Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis

The mechanism by which human leukocyte antigen B27 (HLA-B27) contributes to ankylosing spondylitis (AS) remains unclear. Genetic studies demonstrate that association with and interaction between polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 influence the risk of AS. It has been hypothesised that ERAP1-mediated HLA-B27 misfolding increases endoplasmic reticulum (ER) stress, driving an interleukin (IL) 23-dependent, pro-inflammatory immune response. We tested the hypothesis that AS-risk ERAP1 variants increase ER-stress and concomitant pro-inflammatory cytokine production in HLA-B27 + but not HLA-B27-AS patients or controls. Forty-nine AS cases and 22 healthy controls were grouped according to HLA-B27 status and AS-associated ERAP1 rs30187 genotypes: HLA-B27 + ERAP1 risk, HLA-B27 + ERAP1 protective, HLA-B27-ERAP1 risk and HLA-B27-ERAP1 protective. Expression levels of ER-stress markers GRP78 (8 kDa glucose-regulated protein), CHOP (C/EBP-homologous protein) and inflammatory cytokines were determined in peripheral blood mononuclear cell and ileal biopsies. We found no differences in ER-stress gene expression between HLA-B27 + and HLA-B27-cases or healthy controls, or between cases or controls stratified by carriage of ERAP1 risk or protective alleles in the presence or absence of HLA-B27. No differences were observed between expression of IL17A or TNF (tumour necrosis factor) in HLA-B27 + ERAP1 risk, HLA-B27 + ERAP1 protective and HLA-B27-ERAP1 protective cases. These data demonstrate that aberrant ERAP1 activity and HLA-B27 carriage does not alter ER-stress levels in AS, suggesting that ERAP1 and HLA-B27 may influence disease susceptibility through other mechanisms. © 2015 Macmillan Publishers Limited.

Promotion of a cancer-like phenotype, through chronic exposure to inflammatory cytokines and hypoxia in a bronchial epithelial cell line model

Globally, lung cancer accounts for approximately 20% of all cancer related deaths. Five-year survival is poor and rates have remained unchanged for the past four decades. There is an urgent need to identify markers of lung carcinogenesis and new targets for therapy. Given the recent successes of immune modulators in cancer therapy and the improved understanding of immune evasion by tumours, we sought to determine the carcinogenic impact of chronic TNF-α and IL-1β exposure in a normal bronchial epithelial cell line model. Following three months of culture in a chronic inflammatory environment under conditions of normoxia and hypoxia (0.5% oxygen), normal cells developed a number of key genotypic and phenotypic alterations. Important cellular features such as the proliferative, adhesive and invasive capacity of the normal cells were significantly amplified. In addition, gene expression profiles were altered in pathways associated with apoptosis, angiogenesis and invasion. The data generated in this study provides support that TNF-α, IL-1β and hypoxia promotes a neoplastic phenotype in normal bronchial epithelial cells. In turn these mediators may be of benefit for biomarker and/or immune-therapy target studies. This project provides an important inflammatory in vitro model for further immuno-oncology studies in the lung cancer setting.

Domestic violence on #qanda: The “Man” question in live Twitter discussion on the Australian Broadcasting Corporation's Q&A

Domestic violence is currently undergoing a period of heightened visibility in Australia. This article uses social media to analyze public discussions about this violence with respect to a specific theoretical frame, which Adrian Howe has called the “Man” question: where and how are men visible or invisible in narratives about their violence against women? The article presents a qualitative study of the Twitter conversation surrounding a special episode of the Australian Broadcasting Corporation's television program Q&A, themed around family violence, which aired in February 2015. We found that the place of men in this conversation was contested. Some tweets privileged men's voices and concerns, as did the organization and production of the program. However, feminist voices were also highly visible via presenting facts, legitimating survivor voices, and recuperating anti-feminist memes to challenge hegemonic patriarchal discourses on men's violence against women. La violence conjugale connait actuellement une visibilité accrue en Australie. Les auteures du présent article utilisent les réseaux sociaux pour analyser les débats publics sur cette violence selon un cadre théorique précis, qu'Adrian Howe a appelé la question de « l'homme » : où et comment les hommes sont-ils visibles ou invisibles dans les récits de leur violence envers les femmes? L'article présente une étude qualitative d'une conversation sur Twitter au sujet d'un épisode axé sur la famille diffusé en février 2015 dans le cadre de l'émission Q & A, à la télévision nationale d'Australie. Nous avons remarqué que dans cette conversation la place des hommes était remise en question. Certains tweets privilégiaient les voix et les craintes des hommes, comme l'ont fait les organisateurs et les producteurs de l'émission. Cependant, il y avait une forte présence de voix féministes dans la présentation des faits, légitimant le point de vue des survivantes et relevant des éléments culturels antiféministes afin de défier les discours hégémoniques et patriarcaux sur la violence des hommes envers les femmes.