Search results for "ACTIVATION"
showing 10 items of 2079 documents
The STAT3 Inhibitor Galiellalactone Reduces IL6-Mediated AR Activity in Benign and Malignant Prostate Models
2018
IL6/STAT3 signaling is associated with endocrine therapy resistance in prostate cancer, but therapies targeting this pathway in prostate cancer were unsuccessful in clinical trials so far. The mechanistic explanation for this phenomenon is currently unclear; however, IL6 has pleiotropic effects on a number of signaling pathways, including the androgen receptor (AR). Therefore, we investigated IL6-mediated AR activation in prostate cancer cell lines and ex vivo primary prostate tissue cultures in order to gain a better understanding on how to inhibit this process for future clinical trials. IL6 significantly increased androgen-dependent AR activity in LNCaP cells but importantly did not infl…
Melatonin protects rats from radiotherapy-induced small intestine toxicity
2017
Radiotherapy-induced gut toxicity is among the most prevalent dose-limiting toxicities following radiotherapy. Prevention of radiation enteropathy requires protection of the small intestine. However, despite the prevalence and burden of this pathology, there are currently no effective treatments for radiotherapy-induced gut toxicity, and this pathology remains unclear. The present study aimed to investigate the changes induced in the rat small intestine after external irradiation of the tongue, and to explore the potential radio-protective effects of melatonin gel. Male Wistar rats were subjected to irradiation of their tongues with an X-Ray YXLON Y.Tu 320-D03 irradiator, receiving a dose o…
Intracellular activation of ovastacin mediates pre-fertilization hardening of the zona pellucida
2017
Study question How and where is pro-ovastacin activated and how does active ovastacin regulate zona pellucida hardening (ZPH) and successful fertilization? Study finding Ovastacin is partially active before exocytosis and pre-hardens the zona pellucida (ZP) before fertilization. What is known already The metalloproteinase ovastacin is stored in cortical granules, it cleaves zona pellucida protein 2 (ZP2) upon fertilization and thereby destroys the ZP sperm ligand and triggers ZPH. Female mice deficient in the extracellular circulating ovastacin-inhibitor fetuin-B are infertile due to pre-mature ZPH. Study design, samples/materials, methods We isolated oocytes from wild-type and ovastacin-de…
Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that dif…
2017
OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the i…
Existence of muscarinic acetylcholine receptor (mAChR) and fibroblast growth factor receptor (FGFR) heteroreceptor complexes and their enhancement of…
2017
Abstract Background Recently, it was demonstrated that G-protein-coupled receptors (GPCRs) can transactivate tyrosine kinase receptors in absence of their ligands. In this work, driven by the observation that mAChRs and fibroblast growth factor receptors (FGFRs) share signalling pathways and regulation of brain functions, it was decided to explore whether mAChRs activation may transactivate FGFRs and, if so, to characterize the related trophic effects in cultured hippocampal neurons. Methods Oxotremorine-M transactivation of FGFRs and related trophic effects were tested in primary hippocampal neurons. Western blotting and in situ proximity ligation assay (PLA) were used to detect FGFR phosp…
Polymorphonuclear leukocyte integrins in deep venous thrombosis
2005
The polymorphonuclear leukocytes (PMN) have a role in the pathophysiology of deep venous thrombosis (DVT). We examined the phenotypical expression of PMN beta2-integrins (CD l l a, CDl l b, CD 11c) in a group of 19 subjects with leg DVT. PMN cells were incubated with fluorescent monoclonal antibodies against CD11a, CD11b, CD11c, and the evaluation was made by flow cytofluorimetry. The same integrins were determined after in vitro activation with 4-phorbol 12-myristate 13-acetate (PMA) and N-formylmethionyl-leucyl-phenylalanine (fMLP). In DVT subjects, at baseline, the phenotypical expression of CD11b was decreased and that of CD11c increased when compared with normal controls. In normal su…
Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy
2016
Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encod…
Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma : Final …
2016
Purpose Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome–negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Patients and Methods This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 μg/m2/day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate. Results B…
Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
2018
ObjectivePrimary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportiona…
The canonical but not the noncanonical wnt pathway inhibits the development of allergic airway disease
2018
Abstract Asthma is a syndrome with multifactorial causes, resulting in a variety of different phenotypes. Current treatment options are not curative and are sometimes ineffective in certain disease phenotypes. Therefore, novel therapeutic approaches are required. Recent findings have shown that activation of the canonical Wnt signaling pathway suppresses the development of allergic airway disease. In contrast, the effect of the noncanonical Wnt signaling pathway activation on allergic airway disease is not well described. The aim of this study was to validate the therapeutic effectiveness of Wnt-1–driven canonical Wnt signaling compared with Wnt-5a–driven noncanonical signaling in murine mo…