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Novel inhibitors of the cellular renin-angiotensin system components, poricoic acids, target Smad3 phosphorylation and Wnt/β-catenin pathway against renal fibrosis : New RAS inhibitor poricoic acid against renal fibrosis

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      Animal research: reporting in vivo experiments: the ARRIVE guidelines.

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        Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity.

        Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches. These strategies include blockade of immune-inhibitory receptors on activated T cells; for example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1 (refs 3-5). However, only a subset of patients responds to these treatments, and data suggest that therapeutic benefit is preferentially achieved in patients with a pre-existing T-cell response against their tumour, as evidenced by a baseline CD8(+) T-cell infiltration within the tumour microenvironment. Understanding the molecular mechanisms that underlie the presence or absence of a spontaneous anti-tumour T-cell response in subsets of cases, therefore, should enable the development of therapeutic solutions for patients lacking a T-cell infiltrate. Here we identify a melanoma-cell-intrinsic oncogenic pathway that contributes to a lack of T-cell infiltration in melanoma. Molecular analysis of human metastatic melanoma samples revealed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. Using autochthonous mouse melanoma models we identified the mechanism by which tumour-intrinsic active β-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy. Specific oncogenic signals, therefore, can mediate cancer immune evasion and resistance to immunotherapies, pointing to new candidate targets for immune potentiation.
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          Is Open Access

          The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY

          Abstract The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, www.guidetopharmacology.org) and its precursor IUPHAR-DB, have captured expert-curated interactions between targets and ligands from selected papers in pharmacology and drug discovery since 2003. This resource continues to be developed in conjunction with the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS). As previously described, our unique model of content selection and quality control is based on 96 target-class subcommittees comprising 512 scientists collaborating with in-house curators. This update describes content expansion, new features and interoperability improvements introduced in the 10 releases since August 2015. Our relationship matrix now describes ∼9000 ligands, ∼15 000 binding constants, ∼6000 papers and ∼1700 human proteins. As an important addition, we also introduce our newly funded project for the Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb, www.guidetoimmunopharmacology.org). This has been ‘forked’ from the well-established GtoPdb data model and expanded into new types of data related to the immune system and inflammatory processes. This includes new ligands, targets, pathways, cell types and diseases for which we are recruiting new IUPHAR expert committees. Designed as an immunopharmacological gateway, it also has an emphasis on potential therapeutic interventions.
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            Author and article information

            Affiliations
            [1 ]Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science; Northwest University; Xi'an Shaanxi 710069 China
            [2 ]School of Pharmacy; Zhejiang Chinese Medical University; Hangzhou Zhejiang 310053 China
            [3 ]Division of Nephrology and Hypertension, School of Medicine; University of California Irvine; Irvine CA 92897 USA
            [4 ]Department of Internal Medicine; University of New Mexico, Comprehensive Cancer Center; Albuquerque NM 87131 USA
            Journal
            British Journal of Pharmacology
            British Journal of Pharmacology
            Wiley
            00071188
            July 2018
            July 2018
            May 22 2018
            : 175
            : 13
            : 2689-2708
            10.1111/bph.14333
            © 2018

            http://doi.wiley.com/10.1002/tdm_license_1.1

            http://onlinelibrary.wiley.com/termsAndConditions#vor

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