[A case of left-sided ulcerative colitis successfully treated with mesalazine enema but not steroid suppository].
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Adult↗
Biomedical subjects
H Tsubouchi
Publications and source records attributed to H Tsubouchi.
Sensitivity of human pancreatic adenocarcinoma tumor lines to chemotherapy, radiotherapy, and hyperthermia.
BACKGROUND: Surgical treatment of pancreatic adenocarcinoma has failed to produce many cures secondary to high rates of intraperitoneal relapses and liver metastases. The aim of this ex vivo study was to evaluate the inherent chemosensitivity, radiosensitivity and hyperthermic sensitivity of pancreatic adenocarcinoma and to investigate the usefulness of a 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay utilized in each sensitivity test. METHODS: Nine human pancreatic adenocarcinomas were tested ex vivo after growth in nude mice. After 72 hr of chemotherapy, radiotherapy and hyperthermia, efficacy was assessed using MTT assay to determine the ratio of surviving fraction of treated cells-to-that of untreated control cells (TIC ratio). RESULTS: Tumor sensitivities as measured by the IC50 (drug concentration producing 50% growth inhibition) varied largely between drugs, ranging larger than 3 x 10(5) ng/mL for 5-FU, larger than 1.5 x 10(2) ng/mL for MMC, 20 ng/mL to 1.4 x 10(3) ng/mL for ADM, and 80 ng/mL to 2.4 x 10(3) ng/mL for CDDP. D0 (dose of radiation reducing the surviving fraction to 37%) ranged from 3.2 to 8.3 Gy (mean +/- standard deviation; 5.8 +/- 1.6 Gy). For hyperthermia, the mean T50 (duration of hyperthermia reducing the surviving fraction to 50%) at 43 degrees C was 9.4 +/- 3.3 min 4.8 to 14.2 min). The T/C ratio at 43 degrees C for 12 min was less than that at 41 degrees C for 30 min (p = .01; the Wilcoxon signed-ranks test). No clear relationship among chemosensitivity, radiosensitivity, hyperthermic sensitivity and pathologic features could be established. CONCLUSIONS: Nine human pancreatic adenocarcinomas varied widely in their sensitivity to chemotherapies, especially for 5-FU. These results suggested that MTT assay may be useful in excluding some less sensitive cases of pancreatic cancer. For hyperthermia, sufficient therapeutic time and temperature may realize enough effect against pancreatic adenocarcinoma.
Adenocarcinoma↗
Hepatoma-specific gene therapy through retrovirus-mediated and targeted gene transfer using an adenovirus carrying the ecotropic receptor gene.
Tissue-specific transcriptional regulatory sequences have been inserted in retrovirus vectors for therapeutic gene expression in cancer gene therapy. However, the transcriptional activity of these sequences is generally low, and the proviral DNA integration appears to increase the possibility of genomic DNA alteration in nontarget cells. Therefore, retrovirus-mediated targeted gene transduction into human hepatoma cells was evaluated using transient expression of an ecotropic receptor gene, mouse cationic amino acid transporter-1 (MCAT-1). Two recombinant adenoviruses, AxCAMCAT and AxAFMCAT, carrying the MCAT-1 gene under the control of the CAG and human alpha-fetoprotein (AFP) promoter, respectively, were generated. The preinfection with AxCAMCAT allowed highly efficient ecotropic retroviral infection of human cells. In addition, after AxAFMCAT infection, retroviral infection occurred only in AFP-producing hepatoma cells, resulting in selective cytotoxicity induced by the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) system. Transient expression of the MCAT-1 gene under the control of the AFP promoter permits ecotropic retrovirus-mediated gene transduction specifically in AFP-producing human hepatoma cells, resulting in selective induction of the suicide killing effect while the therapeutic gene is driven from ubiquitously expressed promoters.
3T3 Cells↗
Hepatocyte growth factor for liver disease.
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Animals↗
Hepatocyte growth factor and pancreatic cancer cells.
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Cell Division↗
Aeromonas sobria infection with severe soft tissue damage and segmental necrotizing gastroenteritis in a patient with alcoholic liver cirrhosis.
A 49-year-old man, who had a 3-year history of liver dysfunction but had not been treated, was admitted to the hospital with a sudden onset of fever and generalized muscle pain. He subsequently developed generalized purpura with scattered hemorrhagic bullae of the skin and massive bloody stools. Aeromonas sobria was proven by culture of both blood and bullous fluid. In spite of the extensive treatment with antibiotics and other medications in the intensive care unit (ICU), the patient went into septic shock and died 2 days after admission. Pathological examination on autopsy revealed segmental necrotizing gastroenteritis with bacterial colonies and alcoholic liver cirrhosis, in addition to extensive severe soft tissue damage involving cellulitis and rhabdomyolysis and epidermolysis. Although the prognosis for Vibrio vulnificus infection with severe soft tissue damage in patients with liver cirrhosis, malignancy, diabetes mellitus or other pre-existing diseases is poor, the unfavorable progression of Aeromonas species, especially A. sobria infection is rare. This is thought to be the first report of an autopsied case.
Aeromonas↗
Modulation of T-cell responses to a recall antigen in human T-cell leukemia virus type 1-infected individuals.
To determine the mechanism of the purified protein derivative (PPD)-specific hyporesponsiveness in Mycobacterium bovis BCG-vaccinated human T-cell leukemia virus type 1 (HTLV-1)-infected individuals, we examined cytokine production in response to PPD in the following four groups of individuals: (i) HTLV-negative, PPD nonresponders (n = 11; NN); (ii) HTLV-negative, PPD responders (n = 18; NP); (iii) HTLV-positive, PPD nonresponders (n = 15; PN); and (iv) HTLV-positive, PPD responders (n = 15; PP). In vitro stimulation with PPD resulted in both proliferative responses and gamma interferon (IFN-gamma) production in NP and PP (P < 0.02), with minimal proliferation and IFN-gamma production in the NN and PN groups. Further, PPD-specific interleukin 10 (IL-10) production was significantly reduced in the PN group (P < 0.01), while the other groups had comparable levels. Cytokine reconstitution experiments demonstrated that while addition of recombinant IL-12 (rIL-12) plus anti-IL-4 restored PPD-specific responses in the NN group, it had no effect in the PN group. However, addition of rIL-12 resulted in the increased production of IFN-gamma in both nonresponder groups (NN and PN), suggesting that the lack of IFN-gamma production was not responsible for the PPD anergy. We conclude that PPD-specific anergy in HTLV-1-infected individuals appears to be due in part to their inability to respond to rIL-12.
Antigens, Bacterial↗
Suppression of skin reactivity to purified protein derivative by hepatitis C virus among HTLV-I carriers in Japan.
In a population endemic for HTLV-I and hepatitis C virus (HCV), HTLV-I infection has been associated with a suppressed cell-mediated immunity measured by anergy to purified protein derivative (PPD). However, the effect of HCV and the impact of coinfection with HTLV-I and HCV have not been previously evaluated. To approach this issue, PPD reactivity was analyzed among 300 study subjects in the community-based Miyazaki Cohort Study. An erythema of <10 mm in diameter 48 hours after subcutaneous injection of the antigen defined PPD anergy. Logistic regression was used to estimate the relative risks. With adjustment for age, gender, and HTLV-I seropositivity, anti-HCV positivity was not independently associated with PPD anergy (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 0.6-1.9). Subjects with both anti-HCV and anti-HTLV-I had a fivefold risk of PPD anergy relative to those free of both infections (OR = 5.2; 95% CI = 1.9-13.8). The risk was nearly threefold among those with anti-HTLV alone (OR = 2.8; 95% CI = 1.4-5.3). Thus, coinfected study subjects were 1.9 times more likely to have PPD anergy compared with those singly infected with HTLV-I (p = .34). HCV infection may slightly increase the risk of PPD anergy among HTLV-I carriers.
Adult↗
Distinct roles of two separable in vitro activities of yeast Mre11 in mitotic and meiotic recombination.
UNLABELLED: In Saccharomyces cerevisiae, Mre11 protein is involved in both double-strand DNA break (DSB) repair and meiotic DSB formation. Here, we report the correlation of nuclease and DNA-binding activities of Mre11 with its functions in DNA repair and meiotic DSB formation. Purified Mre11 bound to DNA efficiently and was shown to have Mn2+-dependent nuclease activities. A point mutation in the N-terminal phosphoesterase motif (Mre11D16A) resulted in the abolition of nuclease activities but had no significant effect on DNA binding. The wild-type level of nuclease activity was detected in a C-terminal truncated protein (Mre11DeltaC49), although it had reduced DNA-binding activity. Phenotypes of the corresponding mutations were also analyzed. The mre11D16A mutation conferred methyl methanesulfonate-sensitivity to mitotic cells and caused the accumulation of unprocessed meiotic DSBs. The mre11DeltaC49 mutant exhibited almost wild-type phenotypes in mitosis. However, in meiosis, no DSB formation could be detected and an aberrant chromatin configuration was observed at DSB sites in the mre11DeltaC49 mutant. These results indicate that Mre11 has two separable functional domains: the N-terminal nuclease domain required for DSB repair, and the C-terminal dsDNA-binding domain essential to its meiotic functions such as chromatin modification and DSB formation. KEYWORDS: DNA binding/double-strand break repair/DSB formation/Mre11/nuclease
Bacteriophage M13↗
Up-regulation of vascular endothelial growth factor induced by hepatocyte growth factor/scatter factor stimulation in human glioma cells.
Recent findings suggest that hepatocyte growth factor/scatter factor (HGF/SF) contributes to the malignant progression of human gliomas. We investigated the effect of HGF/SF on vascular endothelial growth factor (VEGF) expression of c-Met/HGF receptor-positive human glioma cell lines. Treatment of the glioma cells with various concentrations of HGF/SF resulted in an enhanced secretion of VEGF proteins accompanying increased transcription of VEGF mRNA in a dose-dependent fashion. Since malignant gliomas frequently co-express HGF/SF and its receptor, these results suggest that HGF/SF could act as an indirect angiogenic factor through autocrine induction of VEGF expression and secretion in malignant gliomas.
Endothelial Growth Factors↗
Predictors of level of circulating abnormal lymphocytes among human T-lymphotropic virus type I carriers in Japan.
Human T-lymphotropic virus type I (HTLV-I) carriers often have abnormal lymphocytes (Ably) that resemble malignant cells of adult T-cell leukemia (ATL). To identify predictors of the level of Ably in a longitudinal study of asymptomatic HTLV-I carriers, we analyzed data from 215 subjects (67 men and 148 women) with multiple Ably measurements on blood smears. Ably+ (those having Ably > 0.6% of leukocytes counted on a blood smear at least once) was strongly associated with a high proviral load (OR 8.9; 95% CI 4.1, 19.5). The association among those defined as Ably++ (Ably > 0.6% at all screens or Ably > 1.6% at least once) was higher (19.7; 6.9, 56.1). Ably++ was also significantly associated with male gender (2.8; 1.0, 7.8). Multivariate analysis of Ably level indicates that men with a high proviral load, high anti-HTLV-I titer and low anti-Tax reactivity have the highest Ably level.
Carrier State↗
Evaluation of hepatocyte growth factor activator inhibitor expression in normal and malignant colonic mucosa.
Gene expression of hepatocyte growth factor activator inhibitor (HAI), a recently identified Kunitz-type serine proteinase inhibitor, was analyzed in a series of human colorectal carcinoma cell lines and in human colorectal tissues. All of the 14 cell lines derived from adenocarcinoma of the colorectum expressed HAI in vitro, whereas a colon carcinoma cell line of neuroendocrine origin did not. In vivo, HAI was consistently expressed in the normal colorectal mucosa. Although the expression of HAI mRNA was conserved in adenocarcinoma tissues of the colorectum, the levels of expression were decreased in the adenocarcinoma tissues compared to the normal counterparts. There was a tendency towards an inverse correlation, albeit not well defined, between the amounts of HAI mRNA and the tumor progression. Immunohistochemical study indicated that HAI protein is present predominantly on the surface of epithelial cells of the colon and the immunoreactivity was decreased in the adenocarcinoma cells.
Adult↗
Intrafamilial transmission of HTLV-I and its association with anti-Tax antibody in an endemic population in Japan.
To assess the relationship of anti-Tax antibody to human T-cell lymphotropic virus type-I (HTLV-I) transmission, the sero-prevalence of HTLV-I was analyzed among married couples and among mother/child (both adults) pairs. HTLV-I seroprevalence was significantly higher among wives with anti-Tax+ than those with anti-Tax- HTLV-I carrier husbands (82.4% vs. 59.5%). However, in the group of wives aged 60 years or older, there was no statistical difference in HTLV-I seropositivity based on the husbands' anti-Tax sero-status. In the group whose wives were less than 60 years old, more anti-Tax sero-positive than sero-negative husbands had high DNA levels (57.1% and 20.0%), whereas in the group of husbands whose wives were aged 60 years or older, the number of anti-Tax sero-positive and sero-negative individuals with high DNA levels was similar. HTLV-I sero-prevalence was significantly higher among the adult men with anti-Tax+ carrier mothers than those with anti-Tax- carrier mothers (52.0% vs. 14.3%). For women, HTLV-I sero-prevalence did not differ significantly according to their mothers' anti-Tax sero-status. Our results suggest that the presence of anti-Tax antibody in HTLV-I carriers is an age-dependent risk factor for male-to-female HTLV-I transmission. Furthermore, the effect of the mother's anti-Tax antibody as a risk factor for vertical HTLV-I transmission could be observed in men even after becoming adults.
Adult↗
Hypercalcemia associated with parathyroid hormone-related protein produced by B-cell type primary malignant lymphoma of the kidney.
A patient with primary non-Hodgkin's (B-cell type) lymphoma of the kidney developed hypercalcemia at the terminal stage of the disease. Although the plasma parathyroid hormone level was low, urinary cyclic AMP excretion was elevated. Serum osteocalcin (BGP) was suppressed and the plasma level of 1,25(OH)2D was within the normal range. Serum concentrations of PTH-related protein (PTHrP)-like immunoreactivity (PRP-LI) were elevated, and the tissue concentration of PRP-LI in the postmortem lymph node showed high level along with elevated serum PRP-LI, furthermore the production of PTHrP by the tumor was demonstrated by immunohistochemistry and Northern blotting analysis. These findings indicate that the hypercalcemia of the patient was caused by the PTHrP-producing B-cell lymphoma. Hypercalcemia was restored to normocalcemia by bisphosphonate treatment. Our case will add further information on humoral hypercalcemia in B-cell lymphoma, which rarely has been demonstrated to produce PTHrP.
Autopsy↗
High-dose (9 MU) long-term (60 weeks) alfa-interferon therapy for chronic hepatitis patients infected with HCV genotype 1b.
Efficacy of standard regimens (e.g., 3-6 MU for 24 weeks) of alfa-IFN therapy for chronic hepatitis C has been limited, particularly in patients with HCV/1b. To see if higher-dose longer term treatment is more effective, we tried a 9 MU 60-week regimen. HCV/1b-infected chronic hepatitis patients received 9 MU IFN alpha 2a everyday but Sunday for 2 weeks and thrice a week for next 10 weeks, and 76 patients became HCV RNA-negative while 81 remained positive. The RNA-negative patients were then randomized to receive 3 MU (group I, n = 37) or 9 MU (group II, n = 39) for 48 weeks. Of the RNA-positive patients, only those with normal ALT received another 9 MU 48-week treatment (group III, n = 45). Sustained responders (SR) were defined as those with negative RNA and normal ALT 6 months after the therapy. SR rates based on intent-to-treat principle did not differ significantly between groups I and II (30% vs 41%), but those based on the protocol-compatible cases showed a significantly lower than those in group II. Adverse effects of IFN, developed more frequently in groups II and III than in group I, were mostly reversible. In conclusion, our results encourage 9 MU 60-week IFN alpha treatment in HCV/1b-infected patients with careful attention to adverse effects, and suggest that the treatment should be discontinued if HCV RNA does not disappear within 12 weeks.
Genotype↗
Etiological analysis of focal nodular hyperplasia of the liver, with emphasis on similar abnormal vasculatures to nodular regenerative hyperplasia and idiopathic portal hypertension.
Pathological studies were performed on 23 cases of focal nodular hyperplasia (FNH) under the hypothesis that FNH is a hyperplastic lesion caused by abnormal vasculatures of portal tracts within the nodule. For a comparison of the histological features of portal tracts, nodular regenerative hyperplasia (NRH), idiopathic portal hypertension (IPH), chronic hepatitis and so-called normal liver were used as control tissues. Extranodular areas of FNH nodules were also examined. Clinical data were briefly summarized. Most of the portal tracts within FNH nodules showed various abnormal findings, such as dilatation and/or stenosis of portal vein, muscular thickening of arterial wall with dilated or stenotic lumina, lymphocyte infiltration, and bile ductule proliferation. However, portal vein thrombi were not found. These findings were not thought to represent compensatory reaction to portal vein thrombosis. Similar abnormal features were also observed in extranodular areas of FNH although to a milder degree. These abnormal features resembled those of NRH and IPH. Moreover, the characteristic scar-like tissues within FNH nodules were proved to be abnormally large portal tracts including large feeding arteries, portal veins and bile ducts. It has been believed that septa and scar-like tissue within FNH nodules are not portal tracts and that arterial malformation independent of portal tracts are related to the development of FNH. In addition, venous structures within FNH modules have until now not been considered to be portal veins. However, this study revealed that severe anomaly of portal tracts including portal veins and hepatic arterial branches existed in FNH nodules. Moreover, portal tracts in extranodular areas were also abnormal. Clinically, only one patient had a history of oral contraceptives. Based on these findings, congenital anomaly of the portal tracts histologically resembling the abnormal portal tracts of NRH and IPH may be related to the pathogenesis of FNH.
Adult↗
A novel mre11 mutation impairs processing of double-strand breaks of DNA during both mitosis and meiosis.
Using complementation tests and nucleotide sequencing, we showed that the rad58-4 mutation was an allele of the MRE11 gene and have renamed the mutation mre11-58. Two amino acid changes from the wild-type sequence were identified; one is located at a conserved site of a phosphodiesterase motif, and the other is a homologous amino acid change at a nonconserved site. Unlike mre11 null mutations, the mre11-58 mutation allowed meiosis-specific double-strand DNA breaks (DSBs) to form at recombination hot spots but failed to process those breaks. DSB ends of this mutant were resistant to lambda exonuclease treatment. These phenotypes are similar to those of rad50S mutants. In contrast to rad50S, however, mre11-58 was highly sensitive to methyl methanesulfonate treatment. DSB end processing induced by HO endonuclease was suppressed in both mre11-58 and the mre11 disruption mutant. We constructed a new mre11 mutant that contains only the phosphodiesterase motif mutation of the Mre11-58 protein and named it mre11-58S. This mutant showed the same phenotypes observed in mre11-58, suggesting that the phosphodiesterase consensus sequence is important for nucleolytic processing of DSB ends during both mitosis and meiosis.
DNA Damage↗
CD45RO expression on peripheral lymphocytes as a prognostic marker for adult T-cell leukemia.
Adult T-cell leukemia (ATL) is an aggressive hematological malignancy etiologically linked to HTLV-I. The clinical subtype classification, age, performance status, serum calcium and LDH levels are major prognostic factors of ATL, but these criteria and factors do not always correlate with prognosis. CD45 is expressed on cells of the hematopoietic system, and plays a pivotal role in antigen-stimulated proliferation of T-lymphocytes. CD45RO is a very light weight isoform of CD45 expressed on activated T-cells. Recent studies have shown that peripheral lymphocytes show two patterns of CD45RO expression in HTLV-I infected individuals which appears to correlate with their clinical outcome. The acute type ATL patients have pattern A with CD45RO+ lymphocytes with intermediate expression (CD45ROint cells), and show a better prognosis than those who do not have any CD45ROint cells. Further studies demonstrated that CD45ROint cells were not infected with HTLV-I, and as a result we suggest that CD45RO expression be considered a marker of host immunity in acute type ATL clinical course, in contrast to the levels of WBC or LDH which are regarded as tumor markers and indicators of tumor mass.
Adult↗