Hypoxia upregulates neutrophil degranulation and potential for tissue injury.

BACKGROUND: The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown. METHODS AND RESULTS: Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release. CONCLUSION: Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion.Supported by the British Lung Foundation, Papworth Hospital NHS Foundation Trust, BBSRC and the Cambridge NIHR-Biomedical Research Centre. CS was funded by Wellcome Trust Early Postdoctoral Research Fellowship for Clinician Scientists (WT101692MA).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by BMJ Publishing Group

Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents Toxicology and Applied Pharmacology

Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinear mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2 years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes

Mothering in multicultural context: experiences of Filipino immigrant mothers in Calgary

Bibliography: p. 140-153Both mothering and culture are recognized within psychology as playing important, sometimes crucial roles in psychological and social development, and are thus important areas of research. This project uses a discursive approach to examine how Filipino immigrant mothers to Canada approach and negotiate their experience of raising Canadian children: how do they talk about culture and motherhood? How do they position themselves in relation to their Filipino heritage and to the host Canadian culture? From which cultural resources and mothering ideologies do they draw, and how do they use or resist these resources and ideologies through their use of language? Eleven Filipino immigrant mothers volunteered to participate in five separate conversation sessions during which we talked about culture and mothering. The conversations were then audiotaped and transcribed for discursive analysis. I identify and discuss two broad issues that emerged in our conversations. Firstly, whatever the topic of discussion happened to be, an important concern of the mothers was to take up and justify subject positions with regard to 'good' mothering. Further, in attempts to resolve the tension between versions of the 'good' mother, the participant mothers oriented themselves to questions of presence and absence: does a 'good' mother have to be physically present to her children? Can physical absence from one's children be constructed as consistent with being a 'good' mother? Secondly, the importance of honouring both host and heritage cultures was evident in our conversations, particularly at moments when approval or censure of either culture were expressed. Participant mothers were careful not to be so loyal to Filipino heritage as to appear ungrateful to Canada, or so grateful to Canada as to betray Filipino heritage. Ways in which the current project arises from, contributes to, and extends existing literature on culture and mothering are discussed

Characterization and quantification of the cholesterol oxidation product fraction of the intramuscular fat from pork loin (fresh and marinated) with different irradiation and packaging during storage

© 2014 CSIC. A study of the effect of E-beam (1 and 2 kGy) on the cholesterol oxidation product (COP) composition of fresh and marinated pork loin stored at 4 and 8 °C under different atmospheres (air, vacuum and carbon dioxide enriched ) has been carried out for the first time. The combined statistical treatment of the distinct variables showed that minor differences were found in some cholesterol oxidation products of fresh loin due to storage temperature, packaging method and storage time. No effect of irradiation (up to 2 KGy) on the COP amount was found, concluding that E-beam can be a useful tool to extend the shelf-life of fresh and marinated loin without changes in the COP fraction.This study was supported by projects P08-AGR-03498, AGL-2007-65235-C02-02 and CSD 2007-00016 of the program CONSOLIDER INGENIO 2010.Peer Reviewe

Carcinogenicity of Biopharmaceuticals

This book provides an overview of the nonclinical testing strategies that are used to asses and de-risk the genotoxicity and carcinogenicity properties of human pharmaceuticals. It includes a review of relevant ICH guidelines, numerous case studies where follow-up studies were conducted to further investigate positive findings, and practical considerations for the use of alternative and emerging tests

Carcinogenicity of Biopharmaceuticals

This book provides an overview of the nonclinical testing strategies that are used to asses and de-risk the genotoxicity and carcinogenicity properties of human pharmaceuticals. It includes a review of relevant ICH guidelines, numerous case studies where follow-up studies were conducted to further investigate positive findings, and practical considerations for the use of alternative and emerging tests

Subcutaneous fat triacylglycerols profile from iberian pigs as a tool to differentiate between intensive and extensive fattening systems

Triacylglycerols of subcutaneous fat of Iberian pigs reared on two different feeding systems, extensive and intensive, have been determined by gas chromatography with a flame ionization detector. Analyses were performed on a column coated with a bonded stationary phase (50% phenyl-50% methylpolysiloxane) with hydrogen as the carrier gas. Lipids were extracted by melting the subcutaneous fat in a microwave oven and then filtering and dissolving in hexane. A total amount of 1995 samples from several campaigns were considered. Palmitoyl-stearyl-oleoyl glycerol and palmitoyl-dioleoyl glycerol were the most abundant triacylglycerols found in the samples. A study on the discriminating power of the triacylglycerols to differentiate samples according to the pig feeding system was performed. By using the triacylglycerols as chemical descriptors, principal component analysis, linear discriminant analysis, and soft independent modeling of class analogy were applied. Dioleoyl-linoleoyl glycerol and oleoyl-dilinoleoyl glycerol were the most discriminating variables. Variable-variable plots of these two glycerols allow separation of the samples according to their content. © 2012 American Chemical Society.This study was supported by project PET 2007_0015.Peer Reviewe