Fas and fas ligand in human hepatocellular carcinoma.
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Apoptosis↗
Biomedical subjects
T Takehara
Publications and source records attributed to T Takehara.
Generation of hepatitis C virus-specific cytotoxic T lymphocytes from healthy individuals with peptide-pulsed dendritic cells.
BACKGROUND AND AIMS: In hepatitis C virus (HCV) infection, cytotoxic T lymphocytes (CTL) are involved in liver inflammation and contribute to the reduction of viral load. Antibodies for HCV-CTL precursor frequencies (CTLpf) are relatively low in chronic hepatitis C, and this may be related to the poor CTL response in vivo. The aim of this study was to assess the efficacy of dendritic cells (DC) as antigen-presenting cells in CTL generation from low CTLpf. METHODS: To confirm the rationale of using DC to prime naive T cells, five HCV-uninfected individuals were enrolled in the study. We obtained DC by maturation from peripheral progenitors under stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4 and IL-1alpha. Autologous T cells were cultured with DC or concanavalin-A-induced blasts loaded with four HCV-derived peptides bearing human leukocyte antigen (HLA)-A*0201 or -A24 motifs for 28 days under IL-7 and IL-2 stimulation. The lytic activity against peptide-pulsed targets was assessed by using a [51Cr]-releasing assay. RESULTS: The DC strongly expressed HLA class I, II, B7-1 and B7-2, but not phenotypic markers of T-, B-, natural killer (NK)-cells or monocytes. The CD8-positive, HLA-class I-restricted and HCV peptide-specific CTL were generated with DC from HLA-A antigen-matched subjects, whereas no CTL activity was detected with concavalin (Con-A) blasts. We were thus able to generate HCV specific CTL from naive precursors with peptide-pulsed DC. CONCLUSIONS: This DC-based system can be used to generate CTL of desired antigen specificity, even from a source with low CTLpf.
Adult↗
Expression and role of Bcl-xL in human hepatocellular carcinomas.
Transformed hepatocytes survive various apoptotic insults during their growth in vivo. However, molecular mechanisms that inhibit apoptosis and support their survival are not well understood. In this study, we investigated the expression and role of Bcl-xL, an antiapoptotic member of the Bcl-2 family, in human hepatocellular carcinoma (HCC). The Bcl-xL protein was expressed in HepG2, Hep3B, and Huh7 human hepatoma cell lines at high levels, but none of these cells expressed Bcl-2. Down-modulation of Bcl-xL by antisense oligonucleotide activated apoptosis in HepG2 cells in response to cellular stresses induced by staurosporine treatment or by serum starvation. Ectopic expression of transcriptionally active p53 alone was not sufficient for the activation of apoptosis in p53-null Hep3B cells, but apoptosis was induced when endogenous Bcl-xL was simultaneously inhibited by antisense oligonucleotide in these cells. Bcl-xL was expressed in all 20 surgically resected human HCC tissues when examined by Western blot analysis and immunohistochemistry, and levels of its expression were higher in a subset of HCC tissues than those of adjacent nontumor liver tissues or normal livers. We conclude that Bcl-xL expressed in human HCC cells inhibits apoptosis produced by various cellular stresses, such as staurosporine treatment, serum starvation, and p53 activation, and may play an important role in their survival.
Apoptosis↗
Association of body mass index with blood pressure in 80-year-old subjects.
OBJECTIVE: Little data are available on the association between obesity and high blood pressure in elderly individuals, particularly in subjects over 80 years of age. The aim of the present study was to determine the association between body mass index (BMI) and blood pressure in 80-year-old subjects. METHODS: This study was part of the 8020 Data Bank Survey, which was designed to collect the baseline data of systemic and dental health conditions in 80-year-old subjects. We studied the cross-sectional association of BMI with blood pressures in 645 Japanese (258 men and 387 women), who were 80 years old. RESULTS: Mean systolic blood pressure rose from 146.6 mmHg in the first quintile of BMI to 147.5 mmHg in the second, 150.3 mmHg in the third, 151.6 mmHg in the fourth, and 156.4 mmHg in the fifth quintiles (test for trend, P = 0.006). Mean diastolic blood pressure rose from 75.8 mmHg in the lowest quintile of BMI to 81.8 mmHg in the highest (test for trend, P = 0.002). We performed multiple regression analysis, controlling for factors known to influence blood pressure values, such as sex, alcohol intake, current smoking status and serum glucose, total cholesterol and creatinine concentrations. The association between BMI and systolic and diastolic blood pressure, respectively, was highly statistically significant in all analyses. CONCLUSION: These results show that a close relationship is present between obesity and high blood pressure, even in very old subjects.
Aged↗
Influence of dentition status on physical disability, mental impairment, and mortality in institutionalized elderly people.
The loss of teeth is known to influence the mastication of foods and nutritional status. Therefore, we hypothesize that poor dentition status can impair the systemic health of the aged. To clarify the influence of dentition status on deterioration in physical ability, mental impairment, and mortality, we conducted a six-year prospective cohort study of the institutionalized elderly living in 29 of the 30 institutions for the elderly in Kitakyushu, Japan. Bivariate analysis revealed that worse dentition status at baseline led to significantly worse physical and mental impairment, and higher mortality. In a multiple logistic regression analysis, the physical ability of edentulous subjects without dentures significantly deteriorated compared with that of dentate subjects with 20 or more teeth. The six-year mortality rate of the edentulous subjects without dentures was significantly higher than that of the subjects with 20 or more teeth. Poorer dentition status, especially edentulousness without dentures, may therefore be related to deterioration in the systemic health of the aged.
Aged↗
Relationship between tooth loss and electrocardiographic abnormalities in octogenarians.
Recent reports have suggested that periodontal disease is a risk factor for coronary heart disease (CHD). However, little is known about the relationship between periodontal disease and CHD in the very elderly. Therefore, we evaluated the association between tooth loss and abnormal ECG findings in octogenarians. Of the 1,282 octogenarians in Fukuoka Prefecture, Japan, 697 participated. Oral examinations--including a tooth count and an assessment of the Community Periodontal Index--and a 12-lead ECG were performed. Logistic regression analysis revealed that individuals with < 20 teeth had increased prevalence of ST segment depression, and T-wave abnormalities, after we adjusted for gender, smoking, serum cholesterol and glucose, blood pressure, and body mass index. Compared with individuals with > or = 20 teeth, edentulous individuals had an increased prevalence of T-wave abnormalities and arrhythmias after adjustment for coronary risk factors. We conclude that tooth loss may be an independent predictor of abnormal ECG findings in octogenarians.
Aged↗
Oral health condition and endemic goitre, in an iodine-deficient area in Bali, Indonesia.
Iodine deficiency is a major determinant of endemic goiter which affects bone growth. The purpose of this study was to clarify the relationship between iodine deficiency and oral health. A cross-sectional survey was carried out on 181 inhabitants aged 17 to 40 years in two villages in an iodine-deficient area in Bali, Indonesia. Thyroid swelling, serum level of thyroid-stimulating hormone, DMFT index, plaque index, gingival index, dietary habits and socioeconomic status were examined. Thirty two subjects (21%) had thyroid swelling considered to be endemic goiter, with the highest prevalence in females aged 21 to 30 years (40-41%). The DMFT, food habits, and socioeconomic status were different between both villages. Multiple regression analysis adjusted for age, sex, and location (village) did not detect any association between DMFT and serum thyroid-stimulating hormone level or thyroid swelling. Further studies will be required to confirm these findings.
Adolescent↗
Robustness of the two-dimensional structure of recognition of facial expression: evidence under different intensities of emotionality.
Many studies have indicated that recognition of facial expression is geometrically represented in terms of two underlying bipolar dimensions, pleasure-displeasure and the intensity of arousal. A psychological space defined by these two dimensions has been found under particular conditions using prototype faces: however, the question arises whether this two-dimensional psychological space is also an accurate representation for faces with lower emotional intensity. To test this we prepared four different conditions of emotional intensity (100%, 75%, 50%, and 25% of emotionality) for six basic facial expressions using morphing. Participants (29 for the 100%, 30 for 75%, 35 for 50%, and 34 for the 25% condition) in each condition rated the facial stimuli on a 6-point scale of "not at all" and "very much so". Multidimensional scaling for each condition clearly indicated a two-dimensional representation and multiple correlations showed significant similarity across conditions (p < .001). This shows that the two-dimensional representation of recognition of facial expression is robust.
Adult↗
[Small cell carcinoma of the prostate: a case report].
A 81-year-old man was admitted to our department with the chief complaints of pollakisuria and difficulty in voiding. He presented with increased serum PSA level (over 100 ng/ml). We performed biopsy of the prostate and found a moderately differentiated adenocarcinoma. Various urological examinations showed metastases to paraaortic lymph nodes and systemic bones. He was started-on hormonal therapy. Nine months from the start of hormonal therapy, this therapy was effective and the serum PSA level was decreased to 14 ng/ml. Thereafter, the serum PSA level and the tumor volume were increased and he died 29 months from the start of treatment. The autopsy revealed small cell carcinoma with adenocarcinoma of the prostate.
Aged↗
[Antiviral therapy for patients with chronic hepatitis C].
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Antiviral Agents↗
Silicone granuloma on the entry points of acupuncture, venepuncture and surgical needles.
We describe a case of epithelioid granuloma on the entry points of needles used for acupuncture, venepuncture and for taking skin biopsy. The acupuncture needles used at each session were silicone coated. Silicon was detected in the vacuoles of macrophages and multiple nucleated giant cells by X-ray microanalysis. To our knowledge, this is the first case of silicone granuloma arising on the entry points of acupuncture, venepuncture and surgical needles.
Acupuncture Therapy↗
Sequencing, expression and biochemical characterization of the Porphyromonas gingivalis pepO gene encoding a protein homologous to human endothelin-converting enzyme.
We have determined the nucleotide sequence of the clone pAL2 obtained from Porphyromonas gingivalis 381 in the previous study [Ansai et al. (1995) Microbiology 141, 2047-20521. The DNA sequence analysis of this fragment revealed one complete ORF and one incomplete ORF. The ORF encoded a protein (PgPepO) of 690 amino acids with a calculated molecular weight of 78796. The deduced amino acid sequence exhibited a significant homology with human endothelin-converting enzyme (ECE)-1. Recombinant PgPepO was purified to homogeneity and characterized. The purified enzyme was strongly inhibited by phosphoramidon, and converted big endothelin-1 to endothelin-1. Furthermore, the purified PgPepO strongly cross-reacted with a monoclonal antibody against rat ECE-1. These results indicate that PgPepO has striking similarity to mammalian ECE in structure and function.
Amino Acid Sequence↗
Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals.
In hepatitis C virus (HCV) infection, Th responses are implicated in the pathogenesis of liver disease. The dendritic cell (DC) is the most potent activator of CD4 T cells for supporting Th1 differentiation. To clarify the roles of DC of HCV-infected individuals in the development of CD4 T cell responses, we generated peripheral DC with GM-CSF and IL-4 from 24 chronic hepatitis C patients and 14 healthy donors. We then compared their potentials for stimulating allogeneic CD4 T cells, autologous CD4 T cells against influenza A or HCV core Ags, and cytokine production. The DC from the patients (HCV-DC) expressed lower degrees of CD86 than DC from the donors (N-DC), whereas no difference was found in the HLA molecules and other costimulators. HCV-DC stimulated allogeneic T cells less than N-DC; however, influenza A- or core-pulsed HCV-DC retained the potentials for autologous T cell proliferation. In allogeneic DC/T cell cultures, the IFN-gamma levels with HCV-DC were lower than those with N-DC, which may be related to the low expressions of IL-12 p35 and p40 transcripts in HCV-DC. The stimulation with LPS disclosed that HCV-DC is less potent in IL-12 p70 production than N-DC. In the autologous cultures, the pulsing of the Ags to HCV-DC increased the IL-12 p40 and IFN-gamma production and up-regulated the transcription of both IL-12 subunits. Exogenous IL-2 or IL-12 restored the low allogeneic T cell proliferation with HCV-DC in a dose-dependent manner. Therefore, low expression of CD86 and/or IL-12 is crucially involved in the low allostimulatory capacity of HCV-DC. Low IL-12 and low IFN-gamma milieu with HCV-DC on encounters with alloantigens may impede Th1 polarization.
Adult↗
Characterization of free alpha- and beta-chains of recombinant macrophage-stimulating protein.
Human serum macrophage-stimulating protein (MSP) induces motile activity of murine resident peritoneal macrophages and is a growth and motility factor for epithelial cells. It belongs to the plasminogen-related family of kringle proteins, and is secreted as a single-chain, 78-kDa, biologically inactive pro-MSP. Proteolytic cleavage of pro-MSP at a single site yields active MSP, a disulfide-linked alphabeta-chain heterodimer. However cleavage of recombinant pro-MSP yielded not only the disulfide-linked heterodimer, but also free alpha- and beta-chains, indicating that some of the recombinant molecules lacked an alphabeta-chain disulfide. We purified the free chains for characterization. The beta-chain of MSP has three extra cysteines, Cys527, Cys562, and Cys672, which are not found in the plasminogen beta-chain. Disulfide bond analysis showed a Cys527-Cys562, but also a Cys588-Cys672. Coopting Cys588 by Cys672 prevented the expected formation of a disulfide between alpha-chain Cys468 and beta-chain Cys588. Concomitant studies determined structures of oligosaccharides at the three Asn-linked glycosylation sites of MSP. The oligosaccharides at the three Asn loci are heterogeneous; 11 different sugars were identified, all being sialylated fucosyl biantennary structures. We also located the pro-MSP signal peptide cleavage site at Gly18-Gln19 and the scissile bond for formation of mature MSP at Arg483-Val484.
Amino Acids↗
Intracellular single-chain antibody against hepatitis B virus core protein inhibits the replication of hepatitis B virus in cultured cells.
Hepatitis B virus (HBV) is one of the major causes of chronic liver diseases and hepatocellular carcinoma. In this study, we used a single chain antibody (sFv), which is a man-made antibody with a strong affinity of immunoglobulin, to inhibit HBV replication. Because HBV replication can only take place in the viral nucleocapsid made of HBV core protein (HBc), we generated anti-HBc sFv and examined whether intracellular anti-HBc sFv could inhibit viral replication in the human hepatoblastoma-derived cell line that produces HBV (HB611). With respect to HBV replication intermediates, both single-stranded and partially double-stranded DNA intermediates were markedly suppressed in the cells expressing anti-HBc sFv, although HBV RNA intermediates were not affected. This suggested that intracellular anti-HBc sFv inhibited HBV DNA replication by inhibiting reverse transcription from HBV pregenome RNA to single-stranded DNA. Because the sFv-HBc complex was detected in the cells expressing anti-HBc sFv by immunoprecipitation analysis but the quantity of intracellular HBc was not affected, the anti-HBc sFv was suggested to inhibit HBV DNA replication by interfering with the function of HBc. These results indicate that intracellular sFv against HBc might be effective as a novel active molecule for gene therapy of hepatitis B.
Amino Acid Sequence↗
B7-1 (CD80)-gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouse hepatocellular carcinoma.
Human hepatocellular carcinoma (HCC) frequently recurs after primary therapy, resulting in poor prognosis. To try to find a way to prevent this, we examined the combined effectiveness of B7-1 (CD80)-gene transfer and interleukin-12 (IL-12) on the induction of protective antitumor immunity against poorly immunogenic BNL1ME A.7R. 1 (BNL) mouse HCC cells. We introduced mouse B7-1 gene into BNL1ME A. 7R.1 cells. Overexpression of B7-1 on BNL1ME A.7R.1 cells resulted in significant inhibititon of subcutaneous tumor development in syngeneic BALB/c mice, but not in complete rejection, suggesting that strong expression of B7-1 molecules may enhance the immunogenicity of BNL1ME A.7R.1 cells in immunocompetent mice. Lymphocyte study revealed that the cytolytic activity generated by immunization with B7-1 transfectants against BNL1ME A.7R.1 cells was mediated mainly by CD8(+) cytotoxic T lymphocytes (CTL). We examined the synergistic effect of IL-12 and immunization with B7-1 transfectants. The combination led to rejection of BNL1ME A.7R.1 cells in 6 of 10 tested mice and delayed tumor development in the remaining mice. Furthermore, the combined treatment against pre-established BNL1ME A.7R.1 tumors resulted in rejection in 3 of 8 tested mice or in significant inhibition of tumor growth in the remaining mice. In vivo lymphocyte subset depletion study indicated that the combined antitumor effect was dependent on the presence of both CD8(+) and CD4(+) T cells. In conclusion, the combination of immunization of B7-1-transfected HCC cells and IL-12 could induce protective and therapeutic immunity against parental HCC cells, and this combination may be therapeutically useful for suppressing recurrence of HCC.
Animals↗
Involvement of transporter associated with antigen processing 2 (TAP2) gene polymorphisms in hepatitis C virus infection.
BACKGROUND & AIMS: Transporter associated with antigen processing (TAP) has essential roles in the antigen-presenting systems, translocating antigenic peptides from the cytosol into the endoplasmic reticulum. The aim of this study was to clarify whether TAP polymorphisms are involved in hepatitis C virus (HCV) infection. METHODS: The 145 HCV-infected Japanese patients examined in this study were categorized into two groups: 36 carriers with persistently normal alanine transaminase (ALT) values and 109 patients with chronic liver disease (CLD). TAP2 gene phenotypes were determined by means of polymerase chain reaction-restriction fragment length polymorphism, and their frequencies were compared between the two groups. RESULTS: Frequencies of TAP2*0101, *0102, and *0201 were not different between the two groups. However, TAP2*0103 frequency in carriers with normal ALT levels was significantly higher than that in patients with CLD (44% vs. 16%; P = 0.00064, Pc < 0.005). Although the TAP2*0103 allele was tightly linked with class II DRB1*1302-DQB1*0604 haplotype in this study, the TAP2*0103 frequency in the normal ALT group was also significantly higher than that in the CLD group even in DRB1*1302-DQB1*0604-negative patients (31% vs. 10%; P = 0.0076, Pc < 0.05). CONCLUSIONS: These findings suggest that TAP2*0103 may be closely associated with low serum ALT activity in HCV-infected Japanese patients.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Interleukin 1beta protects mice from Fas-mediated hepatocyte apoptosis and death.
BACKGROUND & AIMS: Fas-mediated apoptosis is one of the major death processes of hepatocytes in liver diseases. The aim of this study was to determine whether interleukin (IL)-1beta regulates the Fas-mediated apoptotic process of differentiated hepatocytes in vivo. METHODS: IL-1beta was injected into Balb/cA mice 5 hours before lethal challenge with agonistic anti-Fas administration. Survival and hepatocyte apoptotic process of these mice were examined. RESULTS: IL-1beta pretreatment prolonged animal survival in a dose-dependent manner, and 500 ng of IL-1beta completely protected mice from lethality. Both serum alanine aminotransferase value and hepatic DNA fragmentation were significantly suppressed by IL-1beta pretreatment. IL-1beta affected neither hepatic distribution of anti-Fas antibody nor Fas expression levels on hepatocytes but significantly suppressed Fas-induced activation of hepatic caspase 3-like protease. Suppression of Fas-induced activation of the caspase by IL-1beta was diminished by coadministration with D-galactosamine and reversed by coinjection with an excess amount of uridine. CONCLUSIONS: These results suggest that IL-1beta suppresses Fas-mediated hepatocyte apoptosis by inducing molecule(s) that suppress the apoptosis control machinery upstream of caspase 3. This observation raises the possibility that IL-1beta acts as a negative regulator of Fas-mediated hepatocyte apoptosis during liver injury.
Alanine Transaminase↗