Lysophosphatidic Acid Induces Neointima Formation Through PPARγ Activation

Neointimal lesions are characterized by accumulation of cells within the arterial wall and are a prelude to atherosclerotic disease. Here we report that a brief exposure to either alkyl ether analogs of the growth factor–like phospholipid lysophosphatidic acid (LPA), products generated during the oxidative modification of low density lipoprotein, or to unsaturated acyl forms of LPA induce progressive formation of neointima in vivo in a rat carotid artery model. This effect is completely inhibited by the peroxisome proliferator-activated receptor (PPAR)γ antagonist GW9662 and mimicked by PPARγ agonists Rosiglitazone and 1-O-hexadecyl-2-azeleoyl-phosphatidylcholine. In contrast, stearoyl-oxovaleryl phosphatidylcholine, a PPARα agonist and polypeptide epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor failed to elicit neointima. The structure-activity relationship for neointima induction by LPA analogs in vivo is identical to that of PPARγ activation in vitro and disparate from that of LPA G protein–coupled receptor activation. Neointima-inducing LPA analogs up-regulated the CD36 scavenger receptor in vitro and in vivo and elicited dedifferentiation of cultured vascular smooth muscle cells that was prevented by GW9662. These results suggest that selected LPA analogs are important novel endogenous PPARγ ligands capable of mediating vascular remodeling and that activation of the nuclear transcription factor PPARγ is both necessary and sufficient for neointima formation by components of oxidized low density lipoprotein

Expression of CXCL10 is associated with response to radiotherapy and overall survival in squamous cell carcinoma of the tongue

Five-year survival for patients with oral cancer has been disappointingly stable during the last decades, creating a demand for new biomarkers and treatment targets. Lately, much focus has been set on immunomodulation as a possible treatment or an adjuvant increasing sensitivity to conventional treatments. The objective of this study was to evaluate the prognostic importance of response to radiotherapy in tongue carcinoma patients as well as the expression of the CXC-chemokines in correlation to radiation response in the same group of tumours. Thirty-eight patients with tongue carcinoma that had received radiotherapy followed by surgery were included. The prognostic impact of pathological response to radiotherapy, N-status, T-stage, age and gender was evaluated using Cox's regression models, Kaplan-Meier survival curves and chi-square test. The expression of 23 CXC-chemokine ligands and their receptors were evaluated in all patients using microarray and qPCR and correlated with response to treatment using logistic regression. Pathological response to radiotherapy was independently associated to overall survival with a 2-year survival probability of 81 % for patients showing a complete pathological response, while patients with a non-complete response only had a probability of 42 % to survive for 2 years (p = 0.016). The expression of one CXC-chemokine, CXCL10, was significantly associated with response to radiotherapy and the group of patients with the highest CXCL10 expression responded, especially poorly (p = 0.01). CXCL10 is a potential marker for response to radiotherapy and overall survival in patients with squamous cell carcinoma of the tongue

“We’re just stuck in a daily routine”:Implications of the temporal dimensions, demands and dispositions of mothering for leisure time physical activity

The reduced physical activity of women when they become mothers is a public health priority. Existing studies show that mothers have little time for leisure, or time that is fragmented and requiring negotiation with others. However, the temporal features of mothering are undertheorised and qualitative studies tend to focus on how mothers can skilfully construct physically active identities and balance societal expectations about being a "good mother". In line with other research that focuses on the configuration of everyday practices that condition the "possibilities" for health-related practices like physical activity, we shift our focus away from the resisting capacities of mothers to the temporal features of mothering practices. We interrogate the lived experiences of 15 mothers of preschool children in deprived urban areas and illuminate the inherent temporal dimensions, demands and dispositions of mothering practices that condition the possibility of leisure time physical activity being undertaken. Together, these temporal features mean mothering practices can readily work against leisure time physical activity. The focus on the mothering practices rather than mothers brings a novel perspective for developing public health policy designed to support mothers into regular leisure time physical activity

Characterization of Chromosomal Instability in Murine Colitis-Associated Colorectal Cancer

Patients suffering from ulcerative colitis (UC) bear an increased risk for colorectal cancer. Due to the sparsity of colitis-associated cancer (CAC) and the long duration between UC initiation and overt carcinoma, elucidating mechanisms of inflammation-associated carcinogenesis in the gut is particularly challenging. Adequate murine models are thus highly desirable. For human CACs a high frequency of chromosomal instability (CIN) reflected by aneuploidy could be shown, exceeding that of sporadic carcinomas. The aim of this study was to analyze mouse models of CAC with regard to CIN. Additionally, protein expression of p53, beta-catenin and Ki67 was measured to further characterize murine tumor development in comparison to UC-associated carcinogenesis in men.The AOM/DSS model (n = 23) and IL-10(-/-) mice (n = 8) were applied to monitor malignancy development via endoscopy and to analyze premalignant and malignant stages of CACs. CIN was assessed using DNA-image cytometry. Protein expression of p53, beta-catenin and Ki67 was evaluated by immunohistochemistry. The degree of inflammation was analyzed by histology and paralleled to local interferon-γ release.CIN was detected in 81.25% of all murine CACs induced by AOM/DSS, while all carcinomas that arose in IL-10(-/-) mice were chromosomally stable. Beta-catenin expression was strongly membranous in IL-10(-/-) mice, while 87.50% of AOM/DSS-induced tumors showed cytoplasmatic and/or nuclear translocation of beta-catenin. p53 expression was high in both models and Ki67 staining revealed higher proliferation of IL-10(-/-)-induced CACs.AOM/DSS-colitis, but not IL-10(-/-) mice, could provide a powerful murine model to mechanistically investigate CIN in colitis-associated carcinogenesis

Male/Female Is Not Enough: Adding Measures of Masculinity and Femininity to General Population Surveys

Survey research and sociological theory each provide insights into how and why people and groups act, think, and feel. Sociological theories identify what concepts are important for understanding and representing the social world. That is, sociological theories inform what to measure in surveys, and, to a certain extent, how to measure it. Survey research permits sociologists to carefully specify what is to be measured vis a vis sociological theory, setting surveys apart as a social research tool. It is this level of specification of concepts and measures that allow surveys to provide continued value at a time when “big data” proliferate. High quality survey measurement and estimation is necessary for sociologists to evaluate sociological theory among generalizable samples with well-developed questions, leading to further refinement and improvement of the theory and improved understanding of the social world. High quality surveys also provide insights into where sociological theories fail and where they must be adjusted for different subgroups, as well as basic insights into the prevalence of outcomes of interest. Together, sociological theory and survey methods produce insights about society that can inform decision-making and social policy. This mutually reinforcing relationship between sociological theory and survey methods requires sociological theory to evolve from insights obtained using survey methods and survey measurement to evolve with advances in in sociological theory. The measurement of sex and gender in surveys is one area where the development of survey measures has not kept pace with sociological theory and empirical, largely qualitative, findings. Contemporary gender theory sees sex and gender as separate concepts, both of which are important for understanding behaviors and outcomes. Yet, virtually all contemporary surveys measure sex as a binary “male” versus “female” categorization and fail to measure gender, ignoring important heterogeneity in gender identification that may exist within sex categories and any overlap that may occur across categories. Both gender scholars and survey researchers are potentially affected by this shortcoming of modern survey measurement. Gender scholars lose an important tool for assessing gender theories, especially on generalizable samples, risking conclusions that are specific to a small group of individuals rather than the population at large. Survey researchers risk producing theoretically obsolete data, limiting the utility of the data or potentially generating misleading conclusions. Survey data that fail to capture and reflect modern and complex understandings of our social realities also face increased risk of being replaced by “big data” such as administrative and social media data. Survey data that do reflect modern and complex understandings can bring value not available in administrative or other data and are therefore unlikely to be replaced. This paper is part of a growing chorus advocating for updates to how modern surveys measure sex and gender. We argue that the reliance on a single binary measure of sex (male or female) is out of step with current sociological understandings of sex and gender. In response, we propose and test a new theoretically-informed gradational measure of gender identification in a nationally representative mail survey. We evaluate whether respondents answer the gender measure and examine the reliability and predictive validity of the measure. In particular, we examine whether measuring gender gradationally adds explanatory value beyond sex on important social outcomes such as sexuality, childcare, grocery shopping, housework, working for pay, and military service. We also examine whether sex moderates the effect of gender identification in the ways that sociological theory would suggest on these outcomes

Lipid Metabolites Enhance Secretion Acting on SNARE Microdomains and Altering the Extent and Kinetics of Single Release Events in Bovine Adrenal Chromaffin Cells

Lipid molecules such as arachidonic acid (AA) and sphingolipid metabolites have been implicated in modulation of neuronal and endocrine secretion. Here we compare the effects of these lipids on secretion from cultured bovine chromaffin cells. First, we demonstrate that exogenous sphingosine and AA interact with the secretory apparatus as confirmed by FRET experiments. Examination of plasma membrane SNARE microdomains and chromaffin granule dynamics using total internal reflection fluorescent microscopy (TIRFM) suggests that sphingosine production promotes granule tethering while arachidonic acid promotes full docking. Our analysis of single granule release kinetics by amperometry demonstrated that both sphingomyelinase and AA treatments enhanced drastically the amount of catecholamines released per individual event by either altering the onset phase of or by prolonging the off phase of single granule catecholamine release kinetics. Together these results demonstrate that the kinetics and extent of the exocytotic fusion pore formation can be modulated by specific signalling lipids through related functional mechanisms