Proteases in Plasma and Kidney of db/db Mice as Markers of Diabetes-Induced Nephropathy

Db/db mice are overweight, dyslipidemic and develop diabetic complications, relevant for similar complications in human type 2 diabetes. We have used db/db and db/+ control mice to investigate alterations in proteinase expression and activity in circulation and kidneys by SDS-PAGE zymography, electron microscopy, immunohistochemistry, Western blotting, and in situ zymography. Plasma from db/db mice contained larger amounts of serine proteinases compared to db/+ mice. Kidneys from the db/db mice had a significantly larger glomerular surface area and somewhat thicker glomerular basement membranes compared to the db/+ mice. Furthermore, kidney extracts from db/+ mice contained metalloproteinases with Mr of approximately 92000, compatible with MMP-9, not observed in db/db mice. These results indicate that higher levels of serine proteinases in plasma may serve as potential markers for kidney changes in db/db mice, whereas a decrease in MMP-9 in the kidney may be related to the glomerular changes

The skeletal phenotype of chondroadherin deficient mice

Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their a2b1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3–6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the a1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth

Prognostic significance of osteopontin expression in early-stage non-small-cell lung cancer

Osteopontin (OPN) is a multifunctional protein, which has recently been shown to be linked to tumorigenesis, progression and metastasis in different malignancies. Since non-small-cell lung cancer (NSCLC)'s prognosis remains bad, with few predictors of outcome, the purpose of this study was to evaluate if OPN might be involved in NSCLC's biology and therefore represent a prognostic marker and a target for new therapeutic trials. Immunohistochemistry was used to detect OPN expression, evaluated as percentage of neoplastic cells with cytoplasmic immunoreactivity, in a wide cohort of patients with stage I NSCLC (136 cases). The median value of this series (20% of positive cells) was used as the cutoff value to distinguish tumours with low (<20%) from tumours with high (⩾20%) OPN expression. A statistically significant correlation between high levels of OPN and shorter overall (P=0.034) and disease-free (P=0.011) survival in our patients was shown. Our results support the hypothesis that high OPN expression is a significantly unfavourable prognostic factor for the survival of patients with stage I NSCLC. This conclusion has notable importance in terms of the biological characterization of early-stage tumours and therapeutic opportunities

Expression of Osteopontin in oesophageal squamous cell carcinoma

Osteopontin is a multifunctional 34 kDa extracellular matrix protein with a cell-binding domain. It is involved cell adhesion and cell migration and is therefore considered to influence tumorigenesis and/or metastasis. The purpose of the present study was to evaluate the clinical significance of Osteopontin expression in oesophageal squamous cell carcinoma (ESCC). In the present study, we immunohistochemically investigated the relationship between Osteopontin expression and clinicopathological factors including prognosis in surgical specimens of primary tumours in 175 patients with ESCC. Osteopontin was expressed in 48% of 175 patients. Osteopontin expression was significantly correlated with lymph node metastasis, lymphatic invasion, and stage (P=0.0015, 0.037 and 0.033, respectively). Tumours with expressing Osteopontin exhibited more lymph node metastasis, lymphatic invasion and advanced stage than the tumour with negative Osteopontin expression. Five-year survival rate was better in patients with negative Osteopontin expression than in those with positive Osteopontin expression (P=0.035). However, multivariate analysis revealed that Osteopontin expression was not an independent prognostic factor. As our findings suggest that Osteopontin may play an important role in progress of ESCC, the evaluation of Osteopontin expression is useful for predicting the malignant properties of ESCC

Monomeric Tartrate Resistant Acid Phosphatase Induces Insulin Sensitive Obesity

Obesity is associated with macrophage infiltration of adipose tissue, which may link adipose inflammation to insulin resistance. However, the impact of inflammatory cells in the pathophysiology of obesity remains unclear

Strategic Belief Management

While (managerial) beliefs are central to many aspects of strategic organization, interactive beliefs are almost entirely neglected, save for some game theory treatments. In an increasingly connected and networked economy, firms confront coordination problems that arise because of network effects. The capability to manage beliefs will increasingly be a strategic one, a key source of wealth creation, and a key research area for strategic organization scholars. KEYWORDS: Interactive beliefs, coordination, network economy, common knowledge. JEL CODE: D84, M3

CD1c-expression by monocytes : implications for the use of commercial CD1c(+) dendritic cell isolation kits

Conventional dendritic cells (cDCs) comprise a heterogeneous population of cells that are important regulators of immunity and homeostasis. CD1c(+) cDCs are present in human blood and tissues, and found to efficiently activate naive CD4(+) T cells. While CD1c is thought to specifically identify this subset of human cDCs, we show here that also classical and intermediate monocytes express CD1c. Accordingly, the commercial CD1c (BDCA-1) Dendritic Cell Isolation Kit isolates two distinct cell populations from blood: CD1c(+) CD14 cDCs and CD1c(+) CD14(+) monocytes. CD1c(+) cDCs and CD1c(+) monocytes exhibited strikingly different properties, including their differential regulation of surface marker expression, their levels of cytokine production, and their ability to stimulate naive CD4(+) T cells. These results demonstrate that a commercial CD1c (BDCA-1) Dendritic Cell Isolation Kit isolates two functionally different cell populations, which has important implications for the interpretation of previously generated data using this kit to characterize CD1c(+) cDCs