Induction of cyclooxygenase protein and stimulation of prostaglandin E2 release by epidermal growth factor in cultured guinea pig gastric mucous cells

The present study was undertaken to investigate whether epidermal growth factor (EGF) could stimulate prostaglandin E₂ release, and if so, by what mechanism EGF would exert such an effect in gastric mucosal cells. In cultured guinea pig gastric mucous cells, EGF dosedependently stimulated prostaglandin E₂ release, with maximal stimulation observed at 10 ng/ml. EGF stimulated an increase in cyclooxygenase activity, which was reduced by protein synthesis inhibitor, actinomycin D, and cycloheximide. EGF also stimulated the enzyme protein synthesis estimated by Western blot analysis, whereas EGF did not stimulate phospholipase A₂ activity. These results suggest that such an effect of EGF onde novo synthesis of cyclooxygenase protein and prostaglandin E₂ release may be involved at least in part in the mechanism of EGF-induced local regulation of gastric mucosal integrity.     

Mitochondrial ubiquitin ligase MITOL blocks S-nitrosylated MAP1B-light chain 1-mediated mitochondrial dysfunction and neuronal cell death

Nitric oxide (NO) is implicated in neuronal cell survival. However, excessive NO production mediates neuronal cell death, in part via mitochondrial dysfunction. Here, we report that the mitochondrial ubiquitin ligase, MITOL, protects neuronal cells from mitochondrial damage caused by accumulation of S-nitrosylated microtubule-associated protein 1B-light chain 1 (LC1). S-nitrosylation of LC1 induces a conformational change that serves both to activate LC1 and to promote its ubiquination by MITOL, indicating that microtubule stabilization by LC1 is regulated through its interaction with MITOL. Excessive NO production can inhibit MITOL, and MITOL inhibition resulted in accumulation of S-nitrosylated LC1 following stimulation of NO production by calcimycin and N-methyl-D-aspartate. LC1 accumulation under these conditions resulted in mitochondrial dysfunction and neuronal cell death. Thus, the balance between LC1 activation by S-nitrosylation and down-regulation by MITOL is critical for neuronal cell survival. Our findings may contribute significantly to an understanding of the mechanisms of neurological diseases caused by nitrosative stress-mediated mitochondrial dysfunction.     

Association between bleeding severity and long-term mortality in patients experiencing vascular complications after percutaneous coronary intervention

Vascular complications (VCs) occur in 3% to 8% of percutaneous coronary interventions (PCIs). However, only a portion of patients who experience VCs bleed significantly. The aim of this study was to assess the covariates associated with the amount of blood loss in patients experiencing postprocedural VCs as well as the effect of the degree of blood loss on long-term mortality. Overall, 7,718 unselected patients who underwent PCI through femoral access were evaluated. Those experiencing VCs were identified and stratified with regard to the degree of hematocrit (HCT) decrease after the procedure. In total, 444 patients (5.8%) had VCs. Compared to those without VCs, patients with VCs were older and had more extensive co-morbidities. Severe blood loss was most frequent in those who had vascular perforation requiring surgical repair or in those who had retroperitoneal bleeding. Overall, <25% of patients with hematoma had severe blood loss. The raw 1-year mortality was doubled in patients with minimal or moderate HCT decrease and was tripled in those with severe decreases in HCT. Similarly, the rate of definite stent thrombosis was tripled in patients with VCs and moderate or severe decreases in HCT. After adjustment, only patients with VCs and the greater HCT decreases had an increased risk for death at 1 year (hazard ratio 1.80, 95% confidence interval 1.03 to 3.14). Independent predictors of severe HCT decrease included age, female gender, glycoprotein IIb/IIIa inhibitor use, and activated clotting time peak. Bivalirudin and closure devices were independently associated with less frequent severe HCT decrease. In conclusion, VCs do not entail an increased risk for death at 1 year unless associated with severe blood loss. The use of bivalirudin and closure devices seems to reduce the risk for such complications.     

Cancer-associated fibroblasts and CD163-positive macrophages in oral squamous cell carcinoma: their clinicopathological and prognostic significance

J Oral Pathol Med (2012) 41 : 444–451 Background: Stromal cells are believed to affect cancer invasion and metastasis. The purpose of this study was to evaluate the distribution of cancer‐associated fibroblasts (CAFs) and the incidence of tumor‐associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC), focusing on clinicopathological factors and patient prognosis, as well as cancer invasion. Methods: The study included 108 patients with OSCC. Anti‐α‐smooth muscle actin, CD68, and CD163 antibodies were used to identify CAFs and TAMs. CAFs were divided into 4 grades on the basis of staining intensity: negative (0), scanty (1), focal (2), and abundant (3). The most intensive areas of macrophage concentration in each tumor invasive stroma were also evaluated. Results: The cancer specimens were divided into Grade 0/1, Grade 2, and Grade 3 on the basis of CAF grade. In addition, they were divided into low‐ and high‐grade groups on the basis of the number of CD68‐positive and CD163‐positive macrophages. The latter were significantly increased in the Grade 2 CAF group compared to the Grade 0/1 group (P = 0.009). Kaplan–Meier and multivariate survival analyses revealed that Grade 2 CAFs (P = 0.003) and high CD163‐positive macrophage levels (P = 0.007) significantly correlated with a poor outcome in patients with OSCC, and that a high CD163‐positive macrophage level was a significant and an independent prognostic factor (P = 0.045). Conclusions: Cancer‐associated fibroblasts and CD163‐positive macrophages may be potential prognostic predictors of OSCC.