Background A human Fcγ-Fcϵ fusion protein (GE2) designed to inhibit FcϵRI signaling by coaggregating FcϵRI with the inhibitory receptor FcγRIIB has been shown to inhibit mast cell activation and ...block cutaneous anaphylaxis. A critical issue remained as to whether the mechanism of GE2 inhibition is competition for IgE binding or inhibitory signaling through FcγRIIB. Objective Our aim was to define the in vitro and in vivo mechanism of action of a mouse homolog of GE2 (mGE) and to assess the potential of human GE2 (hGE2) for therapeutic administration. Methods The in vitro activity of mGE on mediator release and signaling pathways was characterized in IgE-sensitized bone marrow–derived mast cells (BMMCs). The in vivo activity of mGE was examined in mouse passive cutaneous and passive systemic anaphylaxis models, and the therapeutic activity of hGE2 was evaluated in Ascaris suum –sensitized cynomolgus monkeys. Results mGE inhibited release of histamine and cytokines by BMMCs from wild-type mice but not by BMMCs from FcγRIIB-deficient mice. In mice mGE blocked IgE-dependent anaphylaxis mediated by mast cells with sustained efficacy. In BMMCs mGE decreased spleen tyrosine kinase and extracellular signal-regulated kinases 1/2 phosphorylation and induced FcγRIIB phosphorylation and the subsequent recruitment of SH2 domain–containing inositol polyphosphate 5′ phosphatase (SHIP) 1 and SH2 domain–containing protein tyrosine phosphatase (SHP) 1/2 phosphatases. When administered therapeutically, hGE2 protected sensitized monkeys from local anaphylaxis for 3 weeks. Conclusion mGE-mediated inhibition of mast cell activation is associated with inhibitory signaling through FcγRIIB that results from activation of SHIP-1 and SHP-1/2 phosphatases.
Vitreoretinal Disease Scott, Ingrid U; Regillo, Carl D; Flynn, Harry W., Jr ...
2017, 20180101
eBook
The management of major vitreoretinal diseases has changed dramatically since publication of the first edition in 1999. The field continues to evolve rapidly and is becoming an increasingly complex, ...multifaceted practice of medicine and surgery. As such, retinal specialists are faced with increasingly sophisticated diagnostic and therapeutic modalities to learn and master. Contributors to this completely updated reference are renowned experts in retinal disease and vitreous disorders.
Divided into four essential sections, the book starts with a basic overview of posterior segment anatomy and physiology. The second section reviews the spectrum of diagnostic tools used in the field from relatively low technology such as the indirect ophthalmoscope to the latest, state-of-the-art optical coherence tomography test. The third and most comprehensive section covers disease states, subdivided into eight categories: retinovascular conditions, macular diseases, inherited vitreoretinal conditions, inflammatory conditions, intraocular tumors, vitreous and retinal detachments, trauma and toxicity, and fundus conditions. The text concludes with specific vitreoretinal procedures.
Key Features
New technologies including spectral domain optical coherence tomography (OCT), intravitreal injections, and microincisional vitrectomy
The utilization of multifocal electroretinography, scanning laser ophthalmoscopy, and fundus autofluorescence
Advances in treatment of macular edema and age-related macular degeneration with anti-VEGF therapy
Summaries of the latest and most important clinical trials
Richly illustrated with more than 700 color state-of-the art retinal images and surgical procedure drawings
Clinical pearls, controversies, and special considerations highlighted in color boxes in every chapter
This up-to-date, clinically-oriented resource will greatly benefit ophthalmology residents and ophthalmologists with comprehensive practices.
Motivation: The CEBS data repository is being developed to promote a systems biology approach to understand the biological effects of environmental stressors. CEBS will house data from multiple gene ...expression platforms (transcriptomics), protein expression and protein–protein interaction (proteomics), and changes in low molecular weight metabolite levels (metabolomics) aligned by their detailed toxicological context. The system will accommodate extensive complex querying in a user-friendly manner. CEBS will store toxicological contexts including the study design details, treatment protocols, animal characteristics and conventional toxicological endpoints such as histopathology findings and clinical chemistry measures. All of these data types can be integrated in a seamless fashion to enable data query and analysis in a biologically meaningful manner. Results: An object model, the SysBio-OM (Xirasagar et al., 2004) has been designed to facilitate the integration of microarray gene expression, proteomics and metabolomics data in the CEBS database system. We now report SysTox-OM as an open source systems toxicology model designed to integrate toxicological context into gene expression experiments. The SysTox-OM model is comprehensive and leverages other open source efforts, namely, the Standard for Exchange of Nonclinical Data () which is a data standard for capturing toxicological information for animal studies and Clinical Data Interchange Standards Consortium () that serves as a standard for the exchange of clinical data. Such standardization increases the accuracy of data mining, interpretation and exchange. The open source SysTox-OM model, which can be implemented on various software platforms, is presented here. Availability: A universal modeling language (UML) depiction of the entire SysTox-OM is available at and the Rational Rose object model package is distributed under an open source license that permits unrestricted academic and commercial use and is available at . Currently, the public toxicological data in CEBS can be queried via a web application based on the SysTox-OM at Contact:xirasagars@saic.com Supplementary information: Supplementary data are available at Bioinformatics online.
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