Institutes
Refine
Year of publication
- 2012 (23) (remove)
Document Type
- Article (20)
- Doctoral Thesis (2)
- Conference Proceeding (1)
Language
- English (23) (remove)
Has Fulltext
- yes (23) (remove)
Is part of the Bibliography
- no (23) (remove)
Keywords
- Apoptosis (3)
- Herb induced liver injury (2)
- Herbal hepatotoxicity (2)
- 9-aminoacridine (1)
- ADAM15 (1)
- Alcohol (1)
- All-oral therapy (1)
- Animal model (1)
- Antiviral therapy (1)
- Bone tumor (1)
- Burns (1)
- Calcium gluconate (1)
- Cancer (1)
- Cartilage (1)
- Cartilage Biology (1)
- Cell Metabolism (1)
- Cell Migration (1)
- Chaperone (1)
- Chondrocytes (1)
- Chronic hepatitis C (1)
- Dendritic Cells (1)
- Digital subtraction angiography (1)
- Directly acting antiviral agent (1)
- Focal Adhesion Kinase (1)
- Gene Regulation (1)
- Glioma (1)
- Hepatitis C virus (1)
- Herbal medicine (1)
- Hydrofluoric acid (1)
- Hypoxia (1)
- IAP Proteins (1)
- IAP-IAP (1)
- Innate Immunity (1)
- Interleukin (1)
- Interleukin-1 (1)
- Interleukin-36 (1)
- MAP Kinases (MAPKs) (1)
- ML-IAP (1)
- Macrophages (1)
- Mitochondria (1)
- Mitochondrial Apoptosis (1)
- Mitochondrial Metabolism (1)
- Mitochondrial Permeability Transition (1)
- Mitochondrial Transport (1)
- Molecular Chaperone (1)
- Null responder (1)
- Paracoccus denitrificans (1)
- Pelargonium sidoides (1)
- Pelargonium sidoides questionable hepatotoxicity (1)
- Pentose Pathway (1)
- Pharmacovigilance (1)
- RAF (1)
- RIP (1)
- Rabbit (1)
- Radiofrequency ablation (1)
- Rhabdomyosarcoma (1)
- SVR (1)
- Safety (1)
- Signaling (1)
- T-bet (1)
- TIGAR (1)
- Trail (1)
- Tumor therapy (1)
- Ubiquitin signaling (1)
- Ubiquitin-binding module (1)
- Ubiquitination (1)
- Ubiquitylation (1)
- VX-2 (1)
- Vasospasm (1)
- XIAP (1)
- cardiolipin (1)
- health-care personnel (1)
- heart (1)
- hepatotoxicity (1)
- maternity protection law (1)
- matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (1)
- occupationally acquired viral infections (1)
- p53 (1)
- pregnancy (1)
- yeast (1)
Introduction. Balapiravir (R1626, RG1626) is the prodrug of a nucleoside analogue inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (R1479, RG1479). This phase 2, double-blind international trial evaluated the optimal treatment regimen of balapiravir plus peginterferon alfa-2a (40KD)/ribavirin.
Material and methods. Treatment-naive genotype 1 patients (N = 516) were randomized to one of seven treatment groups in which they received balapiravir 500, 1,000, or 1,500 mg twice daily, peginterferon alfa2a (40KD) 180 or 90 Mg/week and ribavirin 1,000/1,200 mg/day or peginterferon alfa-2a (40KD)/ribavirin. The planned treatment duration with balapiravir was reduced from 24 to 12 weeks due to safety concerns.
Results. The percentage of patients with undetectable HCV RNA was consistently higher in all balapiravir groups from week 2 to 12. However, high rates of dose modifications and discontinuations of one/all study drugs compromised the efficacy assessment and resulted in similar sustained virological response rates in the balapiravir groups (range 32-50%) and the peginterferon alfa-2a (40KD)/ribavirin group (43%). Balapiravir was discontinued for safety reasons in 28-36% of patients (most often for lymphopenia) and the percentage of patients with serious adverse events (especially hematological, infection, ocular events) was dose related. Serious hematological adverse events (particularly neutropenia, lymphopenia) were more common in balapiravir recipients. Two deaths in the balapiravir/peginterferon alfa-2a/ribavirin combination groups were considered possibly related to study medication.
Conclusion. Further development of balapiravir for the treatment of chronic hepatitis C has been halted because of the unacceptable benefit to risk ratio revealed in this study (www.ClinicalTrials.gov NCT 00517439).
ADAM15 protein amplifies focal adhesion kinase phosphorylation under genotoxic stress conditions
(2012)
ADAM15, a disintegrin and metalloproteinase, is capable of counteracting genotoxic stress-induced apoptosis by the suppression of caspase-3 activation. A cell line expressing the membrane-bound ADAM15 without its cytoplasmic tail, however, lost this anti-apoptotic property, suggesting a crucial role of the intracellular domain as a scaffold for recruitment of survival signal-transducing kinases. Accordingly, an enhanced phosphorylation of FAK at Tyr-397, Tyr-576, and Tyr-861 was detected upon genotoxic stress by camptothecin in ADAM15-transfected T/C28a4 cells, but not in transfectants expressing an ADAM15 mutant without the cytoplasmic tail. Accordingly, a specific binding of the cytoplasmic ADAM15 domain to the C terminus of FAK could be shown by mammalian two-hybrid, pulldown, and far Western studies. In cells expressing full-length ADAM15, a concomitant activation of Src at Tyr-416 was detected upon camptothecin exposure. Cells transfected with a chimeric construct consisting of the extracellular IL-2 receptor α-chain and the cytoplasmic ADAM15 domain were IL-2-stimulated to prove that the ADAM15 tail can transduce a percepted extracellular signal to enhance FAK and Src phosphorylation. Our studies further demonstrate Src binding to FAK but not a direct Src interaction with ADAM15, suggesting FAK as a critical intracellular adaptor for ADAM15-dependent enhancement of FAK/Src activation. Moreover, the apoptosis induction elicited by specific inhibitors (PP2, FAK 14 inhibitor) of FAK/Src signaling was significantly reduced by ADAM15 expression. The newly uncovered counter-regulatory response to genotoxic stress in a chondrocytic survival pathway is potentially also relevant to apoptosis resistance in neoplastic growth.