Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells

Cell adhesion to the extracellular matrix appears to trigger a cascade of intracellular signalings. We have previously shown that treatment of ovarian cancer cells, NOM1, with fibronectin (FN) stimulated matrix metalloproteinase (MMP)-9 secretion and thereby activated the invasiveness of cells via the FAK/Ras signaling pathway. By use of chemical inhibitors, we investigated the downstream effectors critical for FN-dependent secretion of MMP-9. Treatment of cells with MEK1 inhibitors, U0126 and PD98059, dramatically suppressed the secretion of MMP-9 activated by FN. Similarly, PI-3 kinase inhibitors, Wortmannin and LY294002, strongly suppressed the FN-dependent secretion of MMP-9 together with the inhibition of Akt activation. In contrast, a specific PKC inhibitor (GF109203X) showed no inhibitory effect on the FN-dependent MMP-9 secretion. Moreover, we found that both the MEK1 inhibitor and the PI3-K inhibitor, but not the PKC inhibitor, strongly suppressed the invasiveness of NOM1 cells. Taken together, our results suggest that activation of dual signaling pathways, MEK1-MAPK and PI3K-Akt, is required for the FN-dependent activation of MMP-9 secretion. Our results suggest the importance of these signaling molecules as a chemotherapeutic target for cancer. This revised version was published online in July 2006 with corrections to the Cover Date.     

Serial change of myocardial fatty acid metabolism in a case with severe myocardial ischemia

A 66-year-old-man was admitted to our hospital because of chest pain on effort in October 1999. The initial images of 123I-BMIPP myocardial SPECT (BM) showed moderately decreased tracer uptake in the apex and the delayed images revealed redistribution in the apex. Coronary angiography revealed 99% stenosis in the proximal portion of the left anterior descending artery. Since sudden onset anaphylactic shock induced by contrast media developed, so percutaneous transluminal coronary angioplasty was not performed. The patient's symptoms were improved with medical treatment. On BM in March 2000, the initial images indicated slightly reduced uptake in the apico-anteroseptal region and the delayed images revealed mildly redistribution in the same area. BM in September 2000, the initial images showed moderately reduced uptake in the apico-anteroseptal region and the delayed images revealed high washout in the same area. The patient's symptoms markedly deferiorrated in March 2001, and BM initial images revealed slightly reduced uptake in the apico-anteroseptal region and the delayed images revealed redistribution in the same area again. During the clinical course, electrocardiography and 99mTc-tetrofosmin myocardial SPECT revealed no marked changes. We consider that 123I-BMIPP myocardial SPECT is useful in estimating myocardial ischemia.     

Clinical usefulness of an ATP heat sensitivity test using endoscopic biopsy materials from esophageal cancer patients

The usefulness of a heat sensitivity test which involved performing an ATP assay on endoscopic biopsy materials for predicting the clinical response to hyperthermia was investigated in esophageal cancer patients. Following in vitro heat treatment of FM3A tumor cells, the heat sensitivity detected by ATPA was significantly correlated with that in the colony-forming assay, and the percent inhibition of the ATP level in the tumor cells was correlated with in vivo tumor growth. The heat sensitivity of the biopsy materials evaluated by ATPA correlated well with that of the resected specimens in 18 esophageal cancer patients, while the clinical response to thermal therapy was well predicted by the heat sensitivity of the biopsy materials evaluated by ATPA in seven of the patients. These results indicate that the heat sensitivity test conducted by performing an ATPA on endoscopic biopsy materials could be a useful indicator for predicting the clinical response to thermal therapy.     

Haemophagocytic syndrome associated with Epstein-Barr virus infection and promoted by tuberculosis reactivation in a patient undergoing chronic haemodialysis

SUMMARY: A 73-year-old man who had been undergoing chronic haemodialysis (CHD) for 3 years developed haemophagocytic syndrome (HPS) that might have been triggered by Epstein-Barr virus (EBV) infection. the patient finally died of miliary tuberculosis (TB) reactivation that promoted the progression of HPS. Immunological abnormalities in patients undergoing CHD may be notable. the early diagnosis of TB reactivation may be important for reducing the mortality in cases of HPS, as a high incidence of TB is encountered in patients undergoing CHD. In contrast, the simultaneous occurrence of an EBER-positive hybridization signal with T cell-specific immunolabelling of CD45RO cells was well detected in the spleen and lymph nodes, and interferon gamma was elevated in the serum. These findings coincide with the reported preferential expansion of T cells rather than B cells in EBV infection, and support the hypothesis that systemic hypercytokinaemia caused by the proliferation of EBV-infected T cells may play a crucial role in the development of HPS.     

Long-lasting change in the membrane-associated protein kinase C activity in the hippocampal kindled rat

The effect of hippocampal kindling on protein kinase C (PKC) activity and protein concentration was investigated in rat amygdala/pyriform cortex (AM/PC) and right (contralateral) and left (ipsilateral) hippocampus (HIPP). There was no difference in cytosolic PKC activity between control and kindled groups in any part of the brain. The membrane-associated PKC activity was altered as follows. One week after the last seizure, it was significantly increased in both right (by 26%, P less than 0.05) and left HIPP (by 30%, P less than 0.02). Four weeks after the last seizure, it was significantly increased in the AM/PC (by 14%, P less than 0.02), right HIPP (by 37%, P less than 0.01) and left HIPP (by 24%, P less than 0.05). The protein concentrations in the crude cytosolic extracts prior to elution of PKC through DE-52 columns were significantly increased in the AM/PC (by 11%, P less than 0.05) and right HIPP (by 18%, P less than 0.02) 4 weeks after the last seizure. In the membrane extracts, there was a significant increase by 23% (P less than 0.02) in the left HIPP 1 week after the last seizure. In the fraction co-eluted with PKC, a significant increase in protein concentration of the cytosolic preparation was confirmed in the AM/PC (by 12%, P less than 0.05) as well as in the left HIPP (by 15%, P less than 0.05) 4 and 1 weeks respectively after the last seizure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vitreomacular observations II. Data on the pathogenesis of idiopathic macular breaks

• Background: The pathogenesis of idiopathic macular breaks is still uncertain. Their formation has been ascribed to anteriorly oriented intravitreous traction and to shrinkage of the prefoveal cortical vitreous. The validity of both hypotheses is considered in this paper. • Methods: In order to clarify the pathogenesis of idiopathic macular breaks 127 consecutive patients had their vitreous examined and photographed with the El Bayadi-Kajiura precorneal lens and a slit-lamp microscope. • Results: A comparison with 127 matched controls demonstrated that the vitreous was significantly more often attached in eyes with a macular break than in controls (P<0.01). In eyes with a macular break the vitreous was significantly more often attached in early cases (Gass stage 1) than in Gass stages 3 and 4 (P<0.01). Still photographs and observation of the movements of the operculum demonstrated that, in some cases of stage 3 and also in stage 4, it moved inside the partially liquefied posterior vitreous, anteriorly to the retinal surface and frequently without evidence of posterior vitreous detachment over the macular area. The following anatomical features characterize the vitreomacular area: extremely thin hyaloid membrane (<100 μm) and inner limiting lamina (10 nm) that adhere strongly to each other and to the underlying Mueller cells. There is no evidence that these structures can shrink selectively to cause a macular break. The premacular vitreous gel contains collagen fibers that attach posteriorly to the macula and anteriorly to the vitreous base. • Conclusions: Our working hypothesis is that when detachment of the posterior vitreous is abnormally delayed, anteroposterior traction by collagen fibers may pull a foveal operculum off the retina. Our observations make this hypothesis attractive. However, the generally accepted hypothesis of Johnson and Gass cannot be entirely dismissed. In reality, since the two hypotheses are not mutually exclusive, they may both the partially correct.