Relationship of the aberrant DNA hypermethylation of cancer-related genes with carcinogenesis of endometrial cancer

Epigenetic abnormalities including the aberrant DNA hypermethylation of the promoter CpG islands play a key role in the mechanism of gene inactivation in cell carcinogenesis. To identify the genes associated with aberrant DNA hypermethylation in endometrial carcinogenesis, we studied the hypermethylation of the promoter regions of five genes: hMLH1, APC, E-cadherin, RAR-beta and p16. The frequencies of aberrant hypermethylation were 40.4% (21/52) in hMLH1, 22% (11/50) in APC, 14% (7/50) in E-cadherin, and 2.3% (1/44) in RAR-beta in endometrial cancer specimens. No aberrant DNA methylation was found in p16. In atypical endometrial hyperplasia, the frequencies of aberrant methylation were 14.3% (2/14) in hMLH1 and 7.3% (1/14) in APC, whereas normal endometrial cells showed no aberrant hypermethylation of any of the five genes. The high frequencies of the aberrant DNA hypermethylation of hMLH1, APC and E-cadherin suggest that the methylation of the DNA mismatch repair and Wnt signal-related genes may be associated with endometrial carcinogenesis.     

High prevalence of HER-2/neu and p53 overexpression in inflammatory breast cancer

BACKGROUND: Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Although the survival of patients with IBC has been greatly improved by the use of combined treatment modalities, women with IBC still have lower survival rates. We have summarized a single-center experience involving IBC patients. Our objectives are to clarify molecular alterations of HER-2/neu and p53 in IBC and to investigate the prognostic factors. METHODS: Between January 1990 and December 2000, 57 patients with IBC were referred to the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The incidence of IBC among primary breast cancers was 1.0% (57/5,757) in our hospital. Forty-six patients meeting Haagensen's criteria for inflammatory breast carcinoma were evaluated. All patients had biopsy-proven carcinomas but no distant metastases at referral. The median age at diagnosis for IBC was 51.8 (range, 28 to 70). All patients underwent a mastectomy. Chemotherapy was performed pre- or post-operatively. Three-year and 5-year survival rates were 56.5%, and 40.7%, respectively. Expressions of HER-2/neu and the p53 protein were determined retrospectively by immunohistochemical (IHC) staining of thin paraffin-embedded sections of primary tumors. RESULTS: Of 46 patients, 23 (50.0%) with tumors testing positive for HER-2/neu fared somewhat worse than those with negative tumors, but the differences were not significant for either overall survival (OS) or disease-free survival (DFS). Of 46 patients, 19 (41.3%) whose tumors were positive for p53 fared somewhat better than patients with negative tumors, with no significant differences in either OS or DFS. Patients presenting with less than ten pathologically involved axillary lymph nodes showed significantly better OS and DFS. CONCLUSIONS: Overexpression of HER-2/neu and the p53 protein were not significant prognostic factors in inflammatory breast cancer. However, the increased incidence of HER-2/neu and the poor outcome of IBC may be of clinical interest, suggesting the need for clinical trials of antibody therapy targeted to HER-2/neu. Moreover, a high prevalence of p53 may be useful in determining the specific use of chemotherapy.     

Capsaicin inhibits catecholamine secretion and synthesis by blocking Na+ and Ca2+ influx through a vanilloid receptor-independent pathway in bovine adrenal medullary cells

We report here the effects of capsaicin, a flavoring ingredient in the hot pepper Capsicum family, on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. Capsaicin inhibited catecholamine secretion (IC₅₀=9.5, 11.8, and 62 μM) stimulated by carbachol, an agonist of the nicotinic acetylcholine receptor, by veratridine, an activator of voltage-dependent Na⁺ channels, and by high K⁺, an activator of voltage-dependent Ca²⁺ channels, respectively. Capsaicin also suppressed carbachol-induced ²²Na⁺ influx (IC₅₀=5.0 μM) and ⁴⁵Ca²⁺ influx (IC₅₀=24.4 μM), veratridine-induced ²²Na⁺ influx (IC₅₀=2.4 μM) and ⁴⁵Ca²⁺ influx (IC₅₀=1.1 μM), and high K⁺-induced ⁴⁵Ca²⁺ influx (IC₅₀=5.8 μM). The reduction in catecholamine secretion caused by capsaicin was not overcome by increasing the concentration of carbachol. Furthermore, capsazepine (10 μM), a competitive antagonist for the transient receptor potential vanilloid 1, and ruthenium red (30 μM), a nonselective cation channel antagonist, did not block the inhibition by capsaicin of catecholamine secretion. Capsaicin also suppressed both basal and carbachol-stimulated ¹⁴C-catecholamine synthesis (IC₅₀=10.6 and 26.4 μM, respectively) from [¹⁴C] tyrosine but not from l-3, 4-dihydroxyphenyl [3-¹⁴C] alanine ([¹⁴C] DOPA) as well as tyrosine hydroxylase activity (IC₅₀=8.4 and 39.0 μM, respectively). The present findings suggest that capsaicin inhibits catecholamine secretion and synthesis via suppression of Na⁺ and Ca²⁺ influx through a vanilloid receptor-independent pathway.     

Effects of physical exercise on depression, neuroendocrine stress hormones and physiological fitness in adolescent females with depressive symptoms

BACKGROUND: Regular physical exercise may improve a variety of physiological and psychological factors in depressive persons. However, there is little experimental evidence to support this assumption for adolescent populations. We conducted a randomized controlled trial to investigate the effect of physical exercise on depressive state, the excretions of stress hormones and physiological fitness variables in adolescent females with depressive symptoms. METHODS: Forty-nine female volunteers (aged 18-20 years; mean 18.8 +/- 0.7 years) with mild-to-moderate depressive symptoms, as measured by the Centre for Epidemiologic Studies Depression (CES-D) scale, were randomly assigned to either an exercise regimen or usual daily activities for 8 weeks. The subjects were then crossed over to the alternate regimen for an additional 8-week period. The exercise program consisted of five 50-min sessions per week of a group jogging training at a mild intensity. The variables measured were CES-D rating scale, urinary cortisol and epinephrine levels, and cardiorespiratory factors at rest and during exercise endurance test. RESULTS: After the sessions of exercise the CES-D total depressive score showed a significant decrease, whereas no effect was observed after the period of usual daily activities (ANOVA). Twenty-four hour excretions of cortisol and epinephrine in urine were reduced due to the exercise regimen. The training group had a significantly reduced resting heart rate and increased peak oxygen uptake and lung capacity. CONCLUSIONS: The findings of this study suggest that a group jogging exercise may be effective in improving depressive state, hormonal response to stress and physiological fitness of adolescent females with depressive symptoms.     

Genotype announcement to Japanese smokers who attended a health checkup examination

BACKGROUND: Genotype announcement may be one of the effective methods to induce smoking cessation, but the studies are limited throughout the world. METHODS: Subjects were smokers who attended a health checkup examination provided by a local government in Hokkaido, Japan, 2003. Those who agreed to know their genotypes were informed of the genotypes of glutathione S-transferease (GST) M1 present/null, GSTT1 present/null, and NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T (Pro187Ser). RESULTS: Out of 143 smokers (92 males and 51 females), 101 individuals participated in the present study. A postal questionnaire one year after the genotype announcement found that 8 persons (6 males and 2 females) of 41 respondents had quitted smoking. Two of 8 quitters stated that they had quitted smoking due to the announcement. There were none who regretted the genotype tests. CONCLUSION: Although the cessation rate, 7.9% (8/101) at least, was not marked, no harmful effects were observed among the respondents.     

Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury

Recanalization and neuroprotection have been mainly targeted for the specific treatment of acute ischemic stroke. Free radicals play a crucial role in brain ischemic injury by exacerbating membrane damage through peroxidation of unsaturated fatty acids of cell membrane, leading to neuronal death and brain edema. Free radicals have been implicated in stroke pathophysiology as pivotal contributors to cell injury. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a novel potent free radical scavenger that has been clinically used to reduce the neuronal damage following ischemic stroke. Edaravone exerts neuroprotective effects by inhibiting endothelial injury and by ameliorating neuronal damage in brain ischemia. Edaravone provides the desirable features of NOS: it increases eNOS (beneficial NOS for rescuing ischemic stroke) and decreases nNOS and iNOS (detrimental NOS). Post- reperfusion brain edema and hemorrhagic events induced by thrombolytic therapy may be reduced by edaravone pretreatment. Increased productions of superoxide and NO in the brain after reperfusion and a concomitant surge in oxygen free radicals with increased NO during recirculation lead to formation of peroxynitrite, a superpotent radical. Edaravone, which inhibits oxidation and enhances NO production derived from increased eNOS expression, may improve and conserve cerebral blood flow without peroxynitrite generation during reperfusion. Clinical experience with edaravone suggests that this drug has a wide therapeutic time window. The combination therapy (a thrombolytic plus edaravone) is likely to target brain edema, reduce stroke death and improve the recovery from neurological deficits in stoke patients.     

Molecular mechanisms and therapeutic strategies of chronic renal injury: the role of nuclear factor kappaB activation in the development of renal fibrosis

Tubulointerstitial fibrosis is a common feature of many progressive renal diseases and is a main determinant that leads to an irreversible loss of renal function. In chronic cyclosporin A nephrotoxicity, we previously reported that inflammatory responses such as macrophage infiltration preceded interstitial fibrosis. This inflammation was accompanied by an elevation in renal nuclear factor kappaB (NF-kappaB) activity. Similar findings were obtained in chronic tacrolimus nephrotoxicity and obstructive nephropathy. Inhibition of NF-kappaB markedly attenuated renal inflammation and interstitial fibrosis in these models. Furthermore, administration of oral adsorbent (Kremezin) significantly attenuated the increase in renal NF-kappaB activity and concomitantly reduced interstitial inflammation and renal fibrosis in chronic renal failure rats. Elimination of indoxyl sulfate by this adsorbent is likely involved in this mechanism since it is known that indoxyl sulfate activates NF-kappaB in renal tubular cells. It is suggested that strategy aiming at NF-kappaB inhibition is important to prevent the progression of renal fibrosis.     

TYROSINEMIA

A case of tyrosinemia in a three-month-old boy is presented. The patient appeared jaundiced initially with markedly elevated levels of serum tyrosine and a positive Millon-reacting urine. Jaundice persisted and hepatospleno-megaly gradually increased. He died due to liver failure on the 51st day after admission. At autopsy, the liver showed the features of severe giant cell hepatitis including giant cell formation, fibrosis and bile retention. The pancreas and the brain showed characteristic postmortem Andings as previously reported in patients with tyrosinemia. ACTA PATH. JAP. 29: 615–622, 1979.