Refine
Has Fulltext
- yes (534)
Is part of the Bibliography
- yes (534)
Year of publication
Document Type
- Journal article (318)
- Doctoral Thesis (215)
- Preprint (1)
Keywords
- multiple myeloma (38)
- Aspergillus fumigatus (34)
- Multiples Myelom (17)
- Plasmozytom (16)
- HIV (14)
- apoptosis (13)
- Dendritische Zelle (12)
- Aspergillus (11)
- T cells (11)
- cancer (10)
- Stammzelltransplantation (9)
- inflammation (9)
- Aspergillose (8)
- Immuntherapie (8)
- NAFLD (8)
- cytokines (8)
- Apoptosis (7)
- B cells (7)
- Diabetes mellitus (7)
- Dickdarmkrebs (7)
- Multiple myeloma (7)
- Therapeutisches Drug Monitoring (7)
- dendritic cells (7)
- immunotherapy (7)
- stem cell transplantation (7)
- theranostics (7)
- Apoptose (6)
- COVID-19 (6)
- CXCR4 (6)
- Immunreaktion (6)
- Monoklonaler bispezifischer Antikörper (6)
- PET (6)
- T-Lymphozyt (6)
- allogeneic stem cell transplantation (6)
- Akute myeloische Leukämie (5)
- Antigen CD40 (5)
- Dendritische Zellen (5)
- Hepatitis C (5)
- Immunsystem (5)
- Multiple Myeloma (5)
- NK cells (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)
- 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)
- TDM (4)
- Transplantat-Wirt-Reaktion (4)
- allogene Stammzelltransplantation (4)
- aspergillus fumigatus (4)
- colorectal cancer (4)
- deep learning (4)
- fungal infection (4)
- galactomannan (4)
- innate immunity (4)
- invasive pulmonary aspergillosis (4)
- lenalidomide (4)
- lymphoma (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)
- SARS-CoV-2 (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)
- anxiety (3)
- autologous stem cell transplantation (3)
- biomarker (3)
- butyrate (3)
- cancer immunotherapy (3)
- cell staining (3)
- chemotherapy (3)
- chimeric antigen receptor (3)
- colonoscopy (3)
- colorectal carcinoma (3)
- dendritische Zellen (3)
- depression (3)
- echocardiography (3)
- endoscopy (3)
- fatty liver disease (3)
- fear of progression (3)
- follow-up (3)
- immune cells (3)
- immunosuppression (3)
- insulin (3)
- invasive aspergillosis (3)
- machine learning (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 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)
- 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)
- TRAF1 (2)
- TRAF2 (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)
- antibody (2)
- antimikrobielle Peptide (2)
- antirheumatic agents (2)
- artificial intelligence (2)
- autoimmunity (2)
- autologe Stammzelltransplantation (2)
- automation (2)
- beta-D-glucan (2)
- biomarkers (2)
- bone marrow (2)
- bone marrow immune-microenvironment (2)
- bortezomib (2)
- cancer microenvironment (2)
- cancer stem cells (2)
- cell death (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)
- gastroenterology (2)
- gastrointestinale Tumore (2)
- gemcitabine (2)
- gene (2)
- gene expression (2)
- gene regulation (2)
- giant cell arteritis (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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- PI (1)
- PML (1)
- PMR (1)
- POU6F2-AS2 (1)
- PPARgamma (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)
- 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)
- TWEAK (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)
- 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)
- 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)
- africans (1)
- after-care (1)
- agar diffusion test (1)
- agonist (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 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 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 of differentiation (1)
- coagulation (1)
- cognitive hypnotherapy (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)
- 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)
- 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)
- 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 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- platelets (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)
- polymyalgia rheumatica (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)
- 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)
- 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)
- thromboembolism (1)
- thrombopoiesis (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)
- transient elastography (1)
- transient regulatory T-cell targeting (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 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)
- 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 (534) (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)
Introduction: National and international guidelines recommend early integration of evidence-based multimodal interventions and programs, especially with a focus on relaxation techniques and other Mind–Body-based methods to maintain the quality of life of oncology patients, improve treatment tolerability, and promote healthy lifestyle behaviors. Consequently, we aim to understand what drives patients and how they navigate integrative medicine to best advise them. This study aimed to detect possible topics of particular interest to patients and identify the patient groups that could benefit most from further programs. Furthermore, we aimed to investigate if patients are open-minded toward integrative oncology concepts and learn about their motivational level to maintain or change behavior.
Methods: Between August 2019 and October 2020 we surveyed patients undergoing oncological therapy in a university oncological outpatient center using a custom-developed questionnaire based on established Mind–Body Medicine concepts.
Results: We included 294 patients with various cancers. More than half reported problems sleeping through (61%) and 42% felt stressed frequently, invariably rating this as detrimental to their health. Moreover, a slight majority (52%) felt physically limited due to their disease and only 30% performed defined exercise programs. Women were significantly more likely to feel stressed and reported with alarming frequency that they often feel “everything was up to them.” The 40–65-year-olds reported significantly less restful sleep, more stress and were more dissatisfied with their situation. However, this group already used natural remedies most frequently and was most often motivated to use relaxation techniques in the next 6 months. The lower the perceived individual energy level (EL), the less frequently patients did sport, the more frequently they felt their disease impaired their activity, mostly feeling stressed and tense. We also found significant associations between negative emotions/thoughts and the variables “sleep,” “use of relaxation techniques,” “personal stress perception,” and “successful lifestyle modification.”
Conclusion: Mind–Body programs that focus on patient’s individual resources, with tools to explore impairing patterns of self-perception and cognitive biases, can be a valuable resource for oncology patients and should therefore be part of an integrative medical treatment concept.
Butyrophilin (BTN)–3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during T cell receptor (TCR)-mediated sensing of phosphoantigens (PAg) derived from microbes and tumors. However, the molecular rules governing PAg sensing remain largely unknown. Here, we establish three mechanistic principles of PAg-mediated γδ T cell activation. First, in humans, following PAg binding to the intracellular BTN3A1-B30.2 domain, Vγ9Vδ2 TCR triggering involves the extracellular V-domain of BTN3A2/BTN3A3. Moreover, the localization of both protein domains on different chains of the BTN3A homo-or heteromers is essential for efficient PAg-mediated activation. Second, the formation of BTN3A homo-or heteromers, which differ in intracellular trafficking and conformation, is controlled by molecular interactions between the juxtamembrane regions of the BTN3A chains. Finally, the ability of PAg not simply to bind BTN3A-B30.2, but to promote its subsequent interaction with the BTN2A1-B30.2 domain, is essential for T-cell activation. Defining these determinants of cooperation and the division of labor in BTN proteins improves our understanding of PAg sensing and elucidates a mode of action that may apply to other BTN family members.
Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87% and 80% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24% of non-ICU and 3% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5% of non-ICU and 10% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19.
Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson’s disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c\(^+\) cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c\(^+\) cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut.
Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity
(2023)
Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.
Komplementärmedizinische Angebote in der Onkologie erleben eine hohe Nachfrage. Diese Studie sollte klären, ob bei Patienten ein Mehrbedarf an ganzheitlichen, tagesklinischen Angeboten besteht. Im Rahmen dieser Fragebogen-basierten Analyse sollten Zielgruppen identifiziert werden, die besonders hiervon profitieren könnten. Mithilfe eines Fragebogens wurden zwischen 08/2019 und 10/2020 294 ambulant behandelte onkologische Patienten des Comprehensive Cancer Centers Mainfranken an der Universitätsklinik Würzburg befragt. Der Fragebogen ist angelehnt an das etablierte Curriculum Mind-Body-Medizin der Kliniken Essen-Mitte und umfasst zehn Untergruppen. Statistisch signifikante Zusammenhänge wurden durch Anwendung des Chi-Quadrat Tests ermittelt. In allen untersuchten Lebensbereichen fanden sich Hinweise auf einen Mehrbedarf an komplementärmedizinischen Angeboten. Ein Drittel der Patienten gab an, aus eigener Kraft keine überdauernden Lebensstiländerungen herbeiführen zu können. Das höchste Gesundheitsbewusstsein zeigte sich in den Bereichen Ernährung, Bewegung und Entspannung. Trotzdem führte ein Großteil der Befragten empfohlene Maßnahmen nicht durch. Insbesondere die Bereiche Schlaf, Energielevel und psychische Belastung wiesen das größte Verbesserungspotential auf. Defizite in diesen Bereichen beeinflussten sich gegenseitig und konnten mit Unzufriedenheit und negativen Gedanken sowie geringer Veränderungsmotivation in Verbindung gebracht werden. Besonders betroffen waren erwerbstätige Patienten im Alter zwischen 40-65 Jahren. Frauen zeigten sich deutlich motivierter als Männer komplementärmedizinische Angebote zu nutzen. Gemäß unseren Ergebnissen und evidenzbasierten Empfehlungen der S3-Leitlinie Komplementärmedizin ergibt sich ein Mehrbedarf nach folgenden Angeboten: Supervidierte Sportprogramme, MBSR, Tai Chi/ Qigong, individuelle Ernährungsberatung und Selbsthilfegruppen für Angehörige. Durch Vermittlung von Gesundheitsbewusstsein sollten insbesondere Patientengruppen motiviert werden, die aus eigener Kraft ihre Situation nicht verbessern können. Um den Erfolg von gesundheitsfördernden Lebensstiländerungen überdauernd zu sichern, ist weitere Unterstützung nötig.
Background
Research in the field of surgery is mainly driven by aiming for trauma reduction as well as for personalized treatment concepts. Beyond laparoscopy, other proposed approaches for further reduction of the therapeutic trauma have failed to achieve clinical translation, with few notable exceptions. We believe that this is mainly due to a lack of flexibility and high associated costs. We aimed at addressing these issues by developing a novel minimally invasive operating platform and a preoperative design workflow for patient-individual adaptation and cost-effective rapid manufacturing of surgical manipulators. In this article, we report on the first in-vitro cholecystectomy performed with our operating platform.
Methods
The single-port overtube (SPOT) is a snake-like surgical manipulator for minimally invasive interventions. The system layout is highly flexible and can be adapted in design and dimensions for different kinds of surgery, based on patient- and disease-specific parameters. For collecting and analyzing this data, we developed a graphical user interface, which assists clinicians during the preoperative planning phase. Other major components of our operating platform include an instrument management system and a non-sterile user interface. For the trial surgery, we used a validated phantom which was further equipped with a porcine liver including the gallbladder.
Results
Following our envisioned preoperative design workflow, a suitable geometry of the surgical manipulator was determined for our trial surgery and rapidly manufactured by means of 3D printing. With this setup, we successfully performed a first in-vitro cholecystectomy, which was completed in 78 min.
Conclusions
By conducting the trial surgery, we demonstrated the effectiveness of our PLAFOKON operating platform. While some aspects – especially regarding usability and ergonomics – can be further optimized, the overall performance of the system is highly promising, with sufficient flexibility and strength for conducting the necessary tissue manipulations.
Objective
The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer.
Materials and methods
A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations.
Results
Metastasis-directed radiotherapy results in high local control (often > 90% within a follow-up of 1–2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels.
Conclusion
ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations.
Background
Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials.
Methods
We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality).
Findings
Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21.4% for NACT versus 15.9% for adjuvant chemotherapy (5.5% increase [95% CI 2.4-8.6]; rate ratio 1.37 [95% CI 1.17-1.61]; p = 0.0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38.2% for NACT vs 38.0% for adjuvant chemotherapy; rate ratio 1.02 [95% CI 0.92-1.14]; p = 0.66), breast cancer mortality (34.4% vs 33.7%; 1.06 [0.95-1.18]; p = 0.31), or death from any cause (40.9% vs 41.2%; 1.04 [0.94-1.15]; p = 0.45).
Interpretation
Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. Copyright (c) The Author(s). Published by Elsevier Ltd.
After priming in Peyer's patches (PPs) and mesenteric lymph nodes (mLN) T- cells infiltrate the intestine through lymphatic draining and homing through the bloodstream. However, we found that in mouse models of acute graft-versus-host disease (GvHD), a subset of alloreactive T-cells directly migrates from PPs to the adjacent intestinal lamina propria (LP), bypassing the normal lymphatic drainage and vascular trafficking routes. Notably, this direct migration occurred in irradiated and unirradiated GvHD models, indicating that irradiation is not a prerequisite for this observed behavior.
Next, we established a method termed serial intravascular staining (SIVS) in mouse models to systematically investigate the trafficking and migration of donor T- cells in the early stages of acute GvHD initiation. We found that the direct migration of T-cells from PPs to LP resulted in faster recruitment of cells after allogeneic hematopoietic cell transplantation (allo-HCT). These directly migrating T-cells were found to be in an activated and proliferative state, exhibiting a TH1/TH17-like phenotype and producing cytokines such as IFN-γ and TNF-α. Furthermore, we observed that the directly migrating alloreactive T-cells expressed specific integrins (α4+, αE+) and chemokine receptors (CxCR3+, CCR5+, and CCR9+). Surprisingly, blocking these integrins and chemokine-coupled receptors did not hinder the direct migration of T- cells from PPs to LP, suggesting the involvement of alternative mechanisms. Previous experiments ruled out the involvement of S1PR1 and topographical features of macrophages, leading us to hypothesize that mediators of cytoskeleton reorganization, such as Coro1a, Dock2, or Cdc42, may play a role in this unique migration process.
Additionally, we observed that directly migrating T-cells created a local inflammatory microenvironment, which attracts circulating T-cells. Histological analysis confirmed that alloreactive PPs-derived T-cells and bloodborne T-cells colocalized. We employed two experimental approaches, including either photoconversion of T-cells in PPs or direct transfer of activated T-cells into the vasculature, to demonstrate this colocalization. We hypothesize that cytokines released by migrating T-cells, such as IFN-γ and TNF-α, may play a role in recruiting T-cells from the vasculature, as inhibiting chemokine-coupled receptors did not impair recruitment.
Obwohl es in den letzten 10-15 Jahren gelang, multiple MM-Genome mittels NGS auf eine kosteneffiziente Art und mit geringem Zeit- und Materialaufwand zu sequenzieren und hierdurch zum Teil bahnbrechende Erkenntnisse gewonnen werden konnten, sind molekulargenetische Untersuchungen im diagnostischen Workflow des MMs bisher nicht ausreichend implementiert, um eine personalisierte Therapieentscheidung zu ermöglichen.
Vor diesem Hintergrund wurde in der vorliegenden Arbeit eine Gruppe an Patienten mit NDMM und RRMM anhand klinischer Parameter charakterisiert und durch Verwendung des M³P-Panels auf das Vorliegen bestimmter molekulargenetischer Veränderungen untersucht. Zusammenfassend lässt sich sagen, dass unsere Analyse die bisher veröffentliche M³P-Prävalenz in MM-Tumorproben bestätigt. Zu den am häufigsten mutierten Genen gehörten KRAS, NRAS, DIS3, ATM und BRAF. In der Gruppe der Patienten mit NRAS-Mutation oder del17p war die Zahl der relevanten Mutationen deutlich höher als ohne Vorliegen der entsprechenden Veränderung. Der Nachweis eines Double-Hit-Myeloms war erwartungsgemäß der stärkste ungünstige Faktor in unserer Kohorte. Unter den Patienten mit CRBN-Mutation waren alle IMiD-vorbehandelt und zeigten im Verlauf eine Refraktärität gegenüber dieser Substanzgruppe auf. Bezüglich der Überlebensanalysen bestätigten unsere Ergebnisse bereits bekannte prognostische Risikofaktoren wie Hochrisikozytogenetik, insbesondere del17p und gain1q, eine TP53-Mutation sowie ISS- und R-ISS-Stadium III.
Die Ergebnisse der Mutationsanalysen dieser Arbeit verdeutlichen den großen wissenschaftlichen und therapeutischen Nutzen, der von molekulargenetischen Untersuchungen ausgeht. Zukünftig werden auch beim MM Therapieentscheidungen auf Grundlage genetischer Diagnostik getroffen werden, mit dem Ziel die Behandlung für MM-Patienten weiter zu verbessern.
A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [\(^{68}\)Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [\(^{68}\)Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [\(^{177}\)Lu]/[\(^{90}\)Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.
Purpose
Oncologists are at an increased risk of developing burnout, leading to negative consequences in patient care and in professional satisfaction and quality of life. This study was designed to investigate exhaustion and disengagement among German oncologists and assess the prevalence of burnout among oncologists within different professional settings. Furthermore, we wanted to examine possible relations between sociodemographic factors, the oncological setting, professional experience and different aspects of burnout.
Methods
In a cross-sectional study design, an Internet-based survey was conducted with 121 oncologists between April and July 2020 using the Oldenburg Burnout Inventory, which contains items on exhaustion, disengagement, and burnout. Furthermore, sociodemographic data of the participants were assessed. The participants were members of the Working Group Medical Oncology (Arbeitsgemeinschaft Internistische Onkologie) within the German Cancer Society.
Results
The survey showed a burnout prevalence of 43.8%, which correlated with age and professional experience; that is, the prevalence is particularly high among younger oncologists. Exhaustion is closely related to employment status; that is, it was significantly higher among employed oncologists. There were remarkably low levels of disengagement among oncologists, highlighting the own demand to fulfil job requirements despite imminent or actual overburdening in daily work.
Conclusion
More support is necessary to mitigate the professional stressors in the healthcare system. To ensure quality medical care, employees should be offered preventive mental health services early in their careers.
Objective
Blindness is a feared complication of giant cell arteritis (GCA). However, the spectrum of pathologic orbital imaging findings on magnetic resonance imaging (MRI) in GCA is not well understood. In this study, we assess inflammatory changes of intraorbital structures on black blood MRI (BB-MRI) in patients with GCA compared to age-matched controls.
Methods
In this multicenter case-control study, 106 subjects underwent BB-MRI. Fifty-six patients with clinically or histologically diagnosed GCA and 50 age-matched controls without clinical or laboratory evidence of vasculitis were included. All individuals were imaged on a 3-T MR scanner with a post-contrast compressed-sensing (CS) T1-weighted sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) BB-MRI sequence. Imaging results were correlated with available clinical symptoms.
Results
Eighteen of 56 GCA patients (32%) showed inflammatory changes of at least one of the intraorbital structures. The most common finding was enhancement of at least one of the optic nerve sheaths (N = 13, 72%). Vessel wall enhancement of the ophthalmic artery was unilateral in 8 and bilateral in 3 patients. Enhancement of the optic nerve was observed in one patient. There was no significant correlation between imaging features of inflammation and clinically reported orbital symptoms (p = 0.10). None of the age-matched control patients showed any inflammatory changes of intraorbital structures.
Conclusions
BB-MRI revealed inflammatory findings in the orbits in up to 32% of patients with GCA. Optic nerve sheath enhancement was the most common intraorbital inflammatory change on BB-MRI. MRI findings were independent of clinically reported orbital symptoms.
Key Points
• Up to 32% of GCA patients shows signs of inflammation of intraorbital structures on BB-MRI.
• Enhancement of the optic nerve sheath is the most common intraorbital finding in GCA patients on BB-MRI.
• Features of inflammation of intraorbital structures are independent of clinically reported symptoms.
Background
CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs.
Methods
Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden.
Results
Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found.
Conclusions
In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.
Objectives
Mechanisms of wound healing are often impaired in patients with osteonecrosis of the jaw (ONJ). According to the guidelines for the treatment of this disease, early surgical intervention is indicated. However, surgery often faces complications such as wound healing disorders. The application of platelet-rich fibrin (PRF) after necrosectomy between bone and mucosa may constitute a promising approach to improve surgical results. An aspect that was not investigated until now is that PRF acts as a “bio-carrier” for antibiotics previously applied intravenously.
Materials and methods
We investigated the antimicrobial properties of PRF in 24 patients presenting ONJ undergoing systemic antibiosis with ampicillin/sulbactam. We measured the concentration of ampicillin/sulbactam in plasma and PRF and performed agar diffusion tests. Ampicillin/sulbactam was applied intravenously to the patient 10 minutes for blood sampling for PRF. No further incorporation of patients’ blood or PRF product with antibiotic drugs was obtained. Four healthy patients served as controls.
Results
Our results revealed that PRF is highly enriched with ampicillin/sulbactam that is released to the environment. The antibiotic concentration in PRF was comparable to the plasma concentration of ampicillin/sulbactam. The inhibition zone (IZ) of PRF was comparable to the standard ampicillin/sulbactam discs used in sensitivity testing.
Conclusions
The results of our study demonstrated that PRF is a reliable bio-carrier for systemic applied antibiotics and exhibits a large antimicrobial effect.
Clinical relevance
We describe a clinically useful feature of PRF as a bio-carrier for antibiotics. Especially when applied to poorly perfused tissues and bone such as in ONJ, the local release of antibiotics can reduce wound healing disorders like infections.
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.
Pilot study of a new freely available computer-aided polyp detection system in clinical practice
(2022)
Purpose
Computer-aided polyp detection (CADe) systems for colonoscopy are already presented to increase adenoma detection rate (ADR) in randomized clinical trials. Those commercially available closed systems often do not allow for data collection and algorithm optimization, for example regarding the usage of different endoscopy processors. Here, we present the first clinical experiences of a, for research purposes publicly available, CADe system.
Methods
We developed an end-to-end data acquisition and polyp detection system named EndoMind. Examiners of four centers utilizing four different endoscopy processors used EndoMind during their clinical routine. Detected polyps, ADR, time to first detection of a polyp (TFD), and system usability were evaluated (NCT05006092).
Results
During 41 colonoscopies, EndoMind detected 29 of 29 adenomas in 66 of 66 polyps resulting in an ADR of 41.5%. Median TFD was 130 ms (95%-CI, 80–200 ms) while maintaining a median false positive rate of 2.2% (95%-CI, 1.7–2.8%). The four participating centers rated the system using the System Usability Scale with a median of 96.3 (95%-CI, 70–100).
Conclusion
EndoMind’s ability to acquire data, detect polyps in real-time, and high usability score indicate substantial practical value for research and clinical practice. Still, clinical benefit, measured by ADR, has to be determined in a prospective randomized controlled trial.
Bereits in Vorstudien konnte dargelegt werden, dass eine signifikante Korrelation zwischen der T-Zell-Zytokin-Antwort und der berufs- bzw. umweltbedingten Schimmelpilzbelastung besteht. Ziel der vorliegenden Studie war, eine mögliche Kombination von Biomarkern ausfindig zu machen, die veränderte T-Zell-Antworten auf A. fumigatus- Antigene bei beruflich Exponierten im Vergleich zu Kontrollprobanden/-innen vorhersagen kann. Um geeignete Marker für das Bio-Monitoring zu finden, wurden zur T-Zell-Aktivierung ein myzeliales A. fumigatus - Lysat und 12 proteinogene Antigene in ELISpot-Versuchen für die Signaturzytokine IFN-γ (TH1), IL-5 (TH2) und IL-17A (TH17) der Haupt-TH-Subpopulationen getestet.
Es zeigten sich bei den Biolandwirten/-innen erwartungsgemäß erhöhte TH1- und TH2-Antworten auf die Mehrzahl der verwendeten spezifischen A. fumigatus-Antigene, die möglicherweise eine Schimmelpilzbelastung serologisch nachweisbar machen. Insbesondere die spezifischen A. fumigatus-Antigene Aspf22, CatB und CipC konnten eine Trennschärfe zwischen den beiden Kohorten hinsichtlich ihrer IFN-γ- und IL-5-Zytokinantwort erzielen. Unterschiede in der TH17-Antwort aufgrund chronischer beruflicher Sporenbelastung ohne Krankheitskorrelat konnten nicht explizit festgestellt werden. Weiterhin ergab sich, dass erhöhte TH2-Immunreaktionen, sofern sie mit einer adäquaten TH1-gerichteten Immunantwort einhergehen und damit eine ausgeglichene TH2/TH1-Balance besteht, nicht zwangsläufig zu Hypersensitivitätserkrankungen führen. Im Vergleich zu Langzeitexponierten wurden teilweise überlappende TH-Zellfrequenzen bei beruflich exponierten Biolandwirten/-innen ermittelt. Welche entscheidende Rolle Treg-Zellen bei der Eindämmung überschießender Immunantworten einnehmen, kann hieraus erahnt werden.
For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM.
(1) Background: Interventional endoscopic procedures are growing more popular, requiring innovative instruments and novel techniques. Three-dimensional printing has demonstrated great potential for the rapid development of prototypes that can be used for the early assessment of various concepts. In this work, we present the development of a flexible endoscopic instrument and explore its potential benefits. (2) Methods: The properties of the instrument, such as its maneuverability, flexibility, and bending force, were evaluated in a series of bench tests. Additionally, the effectiveness of the instrument was evaluated in an ex vivo porcine model by medical experts, who graded its properties and performance. Furthermore, the time necessary to complete various interventional endoscopic tasks was recorded. (3) Results: The instrument achieved bending angles of ±216° while achieving a bending force of 7.85 (±0.53) Newtons. The time needed to reach the operating region was 120 s median, while it took 70 s median to insert an object in a cavity. Furthermore, it took 220 s median to insert the instrument and remove an object from the cavity. (4) Conclusions: This study presents the development of a flexible endoscopic instrument using three-dimensional printing technology and its evaluation. The instrument demonstrated high bending angles and forces, and superior properties compared to the current state of the art. Furthermore, it was able to complete various interventional endoscopic tasks in minimal time, thus potentially leading to the improved safety and effectiveness of interventional endoscopic procedures in the future.
Tuberculosis (TB) is one of the leading causes of death by an infectious disease. It remains a major health burden worldwide, in part due to misdiagnosis. Therefore, improved diagnostic tests allowing the faster and more reliable diagnosis of patients with active TB are urgently needed. This prospective study examined the performance of the new molecular whole-blood test T-Track\(^®\) TB, which relies on the combined evaluation of IFNG and CXCL10 mRNA levels, and compared it to that of the QuantiFERON\(^®\)-TB Gold Plus (QFT-Plus) enzyme-linked immunosorbent assay (ELISA). Diagnostic accuracy and agreement analyses were conducted on the whole blood of 181 active TB patients and 163 non-TB controls. T-Track\(^®\) TB presented sensitivity of 94.9% and specificity of 93.8% for the detection of active TB vs. non-TB controls. In comparison, the QFT-Plus ELISA showed sensitivity of 84.3%. The sensitivity of T-Track\(^®\) TB was significantly higher (p < 0.001) than that of QFT-Plus. The overall agreement of T-Track\(^®\) TB with QFT-Plus to diagnose active TB was 87.9%. Out of 21 samples with discordant results, 19 were correctly classified by T-Track\(^®\) TB while misclassified by QFT-Plus (T-Track\(^®\) TB-positive/QFT-Plus-negative), and two samples were misclassified by T-Track\(^®\) TB while correctly classified by QFT-Plus (T-Track\(^®\) TB-negative/QFT-Plus-positive). Our results demonstrate the excellent performance of the T-Track\(^®\) TB molecular assay and its suitability to accurately detect TB infection and discriminate active TB patients from non-infected controls.
We assume that a specific health constraint, e.g., a certain aspect of bodily function or quality of life that is measured by a variable X, is absent (or irrelevant) in a healthy reference population (Ref0), and it is materially present and precisely measured in a diseased reference population (Ref1). We further assume that some amount of this constraint of interest is suspected to be present in a population under study (SP). In order to quantify this issue, we propose the introduction of an intuitive measure, the population comparison index (PCI), that relates the mean value of X in population SP to the mean values of X in populations Ref0 and Ref1. This measure is defined as PCI[X] = (mean[X|SP] − mean[X|Ref0])/(mean[X|Ref1] − mean[X|Ref0]) × 100[%], where mean[X|.] is the average value of X in the respective group of individuals. For interpretation, PCI[X] ≈ 0 indicates that the values of X in the population SP are similar to those in population Ref0, and hence, the impairment measured by X is not materially present in the individuals in population SP. On the other hand, PCI[X] ≈ 100 means that the individuals in SP exhibit values of X comparable to those occurring in Ref1, i.e., the constraint of interest is equally present in populations SP and Ref1. A value of 0 < PCI[X] < 100 indicates that a certain percentage of the constraint is present in SP, and it is more than in Ref0 but less than in Ref1. A value of PCI[X] > 100 means that population SP is even more affected by the constraint than population Ref1.
Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline.
While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future.
Background
Endoscopic vacuum therapy (EVT) is an effective treatment option for leakage of the upper gastrointestinal (UGI) tract. The aim of this study was to evaluate the clinical impact of quality improvements in EVT management on patients’ outcome.
Methods
All patients treated by EVT at our center during 2012–2021 were divided into two consecutive and equal-sized cohorts (period 1 vs. period 2). Over time several quality improvement strategies were implemented including the earlier diagnosis and EVT treatment and technical optimization of endoscopy. The primary endpoint was defined as the composite score MTL30 (mortality, transfer, length-of-stay > 30 days). Secondary endpoints included EVT efficacy, complications, in-hospital mortality, length-of-stay (LOS) and nutrition status at discharge.
Results
A total of 156 patients were analyzed. During the latter period the primary endpoint MTL30 decreased from 60.8 to 39.0% (P = .006). EVT efficacy increased from 80 to 91% (P = .049). Further, the need for additional procedures for leakage management decreased from 49.9 to 29.9% (P = .013) and reoperations became less frequent (38.0% vs.15.6%; P = .001). The duration of leakage therapy and LOS were shortened from 25 to 14 days (P = .003) and 38 days to 25 days (P = .006), respectively. Morbidity (as determined by the comprehensive complication index) decreased from 54.6 to 46.5 (P = .034). More patients could be discharged on oral nutrition (70.9% vs. 84.4%, P = .043).
Conclusions
Our experience confirms the efficacy of EVT for the successful management of UGI leakage. Our quality improvement analysis demonstrates significant changes in EVT management resulting in accelerated recovery, fewer complications and improved functional outcome.
Background
Pancreatic adenocarcinoma (PDAC) patients with preoperative carbohydrate antigen 19-9 (CA19-9) serum levels higher than 500 U/ml are classified as biologically borderline resectable (BR-B). To date, the impact of cholestasis on preoperative CA19-9 serum levels in these patients has remained unquantified.
Methods
Data on 3079 oncologic pancreatic resections due to PDAC that were prospectively acquired by the German Study, Documentation and Quality (StuDoQ) registry were analyzed in relation to preoperative CA19-9 and bilirubin serum values. Preoperative CA19-9 values were adjusted according to the results of a multivariable linear regression analysis of pathologic parameters, bilirubin, and CA19-9 values.
Results
Of 1703 PDAC patients with tumor located in the pancreatic head, 420 (24.5 %) presented with a preoperative CA19-9 level higher than 500 U/ml. Although receiver operating characteristics (ROC) analysis failed to determine exact CA19-9 cut-off values for prognostic indicators (R and N status), the T, N, and G status; the UICC stage; and the number of simultaneous vein resections increased with the level of preoperative CA19-9, independently of concurrent cholestasis. After adjustment of preoperative CA19-9 values, 18.5 % of patients initially staged as BR-B showed CA19-9 values below 500 U/ml. However, the postoperative pathologic results for these patients did not change compared with the patients who had CA19-9 levels higher than 500 U/ml after bilirubin adjustment.
Conclusions
In this multicenter dataset of PDAC patients, elevation of preoperative CA19-9 correlated with well-defined prognostic pathologic parameters. Bilirubin adjustment of CA19-9 is feasible but does not affect the prognostic value of CA19-9 in jaundiced patients.
Articular cartilage defects represent one of the most challenging clinical problem for orthopedic surgeons and cartilage damage after trauma can result in debilitating joint pain, functional impairment and in the long-term development of osteoarthritis. The lateral cartilage-cartilage integration is crucial for the long-term success and to prevent further tissue degeneration. Tissue adhesives and sealants are becoming increasingly more popular and can be a beneficial approach in fostering tissue integration, particularly in tissues like cartilage where alternative techniques, such as suturing, would instead introduce further damage. However, adhesive materials still require optimization regarding the maximization of adhesion strength on the one hand and long-term tissue integration on the other hand. In vitro models can be a valuable support in the investigation of potential candidates and their functional mechanisms. For the conducted experiments within this work, an in vitro disc/ring model obtained from porcine articular cartilage tissue was established. In addition to qualitative evaluation of regeneration, this model facilitates the implementation of biomechanical tests to quantify cartilage integration strength. Construct harvesting for histology and other evaluation methods could be standardized and is ethically less questionable compared to in vivo testing. The opportunity of cell culture technique application for the in vitro model allowed a better understanding of cartilage integration processes.
Tissue bonding requires chemical or physical interaction of the adhesive material and the substrate. Adhesive hydrogels can bind to the defect interface and simultaneously fill the gap of irregularly shaped defect voids. Fibrin gels are derived from the physiological blood-clot formation and are clinically applied for wound closure. Within this work, comparisons of different fibrin glue formulations with the commercial BioGlue® were assessed, which highlighted the need for good biocompatibility when applied on cartilage tissue in order to achieve satisfying long-term integration. Fibrin gel formulations can be adapted with regard to their long-term stability and when applied on cartilage disc/ring constructs improved integrative repair is observable. The kinetic of repairing processes was investigated in fibrin-treated cartilage composites as part of this work. After three days in vitro cultivation, deposited extracellular matrix (ECM) was obvious at the glued interface that increased further over time. Interfacial cell invasion from the surrounding native cartilage was detected from day ten of tissue culture. The ECM formation relies on molecular factors, e.g., as was shown representatively for ascorbic acid, and contributes to increasing integration strengths over time. The experiments performed with fibrin revealed that the treatment with a biocompatible adhesive that allows cartilage neosynthesis favors lateral cartilage integration in the long term. However, fibrin has limited immediate bonding strength, which is disadvantageous for use on articular cartilage that is subject to high mechanical stress. The continuing aim of this thesis was to further develop adhesive mechanisms and new adhesive hydrogels that retain the positive properties of fibrin but have an increased immediate bonding strength.
Two different photochemical approaches with the advantage of on-demand bonding were tested. Such treatment potentially eases the application for the professional user. First, an UV light induced crosslinking mechanism was transferred to fibrin glue to provide additional bonding strength. For this, the cartilage surface was functionalized with highly reactive light-sensitive diazirine groups, which allowed additional covalent bonds to the fibrin matrix and thus increased the adhesive strength. However, the disadvantages of this approach were the multi-step bonding reactions, the need for enzymatic pretreatment of the cartilage, expensive reagents, potential UV-light damage, and potential toxicity hazards. Due to the mentioned disadvantages, no further experiments, including long-term culture, were carried out. A second photosensitive approach focused on blue light induced crosslinking of fibrinogen (RuFib) via a photoinitiator molecule instead of using thrombin as a crosslinking mediator like in normal fibrin glue. The used ruthenium complex allowed inter- and intramolecular dityrosine binding of fibrinogen molecules. The advantage of this method is a one-step curing of fibrinogen via visible light that further achieved higher adhesive strengths than fibrin. In contrast to diazirine functionalization of cartilage, the ruthenium complex is of less toxicological concern. However, after in vitro cultivation of the disc/ring constructs, there was a decrease in integration strength. Compared to fibrin, a reduced cartilage synthesis was observed at the defect. It is also disadvantageous that a direct adjustment of the adhesive can only be made via protein concentration, since fibrinogen is a natural protein that has a fixed number of tyrosine binding sites without chemical modification.
An additional cartilage adhesive was developed that is based on a mussel-inspired adhesive mechanism in which reactivity to a variety of substrates is enabled via free DOPA amino acids. DOPA-based adhesion is known to function in moist environments, a major advantage for application on water-rich cartilage tissue surrounded by synovial liquid. Reactive DOPA groups were synthetically attached to a polymer, here POx, to allow easy chemical modifiability, e.g. insertion of hydrolyzable ester motifs for tunable degradation. The possibility of preparing an adhesive hybrid hydrogel of POx in combination with fibrinogen led to good cell compatibility as was similarly observed with fibrin, but with increased immediate adhesive strength. Degradation could be adjusted by the amount of ester linkages on the POx and a direct influence of degradation rates on the development of integration in the in vitro model could be shown.
Hydrogels are well suited to fill defect gaps and immediate integration can be achieved via adhesive properties. The results obtained show that for the success of long-term integration, a good ability of the adhesive to take up synthesized ECM components and cells to enable regeneration is required. The degradation kinetics of the adhesive must match the remodeling process to avoid intermediate loss of integration power and to allow long-term firm adhesion to the native tissue.
Hydrogels are not only important as adhesives for smaller lesions, but also for filling large defect volumes and populating them with cells to produce tissue engineered cartilage. Many different hydrogel types suitable for cartilage synthesis are reported in the literature. A long-term stable fibrin formulation was tested in this work not only as an adhesive but also as a bulk hydrogel construct. Agarose is also a material widely used in cartilage tissue engineering that has shown good cartilage neosynthesis and was included in integration assessment. In addition, a synthetic hyaluronic acid-based hydrogel (HA SH/P(AGE/G)) was used. The disc/ring construct was adapted for such experiments and the inner lumen of the cartilage ring was filled with the respective hydrogel. In contrast to agarose, fibrin and HA-SH/P(AGE/G) gels have a crosslink mechanism that led to immediate bonding upon contact with cartilage during curing. The enhanced cartilage neosynthesis in agarose compared to the other hydrogel types resulted in improved integration during in vitro culture. This shows that for the long-term success of a treatment, remodeling of the hydrogel into functional cartilage tissue is a very high priority. In order to successfully treat larger cartilage defects with hydrogels, new materials with these properties in combination with chemical modifiability and a direct adhesion mechanism are one of the most promising approaches.
Prevention of the effectiveness of anti-tumor immune responses is one of the canonical cancer hallmarks. The competition for crucial nutrients within the tumor microenvironment (TME) between cancer cells and immune cells creates a complex interplay characterized by metabolic deprivation. Extensive efforts have recently been made to understand better the dynamic interactions between cancer cells and surrounding immune cells. Paradoxically, both cancer cells and activated T cells are metabolically dependent on glycolysis, even in the presence of oxygen, a metabolic process known as the Warburg effect. The intestinal microbial community delivers various types of small molecules that can potentially augment the functional capabilities of the host immune system. Currently, several studies are trying to explore the complex functional relationship between the metabolites secreted by the human microbiome and anti-tumor immunity. Recently, it has been shown that a diverse array of commensal bacteria synthetizes bioactive molecules that enhance the efficacy of cancer immunotherapy, including immune checkpoint inhibitor (ICI) treatment and adoptive cell therapy with chimeric antigen receptor (CAR) T cells. In this review, we highlight the importance of commensal bacteria, particularly of the gut microbiota-derived metabolites that are capable of shaping metabolic, transcriptional and epigenetic processes within the TME in a therapeutically meaningful way.
The cancer stem cell hypothesis is a cancer development model which elicited great interest in the last decades stating that cancer heterogeneity arises from a stem cell through asymmetrical division. The Cancer Stem Cell subset is described as the only population to be tumorigenic and having the potential to renew. Conventional therapy often fails to eradicate CSC resulting in tumor relapse. Consequently, it is of great inter-est to eliminate this subset of cells to provide the best patient outcome. In the last years several approaches to target CSC were developed, one of them being immunotherapeu-tic targeting with antibodies. Since markers associated with CSC are also expressed on normal stem cells or healthy adjacent tissue in colorectal cancer, dual targeting strate-gies are preferred over targeting only a single antigen. Subsequently, the idea of dual targeting two CSC markers in parallel by a newly developed split T cell-engaging anti-body format termed as Hemibodies emerged. In a preliminary single cell RNA sequenc-ing analysis of colorectal cancer cells CD133, CD24, CD166 and CEA were identified as suitable targets for the combinatorial targeting strategy. Therefore, this study focused on trispecific and trivalent Hemibodies comprising a split binding moiety against CD3 and a binding moiety against either CD133, CD24, CD166 or CEA to overcome the occurrence of resistance and to efficiently eradicate all tumor cells including the CSC compartment. The study showed that the Hemibody combinations CD133xCD24, CD133xCD166 and CD133xCEA are able to eliminate double positive CHO cells with high efficacy while having a high specificity indicated by no killing of single antigen positive cells. A thera-peutic window ranging between one to two log levels could be achieved for all combina-tions mentioned above. The combinations CD133xCD24 and CD133xCD166 further-more proved its efficacy and specificity on established colorectal cancer cell lines. Be-sides the evaluation of specificity and efficacy the already introduced 1st generation of Hemibodies could be improved into a 2nd generation Hemibody format with increased half-life, stability and production yield. In future experiments the applicability of above-mentioned Hemibodies will be proven on patient-derived micro tumors to also include variables like tumor microenvironment and infiltration.
At the beginning of the COVID-19 pandemic, patients with primary and secondary immune disorders — including patients suffering from cancer — were generally regarded as a high-risk population in terms of COVID-19 disease severity and mortality. By now, scientific evidence indicates that there is substantial heterogeneity regarding the vulnerability towards COVID-19 in patients with immune disorders. In this review, we aimed to summarize the current knowledge about the effect of coexistent immune disorders on COVID-19 disease severity and vaccination response. In this context, we also regarded cancer as a secondary immune disorder. While patients with hematological malignancies displayed lower seroconversion rates after vaccination in some studies, a majority of cancer patients’ risk factors for severe COVID-19 disease were either inherent (such as metastatic or progressive disease) or comparable to the general population (age, male gender and comorbidities such as kidney or liver disease). A deeper understanding is needed to better define patient subgroups at a higher risk for severe COVID-19 disease courses. At the same time, immune disorders as functional disease models offer further insights into the role of specific immune cells and cytokines when orchestrating the immune response towards SARS-CoV-2 infection. Longitudinal serological studies are urgently needed to determine the extent and the duration of SARS-CoV-2 immunity in the general population, as well as immune-compromised and oncological patients.
Ziel dieser Arbeit war es, den Einfluss psychosozialer Belastungsfaktoren auf den Verlauf einer Stammzelltransplantation zu untersuchen. Die primäre Fragestellung war, ob sich das Vorliegen einer posttraumatischen Belastungsstörung (PTSD) auf die Dauer der Immunrekonstitution, gemessen an der Aplasiezeit, auswirkt. Der Untersuchung liegen Daten aus der Medizinischen Klinik und Poliklinik II des Universitätsklinikums Würzburg zugrunde, die im Rahmen einer monozentrischen Querschnittsstudie erhoben wurden. An der Studie nahmen 50 Patienten mit der Diagnose eines Multiplen Myeloms teil, die am Tag ihrer ersten autologen Stammzelltransplantation befragt wurden. Anhand von Fragebögen konnten die Patienten Angaben zu ihrer individuellen psychischen Belastung machen. Für die statistische Auswertung wurden die Angaben aus dem NCCN-Distress-Thermometer und dem PCL-C ausgewertet.
Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug–drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim\(^®\) Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (C\(_{max}\)) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.
(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.
Li-Fraumeni-syndrome (LFS) is a rare, highly penetrant cancer predisposition syndrome (CPS) caused by pathogenic variants (PVs) in TP53. Physical activity (PA) and a Mediterranean diet lead to cancer reduction or survival benefits and increased quality of life (QoL), but this is yet unstudied among LFS. TP53 PV carriers (PVC) and their relatives were questioned on dietary patterns (Mediterranean Diet Adherence Screener), PA (Freiburg Questionnaire), QoL (Short-form-Health-Survey-12), smoking, alcohol consumption and perception of cancer risk in a German bi-centric study from March 2020–June 2021. The study enrolled 70 PVC and 43 relatives. Women compared to men (6.49 vs. 5.38, p = 0.005) and PVC to relatives (6.59 vs. 5.51; p = 0.006) showed a healthier diet, associated with participation in surveillance (p = 0.04) and education (diet p = 0.02 smoking p = 0.0003). Women smoked less (2.91 vs. 5.91 packyears; p = 0.03), psychological well-being was higher among men (SF-12: males 48.06 vs. females 41.94; p = 0.004). PVC rated their own cancer risk statistically higher than relatives (72% vs. 38%, p < 0.001) however, cancer risk of the general population was rated lower (38% vs. 70%, p < 0.001). A relative’s cancer-related death increased the estimated personal cancer risk (p = 0.01). The possibilities of reducing cancer through self-determined health behavior among PVC and relatives has not yet been exhausted. Educating families with a CPS on cancer-preventive behavior requires further investigation with regard to acceptance and real-life implementation.
In recent years, it has become increasingly apparent that bone marrow (BM) failures and myeloid malignancy predisposition syndromes are characterized by a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of children and adults with unexplained hematopoiesis defects. Clinically, hypocellular BM failure still represents a challenge in pathobiology-guided treatment. There are three fundamental topics that emerged from our review of the existing data. An exogenous stressor, an immune defect, and a constitutional genetic defect fuel a vicious cycle of hematopoietic stem cells, immune niches, and stroma compartments. A wide phenotypic spectrum exists for inherited and acquired BM failures and predispositions to myeloid malignancies. In order to effectively manage patients, it is crucial to establish the right diagnosis. New theragnostic windows can be revealed by exploring BM failure pathomechanisms.
Complement 1q/tumor necrosis factor-related proteins (CTRPs): structure, receptors and signaling
(2023)
Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in the subunits of the complement protein C1q. We performed a basic PubMed literature search for articles mentioning the various CTRPs or their receptors in the abstract or title. In this narrative review, we briefly summarize the biology of CTRPs and focus then on the structure, receptors and major signaling pathways of CTRPs. Analyses of CTRP knockout mice and CTRP transgenic mice gave overwhelming evidence for the relevance of the anti-inflammatory and insulin-sensitizing effects of CTRPs in autoimmune diseases, obesity, atherosclerosis and cardiac dysfunction. CTRPs form homo- and heterotypic trimers and oligomers which can have different activities. The receptors of some CTRPs are unknown and some receptors are redundantly targeted by several CTRPs. The way in which CTRPs activate their receptors to trigger downstream signaling pathways is largely unknown. CTRPs and their receptors are considered as promising therapeutic targets but their translational usage is still hampered by the limited knowledge of CTRP redundancy and CTRP signal transduction.
Die CDI ist weltweit die häufigste Ursache der antibiotikaassoziierten nosokomialen Diarrhoe. Sie geht mit steigender Inzidenz, Hospitalisierung und hohen Behandlungskosten in Milliardenhöhe einher. Auch im ambulanten Sektor werden steigende Infektionszahlen gemeldet, die nicht nur ein Problem für die Krankenhäuser, sondern auch für die Pflegeeinrichtungen darstellen.
Ziel dieser Arbeit war es, retrospektiv die CDI-Fälle des Klinikums Aschaffenburg-Alzenau (ausgenommen Kinderklinik) im Zeitraum 01.01.2013 - 25.05.2015 zu erfassen und die antibiotische Initialtherapie zu ermitteln. Für die Diagnose einer CDI wurde ein positiver Toxinnachweis in der Stuhlkultur vorausgesetzt. Im weiteren Fokus standen die Rezidivhäufigkeit, die antibiotische Folgetherapie, die Komplikationen bis hin zu den Todesursachen sowie Präventionsmaßnahmen.
Im o.g. Zeitraum waren 299 Patienten und Patientinnen mit einer CDI hospitalisiert. Das mittlere Alter lag bei 73,8 Jahren. Es handelte sich in der Mehrzahl um multimorbide und immunsupprimierte Patienten und Patientinnen. 61% waren antibiotisch vorbehandelt. Am häufigsten verwendet wurden Breitbandpenicilline (36%), Cephalosporine der 3. Generation (12%) und Fluorchinolone (10%). Über 1/3 der Patienten und Patientinnen wurde mit Mehrfachkombinationen behandelt und bei 2% war eine zytostatische Behandlung vorausgegangen. In der Initialtherapie der CDI kam bei fast der Hälfte Erkrankten (47%) Metronidazol zur Anwendung. Die Rezidivrate lag bei 20%, Mehrfachrezidive traten bei 5,7% auf. Die antibiotische Folgetherapie der CDI erfolgte bei 39% der Patienten und Patientinnen mit Vancomycin oder Fidaxomicin entsprechend den damals geltenden Empfehlungen leitlinienkonform. Rund ¼ aller Erkrankten verstarben, davon 17% CDI-assoziiert. Der fäkale Stuhltransfer, der ab dem 2. Rezidiv empfohlen wird, und die Genotypisierung bei Mehrfachrezidiven wurde in keinem Fall durchgeführt.
2021 wurde die CDI-Behandlungsleitlinie der ESCMID aktualisiert. Statt dem Einsatz von Metronidazol werden nun Fidaxomicin oder Vancomycin, in Rezidivsituationen die Standardantibiose um den Antikörper Bezlotoxumab ergänzt. 06/2023 erschien die Konsultationsfassung der S2k-Leitlinie “Gastrointestinale Infektionen und Morbus Whipple” der DGVS. Die Empfehlungen gleichen sich.
Es kann festgehalten werden, dass die CDI auch im Klinikum Aschaffenburg-Alzenau ein ernstes Problem darstellt, das Präventionsmaßnahmen bedarf. Die Rezidiv- und
Todesraten sind hoch.
In dieser Arbeit konnte bestätigt werden, dass der unbedachte Einsatz von Antibiotika ein wichtiger Hauptrisikofaktor für die Entstehung einer CDI ist. Daher sollte die Indikation für eine antibiotische Therapie streng gestellt werden. Die Daten zeigen ferner, dass die Umsetzung aktueller Leitlinienempfehlungen nicht oder zeitlich verzögert erfolgte.
Seit der Etablierung und Umsetzung des ABS 2017 am Klinikum Aschaffenburg-Alzenau konnte ein Rückgang der CDI um 21% verzeichnet werden. Ein ABS ist eine Möglichkeit die konsequente Anwendung aktueller Empfehlungen im klinischen Alltag umzusetzen und so zu einer höheren Erfolgsrate der Behandlung und einer niedrigeren Rezidivrate beizutragen. Die Umsetzung einer gezielten frühen Diagnostik, Schutz- und Isoliermaßnahmen, Surveillance und regelmäßige Fort- und Weiterbildung der Mitarbeiter*innen sind weitere wichtige Bausteine, die zur Prävention der CDI beitragen.
In den letzten Jahrzehnten haben Inzidenz und Prävalenz von GEP NET deutlich zugenommen (Yao et al. 2008). Den SSTR kommt eine entscheidende Rolle bei zahlreichen etablierten Therapieverfahren zu. Allerdings stoßen die meisten Therapien bei G3 Tumoren oder bei langfristigem Einsatz an ihre Grenzen, was die Etablierung neuer, molekular zielgerichteter Therapien notwendig macht. Die Inhibition des Wnt-Signalweges stellt einen möglichen Ansatzpunkt für Therapien dar.
Ziel dieser Arbeit war es die Wirkung der Wnt-Modulatoren Quercetin und Lithiumchlorid auf die Wnt-Aktivität sowie die Expression von Somatostatinrezeptoren und CXCR4 in den neuroendokrinen Tumorzelllinien QGP-1 und BON-1 zu untersuchen.
Durch Real-Time PCR, Western Blots und Immunhistochemie wurden die Effekte auf RNA-, und Proteinebene sowie morphologisch analysiert und ausgewertet.
An den verwendeten Zelllinien konnte gezeigt werden, dass Quercetin die Wnt-Signalgebung inhibierte, die SSTR-Expression steigerte und die CXCR4-Expression senkte. Lithiumchlorid bewirkte eine Wnt-Aktivierung und konnte über diesen Weg eine gesteigerte Expression von CXCR4 erzielen.
Es konnte gezeigt werden, dass ein Zusammenhang zwischen der Aktivität des Wnt- Signalwegs und der Befähigung der GEP-NET Zelllinien zur SSTR- und CXCR4-Expression bestand.
Die Wnt-Inhibierung kann über den Effekt der Steigerung von SSTR Teil neuer Therapiestrategien sein. So ist z.B. eine „add-on“ Therapie von Wnt-Inhibitoren wie Quercetin zusammen mit der PRRT denkbar.
T-Zell-aktivierende Formate, wie BiTE (bispecific T-cell engagers) Antikörper und CAR T Zellen haben in den vergangen Jahren die Therapiemöglichkeiten für Tumorpatienten erweitert. Diese Therapeutika verknüpfen T-Zellen mit malignen Zellen über je ein spezifisches Oberflächenmolekül und initiieren, über eine T-Zell-vermittelte Immunantwort, die Lyse der Tumorzelle. Tumorspezifische Antigene sind jedoch selten. Häufig werden Proteine adressiert, die neben den Tumorzellen auch auf gesunden Zellen exprimiert werden. Die Folgen sind toxische Effekte abseits der Tumorzellen auf Antigen-positiven gesunden Zellen (on target/off tumor), welche nicht nur die Dosis des Therapeutikums und dessen Effektivität limitieren, sondern zu geringen bis letalen Begleiterscheinungen führen können. Der Bedarf an effektiven Therapieformen mit geringen Nebenwirkungen ist folglich immer noch sehr hoch. Diese Lücke soll durch ein neues Antikörperformat, sogenannten Hemibodies, geschlossen werden. Hemibodies sind eine neue Klasse von T-Zell-aktivierenden Antikörpern, die sich gegen eine Antigenkombination und nicht einzelne Antigene auf Tumorzellen richten. Sie bestehen aus zwei komplementären Molekülen mit je einer Antigen-bindenden Sequenz, die entweder mit der leichten (VL) oder der schweren (VH) Kette eines T-Zell-aktivierenden anti CD3 Antikörpers fusioniert ist. Nur wenn beide Hemibody-Fragmente gleichzeitig in unmittelbarer Nähe an ihr jeweiliges Antigenepitop auf der Tumorzelle binden, komplementieren die beiden Antikörperkonstrukte über das geteilte anti-CD3 und bilden einen trivalenten T Zell aktivierenden Komplex aus. Diese funktionale Einheit rekrutiert T-Zellen zur Tumorzelle und induzierte die T-Zell-vermittelte Lyse der malignen Zelle.
Im Rahmen der vorliegenden Arbeit wurden geeignete Antigenkombinationen identifiziert und die erste effektive und spezifische Hemibody-basierte Immuntherapie gegen das Multiple Myelom (MM), ohne Nebenwirkungen auf Antigen-einfach-positiven gesunden Zellen, entwickelt. Basierend auf einer umfangreichen Analyse von Kandidaten-Antigenen wurden Kombinationen aus bekannten MM Zielmolekülen, wie BCMA, CD38, CD138, CD229 und SLAMF7, und für das MM unbekannte Oberflächenmolekülen, wie CHRM5 und LAX1, untersucht. Gegen die vielversprechendsten Antigene wurden Hemibodies entwickelt und produziert. Im Zusammenhang mit Analysen zur Produzierbarkeit sowie biochemischen und funktionalen Charakterisierungen, konnte aus 75 initialen Hemibody-Kombinationen drei Kombinationen mit geeigneten Eigenschaften identifiziert werden. Die Bindung von zwei Hemibody-Partnern auf der Oberfläche der MM Zelle führte zur Ausbildung eines trivalenten T-Zell-rekrutierenden Komplexes. Dieser initiierte nachfolgend über eine T-Zell-vermittelte Immunantwort die spezifische Lyse der malignen Zellen, ohne die Viabilität von Antigen-einfach-positiven gesunden Körper- oder Effektor-Zellen zu beeinflussen. Zusätzlich führte eine Hemibody-Therapie in vivo in einem NOD SCID MM-Mausmodel innerhalb von 7 Tagen zur kompletten Remission der MM Zellen. Diese Daten zeigten Hemibodies als ein neues, sehr vielversprechendes Antikörperformat für eine effektive und tumorspezifische Immuntherapie mit potentiell geringen Nebenwirkungen.
Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.
This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile.
Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) has been originally identified as a protein interacting with TNF receptor 2 (TNFR2) but also binds to several other receptors of the TNF receptor superfamily (TNFRSF). TRAF2, often in concert with other members of the TRAF protein family, is involved in the activation of the classical NFκB pathway and the stimulation of various mitogen-activated protein (MAP) kinase cascades by TNFRSF receptors (TNFRs), but is also required to inhibit the alternative NFκB pathway. TRAF2 has also been implicated in endoplasmic reticulum (ER) stress signaling, the regulation of autophagy, and the control of cell death programs. TRAF2 fulfills its functions by acting as a scaffold, bringing together the E3 ligase cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 with their substrates and various regulatory proteins, e.g., deubiquitinases. Furthermore, TRAF2 can act as an E3 ligase by help of its N-terminal really interesting new gene (RING) domain. The finding that TRAF2 (but also several other members of the TRAF family) interacts with the latent membrane protein 1 (LMP1) oncogene of the Epstein–Barr virus (EBV) indicated early on that TRAF2 could play a role in the oncogenesis of B-cell malignancies and EBV-associated non-keratinizing nasopharyngeal carcinoma (NPC). TRAF2 can also act as an oncogene in solid tumors, e.g., in colon cancer by promoting Wnt/β-catenin signaling. Moreover, tumor cell-expressed TRAF2 has been identified as a major factor-limiting cancer cell killing by cytotoxic T-cells after immune checkpoint blockade. However, TRAF2 can also be context-dependent as a tumor suppressor, presumably by virtue of its inhibitory effect on the alternative NFκB pathway. For example, inactivating mutations of TRAF2 have been associated with tumor development, e.g., in multiple myeloma and mantle cell lymphoma. In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes.
Die molekulare Chimärismusdiagnostik stellt einen essenziellen Teil der Therapieüberwachung nach allogener HSZT dar. In der Uniklinik Würzburg wird hierbei mittels qPCR eines Panels von 21 Allelen eine Informativität von 95 % und eine Sensitivität von 0,1-0,01 % erreicht. Ziel der Arbeit war eine Optimierung dieser in unserem Labor angewandten Methode zur Chimärismusanalyse in puncto Sensitivität und Informativität.
Es wurde untersucht, ob durch Steigerung des DNA-Inputs in die qPCR eine Sensitivitätserhöhung erzielt werden kann, ohne dass PCR-Inhibition auftritt. Dabei erwies sich ein DNA-Input von 250 ng als ideal für eine verlässlichere Detektion von 0,01 % Empfängerzellen. PCR-Inhibition trat nicht auf. Zur Deckung des damit einhergehendem erhöhten DNA-Bedarf wurden verschiedene Elutionsmethoden der DNA-Extraktion verglichen, wobei durch Extraktion mit dem QIAamp DNA Blood Midi-Kit und Elution mit 2 x 200 μl AE-Puffer der höchste DNA-Ertrag gewonnen wurde.
Zur Erhöhung der Informativität wurde die Anwendbarkeit eines Primersets für qPCR des SNP rs713753 evaluiert. Hierbei zeigte sich eine mäßige Eignung: Beide Allele des SNP gemeinsam ergaben eine gute Informativität für Empfängerdiskriminierung von 37,5 %. Die qPCR-Effizienzen der lokusspezifischen Referenz und des Allels C waren nahezu optimal, die des Allels T lag lediglich bei 0,87. Die Sensitivität der spezifischen Allele lag bei max. 0,1 %. Sofern auch hier eine Sensitivitätssteigerung durch Erhöhung des DNA-Inputs in die qPCR ohne Auftreten unspezifischer Amplifikation möglich ist, wäre eine Integration der qPCR des SNP rs713753 in die Routinediagnostik denkbar.
Zusammenfassend ist eine Optimierung der in unserem Labor angewandten Methode zur Chimärismusdiagnostik hinsichtlich Sensitivität und Informativität durchaus möglich. Eine Erhöhung des DNA-Inputs ist dabei am simpelsten umsetzbar; zur Etablierung weiterer Allele bedarf es zusätzlicher Experimente.
Aspergillus fumigatus ist ein opportunistisches fungales Humanpathogen, das ein breites Erkrankungsspektrum von der invasiven Aspergillose (IA) in immunkompromittierten Patienten bis zu einer Reihe von Hypersensitivitätserkrankungen in immunkompetenten Individuen hervorrufen kann. Die Diagnostik für A. fumigatus assoziierte Krankheitsbilder beruht auf mehreren diagnostischen Tests, die auch in ihrer Kombination oft zu späten und unzuverlässigen Diagnosen führen, was wiederum zu einer suboptimalen Patientenversorgung, erhöhter Mortalität und gesteigerten Kosten für das Gesundheitssystem führt. Es besteht daher die unbedingte Notwendigkeit, neue und bessere diagnostische Tests zur Detektion von A. fumigatus zu entwickeln. T Zell Assays sind vielversprechende, innovative diagnostische Tests, die bereits für andere Infektionskrankheiten in der Routinediagnostik eingesetzt werden. Erste Versuche wurden bereits unternommen, diese Assays auch für A. fumigatus assoziierte Erkrankungen einzusetzen. Die gängigsten, auf mononukleären Zellen des peripheren Blutes (PBMC)-basierten T Zell Assays sind der Enzyme-linked Immunosorbent Assay (ELISA), Enzyme-linked Immuno Spot Assay (ELISPOT) und die Durchflusszytometrie. Das Ziel dieser Dissertation war die Entwicklung eines klinisch einsetzbaren T-Zell-Assays für A. fumigatus assoziierte Erkrankungen.
Die in der Literatur beschriebenen Assays zeigten in unseren Experimenten bei der Anwendung für mykologische Fragestellungen eine hohe Suszeptibilität gegenüber bereits kurzen präanalytischen Lagerzeiten und Krykonservierung, was einen klinischen Einsatz erschwerte. Wir entwickelten deshalb einen Vollblut basierten ELISA (VB-ELISA) mit dualer Kostimulation (α-CD28 und α-CD49d), hoher Reproduzierbarkeit und verbesserter Robustheit gegenüber präanalytischen Einflussfaktoren. Der VB ELISA konnte hohe Differenzen zwischen Typ 1 T Helferzellen (Th1) , Th2 und Th17 Zytokinkonzentrationen bei Patienten mit Aspergillus assoziierten Hypersensitivitätskrankheitsbildern und Kontrollpatienten feststellen. Um zu testen, ob dieser Anstieg auf die Erkrankung zurückzuführen ist oder auch bei hoher Aspergillus-Umweltexposition vorzufinden ist, wurde der Assay in Aspergillus exponierten gesunden ökologischen Landwirten getestet. In dieser Gruppe fanden wir ebenfalls eine erhöhte Th1 und Th2 Expansion und Zytokinsekretion gegenüber gesunden Kontrollspendern, jedoch wurde nur ein geringer Anstieg des Th17 Signalzytokines IL-17 detektiert. Die Detektion von IL-17 im VB-ELISA in Kombination mit anderen Zytokinmarkern ist daher ein vielversprechender Biomarker für die Diagnose von A. fumigatus assoziierten Hypersensitivitätserkrankungen.
Neben diesen Hypersensitivitätserkrankungen haben wir den VB-ELISA auch in immunkompromittierten Patienten nach allogener Stammzelltransplantation (alloSZT), einer Hochrisikogruppe für die IA und die durch das humane Cytomegalovirus (HCMV) ausgelöste Zytomegalie, evaluiert. Während in unserer monozentrischen Pilotstudie aufgrund der geringen Inzidenz keine Evaluation an IA-Patienten erfolgen konnte, wurde mittels VB-ELISA eine hohe Konkordanz der HCMV-spezifischen T Zell Antwort mit der HCMV Serologie sowie eine vergleichbare Leistung zum ELISPOT, dem am häufigsten eingestetzen Assay für diese Fragestellung, festgestellt.
Zusammenfassend haben wir mit dem VB ELISA einen vielversprechenden und breitflächig im Spektrum A. fumigatus assoziierter Erkrankungen einsetzbaren T Zell Assay entwickelt, der in der Zukunft in großen Studien mit klar definierten Patientenkohorten getestet werden sollte. Auf Grund von Daten aus Folgestudien, die auf dieser Arbeit basieren, ist des Weiteren davon auszugehen, dass der VB-ELISA auf Grund seiner Stärken potenziell in einer Vielzahl von Anwendungsgebieten und Pathogenen (eine Folgestudie mit SARS-CoV-2 wurde vor kurzem veröffentlicht) universell eingesetzt werden kann. Neben der Immundiagnostik für diverse Infektionserkrankungen könnte der Assay außerdem für T Zell Antworten auf Vakzinierungen und Immuntherapien, in vivo Experimente und in vitro Toxizitätstests verwendet werden.
Die Nicht-alkoholische Fettlebererkrankung (NAFLD) ist eine der häufigsten chronischen Lebererkrankungen der westlichen Welt. Die Pathogenese der Erkrankung ist noch nicht vollständig erforscht und wirksame medikamentöse Therapien sind bisher nicht zugelassen. Wachsende Evidenz zeigt, dass das Interleukin-6-Typ-Zytokin Oncostatin M (OSM) eine wichtige Rolle in der Pathogenese der NAFLD spielt. Die japanische Arbeitsgruppe um Komori et al. zeigte an OSM-Rezeptor-β-defizienten (Osmr-KO-) Mäusen sowie durch OSM-Behandlung von genetisch und ernährungsbedingt adipösen Mäusen, dass OSM vor einer hepatischen Steatose und metabolischer Komorbidität schützen kann. Andere Publikationen suggerieren, dass OSM an NAFLD-Entwicklung und -Progression beteiligt ist, indem es die Expression von Genen der β-Oxidation und Very-Low-Density-Lipoprotein (VLDL-) Sekretion reprimiert und die Expression profibrogenetischer Gene fördert. Low-Density-Lipoprotein-Rezeptor-defiziente- (Ldlr-KO-) Mäuse sind seit Langem als Atherosklerose-Modell etabliert und wurden zuletzt auch als physiologisches Modell für NAFLD identifiziert.
Um die Rolle von OSM in der NAFLD-Pathogenese zu beleuchten, wurden Osmr-KO-Mäuse auf Wildtyp- (WT-) und Ldlr-KO-Hintergrund untersucht, die über 12 Wochen eine fett- und cholesterinreiche Western Diet erhielten und anschließend für die Organentnahme geopfert wurden. Im Vorfeld dieser Arbeit wurden Körpergewicht, Blutglukose, Serum-Cholesterin und Lebergewicht der Tiere gemessen. Hierbei zeigte sich ein erhöhtes Körpergewicht, unveränderte Blutglukose, erhöhtes Serum-Cholesterin sowie ein erhöhtes Lebergewicht in Osmr-KO- gegenüber WT-Mäusen. Andersherum waren Körpergewicht, Blutglukose, Serum-Cholesterin und Lebergewicht in Ldlr-Osmr-KO- gegenüber Ldlr-KO-Mäusen vermindert. Im Rahmen der vorliegenden Arbeit erfolgte die histologische Untersuchung des Lebergewebes, die Messung von Serum-Triglyzeriden und Fettsäuren sowie die Untersuchung der hepatischen Genexpression. An kultivierten Zellen der humanen Hepatom-Zelllinie HepG2 wurde eine mögliche Regulation der CYP7A1-Genexpression durch OSM untersucht. CYP7A1 ist als Schrittmacherenzym der Gallensäuresynthese an der hepatischen Cholesterin-Clearance beteiligt.
Osmr-KO-Mäuse zeigten gegenüber WT-Mäusen histologisch eine verstärkte hepatische Steatose. Bei der Untersuchung der mRNA-Expression von Genen mit Beteiligung an der hepatischen Lipidhomöostase zeigte sich eine Minderexpression von Ldlr in Osmr-KO-Mäusen. Weiterhin zeigte sich eine etwas geringere Expression von Cyp7a1 in Osmr-KO-Mäusen. Die Expression aller anderen untersuchten Gene, die an Fettsäuresynthese, Cholesterintransport und –metabolismus beteiligt sind, lieferten keine Erklärung für eine erhöhte hepatische Lipidakkumulation in Osmr-KO-Mäusen. Ldlr-Osmr-KO-Mäuse hatten gegenüber Ldlr-KO-Mäusen eine geringer ausgeprägte hepatische Steatose. Die mRNA-Expression von Genen der Fettsäuresynthese, der Cholesterinbiosynthese und des Cholesterintransports waren in Ldlr-Osmr-KO- gegenüber Ldlr-KO-Mäusen nicht wesentlich verändert. Allerdings fiel eine deutliche Hochregulation von Cyp7a1 in Ldlr-Osmr-KO-Mäusen auf. Darüber hinaus war Osm in Ldlr-KO-Mäusen gegenüber WT-Mäusen stärker exprimiert. Um eine Regulation von CYP7A1 durch OSM nachzuweisen, wurde die Genexpression in HepG2-Zellen nach Stimulation mit OSM untersucht. Hierbei zeigte sich, dass OSM die mRNA-Expression von CYP7A1 supprimierte. Dieser Effekt war durch die Zugabe von Inhibitoren der Januskinasen (JAK), Mitogen Activated Protein Kinase/ERK-Kinase (MEK) und Extracellular-signal Regulated Kinase ½ (ERK1/2) reversibel. Die CYP7A1-Suppression durch OSM ging mit einer verminderten Expression des Transkriptionsfaktor-Gens HNF4A einher.
Osmr-KO-Mäuse zeigten gegenüber WT-Mäusen nach 12 Wochen Western Diet verstärkte Adipositas, Dyslipidämie sowie eine hepatische Steatose. Die Analyse der hepatischen mRNA-Expression legt nahe, dass die Minderexpression von Ldlr in Osmr-KO-Mäusen im Vergleich zu WT-Mäusen zur Verstärkung der Dyslipidämie und hepatischen Steatose beigetragen hat. Weiterhin kann die geringere Expression von Cyp7a1 in Osmr-KO-Mäusen durch daraus resultierende Akkumulation von Cholesterin zur erhöhten hepatischen Lipidakkumulation in diesen Mäusen beigetragen haben. Ldlr-KO-Mäuse zeigten nach 12 Wochen Western Diet ebenfalls eine hepatische Steatose. Diese war in Ldlr-Osmr-KO-Mäusen gegenüber Ldlr-KO-Mäusen geringer ausgeprägt. Die erhöhte Expression von Cyp7a1 in Ldlr-Osmr-KO-Mäusen kann die Verbesserung von hepatischer Lipidakkumulation und Dyslipidämie durch erhöhte Cholesterinmetabolisierung zu Gallensäuren erklären. Übereinstimmend mit der Cyp7a1-Regulation in LDLR-defizienten Mäusen zeigte sich in vitro, dass OSM die Expression von CYP7A1 in HepG2-Zellen vermindert und sich so negativ auf die hepatische Lipidhomöostase auswirken kann. Insgesamt implizieren diese Ergebnisse eine divergierende Rolle von OSM bei der Entwicklung einer hepatischen Steatose abhängig vom genetischen Hintergrund. OSM scheint bei WT-Mäusen für die Erhaltung der metabolischen Gesundheit wichtig zu sein. Bei Ldlr-KO-Mäusen hingegen scheint OSM die Entwicklung von Adipositas, Dyslipidämie und hepatischer Steatose zu fördern. Die differenzielle Rolle in WT- und Ldlr-KO-Mäusen könnte durch unterschiedliche Osm-Expressionsspiegel zustande kommen: Während basale OSMRβ-Signaltransduktion durch geringe OSM-Spiegel in WT-Mäusen für die Lipidhomöostase essenziell zu sein scheint, könnte erhöhte oder prolongierte OSMRβ-Signaltransduktion durch höhere OSM-Spiegel in Ldlr-KO-Mäusen das Fortschreiten der hepatischen Steatose fördern. Dies stellt OSM als mögliches NAFLD-Therapeutikum in Frage. Um die Hypothese zu überprüfen, dass OSM abhängig von der Höhe und Kinetik der Spiegel günstige oder ungünstige Effekte auf die NAFLD-Entwicklung hat, sollte in zukünftigen Experimenten der Einfluss kurz- und langfristiger Behandlung von WT-Mäusen mit OSM unterschiedlicher Konzentrationen auf die Entwicklung einer hepatischen Steatose untersucht werden.
Background: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. Cases: Severe pancytopenia with grade 2-3 anemia was marked 2–3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb's tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. Conclusion: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism.
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.
Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life “American lifestyle-induced obesity syndrome” (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r\(^{−/−}\)- but not Il-1r\(^{−/−}\) mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.
Due to the low frequency of abnormalities affecting the spleen, this organ is often overlooked during radiological examinations. Here, we report on the unexpected finding, that the spleen signal on diffusion-weighted MRI (DW-MRI) is associated with clinical parameters in patients with plasma cell dyscrasias. Methods: We investigated the spleen signal on DW-MRI together with clinical and molecular parameters in 295 transplant-eligible newly diagnosed Multiple Myeloma (NDMM) patients and in 72 cases with monoclonal gammopathy of undetermined significance (MGUS). Results: Usually, the spleen is the abdominal organ with the highest intensities on DW-MRI. Yet, significant signal loss on DW-MRI images was seen in 71 of 295 (24%) NDMM patients. This phenomenon was associated with the level of bone marrow plasmacytosis (P=1x10(-10)) and International Staging System 3 (P=0.0001) but not with gain(1q), and del(17p) or plasma cell gene signatures. The signal was preserved in 72 individuals with monoclonal gammopathy of undetermined significance and generally re-appeared in MM patients responding to treatment, suggesting that lack of signal reflects increased tumor burden. While absence of spleen signal in MM patients with high risk disease defined a subgroup with very poor outcome, re-appearance of the spleen signal after autologous stem cell transplantation was seen in patients with improved outcome. Our preliminary observation suggests that extramedullary hematopoiesis in the spleen is a factor that modifies the DW-MRI signal of this organ. Conclusions: The DW-MRI spleen signal is a promising marker for tumor load and provides prognostic information in MM.
Im Rahmen dieser Studie wurde die Lebensqualität (QoL) von Patienten mit Multiplem Myelom zu verschiedenen Therapiezeitpunkten untersucht. Dabei erwies sich die erstmals im Rahmen einer Studie mit Myelompatienten angewandte Kombination aus PHQ-4, EORTC QLQ-C30 und dem spezifischen -MY20 Fragebogen als geeignetes Instrument zur validen Erfassung von Ängstlichkeit/Depressivität und Lebensqualität. Insgesamt schätzten Erstlinienpatienten, Männer und jüngere Patienten vor, während und nach der Therapie ihre Lebensqualität positiver ein, sodass insbesondere Rezidivpatienten, Frauen und ältere Patienten von einer intensivierten therapiebegleitenden supportiven Betreuung profitieren könnten. Es sollte bei der Therapiewahl berücksichtigt werden, dass Erstlinienpatienten zum einen über eine insgesamt bessere allgemeine QoL und geringere Schmerzen als Rezidivpatienten berichteten und zum anderen es durch die systemische Therapie bei diesen zu einer weiteren Verbesserung kommen kann. Unabhängig hiervon korrelierte der ECOG-Status signifikant mit der QoL und sollte daher regelmäßig erhoben werden. Während der Therapie kam es bei Myelompatienten v.a. zu einer negativeren Wahrnehmung des eigenen Körperbilds, einer Abnahme der kognitiven Funktion und einer Zunahme der Therapienebenwirkungen, sodass interdisziplinäre Behandlerteams neben einem optimalen Nebenwirkungsmanagement auch in der klinischen Routine noch nicht so fest etablierte Ressourcen berücksichtigen sollten, wie z.B. psychoedukative Interventionen, Entspannungsverfahren oder auch kognitives Training. Eine der wichtigsten Erkenntnisse der Studie war die signifikant reduzierte Lebensqualität bei Patienten mit vermehrter Ängstlichkeit/Depressivität, die die Notwendigkeit eines regelmäßigen Screenings in der klinischen Routine aufzeigt, um Risikopatienten entsprechend zu identifizieren. Trotz der vermuteten Lebensqualitätsbeeinflussung durch die intensivere, längere Therapie, zeigten sich bei Tandemtransplantierten nicht mehr Lebensqualitätsvariablen signifikant negativ beeinflusst als beim Gesamtkollektiv, sodass diese Beobachtung eine wertvolle Entscheidungshilfe für Patienten sein könnte, die aus Sorge vor einer reduzierten Lebensqualität transplantationsbasierten Konzepten zurückhaltend gegenüberstehen. Unter Berücksichtigung der o.g. Limitationen, konnte zusätzlich eine deutliche positive Beeinflussung der Lebensqualität durch Teilnahme an klinischen Therapiestudien aufgezeigt werden, sodass Patienten evtl. von einer noch intensiveren multiprofessionellen Begleitung wie sie in Studiensettings gegeben ist profitieren könnten.
The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for HLA-E, in order to study the effect of HLA-E as a natural killer (NK)-alloreactivity mediator on HSCT outcome in an acute leukemia (AL) setting. Overall survival (OS), disease free survival (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were set as endpoints. Analysis of our data revealed a significant correlation between HLA-E mismatch and improved HSCT outcome, as shown by both univariate (53% vs. 38%, P=0.002, 5-year OS) and multivariate (hazard ratio (HR)=0.63, confidence interval (CI) 95%=0.48–0.83, P=0.001) analyses. Further subgroup analysis demonstrated that the positive effect of HLA-E mismatch was significant and pronounced in advanced disease patients (n=120) (5-year OS: 50% vs. 18%, P=0.005; HR=0.40, CI 95%=0.22–0.72, P=0.002; results from univariate and multivariate analyses, respectively). The study herein is the first to report an association between HLA-E incompatibility and improved post–transplant prognosis in AL patients who have undergone matched unrelated HSCT. Combined NK and T cell HLA-E-mediated mechanisms may account for the better outcomes observed. Notwithstanding the necessity for in vitro and confirmational studies, our findings highlight the clinical relevance of HLA-E matching and strongly support prospective HLA-E screening upon donor selection for matched AL unrelated HSCTs.
Using data from the German Hepatitis C-Registry (Deutsche Hepatitis C-Register, DHC-R), we report the real-world safety and effectiveness of glecaprevir/pibrentasvir (GLE/PIB) treatment and its impact on patient-reported outcomes (PROs) in underserved populations who are not typically included in clinical trials, yet who will be crucial for achieving hepatitis C virus (HCV) elimination. The DHC-R is an ongoing, non-interventional, multicenter, prospective, observational cohort study on patients treated for chronic HCV infection in Germany. The data cutoff was 17 January 2021. The primary effectiveness endpoint was sustained virologic response at post-treatment Week 12 (SVR12). Safety outcomes were assessed in all patients receiving GLE/PIB. PROs were assessed using the SF-36 survey. Of 2354 patients, 1964 had valid SVR12 data (intention-to-treat analysis). Of these, 1905 (97.0%) achieved SVR12 with rates similar across the comorbidities analyzed, except for people who actively use drugs (PWUD (active)) (86.4%). Excluding those who discontinued treatment and did not achieve SVR12, or were reinfected with HCV, the rate was 99.3%, with similar results regardless of comorbidity. PWUD (active) and those with psychiatric disorders had the most meaningful improvements in PROs. Adverse events (AEs) occurred in 631/2354 patients (26.8%), and serious AEs in 44 patients (1.9%). GLE/PIB was highly effective and well tolerated in this real-world study of patient groups key to HCV elimination.
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.
The optimal treatment sequence of tyrosine kinase inhibitor (TKI)-based therapy in patients with hepatocellular carcinoma (HCC) remains unclear. Therefore, sequential systemic therapy after first-line therapy with sorafenib or lenvatinib was compared in a retrospective real-world cohort. In total, 164 patients with HCC were included. Child B cirrhosis was present in 26 patients (16.5%), whereas 132 patients (83.5%) had preserved liver function. In total, 72 patients (44%) discontinued systemic therapy after first-line therapy while 51 (31%) and 31 (19%) patients received 2 or more treatment lines. Most notably, median overall survival (mOS) was influenced by liver functional status and patient performance status at the beginning of first-line therapy. Patients receiving a sequential therapy regimen had significantly longer mOS compared to patients that discontinued systemic therapy after omitting first-line treatment. The choice of the initial TKI did not impact mOS. A clear deterioration of liver function could be observed during the course of TKI-based treatment.
Cancer-related fatigue (CRF) is a burdensome sequela of cancer treatments. Besides exercise, recommended therapies for CRF include yoga, psychosocial, and mindfulness-based interventions. However, interventions conducted vary widely, and not all show a significant effect. This meta-analysis aimed to explore intervention characteristics related to greater reductions in CRF. We included randomized controlled trials published before October 2021. Standardized mean differences were used to assess intervention efficacy for CRF and multimodel inference to explore intervention characteristics associated with higher efficacy. For the meta-analysis, we included 70 interventions (24 yoga interventions, 31 psychosocial interventions, and 15 mindfulness-based interventions) with 6387 participants. The results showed a significant effect of yoga, psychosocial, and mindfulness-based interventions on CRF but with high heterogeneity between studies. For yoga and mindfulness-based interventions, no particular intervention characteristic was identified to be advantageous for reducing CRF. Regarding psychosocial interventions, a group setting and work on cognition were related to higher intervention effects on CRF. The results of this meta-analysis suggest options to maximize the intervention effects of psychosocial interventions for CRF. The effects of yoga and mindfulness-based interventions for CRF appear to be independent of their design, although the limited number of studies points to the need for further research.
In early 2022, the Coronavirus disease 2019 (COVID-19) remains a global challenge. COVID-19 is caused by an increasing number of variants of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we report an outbreak of SARS-CoV-2 breakthrough infections related to a student festive event with 100 mostly vaccinated guests, which took place in Northern Bavaria, Germany, in October 2021. The data were obtained by retrospective guest interviews. In total, 95 students participated in the study, with 94 being fully vaccinated and 24 reporting infection by the delta variant. Correlation analyses among 15 examined variables revealed that time spent at the event, conversation with the supposed index person, and a homologous viral vector vaccination regime were significant risk factors for infection. Non-significant observations related to higher rates of infection included time since last vaccination, shared use of drinking vessels, and number of individual person-to-person contacts at the event. Our data suggest that a high rate of breakthrough infections with the delta variant occurs if no preventive measures are practiced. To limit infection risk, high-quality testing of participants should be considered a mandatory measure at gatherings, irrespective of the participants' vaccination status.
Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (−0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.
Occupational mold exposure can lead to Aspergillus-associated allergic diseases including asthma and hypersensitivity pneumonitis. Elevated IL-17 levels or disbalanced T-helper (Th) cell expansion were previously linked to Aspergillus-associated allergic diseases, whereas alterations to the Th cell repertoire in healthy occupationally exposed subjects are scarcely studied. Therefore, we employed functional immunoassays to compare Th cell responses to A. fumigatus antigens in organic farmers, a cohort frequently exposed to environmental molds, and non-occupationally exposed controls. Organic farmers harbored significantly higher A. fumigatus-specific Th-cell frequencies than controls, with comparable expansion of Th1- and Th2-cell frequencies but only slightly elevated Th17-cell frequencies. Accordingly, Aspergillus antigen-induced Th1 and Th2 cytokine levels were strongly elevated, whereas induction of IL-17A was minimal. Additionally, increased levels of some innate immune cell-derived cytokines were found in samples from organic farmers. Antigen-induced cytokine release combined with Aspergillus-specific Th-cell frequencies resulted in high classification accuracy between organic farmers and controls. Aspf22, CatB, and CipC elicited the strongest differences in Th1 and Th2 responses between the two cohorts, suggesting these antigens as potential candidates for future bio-effect monitoring approaches. Overall, we found that occupationally exposed agricultural workers display a largely balanced co-expansion of Th1 and Th2 immunity with only minor changes in Th17 responses.
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.
Einführung: Beim Multiplen Myleom handelt es sich um eine bösartige Proliferation der Plasmazellen, wenn es auch nur 1% aller bösartigen Erkrankungen ausmacht, muss angesichts der steigenden Lebenserwartung von einer Zunahme der Fälle ausgegangen werden.
Methoden: Diese Dissertation soll als Übersichtsarbeit zur QoL und Coping bei MM-Patienten und deren Angehörigen dienen. Es konnten 101 relevante Studien in der Literaturrecherche gefunden werden.
Resultate: In allen Bereichen lag bei MM-Patienten, abgesehen von frühen Stadien oder bei Patienten mit CR, eine schlechtere QoL als bei der Referenzpopulation vor. Diese Ergebnisse waren unabhängig vom verwendeten QoL-Erhebungsinstrument. Vor allem die Tatsache, dass Multiples Myleom unheilbar ist, ist für die Patienten sehr belastend. Es lagen die unterschiedlichsten Coping-Mechanismen bei den Patienten und deren Angehörigen vor. Soziale Unterstützung war meistens der QoL förderlich, wenn es auch problematische Formen gab. Es konnten diverse, teils widersprüchliche Korrelationen von QoL und demographischen Faktoren, wie Alter und Geschlecht gefunden werden.
Diskussion: Auch wenn in den letzten Jahren vermehrt in diesem Gebiet geforscht wurde, gestaltete es sich als schwierig Studien zu dem Thema zu finden und es bleibt zu hoffen, dass zukünftig ein größerer Fokus hier gelegt wird.
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.
Background
The efficiency of artificial intelligence as computer-aided detection (CADe) systems for colorectal polyps has been demonstrated in several randomized trials. However, CADe systems generate many distracting detections, especially during interventions such as polypectomies. Those distracting CADe detections are often induced by the introduction of snares or biopsy forceps as the systems have not been trained for such situations. In addition, there are a significant number of non-false but not relevant detections, since the polyp has already been previously detected. All these detections have the potential to disturb the examiner's work.
Objectives
Development and evaluation of a convolutional neuronal network that recognizes instruments in the endoscopic image, suppresses distracting CADe detections, and reliably detects endoscopic interventions.
Methods
A total of 580 different examination videos from 9 different centers using 4 different processor types were screened for instruments and represented the training dataset (519,856 images in total, 144,217 contained a visible instrument). The test dataset included 10 full-colonoscopy videos that were analyzed for the recognition of visible instruments and detections by a commercially available CADe system (GI Genius, Medtronic).
Results
The test dataset contained 153,623 images, 8.84% of those presented visible instruments (12 interventions, 19 instruments used). The convolutional neuronal network reached an overall accuracy in the detection of visible instruments of 98.59%. Sensitivity and specificity were 98.55% and 98.92%, respectively. A mean of 462.8 frames containing distracting CADe detections per colonoscopy were avoided using the convolutional neuronal network. This accounted for 95.6% of all distracting CADe detections.
Conclusions
Detection of endoscopic instruments in colonoscopy using artificial intelligence technology is reliable and achieves high sensitivity and specificity. Accordingly, the new convolutional neuronal network could be used to reduce distracting CADe detections during endoscopic procedures. Thus, our study demonstrates the great potential of artificial intelligence technology beyond mucosal assessment.
Despite high levels of distress, family caregivers of patients with cancer rarely seek psychosocial support and Internet-based interventions (IBIs) are a promising approach to reduce some access barriers. Therefore, we developed a self-guided IBI for family caregivers of patients with cancer (OAse), which, in addition to patients' spouses, also addresses other family members (e.g., adult children, parents). This study aimed to determine the feasibility of OAse (recruitment, dropout, adherence, participant satisfaction). Secondary outcomes were caregivers’ self-efficacy, emotional state, and supportive care needs. N = 41 family caregivers participated in the study (female: 65%), mostly spouses (71%), followed by children (20%), parents (7%), and friends (2%). Recruitment (47%), retention (68%), and adherence rates (76% completed at least 4 of 6 lessons) support the feasibility of OAse. Overall, the results showed a high degree of overall participant satisfaction (96%). There were no significant pre-post differences in secondary outcome criteria, but a trend toward improvement in managing difficult interactions/emotions (p = .06) and depression/anxiety (p = .06). Although the efficacy of the intervention remains to be investigated, our results suggest that OAse can be well implemented in caregivers’ daily lives and has the potential to improve family caregivers’ coping strategies.
Invasive fungal infections are associated with increased mortality in hematological patients. Despite considerable advances in antifungal therapy, the evaluation of suspected treatment failure is a common clinical challenge requiring extensive diagnostic testing to rule out potential causes, such as mixed infections. We present a 64-year-old patient with secondary AML, diabetes mellitus, febrile neutropenia, and sinusitis. While cultures from nasal tissue grew Aspergillus flavus, a microscopic examination of the tissue was suggestive of concomitant mucormycosis. However, fluorescence in situ hybridization (FISH) using specific probes targeting Aspergillus and Mucorales species ruled out mixed infection. This was confirmed by specific qPCR assays amplifying the DNA of Aspergillus, but not of Mucorales. These results provided a rational basis for step-down targeted therapy, i.e., the patient received posaconazole after seven days of calculated dual therapy with liposomal amphotericin B and posaconazole. Despite clinical response to the antifungal therapy, he died due to the progression of the underlying disease within two weeks after diagnosis of fungal infection. Molecular diagnostics applied to tissue blocks may reveal useful information on the etiology of invasive fungal infections, including challenging situations, such as with mixed infections. A thorough understanding of fungal etiology facilitates targeted therapy that may improve therapeutic success while limiting side effects.
Altered features of tumor cells acquired across therapy can result in the survival of treatment-resistant clones that may cause minimal residual disease (MRD). Despite the efficacy of ibrutinib in treating relapsed/refractory mantle cell lymphoma, the obstacle of residual cells contributes to relapses of this mature B-cell neoplasm, and the disease remains incurable. RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line following ibrutinib incubation of up to 4 d, corroborated our previously postulated resistance mechanism of a metabolic switch to reliance on oxidative phosphorylation (OXPHOS) in surviving cells. Besides, we had shown that treatment-persisting cells were characterized by increased CD52 expression. Therefore, we hypothesized that combining ibrutinib with another agent targeting these potential escape mechanisms could minimize the risk of survival of ibrutinib-resistant cells. Concomitant use of ibrutinib with OXPHOS-inhibitor IACS-010759 increased toxicity compared to ibrutinib alone. Targeting CD52 was even more efficient, as addition of CD52 mAb in combination with human serum following ibrutinib pretreatment led to rapid complement-dependent-cytotoxicity in an ibrutinib-sensitive cell line. In primary mantle cell lymphoma cells, a higher toxic effect with CD52 mAb was obtained, when cells were pretreated with ibrutinib, but only in an ibrutinib-sensitive cohort. Given the challenge of treating multi-resistant mantle cell lymphoma patients, this work highlights the potential use of anti-CD52 therapy as consolidation after ibrutinib treatment in patients who responded to the BTK inhibitor to achieve MRD negativity and prolong progression-free survival.
Growing evidence points to multiple myeloma (MM) and its stromal microenvironment using several mechanisms to subvert effective immune and anti-tumor responses. Recent advances have uncovered the tumor-stromal cell influence in regulating the immune-microenvironment and have envisioned targeting these suppressive pathways to improve therapeutic outcomes. Nevertheless, some subgroups of patients include those with particularly unfavorable prognoses. Biological stratification can be used to categorize patient-, disease- or therapy-related factors, or alternatively, these biological determinants can be included in a dynamic model that customizes a given treatment to a specific patient. Genetic heterogeneity and current knowledge enforce a systematic and comprehensive bench-to-bedside approach. Given the increasing role of cancer stem cells (CSCs) in better characterizing the pathogenesis of solid and hematological malignancies, disease relapse, and drug resistance, identifying and describing CSCs is of paramount importance in the management of MM. Even though the function of CSCs is well-known in other cancer types, their role in MM remains elusive. With this review, we aim to provide an update on MM homing and resilience in the bone marrow micro milieu. These data are particularly interesting for clinicians facing unmet medical needs while designing novel treatment approaches for MM.
Background
Multiple myeloma (MM) is the third most common hematologic malignancy with increasing importance due to improving treatment strategies and long-term outcomes in an aging population. This study aims to analyse influencing factors on health-related quality of life (HRQoL), such as treatment strategies, participation in a clinical trial and patient characteristics like anxiety, depression, gender, and age. A better understanding of the individual factors in context with HRQoL could provide a helpful instrument for clinical decisions.
Methods
In this prospective observational study, the HRQoL of MM patients with different therapies (first-line and relapse) was quantified by standardized questionnaires (EORTC QLQ-C30 and -MY20) in the context of sociodemographic data, individual anxiety and depressiveness (PHQ-4), and a selected number of clinical parameters and symptoms at defined time-points before, during, and after therapy.
Results
In total, 70 patients were included in the study. The median age of the study cohort was 62 years. 44% were female and 56% were male patients. More than half of the patients were fully active with an ECOG 0. Global health status was significantly higher in patients with first-line treatment and even increased after start of therapy, while the pain level decreased. In contrast, patients with relapsed MM reported a decreasing global health status and increasing pain. Additionally, there was a higher global health status in less anxious/depressive patients. HRQoL decreased significantly after start of chemotherapy in the parameters body image, side effects of treatment, and cognitive functioning. Tandem stem-cell transplantation was not found to be a risk factor for higher impairment of HRQoL. Participation in a clinical study led to an improvement of most aspects of HRQoL. Among others, increased anxiety and depression, female gender, older age, impaired performance status, and recurrent disease can be early indicators for a reduced HRQoL.
Conclusion
This study showed the importance of regular longitudinal assessments of patient reported outcomes (PROs) in routine clinical care. For the first time, to our knowledge, we were able to demonstrate a potential impact between participation in clinical trials and HRQoL. However, due to frequently restrictive inclusion criteria for clinical trials, these MM patients might not be directly comparable with patients treated within standard therapy concepts. Further studies are needed to clarify the relevance of this preliminary data in order to develop an individualized, patient-centred, therapy concept.
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. The best method to prevent CRC is with a colonoscopy. During this procedure, the gastroenterologist searches for polyps. However, there is a potential risk of polyps being missed by the gastroenterologist. Automated detection of polyps helps to assist the gastroenterologist during a colonoscopy. There are already publications examining the problem of polyp detection in the literature. Nevertheless, most of these systems are only used in the research context and are not implemented for clinical application. Therefore, we introduce the first fully open-source automated polyp-detection system scoring best on current benchmark data and implementing it ready for clinical application. To create the polyp-detection system (ENDOMIND-Advanced), we combined our own collected data from different hospitals and practices in Germany with open-source datasets to create a dataset with over 500,000 annotated images. ENDOMIND-Advanced leverages a post-processing technique based on video detection to work in real-time with a stream of images. It is integrated into a prototype ready for application in clinical interventions. We achieve better performance compared to the best system in the literature and score a F1-score of 90.24% on the open-source CVC-VideoClinicDB benchmark.
Introduction: The rates of postoperative recurrence following ileocecal resection due to Crohn’s disease remain highly relevant. Despite this fact, while the Kono-S anastomosis technique initially demonstrated promising results, robust evidence is still lacking. This study aimed to analyze the short- and long-term outcomes of the Kono-S versus side-to-side anastomosis. Methods: A retrospective single-center study was performed including all patients who received an ileocecal resection between 1 January 2019 and 31 December 2021 at the Department of Surgery at the University Hospital of Wuerzburg. Patients who underwent conventional a side-to-side anastomosis were compared to those who received a Kono-S anastomosis. The short- and long-term outcomes were analyzed for all patients. Results: Here, 29 patients who underwent a conventional side-to-side anastomosis and 22 patients who underwent a Kono-S anastomosis were included. No differences were observed regarding short-term postoperative outcomes. The disease recurrence rate postoperatively was numerically lower following the Kono-S anastomosis (median Rutgeert score of 1.7 versus 2.5), with a relevantly increased rate of patients in remission (17.2% versus 31.8%); however, neither of these results reached statistical significance. Conclusion: The Kono-S anastomosis method is safe and feasible and potentially decreases the severity of postoperative disease remission.
Introduction
Malnutrition in cancer patients often remains undetected and underestimated in clinical practice despite studies revealing prevalences from 20 to 70%. Therefore, this study aimed to identify patient groups exposed to an increased nutritional risk in a university oncological outpatient center.
Methods
Between May 2017 and January 2018 we screened oncological patients there using the malnutrition universal screening tool (MUST). Qualitative data were collected by a questionnaire to learn about patients’ individual information needs and changes in patients’ diets and stressful personal nutrition restrictions.
Results
We included 311 patients with various cancers. 20.3% (n = 63) were found to be at high risk of malnutrition, 16.4% (n = 51) at moderate risk despite a mean body mass index (BMI) of 26.5 ± 4.7 kg/m2. The average age was 62.7 (± 11.8) with equal gender distribution (52% women, n = 162). In 94.8% (n = 295) unintended weight loss led to MUST scoring. Patients with gastrointestinal tumors (25%, n = 78) and patients >65 years (22%, n = 68) were at higher risk. Furthermore, there was a significant association between surgery or chemotherapy within six months before survey and a MUST score ≥2 (OR = 3.6). Taste changes, dysphagia, and appetite loss were also particular risk factors (OR = 2.3–3.2). Young, female and normal-weight patients showed most interest in nutrition in cancer. However, only 38% (n = 118) had a nutritional counseling.
Conclusion
This study confirms that using the MUST score is a valid screening procedure to identify outpatients at risk of developing malnutrition. Here one in five was at high risk, but only 1% would have been detected by BMI alone. Therefore, an ongoing screening procedure with meaningful parameters should be urgently implemented into the clinical routine of cancer outpatients as recommended in international guidelines.
Simple Summary
In melanoma patients treated with dabrafenib and trametinib, dose reductions and treatment discontinuations related to adverse events (AE) occur frequently. However, the associations between patient characteristics, AE, and exposure are unclear. Our prospective study analyzed serum (hydroxy-)dabrafenib and trametinib exposure and investigated its association with toxicity and patient characteristics. Additionally, the feasibility of at-home sampling of capillary blood was assessed, and a model to convert capillary blood concentrations to serum concentrations was developed. (Hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or AE. Co-medication with P-glycoprotein inducers was associated with lower trough concentrations of trametinib but not (hydroxy-)dabrafenib. The applicability of the self-sampling of capillary blood was demonstrated. Our conversion model was adequate for estimating serum exposure from micro-samples. The monitoring of dabrafenib and trametinib may be useful for dose modification and can be optimized by at-home sampling and our new conversion model.
Abstract
Patients treated with dabrafenib and trametinib for BRAF\(^{V600}\)-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters.
Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.
(1) Background: We aimed to quantitatively investigate [\(^{68}\)Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [\(^{68}\)Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA = TV × SUV\(_{mean}\)). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman's rank correlation coefficient. (3) Results: Median SUV\(_{mean}\) values were 2.15 in the pancreas (range, 1.05–9.91), 1.42 in the right (range, 0.57–3.06) and 1.41 in the left kidney (range, 0.73–2.97), 1.2 in the heart (range, 0.46–2.59), 0.86 in the spleen (range, 0.55–1.58), 0.65 in the liver (range, 0.31–2.11), and 0.57 in the bone marrow (range, 0.26–0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUV\(_{max}\) (ρ = 0.29, p = 0.07) and TV (ρ = −0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUV\(_{max}\) (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUV\(_{max}\) (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [\(^{68}\)Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs.
Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity.
Methods
Single-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fcγ-receptors (FcγRs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems.
Results
STAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by > 300% in vivo 5 days after treatment. Treg numbers remained as high as 200% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD.
Conclusions
NewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD.
Background
Endoscopic vacuum therapy (EVT) is an evidence-based option to treat anastomotic leakages of the upper gastrointestinal (GI) tract, but the technical challenges and clinical outcomes of patients with large defects remain poorly described.
Methods
All patients with leakages of the upper GI tract that were treated with endoscopic negative pressure therapy at our institution from 2012–2021 were analyzed. Patients with large defects (>30 mm) as an indicator of complex treatment were compared to patients with smaller defects (control group).
Results
Ninety-two patients with postoperative anastomotic or staplerline leakages were identified, of whom 20 (21.7%) had large defects. Compared to the control group, these patients required prolonged therapy (42 vs. 14 days, p < 0.001) and hospital stay (63 vs. 26 days, p < 0.001) and developed significantly more septic complications (40 vs. 17.6%, p = 0.027.) which often necessitated additional endoscopic and/or surgical/interventional treatments (45 vs. 17.4%, p = 0.007.) Nevertheless, a resolution of leakages was achieved in 80% of patients with large defects, which was similar compared to the control group (p = 0.42). Multiple leakages, especially on the opposite side, along with other local unfavorable conditions, such as foreign material mass, limited access to the defect or extensive necrosis occurred significantly more often in cases with large defects (p < 0.001).
Conclusions
Overall, our study confirms that EVT for leakages even from large defects of the upper GI tract is feasible in most cases but comes with significant technical challenges.
Background
Liver steatosis is often observed in chronic HCV infection and associated to genotype or comorbidities. NAFLD is an important risk factor for end-stage liver disease. We aimed to analyse the course of NAFLD as a concomitant disease in a cohort of HCV patients.
Methods
The German Hepatitis C-Registry is a national multicenter real-world cohort. In the current analysis, 8789 HCV patients were included and separated based on the presence of steatosis on ultrasound and/or histology. Fibrosis progression was assessed by transient elastography (TE), ultrasound or non-invasive surrogate scores.
Results
At the time of study inclusion 12.3% (n = 962) of HCV patients presented with steatosis (+S) (higher rate in GT-3). Diabetes mellitus was more frequent in GT-1 patients. HCV patients without steatosis (-S) had a slightly higher rate of fibrosis progression (FP) over time (30.3%) in contrast to HCV patients +S (26%). This effect was mainly observed in GT-3 patients (34.4% vs. 20.6%). A larger decrease of ALT, AST and GGT from baseline to FU-1 (4–24 weeks after EOT) was found in HCV patients (without FP) +S compared to -S. HCV patients -S and with FP presented more often metabolic comorbidities with a significantly higher BMI (+0.58kg/m\(^{2}\)) compared to patients -S without FP. This was particularly pronounced in patients with abnormal ALT.
Conclusion
Clinically diagnosed steatosis in HCV patients does not seem to contribute to significant FP in this unique cohort. The low prevalence of steatosis could reflect a lower awareness of fatty liver in HCV patients, as patients -S and with FP presented more metabolic risk factors.
Background: Acute myeloid leukemia (AML) is both more common and with more biologically aggressive phenotype in the elderly. Allogenic stem cell transplantation (allo-SCT) is the best treatment option in fit patients. Either HLA-matched unrelated donor (MUD) or haploidentical (Haplo) donor are possible alternative for patients in need. Methods: We retrospectively compared non-T-cell-depleted Haplo (n = 250) to 10/10 MUD (n = 2589) in AML patients >= 60 years. Results: Median follow-up was 23 months. Disease status at transplant differs significantly between the two groups (p < 10(-4)). Reduced intensity conditioning (RIC) was administrated to 73 and 77% of Haplo and MUD, respectively (p = 0.23). Stem cell source was the bone marrow (BM) in 52% of the Haplo and 6% of MUD (p < 10(-4)). Anti-thymocyte globulin (ATG) was most frequently used in MUD (p < 10(-4)) while post-Tx cyclophosphamide (PT-Cy) was given in 62% of Haplo. Engraftment was achieved in 90% of the Haplo vs 97% of MUD (p < 10(-4)). In multivariate analysis, no significant difference was found between Haplo and MUD for acute (a) graft versus host disease (GVHD) grade II-IV, relapse incidence (RI), non-relapse mortality (NRM), leukemia free survival (LFS), graft-versus-host-free-relapse free survival (GRFS), and overall survival (OS). Extensive chronic (c) GVHD was significantly higher for MUD as compared to Haplo (HR 2, p = 0.01, 95% CI 1.17-3.47). A propensity score analysis confirmed the higher risk of extensive cGVHD for MUD without differences for other outcomes. Conclusions: Allo-SCT from both Haplo and MUD are valid option for AML patients >= 60 years of age with similar results. Transplantation from MUD was associated with higher extensive cGVHD. Our findings suggest that Haplo is a suitable and attractive graft source for patients >= 60 with AML in need of allo-SCT.
Background
Machine learning, especially deep learning, is becoming more and more relevant in research and development in the medical domain. For all the supervised deep learning applications, data is the most critical factor in securing successful implementation and sustaining the progress of the machine learning model. Especially gastroenterological data, which often involves endoscopic videos, are cumbersome to annotate. Domain experts are needed to interpret and annotate the videos. To support those domain experts, we generated a framework. With this framework, instead of annotating every frame in the video sequence, experts are just performing key annotations at the beginning and the end of sequences with pathologies, e.g., visible polyps. Subsequently, non-expert annotators supported by machine learning add the missing annotations for the frames in-between.
Methods
In our framework, an expert reviews the video and annotates a few video frames to verify the object’s annotations for the non-expert. In a second step, a non-expert has visual confirmation of the given object and can annotate all following and preceding frames with AI assistance. After the expert has finished, relevant frames will be selected and passed on to an AI model. This information allows the AI model to detect and mark the desired object on all following and preceding frames with an annotation. Therefore, the non-expert can adjust and modify the AI predictions and export the results, which can then be used to train the AI model.
Results
Using this framework, we were able to reduce workload of domain experts on average by a factor of 20 on our data. This is primarily due to the structure of the framework, which is designed to minimize the workload of the domain expert. Pairing this framework with a state-of-the-art semi-automated AI model enhances the annotation speed further. Through a prospective study with 10 participants, we show that semi-automated annotation using our tool doubles the annotation speed of non-expert annotators compared to a well-known state-of-the-art annotation tool.
Conclusion
In summary, we introduce a framework for fast expert annotation for gastroenterologists, which reduces the workload of the domain expert considerably while maintaining a very high annotation quality. The framework incorporates a semi-automated annotation system utilizing trained object detection models. The software and framework are open-source.
Ziel der Studie war es, potentielle Serumbiomarker für das Therapieansprechen auf Immuncheckpoint-Inhibition zu detektieren. Patienten, die der Gruppe Responder zugeordnet werden konnten, hatten ein deutlich längeres PFS. Hinzu kommt, dass im Fall der Gruppe Responder Median und Mittelwert der gemessenen Serumparameter Granzym A und B, Interferon Gamma und Perforin von BL zur 1. Messung post treatment ansteigen. Zusätzlich zeigt sich, dass IL-8 Potential als negativ prognostischer Marker hat. Trotz des kleinen und heterogenen Patientenkollektivs lassen sich Trends ableiten, die das Potential der untersuchten Mediatoren zytotoxischer T-Zellen als Serumbiomarker unterstreichen.
Die WHO definiert Gesundheit als völliges körperliches, geistiges und soziales Wohlbefinden. Während diese ganzheitliche Betrachtungsweise seit Menschengedenken nahezu weltweit das Gesundheitswesen prägt, hat die Medizin in Europa mit der naturwissenschaftlichen Erkenntnisrevolution einen Sonderweg eingeschlagen. Hier wird der kranke Organismus in erster Linie als defekter Apparat gesehen, der mit ausgeklügelter Technik zu reparieren ist. Aber auch präziseste Qualitätsarbeit stößt dabei oft an Leistungsgrenzen, weil sie als seelenlos erlebt wird. Daher sehen heute viele Fachgebiete die Notwendigkeit, ihre Behandlungskonzepte zu beseelen und ihre Behandlungserfolge auch anhand der subjektiv von Patienten empfundenen Lebensqualität zu beurteilen. Für die Ermittlung dieses PRO kommen etablierte psychometrische Testverfahren in Frage, die sich auch für routinemäßige Verlaufskontrollen eignen.
In der vorliegenden Arbeit wurde am Beispiel der mHE geprüft, welchen Nutzen eine PRO-Bestimmung bei der Verlaufskontrolle haben kann. Dazu wurde eine prospektive Studie mit anfänglich 75 Patienten durchgeführt. Alle hatten eine mHE und waren entweder alkoholbedingt oder aus anderen Gründen schwer leberkrank. An vier Terminen im Abstand von sechs Monaten wurden die kognitive Leistungsfähigkeit und der emotionale Status überprüft. Die Patienten zeigten anfänglich kognitive Einschränkungen, die sich im Verlauf der individuell abgestimmten Behandlung deutlich verbesserten oder ganz verschwanden. Die globale Testung mit dem MoCA ergab eine hochsignifikante Normalisierung im ersten Behandlungsjahr. Die MoCA-Werte am Studienanfang und -ende waren von der Erkrankungsursache unabhängig. Dieser Befund differenzierte sich in den Spezialtests TMT, PHES und NHPT. Hier zeigten die alkoholbedingt Erkrankten durchweg schlechtere Leistungen als die nicht-alkoholbedingt Erkrankten, erholten sich aber in der Regel auch deutlicher.
Die seelische Gestimmtheit gemäß BDI-II und die mit dem SF-36 MCS ermittelte psychosoziale Befindlichkeit waren in beiden Patientengruppen von Anfang an vergleichsweise günstig. Dabei hatten die alkoholbedingt Erkrankten die besseren Werte, speziell der BDI-II zeigte bei ihnen nach einem halben Jahr eine zusätzliche und bleibende Stimmungsaufhellung an. Der SF-36 PCS zum Körpererleben zeigte hingegen, dass sich die alkoholbedingt Erkrankten zu Studienbeginn in einer deutlich schlechteren Verfassung befanden. Diese verbesserte sich aber kontinuierlich, sodass nach 1,5 Jahren kein Unterschied mehr zu den nicht-alkoholbedingt Erkrankten bestand. Aus diesen Befunden und dem reichhaltigen Erfahrungsgut zur Alkoholkrankheit wird geschlossen, dass der Genesungsprozess bei alkoholbedingtem Leberversagen viel komplexer ist als bei nicht-alkoholbedingtem Leberversagen. Er könnte wesentlich mehr Zeit erfordern und wird offensichtlich anders erlebt. Dieser Patientengruppe könnten besondere physio- und gesprächstherapeutische Angebote eine große Hilfe sein.
Die Arbeit zeigt, dass es möglich ist, mit wenig Aufwand komplementär zu den klinischen Verlaufsbefunden einen informativen PRO-Bericht zu erhalten. Er hilft Angehörigen und medizinischem Personal, die persönlichen Nöte und Hoffnungen der Patienten besser zu verstehen und gegebenenfalls einen Korrekturbedarf im Umgang zu erkennen. Hinzu kam im vorliegenden Fall die Erkenntnis, dass die alkoholbedingt Erkrankten in ihrem Kranksein anders betroffen waren. Die Gründe dafür sind im Nachhinein plausibel, der Sachverhalt als solcher wäre aber ohne diese Spezialuntersuchung wohl nicht erkannt worden. Das Beispiel der PRO-Ermittlung bei der mHE macht den praktischen Wert einer Berücksichtigung des gesamtheitlichen Gesundheitskonzepts der WHO auch in der technikzentrierten „westlichen Medizin“ deutlich.
Background
Assessing serological inflammation is difficult in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients, as standard inflammation parameters, like erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are influenced by interleukin-6-receptor inhibition. Calprotectin in the serum, also named S100A8/S100A9, might be a more useful inflammation parameter in TCZ-treated patients.
Methods
Sixty-nine RA patients taking TCZ were included. Serum-calprotectin levels were assessed, as well as ESR, CRP, need for a change in disease-modifying anti-rheumatic drugs due to RA activity (= active RA), and the RA clinical disease activity score (CDAI). Forty-five RA patients taking tumor-necrosis factor-inhibitors (TNFi) were investigated for the same parameters.
Results
TCZ-treated patients with active RA had higher calprotectin values than not active RA patients (4155.5 [inter quartile range 1865.3–6068.3] vs 1040.0 [676.0–1638.0] ng/ml, P < 0.001). A calprotectin cut-off value of 1916.5 ng/ml resulted in a sensitivity and specificity of 80.0 %, respectively, for the detection of RA disease activity. Calprotectin values correlated with CDAI-scores (r = 0.228; P = 0.011). ESR and CRP were less suitable to detect RA activity in TCZ-treated patients. Also TNFi-treated patients with active RA had higher calprotectin values compared to not active RA (5422.0 [3749.0–8150.8] vs 1845.0 [832.0–2569.0] ng/ml, P < 0.001). The calprotectin value with the best sensitivity and specificity for detecting RA activity was 3690.5 ng/ml among TNFi-treated patients.
Conclusion
Calprotectin in the serum can be a useful inflammation parameter despite TCZ-treatment.
Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells. We show that IL27 induces STAT factor phosphorylation in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation and recapitulates an IFN--like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-, IL27 leads to an up-regulation of TAP2 and MHC-I proteins, which mediate increased tumor immune clearance. However, both cytokines also upregulate proteins such as PD-L1 (CD274) and IDO-1, which are associated with immune escape of cancer. Interestingly, differential expression of these genes was observed within the different cell lines and when comparing IL27 to IFN-. In coculture experiments of hepatocellular carcinoma (HCC) cells with peripheral blood mononuclear cells, pre-treatment of the HCC cells with IL27 resulted in lowered IL2 production by anti-CD3/-CD28 activated T-lymphocytes. Addition of anti-PD-L1 antibody, however, restored IL2 secretion. The levels of other T(H)1 cytokines were also enhanced or restored upon administration of anti-PD-L1. In addition, we show that the suppression of IL27 signaling by IL6-type cytokine pre-stimulationmimicking a situation occurring, for example, in IL6-secreting tumors or in tumor inflammation-induced cachexiacan be antagonized by antibodies against IL6-type cytokines or their receptors. Therapeutically, the antitumor effects of IL27 (mediated, e.g., by increased antigen presentation) might thus be increased by combining IL27 with blocking antibodies against PD-L1 or/and IL6-type cytokines.
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.
Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted.
Background: Non-alcoholic steatohepatitis (NASH) and fibrosis are the main prognostic factors in non-alcoholic fatty liver disease (NAFLD). The FIB-4 score has been suggested as an initial test for the exclusion of progressed fibrosis. However, increasing evidence suggests that also NASH patients with earlier fibrosis stages are at risk of disease progression, emphasizing the need for improved non-invasive risk stratification. Methods: We evaluated whether the apoptosis biomarker M30 can identify patients with fibrotic NASH despite low or intermediate FIB-4 values. Serum M30 levels were assessed by ELISA, and FIB-4 was calculated in an exploration (n = 103) and validation (n = 100) cohort of patients with histologically confirmed NAFLD. Results: The majority of patients with low FIB-4 (cut-off value < 1.3) in the exploration cohort revealed increased M30 levels (>200 U/L) and more than 80% of them had NASH, mostly with fibrosis. NASH was also detected in all patients with intermediate FIB-4 (1.3 to 2.67) and elevated M30, from which ~80% showed fibrosis. Importantly, in the absence of elevated M30, most patients with FIB-4 < 1.3 and NASH showed also no fibrosis. Similar results were obtained in the validation cohort. Conclusions: The combination of FIB-4 with M30 enables a more reliable identification of patients at risk for progressed NAFLD and might, therefore, improve patient stratification.
A disturbance in the symbiotic mutualism between the intestinal microbiome and the human host’s organism (syn. dysbiosis) accompanies the development of a variety of inflammatory and metabolic diseases that comprise the Metabolic Syndrome, chronic inflammatory gut diseases like Crohn’s disease, Non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases, among others. The changed uptake and effectiveness of short chain fatty acids (SCFAs) as well as an increase of the intestinal permeability are common, interdependent disease elements in this regard. Short chain fatty acids are end-products of intestinal bacterial fermentation and affect the mucosal barrier integrity via numerous molecular mechanisms.
There is evidence to suggest, that SCFAs have a modulating influence on Signal transducer and activator of transcription 3 (STAT3) in intestinal epithelial cells. STAT3 is a central gene-transcription factor in signaling pathways of proliferation and inflammation. It can be activated by growth factors and other intercellular signaling molecules like the cytokine Oncostatin M (OSM). The mode of STAT3’s activation exhibits, finally, a decisive influence on the immunological balance at the intestinal mucosa. Therefore, the posttranslational modification of STAT3 under the influence of SCFAs is likely to be a very important factor within the development and -progression of dysbiosis-associated diseases.
In this study, a clear positive in vitro-effect of the short chain fatty acid butyrate on the posttranslational serine727-phosphorylation of STAT3 and its total protein amount in the human adenocarcinoma cell line CACO2 is verified. Moreover, an increased gene expression of the OSM-receptor subunit OSMRβ can be observed after butyrate incubation. Histone deacetylase inhibition is shown to have a predominant role in these effects. Furthermore, a subsequent p38 MAPK-activation by Butyrate is found to be a key molecular mechanism regarding the STAT3-phosphorylation at serine727-residues. To consider the portion of butyrate receptor signaling in this context in future assays, a CACO-2 cell 3D-culture model is introduced in which an improvement of the GPR109A-receptor expression in CACO-2 cells is accomplished.
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.
The known YAP inhibitor verteporfin is capable of repressing IL‐17A production in Th17 cells. However, this effect is mediated independently of YAP and can ameliorate Th17‐mediated experimental autoimmune encephalomyelitis (EAE) upon in vivo administration. The data suggest verteprofin's mode of action for the design of novel therapeutic autoimmune disease intervention.
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.
Schimmelpilze können in Abhängigkeit des Immunstatus und der Vorerkrankungen betroffener Patienten unterschiedliche Krankheitsbilder wie Hypersensitivitäts-erkrankungen oder lebensbedrohliche invasive Infektionen hervorrufen. Da die Diagnosestellung dieser Erkrankungen mitunter komplex und insensitiv ist, sollten im Rahmen dieser Arbeit unterschiedliche Ansätze neuer diagnostischer Assays untersucht werden.
In den letzten Jahren wurden Assays entwickelt, die auf Basis durchflusszytometrisch quantifizierter Pilz-spezifischer T-Zellen aus peripherem Blut einen supportiven Biomarker zur Diagnostik invasiver Mykosen liefern könnten. Da die hierfür isolierten T-Zellen anfällig gegenüber präanalytischer Lagerzeiten und immunsuppressiver Medikation sind, wurden hier Protokolloptimierungen vorgenommen, um anhand eines Vollblut-basierten Assays mit zusätzlicher CD49d-Kostimulation diesen Limitationen entgegen zu wirken. In einer Studie an gesunden Probanden konnte dabei gezeigt werden, dass die Kombination der Durchflusszytometrie mit ausgewählten Zytokin-Messungen (IL-5, IL-10 und IL-17) zu einer verbesserten Erkennung vermehrt Schimmelpilz-exponierter Personen beitragen könnte. Neben Infektionen könnten dabei im umwelt- und arbeitsmedizinischen Kontext Polarisationen der T-Zell-Populationen detektiert werden, welche mit Sensibilisierungen und Hypersensitivität assoziiert werden.
Zusätzlich wurde ein in vitro Transwell® Alveolarmodell zur Simulation pulmonaler Pilzinfektionen für Erreger der Ordnung Mucorales adaptiert, durch Reproduktion wichtiger Merkmale der Pathogenese von Mucormykosen validiert, und für Untersuchungen der Immunpathologie und Erreger-Invasion verwendet. Das Modell wurde anschließend zur in vitro Evaluation von radioaktiv markiertem Amphotericin B mit 99mTc oder 68Ga als nuklearmedizinischen Tracer verwendet. Die untersuchten Schimmelpilze zeigten dabei eine zeit- und dosis-abhängige Aufnahme der Tracer, während bakteriell infizierte Proben nicht detektiert wurden. Die erhobenen Daten dokumentieren ein vielversprechendes Potenzial von Amphotericin B-basierten Tracer, das in zukünftigen in vivo Studien weiter evaluiert werden sollte.
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.
Rolle der gammadelta T-Zellen in der Immunantwort bei Patienten mit gastrointestinalen Tumoren
(2022)
Zusammenfassend konnte im Rahmen der vorliegenden Arbeit die Frage nach der Fähigkeit der selektiven Stimulierung mittels des Phosphorantigens HMBPP und den beiden BTN3 Antikörpern bestätigt werden. Es konnte zudem wie erwartet hierbei ein Unterschied zwischen den beiden Kohorten detektiert werden. Dabei zeigte die Kohorte der Normalspender erwartungsgemäß eine stärkere Aktivierungs- sowie Proliferations-fähigkeit. Normalspender ließen sich signifikant besser mit HMBPP aktivieren und bei bestimmter Konzentration signifikant besser proliferieren, bei BTN3A und sc20.1 konnten keine signifikanten Unterschiede ermittelt werden, allerdings anhand der Mittelwerte eine deutlich stärkere Aktivierung und Proliferation aufgezeigt werden. Außerdem konnten interessante interindividuelle Unterschiede detektiert werden, die neue Erkenntnisse brachten. Mit Hilfe der untersuchten Oberflächenmoleküle CD45RA und CD27 und der Einteilung der gammadelta T-Zellen in unterschiedliche Subgruppen konnten so mögliche Erklärungen für die Unterschiede zwischen den Kohorten aufgezeigt werden. Normalspender zeigten signifikant höhere Anteile an naiven gammadelta T-Zellen und nicht signifikant höhere Anteile an central memory T-Zellen, demnach eine deutliche Verschiebung in Richtung nicht differenzierter Subsets, wohingegen die Tumorkohorte signifikant höhere effector memory T-Zellen aufwiesen und somit eine deutliche Verschiebung in Richtung differenzierter Subsets. Dadurch kann erklärt werden, weshalb Normalspender besser aktiviert werden und besser proliferieren können. Auch die Einteilung in unterschiedliche Profile 1-6 anhand CD28, CD27 und CD16 lieferte Gründe für den Unterschied zwischen den Kohorten, wobei Normalspender der Gruppe 1 und 2, Tumorpatienten der Gruppe 3 und 4 angehörten. Durch Ermittlung weiterer signifikanter Änderungen einiger exprimierter Oberflächenmoleküle CD39, CD161 und PD1 wurde mit Hilfe der vorliegenden Arbeit bekräftigt, dass einige Faktoren betrachtet werden müssen, die die Proliferation und Aktivierung der gammadelta T-Zellen positiv und negativ beeinflussen können. Es konnte jedoch auch erneut verdeutlicht werden, wie komplex und weitgreifend der Aktivierungsmechanismus, die damit verbundene Expansion und die Auslösung der einzelnen Effektorfunktionen ist.
Die vorliegende Dissertation hat sich mit der Fragestellung beschäftigt, inwiefern die Einzelnukleotid-Polymorphismen (kurz SNP) rs10754558 und rs35829419 des NLRP3-Gens mit einer Suszeptibilität für eine NAFL und/oder NASH assoziiert sind.
Die Studienkohorte bestand aus 202 Teilnehmern der Würzburger NAFLD-Kohorte der Universitätsklinik Würzburg, 159 NAFLD-Patienten, die im Rahmen der Fettlebersprechstunde der Universitätsklinik Würzburg behandelt wurden und 43 gesunde Kontrollen. Voraussetzung für die Aufnahme in das Patientenkollektiv der durch die Ethikkomission genehmigten Studie war zuallererst die Aufklärung und Zustimmung des Patienten, außerdem eine klinisch oder histologisch diagnostizierte Fettlebererkrankung. Sekundäre Ursachen einer Fettleber oder andere Lebererkrankungen waren Ausschlusskriterien. Alle Teilnehmer erhielten eine Blutentnahme, 97 NAFLD-Patienten eine Leberbiopsie, davon 10 perkutan und 87 subkapsulär im Zuge einer bariatrischen OP. Die Genotypisierung übernahm das Labor der Universitätsklinik Homburg, die weiteren Analysen der Blutwerte, der peripheren und intrahepatischen Immunzellen und die Begutachtung der Leber-Histologie fanden an der Universitätsklinik Würzburg im Rahmen eines vorherigen Forschungsvorhabens statt (Rau et al., 2016).
Für beide SNPs war das Hardy-Weinberg-Equilibrium im Studien- sowie Patientenkollektiv erfüllt. Zwischen den einzelnen Genotypen und dem Vorliegen einer NAFL und/oder NASH fanden sich für beide SNPs keine signifikanten Zusammenhänge. Für den Wildtyp CC des SNP rs10754558 ergaben sich in der Studienkohorte signifikant höhere AST-Mediane (p=0,018) und häufiger hochnormale (in den oberen 20 % des Normbereichs) ALT-Werte (p=0,02) im Vergleich zu den Genotypen CG und GG. Hier lässt sich über eine protektive Rolle des Minor Allels in Bezug auf Leberwerterhöhungen spekulieren. Da bisher die Funktion von rs10754558 im NLRP3-Gen noch nicht ausreichend erforscht ist, sollten Untersuchungen auf transkriptioneller Ebene folgen und Studien mit anderen Polymorphismen des NLRP3-Gens und mit NAFLD-assoziierter Gene durchgeführt werden, um eine mögliche Assoziation mit anderen für die Entwicklung der NAFLD relevanten SNPs nicht zu übersehen.
In der Analyse mit den Entzündungswerten zeigten sich für die Genotypen CG und GG signifikant erhöhte Frequenzen von Th1-Zellen im peripheren Blut (p=0,003). Zusätzlich lässt sich das vermehrte Vorkommen von Th1-Zellen auch im Rahmen der bestehenden Adipositas bzw. des metabolischen Syndroms im Sinne einer low grade inflammation interpretieren (s. Diskussion). Immerhin sind 95 % der NAFLD-Patienten der Studienkohorte von Adipositas betroffen.
Die Ergebnisse zu SNP rs35829419, einer gain-of-function Variante im NLRP3-Gen, waren nur eingeschränkt beurteilbar, da keine homozygoten Allel-A-Träger vorlagen und die Stichprobenzahl für die Analyse der intrahepatischen Immunzellen viel zu gering war, um aussagekräftig sein zu können. In der gesamten Kohorte stellte sich ein signifikanter Zusammenhang zwischen dem heterozygoten Genotyp von rs35829419 und einer erhöhten Frequenz an Th2-Zellen (p=0,024) im peripheren Blut heraus. Innerhalb der NAFLD gingen frühere Studien bisher eher von einer Th1-dominierten Immunantwort aus (Bertola et al., 2010), wenn nicht gar einer Th2-Defizienz (Guebre-Xabier et al., 2000). Das hier vorliegende Ergebnis könnte immerhin auf eine höhere entzündliche Aktivität bei Minor-Allelträgern hindeuten. Die weitere Untersuchung mit größeren Stichproben und weiteren Polymorphismen, die in der NAFLD-Pathogenese bekanntermaßen eine Rolle spielen, erscheint auch für den SNP rs35829419 sinnvoll.
Im Hinblick auf die zunehmende Prävalenz der NAFLD als Volkskrankheit der westlichen Welt wird die personalisierte Medizin, inklusive Prävention, Diagnostik und Therapie immer mehr an Bedeutung zunehmen. Die Identifizierung von genetischen Risikovarianten, die an der Pathogenese der NAFLD beteiligt sind, ist ein erster Schritt auf dem Weg hin zu besseren Therapiemöglichkeiten.
Das Multiple Myelom (MM) ist eine seltene, maligne Störung der Plasmazellen, welche trotz gehöriger Therapiefortschritte in den letzten Jahrzehnten nach wie vor als unheilbare Erkrankung betrachtet werden muss. Obwohl eine sehr große intra- und interindividuelle Heterogenität beim Multiplen Myelom beobachtet werden kann, gibt es verschiedene Mutationen, die mit höherer Frequenz in Myelompatientinnen und -patienten gefunden werden. Eines dieser häufiger betroffenen Proteine ist KRas mit Mutationen in etwa 20% der Fälle. Da die Ras-Proteine und somit auch ihre Isoform KRas zu Beginn der Ras/Raf/Mek/Erk-Signalkaskade stehen und dementsprechend einen großen Einfluss auf die Übermittlung von Wachstums- und Überlebenssignalen in Zellen besitzen, ist eine nähere funktionelle Analyse verschiedener KRas-Mutationen von großer Relevanz. Während für einige Mutationen von KRas bereits funktionelle Analysen existieren, wurden die häufig auftretende Exon 2-Mutation KRasp.G12A, sowie die beiden seltenen Exon 4-Mutationen KRasp.A146T und KRasp.A146V bisher in ihrer funktionellen Rolle im MM noch nicht näher charakterisiert. Um die funktionellen Aspekte dieser genannten Mutationen von KRas näher zu untersuchen, kamen im Rahmen meiner Versuchsreihe Sleeping Beauty Transposon System basierte Expressionsvektoren zur transienten und dauerhaften Proteinexpression in verschiedenen Myelomzelllinien zum Einsatz. Durch Transfektion dieser Plasmide in die KRas-Wildtyp tragenden Zellen mit nachfolgender Transposition in die genomische DNA konnte gezielt die Überexpression der verschiedenen Mutationen realisiert werden.
So konnte durch die funktionelle Proteinauslese mittels der Anfertigung von Western Blots gezeigt werden, dass jede der drei getesteten Mutationen zu einer verstärkten Phosphorylierung und damit Aktivierung von KRas-nachgeschalteten Proteinen wie z.B. Erk führt. Zusätzlich wurde für die KRas-Mutationen auch ein aktivierender Effekt auf den PI3K/Akt-Signalweg anhand einer erhöhten Phosphorylierung des Proteins Akt nachgewiesen.
Ebenso wie andere bereits besser charakterisierte KRas-Mutationen haben demnach auch die getesteten KRas-Mutationen KRasp.G12A, KRasp.A146T und KRasp.A146V einen positiven Einfluss auf die intrazellulären Überlebenssignale und könnten daher eine elementare Rolle in der Entwicklung des Multiplen Myeloms bei Patientinnen und Patienten spielen. Es gilt daher, die drei in dieser Arbeit untersuchten KRas-Mutationen, zukünftig in die Wirkstoffsuche KRas-spezifischer Therapeutika miteinzubeziehen.