Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy.

Introduction: Post translational modification of proteins plays a significant role in immune recognition. In particular the modification of arginine to citrulline which is mediated by PAD enzymes is increased during cellular stress (autophagy) which permits the presentation of modified epitopes upon MHC class II molecules for recognition by CD4 T cells. Citrullination also occurs in tumour cells as a result of continuous environmental stresses and increased autophagy. We have shown in animal models the efficient stimulation of citrullinated epitope specific CD4 T cells resulting in dramatic elimination/regression of tumours. The ER chaperone glucose-regulated protein 78 (GRP78) is known to also be required for stress-induced autophagy and is directly linked to autophagosome formation. GRP78 is known to be highly expressed by many tumour types. In this study we investigate the potential of targeting citrullinated GRP78 for cancer therapy. Methods: A citrullinated GRP78 specific antibody was used to assess citrullinated GRP78 expression in murine and human tumour cells by flow cytometry. Five peptides were selected and used to vaccinate HLA transgenic mice and immune responses were characterised by ex vivo cytokine ELISpot assay. T cell repertoire in humans was assessed through proliferation assays and cytokine ELISpot assay. Citrullinated peptide was identified in murine B16 melanoma by mass spectrometry and the peptide vaccine was assessed for tumour therapy in a mouse melanoma model. Results: We show the identification CD4 T cell responses to one citrullinated GRP78 epitope that are restricted through HLA DP*0401 and HLA-DR*0101 alleles. This peptide is detected by mass spectrometry in B16 melanoma grown in vivo and citrulline specific CD4 responses to two peptides spanning this epitope mediate efficient therapy of established B16 melanoma tumours in HHDII/DP4 (p<0.0001) transgenic mouse model. Finally, we demonstrate the existence of a repertoire of responses to the citrullinated GRP78 peptide in healthy individuals (p=0.0023) with 13/17 (76%) individuals showing a response to this peptide. Conclusion: We propose that citrullinated GRP78 is a candidate tumour antigen and vaccination against citrullinated GRP78 may provide a promising tumour therapy approach.

Community-based, population-focused preterm birth prevention programs - a review.

PURPOSE: Preterm birth (PTB) is the leading cause of perinatal morbidity and mortality worldwide. Being born too early contributes to approximately 70% of neonatal mortality and approximately half of long-term neurodevelopmental disabilities. Various PTB prevention programs have been described going back more than 30 years, and some have described possible success in decreasing the rate of PTB. In addition, there are also PTB prenatal care clinics in many parts of the world, each with the singular goal of reducing the PTB rate in their region. Interventions can be directed at all women for primary prevention and reducing the risk of PTB or used to mitigate risk in women identified to be at increased risk. METHODS: A Medline and ClinicalTrials.gov ( www.clinicaltrials.gov ) search was performed (1982-2018), using preterm birth prevention program as the primary medical subject heading, reporting randomized clinical trials, quasi-experimental trials, and analytic studies (including retrospective and prospective cohort studies). We also searched Google for preterm birth prevention programs and prenatal care clinics published on-line. RESULTS: Some prevention programs have reported success in lowering rates of PTB, principally using historical controls although the majority were not followed by improved outcomes. CONCLUSION: Increasing knowledge and the use of social media to enhance education should now enable greater effectiveness of new programs. Development of regional and national PTB prevention programs should now be considered.

Neighbourhood family income and adverse birth outcomes among singleton deliveries.

OBJECTIVE: to assess the association between neighbourhood family income and adverse birth outcomes. METHODS: we conducted a retrospective cohort study of 334 231 singleton births during 2004 and 2006 based on the Niday Perinatal Database from Ontario. Median neighbourhood family incomes from the 2001 Canadian census were linked with the Niday Perinatal Database by dissemination areas. Generalized estimating equations were applied to estimate the odds ratios of adverse birth outcomes associated with lower neighbourhood income, with adjustment for maternal confounding variables at the individual level. RESULTS: compared with the highest neighbourhood income quintile, mothers from the lowest quintile were at increased risk of having small for gestational age neonates (OR 1.51; 95% CI 1.46 to 1.57), low birth weight (OR 1.43; 95% CI 1.36 to 1.50), preterm birth (OR 1.17; 95% CI 1.12 to 1.23), low Apgar score (< 7) at five minutes (OR 1.32; 95% CI 1.21 to 1.44), and stillbirth (OR 1.39; 95% CI 1.19 to 1.62). The risks of women from the lowest income quintiles delivering a macrosomic baby (OR 0.81; 95% CI 0.79 to 0.84) or a large for gestational age baby (OR 0.82; 95% CI 0.80 to 0.85) were significantly decreased. No difference in risk of congenital anomaly was found among different income quintiles. CONCLUSION: a lower level of neighbourhood income is associated with increased risks of small for gestational age babies, low birth weight, preterm birth, low Apgar score at five minutes, and stillbirth.

Social disparity and the use of intrapartum epidural analgesia in a publicly funded health care system.

OBJECTIVE: We sought to examine the difference in use of labor epidural analgesia among women from different neighborhood socioeconomic groups. STUDY DESIGN: Neighborhood socioeconomic variables from the 2001 Canadian Census were linked to singleton vaginal births from the Niday perinatal database (2004-2006) in Ontario, Canada. Births were divided into income and education groups by quintiles. Generalized estimating equations were employed to evaluate the association between labor epidural and neighborhood socioeconomic status. Supplementary analysis was conducted after stratifying data by hospital types. RESULTS: Compared with those from the richest neighborhood, women from the poorest quintile were the least likely to receive labor epidural analgesia (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.58-0.61). The differences were smallest in teaching hospitals (OR, 0.73; 95% CI, 0.67-0.79) and largest in small community hospitals (OR, 0.57; 95% CI, 0.50-0.64). Similar association was found in neighborhood education quintiles. CONCLUSION: The use of labor epidural analgesia is decreased with decreasing neighborhood economic and education levels.