Possible role of placental leucine aminopeptidase in the antiproliferative effect of oxytocin in human endometrial adenocarcinoma.

PURPOSE: Oxytocin (OT) was reported to inhibit the proliferation of various neoplastic tissues and cells, however, the regulation system remains unclear. This study examined the role of OT and its regulatory ability in endometrial adenocarcinoma. EXPERIMENTAL DESIGN: To investigate the possible function of placental leucine aminopeptidase (P-LAP) in endometrial adenocarcinoma, we transfected P-LAP cDNA into A-MEC cells, showing the lowest enzyme activity of P-LAP. Also we examined P-LAP protein expression in human endometrial adenocarcinoma. RESULTS: We demonstrated the presence of P-LAP, which is identical to cystine aminopeptidase as oxytocinase, in human endometrial adenocarcinoma tissues and found that the expression of P-LAP increase with advances in the grade. Exposure of endometrial adenocarcinoma cell lines to OT caused dose- and time-dependent inhibition of growth. Treatment with 10(-7) M OT for 72 h reduced cell growth by 62, 25, and 30% in A-MEC, HEC1A, and Ishikawa cells, respectively. P-LAP-transfectant cells not only partially recovered from OT-induced growth inhibition but also showed a higher growth rate than parental cells under condition without OT. An OT receptor antagonist and a protein kinase A inhibitor blocked OT-induced growth inhibition in A-MEC and A-MEC-pc cells but not in A-MEC-LAP cells. CONCLUSIONS: These findings suggested that P-LAP might be functionally positive on carcinoma cell growth by degrading suppressive peptides such as OT.     

Expression of adipocyte-derived leucine aminopeptidase in endometrial cancer. Association with tumor grade and CA-125.

Adipocyte-derived leucine aminopeptidase (A-LAP) is a novel zinc-metallopeptidase involved in angiotensin II (AngII) metabolism, cell migration and antigen presentation. These functions are implicated in the progression of cancer, whereas A-LAP expression and involvement have not been studied in any type of cancer. We investigated the expression of A-LAP in endometrial cancer as well as its association with angiogenesis and clinicopathological features. Immunohistochemical staining of 58 endometrial endometrioid adenocarcinoma specimens revealed that 37 were A-LAP immunoreactive. We also found that A-LAP staining correlated with histological tumor grade in a significant and reverse manner. In addition, serum CA-125 levels in patients with A-LAP positive cancers were significantly higher. However, contrary to our hypothesis that A-LAP suppresses angiogenic activity via AngII metabolism, A-LAP expression was not associated with the microvessel count determined by CD34 immunostaining. Our results suggest that A-LAP is involved in endometrial cancer cell growth and differentiation. However, further studies, especially of the biological roles of A-LAP, are required to confirm this notion.     

Effects of A-site composition of perovskite (Sr1−xBaxZrO3) oxides on H atom adsorption,migration, and reaction

Hydrogen (H) atomic migration over a metal oxide is an important surface process in various catalytic reactions. Control of the interaction between H atoms and the oxide surfaces is therefore important for better catalytic performance. For this investigation, we evaluated the adsorption energies of the H atoms over perovskite-type oxides (Sr_1−xBa_xZrO₃; 0.00 ≤ x ≤ 0.50) using DFT (Density Functional Theory) calculations, then clarified the effects of cation-substitution in the A-site of perovskite oxides on H atom adsorption, migration, and reaction. Results indicated local distortion at the oxide surface as a key factor governing H atom adsorption. Subtle Ba²⁺ substitution for Sr²⁺ sites provoked local distortion at the Sr_1−xBa_xZrO₃ oxide surface, which led to a decrement in the H atom adsorption energy. Furthermore, the effect of Sr²⁺/Ba²⁺ ratio on the H atoms'' reactivities was examined experimentally using a catalytic reaction, which was promoted by activated surface H atoms. Results show that the surface H atoms activated by the substitution of Sr²⁺ sites with a small amount of Ba²⁺ (x = 0.125) contributed to enhancement of ammonia synthesis rate in an electric field, which showed good agreement with predictions made using DFT calculations.

H atom adsorption over perovskite (Sr_1−xBa_xZrO₃) was governed by local lattice distortion, which can be tuned by the A-site cation-doping ratio.     

No association of the 5' promoter region polymorphism of CYP17 with breast cancer risk in Japan.

To examine the association between breast cancer risk and a T-to-C substitution polymorphism at the 5' promoter region of CYP17, a case-control study was conducted at Aichi Cancer Center Hospital in Japan. Subjects were 144 histologically confirmed breast cancer patients diagnosed in the past 4 years and 166 hospital controls without cancer. Allele frequency among controls was 44.9% (95% confidence interval; 39.5 - 50.2) for C allele. Odds ratio (OR) of the polymorphism relative to TT-genotype was 0.97 (0.58 - 1.64) for TC-genotype and 0.81 (0.39 - 1.68) for CC-genotype. Subgroup analyses revealed that the OR was not statistically significant for the subgroups stratified by interval after diagnosis, age at menarche, age at first birth, menopausal status, body mass index, and mother / sisters' history of breast cancer. Consistent with previous studies conducted in other countries, the 5' promoter region polymorphism of CYP17 affected breast cancer risk of Japanese women to a limited extent. Although this is not a large-scale case-control study with population controls, these findings provide enough information to discourage further studies on the association between this polymorphism and breast cancer risk in Japan at large, and suggest that this polymorphism is useless for breast cancer risk estimation.     

Outbreak of multidrug-resistant Mycobacterium tuberculosis infection in the middle and advanced age]

We experienced a small outbreak of multidrug-resistant Mycobacterium tuberculosis infection (MDR-TB) among persons of in the middle and advanced age. The index case was 48-year-old man, and had complained productive cough since January 1996. He visited a doctor due to his symptom, and chest X-ray revealed cavitary lesion and sputum smear was positive for tubercle bacilli. He could not continue his admission because of his absence without leave and drinking, he was discharged on Day 54. The drug resistance was observed for INH (0.1 microgram/ml), RFP, and SM. Later, case 2, 52-year-old male, and case 3, 43-year-old-male, who were companions in mah-jongg with the index case, were diagnosed as pulmonary tuberculosis. The analysis of restriction fragment length polymorphism (RFLP) was done on 3 strains, and all showed the same pattern. Among other companions in mah-jongg with the index case, case 4, 28-year-old male, was treated as MDR-TB, and the drug resistance pattern was the same to that of the index case, but the details were unknown. Case 5, 65-year-old male, was diagnosed as drug sensitive pulmonary tuberculosis, thus he might incidentally suffer from pulmonary tuberculosis at the same time. Case 6, 46-year-old male, who had been treated for alcoholic liver cirrhosis, was introduced to our hospital as his sputum smear was positive, and the drug resistance pattern was observed similar to that of the index case. All the companions in mah-jongg suffered from MDR-TB except case 5. The RFLP analysis showed that the index case, case 2, and case 3 were caused by the same strain of M. tuberculosis. The drug resistance pattern of, case 4 and case 6 was the same to that of the index case. Based on these findings, it is highly suspected that this small outbreak was originated from the index case.     

Two cases of Kimura's disease associated with bronchial asthma]

We encountered two rare cases of Kimura's disease associated with bronchial asthma presenting eosinophilia and hyperimmunoglobulinemia E. Patient 1 was a 26-year-old man who had been admitted to our hospital with recurrent increase in left parotid mass in May 1997. He had previously undergone surgery for local excision at another hospital in September 1987; the excised specimens were re-evaluated and the diagnosis of Kimura's disease was confirmed. Because the patient was suffering from an acute asthma attack on admission, prednisolone (PSL) 30 mg/day was administered orally. PSL reduced the parotid mass and improved control of the asthma. Patient 2 was an 18 year-old man who had been given a diagnosis of Kimura's disease on the basis of histologic findings from a biopsy specimen of a subcutaneous tumor in the left cheek in 1988. Following the diagnosis, the patient was treated with methotrexate for the first several months, and then with loxioprofen for 9 years, but the size of the mass remained unchanged. Bronchial asthma developed in this patient in 1995 and had been treated with theophylline. However, because this therapy caused a deterioration of asthma control, the patient was admitted to our hospital in October 1997 for the treatment of bronchial asthma. Inhaled corticosteroids (beclometasone 0.8 mg/day) in addition to theophylline alleviated the patient's asthma symptoms and yielded improved lung function. Because few cases of Kimura's disease associated with bronchial asthma have been reported, patients with eosinophilia and hyperimmunoglobulinemia E were not necessarily considered at high risk for the onset of bronchial asthma.     

CNS-specific prostacyclin ligands as neuronal survival-promoting factors in the brain

Prostacyclin (PGI2) is a critical regulator of the cardiovascular system, via dilatation of vascular smooth muscle and inhibition of platelet aggregation (Moncada, S. 1982, Br. J. Pharmacol., 76, 3). Our previous studies demonstrated that a novel subtype of PGI2 receptor, which is clearly distinct from a peripheral subtype in terms of ligand specificity, is expressed in the rostral region of the brain, e.g. cerebral cortex, hippocampus, thalamus and striatum, and that (15R)-16-m-17,18,19,20-tetranorisocarbacyclin (15R-TIC) and 15-deoxy-16-m-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC) specifically bind to the central nervous system (CNS)-specific PGI2 receptor. Here, we report that these CNS-specific PGI2 receptor ligands, including PGI2 itself, prevented the neuronal death. They prevented apoptotic cell death of hippocampal neurons induced by high (50%) oxygen atmosphere, xanthine + xanthine oxidase, and serum deprivation. IC50s for neuronal death were approximately 30 and 300 nM for 15-deoxy-TIC and 15R-TIC, respectively, which well correlated with the binding potency for the CNS-specific PGI2 receptor. 6-Keto-PGF1alpha (a stable metabolite of PGI2), peripheral nervous system-specific PGI2 ligands and other prostaglandins (PGs) than PGI2 did not show such neuroprotective effects. In vivo, 15R-TIC protected CA1 pyramidal neurons against ischaemic damage in gerbils. These results indicate that CNS-specific PGI2 ligands have neuronal survival-promoting activity both in vitro and in vivo, and may represent a new type of therapeutic drug for neurodegeneration.     

Intracranial cavity volume can be accurately estimated from the weights of intracranial contents: confirmation by the dental plaster casting method.

Intracranial cavity volume is used to evaluate brain size relative to the intracranial space. This volume can theoretically be obtained from the weights and densities of the brain and surrounding cerebrospinal fluid (weight method). However, the accuracy of this method has not been examined. In this study, we examined the reliability of the weight method, by comparing the intracranial cavity volumes of 41 post-mortem cases obtained by the weight method (ICVw) with those obtained by a dental plaster casting method (ICVcast) which was shown to be unbiased. The ICVw was not significantly different from the ICV cast (P=0.49, paired t-test), and the standard error of difference was 18 ml (1.3% of ICVcast). These results show that the weight method is reliable, and applicable to routine autopsies.     

Effect of anticancer agents on Fas-mediated cytotoxicity against bladder cancer cells

Fas and Fas ligand play an important role in cytotoxic T lymphocyte-mediated cytotoxicity. Like Fas ligand, anti-Fas monoclonal antibody (mAb) induces apoptosis of cells expressing Fas and mimics tumor necrosis factor-α (TNF-α) in its cytotoxic activity, but not in regard to other TNF-α-mediated activities. Since combination treatment with TNF-α and some anticancer chemotherapeutic agents results in synergistic cytotoxicity against various cancer cells, anti-Fas mAb may also synergize with anticancer agents in exerting cytotoxicity. The present study examined this hypothesis using bladder cancer cells. Cytotoxicity was examined by a 1-day microculture tetrazolium dye assay. Treatment of T24 cells with anti-Fas mAb in combination with mitomycin C, methotrexate, or 5-fluorouracil did not overcome their resistance to these agents. However, combination treatment with anti-Fas mAb and adriamycin (ADR) resulted in a synergistic cytotoxic effect on T24 cells, three other bladder cancer lines, and fresh bladder cancer cells derived from four patients. Treatment with ADR enhanced the expression of Fas on T24 cells. The expression of P-glycoprotein was not affected by the antibody-mediated sensitization. This study showed that combination treatment of bladder cancer cells with anti-Fas mAb and ADR can overcome their resistance and that the upregulation of Fas expression by ADR may play a role in the enhanced cytotoxicity. Received: November 4, 1998 / Accepted: April 12, 1999