OLT1177, a ß-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation.

Activation of the NLRP3 inflammasome induces maturation of IL-1ß and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active ß-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1ß and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3. In LPS-stimulated human blood-derived macrophages, OLT1177 decreased IL-1ß levels by 60% and IL-18 by 70% at concentrations 100-fold lower in vitro than plasma concentrations safely reached in humans. OLT1177 also reduced IL-1ß release and caspase-1 activity in freshly obtained human blood neutrophils. In monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), OLT1177 inhibited LPS-induced IL-1ß release by 84% and 36%. Immunoprecipitation and FRET analysis demonstrated that OLT1177 prevented NLRP3-ASC, as well as NLRP3-caspase-1 interaction, thus inhibiting NLRP3 inflammasome oligomerization. In a cell-free assay, OLT1177 reduced ATPase activity of recombinant NLRP3, suggesting direct targeting of NLRP3. Mechanistically, OLT1177 did not affect potassium efflux, gene expression, or synthesis of the IL-1ß precursor. Steady-state levels of phosphorylated NF-κB and IkB kinase were significantly lowered in spleen cells from OLT1177-treated mice. We observed reduced IL-1ß content in tissue homogenates, limited oxidative stress, and increased muscle oxidative metabolism in OLT1177-treated mice challenged with LPS. Healthy humans receiving 1,000 mg of OLT1177 daily for 8 d exhibited neither adverse effects nor biochemical or hematological changes.

Protocol: systematic review of the association between socio-economic status and survival in adult head and neck cancer.

BACKGROUND: Head and neck cancer incidence is increasing worldwide. Despite overall improvements in survival, numerous studies suggest worse survival in more disadvantaged populations; however, this literature has not been systematically reviewed. The aim of this review is to investigate whether lower compared to higher socioeconomic status (SES) influences survival in head and neck squamous cell cancer (HNSCC) and explore possible explanations for any relationship found. METHOD: A systematic strategy will be used to identify articles, appraise their quality and extract data. Online databases including MEDLINE, Web of Knowledge, ESBCO Host and Scopus will be used to locate observational studies of adults with a primary diagnosis of head and neck cancer in EU15+ countries (15 members of the EU, Australia, Canada, Norway, USA and New Zealand) where the outcomes report associations between SES and survival. This will be augmented by searching for grey literature and through reference lists. Data will be extracted using a standardised form. Study quality will be assessed using the Newcastle Ottawa scale and where possible meta-analysis of the pooled data will be conducted. DISCUSSION: This review will quantify the association between SES and survival outcomes for adult head and neck cancer patients in developed countries. The results will help identify gaps in the literature and therefore direct further novel research in the field. Ultimately, this will inform public policy and strategies to reduce the inequalities in HNSCC survival. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016037019 .