatty liver disease (NAFLD), while the role of nutritional protein intake is less clear. In Western diet, meat and other animal products are the main protein source, with varying concentrations of specific amino acids. Whether the amount or composition of protein intake is associated with a higher risk for disease severity has not yet been examined. In this study, we investigated associations of dietary components with histological disease activity by analyzing detailed 14‐day food records in a cohort of 61 patients with biopsy‐proven NAFLD. Furthermore, we used 16S ribosomal RNA gene sequencing to detect associations with different abundances of the gut microbiota with dietary patterns. Patients with definite nonalcoholic steatohepatitis (NAFLD activity score of 5‐8 on liver biopsy) had a significantly higher daily relative intake of protein compared with patients with a NAFLD activity score of 0‐4 (18.0% vs. 15.8% of daily protein‐based calories, P = 0.018). After adjustment for several potentially confounding factors, a higher protein intake (≥17.3% of daily protein‐based calories) remained associated with definite nonalcoholic steatohepatitis, with an odds ratio of 5.09 (95% confidence interval 1.22‐21.25, P = 0.026). This association was driven primarily by serine, glycine, arginine, proline, phenylalanine, and methionine. A higher protein intake correlated with a lower Bacteroides abundance and an altered abundance of several other bacterial taxa. Conclusion: A high protein intake was independently associated with more active and severe histological disease activity in patients with NAFLD. Further studies are needed to investigate the potential harmful role of dietary amino acids on NAFLD, with special attention to meat as their major source.
Since type and duration of an appropriate adjuvant chemotherapy in early-stage ovarian cancer (OC) are still being debated, novel markers for a better stratification of these patients are of utmost importance for the design of an improved chemotherapeutical strategy. In contrast to numerous cancer studies on cellular proliferation based on the immunohistochemistry-driven evaluation of protein expression, we compared mRNA and protein expression of two independent markers of cellular proliferation, Ki-67 and Plk1, in a large cohort of 243 early-stage OC and their relationship with clinicopathological features and survival. Based on marker expression we demonstrate that early-stage OC patients (stages I/II, low-grade, serous) with high expression (Ki-67, Plk1) had a significantly shorter progression-free survival (PFS) and overall survival (OS) compared to patients with low expression (Ki-67, Plk1). Remarkably, based on mRNA expression this significant difference got lost in advanced stages (III/IV): At least for PFS, high levels of Ki-67 and Plk1 correlate with moderately better survival compared to patients with low expressing tumors. Our data suggest that in addition to Ki-67, Plk1 is a novel marker for the stratification of early-stage OC patients to maximize therapeutic efforts. Both, Ki-67 and Plk1, seem to be better suited in early-stages (I/II) as therapeutical targets compared to advanced-stages (III/IV) OC.
A plethora of data has highlighted the role of epigenetics in the development of cancer. Initiation and progression of different cancer types are associated with a variety of changes of epigenetic mechanisms, including aberrant DNA methylation, histone modifications, and miRNA expression. At the same time, advances in the available epigenetic tools allow to investigate and reverse these epigenetic changes and form the basis for the development of anticancer drugs in human oncology. Although human and canine cancer shares several common features, only recently that studies emerged investigating the epigenetic landscape in canine cancer and applying epigenetic modulators to canine cancer. This review focuses on the existing studies involving epigenetic changes in different types of canine cancer and the use of small-molecule inhibitors in canine cancer cells.
Rationale: Bronchiolitis obliterans syndrome (BOS) is a severe, chronic inflammation of the airways leading to an obstruction of the bronchioles. So far, there are only a few studies looking at the long‐term development of pulmonary impairment in children with BOS.
Objective: The objective of this study was to investigate the incidence and long‐term outcome of BOS in children who underwent allogeneic hematopoietic stem cell transplantation (HSCT).
Methods: Medical charts of 526 children undergoing HSCT in Frankfurt/Main, Germany between 2000 and 2017 were analyzed retrospectively and as a result, 14 patients with BOS were identified. A total of 271 lung functions (spirometry and body plethysmography), 26 lung clearance indices (LCI), and 46 chest high‐resolution computed tomography (HRCT) of these 14 patients with BOS were evaluated.
Results: Fourteen patients suffered from BOS after HSCT (2.7%), whereby three distinctive patterns of lung function impairment were observed: three out of 14 patients showed a progressive lung function decline; two died and one received a lung transplant. In five out of 14 patients with BOS persisted with a severe obstructive and secondarily restrictive pattern in lung function (forced vital capacity [FVC] < 60%, forced expiratory volume in 1 second [FEV1] < 50%, and FEV1/FVC < 0.7) and increased LCI (11.67‐20.9), six out of 14 patients recovered completely after moderate lung function impairment and signs of BOS on HRCT. Long‐term FVC in absolute numbers was increased indicating that the children still have lung growth.
Conclusion: Our results showed that the incidence of BOS in children is low. BOS was associated with high mortality and may lead to persistent obstructive lung disease; although, lung growth continued to exist.
Unresolved inflammation maintained by release of danger‐associated molecular patterns, particularly high‐mobility group box‐1 (HMGB1), is crucial for hepatocellular carcinoma (HCC) pathogenesis. To further characterize interactions between leucocytes and necrotic cancerous tissue, a cellular model of necroinflammation was studied in which murine Raw 264.7 macrophages or primary splenocytes were exposed to necrotic lysates (N‐lys) of murine hepatoma cells or primary hepatocytes. In comparison to those derived from primary hepatocytes, N‐lys from hepatoma cells were highly active—inducing in macrophages efficient expression of inflammatory cytokines like C‐X‐C motif ligand‐2 , tumor necrosis factor‐α, interleukin (IL)‐6 and IL‐23‐p19. This activity associated with higher levels of HMGB1 in hepatoma cells and was curbed by pharmacological blockage of the receptor for advanced glycation end product (RAGE)/HMGB1 axis or the mitogen‐activated protein kinases ERK1/2 pathway. Analysis of murine splenocytes furthermore demonstrated that N‐lys did not comprise of functionally relevant amounts of TLR4 agonists. Finally, N‐lys derived from hepatoma cells supported inflammatory splenic Th17 and Th1 polarization as detected by IL‐17, IL‐22 or interferon‐γ production. Altogether, a straightforward applicable model was established which allows for biochemical characterization of immunoregulation by HCC necrosis in cell culture. Data presented indicate a remarkably inflammatory capacity of necrotic hepatoma cells that, at least partly, depends on the RAGE/HMGB1 axis and may shape immunological properties of the HCC microenvironment.
Background and Aim: Several studies observed alterations in the gut microbiota in patients with non‐alcoholic fatty liver disease (NAFLD). However, analyzed patient populations and methods strongly differ among these studies. The aim of this study was to prove the reproducibility of published results and to provide a detailed overview of all findings in our NAFLD cohort using next generation sequencing methods.
Methods: The individual taxonomic microbiota composition of fecal samples from 90 NAFLD patients and 21 healthy controls was analyzed using 16S rRNA gene sequencing. Study participants were grouped according to their disease stage and compared regarding their gut microbiota composition. Studies were identified from PubMed listed publications, and the results were compared with the findings in our cohort.
Results: Results from 13 identified studies were compared with our data. A decreased abundance of the Bacteroidetes and Ruminococcaceae as well as an increased abundance of Lactobacillaceae and Veillonellaceae and Dorea were the most frequently reported changes among NAFLD patients in 4/13, 5/13, 4/13, 2/13, and 3/13 studies, respectively. Even though these alterations in the gut microbiota composition were also observed in our patient cohort, the majority of published differences could not be reproduced, neither in our own nor in other NAFLD cohort studies.
Conclusion: Despite repeatedly reproduced abundance patterns of specific bacteria, the heterogeneous study results did not reveal a consistent disease specific gut microbiota signature. Further prospective studies with homogenous patient cohorts and standardized methods are necessary to phenotype NAFLD by the gut microbiota.
Objective: Clostridial gas gangrene (GG) or clostridial myonecrosis is a very rare but life‐threatening necrotizing soft tissue infection (NSTI) caused by anaerobic, spore‐forming, and gas‐producing clostridium subspecies. It is the most rapidly spreading and lethal infection in humans, also affecting muscle tissue. The high mortality, of up to 100%, in clostridial GG is mediated by potent bacterial exotoxins. Necrotizing fasciitis (NF) is an important differential diagnosis, most often caused by group A streptococci, primarily not affecting musculature but the subcutaneous tissue and fascia. In the early stages of the infection, it is difficult to distinguish between GG and NF. Therefore, we compare both infection types, identify relevant differences in initial clinical presentation and later course, and present the results of our patients in a retrospective review.
Methods: Patients diagnosed with GG from 2008 to 2018 in our level one trauma center were identified. Their charts were reviewed retrospectively and data analyzed in terms of demographic information, microbiological and histological results, therapeutic course, outcome, and mortality rates. The laboratory risk indicator for NF (LRINEC) score was applied on the first blood work acquired. Results were compared to those of a second group diagnosed with NF.
Results: Five patients with GG and nine patients with NF were included in the present study. Patients with GG had a mortality rate of 80% compared to 0% in patients with NF. In eight patients with NF, affected limbs could be salvaged; one NF underwent amputation. LRINEC did not show significant differences between the groups; however, C‐reactive protein was significantly increased (P = 0.009) and hemoglobin (Hb) was significantly decreased (P = 0.02) in patients with GG. Interleukin‐6 and procalcitonin levels did not show significant difference. Patients with GG were older (70.2 vs 50 years). Of the isolated bacteria, 86% were sensitive to the initial calculated antibiotic treatment with ampicillin‐sulbactam or imipenem plus metronidazole plus clindamycin.
Conclusion: Both GG and NF need full‐scale surgical, antibiotic, and intensive care treatment, especially within the first days. Among patients with NSTI, those with clostridial GG have a significantly increased mortality risk due to early septic shock caused by clostridial toxins. In the initial stages, clinical differences are hardly detectable. Immediate surgical debridement is the key to successful therapy for NSTI and needs to be performed as early as possible. However, patients should be treated in a center with an experienced interdisciplinary intensive care team based on a predetermined treatment plan.
Objectives: To assess tolerability and efficacy of lacosamide in adults with cerebrovascular epilepsy etiology (CVEE).
Materials and methods: Exploratory post hoc analyses of a double‐blind, initial monotherapy trial of lacosamide vs carbamazepine‐controlled release (carbamazepine‐CR) (SP0993; NCT01243177); a double‐blind conversion to lacosamide monotherapy trial (SP0902; NCT00520741); and an observational study of adjunctive lacosamide added to one antiepileptic drug (SP0973 VITOBA; NCT01098162). Patients with CVEE were identified based on epilepsy etiology recorded at baseline.
Results: In the initial monotherapy trial, 61 patients had CVEE (lacosamide: 27; carbamazepine‐CR: 34). 20 (74.1%) patients on lacosamide (27 [79.4%] on carbamazepine‐CR) reported treatment‐emergent adverse events (TEAEs), most commonly (≥10%) headache, dizziness, and fatigue (carbamazepine‐CR: headache, dizziness). A numerically higher proportion of patients on lacosamide than carbamazepine‐CR completed 6 months (22 [81.5%]; 20 [58.8%]) and 12 months (18 [66.7%]; 17 [50.0%]) treatment without seizure at last evaluated dose. In the conversion to monotherapy trial, 26/30 (86.7%) patients with CVEE reported TEAEs, most commonly (≥4 patients) dizziness, convulsion, fatigue, headache, somnolence, and cognitive disorder. During lacosamide monotherapy, 17 (56.7%) patients were 50% responders and six (20.0%) were seizure‐free. In the observational study, 36/83 (43.4%) patients with CVEE reported TEAEs, most commonly (≥5%) fatigue and dizziness. Effectiveness was assessed for 75 patients. During the last 3 months, 60 (80%) were 50% responders and 42 (56.0%) were seizure‐free.
Conclusions: These exploratory post hoc analyses suggested lacosamide was generally well tolerated and effective in patients with CVEE, with data from the initial monotherapy trial suggesting numerically better efficacy than carbamazepine‐CR.
Objective: To explore and describe exposure to suicidality in healthcare providers (HCP) working with oncological patients. Special emphasis was put on five central aspects from the HCPs perspective: Exposure, Confidence, Expertise, Distress, and Education.
Methods: A 48‐item online questionnaire was developed and distributed to HCPs working with cancer patients. Three hundred fifty‐four answered questionnaires were analyzed.
Results: Overall 83.3% of HCPs reported to have encountered at least one suicidal patient in the last year. Feeling confident in talking about suicidality was reported by 72.1% of HCPs, with 71.2% of nurses reporting feeling insecure compared with only 5.1% of psychotherapists. Similarly, 22.3% of HCPs felt overwhelmed when confronted with a patient who substantiated his suicidality during consultation. A lack of personal knowledge concerning suicidality in general and in oncological patients in particular, was reported by 39.6% and 49.8%, respectively. In total, 88.1% of HCPs reported feeling distressed when confronted with suicidality, while 81.1% of participants wanted further education regarding suicidality in cancer patients despite that 73.2% had already received some sort of psycho‐oncology education.
Conclusions: Despite the well‐documented fact of elevated suicide rates in cancer patients, there remain deficits in knowledge, which induce feelings of insecurity and helplessness in HCPs. There is a demand for further education concerning the treatment of suicidal cancer patients. Therefore, special curricula addressing this topic should be devised. A general debate about suicidality in cancer patients could help raise awareness of this problem and generate means of prevention.
Type 1 diabetes (T1D) is mainly precipitated by the destruction of insulin-producing β-cells in the pancreatic islets of Langerhans by autoaggressive T cells. The etiology of the disease is still not clear, but besides genetic predisposition the exposure to environmental triggers seems to play a major role. Virus infection of islets has been demonstrated in biopsies of T1D patients, but there is still no firm proof that such an infection indeed results in islet-specific autoimmunity. However, virus infection results in a local inflammation with expression of inflammatory factors, such as cytokines and chemokines that attract and activate immune cells, including potential autoreactive T cells. Many chemokines have been found to be elevated in the serum and expressed by islet cells of T1D patients. In mouse models, it has been demonstrated that β-cells express chemokines involved in the initial recruitment of immune cells to the islets. The bulk load of chemokines is however released by the infiltrating immune cells that also express multiple chemokine receptors. The result is a mutual attraction of antigen-presenting cells and effector immune cells in the local islet microenvironment. Although there is a considerable redundancy within the chemokine ligand-receptor network, a few chemokines, such as CXCL10, seem to play a key role in the T1D pathogenesis. Studies with neutralizing antibodies and investigations in chemokine-deficient mice demonstrated that interfering with certain chemokine ligand-receptor axes might also ameliorate human T1D. However, one important aspect of such a treatment is the time of administration. Blockade of the recruitment of immune cells to the site of autoimmune destruction might not be effective when the disease process is already ongoing. By that time, autoaggressive cells have already arrived in the islet microenvironment and a blockade of migration might even hold them in place leading to accelerated destruction. Thus, an anti-chemokine therapy makes most sense in situations where the cells have not yet migrated to the islets. Such situations include treatment of patients at risk already carrying islet-antigen autoantibodies but are not yet diabetic, islet transplantation recipients, and patients that have undergone a T cell reset as occurring after anti-CD3 antibody treatment.
Objective: Children with pre-school asthma suffer disproportionally more often from severe asthma exacerbations with emergency visits and hospital admissions compared to school children. Despite this high disease burden, there are only a few reports looking at this particular severe asthma cohort. Similarly, there is little real-life research on the distribution of asthma phenotypes and personalized treatment at discharge in this age group. Patients and Methods: Retrospective analysis of the electronic charts of all children aged 1–5 years with asthma hospitalizations (ICD J45) at the Frankfurt University between 2008 and 2017. An acute severe asthma exacerbation was defined as dyspnea, oxygen demand, and/or systemic steroid therapy. Age, gender, duration of hospitalization, asthma phenotype, treatment, and readmission rate were analyzed. Results: Of 572 patients, 205 met the definition of acute severe asthma. The phenotypic characterization showed 56.1% had allergic asthma, 15.2% eosinophilic asthma and 28.7% non-allergic asthma. Of these patients, 71.7% were discharged with inhaled corticosteroids (ICS) or ICS + long-acting-beta-agonists (LABA), 15.1% with leukotriene antagonists (LTRA) and 7.3% salbutamol on demand. The rate of emergency presentations (emergency department and readmission) within 12 months after discharge was high (n = 42; 20.5%). No phenotype tailored treatment was detectable. Neither the number of eosinophils (>300/μl) nor the treatment at discharge had an effect on emergency visits and readmission rate. Conclusion: Despite protective therapy with ICS, ICS + LABA, or LTRA, the readmission rate was high. Thus, current care and treatment strategies should be reevaluated continuously, in order to better control asthma in pre-school children and prevent hospitalization.
Photochemical internalization (PCI) is a technology to induce a localized, intracellular enhancement of therapeutics that are processed through endosomal pathways, including gemcitabine in malignant cells. In addition to a direct phototoxic and tumoricidal effect, PCI specifically disrupts endosomal membranes and, thereby, the compartmentalization of certain cytotoxic compounds to enhance a drug’s intended intracellular target reach within the tissue treated.
Non-resectable extrahepatic cholangiocarcinoma (eCCA) is a common primary tumor and gemcitabine/cisplatin chemotherapy is widely considered standard of care for it. PCI is well suited as an endoscopic intervention, and clinical observations in three subjects participating in a phase I/IIa dose escalation safety trial are described. The trial included patients with perihilar, non-resectable CCA suitable for standard-of-care chemotherapy. Per protocol, a single endoscopic PCI procedure with gemcitabine was conducted at the initiation of standard gemcitabine/cisplatin therapy. Sixteen patients enrolled in the initial dose escalation phase of the trial, which later was extended to explore the safety of a second PCI procedure during chemotherapy.
While limited to a case series, the various clinical observations described here serve to illustrate the effects of localized, perihilar tumor targeting in appropriate patients by any safe methodology, including PCI. As previously indicated by clinical data using other localized treatment modalities, adding a directed, tumor-targeting treatment to systemic therapy to ameliorate the progressively expanding extrahepatic tumor burden can have important effects on the overall outcome of systemic treatment in many patients who have incurable eCCA.
A novel, broad-acting peptide inhibitor of double-stranded DNA virus gene expression and replication
(2020)
Viral infections are a global disease burden with only a limited number of antiviral agents available. Due to newly emerging viral pathogens and increasing occurrence of drug resistance, there is a continuous need for additional therapeutic options, preferably with extended target range. In the present study, we describe a novel antiviral peptide with broad activity against several double-stranded DNA viruses. The 22-mer peptide TAT-I24 potently neutralized viruses such as herpes simplex viruses, adenovirus type 5, cytomegalovirus, vaccinia virus, and simian virus 40 in cell culture models, while being less active against RNA viruses. The peptide TAT-I24 therefore represents a novel and promising drug candidate for use against double-stranded DNA viruses.
Particulate autogenous tooth roots are used for alveolar bone augmentation surgery; however, dental plaque may provoke an inflammatory response that may counteract the desired graft consolidation process. Traditional mechanical cleaning of extracted teeth may be of support to lower a possible inflammatory response of the autograft. To test this assumption, extracted porcine teeth were left either uncleaned or underwent mechanical cleaning with a toothbrush and toothpaste before being fragmented and subjected to acid lysis, termed as unclean acid dentine lysate (ucADL) and clean acid dentine lysate (cADL), respectively. The inflammatory responses of murine macrophage RAW 264.7 cells being exposed to the respective acid dentine lysates were evaluated at the level of inflammatory gene expression and IL6 immunoassays. We report here that acid lysates obtained from uncleaned teeth provoked a robust increase in IL1β, IL6, and COX2 in RAW 264.7 cells. The mechanical removal of dental plaque significantly reduced the inflammatory response. Consistently, Limulus tests revealed that tooth cleaning lowers the presence of endotoxins in dentine lysates. To further prove the involvement of endotoxins, a toll-like receptor 4 (TLR4) inhibitor TAK242 was introduced. TAK242 abolished the inflammatory response provoked by acid lysates obtained from uncleaned teeth in RAW 264.7 cells. Moreover, nuclear translocation and phosphorylation of the TLR4 downstream NFκB-p65 were attenuated at the presence of cleaned versus uncleaned dentine lysates. Taken together, our data support the importance of dental plaque removal of teeth being extracted for alveolar bone augmentation surgery.
The Ebola virus (EBOV) can cause severe infections in humans, leading to a fatal outcome in a high percentage of cases. Neutralizing antibodies against the EBOV surface glycoprotein (GP) can prevent infections, demonstrating a straightforward way for an efficient vaccination strategy. Meanwhile, many different anti‐EBOV antibodies have been identified, whereas the exact binding epitopes are often unknown. Here, the analysis of serum samples from an EBOV vaccine trial with the recombinant vesicular stomatitis virus‐Zaire ebolavirus (rVSV‐ZEBOV) and an Ebola virus disease survivor, using high‐density peptide arrays, is presented. In this proof‐of‐principle study, distinct IgG and IgM antibodies binding to different epitopes of EBOV GP is detected: By mapping the whole GP as overlapping peptide fragments, new epitopes and confirmed epitopes from the literature are found. Furthermore, the highly selective binding epitope of a neutralizing monoclonal anti‐EBOV GP antibody could be validated. This shows that peptide arrays can be a valuable tool to study the humoral immune response to vaccines in patients and to support Ebola vaccine development.
Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiation and chemotherapy by considering timing of treatment. To date little is known about time‐of‐day dependent changes of proliferation and DNA damage in HCC. Using transgenic c‐myc/transforming growth factor (TGFα) mice as HCC animal model, we immunohistochemically demonstrated Ki67 as marker for proliferation and γ‐H2AX as marker for DNA damage in HCC and surrounding healthy liver (HL). Core clock genes (Per1, Per2, Cry1, Cry2, Bmal 1, Rev‐erbα and Clock) were examined by qPCR. Data were obtained from samples collected ex vivo at four different time points and from organotypic slice cultures (OSC). Significant differences were found between HCC and HL. In HCC, the number of Ki67 immunoreactive cells showed two peaks (ex vivo: ZT06 middle of day and ZT18 middle of night; OSC: CT04 and CT16). In ex vivo samples, the number of γ‐H2AX positive cells in HCC peaked at ZT18 (middle of the night), while in OSC their number remained high during subjective day and night. In both HCC and HL, clock gene expression showed a time‐of‐day dependent expression ex vivo but no changes in OSC. The expression of Per2 and Cry1 was significantly lower in HCC than in HL. Our data support the concept of chronotherapy of HCC. OSC may become useful to test novel cancer therapies.
Background: To volumetrically assess the bone microstructure following vertical alveolar ridge augmentation using differently conditioned autogenous tooth roots (TR) and second‐stage implant placement.
Materials and methods: The upper premolars were bilaterally extracted in n = 4 beagle dogs and randomly assigned to either autoclavation (TR‐A) or no additional treatment (TR‐C). Subsequently, TR were used as block grafts for vertical alveolar ridge augmentation in both lower quadrants. At 12 weeks, titanium implants were inserted and left to heal 3 weeks. Microcomputed tomography was used to quantify bone volume per tissue volume (BV/TV), trabecular thickness (Tb.Th), and trabecular spacing (Tb.Sp) at vestibular (v) and oral (o) aspects along the implant and in the augmented upper half of the implant, respectively.
Results: Median BV/TV [TR‐C: 51.33% (v) and 70.42% (o) vs TR‐A: 44.05% (v) and 64.46% (o)], Tb.th [TR‐C: 0.22 mm (v) and 0.27 mm (o) vs TR‐A: 0.23 mm (v) and 0.29 mm (o)] and Tb.Sp [TR‐C: 0.26 mm (v) and 0.13 mm (o) vs TR‐A: 0.29 μm (v) and 0.15 mm (o)] values were comparable in both groups.
Conclusion: Both TR‐C and TR‐A grafts were associated with a comparable bone microstructure within the grafted area.
Sphingosine‐1‐phosphate lyase 1 (S1P lyase or SGPL1) is an essential sphingosine‐1‐phosphate‐degrading enzyme. Its manipulation favors onset and progression of colorectal cancer and others in vivo. Thus, SGPL1 is an important modulator of cancer initiation. However, in established cancer, the impact of retrospective SGPL1 modulation is elusive. Herein, we analyzed how SGPL1 siRNA affects malignancy of the human colorectal cancer cells DLD‐1 and found that in parallel to the reduction of SGPL1 expression levels, migration, invasion, and differentiation status changed. Diminished SGPL1 expression was accompanied with reduced cell migration and cell invasion in scratch assays and transwell assays, whereas metabolic activity and proliferation was not altered. Decreased migration was attended by increased cell–cell‐adhesion through upregulation of E‐cadherin and formation of cadherin‐actin complexes. Spreading cell islets showed lower vimentin abundance in border cells. Furthermore, SGPL1 siRNA treatment induced expression of epithelial cell differentiation markers, such as intestinal alkaline phosphatase and cytokeratin 20. Hence, interference with SGPL1 expression augmented a partial redifferentiation of colorectal cancer cells toward normal colon epithelial cells. Our investigation showed that SGPL1 siRNA influenced tumorigenic activity of established colorectal cancer cells. We therefore suggest SGPL1 as a target for lowering malignant potential of already existing cancer.
Hypersensitivity reactions to non‐steroidal anti‐inflammatory drugs (NSAIDs) – a retrospective study
(2020)
Background: The aim of this study was to verify the validity of clinical history and oral provocation challenges of patients with NSAID hypersensitivity and to identify safe alternatives. The COX‐2 inhibitor etoricoxib, in particular, was studied.
Patients and methods: In all, 104 patients with confirmed diagnoses of NSAID hypersensitivity treated at the Department of Dermatology, Frankfurt University Hospital, Germany between 2004 and 2012 were retrospectively studied.
Results: The medical history and hypersensitivity symptoms during oral provocation testing (OPT) largely coincided and were mostly mild to moderate. Acetylsalicylic acid (ASA) was the most frequent trigger both anamnestically (27.9 %) and during OPT (47.8 %). Etoricoxib caused the fewest reactions during OPT (4.2 %). Acetaminophen led to reactions in only 6.7 % of the cases studied although it was named more often in clinical histories (14 %).
Conclusions: OPT should be the aim whenever possible as most symptoms are mild to moderate. To distinguish between selective and cross‐hypersensitivity reactions, ASA should be part of the test protocol. Furthermore, the findings of this study indicate that etoricoxib and acetaminophen are safe treatment alternatives in case of NSAID hypersensitivity. However, these drugs should not be administered without prior OPT in an inpatient setting, as severe symptoms can occur.
Background: The present study aimed to assess the three‐dimensional changes following soft tissue augmentation using free gingival grafts (FGG) at implant sites over a 3‐month follow‐up period.
Methods: This study included 12 patients exhibiting deficient keratinized tissue (KT) width (i.e., <2 mm) at the vestibular aspect of 19 implants who underwent soft tissue augmentation using FGG at second stage surgery following implant placement. Twelve implants were considered for the statistical analysis (n = 12). The region of interest (ROI) was intraorally scanned before surgery (S0), immediately post‐surgery (S1), 30 (S2) and 90 (S3) days after augmentation. Digital scanned files were used for quantification of FGG surface area (SA) and converted to standard tessellation language (STL) format for superimposition and evaluation of thickness changes between the corresponding time points. FGG shrinkage (%) in terms of SA and thickness was calculated between the assessed time points.
Results: Mean FGG SA amounted to 91 (95% CI: 63 to 119), 76.2 (95% CI: 45 to 106), and 61.3 (95% CI: 41 to 81) mm2 at S1, S2, and S3, respectively. Mean FGG SA shrinkage rate was 16.3% (95% CI: 3 to 29) from S1 to S2 and 33% (95% CI: 19 to 46) from S1 to S3. Mean thickness gain from baseline (S0) to S1, S2, and S3 was 1.31 (95% CI: 1.2 to 1.4), 0.82 (95% CI: 0.5 to 1.12), and 0.37 (0.21 to 0.5) mm, respectively. FGG thickness shrinkage was of 38% (95% CI: 17.6 to 58) from S1 to S2 and 71.8% (95% CI: 60 to 84) from S1 to S3. Dimensional changes from S1 to S3 were statistically significant, P <0.017. Soft tissue healing was uneventful in all patients.
Conclusions: The present three‐dimensional assessment suggests that FGG undergo significant dimensional changes in SA and thickness over a 3‐month healing period.
Purpose: Surgery of KOOS IV vestibular schwannoma remains challenging regarding the balance of extent of tumor resection (EoR) and functional outcome. Our aim was to evaluate the outcome of surgical resection and define a cut-off value for safe resection with low risk for tumor regrowth of KOOS IV vestibular schwannoma.
Methods: All patients presenting at the authors’ institution between 2000 and 2019 with surgically treated KOOS IV vestibular schwannoma were included. Outcome measures included EoR, facial/hearing nerve function, surgical complications and progression of residual tumor during the median follow-up period of 28 months.
Results: In 58 patients, mean tumor volume was 17.1 ± 9.2 cm3, and mean EoR of 81.6 ± 16.8% could be achieved. Fifty-one patients were available for the follow-up analysis. Growth of residual tumor was observed in 11 patients (21.6%) followed by adjuvant treatment with stereotactic radiosurgery or repeat surgery in 15 patients (29.4%). Overall serviceable hearing preservation was achieved in 38 patients (74.5%) and good facial outcome at discharge was observed in 66.7% of patients, significantly increasing to 82.4% at follow-up. Independent predictors for residual tumor growth was EoR ≤ 87% (OR11.1) with a higher EoR being associated with a very low number of residual tumor progression amounting to 7.1% at follow-up (p=0.008).
Conclusions: Subtotal tumor resection is a good therapeutic concept in patients with KOOS IV vestibular schwannoma resulting in a high rate of good hearing and facial nerve function and a very low rate of subsequent tumor progression. The goal of surgery should be to achieve more than 87% of tumor resection to keep residual tumor progression low.
Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia
(2020)
Cardiac ischaemia‐reperfusion (I/R) injury has been attributed to stress signals arising from an impaired mitochondrial electron transport chain (ETC), which include redox imbalance, metabolic stalling and excessive production of reactive oxygen species (ROS). The alternative oxidase (AOX) is a respiratory enzyme, absent in mammals, that accepts electrons from a reduced quinone pool to reduce oxygen to water, thereby restoring electron flux when impaired and, in the process, blunting ROS production. Hence, AOX represents a natural rescue mechanism from respiratory stress. This study aimed to determine how respiratory restoration through xenotopically expressed AOX affects the re‐perfused post‐ischaemic mouse heart. As expected, AOX supports ETC function and attenuates the ROS load in post‐anoxic heart mitochondria. However, post‐ischaemic cardiac remodelling over 3 and 9 weeks was not improved. AOX blunted transcript levels of factors known to be up‐regulated upon I/R such as the atrial natriuretic peptide (Anp) whilst expression of pro‐fibrotic and pro‐apoptotic transcripts were increased. Ex vivo analysis revealed contractile failure at nine but not 3 weeks after ischaemia whilst label‐free quantitative proteomics identified an increase in proteins promoting adverse extracellular matrix remodelling. Together, this indicates an essential role for ETC‐derived signals during cardiac adaptive remodelling and identified ROS as a possible effector.
Aims: Preventing hospitalization by detecting early evidence of heart failure (HF) decompensation in an outpatient setting can improve patient's quality of life and reduce costs of care. The purpose of this study was to assess the value of cardiac acoustic biomarkers (CABs), a combination of cardiohaemic vibrations synchronized with ECG signals, and heart rate (HR) for detecting HF decompensation during first 3 months after hospital discharge for HF.
Methods and results: Patients with an ejection fraction ≤35% (HFrEF) and hospitalized for decompensated HF were enrolled in a prospective observational study. All subjects wore a wearable cardioverter‐defibrillator (ZOLL LifeVest®, Pittsburgh, PA, USA) that is capable of recording CABs and HR. The primary endpoint of the study was the first HF event, defined as HF readmission or HF emergency room visit. From June 2017 through August 2019, 671 patients with HFrEF were enrolled. Eighty‐one patients (12.1%) had a total of 112 HF events. The algorithm detected HF events with a median of 32 days (interquartile range = 11‐45) in advance of the first HF event. The algorithm had a sensitivity of 69%, specificity of 60%, positive predictive value of 19%, and a negative predictive value of 94%. Of note, the baseline (first 7 days post‐enrolment) algorithm using CABs and HR was superior to New York Heart Association classification in detecting patients more likely to have HF decompensation (sensitivity and specificity of 61% and 68% vs. 46% and 55%, respectively).
Conclusions: This prospective international registry showed that an algorithm incorporating CABs and HR data detected HF events 30 days in advance of the event in patients with HFrEF during first 3 months after hospital discharge. Therefore, integrating CAB technology into clinical practice may prevent HF rehospitalizations.
Central cholinergic function and metabolic changes in streptozotocin‐induced rat brain injury
(2020)
As glucose hypometabolism in the brain is an early sign of Alzheimer´s dementia (AD), the diabetogenic drug streptozotocin (STZ) has been used to induce Alzheimer‐like pathology in rat brain by intracereboventricular injection (icv‐STZ). However, many details of the pathological mechanism of STZ in this AD model remain unclear. Here, we report metabolic and cholinergic effects of icv‐STZ using microdialysis in freely moving animals. We found that icv‐STZ at a dose of 3 mg/kg (2 × 1.5 mg/kg) causes overt toxicity reflected in body weight loss. Three weeks after STZ administration, histological examination revealed a high number of glial fibrillary acidic protein reactive cells in the hippocampus, accompanied by Fluoro‐Jade C‐positive cells in the CA1 region. Glucose and lactate levels in microdialysates were unchanged, but mitochondrial respiration measured ex vivo was reduced by 9%–15%. High‐affinity choline uptake, choline acetyltransferase, and acetylcholine esterase (AChE) activities in the hippocampus were reduced by 16%, 28%, and 30%, respectively. Importantly, extracellular acetylcholine (ACh) levels in the hippocampus were unchanged and responded to behavioral and pharmacological challenges. In comparison, extracellular ACh levels and cholinergic parameters in the striatum were unchanged or slightly increased. We conclude that the icv‐STZ model poorly reflects central cholinergic dysfunction, an important characteristic of dementia. The icv‐STZ model may be more aptly described as an animal model of hippocampal gliosis.
The digital and information age has fundamentally transformed the way in which students learn and the study material they have at their disposal, especially in higher education. Students need to possess a number of higher-order cognitive and metacognitive skills, including effective information processing and critical reasoning to be able to navigate the Internet and use online sources, even those found outside of academically curated domains and in the depths of the Internet, and to solve (domain-specific) problems. Linking qualitative and quantitative research and connecting the humanities to empirical educational science studies, this article investigates the role of narratives and their impact on university students’ information seeking and their critical online reasoning (COR). This study focuses on the link between students’ online navigation skills, information seeking behavior and critical reasoning with regard to the specific domains: economics and medicine. For the empirical analysis in this article, we draw on a study that assesses the COR skills of undergraduate students of economics and medicine at two German universities. To measure COR skills, we used five tasks from the computer-based assessment “Critical Online Reasoning Assessment” (CORA), which assesses students’ skills in critically evaluating online sources and reasoning using evidence on contentious issues. The conceptual framework of this study is based on an existing methodology – narrative economics and medicine – and discusses its instructional potential and how it can be used to develop a new tool of “wise interventions” to enhance students’ COR in higher education. Based on qualitative content analyses of the students’ written responses, i.e., short essays, three distinct patterns of information seeking behavior among students have been identified. These three patterns – “Unambiguous Fact-Checking,” “Perspective-Taking Without Fact-Checking,” and “Web Credibility-Evaluating” – differ substantially in their potential connection to underlying narratives of information used by students to solve the CORA tasks. This analysis suggests that training university students in narrative analysis can strongly contribute to enhancing their critical online reasoning.
In der vorliegenden Untersuchung wurde das bovine, Hydroxylapatit-basierte, Knochenersatzmaterial Hypro-Oss® zunächst ex vivo überprüft, anschließend subkutan in den interskapulären Bereich von 12 weiblichen Wistar-Ratten (Testgruppe) eingebracht; bei 12 weiteren Tieren erfolgte eine Sham-Operation ohne Einbringung von Biomaterial (Kontrollgruppe). Anschließend wurde die Gewebereaktion über 30 Tage beobachtet und die Explantate jeweils nach Tag 3, 15 und 30 histologisch und histomorphometrisch untersucht.
Die histologische Analyse zeigte innerhalb des Beobachtungszeitraums von 30 Tagen eine störungsfreie Eingliederung der Hypro-Oss®-Granula in das umliegende Gewebe. Bereits 3 Tage nach Einbringung des Biomaterials waren mononukleäre Zellen erkennbar, die bis Tag 30 weiter zunahmen. Ab diesem Zeitpunkt zeigten sich auch TRAP-positive, CD-68-negative Multinukleäre Zellen, die das Ergebnis einer Fusion von Makrophagen sind und eine Fremdkörperreaktion indizierten. Nach 30 Tagen zeigten sich die Granula histologisch stabil integriert ohne Anzeichen einer immunologischen Abstoßungsreaktion.
Die CD-68-Expression der aufgefundenen Makrophagen und mehrkernigen Riesenzellen bildete ein Kriterium zur Unterscheidung der MNGCs von Osteoklasten, die ebenfalls mehrkernig sind, aber dieses Cluster of Differentiation nicht tragen. Dies charakterisiert die vorgefundenen MNGCs als Fremdkörper-Riesenzellen, da sie ebenso wie die pathologischen Riesenzellen vom Typ Langerhans CD-68 exprimieren.
Dieses Bild bestätigte sich für die Hypro-Oss®-Gruppe in der histomorphometrischen Betrachtung über eine kontinuierliche Zunahme von überwiegend CD-68-positiven Makrophagen bis zum Tag 30, während sie für die Kontrollgruppe über die gesamte Zeit rückläufig waren. Die Multinukleären Zellen erreichten dagegen bereits an Tag 15 ihren Höhepunkt, während in der Kontrollgruppe über den gesamten Beobachtungszeitraum erwartungsgemäß keine MNGCs gefunden wurden.
Der hoch signifikante Anstieg der MNGC-Zahl der Testgruppe bis Tag 15 korreliert positiv mit den Vaskularisationsdaten, was darauf hindeutet, dass die Multinukleären Zellen durch die Einbringung des Biomaterials induziert wurden und über die Sekretion des Signalmoleküls VEGF einen wesentlichen Faktor für die Blutgefäßbildung bilden.
Eine Auffälligkeit hat sich jedoch in Bezug auf das Alleinstellungsmerkmal von Hypro-Oss® gezeigt, welches bei der Aufreinigung nicht erhitzt wird. Diverse Studien haben einen Zusammenhang der Höhe der Sintertemperatur mit der Bildung von MNGCs nachgewiesen, wonach für Hypro-Oss® eine geringe Induzierung von MNGCs zu erwarten gewesen wäre als für vergleichbare, höher erhitzte bovine Knochenersatzmaterialien. Dagegen zeigten die Vaskularisationsdaten unserer Untersuchung für Hypro-Oss® im Vergleich zu 2 anderen bovinen Knochenersatzmaterialien (Bio-Oss® und BEGO OSS®) jedoch signifikant höhere Werte für die Blutgefäßbildung als dies aus der Korrelation von Sintertemperatur mit der Anzahl Multinukleärer Riesenzellen zu erwarten gewesen wäre.
Aufgrund der relativ kurzen Dauer der Beobachtung lassen sich keine belastbaren Ergebnisse in Bezug auf den zu erwartenden Materialabbau und die ossäre Integration von Hypro-Oss® feststellen, welche einer längerfristigen Analyse bedürften als es in dieser Untersuchung möglich war. Es gibt aber klinische Erfahrungsberichte23 hinsichtlich Handling, Heilungsverlauf und Materialintegration von Hypro-Oss® bei Sinusbodenelevation und Guided Bone Regeneration, die auch in der Langfristbetrachtung positive Ergebnisse zeigten. Offen bleibt, ob nicht eine physiologische Wundheilung nur mittels Makrophagen einer pathologischen Wundheilung unter Mitwirkung Multinukleärer Riesenzellen überlegen ist: zumindest robustere Knochenersatzmaterialien wie z.B. das hier untersuchte Hypro-Oss® scheinen dabei weniger sensibel auf Multinukleäre Riesenzellen zu reagieren.
Acute lymphoblastic leukemia (ALL), a neoplastic disorder of blood cells of the lymphoid lineage, is the most frequent childhood cancer. In spite of increasing survival rates, the outcome for adults, infants or relapsed patients is still less favorable, highlighting the need for novel treatment options. Reactive oxygen species (ROS) are important signaling molecules that are involved in a variety of cellular pathways. As high ROS levels lead to oxidative stress and irreversible oxidation of cellular macromolecules, the production and elimination of ROS is tightly controlled. Therefore, cells express several antioxidant molecules and enzymes, including glutathione, catalase and the thioredoxin (Trx) system, to balance ROS levels. As cancer cells were found to have increased ROS levels that could contribute to tumor progression and metastasis, they rely strongly on these antioxidant systems to prevent oxidative damage, making cancer cells especially vulnerable to ROS-inducing treatments. ROS and oxidative stress have been shown to induce programmed cell death via different pathways, however the exact mechanisms that couples oxidative signaling and cell death is not completely understood.
As a disturbance of the cellular redox homeostasis was reported during leukemia development and progression, we wanted to determine the potential of Trx inhibitors for ALL therapy. Additionally, we aimed to further understand the role of ROS and subsequent protein oxidation in the induction and execution of programmed cell death.
First, we demonstrated that the Trx1 inhibitor PX-12 induced cell death in three ALL cell lines. Further analysis of the events leading to PX-12-induced cell death in FADD-deficient (FD) Jurkat cells revealed an increase in ROS levels and oxidation-mediated dimer formation of peroxiredoxin 3 (PRDX3). Interestingly cell death was inhibited by the thiol-containing antioxidant N-acetylcysteine (NAC), but not by non-thiol-containing ROS scavengers. PX-12 treatment further induced cleavage of caspase-9 and -3 and activation of the pro-apoptotic BCL-2 protein BAK, leading us to the conclusion that mitochondria-dependent apoptosis was induced. Interestingly, we could demonstrate an important role for the BH3-only protein NOXA in the mediation of PX-12-induced apoptosis as knock-down of NOXA prevented cell death induction and BAK activation. Our findings give novel insights into the mechanism of PX-12-induced cell death in ALL cell lines and underscores the potential of PX-12 for the treatment of ALL.
To further understand the processes leading to cell death upon inhibition of the Trx system, we analyzed global protein oxidation in Jurkat FD cells upon treatment with the Trx reductase inhibitor Auranofin. In line with previous results, Auranofin induced intrinsic apoptosis that was dependent on BAK and accompanied by increased ROS levels. Using a BIAM Switch Assay followed by mass spectrometry, we demonstrated that Auranofin treatment induced oxidation of over 200 proteins. We identified several proteins whose oxidation upon Auranofin treatment was expected, like Trx1, Trx2 and several peroxiredoxins. Additionally, we verified oxidation of APAF1-interacting protein (APIP) and protein arginine N-methyltransferase (PRMT1) that are both implicated in the regulation of apoptosis. With this analysis we were able to demonstrate that Auranofin treatment leads to changes in global protein oxidation. Whether oxidation of the determined proteins changes their functionality and contributes to apoptosis induction remains to be elucidated.
As we identified BAK as an important player in PX-12- and Auranofin-induced cell death in the previous parts of this study, we wanted to further understand its involvement in ROS-mediated cell death. First analyses in wild-type (WT) and BAK-/- murine embryonic fibroblasts (MEFs) revealed that BAK was essential for Auranofin-induced cell death and that this cell death was caspase-independent in MEFs. Interestingly, BAK oxidation was induced upon treatment with Auranofin, but not upon stimulation with the apoptosis-inducing compound Etoposide. Expression of mutated BAK, with either one or both oxidation-sensitive cysteines mutated to oxidation-insensitive serines, revealed that mutating already one cysteine protected cells from Auranofin , but not Etoposide-induced cell death. Of note, mutation of the BAK BH3 domain rescued MEFs from both, Auranofin- and Etoposide-mediated cell death. The presence of cysteine residues also altered BAK interactions as observed by a mass spectrometric analysis of Auranofin-treated MEFs expressing either WT or cysteine-less BAK. We identified interactions of WT BAK with proteins involved in mitochondrial fission and vesicle transport upon Auranofin treatment. Of note, interaction with proteins involved in apoptosis, like BAX or BCL-XL, was not changed between WT and cysteine-less BAK. Our results demonstrate a critical role for BAK oxidation in Auranofin-induced cell death. Furthermore, we identified novel oxidation-dependent BAK interaction partners.
To conclude, this study highlights the potential of ROS-inducing treatments for ALL therapy and provides novel insights into the redox regulation of programmed cell death.
Aufgrund der starken Heterogenität und Komplexität der akuten myeloischen Leukämie ist diese bis heute nicht zufriedenstellend zu behandeln. Die bestmögliche Therapie wird mittlerweile zunehmend auf die Erkrankung des Einzelnen angepasst. Vermehrt gewinnen Tyrosinkinase-Inhibitoren in der Therapie an Bedeutung. Diese Inhibitoren hemmen Proteine auf zellulärer Ebene.
Bei etwa 30% der AML-Patienten lassen sich Mutationen des FLT3-Gens nachweisen. Das Gen kodiert für die fms like tyrosine kinase 3, eine Rezeptor-Tyrosinkinase an der Zelloberfläche von unreifen Blutzellen des Knochenmarks. Durch Mutationen des FLT3 Gens erhalten diese Zellen einen Proliferationsvorteil gegenüber den physiologischen Blutzellen.
Am häufigsten kommt es zu in frame-Insertionen des FLT3-Gens, vor allem im Bereich der juxtamembranen Domäne: sogenannte interne Tandemduplikationen (ITD). Weiterhin kommen zu einem geringeren Teil Punktmutationen einzelner Codons, zum Beispiel im Bereich des activation loops oder im Bereich des gatekeepers vor. Durch das Auftreten der Punktmutationen, die entweder bereits zum Zeitpunkt der Diagnose vorliegen oder erst während einer Therapie mit einem Tyrosinkinase-Inhibitor entstehen können, verändert sich das Bindungsverhalten vieler solcher gegen FLT3 gerichteten Inhibitoren. Durch Letzteres kann ein mögliches Therapieversagen beispielsweise während der Behandlung mit AC220 (Quizartinib) erklärt werden (Smith et al.).
In der vorliegenden Dissertationsschrift sind Unterschiede der Signalwege zwischen FLT3-ITD und FLT3-ITD mit der zusätzlichen gatekeeper-Punktmutation F691L herausgearbeitet. Dafür wurden die beiden FLT3-Mutationen in den Vektor pMy-IRES-GFP eingebracht und retroviral in Ba/F3-Zellen transduziert. Nach Überprüfung der Expression von FLT3 ITD und dem Wachstumsverhalten unter Zugabe von AC220 (Quizartinib), wurden verschiedene Signalkaskaden von FLT3 mittels Western Blot untersucht. Hierbei zeigten sich sowohl Unterschiede für die Expression von phosphoryliertem ERK als auch von phosphoryliertem STAT5.
Durch verschieden starke Expressionen der FLT3130kDa- und FLT3160kDA-Varianten wurde eine unterschiedliche Lokalisation von FLT3-ITD in Zellen mit und ohne die Mutation F691L postuliert. Allerdings ließ sich diese experimentell mittels Immunfluoreszenz nicht belegen, da die Methode für die verwendeten Suspensionszellen nicht ausreichend geeignet war.
In den durchgeführten Versuchen zum Wachstumsverhalten der Zellen bei der Verwendung von Kinaseinhibitoren konnte bei der Verwendung des SYK-Inhibitors R406 eine dosisabhängige Proliferationshemmung der FLT3-ITD-mutierten Ba/F3- und 32D-Zellen beobachtet werden. Die Hemmung von FLT3 durch R406 wurde in der Literatur bereits beschrieben (Braselmann et al.).
Die abschließenden Experimente der Massenspektrometrie mit SILAC Markierung lassen mit der Detektion von mehreren hundert signifikant regulierten phosphorylierten Proteinen in den beiden FLT3-ITD-exprimierenden Populationen auf die Aktivierung unterschiedlicher Signalwege schließen. Durch das Vergleichen einzelner Teilexperimente ergaben sich Proteine, deren Phosphorylierung mehrfach in die gleiche Richtung reguliert war. Für Zellen, die zusätzlich zur ITD-Mutation die Mutation F691L besaßen, konnten insgesamt sieben hoch-regulierte, phosphorylierte Proteine ermittelt werden, bei denen ein zellulärer Effekt durch die Phosphorylierung der entsprechenden Aminosäurereste in der Literatur beschrieben ist.
Das im Western Blot nachgewiesene, in Zellen mit der Mutation F691L stärker phosphorylierte STAT5 ist aller Voraussicht nach Ursache der nachgewiesenen verstärkten Phosphorylierung von RPS6 im Experiment der globalen Phosphorylierung. Die PIM-Kinasen als Substrate einer STAT5-induzierten Transkription phosphorylieren RPS6 an Serin 235. Dies führt seinerseits zu einer verstärkten Translation von mRNA weiterer Gene. Die genauen Zusammenhänge der hier ermittelten Unterschiede müssen jedoch weiter untersucht werden.
In Zukunft könnte zudem die Untersuchung der beiden Proteine SHP 1 oder HSP90 weitere Aufschlüsse über die unterschiedlichen Signalwege geben. Für beide Proteine wurden Phosphorylierungen detektiert, die in den untersuchten Zellen mit FLT3-ITD bzw. der zusätzlichen Punktmutation F691L unterschiedlich reguliert sind.
Hintergrund. Die Achtung der individuellen Autonomie ist eines von vier medizinethischen Prinzipien, das im Kontext von Medizin und Forschung insbesondere in Bezug auf die informierte Einwilligung einer Person thematisiert wird. Menschen mit Demenz können aufgrund innerer oder äußerer Faktoren in ihrer Einwilligungsfähigkeit beeinträchtigt sein, was zu einer Einschränkung ihres Rechts auf Selbstbestimmung führen kann. Im diesbezüglichen Spannungsfeld zwischen Fürsorge und Autonomie soll Entscheidungsassistenz zur Ermöglichung selbstbestimmter Entscheidungen beitragen.
Zielrichtung der Arbeit. Ziel der vorliegenden Dissertation ist die Definition, Implementierung und Evaluation von Entscheidungsassistenzmaßnahmen für Menschen mit Demenz, um deren Autonomie in Entscheidungsprozessen zu unterstützen. Drei Teilprojekte umfassen die Ermittlung des internationalen Forschungsstands zu Entscheidungsassistenz bei Demenz, die Definition und Pilotierung von Unterstützungstools in der Praxis und die Analyse des individuellen Erlebens der vereinfachten Aufklärungsgespräche durch Menschen mit Demenz.
Methode. Im ersten Teilprojekt wurde eine am PRISMA-Standard orientierte systematische Literaturrecherche in Medline und PsycINFO durchgeführt. Die extrahierten relevanten Informationen wurden inhaltlich systematisiert. Aufbauend auf diesen Ergebnissen wurden im zweiten Teilprojekt konkrete Unterstützungstools definiert und in reale Aufklärungsgespräche (Lumbalpunktion) implementiert. Die Tools wurden in der Pilotierung in der Praxis sowie in einem iterativen Diskussionsprozess mit Experten weiterentwickelt. Im dritten Teilprojekt wurde das individuelle Erleben der Teilnehmer der vereinfachten Aufklärungsgespräche mittels problemzentrierter Interviews untersucht und die Daten einer qualitativen Inhaltsanalyse unterzogen.
Ergebnisse. Die Datenbankrecherche ergab initial 2348 Treffer. Nach Screenings der Titel, Abstracts und Volltexte konnten 11 Artikel eingeschlossen werden. Vier der eingeschlossenen Studien sind Interventionsstudien, die übrigen sieben qualitative Interviewstudien. Die identifizierten Unterstützungsmaßnahmen wurden zunächst den beiden Kategorien Interventionen und Strategien und anschließend unter Zuhilfenahme des Konzepts des Contextual Consents fünf komplexitätssteigernden Dimensionen einer Entscheidungssituation zugeordnet (individuelle, soziale, medizinische, informationelle und Folgendimension). Darauf aufbauend wurden im zweiten Teilprojekt acht Entscheidungsassistenzmaßnahmen abgeleitet: (1) Gesprächsstruktur, (2) Elaborierte klare Sprache, (3) Ambiente / Raumgestaltung, (4) Stichwortlisten, (5) Prioritätenkarten, (6) Visualisierung, (7) Vereinfachte schriftliche Einverständniserklärung sowie (8) Personenzentrierte Haltung des Entscheidungsassistenten (1-7: Tools, 8: Grundeinstellung). Die Tools zielen überwiegend auf eine Komplexitätsreduktion in der informationellen Dimension unter Berücksichtigung der fähigkeitsbezogenen und der bedürfnisbezogenen individuellen Dimension ab. Durch Anpassungen der Informationsdarbietung oder der kommunikativen Interaktion im Gespräch dienen sie mehrheitlich der Förderung des (Informations-) Verständnisses. Die Analyse der qualitativen Daten im dritten Teilprojekt zeigt, dass die Erfahrung der vereinfachten Aufklärungsgespräche durch drei übergreifende Themen gekennzeichnet ist. Die Kategorie Formalität versus Informationsgewinn illustriert die individuelle Bedeutung des Aufklärungsgesprächs für die Teilnehmer und deren Bewertung des Prozesses der informierten Einwilligung. Die Kategorie Wahrnehmung der Unterstützung skizziert die Bewertungen der angewandten Unterstützungstools durch die Teilnehmer. Die Kategorie Der Wahrheit ins Auge sehen müssen stellt dar, dass die erlebte Situation des vereinfachten Aufklärungsgesprächs wesentlich durch die Verdachtsdiagnose Demenz bestimmt ist, die im Rahmen aller Aufklärungsgespräche besprochen wurde.
Fazit. Bislang gibt es wenig empirische Forschung zu Entscheidungsassistenz für Menschen mit Demenz und Unterstützungsmaßnahmen werden überwiegend unsystematisch entwickelt und angewendet. Die Wirksamkeit einzelner Unterstützungsmaßnahmen kann aufgrund fehlender Interventionsstudien selten beurteilt werden. Unterstützungsmaßnahmen zielen überwiegend auf eine Komplexitätsreduktion in der Informationsdarbietung und im kommunikativen Interaktionsprozess ab, wobei sie kognitive Beeinträchtigungen und Interaktions-/ Entscheidungsbedürfnisse von Menschen mit Demenz berücksichtigen. Die definierten Tools können als erste konkret handhabbare Werkzeuge verstanden werden, die das strukturierte Leisten von Entscheidungsassistenz für Menschen mit Demenz erleichtern sollen. Sie sind übertragbar auf verschiedene Entscheidungssituationen. Eine Bewertung der Wirksamkeit der definierten Tools sollte in weiteren Entscheidungssituationen und mit größeren Stichproben weiteruntersucht werden. Die Ergebnisse der Evaluation liefern jedoch erste Hinweise darauf, dass einige Teilnehmer sich von einzelnen Tools unterstützt gefühlt haben und die anvisierte Komplexitätsreduktion in der informationellen Dimension in einigen Fällen erfolgreich war. Eine wesentliche Komplexitätssteigerung in der untersuchten Entscheidungssituation entstand durch die negative Emotionen auslösende Vermittlung einer potentiellen Demenzdiagnose (Folgendimension). Dieses Ergebnis impliziert, dass die definierte „verständnisfördernde Toolbox“ um Unterstützungsmaßnahmen zur emotionalen Entlastung von Menschen mit Demenz erweitert werden muss, da davon ausgegangen werden kann, dass vielfältige Entscheidungssituationen für Menschen mit Demenz emotional hoch belastend sind.
Hintergrund
Obwohl Feedback ein wichtiges und gut untersuchtes Element der medizinischen Ausbildung darstellt, wird es trotz eines großen Bedarfs der Studierenden sowohl im Unterricht als auch in Prüfungssituationen nur selten angewendet. Die Frankfurter Medizinstudierenden beklagen besonders, dass sie zu ihren Objective Structured Clinical Examinations (OSCEs) als Abschlussprüfung im Fach Chirurgie bisher kein detailliertes Feedback erhalten. Auch die Prüfenden beklagen häufig, dass sie die Studierenden weder für herausragende Leistungen loben noch über auftretende Fehler informieren können.
Ziel dieser Arbeit ist deshalb die Erstellung und Implementierung eines strukturierten schriftlichen Feedbacks in eine bestehende OSCE-Prüfung im Fach Chirurgie, das an den Bedürfnissen sowohl der Studierenden als auch der Prüfenden orientiert ist.
Material und Methoden
Das Studiendesign war prospektiv. Im ersten Schritt wurde eine Befragung erfahrener OSCE-Prüfender durchgeführt, um zu erheben, welches Feedback sie gerne an Studierende weitergeben würden. Basierend hierauf wurde ein erster Feedbackbogen erstellt. Dieser umfasste neben vorformulierten Aussagen auch die Möglichkeit Freitextkommentare zu geben und wurde von den Prüfenden für jeden Studierenden in der Wechselzeit zwischen den OSCE-Stationen ausgefüllt. Die Feedbackbögen wurden anschließend eingescannt und per E- Mail an die Studierenden geschickt. Im Anschluss hieran erfolgte eine webbasierte Befragung der Studierenden und der OSCE-Prüfenden, sowie eine tiefergehende Befragung der Studierenden in Form von Fokusgruppen- Interviews.
Basierend auf den Ergebnissen der Umfragen und der Fokusgruppen wurden die Feedbackbögen nochmals grundlegend überarbeitet und im folgenden OSCE erneut angewendet. Die Zufriedenheit der Prüfenden und Studierenden wurde analog zur ersten Befragung erhoben.
Ergebnisse
Insgesamt nahmen 351 Studierende und 51 Prüfende in beiden OSCEs an der Studie teil. In der abschließenden Online-Evaluation gaben 87,5% der Studierenden und 91,6% der Prüfenden an, dass sie zustimmen oder eher zustimmen, dass das schriftliche Feedback in zukünftigen OSCE-Prüfungen weiterhin angewendet werden soll. Mehr als 50% der Studierenden gaben jedoch an, dass das Feedback noch nicht konkret genug sei.
Mehr als ein Viertel der Prüfenden gab an, dass das Ausfüllen der Feedbackbögen zeitlich herausfordernd sei. In allen Fokusgruppen wurde das schriftliche Feedback durch die Studierenden befürwortet.
Schlussfolgerung
Die Implementierung eines strukturierten schriftlichen Feedbacks in einen OSCE ist problemlos möglich. Das schriftliche Feedback wird sowohl von den Prüfenden als auch von den Studierenden als nützlich empfunden.
Inflammation is a highly regulated biological response of the immune system that is triggered by assaulting pathogens or endogenous alarmins. It is now well established that some soluble extracellular matrix constituents, such as small leucine-rich proteoglycans (SLRPs), can act as danger signals and trigger aseptic inflammation by interacting with innate immune receptors. SLRP inflammatory signaling cascade goes far beyond its canonical function. By choosing specific innate immune receptors, coreceptors, and adaptor molecules, SLRPs promote a switch between pro- and anti-inflammatory signaling, thereby determining disease resolution or chronification. Moreover, by orchestrating signaling through various receptors, SLRPs fine-tune inflammation and, despite their structural homology, regulate inflammatory processes in a molecule-specific manner. Hence, the overarching theme of this review is to highlight the molecular and functional specificity of biglycan-, decorin-, lumican-, and fibromodulin-mediated signaling in inflammatory and autoimmune diseases.
The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
Sphingosine‐1‐phosphate (S1P) regulates pathophysiological processes, including liver regeneration, vascular tone control, and immune response. In patients with liver cirrhosis, acute deterioration of liver function is associated with high mortality rates. The present study investigated whether serum S1P concentrations are associated with disease severity in patients with chronic liver disease from compensated cirrhosis (CC), acute decompensation (AD), or acute‐on‐chronic liver failure (ACLF). From August 2013 to October 2017, patients who were admitted to the University Hospital Frankfurt with CC, AD, or ACLF were enrolled in our cirrhosis cohort study. Tandem mass spectrometry was performed on serum samples of 127 patients to assess S1P concentration. Our study comprised 19 patients with CC, 55 with AD, and 51 with ACLF, aged 29 to 76 years. We observed a significant decrease of S1P according to advanced liver injury from CC and AD up to ACLF (P < 0.001). S1P levels further decreased with progression to ACLF grade 3 (P < 0.05), and S1P highly inversely correlated with the Model for End‐Stage Liver Disease score (r = −0.508; P < 0.001). In multivariate analysis, S1P remained an independent predictor of 7‐day mortality with high diagnostic accuracy (area under the curve, 0.874; P < 0.001). Conclusion: In patients with chronic liver disease, serum S1P levels dramatically decreased with advanced stages of liver disease and were predictive of early mortality. Because S1P is a potent regulator of endothelial integrity and immune response, low S1P levels may significantly influence progressive multiorgan failure. Our data justify further elucidation of the diagnostic and therapeutic role of S1P in ACLF.
Analyse der Genauigkeit des neurochirurgischen Operationsroboters Robotic Surgery Assistant (ROSA)
(2020)
In der vorliegenden Arbeit sollte untersucht werden, ob der Roboter ROSA bei der Durchführung von intrakraniellen Biopsien oder Elektrodenimplantationen eine Alternative zur klassischen, rahmenbasierten Stereotaxie darstellt. Dazu sollte die mechanische und die Anwendungsgenauigkeit des Systems ermittelt werden. Zur Bestimmung der mechanischen Genauigkeit wurde eine experimentelle Phantomstudie durchgeführt. Hier wurden durch den Roboter wiederholt zehn Trajektorien an einem Stereotaxiephantom angefahren. Der Abstand der robotischen Nadel zum Zielpunkt im Phantom wurde anhand von Röntgenbildern bestimmt. Die Wiederholung des Versuchsaufbaus unter Variation der Planungsbildgebung erlaubte den Vergleich verschiedener Schichtdicken sowie zwischen low-dose und normal-dose Verfahren. Die Anwendungsgenauigkeit sollte durch die Analyse operativer Ergebnisse der ROSA erfasst werden. Dazu wurde anhand von postoperativen Bildern die Genauigkeit anhand des Abstands zwischen geplanter und tatsächlicher Lage von Stereoelektroenzephalographie-Elektroden ermittelt. Es wurden verschiedene Referenzierungstechniken, die der Orientierung des Roboters dienen und bei denen eine präoperative Planungsbildgebung (CT oder MRT) mit einem Abbild des OP-Gebietes (durch Oberflächenerkennung oder durch einen Stereotaxierahmen) referenziert wird, verglichen, nämlich CT-Laser; CT-Leksell-Rahmen und MRT-Laser. Die Ergebnisse wurden einer statistischen Analyse unterzogen. Dabei zeigte sich, dass der ROSA-Roboter eine sehr hohe mechanische Genauigkeit im Submillimeterbereich erreicht. Genauigkeitseinbußen bei einer größeren Schichtdicke der zur Planung verwendeten Computertomographie sind messbar, aber gering. Ein signifikanter Einfluss bei der Verwendung eines low-dose-Protokolls konnte nicht festgestellt werden. Dennoch zeigte sich, dass der entscheidende Teil der Ungenauigkeiten in der klinischen Anwendung entsteht und dabei insbesondere durch die Referenzierungstechnik bestimmt wird. Referenzierungen, die auf einer Computertomographie basierten, erwiesen sich als zufriedenstellend genau und als konkurrenzfähig zur konventionellen Methode. Der Unterschied zwischen dem rahmenbasierten und dem auf Oberflächenerkennung basierenden Verfahren war dabei so gering, dass letzteres sich angesichts seiner Vorteile in der Anwendung als besonders günstiges Verfahren hervortut. Im Gegensatz dazu stand das MRT-Laser-Verfahren, welches bei relativ hohen Abweichungen nur eingeschränkt anwendbar scheint und sich damit eher für Anwendungsbereiche mit geringeren Genauigkeitsanforderungen eignet, wie bspw. Biopsien. Weiterhin kann der Verlauf der Trajektorie an den höheren Sicherheitsabstand angepassten werden. Bei der Einordnung der ermittelten Genauigkeiten ist zu beachten, dass es viele weitere, von der Referenzierungs- und Bildgebungsmethode unabhängige Einflussfaktoren gibt. In dieser Arbeit war der Einfluss der erfassten externen Paramter zwar limitiert, bei anderen Autoren zeigte sich jedoch ein signifikanter Effekt. Dennoch deckt sich die Gesamtgenauigkeit mit den Ergebnissen anderer Arbeiten.
In Zusammenschau der Ergebnisse weist die vom ROSA-Assistenzsystem assistierte Stereotaxie eine verbesserte Prozessqualität auf, unter anderem durch die erhebliche Zeitersparnis, ggf. der Wegfall des Transports des narkotisierten Patienten, die Adaptionsmöglichkeiten der Prozessteilschritte an den Patienten, sowie eine hohe Nutzerfreundlichkeit. Entscheidend ist jedoch, dass es sich um ein sehr sicheres Verfahren handelt: Durch die hohe Genauigkeit wird das Operationsrisiko minimiert, gleichzeitig erlauben Laser-gestützte Registrierungsverfahren eine Reduktion der Strahlenexposition. Zur Konsolidierung der in dieser Arbeit gewonnenen Erkenntnisse sind weitere klinische Daten notwendig.
Astrozyten erfüllen verschiedene Funktionen im Zentralnervensystem, welche sich in die Bereiche Entwicklung, Durchblutung, Metabolismus, Strukturerhalt und Gliotransmission unterteilen lassen. Astrozyten sind an der synaptischen Informationsverarbeitung beteiligt und wirken an zahlreichen höheren Hirnfunktionen mit. Durch Regulation der synaptischen Transmission und Plastizität sind Astrozyten am Lernverhalten und Erinnerungsvermögen, sowie an der Verhaltensmodulation und Verarbeitung emotionaler Reize involviert. Im Zuge dieser zahlreichen Funktionen können Astrozyten auf externe Stimuli mit der gezielten Freisetzung von Gliotransmittern reagieren.
In kultivierten Astrozyten konnte Keil143 das TGN, bestehend aus Zisternen und Vesikeln, darstellen und mit anti-Rab6 identifizieren. Rab6 mit seinen Subtypen A und B gehört der Superfamilie der monomeren Ras-GTPasen an, die den intrazellulären Membran- und Vesikelverkehr regulieren. Rab6 spielt in HeLa-Zellen beim Transport vesikulärer Organellen vom TGN zur Zellmembran eine wichtige Rolle. Assoziationsanalysen von Rab6A mit vesikulären Glutamattransportern, Serinracemase und Markern der regulierten Exozytose in kultivierten Astrozyten143 deuten darauf hin, dass dieses Rab6A-Organellsystem die ultrastrukturelle Grundlage für die Freisetzung von Gliotransmittern wie D-Serin und Glutamat bildet.
Zur Untersuchung, ob Rab6A tatsächlich ein System der Glia-Neuron-Kommunikation im Gehirn darstellt, war es zunächst unabdingbar das Vorkommen von Rab6A in situ zu untersuchen. Die durchgeführten immunzytochemischen Färbungen an Hirnschnitten der Maus zeigen das gleichmäßige und ubiquitäre Vorkommen von Rab6A in allen untersuchten Hirnregionen. Durch verblindet durchgeführte Kolokalisationsanalysen von Rab6A mit den etablierten astrozytären Markern Glutaminsynthetase (GS), Glial fibrillary acidic protein (GFAP), Aldh1L1 und Sox9 konnte eine Lokalisation von Rab6A in allen Astrozyten gezeigt werden. Weitere Analysen schließen die Lokalisation von Rab6A in Mikroglia (Iba1), NG2-Zellen (NG2) und Oligodendrozyten (CNPase) aus. Die Astrozyten unterscheiden sich in Größe und subzellulärem Verteilungsmuster der Rab6A+ Strukturen, wonach eine Kategorisierung in vier Typen vorgenommen wurde. Anhand der Einteilung kann vermutet werden, dass größere Rab6A+ TGN-Zisternen bis weit in die Zellperipherie transportiert werden und kleine Rab6A+ Vesikel erst dort ausknospen und der Exozytose zugeführt werden. Zur Frage der möglichen astrozytären Subpopulationen konnte gezeigt werden, dass alle untersuchten Astrozyten GS+, Aldh1L1+, Sox9+ und Rab6A+ sind, jedoch nicht GFAP+.
Um die prinzipielle Übertragbarkeit der gewonnenen Befunde auf den Menschen zu überprüfen, wurde reseziertes Cortex-Gewebe von drei Patienten mit unterschiedlicher pathologischer Genese untersucht. Rab6A ist im massiven Ausmaß in humanen Astrozyten lokalisiert, was nahelegt, dass die zuvor an der Maus gewonnenen Ergebnisse auf den Menschen übertragbar sind.
Die mögliche funktionelle Bedeutung von astrozytärem Rab6A im Gehirn wurde an HFS-Schnitten untersucht. Die Untersuchung zeigt einen signifikanten Anstieg der Rab6A+ Intensität in der gesamten Molekularschicht der Fascia dentata der stimulierten im Vergleich zur unstimulierten Seite. Da die HFS ein etabliertes LTP-Modell darstellt, könnte es infolge dieser zu einer strukturellen, intrazellulären Veränderung der Astrozyten mit erhöhter Freisetzung von D-Serin oder Glutamat aus Rab6A+ Vesikeln kommen, was das Lernverhalten beeinflussen könnte. Die dargestellten Ergebnisse legen eine Auswirkung der HFS auf Rab6A nahe.
Zur Bestätigung der immunzytochemischen Untersuchungen wurde die mRNA-Expression von Rab6A in Astrozyten bereits publizierter Transkriptomanalysen untersucht. Die in den Publikationen verwendeten Genom-Chips treffen allenfalls indirekt eine Aussage zu Rab6A, da Rab6 allgemein und nur Rab6B spezifisch untersucht wurde, jedoch keine spezifische Rab6A Sonde erwähnt wird.
Zusammenfassend kann Rab6A als spezifisches und selektiv in Astrozyten vorkommendes Protein dargestellt und als neuer astrozytärer Marker etabliert werden, der auch Astrozyten des humanen Gewebes markiert. Durch die gewonnenen Befunde kann in nachfolgenden Studien die mögliche Bedeutung von Rab6A in neuropathologischen und neurophysiologischen Prozessen untersucht werden.