Refine
Is part of the Bibliography
- yes (46)
Year of publication
Document Type
- Journal article (46) (remove)
Language
- English (46)
Keywords
- apoptosis (11)
- TNF (6)
- cell death (6)
- multiple myeloma (6)
- TNFR2 (5)
- TRAIL (5)
- CD40 (3)
- CD95 (3)
- Fn14 (3)
- NFκB (3)
- TNFR1 (3)
- TWEAK (3)
- death receptors (3)
- Apoptosis (2)
- B cells (2)
- Expression (2)
- Factor receptor (2)
- TNF receptor superfamily (2)
- TNF superfamily (2)
- TRAF2 (2)
- Tumor-necrosis-factor (2)
- antibody (2)
- antibody fusion proteins (2)
- bone disease (2)
- cancer (2)
- cancer therapy (2)
- cancer treatment (2)
- caspase-8 (2)
- cells (2)
- cytokines (2)
- gene expression (2)
- inflammation (2)
- metastasis (2)
- necroptosis (2)
- necrotic cell death (2)
- positron emission tomography (2)
- regulatory T cells (2)
- 14.7K (1)
- ADHD (1)
- AMPK (1)
- Activation (1)
- Adrenocortical Carcinoma (1)
- Alpha therapy (1)
- Autoimmune diseases (1)
- B cell receptors (1)
- BMP (1)
- Big Five (1)
- Bioluminescence (1)
- Bone marrow transplantantation (1)
- Bone morphogenetic protein-2 (1)
- C1q/TNF related protein (CTRP) (1)
- CD27 (1)
- CD40L (1)
- CD70 (1)
- CDH13 (1)
- CMV (1)
- CXCR4 (1)
- CXCR4/SDF-1 (1)
- CYP2C9 (1)
- CYP3A4 (1)
- CYR61 (1)
- Callyspongia siphonella (1)
- Cancer (1)
- CysLTR1 (1)
- Cysteine‐Rich Domain (CRD) (1)
- E3 14.7-kilodalton protein (1)
- FAS (1)
- FDG PET/CT (1)
- Factor-alpha (1)
- FcγR receptor (1)
- GVHD (1)
- Graft-versus-leukemia (1)
- GvHD (1)
- HT29 cells (1)
- HaCaT cells (1)
- Inhibitor (1)
- Ki67 (1)
- LC-HRESIMS (1)
- MDSC (1)
- MPI (1)
- MPS (1)
- Mechanisms (1)
- Myofibroblast differentiation (1)
- NF-Kappa-B (1)
- NF-kappa-B (1)
- NFkB (1)
- NFkappaB (1)
- Nekrose (1)
- PRRT (1)
- Polymorphisms (1)
- Pre‐Ligand Assembly Domain (PLAD) (1)
- Proliferation (1)
- Promoter (1)
- RAF1 (1)
- Receptor (1)
- Regulatory-cells (1)
- Rheumatoid arthritis (1)
- Ruxolitinib (1)
- Single‐Molecule Localization Microscopy (SMLM) (1)
- Smooth-muscle-cells (1)
- Suppression (1)
- T cells (1)
- TGF-beta (1)
- TNF ligand superfamily (1)
- TNF receptor (TNFR) family (1)
- TNF receptor 2 (TNFR2) (1)
- TNF receptor associated factor 1 and 2 (TRAF1, TRAF2) (1)
- TNFR family costimulatory receptors (1)
- TNFR2 agonists (1)
- TNFR2 antagonism (1)
- TRAF1 (1)
- TRAILR1 (1)
- TRAILR2 (1)
- Transcription (1)
- Tregs (regulatory T cells) (1)
- \(^{11}\)C-Methionine-PET (1)
- \(^{18}\)F-FDG PET/CT (1)
- accuracy (1)
- acute (1)
- acute ischemic stroke (1)
- adiponectin (1)
- agonist (1)
- agonistic antibodies (1)
- agreeableness (1)
- alkaloids (1)
- amphibian skin secretions (1)
- anti-TNFRSF receptor (TNFR) antibodies (1)
- antibacterial (1)
- antibiofilm (1)
- antibody fusion protein (1)
- anticancer (1)
- anticancer activity (1)
- antimicrobial peptides (1)
- antitrypanosomal (1)
- anurans (1)
- aryl hydrocarbon receptor (AhR) (1)
- atherosclerosis (1)
- autologous transplantation (1)
- benzo[a]pyrene (1)
- binding (1)
- blood coagulability (1)
- capecitabine (1)
- cardiogenic (1)
- cardiovascular disease (1)
- case report (1)
- cell binding (1)
- cell cycle and cell division (1)
- cell metabolism (1)
- cell proliferation (1)
- cell staining (1)
- cell viability testing (1)
- chemokine receptor (1)
- colorectal cancer (1)
- compartmentalization (1)
- costimulation (1)
- crosslinked coating (1)
- curative resection (1)
- cytokine storm (1)
- dendritic cells (1)
- dendrobates pumilio (1)
- dermatitis (1)
- drug-delivery (1)
- ejection fraction (1)
- encephalitis (1)
- esophagogastric junction (1)
- executive functions (1)
- experience (1)
- extracorporeal membrane oxygenation (1)
- feasibility (1)
- formicidae (1)
- graft versus host disease (1)
- graft vs. host disease (1)
- growth-factor receptor (1)
- hepatic resection (1)
- human keratinocytes (1)
- hymenoptera (1)
- imaging agents (1)
- imaging techniques (1)
- immune cells (1)
- immune regulation (1)
- immunotherapy (1)
- in vivo imaging (1)
- increased risk (1)
- inhibitor (1)
- involvement (1)
- ischemic stroke (1)
- leukemia (1)
- liver resection (1)
- lung resection (1)
- magnetic properties (1)
- malignancies (1)
- management (1)
- mediated apoptosis (1)
- membrane receptor signaling (1)
- metabolism (1)
- metabolomic profiling (1)
- mice impact (1)
- microenvironment (1)
- microhylidae (1)
- mitochondrial dysfunction (1)
- molecular imaging (1)
- molecular medicine (1)
- motor cortex (1)
- mutualisms (1)
- myeloid (1)
- myosin-VI (1)
- nanoparticles (1)
- neurodevelopment (1)
- oral anticancer drugs (1)
- oxindole alkaloids (1)
- paltothyreus tarsatus (1)
- pathways (1)
- patient-doctor-relationship (1)
- peptide receptor (1)
- phosphorylation (1)
- point-of-care echocardiography (1)
- polymorphisms inflammation (1)
- prognosis (1)
- progression (1)
- pyrazolo[3,4-d]pyrimidine (1)
- radionuclide therapy (1)
- receptor cluster (1)
- regulatory T cell (1)
- regulatory T-cell (Treg) (1)
- retrospective study (1)
- ripk1 (1)
- ripk3 (1)
- sarcoidosis (1)
- scFv (1)
- septic (1)
- serum retention (1)
- shock (1)
- signal inhibition (1)
- signal transduction (1)
- signaling (1)
- skin (1)
- small interfering RNAs (1)
- somatostatin receptors (1)
- stem-cell transplantation (1)
- stroke unit (1)
- surface modification (1)
- surgical oncology (1)
- surgical resection (1)
- survival (1)
- survival analysis (1)
- systolic dysfunction (1)
- tetraparesis (1)
- therapeutic drug monitoring (1)
- tisindoline (1)
- toxicity (1)
- treatment response (1)
- tumor necrosis factor (1)
- tumor necrosis factor (TNF) (1)
- von Willebrand factor (1)
- working memory (1)
Institute
- Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) (46) (remove)
Sonstige beteiligte Institutionen
Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48–72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.
An intricate network of molecular and cellular actors orchestrates the delicate balance between effector immune responses and immune tolerance. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) proves as a pivotal protagonist promoting but also suppressing immune responses. These opposite actions are accomplished through specialist cell types responding to TNF via TNF receptors TNFR1 and TNFR2. Recent findings highlight the importance of TNFR2 as a key regulator of activated natural FoxP3+ regulatory T cells (Tregs) in inflammatory conditions, such as acute graft-vs.-host disease (GvHD) and the tumor microenvironment. Here we review recent advances in our understanding of TNFR2 signaling in T cells and discuss how these can reconcile seemingly conflicting observations when manipulating TNF and TNFRs. As TNFR2 emerges as a new and attractive target we furthermore pinpoint strategies and potential pitfalls for therapeutic targeting of TNFR2 for cancer treatment and immune tolerance after allogeneic hematopoietic cell transplantation.
Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) and is activated by its ligand TNF-like weak inducer of apoptosis (TWEAK). The latter occurs as a homotrimeric molecule in a soluble and a membrane-bound form. Soluble TWEAK (sTWEAK) activates the weakly inflammatory alternative NF-κB pathway and sensitizes for TNF-induced cell death while membrane TWEAK (memTWEAK) triggers additionally robust activation of the classical NF-κB pathway and various MAP kinase cascades. Fn14 expression is limited in adult organisms but becomes strongly induced in non-hematopoietic cells by a variety of growth factors, cytokines and physical stressors (e.g., hypoxia, irradiation). Since all these Fn14-inducing factors are frequently also present in the tumor microenvironment, Fn14 is regularly found to be expressed by non-hematopoietic cells of the tumor microenvironment and most solid tumor cells. In general, there are three possibilities how the tumor-Fn14 linkage could be taken into consideration for tumor therapy. First, by exploitation of the cancer associated expression of Fn14 to direct cytotoxic activities (antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxic payloads, CAR T-cells) to the tumor, second by blockade of potential protumoral activities of the TWEAK/Fn14 system, and third, by stimulation of Fn14 which not only triggers proinflammtory activities but also sensitizes cells for apoptotic and necroptotic cell death. Based on a brief description of the biology of the TWEAK/Fn14 system and Fn14 signaling, we discuss the features of the most relevant Fn14-targeting biologicals and review the preclinical data obtained with these reagents. In particular, we address problems and limitations which became evident in the preclinical studies with Fn14-targeting biologicals and debate possibilities how they could be overcome.
Purpose
Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects.
Methods
262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed.
Results
Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6-99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05).
Conclusion
Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.
With the exception of a few signaling incompetent decoy receptors, the receptors of the tumor necrosis factor receptor superfamily (TNFRSF) are signaling competent and engage in signaling pathways resulting in inflammation, proliferation, differentiation, and cell migration and also in cell death induction. TNFRSF receptors (TNFRs) become activated by ligands of the TNF superfamily (TNFSF). TNFSF ligands (TNFLs) occur as trimeric type II transmembrane proteins but often also as soluble ligand trimers released from the membrane-bound form by proteolysis. The signaling competent TNFRs are efficiently activated by the membrane-bound TNFLs. The latter recruit three TNFR molecules, but there is growing evidence that this is not sufficient to trigger all aspects of TNFR signaling; rather, the formed trimeric TNFL–TNFR complexes have to cluster secondarily in the cell-to-cell contact zone for full TNFR activation. With respect to their response to soluble ligand trimers, the signaling competent TNFRs can be subdivided into two groups. TNFRs of one group, designated as category I TNFRs, are robustly activated by soluble ligand trimers. The receptors of a second group (category II TNFRs), however, failed to become properly activated by soluble ligand trimers despite high affinity binding. The limited responsiveness of category II TNFRs to soluble TNFLs can be overcome by physical linkage of two or more soluble ligand trimers or, alternatively, by anchoring the soluble ligand molecules to the cell surface or extracellular matrix. This suggests that category II TNFRs have a limited ability to promote clustering of trimeric TNFL–TNFR complexes outside the context of cell–cell contacts. In this review, we will focus on three aspects on the relevance of receptor oligomerization for TNFR signaling: (i) the structural factors which promote clustering of free and liganded TNFRs, (ii) the signaling pathway specificity of the receptor oligomerization requirement, and (iii) the consequences for the design and development of TNFR agonists.
TNFR1 is a crucial regulator of NF‐ĸB‐mediated proinflammatory cell survival responses and programmed cell death (PCD). Deregulation of TNFα‐ and TNFR1‐controlled NF‐ĸB signaling underlies major diseases, like cancer, inflammation, and autoimmune diseases. Therefore, although being routinely used, antagonists of TNFα might also affect TNFR2‐mediated processes, so that alternative approaches to directly antagonize TNFR1 are beneficial. Here, we apply quantitative single‐molecule localization microscopy (SMLM) of TNFR1 in physiologic cellular settings to validate and characterize TNFR1 inhibitory substances, exemplified by the recently described TNFR1 antagonist zafirlukast. Treatment of TNFR1‐mEos2 reconstituted TNFR1/2 knockout mouse embryonic fibroblasts (MEFs) with zafirlukast inhibited both ligand‐independent preligand assembly domain (PLAD)‐mediated TNFR1 dimerization as well as TNFα‐induced TNFR1 oligomerization. In addition, zafirlukast‐mediated inhibition of TNFR1 clustering was accompanied by deregulation of acute and prolonged NF‐ĸB signaling in reconstituted TNFR1‐mEos2 MEFs and human cervical carcinoma cells. These findings reveal the necessity of PLAD‐mediated, ligand‐independent TNFR1 dimerization for NF‐ĸB activation, highlight the PLAD as central regulator of TNFα‐induced TNFR1 oligomerization, and demonstrate that TNFR1‐mEos2 MEFs can be used to investigate TNFR1‐antagonizing compounds employing single‐molecule quantification and functional NF‐ĸB assays at physiologic conditions.
Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can involve virtually all organ systems. Whereas most patients present without symptoms, progressive and disabling organ failure can occur in up to 10% of subjects. Somatostatin receptor (SSTR)-directed peptide receptor radionuclide therapy (PRRT) has recently received market authorization for treatment of SSTR-positive neuroendocrine tumors.
Methods:
We describe the first case series comprising two patients with refractory multi-organ involvement of sarcoidosis who received 4 cycles of PRRT.
Results:
PRRT was well-tolerated without any acute adverse effects. No relevant toxicities could be recorded during follow-up. Therapy resulted in partial response accompanied by a pronounced reduction in pain (patient #1) and stable disease regarding morphology as well as disease activity (patient #2), respectively.
Conclusion:
Peptide receptor radionuclide therapy in sarcoidosis is feasible and might be a new valuable tool in patients with otherwise treatment-refractory disease. Given the long experience with and good tolerability of PRRT, further evaluation of this new treatment option for otherwise treatment-refractory sarcoidosis in larger patient cohorts is warranted.
Purpose:
The prescribing of oral chemotherapy agents has introduced the new challenge of ensuring patients’ adherence to therapy. Aspects of a close patient–doctor relationship are reported to be correlated with adherence to oral anticancer drugs, but data on capecitabine are scarce.
Patients and methods:
Sixty-four outpatients with a diagnosis of cancer and prescribed capecitabine were recruited from a German Comprehensive Cancer Center. We used the Patient–Doctor Relationship Questionnaire (PDRQ-9), the Medical Adherence Rating Scale (MARS), the Beliefs about Medicines Questionnaire (BMQ), and the Satisfaction with Information about Medicines Scale (SIMS) to assess patients’ perceptions and behavior. Medical data were extracted from the charts.
Results:
Non-adherence was reported by 20% of the 64 participants. The perceived quality of the patient–doctor relationship was high in general, but it did not emerge as a predictor of adherence in our survey (odds ratio [OR]=0.915, P=0.162, 95% CI=0.808–1.036). However, beliefs about medicine (OR=1.268, P<0.002; 95% CI=1.090–1.475) as well as satisfaction with information about medicine (OR=1.252, P<0.040, 95% CI=1.010–1.551) were predictors of adherence and the quality of the patient–doctor relationship was correlated with both variables (r=0.373, P=0.002 for SIMS sum score; r=0.263, P=0.036 for BMQ necessity/concern difference). Overall, adherence to capecitabine was high with a conviction that the therapy is necessary. However, concerns were expressed regarding the long-term effect of capecitabine use. Patients have unmet information needs regarding interactions of capecitabine with other medicines and the impairment of their intimate life.
Conclusions:
In order to ensure adherence to capecitabine, our results seem to encourage the default use of modern and perhaps more impersonal means of information brokerage (eg, email, internet). However, the contents of some of patients’ informational needs as well as the associations of patients’ beliefs and satisfaction about the information received suggest a benefit from a trustful patient–doctor relationship.
Background:
Metastatic Adrenocortical Carcinoma (ACC) is a rare malignancy with a poor 5-year-survival rate (<15%). A surgical approach is recommended in selected patients if complete resection of distant metastasis can be achieved. To date there are only limited data on the outcome after surgical resection of hepatic metastases of ACC.
Methods:
A retrospective analysis of the German Adrenocortical Carcinoma Registry was conducted. Patients with liver metastases of ACC but without extrahepatic metastases or incomplete tumour resection were included.
Results:
Seventy-seven patients fulfilled these criteria. Forty-three patients underwent resection of liver metastases of ACC. Complete tumour resection (R0) could be achieved in 30 (69.8%). Median overall survival after liver resection was 76.1 months in comparison to 10.1 months in the 34 remaining patients with unresected liver metastases (p < 0.001). However, disease free survival after liver resection was only 9.1 months. Neither resection status (R0/R1) nor extent of liver resection were significant predictive factors for overall survival. Patients with a time interval to the first metastasis/recurrence (TTFR) of greater than 12 months or solitary liver metastases showed significantly prolonged survival.
Conclusions:
Liver resection in the case of ACC liver metastases can achieve long term survival with a median overall survival of more than 5 years, but disease free survival is short despite metastasectomy. Time to recurrence and single versus multiple metastases are predictive factors for the outcome.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application.