Immunohistochemical alpha- and beta-catenin and E-cadherin expression and their clinicopathological significance in human lung adenocarcinoma

The E-cadherin/catenin complex (alpha-catenin, beta-catenin, and E-cadherin) plays a crucial role in cell-cell adhesion and tissue remodeling, and abnormalities in these molecules have been suggested to participate in the proliferation and invasive and metastatic potentials of several human carcinomas. However, in human lung adenocarcinomas, its importance has not yet been sufficiently investigated. We immunohistochemically examined the expressions of E-cadherin/catenin complex in 35 primary lung adenocarinomas, and evaluated their expressions in a semiquantitative manner. Correlations between these expression levels, MIB-1 and nuclear p53 indices, and clinicopathological factors were analyzed by subdividing the cases into high- and low-expression groups for each protein. The reduction in membranous E-cadherin/catenin complex expression correlated significantly with low-grade histological differentiation and with high MIB-1 index. Survival analyses were also performed to clarify which factors potentially affected the prognosis of lung adenocarcinoma patients. The low expression of beta-catenin and the high MIB-1 index had a significantly unfavorable influence on the patients' survival. Moreover, the immunohistochemical expression of beta-catenin by cancer cells and MIB-1 index are considered useful prognostic factors for lung adenocarcinoma.     

Biodegradation and bioabsorption innovation of the functionally graded bovine bone-originated apatite with blood permeability

Bioabsorbable and functionally graded apatite (fg-HAp) ceramics were designed using bovine bone by the calcination and partial dissolution-precipitation methods. The fg-HAp ceramics that were developed had gradual distributions of the degree of crystallinity and the grain size of single-phase hydroxyapatite from the surface layer of the pore wall to the bulk structure region. Calcination at 1073 K gave a specific surface area of 30 m2 x g-1 and porosities of 60-80%. The pore structure of the fg-HAp was classified into two regions: a macro-pore region (100-600 microm) originating from spongy bone and a micro-pore region (10-160 nm) related to body fluid permeation and blood permeability. By implantation in subcutaneous tissue of rat, it was confirmed that body fluid permeated the bulk region of the fg-HAp ceramics through the micro-pores. The volumetric populations occupied by body fluid were 60% at 4 weeks and 68% at 8 weeks in the ceramics explants, indicating drastic bioabsorption, although the body fluid was found to be immunopositive for an albumin as the main serum protein in blood. On the fg-HAp ceramics developed here, the bioabsorption rate could be controlled by careful selection of the calcination temperature. These ceramics can be applied as new biomimetic ceramics exhibiting surface and bulk degradations and cellular absorption by giant cells.     

When and how does nonstructural mechanical prosthetic heart valve dysfunction occur?

Objective: We diseuss the clinical aspects related to mechanical valve dysfunction based upon 20 years' experience of our cases.Methods: Between January 1982 and December 2001, 21 patients underwent surgical interventions because of mechanical valve dysfunction. Thirteen men and 8 women (mean age 47±20, range 3–75 years-old), were included.Results: Mitral valve dysfunction was observed in 12 patients. Prosthetic valve stenosis occurred in 6 patients between 2 and 224 months, and paravalvular leaks in 4 between 1 and 71 months after surgery. The other 2 patients suffered from hemolytic anemia with mild paravalvular leaks between 102 and 104 months after surgery. Aortic valve dysfunction was observed in 8 patients including 3 stenotic lesions between 48 and 97 months and 5 paravalvular leaks between 3 and 150 months after surgery. Tricuspid regurgitation was seen in 1 patient with a huge right atrium at 42 months after surgery. Early death was seen in 1 patient. Late death occurred in 1 patient, 17 years after operation. Survival, including early death, was 95.2% at 10 and 15 years. One valve-related complication of bioprosthetic valve endocarditis at the mitral and tricuspid positions occurred 12 years after a reoperation. The freedom from complications was 95.2% at 10 years, and 76.2% at 15 years.Conclusions: Paravalvular leaks without overt endocarditis had latency periods of up to 12 years, and pannus formation was observed 20 years after surgery. Early and late clincal results after surgery for mechanical valve dysfunction were excellent.     

Does action semantic knowledge influence mental simulation in sentence comprehension?

This research investigated whether action semantic knowledge influences mental simulation during sentence comprehension. In Experiment 1, we confirmed that the words of face-related objects include the perceptual knowledge about the actions that bring the object to the face. In Experiment 2, we used an acceptability judgment task and a word-picture verification task to compare the perceptual information that is activated by the comprehension of sentences describing an action using face-related objects near the face (near-sentence) or far from the face (far-sentence). Results showed that participants took a longer time to judge the acceptability of the far-sentence than the near-sentence. Verification times were significantly faster when the actions in the pictures matched the action described in the sentences than when they were mismatched. These findings suggest that action semantic knowledge influences sentence processing, and that perceptual information corresponding to the content of the sentence is activated regardless of the action semantic knowledge at the end of the sentence processing.     

Pigment epithelium-derived factor gene therapy targeting retinal ganglion cell injuries: neuroprotection against loss of function in two animal models

Lentiviral vectors are promising tools for the treatment of chronic retinal diseases including glaucoma, as they enable stable transgene expression. We examined whether simian immunodeficiency virus (SIV)-based lentiviral vector-mediated retinal gene transfer of human pigment epithelium-derived factor (hPEDF) can rescue rat retinal ganglion cell injury. Gene transfer was achieved through subretinal injection of an SIV vector expressing human PEDF (SIV-hPEDF) into the eyes of 4-week-old Wistar rats. Two weeks after gene transfer, retinal ganglion cells were damaged by transient ocular hypertension stress (110?mmHg, 60?min) and N-methyl-d-aspartic acid (NMDA) intravitreal injection. One week after damage, retrograde labeling with 4',6-diamidino-2-phenylindole (DAPI) was done to count the retinal ganglion cells that survived, and eyes were enucleated and processed for morphometric analysis. Electroretinographic (ERG) assessment was also done. The density of DAPI-positive retinal ganglion cells in retinal flat-mounts was significantly higher in SIV-hPEDF-treated rats compared with control groups, in both transient ocular hypertension and NMDA-induced models. Pattern ERG examination demonstrated higher amplitude in SIV-hPEDF-treated rats, indicating the functional rescue of retinal ganglion cells. These findings show that neuroprotective gene therapy using hPEDF can protect against retinal ganglion cell death, and support the potential feasibility of neuroprotective therapy for intractable glaucoma.     

Prognostic value of epidermal growth factor receptor mutations and histologic subtypes with lung adenocarcinoma

The epidermal growth factor receptor (EGFR) mutation status has become one of the most important factors in the treatment of non-small cell lung cancer. However, the relationship between EGFR mutation and the histologic subtype of lung adenocarcinoma remains to be fully elucidated. We examined the relationship between the predominant subtype of adenocarcinoma and the prognosis and investigated the correlation between a new subtype of adenocarcinoma and EGFR mutations. This study included 182 patients with adenocarcinoma who underwent complete resection. The rate of EGFR mutation-positive patients was significantly higher among female patients, never smokers, patients with small tumors (< 3 cm in size), patients with well-differentiated tumors, and patients with a pStage I classification. The rates of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic-predominant subtype were high in male EGFR mutation-positive patients. The prevalence of the acinar and papillary-predominant subtypes was high among EGFR mutation-positive female patients, as was AIS, MIA, and the lepidic-predominant subtype. The progression-free survival (PFS) of the EGFR mutation-positive patients was significantly better than that of the EGFR mutation-negative patients (75.8 vs 67.1%, p = 0.03). However, the multivariate analysis of clinicopathologic and histologic factors did not reveal the prognostic impact of the EGFR mutation status on PFS. The overall survival (OS) of the EGFR mutation-positive patients was significantly better than that of the EGFR mutation-negative patients (93.7 vs 63.4%, p < 0.01). However, in the multivariate analysis the EGFR mutation status was not significantly associated with OS.     

Ca2+ mobilization in the aortic endothelium in streptozotocin-induced diabetic and cholesterol-fed mice

1. Experiments were performed to compare Ca²⁺ mobilization in the aortic endothelium in streptozotocin (STZ)-induced diabetic and cholesterol-fed mice with that in age-matched controls.
2. The intracellular free Ca²⁺ ([Ca²⁺]_i) in the fura PE-3 loaded endothelium of aortic rings was dose-dependently increased by cumulative administration of acetylcholine (ACh). ACh caused a transient rise in [Ca²⁺]_i in Ca²⁺-free medium. The ACh-induced increase in [Ca²⁺]_i in normal or Ca²⁺-free medium was significantly weaker in both STZ-induced diabetic and cholesterol-fed mice.
3. The weaker [Ca²⁺]_i response in Ca²⁺-containing medium in STZ-induced diabetic and cholesterol-fed mice was normalized by chronic administration of cholestyramine.
4. The increased low density lipoprotein (LDL) levels seen in both STZ-induced diabetic and cholesterol-fed mice were normalized by the same chronic administration of cholestyramine (300 mg kg⁻¹, p.o. daily for 10 weeks). Chronic administration of cholestyramine had no effect on the plasma glucose level.
5. Lysophosphatidylcholine (LPC) decreased the [Ca²⁺]_i responses to ACh in the aortic endothelium from normal mice.
6. These results suggest that ACh increases both Ca²⁺ influx and Ca²⁺ release from storage in the aortic endothelium. The weaker [Ca²⁺]_i influx seen in the endothelium of aortae from both STZ-induced diabetic and cholesterol-fed mice was improved by the chronic administration of cholestyramine, and we suggest that this improvement is due, at least in part, to a lowering of the plasma LDL level. It is further suggested that LPC may have an important influence over Ca²⁺ mobilization in the endothelium.

     

Inhibitor of plasminogen activator in human arterial wall: II. Biochemical Characterization

Fibrionlytic inhibitor was prepared from human aortas and some of its biochemical properties were investigated. The fibrinolytic inhibitor suppressed urokinase activity, but did not inhibit plasmin activity when assayed by fibrin plate method and synthetic fluorogenic substrate method. The urokinase inhibitor was a glycoprotein and migrated similar to α-globulin upon fibrin-agar electrophoresis. The molecular weight determined by gel filtration was approximately 98,000. The urokinase inhibitor was immunologically different from other known plasma protease inhibitors, such as α₂-plasmin inhibitor, α₂-macroglobulin, and α₂-antitrypsin. The interaction of urokinase with the inhibitor was dose-dependent. Progressive inactivation of urokinase occurred by increasing time of incubation with the inhibitor at 37°C, and over 90% inhibition of urokinase required 30 min of incubation. The inhibitor of plasminogen activator in human aorta may be noteworthy in relation to thrombogenesis and atherogenesis. Acta pathol. jpn. 34: 749～757, 1984.