Advertisement

Editors’ Picks

        Triplicate tryptase

        Elevated basal serum levels of the mast cell mediator tryptase have been identified in family cohorts with symptom complexes characterized by cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities; however, the relevance of this increase remains unclear in light of the lack of mast cell disease or activation in these individuals. Lyons and colleagues recently identified germline duplications and triplications in the α-tryptase gene TPSAB1 in an analysis of 35 families with increased serum tryptase levels and complex clinical complaints. Interestingly, triplication of this gene on one allele was associated with greater prevalence of clinical phenotypes, indicating a phenotype-gene dosage correlation. This phenotype is inherited most frequently in an autosomal dominant pattern and is associated with increased copy number on a single allele of TPSAB1. Because elevated basal serum tryptase concentrations are associated with increased prevalence of multiple functional and clinical phenotypes, α-tryptase is an attractive potential therapeutic target. (Nat Genet 48: 1564–1569, 2016) Selected by E. Sprecher

        Links between air pollution and AD

        Development of atopic dermatitis (AD) is known to involve both genetic and environmental components, and the numbers of AD cases are increasing globally in concert with increasing air pollution. Polycyclic aromatic hydrocarbons (PAHs), the main organic components of air pollution, bind to the ligand-activated aryl hydrocarbon receptor (AhR). A mouse model for testing chronic exposure to PAHs has been developed using a constitutively active form of AhR, and these animals develop AD-like phenotypes. Hidaka and colleagues demonstrated that chronic and keratinocyte-specific activation of AhR induced clinical features of human AD as well as alloknesis, a sensory abnormality involving hypersensitivity and pruritic paresthesia often observed in AD patients. Additionally, the neurotrophic artemin gene Artn was identified as an AhR target, leading to epidermal hyper-innervation and inflammation. Interestingly, exposure to air pollutants increased artemin expression, alloknesis, and allergic inflammation in mice via AhR, and AhR activation in the epidermis of human AD patients correlated with artemin expression. These findings indicate that AhR is the molecular link between air pollution and AD and suggest the potential for targeting artemin or the AhR system as an approach for treating pruritus in AD. (Nat Immunol 18: 64–73, 2017) Selected by A. Irvine

        Phase 3 Fabry’s disease trial

        The rare progressive X-linked disorder Fabry’s disease is caused by functional deficiency of lysosomal α-galactosidase and consequent accumulation of globotriaosyl-ceramide (GL-3), resulting in multisystem disease and premature death. Germain and colleagues presented the results of a phase 3 clinical trial to evaluate the safety and efficacy of migalastat, a pharmacologic chaperone molecule that binds the active side of α-galactosidase to stabilize some mutant enzymes and facilitate proper trafficking to lysosomes for catabolism of accumulated substrates. As Fabry’s disease is treated by lifelong recurrent enzyme-replacement infusions, oral administration of the low-molecular weight iminosugar migalastat raises the possibility of an easier treatment strategy without associated immunogenicity. In this trial, however, the percentage of patients that harbored mutant enzyme forms that were or were not suitable for migalastat therapy and exhibited a decrease in GL-3 inclusions of 50% or more did not differ significantly between the treatment group and the placebo group at 6 months, although some improvements in only patients with a mutation suitable for migalastat therapy were observed after longer time periods. (N Engl J Med 375:545–555, 2016) Selected by T. Nijsten

        Precision medicine advances

        Aberrant Notch activity has been identified in many cancers, and targeting protein-protein interactions in this signaling pathway has become an important avenue for therapeutic exploration. Using computer-aided drug design in combination with an in vitro assay of Notch complex formation, Astudillo and colleagues recently identified the small molecule inhibitor of Mastermind recruitment-1 (IMR-1) as a molecule that directly inhibits the formation of the Notch transcriptional activation complex. More specifically, IMR-1 prevents recruitment of Maml1 to the Notch transcriptional complex, resulting in inhibition of Notch target gene transcription. Furthermore, in a patient-derived tumor xenograft model, treatment with IMR-1 substantially decreased tumor growth. This novel small molecule may provide a therapeutic strategy for targeting the Notch signaling pathway and offer a complementary or alternative approach for advancing the goal of precision medicine, which, based on previous paradigms, will likely involve combinatorial strategies. (Cancer Res 76:3593–3603, 2016) Selected by H. Schaider

        Oncogenic pair

        The receptor tyrosine kinase MET, which binds to the ligand hepatocyte growth factor (HGF), is abundant in a subset of human skin cancers due to transcriptional upregulation or gene amplification. In mouse models of carcinogenesis, Cataisson and colleagues demonstrated that HGF-activated MET is a fully functional tumor initiator. In fact, in MT-HGF mice with increased HGF ligand, the incidence of skin squamous tumors was increased. Interestingly, downstream signaling from MET activation shared many of the phenotypic and biochemical characteristics of oncogenic RAS signaling in keratinocytes. Furthermore, epidermal growth factor receptor (EGFR) was identified as an obligatory effector of MET-driven mouse skin carcinogenesis, and inhibition of EGFR induced regression of the MT-HGF mouse squamous tumors. Taken together, these findings illuminate HGF and MET as a relevant oncogenic pair for the propagation of human skin cancers via EGFR activation. (Sci Signal 9: ra62, 2016) Selected by B.A. Gilchrest