Cleavage of the urokinase receptor (uPAR) on oral cancer cells : regulation by transforming growth factor - beta 1 (TGF-beta 1) and potential effects on migration and invasion

Background: Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion. Methods: Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - beta 1 (TGF-beta 1). The role of uPAR cleavage in cell proliferation and migration was analysed using real- time cell analysis and invasion was assessed using the myoma invasion model. Results: We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF-beta 1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR. Conclusions: These results show that soluble factors in the tumour microenvironment, such as TGF-beta 1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy.Peer reviewe

Psychosocial family factors and glycemic control among children aged 1-15 years with type 1 diabetes: a population-based survey

Background: Being the parents of children with diabetes is demanding. Jay Belsky’s determinants of parenting model emphasizes both the personal psychological resources, the characteristics of the child and contextual sources such as parents’ work, marital relations and social network support as important determinants for parenting. To better understand the factors influencing parental functioning among parents of children with type 1 diabetes, we aimed to investigate associations between the children’s glycated hemoglobin (HbA1c) and 1) variables related to the parents’ psychological and contextual resources, and 2) frequency of blood glucose measurement as a marker for diabetes-related parenting behavior. Methods: Mothers (n = 103) and fathers (n = 97) of 115 children younger than 16 years old participated in a population-based survey. The questionnaire comprised the Life Orientation Test, the Oslo 3-item Social Support Scale, a single question regarding perceived social limitation because of the child’s diabetes, the Relationship Satisfaction Scale and demographic and clinical variables. We investigated associations by using regression analysis. Related to the second aim hypoglycemic events, child age, diabetes duration, insulin regimen and comorbid diseases were included as covariates. Results: The mean HbA1c was 8.1%, and 29% had HbA1c ≤ 7.5%. In multiple regression analysis, lower HbA1c was associated with higher education and stronger perceptions of social limitation among the mothers. A higher frequency of blood glucose measurement was significantly associated with lower HbA1c in bivariate analysis. Higher child age was significantly associated with higher HbA1c both in bivariate and multivariate analysis. A scatterplot indicated this association to be linear. Conclusions: Most families do not reach recommended treatment goals for their child with type 1 diabetes. Concerning contextual sources of stress and support, the families who successfully reached the treatment goals had mothers with higher education and experienced a higher degree of social limitations because of the child’s diabetes. The continuous increasing HbA1c by age, also during the years before puberty, may indicate a need for further exploring the associations between child characteristics, context-related variables and parenting behavior such as factors facilitating the transfer of parents’ responsibility and motivation for continued frequent treatment tasks to their growing children

Multinational study in children and adolescents with newly diagnosed type 1 diabetes: association of agem ketoacidosis,HLA status, and autoantibodies on residual beta-cell function and glycemic control 12 months after diagnosis.

OBJECTIVE: To identify predictors of residual beta-cell function and glycemic control during the first 12 months after the diagnosis of type 1 diabetes (T1D). SUBJECTS AND METHODS: Clinical information and blood samples were collected from 275 children. HbA1c, antibodies, HLA typing and mixed meal-stimulated C-peptide levels 1, 6, and 12 months after diagnosis were analyzed centrally. RESULTS: Mean age at diagnosis was 9.1 yr. DKA with standard bicarbonate <15 mmol/L was associated with significantly poorer residual beta-cell function 1 (p = 0.004) and 12 months (p = 0.0003) after diagnosis. At 12 months, the decline in stimulated C-peptide levels compared with the levels at 1 month was 69% in the youngest age group and 50% in patients 10 yr and above (p < 0.001). Stimulated C-peptide at 12 months was predicted by younger age (p < 0.02) and bicarbonate levels at diagnosis (p = 0.005), and by stimulated C-peptide (p < 0.0001), postmeal blood glucose (p = 0.0004), insulin antibodies (IA; p = 0.02) and glutamic acid decarboxylase antibodies (GADA; p = 0.0004) at 1 month. HbA1c at 12 months was predicted by HbA1c at diagnosis (p < 0.0001), GADA at 1 month (p = 0.01), and non-white Caucasian ethnicity (p = 0.002). CONCLUSIONS: Younger age, ketoacidosis at diagnosis, and IA and GADA 1 month after diagnosis were the strongest explanatory factors for residual beta-cell function at 12 months. Glycemic control at 12 months was influenced predominantly by ethnicity, HbA1c at diagnosis, and GADA at 1 month

Associations between physical activity, sedentary behavior, and glycemic control in a large cohort of adolescents with type 1 diabetes: the Hvidoere Study Group on Childhood Diabetes.

Background: The Hvidoere Study Group on Childhood Diabetes has demonstrated persistent differences in metabolic outcomes between pediatric diabetes centers. These differences cannot be accounted for by differences in demographic, medical, or treatment variables. Therefore, we sought to explore whether differences in physical activity or sedentary behavior could explain the variation in metabolic outcomes between centers. Methods: An observational cross-sectional international study in 21 centers, with demographic and clinical data obtained by questionnaire from participants. Hemoglobin A1c (HbA1c) levels were assayed in one central laboratory. All individuals with diabetes aged 11-18 yr (49.4% female), with duration of diabetes of at least 1 yr, were invited to participate. Individuals completed a self-reported measure of quality of life (Diabetes Quality of Life - Short Form [DQOL-SF]), with well-being and leisure time activity assessed using measures developed by Health Behaviour in School Children WHO Project. Results: Older participants (p < 0.001) and females (p < 0.001) reported less physical activity. Physical activity was associated with positive health perception (p < 0.001) but not with glycemic control, body mass index, frequency of hypoglycemia, or diabetic ketoacidosis. The more time spent on the computer (r = 0.06; p < 0.05) and less time spent doing school homework (r = -0.09; p < 0.001) were associated with higher HbA1c. Between centers, there were significant differences in reported physical activity (p < 0.001) and sedentary behavior (p < 0.001), but these differences did not account for center differences in metabolic control. Conclusions: Physical activityis strongly associated with psychological well-being but has weak associations with metabolic control. Leisure time activity is associated with individual differences in HbA1c but not with intercenter differences. © 2009 John Wiley & Sons A/S