ORCID Profile
0000-0003-0416-0397
Current Organisation
Monash University
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Publisher: Springer Science and Business Media LLC
Date: 26-09-2019
Publisher: BMJ
Date: 08-2018
DOI: 10.1136/BMJOPEN-2017-020014
Abstract: Demographic, behavioural and environmental factors have been associated with increased risk of head and neck cancer (HNC). We will review published reports and explore connections between risk factors and HNC incidence. This protocol aims to provide strategies for a systematic review and meta-analysis of HNC risk factor analysis in India. It also provides guidelines in order to visualise obtained HNC risk factor data in the form of a heat-map highlighting variations across gender, age and geographical location. We will identify well-established HNC risk factors and perform a comprehensive systematic review and meta-analysis to quantify each risk factor’s impact on HNC incidence. A systematic search will be performed to identify the studies and published reports of HNC risk factors in India. Meta-analysis will be conducted to estimate the proportional contribution of the most prevalent risk factor in HNC on a city-wide basis in Indian states and territories. The review protocol draws on publicly available anonymised data without directly involving human participants and therefore requires neither formal human ethical review nor approval by a human research ethics committee. We published an outline of the protocol in the International Prospective Register of Systematic Reviews (PROSPERO) in 2017. The results will provide an updated analysis of HNC risk factor prevalence in India, and we will discuss the applicability of rehabilitation care. We plan to disseminate the findings of this systematic review through publication in a peer-reviewed journal and presentation at relevant conference proceedings. CRD42017077758.
Publisher: American Chemical Society (ACS)
Date: 07-01-2020
Publisher: Medknow
Date: 2019
Publisher: MDPI AG
Date: 30-03-2022
DOI: 10.3390/BIOMEDICINES10040814
Abstract: How immune tolerance is lost to pancreatic β-cell peptides triggering autoimmune type 1 diabetes is enigmatic. We have shown that loss of the proinsulin chaperone glucose-regulated protein (GRP) 94 from the endoplasmic reticulum (ER) leads to mishandling of proinsulin, ER stress, and activation of the immunoproteasome. We hypothesize that inadequate ER proinsulin folding capacity relative to biosynthetic need may lead to an altered β-cell major histocompatibility complex (MHC) class-I bound peptidome and inflammasome activation, sensitizing β-cells to immune attack. We used INS-1E cells with or without GRP94 knockout (KO), or in the presence or absence of GRP94 inhibitor PU-WS13 (GRP94i, 20 µM), or exposed to proinflammatory cytokines interleukin (IL)-1β or interferon gamma (IFNγ) (15 pg/mL and 10 ng/mL, respectively) for 24 h. RT1.A (rat MHC I) expression was evaluated using flow cytometry. The total RT1.A-bound peptidome analysis was performed on cell lysates fractionated by reverse-phase high-performance liquid chromatography (RP-HPLC), followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein (NLRP1), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), and (pro) IL-1β expression and secretion were investigated by Western blotting. GRP94 KO increased RT1.A expression in β-cells, as did cytokine exposure compared to relevant controls. Immunopeptidome analysis showed increased RT1.A-bound peptide repertoire in GRP94 KO/i cells as well as in the cells exposed to cytokines. The GRP94 KO/cytokine exposure groups showed partial overlap in their peptide repertoire. Notably, proinsulin-derived peptide ersity increased among the total RT1.A peptidome in GRP94 KO/i along with cytokines exposure. NLRP1 expression was upregulated in GRP94 deficient cells along with decreased IκBα content while proIL-1β cellular levels declined, coupled with increased secretion of mature IL-1β. Our results suggest that limiting β-cell proinsulin chaperoning enhances RT1.A expression alters the MHC-I peptidome including proinsulin peptides and activates inflammatory pathways, suggesting that stress associated with impeding proinsulin handling may sensitize β-cells to immune-attack.
No related grants have been discovered for Ritchlynn Aranha.