Beta-catenin expression in hepatocellular carcinoma: a possible participation of beta-catenin in the dedifferentiation process

BACKGROUND: beta-Catenin is known as a multifunctional protein acting as a regulator of the cadherin-mediated cell-cell adhesion system and in the Wingless/Wnt signal transduction pathway. Recent studies reported mutation of the beta-catenin gene in some tissues of hepatocellular carcinoma (HCC). METHODS: 'Nodule-in-nodule' appearance is a feature of well-differentiated HCC containing a distinct nodule of less-differentiated cancer tissue inside, and it is presumed to be a morphological expression of the dedifferentiation process. The present study immunohistochemically investigated the beta-catenin expression according to the dedifferentiation process of HCC, that is, in small well-differentiated HCC with indistinct margins, HCC with a 'nodule-in-nodule' appearance, moderately differentiated HCC, which does not have a 'nodule-in-nodule' appearance, and sarcomatous HCC. RESULTS: The expression of beta-catenin was observed in approximately 70% of small well-differentiated HCC with indistinct margins. In HCC with a 'nodule-in-nodule' appearance, membranous expression of beta-catenin was higher in the well-differentiated cancer tissues than in the less-differentiated cancer tissues (P < 0.01), cytoplasmic expression was higher in the less-differentiated cancer tissues (P < 0.01), and nuclear expression was higher in the less-differentiated cancer tissues (P < 0.001). In moderately differentiated HCC, tumors with membranous expression of beta-catenin had more frequent intrahepatic metastasis than those without having the expression (P < 0.001). CONCLUSIONS: Accumulation of beta-catenin was already present in the early stage of HCC, and in less-differentiated cancer tissue the membranous expression of beta-catenin could be related to intrahepatic metastasis.     

Effect of cigarette smoking on the gastric mucosal blood volume index and hemoglobin oxygenation in man

The acute effect of cigarette smoking on the gastric mucosal blood volume index and the oxygen saturation of hemoglobin (SO₂) in the gastric mucosa was investigated in 12 young male volunteers using reflectance spectrophotometry during endoscopy. Six of these volunteers were habitual smokers who had smoked more than 20 cigarettes a day for more than five years. The others were non-habitual smokers who smoked less than 20 cigarettes a year. The indices of mucosal blood volume and the mucosal blood SO₂ level were calculated from the spectra obtained at the lesser curvature of the lower corpus of the stomach before and after cigarette smoking. The indices of mucosal blood volume and mucosal blood SO₂ decreased significantly after one to three puffs of cigarette smoking in all subjects as compared to the value before smoking, and the degree of decrease in these parameters was significantly greater in the non-habitual smokers than in the habitual smokers. These results suggest that only one to three puffs of cigarette smoking causes a decrease in the mucosal blood volume and the mucosal blood SO₂ which might be related to weakening of mucosal defensive factors. This work was supported by a grant from the Japan Tobacco Corporation.     

Trends in clinical characteristics, treatment and prognosis of hepatocellular carcinoma

BACKGROUND/AIMS: This study was undertaken to evaluate the serial changes of various factors in patients with hepatocellular carcinoma, including hepatitis viruses, age distribution, female-to-male ratio, size and the number of hepatocellular carcinoma tumors at initial detection, the types of treatment and survival during a 12-year period. METHODOLOGY: Seven hundred and four consecutive patients with hepatocellular carcinoma lesions observed from Jan 1989 to Dec 2000 (12 years) at the Internal Medicine Department, Saga Prefectural Hospital Koseikan were retrospectively enrolled in the study. The follow-up period was divided into four terms as follows: 1989-91, 1992-94, 1995-97 and 1998-2000. The serial changes of causal hepatitis viruses, age distribution, gender ratio, tumor size, the number of hepatocellular carcinoma tumors at initial detection, the types of treatment and survival were analyzed and compared among the four different terms. RESULTS: Regarding viral markers, the association of an HCV infection has become more predominant in hepatocellular carcinoma cases, while the ratio of hepatocellular carcinoma patients infected with HBV has decreased during this 12-year period. In addition, the rate of hepatocellular carcinoma measuring 3 cm or less in diameter or solitary hepatocellular carcinoma at initial detection has increased during the 12-year period. The female-to-male ratio has increased from 33.6% in 1989-1991, 34.8% in 1992-1994, 48.7% in 1995-1997 to 60.6% in 1998-2000, respectively. Due to increased early detection, the types of treatment for hepatocellular carcinoma have shifted from arterial interventional therapy to local ablation therapy combined with or without interventional therapy. Therefore, although the age distribution of all 704 hepatocellular carcinoma patients has shifted to slightly older ages as shown by the ages of 64.1 years old, 63.4 years old, 66.6 years old and 67.3 years old in the four terms, respectively, the survival of the patients with hepatocellular carcinoma proved to had become significantly longer than before during the 12-year period. CONCLUSIONS: Hepatocellular carcinoma patients tended to show an increased prevalence of HCV, a higher age distribution, an increasing female prevalence, an earlier detection, advanced multidisciplinary therapies and prolonged survival in the last 12 years.     

Developmental exposure to pentachlorophenol affects the expression of thyroid hormone receptor β1 and synapsin I in brain, resulting in thyroid function vulnerability in rats

Pentachlorophenol (PCP), a component of biocides and a contaminant in diverse tissue samples from humans from various geographic areas, disrupts regulatory effects of thyroid hormones. Here we examined the effects of developmental exposure of rats to PCP on various aspects of brain development, male reproductive function, and adrenal function, all of which are under thyroid hormones regulation. PCP was administered to dams and their offspring via drinking water (6.6 mg l⁻¹) during gestation and lactation. Tissue samples were obtained from dams, 3-week-old weanling pups, and 12-week-old pups. Gene expressions of thyroid hormone receptor β1 and synapsin I, factors that promote brain growth, was increased in the cerebral cortex of PCP-treated weanling females, whereas plasma concentrations of total thyroxine were decreased in dams and weanling pups, and plasma thyroid-stimulating hormone concentrations were higher in PCP-treated weanling males. PCP caused a decrease in plasma corticosterone concentrations in 12-week-old female rats, but not in male rats or weanling females. PCP-treated male pups had significantly increased testis weight at 12 week of age. No overt signs of toxicity were noted throughout this study. Our results show that PCP exposure during development causes thyroid function vulnerability, testicular hypertrophy in adults, and aberrations of brain gene expression.     

Targeting human mast cells expressing g-protein-coupled receptors in allergic diseases

The G-protein-coupled receptors (GPCRs) are the largest known group of integral membrane receptor proteins and are the most common targets of pharmacotherapy. Mast cells (MCs) have been reported to play an important role in allergic diseases, such as urticaria and bronchial asthma. There is an increasing body of clinical evidence that MCs are recruited into allergic reactions by non-IgE-dependent mechanisms. Human MCs are activated and secrete histamine in response to neuropeptides, such as substance P and somatostatin, mediated by a GPCR, MRGX2. The microenvironment surrounding MCs in their resident tissues is likely to contain multiple factors that modify antigen-dependent MC activation. MCs express various GPCRs, and since the function of human MCs is modulated by various GPCR ligands, such as adenosine and sphingosine-1-phosphate, which are present in high levels in the bronchial alveolar lavage fluid of asthmatic patients, the GPCRs expressed on MCs may play an important role in human allergic diseases. The GPCRs expressed on MCs may serve as drug targets for the treatment of allergic diseases.     

Uterine prolapse during late pregnancy in a nulliparous woman

A pregnancy that is complicated by a uterine prolapse is rare and primarily occurs in multiparous women during their first or second trimester. In the present report, we describe a case of a 31-year-old nulliparous woman who experienced sudden uterine prolapse at 38 weeks’ gestation without labor pains. The cervix was congested, the cervical mucosa was partially lacerated, and bleeding was noted; the protruding cervix could not be repositioned into her vagina. Although the cervical congestion worsened over time, she still did not experience any labor pains. She was delivered by emergency cesarean section. Following delivery, the prolapse promptly improved and did not recur before her 1-month postpartum examination. To our knowledge, this is the first case where uterine prolapse occurred in a nulliparous woman during late gestation.     

Carbon monoxide-bound hemoglobin-vesicles for the treatment of bleomycin-induced pulmonary fibrosis

Carbon monoxide (CO) has potent anti-inflammatory and anti-oxidant effects. We report herein on the preparation of a nanotechnology-based CO donor, CO-bound hemoglobin-vesicles (CO-HbV). We hypothesized that CO-HbV could have a therapeutic effect on idiopathic pulmonary fibrosis (IPF), an incurable lung fibrosis, that is thought to involve inflammation and the production of reactive oxygen species (ROS). Pulmonary fibril formation and respiratory function were quantitatively evaluated by measuring hydroxyproline levels and forced vital capacity, respectively, using a bleomycin-induced pulmonary fibrosis mice model. CO-HbV suppressed the progression of pulmonary fibril formation and improved respiratory function compared to saline and HbV. The suppressive effect of CO-HbV on pulmonary fibrosis can be attributed to a decrease in ROS generation by inflammatory cells, NADPH oxidase 4 and the production of inflammatory cells, cytokines and transforming growth factor-β in the lung. This is the first demonstration of the inhibitory effect of CO-HbV on the progression of pulmonary fibrosis via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced pulmonary fibrosis mice model. CO-HbV has the potential for use in the treatment of, not only IPF, but also a variety of other ROS and inflammation-related disorders.     

Effects of Head Motion on the Evaluation of Age-related Brain Network Changes Using Resting State Functional MRI

Purpose:The estimation of functional connectivity (FC) measures using resting state functional MRI (fMRI) is often affected by head motion during functional imaging scans. Head motion is more common in the elderly than in young participants and could therefore affect the evaluation of age-related changes in brain networks. Thus, this study aimed to investigate the influence of head motion in FC estimation when evaluating age-related changes in brain networks.Methods:This study involved 132 healthy volunteers divided into 3 groups: elderly participants with high motion (OldHM, mean age (±SD) = 69.6 (±5.31), N = 44), elderly participants with low motion (OldLM, mean age (±SD) = 68.7 (±4.59), N = 43), and young adult participants with low motion (YugLM, mean age (±SD) = 27.6 (±5.26), N = 45). Head motion was quantified using the mean of the framewise displacement of resting state fMRI data. After preprocessing all resting state fMRI datasets, several resting state networks (RSNs) were extracted using independent component analysis (ICA). In addition, several network metrics were also calculated using network analysis. These FC measures were then compared among the 3 groups.Results:In ICA, the number of voxels with significant differences in RSNs was higher in YugLM vs. OldLM comparison than in YugLM vs. OldHM. In network analysis, all network metrics showed significant (P < 0.05) differences in comparisons involving low vs. high motion groups (OldHM vs. OldLM and OldHM vs. YugLM). However, there was no significant (P > 0.05) difference in the comparison involving the low motion groups (OldLM vs. YugLM).Conclusion:Our findings showed that head motion during functional imaging could significantly affect the evaluation of age-related brain network changes using resting state fMRI data.