Refine
Has Fulltext
- yes (350)
Is part of the Bibliography
- yes (350)
Year of publication
Document Type
- Journal article (350) (remove)
Keywords
- Fabry disease (19)
- chronic kidney disease (18)
- heart failure (17)
- adrenocortical carcinoma (13)
- mortality (13)
- inflammation (12)
- echocardiography (10)
- myocardial infarction (10)
- enzyme replacement therapy (9)
- hemodialysis (9)
- prognosis (8)
- biomarker (7)
- cardiomyopathy (7)
- cortisol (7)
- depression (6)
- heart (6)
- obesity (6)
- therapy (6)
- CXCR4 (5)
- PET (5)
- anxiety (5)
- atherosclerosis (5)
- biomarkers (5)
- blood pressure (5)
- cardiovascular disease (5)
- cardiovascular diseases (5)
- metabolomics (5)
- mouse (5)
- paraganglioma (5)
- pheochromocytoma (5)
- prevalence (5)
- type 2 diabetes (5)
- Cushing’s syndrome (4)
- cardiovascular events (4)
- coronary heart disease (4)
- cytokines (4)
- diabetes mellitus (4)
- diagnosis (4)
- epidemiology (4)
- fibrosis (4)
- hypercortisolism (4)
- hypertension (4)
- ischemic stroke (4)
- miRNA (4)
- mice (4)
- oxidative stress (4)
- radial (4)
- risk factors (4)
- survival (4)
- systematic literature review (4)
- theranostics (4)
- vitamin D (4)
- ACTH (3)
- CMR (3)
- COVID-19 (3)
- FGFR (3)
- Heart failure (3)
- MRI (3)
- SOAT1 (3)
- adrenocortical cancer (3)
- agalsidase alfa (3)
- agalsidase beta (3)
- age (3)
- amyloidosis (3)
- blood (3)
- cancer (3)
- cardiac hypertrophy (3)
- cardiac magnetic resonance imaging (3)
- cognitive decline (3)
- cognitive impairment (3)
- coronary artery disease (3)
- desmin (3)
- diabetes (3)
- dialysis (3)
- diet (3)
- end-stage renal disease (3)
- endoradiotherapy (3)
- follow-up (3)
- genetics (3)
- guidelines (3)
- hypertrophic cardiomyopathy (3)
- immune response (3)
- immunohistochemistry (3)
- impact (3)
- kidney (3)
- left ventricular hypertrophy (3)
- liraglutide (3)
- lymphocytes (3)
- machine learning (3)
- management (3)
- medicine (3)
- melanoma (3)
- mitotane (3)
- multicenter (3)
- osteoporosis (3)
- outcomes (3)
- quality of life (3)
- safety (3)
- treatment (3)
- 18F-FDG (2)
- 4D flow (2)
- C-X-C motif chemokine receptor 4 (2)
- CYP2W1 (2)
- Chronic kidney disease (2)
- Cushing’s disease (2)
- Depression (2)
- Diabetes mellitus (2)
- Enzyme replacement therapy (2)
- FGF-pathway (2)
- Fabry genotype (2)
- Fabry nephropathy (2)
- Fabry phenotype (2)
- GFAP (2)
- Germany (2)
- HFpEF (2)
- KDIGO (2)
- Kidney function (2)
- LDL cholesterol (2)
- MOLLI (2)
- Medicine (2)
- Medizin (2)
- Mortality (2)
- NAFLD (2)
- Neurons (2)
- PPGL (2)
- Positronen-Emissions-Tomografie (2)
- Prevalence (2)
- Quality of life (2)
- Roux-en-Y gastric bypass surgery (2)
- SF-36 (2)
- TAVI (2)
- United States (2)
- WSS (2)
- [68Ga]PentixaFor (2)
- ablation (2)
- acute heart failure (2)
- acute kidney injury (2)
- adenomas (2)
- adrenal (2)
- adrenal cancer (2)
- adrenal crisis (2)
- adrenal insufficiency (2)
- adrenal tumours (2)
- adrenocortical tumors (2)
- aging (2)
- aldosterone (2)
- aneurysm (2)
- antimicrobial resistance (2)
- aortic arch (2)
- arrhythmia (2)
- association (2)
- blood flow (2)
- body mass index (2)
- body weight (2)
- bone (2)
- calcification (2)
- cancer treatment (2)
- carbohydrates (2)
- carcinomas (2)
- cardiac (2)
- cardiac MRI (2)
- cardiac surgery (2)
- cardiology (2)
- cardiovascular genetics (2)
- cardiovascular magnetic resonance (2)
- cardiovascular morbidity (2)
- cardiovascular risk factors (2)
- catecholamines (2)
- chemokine receptor (2)
- chronic cerebrovascular disease (2)
- chronic heart failure (2)
- chronic kidney-disease (2)
- clinical trial (2)
- convection volume (2)
- copeptin (2)
- deep learning (2)
- deformation (2)
- dementia (2)
- desmosomes (2)
- diabetic cardiomyopathy (2)
- diabetic kidney disease (2)
- dialysis adequacy (2)
- diastolic dysfunction (2)
- efficacy (2)
- ejection fraction (2)
- empagliflozin (2)
- gastric bypass (2)
- genome-wide association (2)
- glomerular filtration rate (2)
- glycemic control (2)
- guideline adherence (2)
- hemodiafiltration (2)
- hydrocortisone (2)
- hyperexpression techniques (2)
- identification (2)
- immune cells (2)
- immunotherapy (2)
- infections (2)
- insulin resistance (2)
- internal medicine (2)
- kidneys (2)
- left ventricular ejection fraction (2)
- left ventricular mass (2)
- lysosomal storage disease (2)
- magnetic resonance imaging (2)
- mapping (2)
- medullary thyroid carcinoma (2)
- metaanalysis (2)
- mineral metabolism (2)
- morbidity (2)
- mouse models (2)
- multiple myeloma (2)
- myocardial work (2)
- natriuretic peptide (2)
- neuroendocrine tumor (2)
- neurofilament light chain (2)
- pediatric adrenocortical cancer (2)
- pediatric adrenocortical tumor (2)
- pembrolizumab (2)
- peptide tyrosine tyrosine (PYY) (2)
- placebo-controlled trial (2)
- population (2)
- positron emission tomography (2)
- postmenopausal women (2)
- precision medicine (2)
- primary prevention (2)
- prognostic factors (2)
- prognostic marker (2)
- proteinuria (2)
- pulse wave velocity (2)
- quantification (2)
- radiotherapy (RT) (2)
- randomized controlled trial (2)
- receptor (2)
- recurrence (2)
- regulatory T cells (2)
- renal function (2)
- replacement (2)
- restrictive cardiomyopathy (2)
- sepsis (2)
- sizing (2)
- small interfering RNAs (2)
- stage renal-disease (2)
- stem cell transplantation (2)
- stroke (2)
- sudden cardiac death (2)
- surgery (2)
- therapeutic drug monitoring (2)
- troponin (2)
- tyrosine kinase inhibitor (2)
- uremic toxins (2)
- urine (2)
- validation (2)
- vandetanib (2)
- wall shear stress (2)
- 2- deoxy-2-(18F)fluoro-D-glucose (1)
- 2-deoxy-2-(18F)fluoro-D-glucose (1)
- 2-dimensional speckle tracking (1)
- 3 T (1)
- 4D flow MRI (1)
- 7 T (1)
- 7T (1)
- <sup>18</sup>F-FDG (1)
- <sup>68</sup>Ga-Pentixafor (1)
- A-delta fibers (1)
- ACC (1)
- ACC/AHA classification (1)
- ACM (1)
- AKI (1)
- ALT (1)
- ARDS (acute respiratory distress syndrome) (1)
- ARVC (1)
- ASE formula (1)
- ATP generation (1)
- ATRX (1)
- Addison's disease (1)
- Addisons disease (1)
- Adrenocortial carcinomas (1)
- African-americans (1)
- Agalsidase beta (1)
- Akutes Nierenversagen (1)
- Alpha-Galactosidase (1)
- Alpha-galactosidase (1)
- Alzheimer’s dementia (1)
- Amino acids (1)
- Anderson-Fabry Disease (1)
- Angst (1)
- Antigen 4 (1)
- Aorta (1)
- Aortic arch (1)
- Aplastic anemia (1)
- Apoptosis (1)
- Artificial Nuclear Pores (1)
- Atherosclerosis (1)
- Autoimmune-Diseases (1)
- B (1)
- B cells (1)
- BET Inhibitor (1)
- BIRC7 (1)
- BRAF mutation (1)
- BRAF(V600E) mutation (1)
- BRD4 (1)
- Biochemical-Diagnosis (1)
- Bioluminescence (1)
- Brain atrophy (1)
- Brownian ratchet (1)
- C-reactive protein (1)
- C-terminal HSP90 inhibitors (1)
- CASP (1)
- CCR7 (1)
- CD4+ T-cells (1)
- CD9 (1)
- CIED malfunction; pacemaker (PM) (1)
- CKD (1)
- CML (1)
- COH29 (1)
- COMT (1)
- COPD diagnosis (1)
- COVID‐19 vaccination (1)
- CRH stimulation test (1)
- CTNNB1 (1)
- CXCR7 (1)
- CYP2B6 (1)
- Ca cycling (1)
- Ca2+i handling (1)
- Calcineurin-NFATsignaling (1)
- Calcium Citrate (1)
- Calibration (1)
- Cancer genetics (1)
- Cardiac magnetic resonance imaging (1)
- Cardiac resynchronization therapy defibrillator (1)
- CardioMEMS™ HF-System (1)
- Cardiomyopathy (1)
- Cardiovascular diseases (1)
- Cardiovascular hospitalizations (1)
- Cardiovascular risk factors (1)
- Cardiovascular risk prediction (1)
- Carotid intima-media thickness (CIMT) (1)
- Carotid segment (1)
- Carotid ultrasound (1)
- Catheter Lock Solution (1)
- Catheter-related Bloodstream Infections (CRBSI) (1)
- Cell (1)
- Cell lung canger (1)
- Chronic Kidney-disease (1)
- Chronic heart failure (1)
- Chronic heart-failure (1)
- Chronic kidney-disease (1)
- Clinical prediction rule (1)
- Clinical proteomics (1)
- Clinical trial (1)
- Clinical-trials (1)
- Cognitive decline (1)
- Cohort study (1)
- Comorbidities (1)
- Contrast-enhanced CT (1)
- Copeptin (1)
- Coronavirus Disease 2019 (1)
- Cranial sutures (1)
- Cumulative incidence function (1)
- Cushing (1)
- Cushing syndrome (1)
- Cushing's (1)
- Cushing's disease (1)
- Cushings syndrome (1)
- Cytoskeleton (1)
- D313Y genotype (1)
- DHEA-S (1)
- DHEAS (1)
- DIA-MS (1)
- DNA damage (1)
- DOTATOC (1)
- DSC2 (1)
- DSG2 (1)
- Dendritic Cells (1)
- Depression treatment (1)
- Depressive symptomatology (1)
- Desmoplakin (1)
- Diabetic nephropathies (1)
- Diabetic-nephropathy (1)
- Diagnosis (1)
- Diastocic Dysfunction (1)
- Dipeptidyl-peptidase IV inhibitors (1)
- Discovery (1)
- Disease prevalence (1)
- Diversity (1)
- Dokumentationsqualität (1)
- E/e’ (1)
- ECG (1)
- ECV (1)
- EMT (1)
- EP Procedures (1)
- ESC (1)
- EUROASPIRE (1)
- EUROASPIRE survey (1)
- Embryos (1)
- Enhancer elements (1)
- Epidemiology (1)
- Eplerenone (1)
- European Society (1)
- Expression (1)
- Extracellular volume (1)
- Extracorporeal membrane oxygenation (1)
- F-18-FDG PET/CT (1)
- FGF21 (1)
- FGFR-inhibitors (1)
- Fabry (1)
- Fabry Disease (FD) (1)
- Fabry cardiomyopathy (1)
- Fabry pain (1)
- Fabry patient (1)
- Fabry-associated pain (1)
- False positive reactions (1)
- Family Investigation of Nephropathy and Diabetes (1)
- Female patients (1)
- Fibroblast Growth Factor-21 (1)
- Fontan’s Operation (1)
- FoxP3 Expression (1)
- Foxp3 (1)
- Framingham (1)
- G protein coupled receptors (1)
- GH response (1)
- GLA (1)
- GLA protein UCMGP (1)
- GLP-1 (1)
- GMPcGMP-dependent protein kinase I (1)
- GOLD (1)
- GRAPPA (1)
- Galactosidase-A gene (1)
- Gb3 and lyso-Gb3 biomarkers (1)
- General-population (1)
- Genome-wide association studies (1)
- Glial fibrillary acidic protein (1)
- Globotriaosylceramide (1)
- Glomerular-filtration-rate (1)
- Glycaemic control (1)
- Graves disease (1)
- HEK cells (1)
- HIV (1)
- HIV diagnosis and management (1)
- HLA (1)
- HUVEC (1)
- Haemodialysis (1)
- Hazards (1)
- Healthcare research (1)
- Heart failure with preserved ejection fraction (1)
- Heart failure with reduced ejection fraction (1)
- Hematopoietic cell transplant (1)
- Hemodialysis-patients (1)
- Hemoglobin A1C (1)
- HiGHmed (1)
- Hindbrain (1)
- Home monitoring (1)
- Homoarginine (1)
- Hypercortisolism (1)
- Hyperkalemia (1)
- Hyperosmotic Stress (1)
- ICD-coding of CKD (1)
- IDH1/2 (1)
- IGF-I (1)
- IMAZA (1)
- IP3 (1)
- Immune-System (1)
- Immunological Self-Tolerance (1)
- Immunosuppression (1)
- Impella (1)
- Infection control (1)
- Insulin therapy (1)
- Intensivtransport (1)
- Interhospitaltransfer (1)
- Interleukin-6 (1)
- Internet of Things devices (1)
- JQ1 (1)
- Juvenile biventricular cardiomyopathy (1)
- KWIC (1)
- Kaposi sarcoma (1)
- Klotho-related molecules (1)
- L-arginine (1)
- LCNEC (1)
- LMNA (1)
- LND (1)
- LNE (1)
- LV dilatation (1)
- LV mass (1)
- LVNC (1)
- Lag time (1)
- Langzeitbeatmung (1)
- Linagliptin (1)
- Long COVID (1)
- Lyso-Gb3 (1)
- MASS (1)
- MEN1 (1)
- MR (1)
- MR guidance (1)
- MTL30 (1)
- MUST-Score (1)
- Magnetic resonance imaging (1)
- Mass-spectrometry (1)
- Measurement (1)
- Medullärer Schilddrüsenkrebs (1)
- Memory dysfunction (1)
- Men (1)
- Metanephrine (1)
- Methicillin-resistant staphylococcus aureus (1)
- Methodological quality (1)
- Mfn2 KO mice (1)
- Model (1)
- Molecular Channel Transport (1)
- Molekül (1)
- Morbidity (1)
- Morbus Fabry (1)
- Mouse (1)
- Mouse models (1)
- Multiparameter predictor (1)
- Multiple-Sclerosis (1)
- Myeloma (1)
- Myocardial infarction (1)
- Myocardial-Infarction (1)
- N-terminal HSP90 inhibitors (1)
- NASH (1)
- NCI-H295R (1)
- NEC (1)
- NET (1)
- NMR (1)
- NOP10 (1)
- NR3C1 (1)
- NSG animals (1)
- NT-proBNP (1)
- Natural-history data (1)
- Neprilysin inhibition (1)
- Network (1)
- New mexico (1)
- NfL (1)
- Non‐ischaemic cardiogenic shock (1)
- Normetanephrine (1)
- Nrf2 (1)
- OAT1 (1)
- OAT3 (1)
- OK cells (1)
- OSI (1)
- OXPHOS (1)
- Observational study (1)
- Onset hypertrophic cardiomyopathy (1)
- Oral antidiabetic drugs (1)
- Outcome survey (1)
- Outcomes (1)
- P-cresyl sulfate (1)
- PD-L1 (1)
- PF-05231023 (1)
- PHQ-9 (1)
- PRO (1)
- PTA (1)
- PWV (1)
- PYY3-36 (1)
- Pain (1)
- Pain-related evoked potentials (1)
- Palmoplantar keratoderma (1)
- Paraganglioma (1)
- Physical impairment (1)
- Plasma (1)
- Positron-emission-tomography (1)
- Postmarketing Experience (1)
- Predictive value of tests (1)
- Predictors (1)
- Preserved Ejection Fraction (1)
- Primary care (1)
- Probabilities (1)
- Prognostic impact (1)
- Progression (1)
- Protein (1)
- Psychopharmakologie (1)
- Psychotherapie (1)
- RAKI (1)
- RNA Expression (1)
- RNAScope (1)
- RNR (1)
- ROS (1)
- RRM2 (1)
- RYGB (1)
- Racial differences (1)
- Raman micro-spectroscopy (1)
- Recognition of depression (1)
- Regression (1)
- Remote device monitoring (1)
- Research design (1)
- Resistance (1)
- Risk (1)
- Risk-factors (1)
- Rotary EXcitation (REX) (1)
- Roux-en-Y Gastric Bypass (1)
- Roux-en-Y gastric bypass (1)
- SARS‐CoV‐2 infection (1)
- SASHA (1)
- SCORE (1)
- SGLT2 inhibitor (1)
- SGLT2 inhibitors (1)
- SNP (1)
- SR Ca leak (1)
- SR/mitochondria metabolic feedback (1)
- SSTR (1)
- ST-elevation myocardial infarction (1)
- STEMI (1)
- SUMO2 (1)
- Sample-sizes (1)
- Sars-CoV-2 (1)
- Self-navigation (1)
- Septal bulge (1)
- Severe Acute Respiratory Syndrome Coronavirus 2 (1)
- Sex-Hormones (1)
- ShMOLLI (1)
- Skull (1)
- Small fiber neuropathy (1)
- Society (1)
- Somites (1)
- Spin echo (1)
- Stage renal-disease (1)
- Stiffness (1)
- Subdistribution (1)
- Sudden cardiac death (1)
- Suppressive Function (1)
- Survival (1)
- Systemic-Lupus-Erythematosus (1)
- Systole (1)
- T cells (1)
- T-cell (1)
- T-cells (1)
- T1 mapping (1)
- T1-mapping (1)
- T1rho (1)
- T1ρ (1)
- TERT (1)
- TKI (1)
- TNF-alpha (1)
- TT\(_{1rho}\) mapping (1)
- T\(_{1P}\) dispersion (1)
- T\(_{1P}\) mapping (1)
- Tanzania (1)
- Taurolidine (1)
- Teichholz formula (1)
- Test accuracy (1)
- Tests (1)
- Thermodynamics (1)
- Thermodynamik (1)
- Time measurement (1)
- Transport (1)
- Treatment outcome (1)
- Tregs (regulatory T cells) (1)
- USP28 (1)
- USP8 (1)
- Utility (1)
- VAS (1)
- VEMP (1)
- Valvular heart-desease (1)
- Variants (1)
- Ventricular septal rupture (1)
- Weaning (1)
- X-chromosomal inactivation (1)
- XA (1)
- Young-patients (1)
- ZDF rats (1)
- Zebrafish (1)
- Zucker fatty fa/fa rats (1)
- [11C]-Choline PET/CT (1)
- [11C]-Methionine (1)
- [177Lu]/[90Y]PentixaTher (1)
- [177Lu]PentixaTher (1)
- [18F]FDG-PET-CT (1)
- [90Y]PentixaTher (1)
- [99mTc]-Sestamibi scan (1)
- [\(^{68}\)Ga] pentixafor (1)
- \(^{18}\)F-FDG (1)
- \(^{18}\)F-fluorodeoxyglucose (1)
- abdominal lymph node metastases (1)
- absorption (1)
- accelerated atherosclerosis (1)
- activated-receptor gamma (1)
- activation (1)
- acute respiratory distress syndrome (1)
- adaptive immune response (1)
- add-on (1)
- adenovirus (1)
- adenoviruses (1)
- adenylyl cyclase signaling cascade (1)
- adjuvant platinum-based chemotherapy (1)
- adjuvant therapy (1)
- adjuvant treatment (1)
- adrenal cortex hormones (1)
- adrenal cortex neoplasms (1)
- adrenal gland (1)
- adrenal glands (1)
- adrenal imaging (1)
- adrenal surgery (1)
- adrenal tumor (1)
- adrenal tumors (1)
- adrenalectomia (1)
- adrenocortical (1)
- adrenocortical adenocarcinoma (1)
- adrenocortical adenoma (1)
- adrenocortical carcinoma (ACC) (1)
- adrenocortical cell line (1)
- adrenocortical development (1)
- adrenocortical tissues (1)
- adrenocortical tumor (1)
- adult female patients (1)
- adult male patients (1)
- adult patients (1)
- adverse effects (1)
- afatinib (1)
- agalsidase-beta (1)
- agnoists (1)
- albumin excretion rate (1)
- albuminuria (1)
- alcohol (1)
- alkaline phosphatase (1)
- allocation (1)
- allogeneic hematopoietic stem cell transplantation (1)
- alpha galactosidase (1)
- alpha-galactosidase-A (1)
- alpha/delta agonist GFT505 (1)
- amphiphilic block copolymer (1)
- anaemia (1)
- anatomy (1)
- androgens (1)
- anemia (1)
- animal model (1)
- animal models of human disease (1)
- antagonist (1)
- anti-drug antibodies (1)
- anti-myocardial (1)
- antibiotic prescription (1)
- antibodies (1)
- anticoagulation (1)
- antidiabetic agents (1)
- antimicrobial stewardship (1)
- antiphospholipid syndrome (1)
- antiretroviral therapy (1)
- antiretrovirals (1)
- anti‐SARS‐CoV‐2‐spike IgG (1)
- aorta (1)
- aortic valve (1)
- aortic valve disease (1)
- aortic valve disease percutaneous intervention (AVDP) (1)
- aortic valve stenosis (1)
- aortic valve stenosis (AS) (1)
- apolipoprotein E (1)
- apolipoprotein-E (1)
- apoptosis (1)
- arial fibrillation (1)
- arrhythmogenic cardiomyopathy (1)
- arterial elasticity (1)
- arterial stiffening (1)
- assay systems (1)
- astrocytoma (1)
- at-home sampling (1)
- atheriosclerosis (1)
- atherogenic dyslipidaemia (1)
- atherosclerosis risk (1)
- atrial fibrillation (1)
- atypical (1)
- autoantibodies (1)
- autoantibody (1)
- autoimmune cardiomyopathy (1)
- autonomous cortisol secretion (1)
- avascular necrosis (1)
- awareness (1)
- balance (1)
- bardoxolone methyl (1)
- battery depletion (1)
- behavior (1)
- biocompatibility (1)
- bioinformatic clustering (1)
- biological models (1)
- biomarker prediction (1)
- biopsy (1)
- biopsy findings (1)
- bis-sulfate (1)
- blood coagulation factor XIII (1)
- blood plasma (1)
- blood pressure monitoring (1)
- blood-glucose control (1)
- blood–brain barrier (1)
- bone formation (1)
- bone metabolism (1)
- bone mineral density (1)
- brain natriuretic peptide (1)
- brain pathology (1)
- branched-chain amino acids (1)
- bull’s eye plot (1)
- buparlisib (1)
- c-MYC (1)
- calcineurin signaling cascade (1)
- calcium (1)
- calcium imaging (1)
- canagliflozin (1)
- cancer detection (1)
- cancer diagnosis (1)
- cancer risk (1)
- cancer risk factors (1)
- cancer types (1)
- cancer-testis antigens (1)
- candidate genes (1)
- carcinogenesis (1)
- carcinoma (1)
- carcinoma metastases to pancreas (1)
- cardiac amyloidosis (1)
- cardiac arrest (1)
- cardiac dysfunction (1)
- cardiac energy metabolism (1)
- cardiac function (1)
- cardiac glycosides (1)
- cardiac implantable electronic devices (CIED) (1)
- cardiac implants (1)
- cardiac magnetic resonance (1)
- cardiac pacing (1)
- cardiac resynchronization therapy (CRT) (1)
- cardiac thrombi (1)
- cardiac training group (1)
- cardiac transplantation (1)
- cardiac variant (1)
- cardiac ventricles (1)
- cardiogenetics (1)
- cardiomyopathies (1)
- cardiopulmonary bypass (1)
- cardiovascular MRI (1)
- cardiovascular care (1)
- cardiovascular death (1)
- cardiovascular drugs (1)
- cardiovascular magnetic-resonance (1)
- cardiovascular mortality (1)
- cardiovascular munster procam (1)
- cardiovascular outcomes (1)
- cardiovascularm disease (1)
- carotid artery disease (1)
- case report (1)
- caspase-3 (1)
- catenin (1)
- catheter tip (1)
- cell biology (1)
- cell cultures (1)
- cell fusion (1)
- cell staining (1)
- cells (1)
- cellular physiology (1)
- central nervous system (1)
- cerebrovascular diseases (1)
- channel transport (1)
- checkpoint inhibitors (1)
- child (1)
- cholesterol (1)
- cholesterol metabolism (1)
- chromosomes (1)
- chronic distress (1)
- chronic heart failure (CHF) (1)
- chronic kidney disease (CKD) (1)
- chronic myeloid leukemia (1)
- chronic thromboembolic pulmonary hypertension (1)
- chronotype (1)
- cigarette smoking (1)
- circadian rhythms (1)
- circadian therapy (1)
- circulating microRNA (1)
- classification (1)
- clearance (1)
- clinical (1)
- clinical data warehouse (1)
- clinical genetics (1)
- clinical manifestations (1)
- clinical routine data (1)
- clinical study (1)
- clinical systems (1)
- clonal hematopoiesis of indeterminate potential (1)
- cloning of putative human promoter sequence (1)
- closure AV fistula/AVM (CLAV) (1)
- coa reductase inhibitors (1)
- coagulation (1)
- coaptation line (1)
- coherent anti-Stokes Raman scattering (CARS) microscopy (1)
- colestilan (1)
- colloids (1)
- color-coded (1)
- combination (1)
- comorbidity (1)
- comparability (1)
- comparative genomic hybridization (1)
- complex (1)
- complex‐valued machine learning (1)
- complication (1)
- comprehensive psychosomatic assessment (1)
- computed tomography (1)
- confounders (1)
- congenital adrenal hyperplasia (1)
- consensus conference (1)
- contact force (1)
- contractility (1)
- converting enzyme-inhibition (1)
- cornea verticillata (1)
- coronary calcification (1)
- coronary-artery calcification (1)
- coronary-heart-disease (1)
- correction (1)
- cortical OAT1 (1)
- cortisol-producing adenoma (1)
- costs (1)
- creatine synthesis (1)
- creatinine (1)
- cryptogenic stroke (1)
- cyclic (1)
- cyclic nucleotides such as cyclic adenosine monophosphate (1)
- cytochrome P450 3A4 (CYP3A4) (1)
- cytoplasmic staining (1)
- cytosol (1)
- dabrafenib (1)
- data augmentation (1)
- data warehouse (1)
- death rates (1)
- deep-vein thrombosis (1)
- deficient mice (1)
- demography (1)
- desmin-related myopathy (1)
- desminopathy (1)
- desmocollin-2 (1)
- desmoglein-2 (1)
- deubiquitinases (1)
- dexamethasone suppression test (1)
- diabetes complications (1)
- diabetes insipidus (1)
- diabetes mellitus type 2 (1)
- diabetic mouse (1)
- diabetic nephropathy (1)
- diagnosis in Fabry disease (1)
- diagnostic medicine (1)
- dialysate (1)
- dialyzer membrane (1)
- diastolic function (1)
- dietary approaches to stop hypertension (1)
- dietary sodium restriction (1)
- digital Health (1)
- digital phenotyping (1)
- digital subtraction angiography (1)
- digitalis (1)
- digitoxin (1)
- dilated cardiomyopathy (1)
- dilated cardiomyopathy with ataxia (1)
- dimensions (1)
- disease (1)
- disease score (1)
- disease severity (1)
- dissection (1)
- distant metastases (1)
- dobutamine stress echocardiography (1)
- documentation quality (1)
- dogs (1)
- double knockout mice (1)
- double-blind (1)
- doule blind (1)
- down regulation (1)
- drug interaction (1)
- drug intoxication (1)
- drug monitoring (1)
- drug therapy (1)
- drug toxicity (1)
- drug transporter (1)
- drug treatment (1)
- drug–drug interactions (DDIs) (1)
- dynamic (1)
- dysfunction (1)
- early prognosis (1)
- early-stage osteonecrosis (1)
- ecological momentary assessment (1)
- ectopic (1)
- eculizumab (1)
- electronic data capture (1)
- electronic health records (1)
- electrophysiology (1)
- electroporation (1)
- end stage renal disease (1)
- end-stage kidney disease (1)
- endocrine cancer (1)
- endocrinology (1)
- endogenous hypercortisolism (1)
- endothelial (1)
- endothelial cell interactions (1)
- endothelin-1 (1)
- endovascular (1)
- energy homeostasis (1)
- enoxaparin (1)
- entresto (1)
- entropy production (1)
- environmental health (1)
- environmental impact (1)
- eosinophils (1)
- epithelial markers (1)
- erythropoietin (1)
- estrogens (1)
- euroaspire (1)
- evidence-based practice (1)
- expression (1)
- extended matching questions (1)
- extracellular matrix (1)
- extracellular matrix remodeling (1)
- fabry disease (1)
- factor XI (1)
- factor XII (1)
- failure (1)
- fall (1)
- fatal cardiovascular disease (1)
- fatty acids (1)
- fatty liver (1)
- feature selection (1)
- female Fabry patients (1)
- ferritin (1)
- fetuin A (1)
- fibroblast growth factor-23 (1)
- filamin-C (1)
- flow (1)
- flow dynamics (1)
- flow patterns (1)
- fluorescence resonance energy transfer (1)
- focal semental glomerulosclerosis (1)
- focused surgical approach (1)
- food consumption (1)
- fourth (1)
- fractionation membranev (1)
- fracture (1)
- fragmin (1)
- free energy (1)
- free light chains (1)
- functional magnetic resonance imaging (1)
- functional regurgitation (1)
- gastric cancer (1)
- gefitinib (1)
- gene (1)
- gene expression (1)
- gene variant (1)
- gene-environment interaction (1)
- gene-therapy (1)
- genetic analysis (1)
- genetic cardiomyopathy (1)
- genetic loci (1)
- genetic renal disease (1)
- genetically modified animals (1)
- genome-wide association study (1)
- genotype/phenotype correlation (1)
- genotyping (1)
- giant cell arteritis (1)
- glial damage (1)
- glial fibrillary acidic protein (1)
- glioblastoma (1)
- global outcomes (1)
- glomerular-filtration-rate (1)
- glomerulonephritis (1)
- glucocorticoid excess (1)
- glucocorticoid replacement (1)
- glucocorticoid replacement regimens (1)
- glucocorticoid replacement therapy (1)
- glucose homeostasis (1)
- glucose tolerance test (1)
- graft (1)
- graft versus host disease (1)
- green fluorescent protein (1)
- growth differentiation factor 15 (1)
- growth hormone deficiency (1)
- guideline implementation (1)
- guideline-directed medical therapy (1)
- gut microbiome (1)
- haemodiafiltration (1)
- haemodialysis (1)
- haplotype (1)
- hashimotos-thyroiditis (1)
- healing and remodelling processes (1)
- health care (1)
- health care research (1)
- health economics (1)
- health policy (1)
- health questionnaire (1)
- health risk assessment (1)
- healthcare workers (1)
- hearing loss (1)
- heart disease (1)
- heart failure training group (1)
- heart failure with mid-range ejection fraction (1)
- heart failure with reduced ejection fraction (1)
- heart rate (1)
- heme oxygenase-1 (1)
- hemoglobin (1)
- heodialysis patients (1)
- high denisty lipoprotein (1)
- high dose dexamethasone suppression test (1)
- high-dose atorvastatin (1)
- high-resolution analysis (1)
- hip fracture (1)
- histopathology (1)
- home telemonitoring (1)
- homeostasis (1)
- homeostasisIon channels (1)
- hormones (1)
- hospitalization (1)
- human behaviour (1)
- human serum albumin (1)
- hydroxy-dabrafenib (1)
- hypercholesterolemia (1)
- hyperosmolality (1)
- hyperparathyroidism (1)
- hyperphosphataemia (1)
- hypersensitivity (1)
- hypertensive cardiomyopathy (1)
- hyponatremia (1)
- hypopituitary patients (1)
- hypothalamic gene expression (1)
- iPSC-CMs (1)
- identical twins (1)
- idiopathic osteonecrosis (1)
- imaging (1)
- imaging TTE/TEE (ITTE) (1)
- immune check inhibitor (1)
- immune checkpoint inhibitor (ICI) (1)
- immune system (1)
- immune-related adverse events (1)
- immunity (1)
- immuno-modulation (1)
- immunoassays (1)
- immunofluorescence (1)
- immunohistochemistry techniques (1)
- immunosenescence (1)
- immunotherapy-induced hypophysitis (1)
- implantable cardioverter defibrillator (ICD) (1)
- implantation (1)
- in silico analysis (1)
- in vivo (1)
- inappropriate prescription (1)
- incidence (1)
- incremental cost-effectiveness ratio (ICER) (1)
- indoxyl sulfate (1)
- induced insulin-release (1)
- inebilizumab (1)
- infarction size (1)
- infection (1)
- inflammaging (1)
- information extraction (1)
- inherited metabolic disorders (1)
- inos (1)
- insufficiency (1)
- insulin tolerance test (1)
- intake (1)
- intensive care medicine (1)
- intensive care transport (1)
- intensive glucose control (1)
- interhospital transfer (1)
- interleukin-6 (1)
- interleukin-8 (1)
- intermediate filaments (1)
- interparticle interaction (1)
- intragastric balloon (1)
- ionic strength (1)
- ipilimumab (1)
- iron (1)
- ischaemic cardiomyopathy (1)
- ischemia (1)
- ischemia-reperfusion injury (1)
- ischemic (1)
- ischemic acute kidney injury model (1)
- isoproterenol (1)
- isturisa (1)
- italian population (1)
- kidney disease (1)
- kidney disease; (1)
- kidney ischemia/reperfusion injury (1)
- kidney-disease CKD (1)
- kinase (1)
- kinase inhibitors (1)
- kinases (1)
- lactase persistence (1)
- lactic acidosis (1)
- lactose (1)
- large animal models (1)
- late gadolinium enhancement (1)
- laxative (1)
- leaflet (1)
- left lateral wall (1)
- left ventricular geometric abnormality (1)
- left ventricular geometry (1)
- left ventricular mass index (1)
- left ventricular performance (1)
- left ventricular remodeling (1)
- left ventricular thrombusv (1)
- left-ventricular hypertrophy (1)
- leptin system (1)
- lesion formation (1)
- lesion size (1)
- lesions (1)
- leukocyte adhesion (1)
- leukocytes (1)
- lifestyle (1)
- linkage (1)
- lipid droplets (1)
- lipid-lowering therapy (1)
- lipoprotein apheresis (1)
- lipoprotein(a) (1)
- lipoxygenase (1)
- liquid chromatography tandem mass spectrometry (LC-MS/MS (1)
- liquid chromatography tandem mass spectrometry (LC-MS/MS) (1)
- liquid chromatography–tandem mass spectrometry (LC–MS/MS) (1)
- livin (1)
- lncRNA (1)
- long-term ventilation (1)
- longitudinal studies (1)
- loss (1)
- low molecular weight (1)
- low-gradient AS (1)
- lower limit of normal (1)
- lung cancer (1)
- lymph node dissection (1)
- lymph nodes (1)
- lymphadenectomy (1)
- lysosomal storage disorder (1)
- lyso‐Gb3 (1)
- m exercise training (1)
- mHealth (1)
- macrophage (1)
- macrovascular (1)
- magnetic resonance (1)
- magnetic resonance spectroscopy (1)
- magnetic resonsance imaging (1)
- malignant tumors (1)
- malnutrition (1)
- marrow (1)
- mass spectrometry (1)
- mass spectronomy (1)
- meat (1)
- medical data integration center (1)
- medical dialysis (1)
- medical informatics initiative (1)
- medical students (1)
- medical therapy (1)
- medication extraction (1)
- medium cut-off dialyzer (1)
- medullary thyroid cancer (1)
- men born (1)
- menopause (1)
- mental impairment (1)
- mesenchymal markers (1)
- meta-analysis (1)
- metabolically unhealthy obesity (1)
- metabolism (1)
- metachronous (1)
- metanephrine (1)
- metastasis (1)
- metastatic (1)
- metformin (1)
- methoxytyramine (1)
- metyrapone (1)
- miR-182-5p (1)
- miR-183 cluster (1)
- miR-483-5p (1)
- mices (1)
- microscopy (1)
- microvascular (1)
- mild (1)
- mineral bone density (1)
- mineralocorticoid antagonist (1)
- minerals (1)
- mitochondria (1)
- mitochondria function and morphology (1)
- mitochondrial DNA copy number (1)
- mitochondrial mRyR1 (1)
- mitofusin 2 (1)
- mitral valve (1)
- mobile crowdsensing (1)
- mobile health (1)
- model (1)
- modified-release hydrocortisone (1)
- molecular biology (1)
- molecular diagnostics (1)
- molecular medicine (1)
- monocytes (1)
- motion detector (1)
- multi-tyrosine kinase inhibitor (1)
- multidetector computed-tomography (1)
- multiple choice questions (1)
- multiple sclerosis (1)
- multivariate data analysis (1)
- mutation (1)
- mutation databases (1)
- mutation triggers (1)
- mutations (1)
- myocardial aging (1)
- myocardial lipid content (1)
- myocardial work efficiency (1)
- myocardial fibrosis (1)
- myocardial-infarction (1)
- myocardium (1)
- natural history (1)
- natural-history data (1)
- nerve fibers (1)
- neural networks (1)
- neuroblastoma – diagnosis (1)
- neurofibromatosis type 1 (1)
- neuroinflammation (1)
- neurological (1)
- neurological complications (1)
- neurology (1)
- neuromyelitis optica spectrum disorders (1)
- neurons (1)
- neuropathy (1)
- neuroscience (1)
- neutral loss (1)
- neutrophils (1)
- nictric-oxide (1)
- nitric oxide (1)
- nitric oxide synthase (1)
- nivolumab (1)
- non-equilibrium thermodynamics (1)
- non-triggered (1)
- noncontact monitoring (1)
- nontraumatic osteonecrosis of the femoral head (1)
- normal adrenal glands (1)
- normal values (1)
- normetanephrine (1)
- notch signaling (1)
- nuclear staining (1)
- nutritional counseling (1)
- nutritional medical needs (1)
- nutritional risk screening (1)
- obesity surgery (1)
- observational study (1)
- occupational-status (1)
- oligonucleotides (1)
- on-site examination (1)
- oncology (1)
- oncology outpatients (1)
- openEHR (1)
- operation (1)
- opossum kidney cells (1)
- oral glucose (1)
- organoid (1)
- oscillating biomagnetic fields (1)
- osilodrostat (1)
- osimertinib (1)
- osmotic stimulation (1)
- osteocalcin (1)
- outcome (1)
- overload (1)
- p-cresyl sulfate (1)
- p.Asn215Ser (1)
- p.N215S (1)
- paediatric patients (1)
- paired (1)
- pandemia (1)
- panel (1)
- papillary (1)
- papillary thyroid carcinoma (PTC) (1)
- parallel imaging (1)
- parathyroid adenoma (1)
- parathyroid carcinoma (1)
- parathyroid hormone (1)
- paravalvular regurgitation (1)
- pathogenesis (1)
- pathophysiology (1)
- patient survival (1)
- patients’ awareness (1)
- pediatric (1)
- pediatric adrenocortical adenoma (1)
- pediatric adrenocortical carcinoma (1)
- peptide tyrosine tyrosine 3-36 (PYY3-36) (1)
- peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) (1)
- percutaneous valve therapy (PVT) (1)
- perioperative chemotherapy (1)
- peripartum cardiomyopathy (1)
- peripheral blood mononuclear cells (1)
- peritoneal carcinomatosis (1)
- personalised medicine (1)
- personalized antimicrobial therapy (1)
- personalized medicine (1)
- personalized treatment (1)
- pharmacoepidemiology (1)
- pharmacokinetics (1)
- pharmacotherapy (1)
- phase IV (1)
- phase-contrast CMR (1)
- phase-contrast MRI (1)
- phenotype (1)
- pheochromocytoma/paraganglioma (1)
- phosphate homeostasis (1)
- phosphatidylcholines (1)
- phospholipid fatty acids (1)
- phosphorylated tau protein (1)
- phosphorylation (1)
- physical activity (1)
- physicians’ awareness (1)
- physiologically based pharmacokinetic (PBPK) modeling (1)
- pig (1)
- pioglitazone (1)
- piperacillin/tazobactam (1)
- pituitary (1)
- pituitary adenomas (1)
- pituitary gland (1)
- placebo (1)
- plant-derived metabolites (1)
- plaque (1)
- plaque characteristics (1)
- plasma (1)
- plasma NMR (1)
- plasma proteins (1)
- plasmid construction (1)
- platelet adhesion (1)
- platelets (1)
- pleural mesothelioma (1)
- podocyte (1)
- polarization (1)
- poly(2-oxazoline) (1)
- polyglandular autoimmune syndrome (1)
- polymorphism (1)
- polymyalgia rheumatica (1)
- population pharmacokinetics (1)
- population-based (1)
- population-based study (1)
- posaconazole (1)
- post-processing (1)
- post-traumatic stress disorder (1)
- postoperativ (1)
- posttraumatische Belastungsstörung (1)
- poultry (1)
- preanalytical conditions (1)
- preclinical research (1)
- prediction model (1)
- predictive marker (1)
- premature mortality (1)
- preserved ejection fraction (1)
- preventive medicine (1)
- primary aldosteronism (1)
- primary healthcare (1)
- primary hyperparathyroidism (1)
- primary hypophysitis (1)
- primary polydipsia (1)
- prognostic biomarker (1)
- prognostic markers (1)
- progression (1)
- propionic acid (1)
- prospective (1)
- prostaglandin e2 (1)
- prostate cancer (1)
- protein binding (1)
- protein expression (1)
- protein-bound solutes (1)
- protein-bound uremic toxins (1)
- proteomic (1)
- pseudo-severe AS (1)
- psychiatric disorders (1)
- psychopharmacology (1)
- psychotherapy (1)
- public health (1)
- pulmonary artery pressure (1)
- pulmonary cancer (1)
- pulse-wave velocity (1)
- quantitative MRI (1)
- radical resection (1)
- radii (1)
- radiofrequency ablation (1)
- radioiodine (1)
- radioiodine therapy (1)
- radiotherapy (1)
- randomized controlled-trial (1)
- randomized trial (1)
- randomized trials (1)
- rare diseases (1)
- rat kidney (1)
- ravulizumab (1)
- real-world (1)
- rearranged during transfection (1)
- recombination hotspot (1)
- recommendations (1)
- recovery (1)
- recurrence free survival (1)
- recurrence survival (1)
- recurrence-free survival (1)
- recurrent Tako-Tsubo cardiomyopathy (1)
- reference data (1)
- reference intervals (1)
- refugee healthcare (1)
- regression analysis (1)
- regulation of expression (1)
- regurgitation (1)
- remote monitoring (1)
- removal (1)
- renal artery (1)
- renal disease (1)
- renal dysfunction (1)
- renal fibrosis (1)
- renal osteodystrophy (1)
- renal replacement therapy (1)
- renal system (1)
- renoprotection (1)
- repeated (1)
- repeated surgery (1)
- reperfusion (1)
- replacement therapy (1)
- reporter gen assay (1)
- reproductive disorders (1)
- research infrastructure (1)
- residual cardiovascular risk (1)
- respiratory signs and symptoms (1)
- retrospective (1)
- review (1)
- re‐transplantation (1)
- rheumatoid arthritis (1)
- right ventricular dysfunction (1)
- risk (1)
- risk factor control (1)
- risk prediction scores (1)
- rodent model (1)
- root (1)
- ruxolitinib (1)
- rygb (1)
- sacubitril-valsartan (1)
- sarcoidosis (1)
- satralizumab (1)
- scale (1)
- sclerostin (1)
- secondary data usage (1)
- secondary prevention (1)
- segmentation (1)
- self-gating (1)
- self-navigation (1)
- selpercatinib (1)
- semantic interoperability (1)
- septal hypertrophy (1)
- sequence databases (1)
- seroprevalence (1)
- serotonin (1)
- serotonin transporter deficient mice (1)
- serum (1)
- serum creatinine (1)
- sevelamer (1)
- severe renal insufficiency (1)
- sex addiction (1)
- sex differences (1)
- sex hormones (1)
- shear stress (1)
- shimming (1)
- short Synacthen test (1)
- short term (1)
- short-chain fatty acids (1)
- signal voids (1)
- signs (1)
- signs and symptoms (1)
- single nucleotide polymorphisms (1)
- skin diseases (1)
- sleeve gastrectomy (1)
- small animal (1)
- smoking (1)
- sodium (1)
- sodium-glucose co-transporter-2 inhibitors (1)
- solubility enhancement (1)
- somatic mutations (1)
- somatostatin receptor (1)
- speckle tracking imaging (1)
- speech recognition (1)
- sphingolipids (1)
- spin lock (1)
- spin-lock (1)
- spironolactone (1)
- sports and exercise medicine (1)
- standard heparin (1)
- standardization (1)
- state space (1)
- statement (1)
- statins (1)
- statistical mechanics (1)
- stenosis (1)
- steroid disulfate (1)
- steroid measurement (1)
- stress instructions (1)
- subjective health-status (1)
- sudden death (1)
- sulfation (1)
- sulfonation (1)
- sulfonylurea (1)
- sulfurylation (1)
- super-obesity (1)
- surgical and invasive medical procedures (1)
- surgical oncology (1)
- surgical repair (1)
- surgical treatment (1)
- surveillance (1)
- susceptibility (1)
- symptoms (1)
- systemic micro-inflammation oxidative stress (1)
- systems biology (1)
- t-lymphocytes (1)
- target therapies (1)
- targeted gene panel (1)
- targeted metabolomics (1)
- targeted therapy (1)
- targeted treatment (1)
- task force (1)
- telemedicine (1)
- telomeres (1)
- temperature (1)
- tenting (1)
- term fenofibrate therapy (1)
- therapeutic approach (1)
- therapeutic management (1)
- therapeutic options (1)
- thermodynamics (1)
- third (1)
- three-dimensional echocardiography (1)
- thromboinflammation (1)
- thrombopoiesis (1)
- thyroid carcinoma (TC) (1)
- tight junctions (1)
- timing (1)
- tissue (1)
- tocilizumab (1)
- tomography (1)
- toxic cardiomyopathy (1)
- trametinib (1)
- transcatheter valveimplantation (TVI) (1)
- transfection (1)
- transfer learning (1)
- transgenic rats (1)
- translation (1)
- translational research (1)
- transport experiments (1)
- treatment outcome (1)
- trial design (1)
- tricuspid pressure gradient (1)
- triglyceride-rich lipoproteins (1)
- troponin T (1)
- tumor (1)
- tumor microenvironment (1)
- tumor necrosis factor-α (1)
- tumor-infiltrating (1)
- tumors (1)
- type 2 (1)
- type 2 diabetes mellitus (1)
- type-1 diabetes mellitus (1)
- type-2 diabetes mellitus (1)
- tyrosine kinase inhibitor (TKI) (1)
- tyrosine kinase inhibitors (1)
- ublituximab (1)
- ultrahigh field (1)
- ultrahigh-field (1)
- ultrahigh-field MRI (1)
- unfractionated heparin (1)
- univentricular heart (1)
- unsupervised clustering (1)
- uremic toxin (1)
- urinary protein excretion (1)
- usability (1)
- use (1)
- user-centered design (1)
- validity (1)
- variant (1)
- vascular calcification (1)
- vascular disease (1)
- vascular surgery (1)
- vemurafenib (1)
- ventricular tachycardia (1)
- vertigo (1)
- viral cardiomyopathy (1)
- viral infection (1)
- vitamins (1)
- volume (1)
- volumetric absorptive micro-sampling (VAMS) (1)
- weaning (1)
- whole exome sequencing (1)
- wires (1)
- yellow fluorescent protein (1)
- zebrafish (1)
- α-galactosidase A (1)
- α‐GalA 3D‐structure (1)
Institute
- Medizinische Klinik und Poliklinik I (350) (remove)
Sonstige beteiligte Institutionen
- Zentraleinheit Klinische Massenspektrometrie (4)
- Apotheke, Universitätsklinikum Würzburg (1)
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (1)
- Datenintegrationszentrum Würzburg (DIZ) (1)
- Interdisziplinäre Biomaterial- und Datenbank Würzburg (ibdw) (1)
- Interdisziplinäres Amyloidosezentrum Nordbayern (1)
- Johns Hopkins School of Medicine (1)
- Johns Hopkins University School of Medicine (1)
- Klinische Studienzentrale (Universitätsklinikum) (1)
- Krankenhaushygiene und Antimicrobial Stewardship, Universitätsklinikum Würzburg (1)
Context
The adrenal cortex produces specific steroid hormones including steroid sulfates such as dehydroepiandrosterone sulfate (DHEAS), the most abundant steroid hormone in the human circulation. Steroid sulfation involves a multistep enzyme machinery that may be impaired by inborn errors of steroid metabolism. Emerging data suggest a role of steroid sulfates in the pathophysiology of adrenal tumors and as potential biomarkers.
Evidence Acquisition
Selective literature search using “steroid,” “sulfat*,” “adrenal,” “transport,” “mass spectrometry” and related terms in different combinations.
Evidence Synthesis
A recent study highlighted the tissue abundance of estrogen sulfates to be of prognostic impact in adrenocortical carcinoma tissue samples using matrix-assisted laser desorption ionization mass spectrometry imaging. General mechanisms of sulfate uptake, activation, and transfer to substrate steroids are reasonably well understood. Key aspects of this pathway, however, have not been investigated in detail in the adrenal; these include the regulation of substrate specificity and the secretion of sulfated steroids. Both for the adrenal and targeted peripheral tissues, steroid sulfates may have relevant biological actions beyond their cognate nuclear receptors after desulfation. Impaired steroid sulfation such as low DHEAS in Cushing adenomas is of diagnostic utility, but more comprehensive studies are lacking. In bioanalytics, the requirement of deconjugation for gas-chromatography/mass-spectrometry has precluded the study of steroid sulfates for a long time. This limitation may be overcome by liquid chromatography/tandem mass spectrometry.
Conclusions
A role of steroid sulfation in the pathophysiology of adrenal tumors has been suggested and a diagnostic utility of steroid sulfates as biomarkers is likely. Recent analytical developments may target sulfated steroids specifically.
Aims/Introduction
In the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care improved clinically relevant kidney outcomes by 39%, slowed progression of chronic kidney disease, and reduced albuminuria in patients with type 2 diabetes and established cardiovascular disease. This exploratory analysis investigated the effects of empagliflozin on the kidneys in Asian patients.
Materials and Methods
Participants in the EMPA-REG OUTCOME® trial were randomized (1:1:1) to empagliflozin 10 mg, 25 mg or a placebo. In patients of Asian race, we analyzed incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal-replacement therapy or renal death) and its components, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio changes, and renal safety.
Results
Of 7,020 treated patients, 1,517 (26.1%) were Asian. In this subgroup, consistent with the overall trial population, empagliflozin reduced the risk of incident or worsening nephropathy (hazard ratio 0.64, 95% confidence interval 0.49–0.83), progression to macroalbuminuria (hazard ratio 0.64, 95% confidence interval 0.49–0.85) and the composite of doubling of serum creatinine, initiation of renal-replacement therapy or renal death (hazard ratio 0.48, 95% confidence interval 0.25–0.92). Furthermore, empagliflozin-treated participants showed slower eGFR decline versus placebo, and showed rapid urine albumin-to-creatinine ratio reduction at week 12, maintained through week 164, with effects most pronounced in those with baseline microalbuminuria or macroalbuminuria. The kidney safety profile of empagliflozin in the Asian subgroup was similar to the overall trial population.
Conclusions
In Asian patients from the EMPA-REG OUTCOME® trial, empagliflozin improved kidney outcomes, slowed eGFR decline and lowered albuminuria versus placebo, consistent with the overall trial population findings.
Background
The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease.
Methods
To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events.
Results
In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25–34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55–64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65–74 years), and rarely in females (3%).
Conclusion
p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.
Aims
Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides – although regularly used for HF treatment – remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF).
Methods
Patients with chronic HF, New York Heart Association (NYHA) functional class III–IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8–18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF.
Conclusion
The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.
Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.
Aims
Vitamin D deficiency is prevalent in heart failure (HF), but its relevance in early stages of heart failure with preserved ejection fraction (HFpEF) is unknown. We tested the association of 25-hydroxyvitamin D [25(OH)D] serum levels with mortality, hospitalizations, cardiovascular risk factors, and echocardiographic parameters in patients with asymptomatic diastolic dysfunction (DD) or newly diagnosed HFpEF.
Methods and results
We measured 25(OH)D serum levels in outpatients with risk factors for DD or history of HF derived from the DIAST-CHF study. Participants were comprehensively phenotyped including physical examination, echocardiography, and 6 min walk test and were followed up to 5 years. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. We included 787 patients with available 25(OH)D levels. Median 25(OH)D levels were 13.1 ng/mL, mean E/e′ medial was 13.2, and mean left ventricular ejection fraction was 59.1%. Only 9% (n = 73) showed a left ventricular ejection fraction <50%. Fifteen per cent (n = 119) of the recruited participants had symptomatic HFpEF. At baseline, participants with 25(OH)D levels in the lowest tertile (≤10.9 ng/L; n = 263) were older, more often symptomatic (oedema and fatigue, all P ≤ 0.002) and had worse cardiac [higher N-terminal pro-brain natriuretic peptide (NT-proBNP) and left atrial volume index, both P ≤ 0.023], renal (lower glomerular filtration rate, P = 0.012), metabolic (higher uric acid levels, P < 0.001), and functional (reduced exercise capacity, 6 min walk distance, and SF-36 physical functioning score, all P < 0.001) parameters. Increased NT-proBNP, uric acid, and left atrial volume index and decreased SF-36 physical functioning scores were independently associated with lower 25(OH)D levels. There was a higher risk for lower 25(OH)D levels in association with HF, DD, and atrial fibrillation (all P ≤ 0.004), which remained significant after adjusting for age. Lower 25(OH)D levels (per 10 ng/mL decrease) tended to be associated with higher 5 year mortality, P = 0.05, hazard ratio (HR) 1.55 [1.00; 2.42]. Furthermore, lower 25(OH)D levels (per 10 ng/mL decrease) were related to an increased rate of cardiovascular hospitalizations, P = 0.023, HR = 1.74 [1.08; 2.80], and remained significant after adjusting for age, P = 0.046, HR = 1.63 [1.01; 2.64], baseline NT-proBNP, P = 0.048, HR = 1.62 [1.01; 2.61], and other selected baseline characteristics and co-morbidities, P = 0.043, HR = 3.60 [1.04; 12.43].
Conclusions
Lower 25(OH)D levels were associated with reduced functional capacity in patients with DD or HFpEF and were significantly predictive for an increased rate of cardiovascular hospitalizations, also after adjusting for age, NT-proBNP, and selected baseline characteristics and co-morbidities.
Long-term effects of migalastat therapy in clinical practice are currently unknown. We evaluated migalastat efficacy and biomarker changes in a prospective, single-center study on 14 patients with Fabry disease (55 ± 14 years; 11 men). After 1 year of open-label migalastat therapy, patients showed significant changes in alpha-galactosidase-A activity (0.06–0.2 nmol/minute/mg protein; P = 0.001), left ventricular myocardial mass index (137–130 g/m2; P = 0.037), and serum creatinine (0.94–1.0 mg/dL; P = 0.021), accounting for deterioration in estimated glomerular filtration rate (87–78 mL/minute/1.73 m2; P = 0.012). The enzymatic increase correlated with myocardial mass reduction (r = −0.546; P = 0.044) but not with renal function (r = −0.086; P = 0.770). Plasma globotriaosylsphingosine was reduced in therapy-naive patients (10.9–6.0 ng/mL; P = 0.021) and stable (9.6–12.1 ng/mL; P = 0.607) in patients switched from prior enzyme-replacement therapy. These first real-world data show that migalastat substantially increases alpha-galactosidase-A activity, stabilizes related serum biomarkers, and improves cardiac integrity in male and female patients with amenable Fabry disease mutations.
Contrast and non-contrast MRI based characterization of myocardium by T1-mapping will be of paramount importance to obtain biomarkers, e.g. fibrosis, which determines the risk of heart failure patients.
T1-mapping by the standard post-processing of the modified look-locker inversion recovery (MOLLI) lacks of accuracy when trying to reduce its duration, which on the other hand, is highly desirable in patients with heart failure. The recently suggested inversion group fitting (IGF) technique, which considers more parameters for fitting, has a superior accuracy for long T1 times despite a shorter duration. However, for short T1 values, the standard method has a superior precision. A conditional fitting routine is proposed which ideally takes advantage of both algorithms.
Materials and methods
All measurements were performed on a 1.5 T clinical scanner (ACHIEVA, Philips Healthcare, The Netherlands) using a MOLLI 5(n)3(n)3 prototype with n(heart beats) being a variable waiting time between inversion experiments. Phantom experiments covered a broad range of T1 times, waiting times and heart rates. A saturation recovery experiment served as a gold standard for T1 measurement. All data were analyzed with the standard MOLLI, the IGF fit and the conditional fitting routine and the obtained T1 values were compared with the gold standard. In vivo measurements were performed in a healthy volunteer and a total of 34 patients with normal findings, dilative cardiomyopathy and amyloidosis.
Results
Theoretical analysis and phantom experiments provided a threshold value for an apparent IGF
determining processing with IGF post processing for values above, or switching to the standard technique for values below. This was validated in phantoms and patients measurements. A reduction of the waiting time to 1 instead of 3 heart beats between the inversion experiments showed reliable results. The acquisition time was reduced from 17 to 13 heart beats. The in vivo measurements showed ECV values between 25% (18–33%; SD 0.03) in the healthy, 30% (22–40%; SD 0.04) in patients with DCM and 45% (30–60%; SD 0.9) in patients with amyloidosis.
Conclusion
The adopted post-processing algorithm determines long T1 values with high accuracy and short T1 values while maintaining a high precision. Based on reduction of waiting time, and independence of heart rate, it shortens breath hold duration and allows fast T1-mapping, which is frequently a prerequisite in patients with cardiac diseases.
Background
Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations.
Methods
We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients.
Results
Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes.
Conclusions
ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.
Fabry disease (FD) is an X-linked lysosomal storage disorder associated with pain triggered by heat or febrile infections. We modelled this condition by measuring the cytokine expression of peripheral blood mononuclear cells (PBMC) from FD patients in vitro upon stimulation with heat and lipopolysaccharide (LPS). We enrolled 67 FD patients and 37 healthy controls. We isolated PBMC, assessed their gene expression of selected pro- and anti-inflammatory cytokines, incubated them with heat, LPS, globotriaosylceramide (Gb3), and tumor necrosis factor-α (TNF), and measured TNF secretion in the supernatant and intracellular Gb3 accumulation, respectively. We found increased TNF, interleukin (IL-)1β, and toll-like receptor 4 (TLR4) gene expression in FD men (p < .05 to p < .01). TNF and IL-10 were higher, and IL-4 was lower in the subgroup of FD men with pain compared to controls (p < .05 to p < .01). Hereby, TNF was only increased in FD men with pain and classical mutations (p < .05) compared to those without pain. PBMC from FD patients secreted more TNF upon stimulation with LPS (p < .01) than control PBMC. Incubation with Gb3 and an additional α-galactosidase A inhibitor did not further increase TNF secretion, but incubation with TNF greatly increased the Gb3 load in FD PBMC compared to controls (p < .01). Also, LPS incubation and heat challenge (40 °C) increased Gb3 accumulation in PBMC of patients compared to baseline (p < .05 each), while no alterations were observed in control PBMC. Our data show that TNF holds a crucial role in the pathophysiology of FD associated pain, which may open a novel perspective for analgesic treatment in FD pain.
Background
Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients.
Methods
A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type.
Results
Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease.
Conclusions
This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results.
Background
Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease.
Methods
A comprehensive systematic review of published literature on ERT in Fabry disease was conducted in January 2017. The literature analysis included all original articles reporting outcomes of ERT in paediatric patients.
Results
Treatment-related outcomes in the paediatric population were reported in six publications derived from open-label clinical trials and in 10 publications derived from observational or registry-based studies. ERT was shown to significantly reduce plasma and urine GL-3 levels in paediatric patients with Fabry disease. The effect of ERT on GL-3 clearance from renal podocytes appeared to be agalsidase dose-dependent. ERT relieved pain and improved gastrointestinal symptoms and quality of life.
Conclusions
Based on the published literature, the use of ERT in paediatric patients can significantly clear GL-3 accumulation, ameliorate the early symptoms of Fabry disease, and improve quality of life. Treatment with ERT in paediatric patients with Fabry disease may be important to prevent further disease progression and overt organ damage.
Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD.
Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation
(2018)
Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.
Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of ERT. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of ERT on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of ERT in patients with Fabry disease; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods, ERT regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of ERT outcomes in Fabry disease, highlighting that in a rare genetic disorder like Fabry disease, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies.
Background
Plasma or urinary metanephrines are recommended for screening of pheochromocytomas and paragangliomas (PPGLs). Measurements of urinary free rather than deconjugated metanephrines and additional measurements of methoxytyramine represent other developments. For all measurements there is need for reference intervals.
Methods
Plasma free, urinary free and urinary deconjugated O-methylated catecholamine metabolites were measured by LC-MS/MS in specimens from 590 hypertensives and normotensives. Reference intervals were optimized using data from 2,056 patients tested for PPGLs.
Results
Multivariate analyses, correcting for age and body surface area, indicated higher plasma and urinary metanephrine in males than females and sex differences in urinary normetanephrine and free methoxytyramine that largely reflected body size variation. There were positive associations of age with plasma metabolites, but negative relationships with urinary free metanephrine and methoxytyramine. Plasma and urinary normetanephrine were higher in hypertensives than normotensives, but differences were small. Optimization of reference intervals using the data from patients tested for PPGLs indicated that age was the most important consideration for plasma normetanephrine and sex most practical for urinary metabolites.
Conclusion
This study clarifies impacts of demographic and anthropometric variables on catecholamine metabolites, verifies use of age-specific reference intervals for plasma normetanephrine and establishes sex-specific reference intervals for urinary metabolites.
Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma
(2019)
Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is fundamental for cell survival and contributes to different oncogenic signaling pathways. Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several cancer types. We have examined the expression of HSP90 in different adrenal tumors and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC.
Methods: Immunohistochemical expression of HSP90 isoforms was investigated in different adrenocortical tumors and associated with clinical features. Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines.
Results: Within adrenocortical tumors, ACC samples exhibited the highest expression of HSP90β. Within a cohort of ACC patients, HSP90β expression levels were inversely correlated with recurrence-free and overall survival. In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2—and AKT—pathways by luminespib and ganetespib treatment.
Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC.
We previously identified peptides that are actively transported across the intact tympanic membrane (TM) of rats with infected middle ears. To assess the possibility that this transport would also occur across the human TM, we first developed and validated an assay to evaluate transport in vitro using fragments of the TM. Using this assay, we demonstrated the ability of phage bearing a TM-transiting peptide to cross freshly dissected TM fragments from infected rats or from uninfected rats, guinea pigs and rabbits. We then evaluated transport across fragments of the human TM that were discarded during otologic surgery. Human trans-TM transport was similar to that seen in the animal species. Finally, we found that free peptide, unconnected to phage, was transported across the TM at a rate comparable to that seen for peptide-bearing phage. These studies provide evidence supporting the concept of peptide-mediated drug delivery across the intact TM and into the middle ears of patients.
Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.