Is the urokinase-type plasminogen activator system a reliable prognostic factor in gastric cancer?

AIM: The aim of this prospective study was to evaluate the clinical and prognostic impact of immunohistochemically assessed uPA and PAI-1 in patients with gastric cancer. METHODS: This prospective study analyzed specimens obtained from 105 gastric cancer patients who underwent gastrectomy with extended lymphadenectomy. The immunohistochemical expression of uPA and PAI-1 was studied semiquantitatively in the tumor epithelium and was correlated with the clinicopathological features of each patient. RESULTS: Univariate analysis revealed no statistically significant association of uPA levels with pT and pN category (p=0.655 and 0.053, respectively), grading (p=0.374), depth of tumor invasion (p=0.665), UICC classification (p=0.21) and the Laurén classification (p=0.578). PAI-1 expression showed no statistically significant correlation with pT, pN and M category (p=0.589, 0.414, and 0.167, respectively), grading (p=0.273), and the Laurén classification (p=0.368). Only the UICC classification was significantly correlated with PAI-1 (p=0.016). Kaplan-Meier analysis revealed no significant association of uPA and PAI-1 with overall survival (p=0.0929 and 0.0870, respectively). CONCLUSIONS: Our results could not verify any prognostic value of uPA and PAI-1 levels in patients with gastric carcinoma. Therefore, the uPA-system as a biologically defined prognostic marker to identify high-risk gastric cancers should be applied with caution. However, considering the number of patients involved and the borderline level of significance observed in this study, a larger number of events may have resulted in significant differences.     

Early response cytokines and innate immunity: essential roles for TNF receptor 1 and type I IL-1 receptor during Escherichia coli pneumonia in mice

The early response cytokines, TNF and IL-1, have overlapping biologic effects that may function to propagate, amplify, and coordinate host responses to microbial challenges. To determine whether signaling from these early response cytokines is essential to orchestrating innate immune responses to intrapulmonary bacteria, the early inflammatory events induced by instillation of Escherichia coli into the lungs were compared in wild-type (WT) mice and mice deficient in both TNF receptor 1 (TNFR1) and the type I IL-1 receptor (IL1R1). Neutrophil emigration and edema accumulation induced by E. coli were significantly compromised by TNFR1/IL1R1 deficiency. Neutrophil numbers in the circulation and within alveolar septae did not differ between WT and TNFR1/IL1R1 mice, suggesting that decreased neutrophil emigration did not result from decreased sequestration or delivery of intravascular neutrophils. The nuclear translocation of NF-kappa B and the expression of the chemokine macrophage inflammatory protein-2 did not differ between WT and TNFR1/IL1R1 lungs. However, the concentration of the chemokine KC was significantly decreased in the bronchoalveolar lavage fluids of TNFR1/IL1R1 mice compared with that in WT mice. Thus, while many of the molecular and cellular responses to E. coli in the lungs did not require signaling by either TNFR1 or IL1R1, early response cytokine signaling was critical to KC expression in the pulmonary air spaces and neutrophil emigration from the alveolar septae.     

Cholinesterasen mit Nebenjobs

Moonlighting cholinesterases in non-synaptic cholinergic mechanisms The early phylogenetic and ontogenetic appearance of acetylcholine (ACh) and its cholinergic protein components render their possible functionalities, apart from purely neuronal ones, most likely. The capacities of cholinesterases (ChEs) to form large protein complexes opened wide functional fields for them. Already existent in stem cells, ChEs in cooperation with components of the cell matrix (ECM) promote cell differentiation, whereby their enzymatic activity is (at least partially) dispensable. This is independently supported by effects of inactive AChE protein exerted in non-neuronal cells, as well as the discovery of cholinesterase-like adhesion molecules (CLAMs). Therefore, much evidence supports the conclusion that the original functionalities of cholinesterases, and, more generally of cholinergic systems, are to be sought in cell-cell-communication. Here, these views were exemplified by some in vitro and in vivo model studies. In the vertebrate retina early differentiating amacrine cells co-regulate network formation. Similarly potent are cholinergic mechanisms during skeletogenesis. ACh accelerates bone formation, and ChEs not only regulate its concentration, but exert additional structural functions. As much convincing, a study on tadpoles documented that gut formation in Xenopus laevis depends strictly on the AChE protein, but not on its enzymatic activity. A full elucidation of ChE functionalities is essential, since a multitude of anticholinesterases (ChE inhibitors) are widely applied in public life (agriculture, health, security). It is timely that cholinergic research focuses on elucidation of non-synaptic ChEs, and on analyzing non-neuronal cholinergic systems (NNCS) in general.