The protein C anticoagulant pathway plays a fundamental role in the control of coagulation system and inflammatory response. It has been well established that physiological levels of shear stress induce endothelial structural change and modulate gene and protein expression. However, the role of shear stress in protein C pathway remains unknown. In the present study, we evaluated the effect of shear stress on the activation of protein C as well as on the expression of endothelial protein C receptor (EPCR) and thrombomodulin (TM) in human umbilical vein endothelial cells (HUVECs) which were exposed to TNF-alpha alone, shear stress alone, and TNF-alpha under shear stress. We found: (1) Either TNF-alpha or shear stress alone significantly reduced EPCR expression and protein C activation in HUVECs; and simultaneous exposure of HUVECs to TNF-alpha and shear stress resulted in a further decrease of EPCR expression and protein C activation (P<0.05); (2) Simultaneous exposure of HUVECs to TNF-alpha and shear stress resulted in the increase of soluble EPCR level more significantly than did the exposure of HUVECs to either TNF-alpha or shear stress alone (P<0.05); (3) Shear stress significantly increased TM expression on HUVECs, whereas TNF-alpha inhibited TM expression; shear stress could strongly neutralize TNF-alpha's inhibitive effect on TM expression. We therefore conclude that shear stress may play an important role in protein C pathway, which may be fulfilled by regulating EPCR expression and TM expression in endothelial cells.
Antigens, CD ; genetics ; metabolism ; Biomechanical Phenomena ; Cells, Cultured ; Endothelial Cells ; cytology ; metabolism ; Endothelial Protein C Receptor ; Humans ; Protein C ; metabolism ; Receptors, Cell Surface ; genetics ; metabolism ; Shear Strength ; Stress, Mechanical ; Thrombomodulin ; genetics ; metabolism ; Umbilical Veins ; cytology

OBJECTIVETo study the influence of micrometastasis in lymph node on staging and prognosis of non-small-cell lung cancer (NSCLC).

METHODSIn 39 NSCLC patients, micrometastasis in pathologically negative lymph nodes were tested through immunohistochemical cytokeratin (CK) analysis and the relationship between CK(+) and staging, survival were analyzed.

RESULTSIn these 39 patients, the survival of CK(+) and CK(-) patients were 32 months and 48 months respectively (P = 0.0178). Multivariate analysis of Cox regression model showed: clinical stage (P = 0.0288) and relapse or metastasis (P = 0.0053) affected the prognosis while micrometastasis in lymphnodes (P = 0.7740) did not.

CONCLUSIONThe detection of micrometastasis in the lymphnodes may serve as a supplement to the present staging system for lung cancer. Even though the prognosis of patients with micrometastasis being poorer than those without, micrometastasis in the lymph nodes should not be regarded as an independent prognostic factor.

Adult ; Aged ; Carcinoma, Non-Small-Cell Lung ; diagnosis ; metabolism ; secondary ; Female ; Humans ; Keratins ; metabolism ; Lung Neoplasms ; diagnosis ; metabolism ; pathology ; Lymph Nodes ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis

BACKGROUNDTo detect the expression of human epidermal-growth-factor receptor 4 (HER4) and elucidate the relationship between its overexpression and the clinicopathological characteristics in non-small cell lung cancer (NSCLC).

METHODSThe expression of HER4 was detected in 70 cases of paraffin-embedded NSCLC tissues by immunohistochemical assay.

RESULTSHER4 were overexpressed in 91.4% of NSCLC. The overexpression of HER4 was significantly related to lymph node metastasis (P=0.007), TNM stages (P=0.011) and postoperative survival rate (P= 0.0258).

CONCLUSIONSerbB4 is one of the genes to regulate the growth of advanced NSCLC. The artificial interference with HER4 overexpression may be a good way in the treatment of advanced NSCLC.

It has been demonstrated that the activated protein C (APC) plays an important role in the inhibition of inflammation. The activation of protein C can be significantly enhanced by the endothelial cell protein C receptor (EPCR). Previous studies proposed that the APC regulates the inflammatory response in endothelial cells by suppressing the expression of adhesion molecules and the secretion of chemokines and cytokines. However, the precise mechanism of the inhibitory effect of APC on inflammation is still poorly understood. In the present study, we evaluated the anti-inflammatory effect of recombinant human APC (rhAPC) and whether its inhibitory effect is conducted through the EPCR-dependent mechanism on human umbilical vein endothelial cells (HUVECs). By exposing HUVECs to: (1) TNF-alpha; (2) rhAPC plus TNF-alpha; (3) anti EPCR antibody that prevents rhAPC interaction with EPCR; (4) TNF-alpha plus anti EPCR antibody; (5) rhAPC plus TNF-alpha in the presence of anti EPCR antibody, we found that APC was able to significantly inhibit the TNF-alpha-induced secretion of cytokines such as IL-1beta and IL-8, as well as the expression of adhesion molecules such as ICAM-1, VCAM-1 and E-selction in HUVECs. These results reveal a novel pathway by which APC protects endothelial cells from inflammatory mediators through an EPCR-dependent mechanism.
Antigens, CD ; metabolism ; Cells, Cultured ; Cytokines ; metabolism ; Endothelial Protein C Receptor ; Human Umbilical Vein Endothelial Cells ; drug effects ; Humans ; Inflammation ; metabolism ; Protein C ; pharmacology ; Receptors, Cell Surface ; metabolism ; Tumor Necrosis Factor-alpha ; antagonists & inhibitors