Refine
Has Fulltext
- yes (545)
Is part of the Bibliography
- yes (545)
Year of publication
Document Type
- Journal article (329)
- Doctoral Thesis (215)
- Preprint (1)
Keywords
- multiple myeloma (38)
- Aspergillus fumigatus (34)
- Multiples Myelom (17)
- Plasmozytom (16)
- HIV (14)
- apoptosis (13)
- Dendritische Zelle (12)
- T cells (12)
- Aspergillus (11)
- cancer (10)
- immunotherapy (10)
- Stammzelltransplantation (9)
- inflammation (9)
- Aspergillose (8)
- Immuntherapie (8)
- NAFLD (8)
- cytokines (8)
- Apoptosis (7)
- B cells (7)
- COVID-19 (7)
- Diabetes mellitus (7)
- Dickdarmkrebs (7)
- Multiple myeloma (7)
- Therapeutisches Drug Monitoring (7)
- allogeneic stem cell transplantation (7)
- dendritic cells (7)
- stem cell transplantation (7)
- theranostics (7)
- Apoptose (6)
- CXCR4 (6)
- Immunreaktion (6)
- Monoklonaler bispezifischer Antikörper (6)
- NK cells (6)
- PET (6)
- T-Lymphozyt (6)
- Akute myeloische Leukämie (5)
- Antigen CD40 (5)
- Dendritische Zellen (5)
- Hepatitis C (5)
- Immunsystem (5)
- Multiple Myeloma (5)
- Natürliche Killerzelle (5)
- Positronen-Emissions-Tomografie (5)
- Real time quantitative PCR (5)
- Rezidiv (5)
- Rituximab (5)
- TNF (5)
- TRAIL (5)
- Therapie (5)
- aspergillosis (5)
- deep learning (5)
- dendritic cell (5)
- immune response (5)
- infection (5)
- neuroendocrine tumor (5)
- relapse (5)
- therapeutic drug monitoring (5)
- AIDS (4)
- Adhärenz (4)
- Akute Leukämie (4)
- Antikörper (4)
- Candida albicans (4)
- Cytomegalie-Virus (4)
- Fettleber (4)
- Immunsuppression (4)
- Invasive Aspergillose (4)
- Medizin (4)
- Myelom (4)
- NASH (4)
- PRRT (4)
- Polymerase-Kettenreaktion (4)
- Proliferation (4)
- RNS-Interferenz (4)
- Rheumatoid arthritis (4)
- SARS-CoV-2 (4)
- TDM (4)
- Transplantat-Wirt-Reaktion (4)
- allogene Stammzelltransplantation (4)
- aspergillus fumigatus (4)
- colorectal cancer (4)
- depression (4)
- endoscopy (4)
- fungal infection (4)
- galactomannan (4)
- innate immunity (4)
- invasive pulmonary aspergillosis (4)
- lenalidomide (4)
- lymphoma (4)
- machine learning (4)
- medicine (4)
- prostate cancer (4)
- quality of life (4)
- refractory (4)
- rheumatoid arthritis (4)
- stem-cell transplantation (4)
- survival (4)
- therapy (4)
- transplantation (4)
- Adenom-Karzinom-Sequenz (3)
- Allogeneic stem cell transplantation (3)
- B-Zell-Lymphom (3)
- B-Zelle (3)
- Bauchspeicheldrüse (3)
- Blutstammzelle (3)
- Bone marrow transplantation (3)
- Cytokine (3)
- Dasatinib (3)
- Depression (3)
- HIV-Infektion (3)
- Hochdosischemotherapie (3)
- Kolorektales Karzinom (3)
- Lebensqualität (3)
- Leberzellkrebs (3)
- Leberzirrhose (3)
- Lopinavir (3)
- Loss of heterozygosity (3)
- Monoklonaler Antikörper (3)
- Nachsorge (3)
- PCR (3)
- PET/CT (3)
- Pankreas (3)
- Periphere Stammzellentransplantation (3)
- RADS (3)
- RNA interference (3)
- Rheumatoide Arthritis (3)
- SNP (3)
- SSTR (3)
- Survival (3)
- Südafrika (3)
- T cell (3)
- T-Zellen (3)
- T-cells (3)
- Tumor-Nekrose-Faktor <alpha> (3)
- Zelldifferenzierung (3)
- acute myeloid leukemia (3)
- adalimumab (3)
- adherence (3)
- antibody (3)
- anxiety (3)
- autologous stem cell transplantation (3)
- automation (3)
- biomarker (3)
- butyrate (3)
- cancer immunotherapy (3)
- cell death (3)
- cell staining (3)
- chemotherapy (3)
- chimeric antigen receptor (3)
- colonoscopy (3)
- colorectal carcinoma (3)
- dendritische Zellen (3)
- echocardiography (3)
- fatty liver disease (3)
- fear of progression (3)
- follow-up (3)
- gastroenterology (3)
- giant cell arteritis (3)
- immune cells (3)
- immunosuppression (3)
- insulin (3)
- invasive aspergillosis (3)
- memory B cells (3)
- myeloma (3)
- pancreas (3)
- plasma cells (3)
- prognosis (3)
- proliferation (3)
- regression analysis (3)
- resistance (3)
- scleroderma (3)
- systemic sclerosis (3)
- toxicity (3)
- 18F-FDG PET/CT (2)
- 3D printing (2)
- AML (2)
- Activation (2)
- Acute myeloid leukemia (2)
- Adulte Stammzelle (2)
- Antibodies (2)
- Antigen (2)
- Antikörper-Fusionsproteine (2)
- Antimykotika (2)
- Antimykotikum (2)
- Arzneimittelüberwachung (2)
- Autogene Transplantation (2)
- Autologous hematopoietic stem cell transplantation (2)
- B cell (2)
- BCMA (2)
- BRAF mutation (2)
- Biomarker (2)
- Bone-marrow-transplantation (2)
- Butyrat (2)
- C-X-C motif chemokine receptor 4 (2)
- CA19-9 (2)
- CADe (2)
- CAR T cell (2)
- CAR T cells (2)
- CCL4 (2)
- CD38 (2)
- CML (2)
- CMV (2)
- Cancer (2)
- Capecitabin (2)
- Chemotherapie (2)
- Chimerism (2)
- Chimärismus (2)
- Chronisch-myeloische Leukämie (2)
- Clostridium-difficile-Infektion (2)
- Colonkrebs (2)
- Colorectal Cancer (2)
- Compliance (2)
- Diabetes (2)
- Efavirenz (2)
- Expression (2)
- FDG (2)
- FIB-4 (2)
- FcγR (2)
- GVHD (2)
- German Hepatitis C-Registry (2)
- Granulozyt (2)
- GvHD (2)
- HBV (2)
- HDGF (2)
- Helicobacter pylori (2)
- Hemibodies (2)
- Hepatitis B (2)
- Hepatozelluläres Karzinom (2)
- Hyperglykämie (2)
- Hypoxie (2)
- Hämostase (2)
- Imatinib (2)
- Immun-Checkpoint (2)
- Immunglobuline (2)
- Immunmodulation (2)
- Immunologie (2)
- Immunology (2)
- Immunsuppressiva (2)
- Infektiologie (2)
- Inflammasom (2)
- Inflammation (2)
- Insulin (2)
- Interleukin 8 (2)
- Kinder (2)
- Knochenmark (2)
- Kolonkarzinom (2)
- Kreuzreaktion (2)
- LL-37 (2)
- LOH (2)
- Lenalidomid (2)
- Leptin (2)
- Lipodystrophie (2)
- Lymphom (2)
- MUST-Score (2)
- Mangelernährung (2)
- Mucorales (2)
- NLRP3 (2)
- Nestin (2)
- Non-Hodgkin-Lymphom (2)
- Oncology (2)
- Onkologie (2)
- PD-L1 (2)
- Progredienzangst (2)
- Protein-Tyrosin-Kinasen (2)
- Psychoneuroimmunologie (2)
- Punktmutation (2)
- Pyrimidin-Synthese (2)
- RT-PCR (2)
- Real-time PCR (2)
- Rectal cancer (2)
- Resistenz (2)
- Ribavirin (2)
- Ruxolitinib (2)
- Schwangerschaft (2)
- Signalkette (2)
- Signaltransduktion (2)
- Stammzelle (2)
- Surgery (2)
- Systemic sclerosis (2)
- TNF receptor superfamily (2)
- TRAF1 (2)
- TRAF2 (2)
- TWEAK (2)
- Th17 (2)
- Therapietreue (2)
- Thrombozyt (2)
- Transfektion (2)
- Transkription (2)
- Tumor-necrosis-factor (2)
- Uridin (2)
- Vitamin D (2)
- Wnt (2)
- YB-1 (2)
- [68Ga]PentixaFor (2)
- actin (2)
- activation (2)
- acute leukemia (2)
- acute lymphoblastic leukemia (2)
- acute myeloid leukaemia (2)
- adaptive immunity (2)
- adiponectin (2)
- adverse events (2)
- allogeneic hematopoietic stem cell transplantation (2)
- alloreactive T cells (2)
- amplicon sequencing (2)
- amyloidosis (2)
- anastomotic leakage (2)
- anemia (2)
- angeborenes Immunsystem (2)
- antimikrobielle Peptide (2)
- antirheumatic agents (2)
- artificial intelligence (2)
- autoimmunity (2)
- autologe Stammzelltransplantation (2)
- beta-D-glucan (2)
- biomarkers (2)
- bone marrow (2)
- bone marrow immune-microenvironment (2)
- bortezomib (2)
- cancer microenvironment (2)
- cancer stem cells (2)
- chemokines (2)
- cholestasis (2)
- chronic hepatitis C (2)
- chronic myelogenous leukemia (2)
- corticosteroids (2)
- cytotoxic T cells (2)
- cytotoxicity (2)
- daratumumab (2)
- dasatinib (2)
- deformation (2)
- diabetes mellitus (2)
- differentiation (2)
- ejection fraction (2)
- endoluminal (2)
- endoradiotherapy (2)
- endothelial cells (2)
- extramedullary disease (2)
- fatigue (2)
- fibrosis (2)
- fluorescence imaging (2)
- fungal infections (2)
- gastrointestinale Tumore (2)
- gemcitabine (2)
- gene (2)
- gene expression (2)
- gene regulation (2)
- graft versus host disease (2)
- hematologic malignancies (2)
- hematopoietic stem cell transplantation (2)
- hepatitis C virus (2)
- high risk (2)
- human dendritic cells (2)
- ileocecal resection (2)
- immunoassay (2)
- infectious diseases (2)
- innate immune response (2)
- interferon (2)
- invasive fungal infection (2)
- invasive fungal infections (2)
- kolorektales Karzinom (2)
- leukemia (2)
- loss of heterozygosity (2)
- management (2)
- metabolism (2)
- mitochondrial toxicity (2)
- molecular imaging (2)
- mortality (2)
- mouse model (2)
- mouse models (2)
- multiples Myelom (2)
- murine model (2)
- mycophenolic acid (2)
- nab-paclitaxel (2)
- natural killer cells (2)
- negative pressure (2)
- obesity (2)
- object detection (2)
- oncology (2)
- organoids (2)
- oxidative stress (2)
- pancreatic cancer (2)
- peptide receptor radionuclide therapy (2)
- pharmacokinetics (2)
- phosphorylation (2)
- platelets (2)
- polymyalgia rheumatica (2)
- pomalidomide (2)
- posaconazole (2)
- psychological distress (2)
- real world evidence (2)
- real-time PCR (2)
- regulatory T cells (2)
- risk factors (2)
- risk stratification (2)
- signal transduction (2)
- sofosbuvir (2)
- somatostatin receptor (2)
- spleen (2)
- stem cells (2)
- surgical therapy (2)
- transfection (2)
- treatment outcome (2)
- tumour immunology (2)
- vacuum-assisted closure (2)
- Überleben (2)
- /immunofluorescence (1)
- 11C-Methionine PET/CT (1)
- 13C-Methacetin-Atemtest (1)
- 177Lu (1)
- 18FDG-PET/CT (1)
- 18q21.1 (1)
- 2,5-diketopiperazines (1)
- 25-hydroxycholesterol 7 alpha-hydroxylase (1)
- 27.9c (1)
- 2p16.3 (1)
- 3 dimensional cell culture model (1)
- 3 fucosyltransferase-VI (1)
- 3D culture (1)
- 4-1BB Agonist (1)
- 4-1BB agonist (1)
- 41BBL (1)
- 5-Fluorouracil (1)
- 5q22.2 (1)
- 68Ga-DOTANOC (1)
- 68Ga-DOTATATE (1)
- 68Ga-DOTATATE/-TOC (1)
- 68Ga-DOTATOC (1)
- 68Ga-Pentixafor PET/CT (1)
- 8p22 (1)
- A. fumigatus (1)
- ABCG2 (1)
- ABL gene (1)
- AIM2 (1)
- AKT-signaling (1)
- ALiOS (1)
- AMPK (1)
- APRI (1)
- ARMS-PCR (1)
- ARONJ (1)
- ASE formula (1)
- ATIP (1)
- ATPase activity (1)
- ATTRv amyloidosis (1)
- AZT (1)
- Active disease (1)
- Acute lymphoblastic leukemia (1)
- Acute lymphocytic leukaemia (1)
- Acute myeloid leukemia (AML) (1)
- Adaptive cell transfer (1)
- Adenom-carcinom-sequence (1)
- Adhesive Hydrogels (1)
- Adiponectin (1)
- Adipositas (1)
- Adoptiver T Zell Transfer (1)
- Aiolos (1)
- Akt (1)
- Aktin (1)
- Alcoholic and Non-Alcoholic Steatohepatitis (1)
- Alkoholische Fettlebererkrankung (1)
- Allelische Verlustanalyse (1)
- Allergie (1)
- Allergiker (1)
- Alloantigen (1)
- Alloantigen Expression (1)
- Allogene Stammzelltransplantation (1)
- Allogene hämatopoetische Stammzelltransplantation (1)
- Allogeneic transplantation (1)
- Alpelisib (1)
- Alpha therapy (1)
- Alpha-dependent apoptosis (1)
- Alternative Medizin (1)
- Aluminiumhydroxid (1)
- Aluminiumhydroxide (1)
- Ambulante Behandlung (1)
- Ambulante Patienten (1)
- Aminobisphosphonate (1)
- Amphibia (1)
- Amyloidose (1)
- Anthropometrie (1)
- Antibiotic stewardship (1)
- Antibiotikatherapie (1)
- Antibody (1)
- Antifungal (1)
- Antigen CD137 (1)
- Antigen CD19 (1)
- Antigen CD95 (1)
- Antigene (1)
- Antigenpräsentation (1)
- Antikörpertherapie (1)
- Antimikrobielle Peptide (1)
- Antiretrovirale Substanz (1)
- Antituberkulotikum (1)
- Antitumorforschung (1)
- Antrhopometry (1)
- Anämie (1)
- Aortenkonstriktion (1)
- Arteriosklerose (1)
- Arthroleptis amphibia (1)
- Arthrose (1)
- Arzneimittelnebenwirkung (1)
- Arzneimittelsicherheit (1)
- Arzneimittel�berwachung (1)
- Ascaris lumbricoides (1)
- Aspergillosis (1)
- Aspergillus fumigatus antigens (1)
- Aspergillus fumigatus-spezifische CD154+/CD4+ Zellen (1)
- Aspergillus sp. (1)
- Autoimmune diseases (1)
- Autoimmunität (1)
- Autoimmuntherapie (1)
- B cell culture (1)
- B cell receptors (1)
- B- Zellen (1)
- B-NHL (1)
- B-Zellen (1)
- B-cell lymphoma (1)
- B-cells (1)
- B-zellen (1)
- BAFF-Receptor (1)
- BAFF-Rezeptor (1)
- BAL (1)
- BCOR (1)
- BCORL1 (1)
- BFU (1)
- BH3-only proteins (1)
- BON-1 (1)
- BONJ (1)
- Bacteria (1)
- Baff (1)
- Bariatrische Operation (1)
- Barrett (1)
- Bauchspeicheldrüsenkrebs (1)
- Bedürfnis (1)
- Benzodiazepine (1)
- Beta-Zellen (1)
- Beta-cell (1)
- Betazelle (1)
- Bewältigungsfähigkeiten (1)
- Biologika (1)
- Bioluminescence (1)
- Bioluminescence imaging (1)
- Biolumineszenzmessung (1)
- Biomechanics (1)
- Biotechnologie (1)
- Bispecific T-cell engager (1)
- Blood (1)
- Blutkontakt (1)
- Blutspiegel (1)
- Blutstillung (1)
- Blutuntersuchung (1)
- Bone marrow cells (1)
- Bone marrow transplantantation (1)
- Breath tests (1)
- Brustkrebs (1)
- Bruton's tyrosine kinase inhibitor CC-292 (1)
- Butyrate <Buttersäuresalze> (1)
- Bypassoperation (1)
- C-IAP1 (1)
- C-Typ Lektin Rezeptoren (1)
- C1q/TNF related protein (CTRP) (1)
- C57BL/KALWRIJ mouse (1)
- CACO-2 (1)
- CAPA (1)
- CAR T (1)
- CAR T-cell (1)
- CAR-T-cell (1)
- CASPASE-3 (1)
- CCL3 (1)
- CCL5 (1)
- CCN1 (1)
- CCS (1)
- CD 40 (1)
- CD11b+ myeloid cells (1)
- CD1c⁺ mDC (1)
- CD1d (1)
- CD20 (1)
- CD27 (1)
- CD274 (1)
- CD27L (1)
- CD319 (1)
- CD4(+) (1)
- CD4(+) T-cells (1)
- CD40 (1)
- CD40 agonist (1)
- CD40-spezifische Antikörperfusionsproteine (1)
- CD40L (1)
- CD57 (1)
- CD70 (1)
- CD95 (1)
- CDI (1)
- CFU (1)
- CIAP1 (1)
- CMR (1)
- CMV T-Zellen (1)
- CMV reactivation (1)
- CMV-Reaktivierung (1)
- CMV-specific cellular immunity (1)
- CNS cancer (1)
- COX2 expression (1)
- CP-690,550 (1)
- CRISPR/Cas9 (1)
- CS1 (1)
- CXCL10 (1)
- CYP2C9 (1)
- CYP3A4 (1)
- CYP7A1 (1)
- Calcitriol (1)
- Cancer genetics (1)
- Cancer risk factors (1)
- Cancer treatment (1)
- Candida sp. (1)
- Capicua transcriptional repressor (1)
- Cardiac Output (1)
- Cartiage Integration (1)
- Cartilage defect (1)
- Casetrain (1)
- Caspase-8 activation (1)
- Cathelicidin (1)
- Cathelicidine (1)
- Cell migration (1)
- Central nervous system (1)
- Central nervous system infection (1)
- Checkpoint-Inhibitor (1)
- Chimäre DNS (1)
- Chimärische Rezeptoren (1)
- Chimärismusdiagnostik (1)
- Cholesterinstoffwechsel (1)
- Chromosom 8 (1)
- Chromosomenanalyse (1)
- Chronic lymphoblastic leukemia (1)
- Chronic myeloid leukaemia (1)
- Chronic myeloid leukemia (1)
- Ciliary beat frequency (1)
- Clinical practice guidelines (1)
- Clinical remission (1)
- Colitis ulcerosa (1)
- Complex (1)
- Compliance <Patient> (1)
- Computerunterstütztes Lernen (1)
- Conditioning regimen (1)
- Copy number changes (1)
- Coronavirus Disease 2019 (1)
- Crohn-Krankheit (1)
- Crohn’s Disease (1)
- Crohn’s disease (1)
- Cytokine receptors (1)
- Cytomegalie (1)
- Cytoplasma (1)
- Cytotoxizität (1)
- D insufficiency (1)
- D serum-levels (1)
- D2S123 (1)
- D5S346 (1)
- DAS28 (1)
- DC (1)
- DExD/H-Box RNA helicase (1)
- DMARD (1)
- DNA damage (1)
- DOTATOC (1)
- DSMM XIV (1)
- DSMMI-Studie (1)
- Dara-KDT-P(A)CE (1)
- Darm (1)
- Darmepithel (1)
- Darminfektion (1)
- Dectin-1 (1)
- Depressivität (1)
- Deutsche Gesellschaft für Hämatologie und Onkologie. Arbeitsgemeinschaft Infektiologie (1)
- Deutsche Gesellschaft für Rheumatologie (1)
- Diabetes mellitus Typ 2 (1)
- Diagnosis (1)
- Diagnostik (1)
- Dihydroorotat-Dehydrogenase (1)
- Distress (1)
- Donor lymphocytes (1)
- Dopamine (1)
- Drug Monitoring (1)
- Drug development (1)
- Drug metabolism (1)
- Drug resistance (1)
- Drug-free remission (1)
- Duchenne muscular dystrophy (1)
- Durchflusscytometrie (1)
- Durchflusszytometrie (1)
- E-Selectin (1)
- E2F3 (1)
- EAE (1)
- EFV (1)
- EGFR (1)
- ELISA (1)
- ELISpot (1)
- EORTC (1)
- ERM (1)
- Effektorfunktionen (1)
- Einfluss (1)
- Einflussfaktoren (1)
- Einstellung zum Tod (1)
- Eisenhomöostase (1)
- Elderly (1)
- Elektroporation (1)
- Emotionsregulierung (1)
- Encephalopathia hepatica (1)
- EndoVAC and small bowel (1)
- Endocytose (1)
- Endozytose (1)
- Enterale Ernährung (1)
- Entwicklung (1)
- Enzyme Regulation (1)
- EpCAM (1)
- Epstein-Barr virus-induced gene 2 (1)
- Ernährungsberatung (1)
- Escherichia Coli (1)
- European experience (1)
- European experts (1)
- European group (1)
- Everolimus (1)
- Expansion (1)
- Extraktionskontrolle (1)
- Extramedullary disease (1)
- FAP (1)
- FDG-PET/CT (1)
- FGF19 (1)
- FOLFIRI (1)
- FOLFOX (1)
- FP635 (1)
- FXR (1)
- Factor receptor (1)
- Fahrradergometer (1)
- Fak regulation (1)
- Fas-Ligand (1)
- Fas-Signalweg (1)
- FcgR (1)
- Fettsucht (1)
- Fettsäurestoffwechsel (1)
- Fibroblast activator protein I (1)
- Fibroblastenwachstumsfaktor (1)
- Fick principle (1)
- Fick-Prinzip (1)
- Fieber (1)
- Fludarabine (1)
- Fludarabine-treosulfan (FT) (1)
- Fluoreszenzakti (1)
- Fluoreszenzmikroskopie (1)
- Fluoreszenzproteine (1)
- Fn14 (1)
- Follow-up (1)
- Fractalkin (1)
- Fructose (1)
- Fruktose (1)
- Fungal (1)
- Funktionelle Validierung (1)
- Fusarium (1)
- Fusionsprotein (1)
- GCA (1)
- GDF (1)
- GDF 15 (1)
- GDF-15 (1)
- GEP-NET (1)
- GI (1)
- GITRL (1)
- GLP-1 (1)
- GRAID (1)
- GSK3 (1)
- GUT-directed hypnotherapy (1)
- GVL (1)
- Gammadelta T Zellen (1)
- Ganzkörperbestrahlung (1)
- Gastrointestinal (1)
- Gaussia princeps luciferase (GpL) (1)
- Geki (1)
- Gelenkknorpel (1)
- Gelenkrheumatismus (1)
- Generalisierte Angststörung (1)
- Genetics research (1)
- Genexpression (1)
- Genklonierung (1)
- Gentechnologie (1)
- Geschlechtsunterschied (1)
- Gesundheitsförderung (1)
- Glucose (1)
- Glucose metabolism (1)
- Glutamat-Decarboxylase (1)
- Glutamate-induced excitotoxicity (1)
- Glycoproteinfucosyltransferasen (1)
- Glykoproteine (1)
- Glykämischer Index (1)
- Graft versus Host Disease (1)
- Graft versus Host disease (1)
- Graft versus Leukemia (1)
- Graft versus Tumor (1)
- Graft-versus-Host-Disease (1)
- Graft-versus-Leukämie-Effekt (1)
- Graft-versus-host disease (1)
- Graft-versus-host-disease (1)
- Graft-versus-leukemia (1)
- Grave’s disease (1)
- Growth-differentiation Factor 15 (1)
- Gruppo-italiano (1)
- Guideline (1)
- Guinea pig model (1)
- Guinean rain forest (1)
- GvL Effekt (1)
- HAART (1)
- HADS-D (1)
- HAQ (1)
- HB-EGF (1)
- HCV (1)
- HCV cure (1)
- HCV genotype 2 (1)
- HCV genotype-2 (1)
- HCV infection (1)
- HD (1)
- HDAC-Inhibitor (1)
- HECT Ligase (1)
- HEV (1)
- HGF (1)
- HIF-1α (1)
- HIV infections (1)
- HIV therapy (1)
- HIV-1-infected subjects (1)
- HIV-infected patients (1)
- HLA antigens (1)
- HLA-E matching (1)
- HNSCC (1)
- HPLC (1)
- HSC (1)
- HSF1 (1)
- HST1 (1)
- HSTC outcome (1)
- HT29 cells (1)
- HUWE1 (1)
- Haematology (1)
- Haploidentical (1)
- Hashimoto Thyreoiditis (1)
- Hashimoto-Thyreoiditis (1)
- Haut (1)
- Hautmodell (1)
- Heavy Light Chain Assay (1)
- Helicobacter (1)
- Helicobacter pylori eradication (1)
- Helicobacter-pylori-Eradikation (1)
- Hematopoietic Cell Transplantation (1)
- Hematopoietic stem cell transplantation (1)
- Hemibody (1)
- Hepatische Enzephalopathie (1)
- Hepatitis (1)
- Hepatitis B virus (1)
- Hepatitis B virus reactivation (1)
- Hepatitis C infection (1)
- Hepatitis E (1)
- Hepatitis-C-Virus (1)
- Hepatoma Derived Growth Factor (1)
- Hepatoma-derived Growth Factor (1)
- Hepatoma-derived growth factor (1)
- Hepatotoxizität (1)
- Hepatozelluläres Karzinom HCC (1)
- Herpes simplex encephalitis (1)
- Herpes simplex virus (1)
- Herz-Lungen-Maschine (1)
- Herzinsuffizienz (1)
- Herzzeitvolumen (1)
- High Performance Liquid Chromatography (1)
- Hippo signaling (1)
- Histon-Deacetylase (1)
- Hitzeschock Proteine (1)
- Hitzeschocktranskriptionsfaktor (1)
- Homing-Rezeptor (1)
- Homingrezeptor (1)
- Hospitalismus <Hygiene> (1)
- Hsp90 (1)
- Human immunodefiency virus (1)
- Humanserum (1)
- Hyaliner Knorpel (1)
- Hypercholesterinämie (1)
- Hyperglycemia (1)
- Hypersensitivität (1)
- Hypersensitivitätsreaktion (1)
- Hyperthermie (1)
- Hypertriglyzeridämie (1)
- Hämatopoetische Stammzelltransplantation (1)
- IDO-1 (1)
- IDX-1 (1)
- IE1 (1)
- IFN-gamma (1)
- IFN-γ ELISpot (1)
- IFNG (1)
- IKK (1)
- IKZF1 (1)
- IKZF3 (1)
- IL 10 (1)
- IL 12 (1)
- IL 12p40 (1)
- IL-12 family (1)
- IL28B (1)
- IL28B polymorphisms (1)
- IL8 (1)
- IRF4 (1)
- Ikaros (1)
- Immunantwort (1)
- Immunassay (1)
- Immuncheckpointblockade (1)
- Immuncheckpointinhibition (1)
- Immuncheckpointinhibitor (1)
- Immune cell assays (1)
- Immune receptor signaling (1)
- Immunfluoreszenz (1)
- Immunoassay (1)
- Immunoblot (1)
- Immunocompromised patient (1)
- Immunoglobulins (1)
- Immunosuppressant (1)
- Immunotherapie (1)
- Immunotherapy (1)
- Immunreaction (1)
- Immunrekonstitution (1)
- Immunstimulation (1)
- Immunzellassays (1)
- Impfstoff (1)
- Impfung (1)
- Impfvektor (1)
- Improved survival (1)
- Induced apoptosis (1)
- Infections (1)
- Infectious Diseases (1)
- Infectious complications (1)
- Infectious disease (1)
- Infectious diseases (1)
- Infektion (1)
- Influenzae type B (1)
- Integrin aV (1)
- Interaktionsanalyse (1)
- Interferon <gamma-> (1)
- Interferon alpha (1)
- Interleukin 13 (1)
- Interleukin 1beta (1)
- Interleukin 2 (1)
- Interleukin 4 (1)
- Interleukin 5 (1)
- Interleukin 6 (1)
- Interleukin-10 (1)
- Interleukin-2 (1)
- Interleukin-5 (1)
- Intestamin® (1)
- Intracellular domain (1)
- Invasive Aspergillosis (1)
- Invasive Mykosen (1)
- Invasive Mykosen bei immunsupprimierten Patienten (1)
- Invasive aspergillosis (1)
- Invasive fungal-infections (1)
- Isolation (1)
- JAK2 (1)
- JCV (1)
- JNK (1)
- Jak kinases (1)
- K+-ATPase (1)
- K-ras (1)
- KAR (1)
- KIR (1)
- KRAS (1)
- KRas (1)
- Kappa-B activation (1)
- Kappa-B pathway (1)
- Kartierung (1)
- Kernpore (1)
- Kernproteine (1)
- Kerntransport (1)
- Kieferosteonekrose (1)
- Killer cell immunoglobulin-like receptors (1)
- Kinderheilkunde (1)
- Klonale T-Zellen (1)
- Klonierung (1)
- Kniegelenkarthrose (1)
- Knochemark (1)
- Knochenmark-Mikromilieu (1)
- Knochenmarkbiopsie (1)
- Knochenmarktransplantation (1)
- Knockdown (1)
- Knorpel (1)
- Kognition bei mHE (1)
- Kohlenhydrate (1)
- Kohlenstoff-13-Exhalationstest (1)
- Kolon (1)
- Komplementärmedizin (1)
- Kono-S anastomosis (1)
- Kontamination (1)
- Kostimulation (1)
- Kreuzpräsentation (1)
- Kreuzreaktivität (1)
- Kulturmedium (1)
- Kursdesign (1)
- Körperarbeit (1)
- Körperflüssigkeit (1)
- Körperpsychotherapie (1)
- Körpertherapie (1)
- LATE DEATHS (1)
- LBH589 (1)
- LEOSS (1)
- LINE-1 retrotransposition (1)
- LL37 (1)
- LPS (1)
- Lactose (1)
- Langzeitaplasie (1)
- Late mortality (1)
- Ldlr-Knockout (1)
- Lebensqualität bei mHE (1)
- Lebererkrankung (1)
- Leberfunktion (1)
- Leberversagen (1)
- Leukaemia-inhibitory factor (1)
- Leukopenie (1)
- Li-Fraumeni syndrome (1)
- Lichtheimia (1)
- Ligand (1)
- Light Sheet Fluorescence Microscopy (1)
- Lipid metabolism (1)
- Lipidstoffwechsel (1)
- Lipoatrophie (1)
- Lipodystrophie-Syndrom (1)
- Lipodystrophy syndrom (1)
- Lipofektion (1)
- Liposomal amphotericin-B (1)
- Liver cirrhosis (1)
- Low-dose acyclovir (1)
- Lymphatische Leukämie (1)
- Lymphomas (1)
- Lymphome (1)
- Lysozym (1)
- M30 (1)
- MAG3 (1)
- MALT (1)
- MALT-Lymphom (1)
- MALT-Lymphoma (1)
- MAP-Kinase (1)
- MAPKAPK2 (1)
- MCL-1 (1)
- MDSC (1)
- MEDAS (1)
- MEK/ERK-signaling (1)
- MGUS (1)
- MHC (1)
- MHC molecules (1)
- MHC-Klasse-I-Peptidom (1)
- MI-RADS (1)
- MICA (1)
- MIP-1β (1)
- MOPC315.BM (1)
- MOR202 (1)
- MPACT (1)
- MRONJ (1)
- MS-18 (1)
- MSI (1)
- MSS (1)
- MTB (1)
- MTUS1 (1)
- MTX (1)
- MUD (1)
- MYC (1)
- Magenlymphom (1)
- Malabsorption (1)
- Malassimilation (1)
- Malignant melanoma (1)
- Malignes Lymphom (1)
- Malnutrition (1)
- Mammakarzinom (1)
- Masernvirus (1)
- Maus (1)
- Mausmodell (1)
- Mechanisms (1)
- Medication-related osteonecrosis of the jaw (1)
- Medicine (1)
- Medikamenten-assoziierte Kiefernekrose (1)
- Megakaryopoese (1)
- Megakaryozyt (1)
- Melanoma (1)
- Memory B cells (1)
- Merkmal (1)
- Mesenchymal stem cells (1)
- Met (1)
- Metabolisches Syndrom (1)
- Metastase (1)
- Methotrexate (1)
- Mevalonatmetabolimus (1)
- Microarray (1)
- Midollo-Osseo (1)
- Migration (1)
- Mikrobiom <Genetik> (1)
- Mikrosatellit (1)
- Mikrosatelliten (1)
- Mikrosatelliteninstabilität (1)
- Mikrosomale Leberfunktion (1)
- Milde Depression (1)
- Minimal residual disease (1)
- Minimale Resterkrankung (1)
- Minor histocompatibility antigen mismatch transplantation (1)
- Mitochondriale Toxizität (1)
- Modifiziertes Vaccinia Ankara Virus (1)
- Moesin (1)
- Molecular Biophysics (1)
- Molecularly targeted therapy (1)
- Molekularbiologie (1)
- Molekulare Diagnostik (1)
- Molekulargenetik (1)
- Mucormycosis (1)
- Multiple (1)
- Multiple Regression (1)
- Multiplex-PCR (1)
- Multivariate analysis (1)
- Myc (1)
- Mycobacterium avium (1)
- Mycophenolatmofetil (1)
- Myeloma (1)
- Myeloma cells (1)
- Myelomas (1)
- Myelose (1)
- Mykose (1)
- Mykosen (1)
- Myokardhypertrphie (1)
- NA (1)
- NADPH oxidase (1)
- NET (1)
- NF-Kappa B (1)
- NF-Kappa-B (1)
- NF-κB/NFAT reporter cells (1)
- NFAT (1)
- NFATc1 (1)
- NFKB (1)
- NFkB (1)
- NFkB-relatedgenes (1)
- NFkappaB (1)
- NFκB (1)
- NGS (1)
- NK (1)
- NK cell (1)
- NK-DC cross-talk (1)
- NK-Zelle (1)
- NK-Zellen (1)
- NK-cells (1)
- NKT Zellen (1)
- NKT cells (1)
- NLRP3 Inflammasom (1)
- NRF2 (1)
- NRTI (1)
- NRTI-Sparing (1)
- Na+ (1)
- Nadelstichverletzungen (1)
- Nasenschleimhaut (1)
- Natürliche Killer-Zellen (1)
- Natürliche Killerzellen (1)
- Nebenwirkung (1)
- Nebenwirkungen interferonbasierte Hepatitis-C-Therapie (1)
- Necrosis (1)
- Neuroendocrine (1)
- Neuroendocrine Tumor (1)
- Neuroendokriner Tumor (1)
- Neuropsychiatrische Nebenwirkungen Interferon alpha (1)
- Neutropenie (1)
- Neutrophil granulocytes interaction (1)
- Neutrophile Granulozyten (1)
- Neutrophiler Granulozyt (1)
- Nevirapin (1)
- Nichtalkoholische Fettlebererkrankung (1)
- Nichtalkoholische Fettleberhepatitis (1)
- Nucleoporine (1)
- Nuklearfaktor Kappa B (1)
- Nup214 (1)
- Nutritional Counseling (1)
- OSM (1)
- OX40L (1)
- Oberflächenmarker (1)
- Occludin (1)
- Off-Pump (1)
- Oldenburg burnout inventory (1)
- Oligomerisation (1)
- Oncostatin M (1)
- Optimierung (1)
- Osmr-Knockout (1)
- Osteoklast (1)
- Osteoporose (1)
- Outpatients (1)
- P14ARF (1)
- P67(PHOX) (1)
- PEG (1)
- PEG-Anlage (1)
- PHQ-4 (1)
- PHQ-9 (1)
- PI (1)
- PML (1)
- PMR (1)
- POU6F2-AS2 (1)
- PPARgamma (1)
- PRO (1)
- PROMISE (1)
- PROM’s (1)
- PSMA (1)
- PSMA-RADS (1)
- PSMC2 (1)
- PTBS (1)
- PTSD (1)
- PU.1 (1)
- Panel-Sequenzierung (1)
- Pankreaskarzinom (1)
- Pankreaskarzinomzentrum (1)
- Parkinson's disease (1)
- Parkinsons-disease (1)
- Pathogenesis (1)
- Patient Reported Outcome (1)
- Patientencompliance (1)
- Patientenversorgung (1)
- Petropedetidae (1)
- Peyer's patch (1)
- Pharmakokinetik (1)
- Phase- (1)
- Phrynobatrachus amphibia (1)
- Plasmaspiegel (1)
- Plasmazellinie (1)
- Plasmide (1)
- Pneumocystis-carinii-pneumonia (1)
- Poly (I:C) (1)
- Poly(I:C) (1)
- Polymerase chain raction (1)
- Polymorphismus (1)
- Pom‐PAD‐Dara (1)
- Posaconazol (1)
- Positron emission tomography (1)
- Poststationär (1)
- Posttraumatische Belastungsstörung (1)
- Prediction (1)
- Primärtherapie (1)
- Prodigy (1)
- Prognostic scoring system (1)
- Progressive multifocal leukoencephalopathy (1)
- Promyelozytenleukämie (1)
- Prospektive klinische Verlaufsstudie (1)
- Protein p8 (1)
- Prädiktiver Biomarker (1)
- Prävention (1)
- Pseudomonas aeruginosa (1)
- Psychischer Stress (1)
- Psychotherapie (1)
- Pyrimidine Synthesis (1)
- QGP-1 (1)
- QoL (1)
- Qualität (1)
- QuantiFERON\(^®\)-TB Gold Plus (1)
- Quercetin (1)
- R-CHOP (1)
- RAD (1)
- RAR (1)
- RIG-I (1)
- RIP1 (1)
- RNA (1)
- RNA Interferenz (1)
- RNA extraction (1)
- RNAi (1)
- RNS-Bindungsproteine (1)
- ROR1 (1)
- RT-qPCR (1)
- RXR (1)
- RYGB (1)
- Radiochemotherapy (1)
- Radionuclide Therapy (1)
- Radiotherapie (1)
- Radiotherapy (1)
- Ranidae (1)
- Reaktive Depression (1)
- Rebreathing (1)
- Recombinant protein (1)
- Regeneration (1)
- Regressionsanalyse (1)
- Regulatory-cells (1)
- Rekombinantes Protein (1)
- Resiquimod (1)
- Respiratory syncytial virus (1)
- Responses (1)
- Reverse Transkriptase (1)
- Reverse Transkriptase-Polymerase-Kettenreaktion (1)
- Reversed Phase-HPLC (1)
- Rezidivtherapie (1)
- Rheumapatient (1)
- Rheumatoid Arthritis (1)
- Rheumatoider arthritis (1)
- Rheumatologie (1)
- Rhizopus (1)
- Rhizopus arrhizus (1)
- Risikofaktoren (1)
- Risk factors (1)
- Rosen-Methode (1)
- Rückatmungssystem (1)
- S100A8/S100A9 (1)
- SF-12 (1)
- SF-36 (1)
- SKY (Spektrale Karyotypisierung) (1)
- SLAMF7 (1)
- SNP Array (1)
- SSTR-RADS (1)
- STAT1 (1)
- STAT3 (1)
- STAT3 activation (1)
- STS (1)
- SVR (1)
- Saccharomyces cerevisiae (1)
- ScFv (1)
- Schilddrüse (1)
- Schimmelpilzallergie (1)
- Schimmelpilze (1)
- Scleroderma (1)
- Score (1)
- Serumbiomarker (1)
- Serumkonzentrationen (1)
- Serumspiegelbestimmung (1)
- Severe Acute Respiratory Syndrome Coronavirus 2 (1)
- Sibling donor (MSD) (1)
- Signal transduction (1)
- Signaling (1)
- Signaling complex (1)
- Signalwegskaskaden (1)
- Simulationsprogramm (1)
- Single Nucleotid Polymorphismus IL28B (1)
- Single chain (1)
- Single nucleotide polymorphism (1)
- Single-chain TNF (1)
- Sjögren’s syndrome (1)
- Skin cancer screening (1)
- Sleeping Beauty (1)
- Small intestine (1)
- Societe Francaise (1)
- Solid Phase Extraction (1)
- Sorafenib (1)
- Spender-Chimärismus (1)
- Spendermerkmal (1)
- Spezifisch (1)
- Spleen (1)
- Splicing (1)
- Stabilisierung (1)
- Stage distribution (1)
- Stammzellen (1)
- Standardisierung (1)
- Stavudin (1)
- Stem cell transplantation (1)
- Stickstoffheterocyclen (1)
- Stimulating factor (1)
- Strahlentherapie (1)
- Strategies to Obtain Tumor-Reactive Cells (1)
- Stress-Kardiomyopathie (1)
- Stressreaktion (1)
- Stromal cells (1)
- Structural Biology (1)
- Sulfadiazin (1)
- Suppression (1)
- Survival analysis (1)
- Synovitis (1)
- Säuglinge (1)
- T Zelle (1)
- T Zellen (1)
- T cell rezeptor transfer (1)
- T-Helfer-Zellen (1)
- T-LGL-Leukämie (1)
- T-LGL-Zellen (1)
- T-Lymphozyten-Rezeptor (1)
- T-Track\(^®\) TB (1)
- T-Zell-Rezeptor Transfer (1)
- T-Zellrezeptor (1)
- T-cell (1)
- T-cell engager (1)
- T-cell transfer (1)
- TB (1)
- TCTP (1)
- TKI (1)
- TLR agonists (1)
- TME (1)
- TNF a (1)
- TNF receptor associated factor 2 (TRAF2) (1)
- TNF-related apoptosis-inducing ligand (1)
- TNFR2 (1)
- TNFR2-spezifische Agonisten (1)
- TNFRSF (1)
- TNFSF14 (1)
- TNFSF4 (1)
- TNM staging (1)
- TNRSF (1)
- TP53 (1)
- TPCA1 (1)
- TRAILR-Mutants (1)
- TSD (1)
- TSLP (1)
- TTR knockdown (1)
- TTR stabilization (1)
- Tansania (1)
- Tdp-43 (1)
- Teichholz formula (1)
- Th17 cells (1)
- Th9 (1)
- Therapeutic Drug Monitoring (1)
- Therapeutisches Drug monitoring (1)
- Therapieabbruch (1)
- Therapieerfolg (1)
- Therapieversagen (1)
- Therapy (1)
- Thiotepa-busulfan-fludarabine (TBF) (1)
- Thromboyztenregeneration (1)
- Tight junction (1)
- Time interval (1)
- Tissue Engineering (1)
- Toll-like Receptor (1)
- Toll-like-Rezeptoren (1)
- Toxoplasmose (1)
- Tracer (1)
- Trainingsprogramm (1)
- Transarterielle Chemoembolisation (1)
- Transcription (1)
- Transkriptionsfaktor (1)
- Translational research (1)
- Transplantation (1)
- Transport (1)
- Treatment (1)
- Tregs (1)
- Trimerisation (1)
- Troponin I (1)
- Trypanosoma (1)
- Tuberkulose (1)
- Tumor Immuntherapie (1)
- Tumor-Nekrose-Faktor (1)
- Tumor-Nekrose-Faktor <alpha-Inhibitor> (1)
- Tumorantigen (1)
- Tumorassoziierte Antigene (1)
- Tumorimmunologie (1)
- Tumornekrosefaktor Liganden Superfamilie (1)
- Tumornekrosefaktor Rezeptor Superfamilie (1)
- Tumorsuppressor-Gen (1)
- Tumorsuppressorgen (1)
- Tumosuppresorgen (1)
- Tutor-System (1)
- Typ I Interferon (1)
- Tyrosine phosphorylation (1)
- Ubiquitin (1)
- Umkehrphasen-HPLC (1)
- Uniparentale Disomie (1)
- Unrelated donor (UD) (1)
- Untertyp (1)
- Upper Guinea (1)
- Uridine (1)
- Urinalkalisierung (1)
- VAS (1)
- VCE (1)
- VLA-1 (1)
- Vaccinia-Virus (1)
- Validation (1)
- Varicella-Zoster-Virus (1)
- Varicella-zoster-virus (1)
- Verhalten und Verhaltensmechanismen (1)
- Versorgungsrealität (1)
- Verträglichkeit Interferon alpha (1)
- Vibrationplattsntraining (1)
- Videokapselendoskopie (1)
- Viral (1)
- Virologie (1)
- Vitamin A (1)
- Vitamin D3 (1)
- WBV (1)
- Wachstum (1)
- Wachstumsfaktoren (1)
- Waldeyer’s tonsillar ring (1)
- Web-based-Training (1)
- Wechselwirkungen (1)
- Western diet (1)
- Wilms tumor protein 1 (1)
- Wireless capsule- endoscopy (1)
- Wue-1 (1)
- X-Ray Chrystallography (1)
- YAP (1)
- ZIP (1)
- ZM336372 (1)
- Zelladhäsion (1)
- Zelladhäsionsblockade (1)
- Zellkontakt (1)
- Zellkultur (1)
- Zelllysat (1)
- Zellmigration (1)
- Zidovudin (1)
- Zielzelle <Immunologie> (1)
- Zilienschlagfrequenz (1)
- Zink (1)
- Zuckeraustauschstoff (1)
- Zufriedenheit mit PEG (1)
- Zukunftsangst (1)
- Zytokin-induzierte Killerzellen (1)
- Zytokine (1)
- Zytotoxizität (1)
- [177Lu]/[90Y]PentixaTher (1)
- [177Lu]PentixaTher (1)
- [18F]FDG PET/CT (1)
- [90Y]PentixaTher (1)
- [\(^{68}\)Ga] Pentixafor (1)
- [\(^{68}\)Ga]Ga-FAPI (1)
- [\(^{68}\)Ga]Pentixafor (1)
- \(^{11}\)C-methionine (1)
- abnormalities (1)
- according to guidelines (1)
- acoustic radiation force impulse imaging (1)
- activating receptors (1)
- active TB (1)
- active antiretroviral therapy (1)
- acute Graft versus Host Disease (1)
- acute graft-versus host disease (1)
- acute graft-versus-host disease (1)
- acute hypobaric hypoxia (1)
- acute kidney injury (1)
- acute leukemia (AL) (1)
- acute lymphoblastic leukaemia (1)
- acute myelogenous leukemia (1)
- acute myeloic leukemia (1)
- acute myeloid-leukemia (1)
- acute respiratory distress syndrome (1)
- adaptive Immunantwort (1)
- adenocarcinoma of the ampulla of Vater (1)
- adenoma-carcinoma-sequence (1)
- adhesion (1)
- adhesion molecule (1)
- adjuvant (1)
- adoptive cell therapy (1)
- adoptive t cell transfer (1)
- adoptive transfer (1)
- adrenocortical carcinoma (1)
- adulte Stammzelle (1)
- adults (1)
- afatinib (1)
- affinity (1)
- africans (1)
- after-care (1)
- agar diffusion test (1)
- agonism (1)
- agonist (1)
- agonistic antibodies (1)
- akute myeloische Leukämie (1)
- all-cause mortality (1)
- allelischer Verlust (1)
- allergic subjects (1)
- alloSCT patients (1)
- alpha1 (1)
- alternative to animal testing (1)
- alveolar epithelium (1)
- ambulant (1)
- ambulatory (1)
- amphotericin B (1)
- amsacrine (1)
- amyloid‐directed antibodies (1)
- amyotrophic lateral sclerosis (1)
- anaplastic medulloblastoma (1)
- anastomotic leak (1)
- androgen deprivation therapy (1)
- angeborene Immunabwehr (1)
- animal model (1)
- annotation (1)
- anti-hDEC205-WT1 antibody fusion protein (1)
- anti-infective vaccination (1)
- anti-proliferative effects (1)
- antibiotic therapy (1)
- anticoagulation (1)
- antifungal (1)
- antifungal agents (1)
- antifungals (1)
- antigen loss (1)
- antigen processing and presentation (1)
- antigen-presenting cells (1)
- antigens (1)
- antileukemia vaccine (1)
- antimicrobial peptide (1)
- antimicrobial responses (1)
- antimicrobials (1)
- antimikrobial peptides (1)
- antiphospholipid syndrome (1)
- antiresorptive drug-related osteonecrosis of the jaw (1)
- antiretroviral therapy (1)
- antithrombotic therapy (1)
- antiviral treatment (1)
- aplastic anemia (1)
- april (1)
- arthritis (1)
- asymptomatic patients (1)
- asymptomatische Patienten (1)
- at-home sampling (1)
- atherosclerosis (1)
- atrial fibrillation (1)
- attitude to death (1)
- autoantibodies (1)
- autoimmune disease (1)
- autoimmune encephalitis (1)
- autologous (1)
- autologous hematopoietic stem cell transplantation (1)
- autologous transplantation (1)
- autologous tumor (1)
- autophagy (1)
- axi-cel (1)
- axonal transcriptome (1)
- bacterial infection (1)
- bcells (1)
- bcl-2 (1)
- behavior and behaviormechanisms (1)
- benzodiazepines (1)
- beta-Zellproliferation (1)
- beta-cell (1)
- beta-cells (1)
- beta-oxidation (1)
- bile (1)
- biliary-tract cancer (1)
- binding (1)
- biodiversity (1)
- biodiversity hotspot (1)
- biofilm formation (1)
- biological fluorescence (1)
- bioluminescence imaging (1)
- biomarkers Myelomas (1)
- biophosphonate (1)
- biophysics (1)
- biopsy (1)
- biosynthesis (1)
- bispecific (1)
- bispecific antobodies (1)
- bispezifisch (1)
- blast cell lysate (1)
- blast-derived RNA (1)
- blinatumomab (1)
- blinatumoman (1)
- blood (1)
- blood count (1)
- blood flow (1)
- bone (1)
- bone adaptation (1)
- bone disease (1)
- bone imaging (1)
- bone marrow angiogenesis (1)
- bone marrow cells (1)
- bone marrow exam (1)
- bone marrow failure (1)
- bone marrow homing (1)
- bone marrow micro-environment (1)
- bone marrow transplantation (1)
- bone-disease (1)
- bone-mineral density (1)
- bortezomib plus dxamethasone (1)
- brain tumor (1)
- breakpoint (1)
- breakthrough infection (1)
- breast cancer (1)
- bridge-to-transplant (1)
- bridging (1)
- bromohydrin pyrophosphat (1)
- bromohydrin pyrophosphate (1)
- bronchoalveolar lavage fluid (1)
- burnout (1)
- bypassoperation (1)
- c-ART (1)
- c-ART Kinder (1)
- c-Jun N-terminal kinase (1)
- c-Jun N-terminale Kinase (1)
- c-reactive protein (1)
- cIAP (1)
- calcium imaging (1)
- calcofluor white staining (1)
- calprotectin (1)
- cancer care (1)
- cancer immune cell therapy (1)
- cancer metabolism (1)
- cancer of unknown primary (CUP) (1)
- cancer predisposition (1)
- cancer prevention (1)
- cancer treatment (1)
- cancer vaccines (1)
- cancer-induced bone disease (1)
- capecitabine (1)
- capture (1)
- carbohydrate (1)
- carcinoma (1)
- carcinoma cells (1)
- cardiac hypertrophy (1)
- cardiac thrombi (1)
- cardiac transplantation (1)
- cardiovascular (1)
- care (1)
- carfilzomib (1)
- caspase activation (1)
- caspase-3 (1)
- cathelicidin (1)
- cathelicidin LL37 (1)
- ceftriaxone (1)
- cell (1)
- cell binding (1)
- cell cycle (1)
- cell of origin (1)
- cell therapy and immunotherapy (1)
- cell viability testing (1)
- cell wall (1)
- celldifferentiation (1)
- cellular inhibitor of apoptosis 1/2 (cIAP1/2) (1)
- cereblon expression (1)
- cerebral aspergillosis (1)
- cerebrospinal fluid (1)
- cfRNA (1)
- chemistry (1)
- chemokine receptor (1)
- chenodeoxycholate (1)
- chewed (1)
- children (1)
- chimeric antigen receptors (1)
- cholesterol 25 hydroxylase (1)
- chromosomale Verlustanalyse (1)
- chronic Hepatitis C (1)
- chronic distress (1)
- chronic heart failure (1)
- chronic kidney disease (1)
- chronic myeloic leukemia (1)
- chronic myeloid leukemia (1)
- chronic phase (1)
- chronisch entzündliche Darmerkrankungen (1)
- chronische berufliche Exposition (1)
- cicatricial pemphigoid (1)
- circulating (1)
- circulating micrornas (1)
- circulating tumor cells (1)
- cirrhosis (1)
- class-I (1)
- clinical imaging (1)
- clinical trial (1)
- clinical-practice (1)
- clostridium difficile infection (1)
- cluster analysis (1)
- cluster of differentiation (1)
- coagulation (1)
- cognitive hypnotherapy (1)
- cognitive impairment (1)
- collagens (1)
- colon cancer (1)
- colon carcinoma (1)
- combination testing (1)
- combination therapy (1)
- commensal bacteria (1)
- common genetic determinants (1)
- common variable immunodeficiency (1)
- common variable immunodeficiency (CVID) (1)
- comorbidities (1)
- comparability (1)
- comparison (1)
- complement system (1)
- compliance (1)
- complication (1)
- complications (1)
- comprehensive management (1)
- comprehensive psychosomatic assessment (1)
- consensus statement (1)
- conservation (1)
- contrast-enhanced ultrasound. (1)
- coping (1)
- coping skills (1)
- coronary artery bypass grafting (1)
- corticosteroids and cyclophosphamide (1)
- costimulation (1)
- critically ill patients (1)
- cross presentation (1)
- cross-linking (1)
- cyclophosphamide (FLAMSA) (1)
- cytarabine dose (1)
- cytochrome P450 3A4 (CYP3A4) (1)
- cytogenetic response (1)
- cytogenetics (1)
- cytokine (1)
- cytokine production (1)
- cytokine-induced killer cells (1)
- cytokinesis (1)
- cytopenia (1)
- cytotoxicity receptors (1)
- d3web.Train (1)
- d4T (1)
- dabrafenib (1)
- daratumumab monotherapy (1)
- ddPCR (1)
- death rates (1)
- deep metric learning (1)
- definition (1)
- degradation (1)
- deletion 17P (1)
- dendritic cell-targeting (1)
- dendritiric cells (1)
- dendritische Zelle (1)
- denritic cells (1)
- derivates (1)
- detoxification (1)
- dexamethasone (1)
- diabetes (1)
- diabetes mellitus type 2 (1)
- diagnostic medicine (1)
- diagnostics (1)
- diarrhea (1)
- different imatinib dose regimens (1)
- differentiated thyroid tumor (1)
- diffuse large B-cell lymphoma (1)
- diffusion weighted mri (1)
- diketopiperazines (1)
- direct-acting antiviral (1)
- direct-acting antivirals (1)
- discharge definition (1)
- discordance (1)
- disease (1)
- disease comorbidities (1)
- disease score (1)
- disease severity (1)
- disease-activity score (1)
- disengagement (1)
- disorder of immunity (1)
- disorders (1)
- dolutegravir (1)
- donor-cell leukemia (1)
- downstream (1)
- drug (1)
- drug adherence (1)
- drug monitoring (1)
- drug resistance (1)
- drug screening (1)
- drug-induced immune hemolytic anemia (1)
- drug–drug interactions (DDIs) (1)
- dual targeting (1)
- duodenal perforation (1)
- duodenal trauma (1)
- e. coli Nissle (1)
- early applied higher imatinib dosages (1)
- early detection (1)
- early onset sepsis (1)
- elderly (1)
- elderly patients (1)
- elderly persons (1)
- electrogastrographic egg activities (1)
- electroporation (1)
- elotuzumab (1)
- emotional regulation (1)
- emtricitabine (1)
- enal impairment (1)
- endoscopic (1)
- endoscopic full thickness resection (eFTR) (1)
- endoscopic instruments (1)
- endoscopic intervention (1)
- endosponge (1)
- engaging aantibody (1)
- engraftment syndrome (1)
- enzyme-linked immunoassays (1)
- epidemiology (1)
- epidemology (1)
- epithelial-mesenchymal transition (1)
- erythropoiesis-stimulating agents (1)
- esophageal perforation (1)
- esophagus (1)
- european leukemia net (1)
- everolimus (1)
- exhaustion (1)
- expression (1)
- extramedullary (1)
- extramedullary hematopoiesis (1)
- familial amyloid polyneuropathy (FAP) (1)
- fatty liver (1)
- fear of cancer (1)
- fever (1)
- few-shot learning (1)
- fibrin D-dimer (1)
- fibroblast activation protein (1)
- fibrosis progression (1)
- fibrotest (1)
- fine-needle-aspiration (1)
- fluorescence (1)
- fluorescence in situ hybridization (FISH) (1)
- fluorescence microscopy (1)
- fluorescent dyes (1)
- folinic acid (1)
- free survival (1)
- fructose (1)
- full-thickness resection device (FTRD) (1)
- functional abdominal pain (1)
- fungal aerosolization (1)
- fungal disease (1)
- fungal host response (1)
- fungal infection model (1)
- fungal molecular diagnostics (1)
- fungal sinusitis (1)
- fungi (1)
- fusion protein (1)
- gRNA-only (1)
- galectin-2 (1)
- gamma delta T cell (1)
- gamma delta T cells (1)
- gamma delta T-Zelle (1)
- gamma delta T-Zellen (1)
- gammadelta T cells (1)
- gastric MALT lymphoma (1)
- gastric bypass (1)
- gastric cancer (1)
- gastric emptying (1)
- gastroduodenoscopie (1)
- gastrointestinal dysfunction (1)
- gastrointestinal infections (1)
- gastrointestinal perforation (1)
- gastrointestinal symptoms (1)
- gastrointestinal tract (1)
- gastrointestinal tumors (1)
- gene expression data (1)
- gene regulation in immune cells (1)
- gene therapy (1)
- gene-environment interaction (1)
- genetic polymorphisms (1)
- genetic susceptibility (1)
- genital warts (1)
- genus (1)
- german people (1)
- glecaprevir/pibrentasvir (1)
- glial fibrillary acidic protein (1)
- glioblastoma (1)
- glucose (1)
- glutamic acid decarboxylase (1)
- glycaemic index (1)
- gp (1)
- gp130 (1)
- graft-versus-host-disease (1)
- graft-versus-leukemia effect (1)
- graftversushostdisease (1)
- granulocytes (1)
- group 3 (1)
- group consensus statement (1)
- growth differentiation factor 15 (1)
- growth-factor receptor 3 (1)
- growth-factor-receptor (1)
- growthfactors (1)
- gut–liver axis (1)
- haematopoietic stem cell (1)
- haploidentical γδ T lymphocytes (1)
- head and neck cancer (1)
- health care (1)
- health-assessment questionnaire (1)
- healthy volunteers (1)
- heart-lung-machine (1)
- heartfailure (1)
- heat shock proteins (1)
- helicase (1)
- helicobacter pylori infection (1)
- hematological malignancies (1)
- hematology (1)
- hematopoetic stem cells (1)
- hematopoietic (1)
- hematopoietic SCT (1)
- hematopoietic cell transplantation (1)
- hematopoietic stem cell transplantation (HSCT) (1)
- hematopoietic stem cells (1)
- hemodialysis (1)
- hemolysis (1)
- hemolytic anemia (1)
- hemostasis (1)
- hepatic stellate cells (1)
- hepatitis (1)
- hepatitis B virus (1)
- hepatitis c (1)
- hepatocellular carcinoma (1)
- hepatoma-derived growth factor (1)
- hepatotoxicity (1)
- high-dose chemotherapy (1)
- high-risk cytogenetics (1)
- high-risk hematology (1)
- highly-active antiretroviral therapy (1)
- homing (1)
- homing receptor (1)
- hospitalization (1)
- host defense (1)
- host genetics (1)
- host response (1)
- host-pathogen interaction (1)
- human (1)
- human biomarker (1)
- human cholangiocellular carcinoma (1)
- human cytomegalovirus (1)
- human cytomegalovirus (HCMV) (1)
- human hepatic cells (1)
- human intrahepatic cholangiocarcinoma (1)
- human leukocyte antigen-E (HLA-E) (1)
- human multiple-myeloma (1)
- human papillomavirus (1)
- human pathogen (1)
- human pathogenic fungi (1)
- humans (1)
- hybrid messenger RNA (1)
- hydroxy-dabrafenib (1)
- hypersensitivity (1)
- hypnotic susceptibility (1)
- hypogammaglobulinemia (1)
- hämatopoetische Stammzelltransplantation (1)
- i-131 uptake (1)
- iNKT (1)
- iNKT-Zellen (1)
- idiotype (1)
- image classification (1)
- imaging the immune system (1)
- immune activation (1)
- immune cell recruitment (1)
- immune control (1)
- immune impairment (1)
- immune modulation (1)
- immune monitoring (1)
- immune reaction (1)
- immune receptors (1)
- immune reconstitution (1)
- immune therapy (1)
- immunity (1)
- immuno-oncology (1)
- immunocompromised patients (1)
- immunogenetics (1)
- immunoglobulin light chain (1)
- immunoglobulin rearrangement (1)
- immunohistochemistry (1)
- immunohistochemistry techniques (1)
- immunology (1)
- immunophenotyping (1)
- immunosurveillance (1)
- immunotherapeutics (1)
- in vitro Testmodell (1)
- in vitro model (1)
- in vivo cell expansion (1)
- inborn errors of immunity (IEIs) (1)
- incidence (1)
- independent marker (1)
- individual mind state (1)
- individualized surgery (1)
- induce cyclooxygenase-2 expression (1)
- induced apoptosis (1)
- induction regimen (1)
- infection detection (1)
- infektion (1)
- inflamatory bowel disease (1)
- inflammasome (1)
- inflammation marker (1)
- inflammation-induced tissue demage (1)
- influencing factors (1)
- infusion (1)
- inhibition (1)
- inhibitor (1)
- inhibitory receptors (1)
- injury (1)
- innalte immunity (1)
- instrument (1)
- insulin signaling (1)
- integrase inhibitor (1)
- integrative Onkologie (1)
- integrins (1)
- intensity of attention (1)
- interaction (1)
- interacts (1)
- interferon alpha (1)
- interferon alpha (IFNα) (1)
- interferon alpha signalling (1)
- interferon gamma (1)
- interferon-alpha (1)
- interferon-free (1)
- intergrin (1)
- intergroupe francophone (1)
- interleukin 1 (1)
- interleukin 13 (1)
- interleukin 18 (1)
- interleukin 1beta (1)
- interleukin 4 (1)
- interleukin 5 (1)
- interleukin 8 (1)
- interleukin-6 (1)
- interleukin-9 (1)
- interleukine 8 (1)
- intermediate dose Ara-C (1)
- intervention (1)
- intestinal barrier (1)
- intestinal-type adenocarcinoma (1)
- intestine (1)
- intramolecular Michael addition (1)
- intratumoral microbiota (1)
- invasive Aspergillose (1)
- invasive Pilzinfektion (1)
- invasive candidiasis (1)
- iohexol (1)
- irinotecan (1)
- iron homeostasis (1)
- iron responisve element (1)
- irritable-bowle-sondrome (1)
- ischemic stroke (1)
- isoforms (1)
- ivory coast (1)
- janus kinase inhibitor (1)
- kardiochirurgisch (1)
- keratin-18 (1)
- kidney (1)
- kidney cancer (1)
- kidney function (1)
- kinase inhibitors (1)
- kinease (1)
- kinesin (1)
- kolorektale Karzinome (1)
- kreuzreaktive T-Zellen (1)
- lactate dehydrogenase cytotoxicity assay (1)
- lactose (1)
- laminin 332 (1)
- large B-cell lymphoma (1)
- large granular lymphocyte (1)
- lasso regression (1)
- left ventricular hypertrophy (1)
- left ventricular mass index (1)
- leitliniengerecht (1)
- lenalidomide-refractory patients (1)
- lentiviral transduction (1)
- leptin (1)
- lesions (1)
- library screening (1)
- life-threatening side-effects (1)
- lifestyle habits (1)
- ligand incompatibility (1)
- ligand trail (1)
- lineage (1)
- lipid metabilism (1)
- lipodystrophy (1)
- lipofection (1)
- liquid biopsy (1)
- liquid chromatography tandem mass spectrometry (LC-MS/MS (1)
- liraglutide (1)
- liver (1)
- liver disease (1)
- liver diseases (1)
- liver fibrosis (1)
- locally advanced disease (1)
- loss-of-function (1)
- low molecular heparin (1)
- lymph node metastases (1)
- lymph node stromal cells (1)
- lymph node transplantation (1)
- lymphocyte activation (1)
- lymphocytes (1)
- lysine biosynthesis (1)
- lysozyme (1)
- mAb engineering (1)
- mRNA (1)
- mRNA translation (1)
- mRNA-Seq (1)
- mRNA-Translation (1)
- mTOR (1)
- magnetic resonance imaging (1)
- malassimilation (1)
- malignant transformation (1)
- malnutrition (1)
- mammalian genomics (1)
- mantle cell lymphoma (1)
- marrow plasma cells (1)
- matrix metallopeptidase-1 (1)
- mebendazole (1)
- mechanical loading (1)
- mechanism (1)
- mechanosensing (1)
- mechanotransduction (1)
- megakaryocytes (1)
- melanoma (1)
- melanoma malignancy (1)
- melanoma therapy (1)
- memory B cell (1)
- mental impairment (1)
- mesenteric lymph node (1)
- messenger RNA (1)
- metabolic syndrom (1)
- metabolic tumor volume (MTV) (1)
- metastasis (1)
- metastasis-directed therapy (1)
- methionine (1)
- methotrexate (1)
- methylation (1)
- miR-122 (1)
- miR-132 (1)
- miR-146 (1)
- miR-155 (1)
- microRNA (1)
- microbiome (1)
- microbiota (1)
- microbiota-derived metabolites (1)
- micronuclei (1)
- microsatellite (1)
- microsatellite instability (1)
- microswimmer (1)
- mikrosatelliteninstabil (1)
- mindfulness (1)
- minimal residual disease (1)
- minimally important difference (1)
- minimally invasive surgery (1)
- mismatch (1)
- missing self (1)
- mitochondrial DNA (1)
- mitochondriale Toxizität (1)
- mixed infection (1)
- modified Rodnan skin score (mRSS) (1)
- modified vaccinia Ankara virus (1)
- mold disease (1)
- mold exposure (1)
- molecular data (1)
- molecular diagnosis (1)
- molecular response in cml (1)
- mono specific antibody (1)
- mono spezifischer Antikörper (1)
- monoclonal antibody (1)
- monoclonal gammopathy (1)
- monoclonal-antibodies (1)
- monocytes (1)
- motivational level (1)
- mouse feeding model (1)
- mouse models DNA damage (1)
- mtDNA (1)
- mucormycosis (1)
- mucous membrane pemphigoid (1)
- multicomponent Ugi-type reaction (1)
- multimodal (1)
- multiparameter flow-cytometry (1)
- multiparameter flow-cytpmetry (1)
- multiparametric flow cytometry (1)
- multiple myeloma Lesions (1)
- multiplex PCR (1)
- multiplex-PCR (1)
- multiplicity of infection (1)
- murin (1)
- muscle (1)
- music (1)
- mutation (1)
- mycophenolate (1)
- mycoses (1)
- mycosis (1)
- myeloid-derived suppressor cells (MDSCs) (1)
- myeloma cells (1)
- myofibroblast (1)
- myokines (1)
- nOAC (1)
- naive T-cell gene editing (1)
- nanoparticle albumin-bound paclitaxel (1)
- nasal mucosa (1)
- natural killer cell (1)
- natural language processing (1)
- naïve B cells (1)
- necroptosis (1)
- necrotic cell death (1)
- neoadjuvant (1)
- neoadjuvant chemotherapy (1)
- nestin (1)
- network (1)
- neuralgic amyotrophy (1)
- neuroendocrine neoplasia (1)
- neuroendocrine tumor (NET) (1)
- neuroimmunology (1)
- neurology (1)
- neutropenia (1)
- neutropenic fever (1)
- neutropenie (1)
- neutrophile Granulozyten (1)
- neutrophils (1)
- new species (1)
- newly diagnosed (1)
- newly-diagnosed myeloma (1)
- nichtalkoholische Fettlebererkrankung (1)
- nichtinvasive Bildgebung (1)
- nicotinamide (1)
- no correlation (1)
- nomogram (1)
- non-interventional (1)
- non-invasive fibrosis assessment (1)
- nonalcoholic fatty liver disease (1)
- none (1)
- normal values (1)
- novel therapies (1)
- nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NFκB) (1)
- nuclear localisation sequence (1)
- nuclear pore complex (1)
- nuclear receptors (1)
- nucleocytoplasmatic transport (1)
- nucleoporine (1)
- nucleoside transporter (1)
- nucleotide excision repair (1)
- nukleäre Lokalisationssequenz (1)
- nutritional counseling (1)
- nutritional medical needs (1)
- nutritional risk screening (1)
- obinutuzumab (1)
- observational (1)
- occult gastrointestinal bleeding (1)
- oesophagogastroduodenoscopy (1)
- off-pump (1)
- older patients (1)
- oligmometastases (1)
- oligomerization (1)
- oligorecurrence (1)
- oncobiome (1)
- oncogenic signalling network (1)
- oncologist (1)
- oncology outpatients (1)
- oncostatin M (1)
- onkogenes Signalnetzwerk (1)
- ontology (1)
- operating platform (1)
- ophthalmic artery (1)
- optic nerve (1)
- oral anticancer drugs (1)
- oral anticoagulant therapy (1)
- oral anticoagulants (1)
- oral microbiome (1)
- orale Antikoagulationstherapie (1)
- orale Chemotherapie (1)
- orbit (1)
- orthotopic xenograft (1)
- osimertinib (1)
- osteokines adaptation (1)
- osteonecrosis of the jaw (1)
- osteoradionecrosis (1)
- outbreak (1)
- outcome (1)
- outcomes research (1)
- outpatient (1)
- outreach (1)
- overall survival (1)
- overdose (1)
- oxaliplatin (1)
- p38 MAPK (1)
- p53 (1)
- p8 (1)
- paediatric cancer (1)
- pan-RCC (1)
- pancreatectomy (1)
- pancreatic adenocarcinoma (1)
- pancreatic adenocarcinoma (PDAC) (1)
- pancreatic beta-cells (1)
- pancreatic head cancer (1)
- pancreatic neoplasms (1)
- pancreatobiliary type (1)
- panobinostat (1)
- paradoxe CRAF-Aktivierung (1)
- participation in clinical trials (1)
- pathogen-associated molecular patterns (1)
- pathogenic TP53 germline variant (1)
- pathophysiology (1)
- pathway (1)
- pathways (1)
- patient access (1)
- patient care (1)
- patient-reported outcomes (1)
- patients with multiple myeloma (1)
- pattern (1)
- pattern recognition receptors (1)
- pcr (1)
- pediatric (1)
- pediatric HIV infection (1)
- peginterferon alpha-2B (1)
- peginterferon alpha-2b (1)
- peptide (1)
- peptide tyrosine tyrosine (PYY) (1)
- peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) (1)
- percutaneus endoscopic gastrostomy (1)
- personalised medicine (1)
- personalized medicine (1)
- pharmacokinetic (1)
- pharmacokinetic interaction (1)
- pharmacology (1)
- phosphatidyl-inositol-3-kinase p110 alpha (1)
- phosphatidylinositol 3-kinase/Akt (1)
- physical activity (1)
- physicians (1)
- physiologically based pharmacokinetic (PBPK) modeling (1)
- plasma D-dimer (1)
- plasma cell disorder (1)
- plasma clearance (1)
- platelet activation (1)
- platelet aggregation (1)
- platelet count (1)
- plus dexamethasone (1)
- point mutation (1)
- point shear wave elastography (1)
- poly(ADP-ribose) polymerase inhibitors (1)
- polymerase-chain-reaktion (1)
- polymorphonuclear neutrophil (1)
- polyp (1)
- population pharmacokinetics (1)
- population-based cohort (1)
- porcine large animal model (1)
- positron emission tomography (1)
- positron emission tomography/computed tomography (1)
- post-hospital (1)
- postoperative bleeding (1)
- posttraumatic stress disorder (1)
- potentially bleeding pathologies (1)
- pp65 (1)
- pre-clinical models (1)
- precision medicine (1)
- precision oncology (1)
- prediction (1)
- predictive biomarker (1)
- predictive factor (1)
- pregnancy (1)
- prenatal paternal depression (1)
- preoperative planning (1)
- prevalence (1)
- primary biliary cholangitis (1)
- primary immunodeficiencies (1)
- primary immunodeficiency (1)
- primary sclerosing cholangitis (1)
- primary systemic amyloidosis (1)
- primär systemische Amyloidose (1)
- probe-based real-time PCR (1)
- progression (1)
- proliferation of beta-cells (1)
- prolonged cytopenia (1)
- prolonged neutropenia (1)
- prophylaxis (1)
- prospective (1)
- prospective feasibility (1)
- prostaglandin E2 (1)
- prostate-specific membrane antigen (1)
- prostate-specific membrane antigen (PSMA) (1)
- proteasome inhibitors (1)
- protein p8 (1)
- psoriasis (1)
- psychischer Stress (1)
- psychology (1)
- psychoneuroimmunology (1)
- psychosocial (1)
- public health (1)
- pulmonary aspergillosis (1)
- pulmonary immune response (1)
- pyrimidine synthesis (1)
- pädiatrische HIV-Infektion (1)
- qRT-PCR (1)
- radiation therapy (1)
- radiogenomics (1)
- radioligand therapy (1)
- radionuclide therapy (1)
- radiotherapy (1)
- rainforest (1)
- raltegravir (1)
- randomized controlled trial (1)
- randomized phase-3 trial (1)
- rapid prototyping (1)
- rare SNP (1)
- real life setting (1)
- real time PCR (1)
- real world data (1)
- real-time (1)
- recall antigen (1)
- receptor expression (1)
- receptor tyrosine kinases (1)
- recognition (1)
- recombinant-human-erythropoietin (1)
- recovery (1)
- rectal sensitivity (1)
- rectum (1)
- recurrence (1)
- recurrent Tako-Tsubo cardiomyopathy (1)
- reference data (1)
- refractory or relapsed (1)
- refraktär (1)
- refraktär und rezidiviert (1)
- region (1)
- relaps (1)
- relapsed (1)
- relapsed and refractory (1)
- relaxation (1)
- renal failure (1)
- renal function (1)
- renal perfusion (1)
- renal scintigraphy (1)
- replikative senescence (1)
- reported outcomes (1)
- reporting and data systems (1)
- respiratory virus (1)
- resting NK cells (1)
- results (1)
- retardeted virus (1)
- retargeted measles virus (1)
- retrospective (1)
- retrospektiv (1)
- reverse transcriptase inhibitors (1)
- review (1)
- rheumatoid (1)
- rheumatoid arhritis (1)
- rheumatoide Arthritis (1)
- ribavirin serum levels (1)
- risk factor (1)
- risk pregnancy (1)
- risk factor analysis (1)
- rituximab (1)
- rs10754558 (1)
- rs35829419 (1)
- ruxolitinib (1)
- safety (1)
- salvage (1)
- sarcoma (1)
- scFv (1)
- scid mice (1)
- screening for distress (1)
- second line therapy (1)
- secondary metabolite gene cluster (1)
- serotonin (1)
- serum biomarkers (1)
- serum concentrations (1)
- serum creatinine (1)
- serum retention (1)
- severe fibrosis (1)
- shRNA (1)
- siRNA (1)
- sialyl Lewis x (1)
- side effects (1)
- signal inhibition (1)
- signaling (1)
- signalling (1)
- significance MGUS (1)
- silkworm (1)
- single chain (1)
- sirolimus (1)
- skeletal mechanobiology (1)
- skin equivalents (1)
- sleeping sickness (1)
- slice culture (1)
- small bowel bleeding (1)
- small interfering RNAs (1)
- smoldering multiple-myeloma (1)
- smoldering myeloma (1)
- somatic symptom burden (1)
- somatostatin receptor (SSTR) (1)
- soziodemographische Analyse (1)
- spatial heterogeneity (1)
- spectral karyotyping (1)
- stable isotope breath tests (1)
- standardization (1)
- standardized reporting (1)
- steatosis (1)
- stem (1)
- stereotactic body radiotherapy (1)
- stimulation (1)
- strategy (1)
- streptococci (1)
- stress (1)
- stress level (1)
- stromal cells (1)
- structural biology (1)
- subcellular localisation (1)
- subunit (1)
- subzelluläre Lokalisation (1)
- sugar replacer (1)
- suicide attempt (1)
- sulfadiazine (1)
- sulfur (1)
- super-resolution microscopy (1)
- superior (1)
- suppression (1)
- surgical care (1)
- surgical manipulator (1)
- susceptibility (1)
- sustained virological response (1)
- symptom burden (1)
- symptoms (1)
- systemic candidiasis (1)
- systemic therapy (1)
- t-lymphocytes (1)
- target validation (1)
- targeted therapies (1)
- targeted therapy (1)
- targeting (1)
- taxonomy (1)
- tcells (1)
- tenofovir disaproxil fumarate (1)
- term-follow-up (1)
- thalidomide maintenance (1)
- therapeutic strategy (1)
- therapeutisches Target (1)
- thrombin (1)
- thromboembolism (1)
- thrombopoiesis (1)
- thrombosis (1)
- thyroid (1)
- tissue engineering (1)
- tocilizumab (1)
- tocilizumab (IL-6 inhibitor) (1)
- total body irradiation/busulfan (1)
- total lesion glycolysis (TLG) (1)
- total lesion methionine uptake (TLMU) (1)
- toxoplasmosis (1)
- trabectedin (1)
- trail-mediated apoptosis (1)
- trametinib (1)
- transactivation (1)
- transanal endoscopic microsurgery (TEM) (1)
- transcription (1)
- transcriptome (1)
- transcriptome profiling (1)
- transcripts (1)
- transformer (1)
- transient elastography (1)
- transient regulatory T-cell targeting (1)
- translational research (1)
- translocation (1)
- transporter protein associated with antigen processing-1 (TAP1) (1)
- transstomal endoluminal vacuum therapy (1)
- transthyretin (1)
- treatment (1)
- treatment failure (1)
- treatment response (1)
- trispecific (1)
- troponin-I (1)
- tsetse fly (1)
- tube nutrition (1)
- tuberculosis (1)
- tumor burden (1)
- tumor microenvironment (1)
- tumor microenvironment (TME) (1)
- tumor necrosis factor (TNF) (1)
- tumor specific antigen (1)
- tumor-associated antigens (1)
- tumor-infiltrating (1)
- tumor-specific CD8+ T cells (1)
- tumormicroenvironment (1)
- tumor‐specific antigen (1)
- type 1 diabetes mellitus (1)
- type I interferons (1)
- tyrosine-kinase inhibitor (1)
- ulcerative colitis (1)
- undetermined significance MGUS (1)
- upper gastrointestinal tract (1)
- uridine (1)
- urine alkalinization (1)
- ursodeoxycholic acid (1)
- vaccine vector (1)
- validation (1)
- valve replacement (1)
- vascularization (1)
- vasculature (1)
- vasculitis (1)
- venetoclax (1)
- venous thromboembolic disease (1)
- verteporfin (1)
- video capsule endoscopy (1)
- video object detection (1)
- viral clearance (1)
- viral infection (1)
- viral load (1)
- viral replication (1)
- virulence (1)
- virus (1)
- virus infection (1)
- virus-infected cells (1)
- virus-specific T-cell (1)
- virusspezifische T-Zellen (1)
- vitamin D (1)
- volumetric absorptive micro-sampling (VAMS) (1)
- warfarin interruption (1)
- water load test (1)
- weight gain (1)
- whole blood specimens (1)
- workplace health promotion (1)
- yoga (1)
- zinc (1)
- zirkulierende Tumorzellen (1)
- zo-1 (1)
- zoledonic acid (1)
- zoledronat (1)
- zoledronate (1)
- zweigeteilte trivalente T-Zell-aktivierende Antikörperderivate (1)
- zytotoxische T-Zellen (1)
- Ängstlichkeit/Depressivität (1)
- Ärztliche Behandlung (1)
- Ösophago-gastro-duodenoskopie (1)
- Ösophagus (1)
- Überlebenszeit (1)
- Übungsprogramm (1)
- β-catenin (1)
- γδ T cells (1)
- γδ T-Zellen (1)
- δγ Lymphozyten (1)
- δγ T cells (1)
Institute
- Medizinische Klinik und Poliklinik II (545) (remove)
Schriftenreihe
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (3)
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (2)
- Betriebsärztlicher Dienst der Universität Würzburg (1)
- Clinical Trial Center (CTC) / Zentrale für Klinische Studien Würzburg (ZKSW) (1)
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- Early Clinical Trial Unit, Comprehensive Cancer Center Mainfranken (1)
- Experimentelle Tumorimmunologie, Frauenklinik, Universität Würzburg (1)
- Interdisciplinary Center for Clinical Research (IZKF), Würzburg, Germany (1)
ResearcherID
- N-2030-2015 (1)
Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. We performed a longitudinal case-control pilot study to identify host-specific, novel, and immune-relevant molecular candidates indicating IPA in patients post allogeneic stem cell transplantation (alloSCT). Supported by differential gene expression analysis of six relevant in vitro studies, we conducted RNA sequencing of three alloSCT patients categorized as probable IPA cases and their matched controls without Aspergillus infection (66 samples in total). We additionally performed immunoassay analysis for all patient samples to gain a multi-omics perspective. Profiling analysis suggested LGALS2, MMP1, IL-8, and caspase-3 as potential host molecular candidates indicating IPA in investigated alloSCT patients. MMP1, IL-8, and caspase-3 were evaluated further in alloSCT patients for their potential to differentiate possible IPA cases and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and appropriate control patients. Possible IPA cases showed differences in IL-8 and caspase-3 serum levels compared with matched controls. Furthermore, we observed significant differences in IL-8 and caspase-3 levels among CAPA patients compared with control patients. With our conceptual work, we demonstrate the potential value of considering the human immune response during Aspergillus infection to identify immune-relevant molecular candidates indicating IPA in alloSCT patients. These human host candidates together with already established fungal biomarkers might improve the accuracy of IPA diagnostic tools.
Although the field of fungal infections advanced tremendously, diagnosis of invasive pulmonary aspergillosis (IPA) in immunocompromised patients continues to be a challenge. Since IPA is a multifactorial disease, investigation from different aspects may provide new insights, helpful for improving IPA diagnosis. This work aimed to characterize the human immune response to Aspergillus fumigatus in a multilevel manner to identify characteristic molecular candidates and risk factors indicating IPA, which may in the future support already established diagnostic assays. We combined in vitro studies using myeloid cells infected with A. fumigatus and longitudinal case-control studies investigating patients post allogeneic stem cell transplantation (alloSCT) suffering from IPA and their match controls.
Characteristic miRNA and mRNA signatures indicating A. fumigatus-infected monocyte-derived dendritic cells (moDCs) demonstrated the potential to differentiate between A. fumigatus and Escherichia coli infection. Transcriptome and protein profiling of alloSCT patients suffering from IPA and their matched controls revealed a distinctive IPA signature consisting of MMP1 induction and LGAL2 repression in combination with elevated IL-8 and caspase-3 levels. Both, in vitro and case-control studies, suggested cytokines, matrix-metallopeptidases and galectins are important in the immune response to A. fumigatus. Identified IPA characteristic molecular candidates are involved in numerous processes, thus a combination of these in a distinctive signature may increase the specificity. Finally, low monocyte counts, severe GvHD of the gut (grade ≥ 2) and etanercept administration were significantly associated with IPA diagnosis post alloSCT. Etanercept in monocyte-derived macrophages (MDM) infected with A. fumigatus downregulates genes involved in the NF-κB and TNF-α pathway and affects the secretion of CXCL10.
Taken together, identified characteristic molecular signatures and risk factors indicating IPA may in the future in combination with established fungal biomarkers overcome current diagnostic challenges and help to establish tailored antifungal therapy. Therefore, further multicentre studies are encouraged to evaluate reported findings.
Im Rahmen dieser Arbeit wurden Gewebe von jeweils 15 kolorektalen MSI- und CSIPrimärtumoren, sowie 3 MSI- und 2 CSI-Tumorzelllinien mittels SNP-Arrayanalyse molekulargenetisch auf uniparentale Disomie (UPD) untersucht. Es konnte bestätigt werden, dass die uniparentale Disomie ein wichtiger Mechanismus zur Inaktivierung von Tumorsuppressorgenen zu sein scheint. Die Ergebnisse zeigen, dass nicht nur in MSI-Tumoren, sondern auch in CSI-Tumoren UPD nachgewiesen werden konnte, wobei der UPD-Anteil an identifizierten LOH-Regionen in MSI-Tumoren mit 94% gegenüber 41% in CSI-Tumoren deutlich höher lag. Interessanterweise wurde auch in 68% der korrespondierenden MSI- und in 27% der entsprechenden CSINormalgewebe UDP festgestellt, was daraufhin deutet, dass hier möglicherweise schon kanzerogene Vorstufen vorliegen. Die Verteilung der UPDs in den 15 Tumorproben der jeweiligen Tumortypen (MSI und CSI) war innerhalb der einzelnen Proben und innerhalb der einzelnen Chromosomen sehr heterogen, es wurden jedoch gemeinsam Regionen mit UPD gefunden. Bei 27% der MSI-Tumoren wurde eine neue Kandidatenregion auf Chromosom 6 (6pter-p22) identifiziert, die auch einige potentielle Tumorkandidatengene, wie das Tumorsuppressorgen NOL7 oder den Transkriptionsfaktor AP2a enthält. In CSI-Tumoren waren die monoallelischen Regionen mit 59% hauptsächlich durch Deletionen charakterisiert, während die MSITumore im Gegensatz nur 3% Deletionen aufwiesen. In CSI-Tumoren fielen insbesondere vier Bereiche auf den Chromosomen 18, 17, 8 und 22 durch allelische Verluste auf und bestätigen damit eine Reihe von früheren Ergebnissen. In bestimmten Regionen (z.B. 22q12.1) wurden sowohl Deletionen als auch UPD festgestellt. Die Region 5q22.2 war fast auschließlich von uniparentaler Disomie betroffen. Ob die UPD vor allem in frühen Stadien der Kolonkarzinogenese eine Rolle spielt und in späteren Stadien eher in chromosomaler, bzw. Mikrosatelliteninstabilität vorkommt, werden weitere Studien zeigen müssen.
Limiting bone resorption and regenerating bone tissue are treatment goals in myeloma bone disease (MMBD). Physical stimuli such as mechanical loading prevent bone destruction and enhance bone mass in the MOPC315.BM.Luc model of MMBD. It is unknown whether treatment with the Bruton's tyrosine kinase inhibitor CC-292 (spebrutinib), which regulates osteoclast differentiation and function, augments the anabolic effect of mechanical loading. CC-292 was administered alone and in combination with axial compressive tibial loading in the MOPC315.BM.Luc model for three weeks. However, neither CC-292 alone nor its use in combination with mechanical loading was more effective in reducing osteolytic bone disease or rescuing bone mass than mechanical stimuli alone, as evidenced by microcomputed tomography (microCT) and histomorphometric analysis. Further studies are needed to investigate novel anti-myeloma and anti-resorptive strategies in combination with physical stimuli to improve treatment of MMBD.
Bile salts accumulating during cholestatic liver disease are believed to promote liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We aimed to characterize the effects of different bile salts on HSC biology and investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen deposition, and activation of signaling pathways were determined. Activation of the human HSC cell line LX 2 was assessed by quantification of α-smooth muscle actin (αSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent signaling was inhibited both pharmacologically and by siRNA. CDC, the most abundant bile salt accumulating in human cholestasis, but no other bile salt tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC proliferation and subsequent collagen deposition. Pharmacological inhibition of the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic proliferation of HSCs. The PI3K p110α-specific inhibitor Alpelisib and siRNA-mediated knockdown of p110α ameliorated pro-fibrogenic activation of mHSC and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is selectively induced by CDC. PI3K p110α may be a potential therapeutic target for the inhibition of bile salt-induced fibrogenesis in cholestasis.
Aspergillus (A.) fumigatus is an opportunistic fungal mold inducing invasive aspergillosis (IA) in immunocompromised patients. Although antifungal activity of human natural killer (NK) cells was shown in previous studies, the underlying cellular mechanisms and pathogen recognition receptors (PRRs) are still unknown. Using flow cytometry we were able to show that the fluorescence positivity of the surface receptor CD56 significantly decreased upon fungal contact. To visualize the interaction site of NK cells and A. fumigatus we used SEM, CLSM and dSTORM techniques, which clearly demonstrated that NK cells directly interact with A. fumigatus via CD56 and that CD56 is re-organized and accumulated at this interaction site time-dependently. The inhibition of the cytoskeleton showed that the receptor re-organization was an active process dependent on actin re-arrangements. Furthermore, we could show that CD56 plays a role in the fungus mediated NK cell activation, since blocking of CD56 surface receptor reduced fungal mediated NK cell activation and reduced cytokine secretion. These results confirmed the direct interaction of NK cells and A. fumigatus, leading to the conclusion that CD56 is a pathogen recognition receptor. These findings give new insights into the functional role of CD56 in the pathogen recognition during the innate immune response.
Background
Causality between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) was reported in various studies. However, the implication of different virological serum markers of HBV infection in patients with both HBV infection and DLBCL is not fully understood. The aim of this study was to investigate the impact of HBV markers on overall survival (OS) and progression-free survival (PFS) in patients with both HBV infection and DLBCL.
Methods
In this study, patients (n = 40) diagnosed with both HBV infection and DLBCL were identified between 2000 and 2017. Six patients with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) co-infection were excluded from this study. We retrospectively analyzed patients’ demographic characteristics, treatment, and the prognostic impact of different HBV markers at first diagnosis of DLBCL (HBsAg, anti-HBs, HBeAg, anti-HBe, and HBV-DNA) on OS and PFS.
Results
The majority of patients (n = 21, 62%) had advanced disease stage (III/IV) at diagnosis. In the first-line therapy, 24 patients (70%) were treated with R-CHOP regimen (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone). HBeAg positive patients had a trend toward inferior OS and PFS compared with HBeAg negative patients. Anti-HBe positive patients had a statistically significant better OS and PFS compared with anti-HBe negative group (both P < .0001). Viremia with HBV-DNA ≥ 2 × 107 IU/L had a significant negative impact on OS and PFS (both P < .0001).
Conclusion
High activity of viral replication is associated with a poor survival outcome of patients with both HBV infection and DLBCL.
We herein report the case of a 73‐year‐old male patient who was diagnosed with leukemic non‐nodal MCL. This patient had received six cycles of bendamustine, which resulted in a transient remission, and a second‐line therapy with ibrutinib, which unfortunately failed to induce remission. We started a treatment with single‐agent obinutuzumab at a dose of 20 mg on day 1, 50 mg on day 2‐4, 330 mg on day 5, and 1000 mg on day 6. The laboratory analysis showed a rapid decrease of leukocyte count. Four weeks later, we repeated the treatment with obinutuzumab at a dose of 1000 mg q4w and started a therapy with venetoclax at a dose of 400 mg qd, which could be increased to 800 mg qd from the third cycle. This combination therapy was well tolerated. The patient achieved a complete remission (CR) after three cycles of obinutuzumab and venetoclax. To date, the patient has a progression‐free survival of 17 months under ongoing obinutuzumab maintenance q4w. This is the first report about obinutuzumab and venetoclax induced CR in rituximab‐intolerant patient with an ibrutinib‐resistant MCL. This case suggests that obinutuzumab‐ and venetoclax‐based combination therapy might be salvage therapy in patients with ibrutinib‐resistant MCL.
Background
Even in the era of novel immunotherapies for multiple myeloma (MM), treatment of late‐stage relapsed/refractory (RR) patients remains challenging. The aim of our study was to analyze the efficacy and safety of the five‐drug combination pomalidomide, bortezomib, doxorubicin, dexamethasone, and daratumumab (“Pom‐PAD‐Dara”) in RRMM.
Methods
We retrospectively analyzed data of 56 patients with RRMM who received Pom‐PAD‐Dara between September 2016 and May 2019.
Results
Patients were heavily pretreated with a median of four prior lines of therapy, including autologous and allogenic stem cell transplant in 50 (89%) and six (11%) patients, respectively. The overall response rate (ORR) was 78% and we observed partial remission, very good partial remission, and complete remission in 27 (48%), 13 (23%) and four (7%) patients, respectively. Median progression‐free survival was 7 months (95% CI, 3.3‐10.7) and the median overall survival was not reached at 24 months. Adverse events grade ≥ 3 were observed 41 (73%) patients and included neutropenia (n = 28, 50%), anemia (n = 22, 39%), thrombocytopenia (n = 21, 38%), and pneumonia (n = 6, 11%).
Conclusion
Pom‐PAD‐Dara represents a promising multiagent regimen in heavily pretreated RRMM patients with high ORR and an acceptable safety profile.
The multi-agent therapy “VDT-PACE” represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a “modified VDT-PACE” incorporating new generation anti-MM agents daratumumab and carfilzomib (“Dara-KDT-P(A)CE”). We retrospectively analyzed 38 patients with RRMM treated with “Dara-KDT-P(A)CE”. The median age was 62 (range 45–82) years, and the patients were heavily pretreated with a median of 5 (range 2–12) prior lines of therapy. Twenty-one (55%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81%) patients. The patients received a median of 2 (range 1–10) cycles of this therapy, and the overall response rate (ORR) was 70%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65% and 79%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95% CI 2.7–5.4) and 8.4 (95% CI 6.7–10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, “Dara-KDT-P(A)CE” is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options.
In the last few years, monoclonal antibodies (mAbs) such as elotuzumab and daratutumab have brought the treatment of multiple myeloma (MM) into the new era of immunotherapy. More recently, chimeric antigen receptor (CAR) modified T cell, a novel cellular immunotherapy, has been developed for treatment of relapsed/refractory (RR) MM, and early phase clinical trials have shown promising efficacy of CAR T cell therapy. Many patients with end stage RRMM regard CAR T cell therapy as their “last chance” and a “hope of cure”. However, severe adverse events (AEs) and even toxic death related to CAR T cell therapy have been observed. The management of AEs related to CAR T cell therapy represents a new challenge, as the pathophysiology is not fully understood and there is still no well-established standard of management. With regard to CAR T cell associated toxicities in MM, in this review, we will provide an overview of experience from clinical trials, pathophysiology, and management strategies.
Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40–80) years. Twenty (44%) and 25 (56%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59%. Extramedullary response was evaluable in 33 patients, nine (27%) of them achieved partial remission (PR) (ORR = 27%). In 15 (33%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95% CI, 3.5–6.5) and ten (95% CI, 7.5–12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.
Utilizing 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT), we performed this pilot study to evaluate the link between cytogenetic/genomic markers and imaging patterns in relapsed/refractory (RR) multiple myeloma (MM). We retrospectively analyzed data of 24 patients with RRMM who were treated at our institution between November 2018 and February 2020. At the last relapse/progression, patients had been treated with a median of three (range 1–10) lines of therapy. Six (25%) patients showed FDG avid extramedullary disease without adjacency to bone. We observed significantly higher maximum standardized uptake values (SUV\(_{max}\)) in patients harboring del(17p) compared with those without del(17p) (p = 0.025). Moreover, a high SUV\(_{max}\) of >15 indicated significantly shortened progression-free survival (PFS) (p = 0.01) and overall survival (OS) (p = 0.0002). One female patient exhibited biallelic TP53 alteration, i.e., deletion and mutation, in whom an extremely high SUV\(_{max}\) of 37.88 was observed. In summary, this pilot study suggested a link between del(17p)/TP53 alteration and high SUV\(_{max}\) on 18F-FDG PET/CT in RRMM patients. Further investigations are highly warranted at this point.
This study aimed to explore the correlation between imaging patterns and clinical features in patients with smoldering multiple myeloma (SMM) who simultaneously underwent 18F-FDG, 11C-Methionine, and 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT). We retrieved and analyzed clinical characteristics and PET imaging data of 10 patients with SMM. We found a significant correlation between bone marrow (BM) plasma cell (PC) infiltration and mean standardized uptake values (SUV\(_{mean}\)) of lumbar vertebrae L2-L4 on 11C-Methionine PET/CT scans (r = 0.676, p = 0.031) and 68Ga-Pentixafor PET/CT scans (r = 0.839, p = 0.002). However, there was no significant correlation between BM involvement and SUV\(_{mean}\) of lumbar vertebrae L2-L4 on 18F-FDG PET/CT scans (r = 0.558, p = 0.093). Similarly, mean target-to-background ratios (TBR\(_{mean}\)) of lumbar vertebrae L2-L4 also correlated with bone marrow plasma cell (BMPC) infiltration in 11C-Methionine PET/CT (r = 0.789, p = 0.007) and 68Ga-Pentixafor PET/CT (r = 0.724, p = 0.018) PET/CT. In contrast, we did not observe a significant correlation between BMPC infiltration rate and TBR\(_{mean}\) in 18F-FDG PET/CT (r = 0.355, p = 0.313). Additionally, on 11C-Methionine PET/CT scans, we found a significant correlation between BMPC infiltration and TBR\(_{max}\) of lumbar vertebrae L2-L4 (r = 0.642, p = 0.045). In conclusion, 11C-Methionine and 68Ga-Pentixafor PET/CT demonstrate higher sensitivity than 18F-FDG PET/CT in detecting BM involvement in SMM.
Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity
(2023)
Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK.
Many new immunotherapeutic approaches aim on the stimulatory targeting of receptors of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) using antibodies with intrinsic or conditional agonism. There is an initial need to characterize corresponding TNFRSF receptor (TNFR)-targeting antibodies with respect to affinity, ligand binding, receptor activation and the epitope recognized. Here, we report a collection of simple and matched protocols enabling the detailed investigation of these aspects by help of Gaussia princeps luciferase (GpL) fusion proteins and analysis of interleukin-8 (IL8) production as an easily measurable readout of TNFR activation. In a first step, the antibodies and antibody variants of interest are transiently expressed in human embryonal kidney 293 cells, either in non-modified form or as fusion proteins with GpL as a reporter domain. The supernatants containing the antibody-GpL fusion proteins can then be used without further purification in cell-free and/or cellular binding studies to determine affinity. Similarly, binding studies with mutated TNFR variants enable the characterization of the antibody binding site within the TNFR ectodomain. Furthermore, in cellular binding studies with GpL fusion proteins of soluble TNFL molecules, the ability of the non-modified antibody variants to interfere with TNFL-TNFR interaction can be analyzed. Last but not least, we describe a protocol to determine the intrinsic and the Fc gamma receptor (FcγR)-dependent agonism of anti-TNFR antibodies which exploits i) the capability of TNFRs to trigger IL8 production in tumor cell lines lacking expression of FcγRs and ii) vector- and FcγR-transfected cells, which produce no or only very low amounts of human IL8. The presented protocols only require standard molecular biological equipment, eukaryotic cell culture and plate readers for the quantification of luminescent and colorimetric signals.
Purpose
Growing evidence implies that transition to parenthood triggers symptoms of mental burden not only in women but likewise in men, especially in high-risk pregnancies. This is the first study that examined and compared the prevalence rates of depression, anxiety, and somatic symptom burden of expectant fathers who face different risk situations during pregnancy.
Methods
Prevalence rates of paternal depression (Edinburgh postnatal depression scale), anxiety (generalized anxiety disorder seven), and somatic symptom burden (somatic symptom scale eight) were examined in two risk samples and one control group in the third trimester of their partners’ pregnancy: risk sample I (n = 41) consist of expectant fathers whose partners were prenatally hospitalized due to medical complications; risk sample II (n = 52) are fathers whose partners were prenatally mentally distressed; and control group (n = 70) are those non-risk pregnancies.
Results
On a purely descriptive level, the data display a trend of higher symptom burden of depression, anxiety, and somatic symptoms in the two risk samples, indicating that expectant fathers, whose pregnant partners were hospitalized or suffered prenatal depression, were more prenatally distressed. Exploratory testing of group differences revealed an almost three times higher prevalence rate of anxiety in fathers whose partner was hospitalized (12.2%) compared to those non-risks (4.3%).
Conclusion
Results underline the need for screening implementations for paternal prenatal psychological distress, as well as specific prevention and treatment programs, especially for fathers in risk situations, such as their pregnant partners’ prenatal hospitalization.
The study was registered with the German clinical trials register (DRKS00020131) on 2019/12/09.
Invasive fungal infections (IFIs) are difficult to diagnose and to treat and, despite several available antifungal drugs, cause high mortality rates. In the past decades, the incidence of IFIs has continuously increased. More recently, SARS-CoV-2-associated lethal IFIs have been reported worldwide in critically ill patients. Combating IFIs requires a more profound understanding of fungal pathogenicity to facilitate the development of novel antifungal strategies. Animal models are indispensable for studying fungal infections and to develop new antifungals. However, using mammalian animal models faces various hurdles including ethical issues and high costs, which makes large-scale infection experiments extremely challenging. To overcome these limitations, we optimized an invertebrate model and introduced a simple calcofluor white (CW) staining protocol to macroscopically and microscopically monitor disease progression in silkworms (Bombyx mori) infected with the human pathogenic filamentous fungi Aspergillus fumigatus and Lichtheimia corymbifera. This advanced silkworm A. fumigatus infection model could validate knockout mutants with either attenuated, strongly attenuated or unchanged virulence. Finally, CW staining allowed us to efficiently visualize antifungal treatment outcomes in infected silkworms. Conclusively, we here present a powerful animal model combined with a straightforward staining protocol to expedite large-scale in vivo research of fungal pathogenicity and to investigate novel antifungal candidates.
Multiple myeloma is a bone marrow plasma cell tumor which is supported by the external growth factors APRIL and IL-6, among others. Recently, we identified eosinophils and megakaryocytes to be functional components of the micro-environmental niches of benign bone marrow plasma cells and to be important local sources of these cytokines. Here, we investigated whether eosinophils and megakaryocytes also support the growth of tumor plasma cells in the MOPC315. BM model for multiple myeloma. As it was shown for benign plasma cells and multiple myeloma cells, IL-6 and APRIL also supported MOPC315. BM cell growth in vitro, IL-5 had no effect. Depletion of eosinophils in vivo by IL-5 blockade led to a reduction of the early myeloma load. Consistent with this, myeloma growth in early stages was retarded in eosinophil-deficient Delta dblGATA-1 mice. Late myeloma stages were unaffected, possibly due to megakaryocytes compensating for the loss of eosinophils, since megakaryocytes were found to be in contact with myeloma cells in vivo and supported myeloma growth in vitro. We conclude that eosinophils and megakaryocytes in the niches for benign bone marrow plasma cells support the growth of malignant plasma cells. Further investigations are required to test whether perturbation of these niches represents a potential strategy for the treatment of multiple myeloma.
The MuvB multiprotein complex, together with B-MYB and FOXM1 (MMB-FOXM1), plays an essential role in cell cycle progression by regulating the transcription of genes required for mitosis and cytokinesis. In many tumors, B-MYB and FOXM1 are overexpressed as part of the proliferation signature. However, the transcriptional targets that are important for oncogenesis have not been identified. Given that mitotic kinesins are highly expressed in cancer cells and that selected kinesins have been reported as target genes of MMB-FOXM1, we sought to determine which mitotic kinesins are directly regulated by MMB-FOXM1. We demonstrate that six mitotic kinesins and two microtubule-associated non-motor proteins (MAPs) CEP55 and PRC1 are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cells.
Suppression of KIF23 and PRC1 strongly suppressed proliferation of MDA-MB-231 cells. The set of MMB-FOXM1 regulated kinesins genes and 4 additional kinesins which we referred to as the mitotic kinesin signature (MKS) is linked to poor outcome in breast cancer patients. Thus, mitotic kinesins could be used as prognostic biomarker and could be potential therapeutic targets for the treatment of breast cancer.
Background
Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation.
Objective
To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke.
Results
In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice.
Conclusion
Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.
In dieser Arbeit wurden die Daten von 90 konsekutiven Patienten mit Multiplem Myelom, welche im Zeitraum vom 11.04.2005 bis zum 08.11.2010 mit einer Hochdosischemotherapie und autologer Stammzelltransplantation in den Kliniken Essen Süd behandelt wurden, retrospektiv untersucht und statistisch ausgewertet. Es konnte gezeigt werden, dass ein gutes Ansprechen nach den Induktionstherapien mit einem guten Ansprechen sechzig Tage nach der Transplantation korreliert. Einen Zusammenhang zwischen dem initialen Ausmaß der Endorganschäden und dem Verlauf oder dem Ansprechen der Hochdosischemotherapie mit autologer Stammzelltransplantation konnte nicht gefunden werden. Das kalendarische Alter spielt im Gegensatz zum Allgemeinzustand und den Vorerkrankungen bei der Einschätzung der zu erwartenden Toxizität eine untergeordnete Rolle. Die beiden Hauptfaktoren, die den Verlauf einer Hochdosischemotherapie mit anschließender peripherer Stammzelltransplantation beeinflussten, waren die Dauer der G-CSF Therapie und die Anzahl der übertragenen Stammzellen. Während die unterschiedlich lange G-CSF Gabe (ab Tag „+3“ vs. Tag „+7“) nur zu einer schnelleren Regeneration der Leukozyten führt und keinen relevanten Effekt auf die untersuchten klinischen Parameter Fieber, Dauer der intravenösen Antibiotikatage, Ausmaß der Mukositis und die Aufenthaltsdauer der Patienten hatte, führte die Steigerung der Anzahl der übertragenen Stammzellen zu einer signifikant schnelleren Regeneration von Thrombozyten und Leukozyten, einem Rückgang der Transfusionshäufigkeit an Erythrozyten und einem geringeren Verbrauch an intravenösen Antibiotika. Zusammenfassend ist die G-CSF Gabe ab Tag „+7“ nach Hochdosistherapie ausreichend, eine längere Gabe erbringt keinen relevanten klinischen Vorteil. Zudem sollte auf eine ausreichende Menge an übertragenen Stammzellen geachtet werden. Zur Beurteilung der zu erwartenden Toxizität ist die Anwendung des HCT-CI-Score einfach und praktikabel.
Im Rahmen dieser Arbeit wurden zunächst bei den gesammelten 14 Tumoren mit einem putativen allelischen Verlust im Bereich 8p21.3-22 nochmals eine LOH-Analyse durchgeführt und die Voruntersuchungen bestätigt. Als zweiter Schritt konnte die Etablierung des MTUS1-Antikörpers erfolgreich durchgeführt werden. Die Paraffinblöcke wurde aus dem Institut für Pathologie herausgesucht und selbstständig Schnitte davon angefertigt. Die immunhistochemische Analyse der MTUS1-Expression ergab einen Expressionsverlust bei 7 von 14 Tumoren und eine Reduktion der Expression bei weiteren 3 der 14 Tumoren. Bei insgesamt 7 von 14 Tumoren scheint somit die Expression von dem allelischen Verlust assoziiert zu sein. Allerdings konnte bei den übrigen 7 Tumoren eine Expression des MTUS1-Gens nachgewiesen werden. Ein allelischer Verlust führt somit nicht immer zu einer Inaktivierung von MTUS1. MTUS1 wird somit nicht immer nach dem klassischen Mechanismen der Knudson-Hypothese (Mutation des ersten Allels gefolgt von der Deletion des zweiten Alles) inaktiviert. Möglicherweise kann in weiteren Studien ein anderes Gen in dem entsprechenden Bereich identifiziert werden, das im Rahmen eines allelischen Verlustes immer komplett inaktiviert wird. Außerdem sollten, da andere Studien eine Relevanz von MTUS1 als Tumorsupressorgen beim kolorektalen Karzinom und auch bei anderen Tumoren zeigen konnten, weitere Studien durchgeführt werden, in denen alternativen Inaktivierungsmechanismen von MTUS1 untersucht werden.
Background: The primary aim of this pilot study was to determine the feasibility and safety of an adoptive transfer and in vivo expansion of human haploidentical gamma delta T lymphocytes.
Methods: Patients with advanced haematological malignancies who are not eligible for allogeneic transplantation received peripheral blood mononuclear cells from half-matched family donors. For that, a single unstimulated leukapheresis product was incubated with both the anti-CD4 and anti-CD8 antibodies conjugated to paramagnetic particles. The depletion procedure was performed on a fully automated CliniMACS (R) device according to the manufacturer's instructions. On average, patients received 2.17 x 10(6)/kg (range 0.9-3.48) γδ T cells with <1% CD4-or CD8-positive cells remaining in the product. All patients received prior lymphopenia-inducing chemotherapy (fludarabine 20-25 mg/m(2) day -6 until day -2 and cyclophosphamide 30-60 mg/kg day -6 and -5) and were treated with 4 mg zoledronate on day 0 and 1.0x10(6) IU/m(2) IL-2 on day +1 until day +6 for the induction of gamma delta T cell proliferation in vivo.
Results: This resulted in a marked in vivo expansion of donor γδ T cells and, to a lower extent, natural killer cells and double-negative αβ T cells (mean 68-fold, eight-fold, and eight-fold, respectively). Proliferation peaked by around day +8 and donor cells persisted up to 28 days. Although refractory to all prior therapies, three out of four patients achieved a complete remission, which lasted for 8 months in a patient with plasma cell leukaemia. One patient died from an infection 6 weeks after treatment.
Conclusion: This pilot study shows that adoptive transfer and in vivo expansion of haploidentical γδ T lymphocytes is feasible and suggests a potential role of these cells in the treatment of haematological diseases.
Aspergillus fumigatus ist ein ubiquitär vorkommender Schimmelpilz, dessen Sporen vom Menschen täglich zu hunderten mit der Atemluft aufgenommen werden. Aufgrund ihrer geringen Größe gelangen die Konidien leicht bis in die Alveolen der Lunge, wo sie normalerweise sofort vom angeborenen Immunsystem beseitigt werden. Immunsupprimierte Menschen leiden an einer qualitativen oder quantitativen Einschränkung dieses Teiles der Immunabwehr, weshalb die Inokulation der Sporen bei ihnen zur Auslösung der lebensgefährlichen Invasiven Aspergillose führen kann, deren Mortalität in der Hochrisikogruppe der Patienten nach hämatopoetischer Stammzelltransplantation über 90% beträgt. Bei diesen Patienten gewinnt die adaptive Immunabwehr an Bedeutung. Dendritische Zellen gehören dem angeborenen Immunsystem an und besitzen einzigartige Fähigkeiten zur Aktivierung und Steuerung der erworbenen Immunabwehr. Durch die Aktivierung naiver T-Zelen und die Sekretion bestimmter immunmodulatorischer Zytokine bestimmen sie die Art der konsekutiv asugelösten T-Helferzellantwort. Lediglich eine T-Helfer 1-Zellantwort wird hierbei mit einer erhöhten Resistenz gegenüber der invasiven Aspergillose in Verbindung gebracht. Die Zytokinsekretion der Dendritischen Zellen wird durch intrazelluläre Signalkaskaden reguliert, welche sich an ihre PRRs anschließen. Für die Erkennung des bakteriellen LPS durch den TLR wurde die Regulation der immunmodulatorischen Zytokine durch die Serin-Threonin-Kinase GSK3 festgestellt. In der vorliegenden Arbeit wurde untersucht, ob es bei der Erkennung von Aspergillus fumigatus durch humane dendritische Zellen ebenfalls einen Zusammenhang mit GSK3 und der Sekretion immunmodulatorischer Zytokine gibt. Dafür wurden aus humanen Monozyten generierte dendritische Zellen mit rekombinanten Antigenen von Aspergillus fumigatus sowie verschiedenen Morphologien stiumuliert und teilweise mit dem GSK3-Inhibitor LiCl gehemmt. Anschließend wurde die Expression bestimmter immunmodulatorischer Zytokine und der GSK3 mittels quantitativer real-time RT-PCR bestimmt. Hierbei konnte für eines der getesteten Antigene, Aspf 1, ein deutlicher Einfluss auf die GSK3-Expression der Zellen festgestellt werden. Ein paralleler Anstieg der Expression proinflammatorischer Zytokine erhärtete die Annahme einer immunregulierenden Rolle der GSK3 bei der Erkennung von Aspergillus fumigatus. Einen deutlicheren Hinweis auf den Zusammenhang zwischen der Aktivität der GSK3 und der Expression proinflammatorischer Zytokine erbrachte die Inhibierung mittels LiCl. Die mit Aspergillus fumigatus stimulierten Zellen reagierten hierauf im Vergleich zu den nicht-inhibierten Zellen mit einer Reduktion der IL12p35-Expression um 86,1% sowie mit einer Reduktion der IL23-Expression um 49,5%. Der letzte Teil der Experimente sollte ausgehend von der Vorstellung, dass verschiedene Aspergillus-Morphologien von unterschiedlichen Rezeptoren erkannt werden quantitative Unterschiede der GSK3-Beteiligung bei der Erkennung von Aspergillus fumigatus durch dendritische Zellen zeigen. Obwohl alle Morphologien des Schimmelpilzes einen Einfluss auf die GSK3-Expression der Zellen zeigten, konnten hierbei keine einheitlichen quantitativen Unterschiede festgestellt werden. Zusammengefasst konnte in der vorliegenden Arbeit die Beteiligung von GSK3 bei der Erkennung von Aspergillus fumigatus durch humane dendritische Zellen gezeigt werden. Außerdem konnten Hinweise auf eine immunregulierende Rolle der GSK3 bei der Abwehr des fakultativ pathogenen Schimmelpilzes erbracht werden, wobei die genaue Einbindung der Serin-Threonin-Kinase in dieser Situation noch unklar ist und weitere Experimente erforderlich macht.
Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001). Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.
Background
The management of rectal cancer (RC) has substantially changed over the last decades with the implementation of neoadjuvant chemoradiotherapy, adjuvant therapy and improved surgery such as total mesorectal excision (TME). It remains unclear in which way these approaches overall influenced the rate of local recurrence and overall survival.
Methods
Clinical, histological and survival data of 658 out of 662 consecutive patients with RC were analyzed for treatment and prognostic factors from a prospectively expanded single-institutional database. Findings were then stratified according to time of diagnosis in patient groups treated between 1993 and 2001 and 2002 and 2010.
Results
The study population included 658 consecutive patients with rectal cancer between 1993 and 2010. Follow up data was available for 99.6% of all 662 treated patients. During the time period between 2002 and 2010 significantly more patients underwent neoadjuvant chemoradiotherapy (17.6% vs. 60%) and adjuvant chemotherapy (37.9% vs. 58.4%). Also, the rate of reported TME during surgery increased. The rate of local or distant metastasis decreased over time, and tumor related 5-year survival increased significantly with from 60% to 79%.
Conclusion
In our study population, the implementation of treatment changes over the last decade improved the patient’s outcome significantly. Improvements were most evident for UICC stage III rectal cancer.
TNF (Tumor Nekrose Faktor) vermittelt seine biologischen Funktionen durch Interaktionen mit TNFR1 (TNFRezeptor 1) und TNFR2 (TNFRezeptor 2). In früheren Arbeiten konnte gezeigt werden, dass der TNFR2 sowohl durch die Induktion von membrangebundenem TNF als auch durch die proteasomale Degradation von TRAF2 (TNFRezeptor-assozierter Faktor 2) die TNFR1-vermittelte Apoptose verstärken kann. Des Weiteren war bekannt, dass TRAF1 (TNFRezeptor-assozierter Faktor 1), ein anderes Mitglied der TRAF-Familie, mit TRAF2 Heterotrimere bilden kann und zudem nach TNF-induzierter NFkappaB- (nuclear factor kappaB) Aktivierung verstärkt exprimiert wird. In der vorliegenden Arbeit konnte nun erstmals gezeigt werden, dass TRAF1 in beide TNFR-Signalkomplexe rekrutiert wird und darin in einem TRAF2/TRAF1-Heterotrimer TRAF2 funktionell ersetzen kann. Darüber hinaus verhindert TRAF1 die Rekrutierung von TRAF2 in lipid rafts sowie dessen anschließende proteasomale Degradation. Auf diese Weise kann TRAF1 die TNFR2-abhängige Verstärkung der TNFR1-induzierten Apoptose verhindern. Im zweiten Teil der vorliegenden Arbeit wurde die TNF-vermittelte Aktivierung der JNK (c-Jun N-terminale Kinase), dessen Regulation durch ROS (reactive oxygen species), Caspasen (Cysteinyl-Aspartat-spezifische Proteasen) sowie NFkappaB-induzierte Faktoren untersucht. TNF induziert in den meisten Zellen zunächst nach zehn bis 30 Minuten eine transiente JNK-Aktivierung, woraufhin bei NFkB-inhibierten Zellen eine zweite andauernde JNK-Aktivierung folgt. Die meisten in der Literatur beschriebenen Studien gehen dabei von einem ROS-abhängigen, Caspase-unabhängigen Mechanismus der persistierenden JNK-Aktivierung aus. Des Weiteren wurde in den vor allem bei embryonale Mausfibroblasten durchgeführten Untersuchungen davon ausgegangen, dass bestimmte NFkappaB-induzierte Radikalfänger die andauernde Aktivierung der JNK verhindern. In dieser Arbeit konnte gezeigt werden, dass in den humanen Zelllinien KB, Jurkat und HaCaT die andauernde Aktivierung der JNK, im Gegensatz zur transienten JNK-Aktivierung, Caspase-abhängig verläuft. Es ergab sich überdies, dass die inhibierende Wirkung des NFkB-Signalweges auf die persistierende JNK-Aktivierung in diesen Zelllinien in erster Linie auf die indirekte Verhinderung der Apoptose durch die Induktion von antiapoptotischen Proteinen wie Flip-L (FLICE-inhibitory protein long) und IAPs (inhibitor of apoptosis) zurückzuführen ist, als auf die direkte Expression von Radikalfängern. Zudem wurde in den untersuchten Zelllinien die Caspase-vermittelte Spaltung von MEKK-1 (MAP/ERK kinase kinase-1) und p21WAF/Cip 1 nachgewiesen, von denen bekannt ist, dass die Spaltprodukte eine JNK-stimulierende Wirkung haben. Dennoch müssen künftige Studien zeigen, ob die Spaltung von p21WAF/Cip 1 und MEKK-1 in Fragmente mit JNK–stimulierender Aktivität oder andere Caspasesubstrate für die Caspase-vermittelte andauernde Aktivierung der JNK verantwortlich sind.
Comparison of nonculture blood-based tests for diagnosing invasive aspergillosis in an animal model
(2016)
The European Aspergillus PCR Initiative (EAPCRI) has provided recommendations for the PCR testing of whole blood (WB) and serum/plasma. It is important to test these recommended protocols on nonsimulated "in vivo" specimens before full clinical evaluation. The testing of an animal model of invasive aspergillosis (IA) overcomes the low incidence of disease and provides experimental design and control that is not possible in the clinical setting. Inadequate performance of the recommended protocols at this stage would require reassessment of methods before clinical trials are performed and utility assessed. The manuscript describes the performance of EAPCRI protocols in an animal model of invasive aspergillosis. Blood samples taken from a guinea pig model of IA were used for WB and serum PCR. Galactomannan and beta-D-glucan detection were evaluated, with particular focus on the timing of positivity and on the interpretation of combination testing. The overall sensitivities for WB PCR, serum PCR, galactomannan, and beta-D-glucan were 73%, 65%, 68%, and 46%, respectively. The corresponding specificities were 92%, 79%, 80%, and 100%, respectively. PCR provided the earliest indicator of IA, and increasing galactomannan and beta-D-glucan values were indicators of disease progression. The combination of WB PCR with galactomannan and beta-D-glucan proved optimal (area under the curve AUC], 0.95), and IA was confidently diagnosed or excluded. The EAPRCI-recommended PCR protocols provide performance comparable to commercial antigen tests, and clinical trials are warranted. By combining multiple tests, IA can be excluded or confirmed, highlighting the need for a combined diagnostic strategy. However, this approach must be balanced against the practicality and cost of using multiple tests.
The COVID-19 pandemic has resulted in large numbers of patients requiring critical care management. With the established association between severe respiratory virus infection and invasive pulmonary aspergillosis (7.6% for COVID-19-associated pulmonary aspergillosis (CAPA)), the pandemic places a significant number of patients at potential risk from secondary invasive fungal disease. We described a case of CAPA with substantial supporting mycological evidence, highlighting the need to employ strategic diagnostic algorithms and weighted definitions to improve the accuracy in diagnosing CAPA.
Reliable standards and criteria for somatostatin receptor (SSTR) positron emission tomography (PET) are still lacking. We herein propose a structured reporting system on a 5-point scale for SSTR-PET imaging, titled SSTR-RADS version 1.0, which might serve as a standardized assessment for both diagnosis and treatment planning in neuroendocrine tumors (NET). SSTR-RADS could guide the imaging specialist in interpreting SSTR-PET scans, facilitate communication with the referring clinician so that appropriate work-up for equivocal findings is pursued, and serve as a reliable tool for patient selection for planned Peptide Receptor Radionuclide Therapy.
More than 25 years after the first peptide receptor radionuclide therapy (PRRT), the concept of somatostatin receptor (SSTR)-directed imaging and therapy for neuroendocrine tumors (NET) is seeing rapidly increasing use. To maximize the full potential of its theranostic promise, efforts in recent years have expanded recommendations in current guidelines and included the evaluation of novel theranostic radiotracers for imaging and treatment of NET. Moreover, the introduction of standardized reporting framework systems may harmonize PET reading, address pitfalls in interpreting SSTR-PET/CT scans and guide the treating physician in selecting PRRT candidates. Notably, the concept of PRRT has also been applied beyond oncology, e.g. for treatment of inflammatory conditions like sarcoidosis. Future perspectives may include the efficacy evaluation of PRRT compared to other common treatment options for NET, novel strategies for closer monitoring of potential side effects, the introduction of novel radiotracers with beneficial pharmacodynamic and kinetic properties or the use of supervised machine learning approaches for outcome prediction. This article reviews how the SSTR-directed theranostic concept is currently applied and also reflects on recent developments that hold promise for the future of theranostics in this context.
C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.
Both prostate-specific membrane antigen (PSMA)- and somatostatin receptor (SSTR)-targeted positron emission tomography (PET) imaging agents for staging and restaging of prostate carcinoma or neuroendocrine tumors, respectively, are seeing rapidly expanding use. In addition to diagnostic applications, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy. While interpreting PSMA- or SSTR-targeted PET/computed tomography (CT) scans, the reader has to be aware of certain pitfalls. Adding to the complexity of the interpretation of those imaging agents, both normal biodistribution, and also false-positive and -negative findings differ between PSMA- and SSTR-targeted PET radiotracers. Herein summarized under the umbrella term molecular imaging reporting and data systems (MI-RADS), two novel RADS classifications for PSMA- and SSTR-targeted PET imaging are described (PSMA- and SSTR-RADS). Both framework systems may contribute to increase the level of a reader’s confidence and to navigate the imaging interpreter through indeterminate lesions, so that appropriate workup for equivocal findings can be pursued. Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e. if the reader is familiar with one system, the other system can readily be applied as well. In the present review we will discuss the most common pitfalls on PSMA- and SSTR-targeted PET/CT, briefly introduce PSMA- and SSTR-RADS, and define a future role of the umbrella framework MI-RADS compared to other harmonization systems.
Standardized reporting is more and more routinely implemented in clinical practice and such structured reports have a major impact on a large variety of medical fields, e.g. laboratory medicine, pathology, and, recently, radiology. Notably, the field of nuclear medicine is constantly evolving, as novel radiotracers for numerous clinical applications are developed. Thus, framework systems for standardized reporting in this field may a) increase clinical acceptance of new radiotracers, b) allow for inter- and intra-center comparisons for quality assurance, and c) may be used in (global) multi-center studies to ensure comparable results and enable efficient data abstraction. In the last two years, several standardized framework systems for positron emission tomography (PET) radiotracers with potential theranostic applications have been proposed. These include systems for prostate-specific membrane antigen (PSMA)-targeted PET agents for the diagnosis and treatment of prostate cancer (PCa) and somatostatin receptor (SSTR)-targeted PET agents for the diagnosis and treatment of neuroendocrine neoplasias. In the present review, those standardized framework systems for PSMA- and SSTR-targeted PET will be briefly introduced followed by an overview of their advantages and limitations. In addition, potential applications will be defined, approaches to validate such concepts will be proposed, and future perspectives will be discussed.
Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of \(^{99m}\)Tc-mercaptoacetyltriglycine (\(^{99m}\)Tc-MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq \(^{177}\)Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3%, range: -27% to +19%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by \(^{99m}\)Tc-MAG3clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.
Körperpsychotherapie etabliert sich zunehmend und ist keine neue Entdeckung. Bereits vor über 120 Jahren war bekannt, dass über den Körper die Psyche erreicht werden kann und damit die verbale Psychotherapie effektiver und gegebenenfalls erst möglich wurde. Wissenschaftliche Untersuchungen sprechen dafür, dass Körperpsychotherapie heute als fünfte Säule der allgemein anerkannten psychotherapeutischen Verfahren (PA, TP, VT, ST) angesehen werden kann. Sie hat sich aus der atemtherapeutischen und der Bewegung der Gymnastik sowie der Verwendung in der Psychoanalyse entwickelt. Sie ist weitestgehend in die tiefenpsychologische und verhaltenstherapeutische Psychotherapie integriert und kann zu den humanistischen Verfahren gezählt werden. Anwendung findet die Körperpsychotherapie beispielsweise in der Psychosomatischen Medizin sowie auf verschiedenen Gebieten der Psychotherapie. Laut den hier vorgelegten Befunden erreicht die Arbeit am Körper nonverbal Verarbeitetes, das sich tief in das implizite Körpergedächtnis eingegraben hat, lange bevor ein junger Mensch das Sprechen erlernte. Eine Möglichkeit, dies konzeptuell einzuordnen und therapeutisch nutzbar zu machen, ist das Modell der „verkörperten Selbstwahrnehmung“ nach Fogel, das Teile des Körperschemas beinhaltet. In der Bindungsbeziehung nicht adäquates Eingehen auf die kindlichen Bedürfnisse hat weitreichende Folgen auf das weitere Leben. In Untersuchungen konnte gezeigt werden, wie sich Störungen in der Entwicklung eines Kindes in Form von Körperschemastörungen und Körperdissoziationen, in Emotionsregulations- und als Entwicklungstraumastörung manifestieren können. Diese sind weit verbreitet und Teil einer Gesellschaft, die auf Leistung und Effizienz ausgerichtet ist und in Zusammenhang mit chronischem Stress stehen. Evolutionsgeschichtlich begründete Überlebensmuster werden durch chronischen Stress aktiviert und sind Ursache zahlreicher Erkrankungen. Hierfür liefert Porges mit seiner Polyvagal-Theorie einen neuen neurobiologischen Erklärungsansatz. Durch eine Imbalance stressauslösender und entspannender Faktoren zugunsten des Stresses werden körpereigene Selbstheilungskräfte der Selbstregulation verhindert und die Resilienzfähigkeit eingeschränkt. Selbstregulation und Resilienz sind vorhanden, wenn das Ruhe- und Bindungssystem dominiert im Gegensatz zur Kampf-, Flucht- und Erstarrungsreaktion. In seiner Hypothese zeigt Porges auf, wie das autonome Nervensystem Verhaltensweisen beeinflusst und wie diesen begegnet werden kann. Durch den sympathischen Zweig wird die An- und Verspannungsreaktion auf körperlicher Seite mit den auch auf der psychischen Seite verbundenen Reaktionen vermittelt. Diesem kann durch die parasympathisch vermittelte Oxytocin-Freisetzung begegnet werden. Durch eine Balance dieser beiden Waagschalen kann körperliche und seelische Gesundheit sowie Resilienzfähigkeit gefördert werden. Die Körperpsychotherapie bietet auch aus meiner Sicht eine noch unterschätzte Möglichkeit, die Balance wieder herzustellen. Eine Methode, die positive durch Oxytocin vermittelte heilsame Reaktionen in Gang zu setzt, stellt die berührende Körperarbeit dar wie sie beispielsweise nach der Rosen-Methode praktiziert wird. Körperpsychotherapie im Allgemeinen kann in der Behandlung von Depressionen, Angst- und psychosomatischen Störungen hilfreich sein. Sie ist empirisch in einer umfassenden Theorie begründet und fundiert auf neurobiologischen und neurowissenschaftlichen Erkenntnissen. Aus Sicht der Autorin handelt es sich bei der Körperpsychotherapie angesichts der vorliegenden Befunde und theoretischen Wirkkonzepte um einen therapeutischen Ansatz, der wesentlich dazu beitragen kann, die Behandlung psychischer Störungen kosteneffizienter und wirksamer zu gestalten. Um differenzierter zwischen theoretischem Potential und tatsächlich nachweisbaren Effekten körperpsychotherapeutischer Methoden unterscheiden zu können, ist es aus meiner Sicht dringend zu empfehlen, körperpsychotherapeutische Arbeitsansätze exakter zu erforschen. Beispielsweise wäre es lang- oder mittelfristig auch wünschenswert, Forschungsdaten für eine präzisere Indikationsstellung zur Verfügung zu haben. Dabei wäre beispielweise zu klären, welche Verfahren für welche Störungsbilder, in welchem Behandlungssetting und für welche Behandlungsdauer in Frage kommen. Auch fehlen hinsichtlich der Kontraindikationen belastbare Forschungsdaten zu den oben benannten Empfehlungen diverser Vertreter der Körperpsychotherapie. Aufgrund des hohen Erklärungspotentials für das individuelle Erleben psychisch beeinträchtigter Personen, das beispielsweise die Polyvagal-Theorie nach Porges oder die verkörperte Selbstwahrnehmung nach Fogel bieten, erscheint mir auch die Forderung nach einer Berücksichtigung körperpsychotherapeutischer Theorien und Methoden in der Ausbildung von Ärzten und Psychologen nachvollziehbar und sinnvoll. Aufgrund der in dieser Arbeit zusammengetragenen Ergebnisse halte ich es für dringend empfehlenswert, die Körperpsychotherapie als eigenständiges Behandlungselement in die fachgerechte Versorgung psychisch Erkrankter aufzunehmen, sofern keine der erwähnten Kontraindikationen dem widersprechen.
INTRODUCTION:
The aim of this study was to evaluate the safety and efficacy of rituximab (RTX) in a large cohort of patients with rheumatoid arthritis in routine care, and to monitor changes in daily practice since the introduction of RTX therapy.
METHODS:
This was a multicentre, prospective, non-interventional study conducted under routine practice conditions in Germany. Efficacy was evaluated using Disease Activity Score in 28 joints (DAS28) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Safety was assessed by recording adverse drug reactions (ADRs). Physician and patient global efficacy and tolerability assessments were also evaluated.
RESULTS:
Overall, 2,484 patients (76.7% female, mean age 56.4 years, mean disease duration 11.7 years) received RTX treatment (22.7% monotherapy). The total observation period was approximately six-years (median follow-up 14.7 months). RTX treatment led to improvements in DAS28 and HAQ-DI that were sustained over multiple courses. DAS28 improvements positively correlated with higher rheumatoid factor levels up to 50 IU/ml. Response and tolerability were rated good/very good by the majority of physicians and patients. Mean treatment intervals were 10.5 and 6.8 months for the first and last 400 enrolled patients, respectively. Infections were the most frequently reported ADRs (9.1%; 11.39/100 patient-years); approximately 1% of patients per course discontinued therapy due to ADRs.
CONCLUSIONS:
Prolonged RTX treatment in routine care is associated with good efficacy and tolerability, as measured by conventional parameters and by physicians' and patients' global assessments. Rheumatoid factor status served as a distinct and quantitative biomarker of RTX responsiveness. With growing experience, physicians repeated treatments earlier in patients with less severe disease activity.
Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines
(2020)
Approximately 20% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRAS\(^{p.G12C}\) entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRAS\(^{p.G12A}\) and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRAS\(^{WT}\), KRAS\(^{p.G12A}\), KRAS\(^{p.A146T}\), and KRAS\(^{p.A146V}\) were overexpressed in HEK293 cells and the KRAS\(^{WT}\) MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.
Bei Patienten mit Erkrankungen des blutbildenden Systems ist die hämatopoetische Stammzelltransplantation (HSZT) eine häufig eingesetzte kurative Therapie. Im Rahmen dieser Transplantation werden nicht nur vom Spender gewonnene hämatopoetische Stammzellen auf den Empfänger übertragen, sondern immer auch im peripheren Blut vorhandene T-Zellen. Dies kann zum einen einen positiven Effekt zum anderen aber auch negative Folgen für den transplantierten Patienten mit sich bringen. Eine negative Auswirkung wäre die sogenannte Graft-vesus-Host Disease (GvHD), bei der die T-Zellen des Spenders Zellen des Empfängers als fremd erkennen und angreifen. Klinisch manifestiert sich dies vor allem an Leber, Haut und Darm mit Ikterus, Dermatitiden und Diarrhoen. Einen gewünschten Effekt, den die übertragenen T-Zellen vor allem bei Patienten mit akuter myeloischer Leukämie (AML) mit sich bringen können, ist der sogenannte Graft-versus-Leukemia (GvL) Effekt. Dabei richten sich vom Spender stammende Immunzellen gegen die Tumorzellen des Empfängers und senken damit das Rezidivrisiko der Leukämie.
In verschiedenen Studien konnte eine positive Korrelation von CMV-Reaktivierung nach HSZT und einem niedrigerem Rezidivrisiko der hämatopoetischen Grunderkrankung gezeigt werden. Diese Doktorarbeit widmet sich auf Grundlage dessen der Frage, ob Cytomegalievirus (CMV)-spezifische cytotoxische T-Zellen (CTL) direkt durch Kreuzreaktivität zum GvL-Effekt beitragen.
Zunächst wurden periphere mononukleäre Zellen (PBMC) aus dem Blut neun gesunder Spender isoliert, die als CMV-seropositiv ausgetestet wurden. Diese wurden mit dem CMVpp65-(NLVPMVATV)-Einzelpeptid stimuliert und in Kultur angereichert. Zusätzlich wurden die expandierten CMV-spezifischen CTL durch eine spezifische Selektion über den Aktivierungsmarker CD137 weiter angereichert. Nach Expansion und Anreicherung zeigten jeweils 75% (Spender 1), 67% (Spender 2), 74% (Spender 3), 86% (Spender 4), 81% (Spender5), 80% (Spender 6), 84% (Spender 7), 51% (Spender 8) und 69% (Spender 9) der CD3+/CD8+-T-Zellen eine IFN-γ-Produktion und CD107a-Expression nach Stimulation mit dem CMVpp65-Einzelpeptid. IFN-γ als Effektormolekül der zytotoxischen Granula der CTL und CD107a als Degranulationsmarker beweisen die spezifische Zytotoxizität. Somit konnte die erfolgreiche Anreicherung funktionsfähiger CMVpp65-spezifischer CTL gezeigt werden. Um zu untersuchen, ob diese nun kreuzreaktiv tumorassoziierte Antigene (TAA) erkennen, wurden sie ebenfalls mit folgenden TAA stimuliert: WT1, Proteinase 3, PRAME, NY-ESO, Muc1 und Bcl-2. Die Stimulation erfolgte entweder über die direkte Zugabe von Einzelpeptiden bzw. Peptidpools oder über die Beladung und Präsentation dieser Peptide bzw. Peptidpools über dendritische Zellen (DC). Die DC wurden aus Monozyten des jeweiligen Spenders generiert. Im Falle von drei Spendern zeigt sich ebenfalls eine deutliche zytotoxische Funktion nach Stimulation mit dem WT1-(DFKDCERRF)-Einzelpeptid durch IFN-γ-Produktion und CD107a-Expression bei 75% (Spender 1), 35% (Spender 4) und 33% (Spender 7) der CD3+/CD8+-T-Zellen. Wie zuvor erwähnt lag der Anteil der CD3+/CD8+-T-Zellen mit spezifischer Zytotoxizität nach Stimulation mit dem CMVpp65-(NLVPMVATV)-Einzelpeptid bei diesen drei besagten Spendern bei 74% (Spender1), 86% (Spender 4) und 84% (Spender7). So ergab sich für diese drei Spender eine gemeinsame Schnittmenge von 48,92% (Spender 1), 21,07% (Spender 4) und 17,45% (Spender 7) derjenigen Zellen, die sowohl nach Stimulation mit CMVpp65-(NLVPMVATV)-Einzelpeptid und WT-(DFKDCERRF)-Einzelpeptid eine zytotoxische Funktion zeigten, sodass von einer kreuzreaktiven Erkennung dieser beiden Peptide in diesen drei Spendern ausgegangen werden muss. Die für diese Spender gezeigte kreuzreaktive Erkennung könnte zum GvL-Effekt bei Leukämie/Myelom-Patienten nach HSZT beitragen.
The human pathogen Aspergillus (A.) fumigatus is a fungal mold that can cause severe infections in immunocompromised hosts. Pathogen recognition and immune cell cross-talk are essential for clearing fungal infections efficiently. Immune cell interactions in particular may enhance individual cell activation and cytotoxicity towards invading pathogens.
This study analyzed the reciprocal cell activation of natural killer (NK) cells and monocyte-derived dendritic cells (moDCs) after stimulation with A. fumigatus cell wall fractions and whole-cell lysates. Furthermore, the impact of the on moDCs expressed fungal receptors Dectin-1 and TLR-2 on NK cell activation was analyzed. Stimulation of moDCs with ligands for Dectin-1 and TLR-2 and transfer of soluble factors on autologous NK cells showed that moDCs could induce NK cell activation solely by secreting factors. In summary, both cell types could induce reciprocal cell activation if the stimulated cell type recognized fungal morphologies and ligands. However, moDCs displayed a broader set of A. fumigatus receptors and, therefore, could induce NK cell activation when those were not activated by the stimulus directly.
Consequently, new fungal receptors should be identified on NK cells. The NK cell characterization marker CD56 was reduced detected in flow cytometry after fungal co-culture. Notably, this decreased detection was not associated with NK cell apoptosis, protein degradation, internalization, or secretion of CD56 molecules. CD56 was shown to tightly attach to hyphal structures, followed by its concentration at the NK-A. fumigatus interaction site. Actin polymerization was necessary for CD56 relocalization, as pre-treatment of NK cells with actin-inhibitory reagents abolished CD56 binding to the fungus. Blocking of CD56 suppressed fungal mediated NK cell activation and secretion of the immune-recruiting chemokines MIP-1α, MIP-1β, and RANTES, concluding that CD56 is functionally involved in fungal recognition by NK cells.
CD56 binding to fungal hyphae was inhibited in NK cells obtained from patients during immune-suppressing therapy after allogeneic stem cell transplantation (alloSCT). Additionally, reduced binding of CD56 correlated with decreased actin polymerization of reconstituting NK cells challenged with the fungus. The immune-suppressing therapy with corticosteroids negatively influenced the secretion of MIP-1α, MIP-1β, and RANTES in NK cells after fungal stimulation ex vivo. Similar results were obtained when NK cells from healthy donors were treated with corticosteroids prior to fungal co-culture. Thus, corticosteroids were identified to have detrimental effects on NK cell function during infection with A. fumigatus.
Non-Alcoholic Fatty Liver Disease Epidemiology, Clinical Course, Investigation, and Treatment
(2014)
Background: The global obesity epidemic has increased the prevalence of fatty liver disease. At present, 14% to 27% of the general population in the industrialized world has non-alcoholic fatty liver disease (NAFLD).
Methods: We review pertinent publications retrieved by a selective search of the PubMed database for the years 1995 to 2013.
Results: The term “non-alcoholic fatty liver disease” covers cases of a wide spectrum of severity, ranging from bland fatty liver without any inflammation and with little or no tendency to progress all the way to non-alcoholic steatohepatitis (NASH) with inflammatory reactions and hepatocyte damage, with or without fibrosis. Some 5% to 20% of patients with NAFLD develop NASH, which undergoes a further transition to higher-grade fibrosis in 10% to 20% of cases. In fewer than 5% of cases, fibrosis progresses to cirrhosis. These approximate figures lead to an estimate of 0.05% to 0.3% for the prevalence of cirrhosis in the general population. About 2% of all cirrhosis patients per year develop hepatocellular carcinoma. The diagnosis of fatty liver disease can be suspected initially on the basis of abnormally high aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) levels and abnormal ultrasonographic findings. The positive predictive value of an ultrasonographic study for mild steatosis is 67% at most. The NAFLD fibrosis score, which is computed on the basis of multiple parameters (age, body-mass index, diabetes status, ASAT, ALAT, platelet count, and albumin level), has a positive predictive value of 82% to 90% and a negative predictive value of 88% to 93%. Liver biopsy is the gold standard for diagnosis but should be performed sparingly in view of its rare but sometimes life-threatening complications, such as hemorrhage. The treatment of NAFLD and NASH consists mainly of changes in lifestyle and nutrition.
Conclusion: NAFLD can, in principle, be reversed. This is only possible with weight reduction by at least 3% to 5%.
Delayed natural killer (NK) cell reconstitution after allogeneic stem cell transplantation (alloSCT) is associated with a higher risk of developing invasive aspergillosis. The interaction of NK cells with the human pathogen Aspergillus (A.) fumigatus is mediated by the fungal recognition receptor CD56, which is relocated to the fungal interface after contact. Blocking of CD56 signaling inhibits the fungal mediated chemokine secretion of MIP-1α, MIP-1β, and RANTES and reduces cell activation, indicating a functional role of CD56 in fungal recognition. We collected peripheral blood from recipients of an allograft at defined time points after alloSCT (day 60, 90, 120, 180). NK cells were isolated, directly challenged with live A. fumigatus germ tubes, and cell function was analyzed and compared to healthy age and gender-matched individuals. After alloSCT, NK cells displayed a higher percentage of CD56\(^{bright}\)CD16\(^{dim}\) cells throughout the time of blood collection. However, CD56 binding and relocalization to the fungal contact side were decreased. We were able to correlate this deficiency to the administration of corticosteroid therapy that further negatively influenced the secretion of MIP-1α, MIP-1β, and RANTES. As a consequence, the treatment of healthy NK cells ex vivo with corticosteroids abrogated chemokine secretion measured by multiplex immunoassay. Furthermore, we analyzed NK cells regarding their actin cytoskeleton by Structured Illumination Microscopy (SIM) and flow cytometry and demonstrate an actin dysfunction of NK cells shown by reduced F-actin content after fungal co-cultivation early after alloSCT. This dysfunction remains until 180 days post-alloSCT, concluding that further actin-dependent cellular processes may be negatively influenced after alloSCT. To investigate the molecular pathomechansism, we compared CD56 receptor mobility on the plasma membrane of healthy and alloSCT primary NK cells by single-molecule tracking. The results were very robust and reproducible between tested conditions which point to a different molecular mechanism and emphasize the importance of proper CD56 mobility.
Humane artifizielle Vollhautmodelle gewinnen im Bereich des Tissue Engineerings zunehmend an Bedeutung und werden mittlerweile in vielen verschiedenen Fachbereichen erforscht, optimiert und sogar als die Grundlagenforschung unterstützende Tierersatzmodelle angewendet. Dieses geht mit hohen Ansprüchen an Qualität und Reproduzierbarkeit dergleichen einher. In der vorliegenden Arbeit wurde erstmals der Einfluss von Kulturbedingen und Spendermaterial auf die Qualität humaner in vitro hergestellter Vollhautmodelle systematisch untersucht. Dazu wurde zunächst ein Katalog an histomorphologischen Qualitätskriterien erarbeitet, der sich an echten humanen Hautbiopsien orientierte und eine Gewichtung dieser Kriterien im Hinblick auf die Verwendung als echte Hautersatzmodelle erlaubte. Für die Herstellung der Hautmodelle wurden die etablierten Medien KGM 2 , KGM 2 variant und EpiLife ® und deren Kultivierungsprotokolle verwendet. Die zelluläre Grundlage der vorliegenden Untersuchungen bildeten die Präputien von sechzehn Kindern nach Zirkumzision. Keratinozyten und Fibroblasten wurden isoliert und mit den drei oben genannten Medien und zugrundeliegenden Kultivierungsprotokollen wurden in jeweils dreifacher Ausführung insgesamt 144 humane Vollhautmodelle erstellt, welche dann entsprechend des Bewertungskataloges beurteilt wurden. Die zugrunde gelegten Bewertungs- und Gütekriterien entsprachen histomorphologischen Parametern. Dazu gehörten die Dicke von Epidermis und Dermis, die Adhärenz zwischen Epidermis und Dermis sowie die Abwesenheit von Zellkernen im Stratum corneum der Epidermis.
Für die Analyse der Einflussfaktoren Spenderalter und Kultivierungsmedium wurden Regressionsmodelle mittels Generalized Estimating Equations angewandt. Das Spenderalter und das Kultivierungsmedium wurden dabei unabhängig voneinander in einer univariaten Analyse untersucht. Bei der Untersuchung des Einflusses des Kulturmediums auf die terminale Differenzierung innerhalb der Epidermis zeigte sich, dass durch Kultivierung mit EpiLife ® signifikant weniger Vollhautmodelle mit Zellkernen im Stratum corneum hergestellt wurden, im Vergleich zur Kultur mit KGM 2 oder KGM 2 variant. Der Einfluss des Kulturmediums auf die Epidermis- und Dermis-Dicke war jeweils nicht signifikant. Trotzdem zeigte sich ein Trend mit einer dünneren Epidermis und Dermis nach EpiLife ® -Kultivierung. Bei der Analyse des Spenderalters konnte ein positiver Einfluss eines jüngeren Spenders auf die Dicke der Epidermis im Vollhautmodell gezeigt werden. Die Epidermis-Dicke war signifikant größer, je jünger ein Vorhautspender war. Ein höheres Spenderalter dagegen führte zu signifikant weniger Ablösung der Epidermis von der Dermis. Keinen Einfluss hatte das Spenderalter auf die Dermis-Dicke und auf die Abwesenheit von Zellkernen in der Hornschicht. Die drei signifikanten Assoziationen in der univariaten Analyse wurden in einer multivariablen Analyse untersucht. Hierbei zeigte sich der Einfluss des Spenderalters auf die Epidermis-Dicke und die dermo-epidermale Adhäsion unter Einfluss der Kulturmedien, der Abwesenheit von Zellkernen in der Hornschicht und der Dermis-Dicke als Kovariablen ebenfalls signifikant. Auch blieb der Einfluss von EpiLife ® auf die Abwesenheit von Zellkernen in der Hornschicht in der multivariablen Analyse signifikant. Es konnte hierbei außerdem ein signifikanter Einfluss der Dermis auf die Epidermis mit Schrumpfung der Epidermis bei Größerwerden der Dermis gezeigt werden. In einer durchgeführten komplexen statistischen Analyse mittels General Linear Model wurde der Einfluss einer Spender-Medium-Interaktion analysiert, ohne das Spenderalter als Variable mit einzubeziehen. Es zeigte sich ein signifikanter Einfluss der Interaktion des Spenders mit dem Kulturmedium auf die Epidermisund Dermis-Dicke und damit auf die Qualität der in vitro hergestellten Vollhautmodelle. Einerseits bestand also ein unabhängiger Einfluss des Spenderalters und des Mediums, andererseits gab es einen Einfluss von der Abhängigkeit einer optimalen Spender-Medium-Kombination auf die Vollhautmodellqualität.
Zusammenfassend konnte in der vorliegenden Arbeit erstmals das komplexe Zusammenspiel von Spenderfaktoren und Kultivierungsbedingungen und deren Auswirkungen auf die Qualität von humanen Vollhautmodellen aufgezeigt werden. Diese Ergebnisse haben Relevanz für den Einsatz dieser Modelle als Tierersatzmodelle in der Forschung. Unter Berücksichtigung dieser Ergebnisse können optimierte organotypische Vollhautmodelle in vitro hergestellt werden, sodass zukünftig komplexere Hautmodelle generiert werden können. In einer Folgearbeit sollen die hier erarbeiteten Grundlagen helfen, Hautmodelle in der Erforschung der akuten GvHD der Haut zu bearbeiten.
Loss of Somatostatin Receptor 2 (SSTR2) expression and rising CXC Chemokine Receptor Type 4 (CXCR4) expression are associated with dedifferentiation in neuroendocrine tumors (NET). In NET, CXCR4 expression is associated with enhanced metastatic and invasive potential and worse prognosis but might be a theragnostic target. Likewise, activation of Wnt/β-catenin signaling may promote a more aggressive phenotype in NET. We hypothesized an interaction of the Wnt/β-catenin pathway with CXCR4 expression and function in NET. The NET cell lines BON-1, QGP-1, and MS-18 were exposed to Wnt inhibitors (5-aza-CdR, quercetin, and niclosamide) or the Wnt activator LiCl. The expressions of Wnt pathway genes and of CXCR4 were studied by qRT-PCR, Western blot, and immunohistochemistry. The effects of Wnt modulators on uptake of the CXCR4 ligand [\(^{68}\)Ga] Pentixafor were measured. The Wnt activator LiCl induced upregulation of CXCR4 and Wnt target gene expression. Treatment with the Wnt inhibitors had opposite effects. LiCl significantly increased [\(^{68}\)Ga] Pentixafor uptake, while treatment with Wnt inhibitors decreased radiopeptide uptake. Wnt pathway modulation influences CXCR4 expression and function in NET cell lines. Wnt modulation might be a tool to enhance the efficacy of CXCR4-directed therapies in NET or to inhibit CXCR4-dependent proliferative signaling. The underlying mechanisms for the interaction of the Wnt pathway with CXCR4 expression and function have yet to be clarified.
Das Ficksche Prinzip gilt als der Goldstandard der Bestimmung des Herzminutenvolumens. Neben der invasiven Bestimmung über einen Pulmonaliskatheter steht die nicht-invasive Rückatmungsmethode (Rebreahting) zur Verfügung. Bereits 1996 ist von FW Schardt eine weitere nicht-invasive ergospirometrische Variante vorgestellt worden, die ohne Rückatmung auskommt. Hier wird der gemischt-venösen Kohlendioxidgehalt basierend auf den Kohlendioxidverbrauch berechnet. Ziel der Arbeit ist eine vergleichende Darstellung der Bestimmungsmethode nach Schardt mit dem als Referenzmethode dienenden Rückatmungsverfahren. Besonderes Augenmerk wird auf Messungen unter hohen Belastungen gelegt, denn hier neigt das Rebreathingverfahren zur Unterschätzung des Herzminutenvolumens, zudem wird die Rückatmung selbst für den Patienten unerträglich. Parallel wurde bei 36 Probanden das Herzminutenvolumen sowohl durch Rebreathing (Qt) wie auch nach Schardt (HMV) ergospirometrisch auf dem Fahrradergometer (in 50 Watt Stufen) bis maximal 350 Watt bestimmt. Ausgewertet wurde die absolute bzw. prozentuale Abweichung des HMV von Qt, sowie HMV vom Mittelwert beider Methoden nach Bland/Altman bzw. Critchley/Critchley. Unter Einbeziehung der Ergebnisse aller Belastungsstufen wird deutlich, dass die Werte für HMV bei niedrigeren Ausgangswerten unter den Werten der Rückatmungsmethode (Qt) liegen. Dagegen werden bei hohen Belastungen für HMV höhere Werte berechnet als für Qt. Die größten Abweichungen sind in Ruhe die zu erkennen. Die Abweichung des HMV vom Mittelwert beider Methoden liegt in Ruhe im Mittel bei 18,8%, unter niedriger Belastung bei 8,7-9,4%. Die Grenzen der Übereinstimmung überschreiten jedoch die Grenzen der Genauigkeit. Die niedrigsten Abweichungen sind bei mittelschwerer Belastung (150-200 Watt) zu verzeichnen, sowie geringe Abweichungen unter sehr hoher Belastung (1,2-4,0%). Die Grenzen der Übereinstimmung liegen innerhalb der Grenzen der Genauigkeit. Die prozentuale Abweichung der Ergebnisse für das Herzminutenvolumen nach Schardt vom Mittelwert beider Methoden liegt über allen Belastungsstufen innerhalb der von Critchley und Critchley geforderten +/- 20 Prozent. Insgesamt konnte gezeigt werden, dass die Methode nach Schardt eine Variante des Fickschen Prinzips liefert, die als einfache, nicht invasive Maßnahme auch unter hoher Belastung und bei wiederholten Messungen anwendbar ist und insbesondere unter mittleren und hohen Belastungen mit der Rebreathingmethode austauschbar ist.
2009 wurde die deutsche S3-Leitlinie „Helicobacter pylori und gastroduodenale Ulkuskrankheit“ publiziert, in der klare Empfehlungen für die Diagnostik, die Indikationen für eine Eradikation, die Therapie und das Follow-Up beschrieben sind. Das Management der H. pylori Infektion im praktischen Alltag zeigt nach dieser Arbeit indessen ein anderes Bild. Ein Optimierungsbedarf für die Zukunft kann daraus abgeleitet werden.
Diese Arbeit beschäftigt sich mit dem poststationären Management von Patienten mit einer H. pylori Infektion im Raum Aschaffenburg. Hierzu wurden 199 Patienten identifiziert, bei denen im Rahmen eines stationären Aufenthaltes im Klinikum Aschaffenburg im Jahr 2011 eine H. pylori Infektion diagnostiziert worden war. Aus den Patientenakten wurden alle relevanten Daten entnommen, wie zum Beispiel Diagnose, Indikation zur H. pylori Eradikation und deren stationäre Initiierung beziehungsweise Empfehlung an den Hausarzt. Nachfolgend wurden die 97 Hausärzte der 199 Patienten angeschrieben und um das ausfüllen eines Fragebogens gebeten. Dieser enthielt sechs Fragen zum poststationären Management der Patienten mit H. pylori Infektion.
Während des stationären Aufenthaltes war bei 88/199 Patienten (44,2%) die Eradikationstherapie begonnen und bei 24 von ihnen (12,1%) bereits abgeschlossen worden. Bei den anderen 64 Patienten sollte die Medikation ambulant fortgeführt werden. Bei 77 Patienten (38,7%) wurde dem Hausarzt die Einleitung einer ambulanten Eradikationsbehandlung empfohlen. 34 Patienten verließen das Krankenhaus ohne Therapie und auch ohne entsprechende Therapieempfehlung.
Die Rücklaufquote der Fragebögen betrug 46,2% (92 von 199 Patienten). Die nachfolgenden Ergebnisse beziehen sich auf diese 92 Patienten (entspricht 100%). Zwei Drittel der Patienten (n=61) stellten sich direkt im Anschluss an die Entlassung aus stationärer Behandlung ihrem Hausarzt vor. Bei 30 Patienten führte der Hausarzt die stationäre begonnene Eradikationstherapie fort (32,6%) oder initiierte sie bei 28 Patienten selbst (30,4%). 17 Patienten erhielten keine Eradikation (18,5%). Die Gründe hierfür waren unterschiedlich, am häufigsten lag ein Informationsdefizit zwischen Klinik und Hausarzt vor. Die französische Triple-Therapie wurde mit 39 mal am häufigsten verordnet, die italienische Triple-Therapie wurde 20 Patienten verschrieben. Andere Behandlungsprotokolle fanden nur vereinzelt Anwendung. Eine Kontrolle des Eradikationserfolges wurde bei 35 Patienten (38%) vorgenommen. Bezieht man die Eradikationskontrolle ausschließlich auf die therapierten Patienten erfolgte diese in der Hälfte der Fälle (49,3%). Von den Patienten mit H. pylori Eradikation und Kontrolle des Eradikationserfolges (n=35) konnten 31 (88,6%) erfolgreich behandelt werden. Die Vorgehensweise nach erfolgloser H. pylori Eradikation umfasste den Versuch einer Zweitlinientherapie, die Überweisung zum Gastroenterologen und den Verzicht auf weitere Maßnahmen.
Zusammenfassend zeigt diese Erhebung, dass es einen klaren Optimierungsbedarf in der Anwendung der Empfehlungen aus der Leitlinie bedarf. Dieser Aspekt sollte zukünftig vermehrt Berücksichtigung finden, nicht zuletzt in der Aktualisierung der Leitlinie 2016.