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Biomedical subjects

N Tanaka

Publications and source records attributed to N Tanaka.

At least 397 records · Page 22Linked to original sources
PubMed2000

Topological analysis of p21WAF1/CIP1 expression in esophageal squamous dysplasia.

In the normal stratified squamous epithelium of the esophagus, only the third to the fifth layers of cells express the cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21). Using immunohistochemical staining, we examined the topological distribution of cells expressing p21, p53, Ki67, and cytokeratin 10 (CK10), a differentiation marker of esophageal squamous cell carcinoma (SCC), in 25 superficial SCCs and 72 dysplastic lesions of the esophagus. Image analysis of p21, p53, and Ki67 expression was also performed in 48 dysplastic lesions. In superficial SCCs, although Ki67- and p53-expressing cells were mainly distributed in the deep layers of tumors despite tumor differentiation, the distribution of p21 correlated with tumor differentiation. In dysplastic lesions, p53- and Ki67-coexpressing cells tended to locate in the same layers and expand in the lower layers of epithelium with the progression of dysplasia. p21-expressing cells shifted to the upper layers of the epithelium with the progression of dysplasia. However, this change was heterogeneous; in some lesions, p21-expressing cells were confined to the superficial layers of atypical cells (confined type), whereas in others, p21-overexpressing cells were scattered among atypical cells (scattered type). CK10 expression was observed in 25% of dysplastic lesions, and the frequency of CK10 expression was significantly higher in the scattered than in the confined type. Our results suggest that esophageal squamous dysplasia represents the earliest pathological process in esophageal squamous carcinogenesis. Our results also suggest that differentiation of esophageal SCC is determined at the stage of dysplasia, and that p21 plays a critical role in the differentiation process.

Adult↗
PubMed2000

Regulation of 25- and 27-hydroxylation side chain cleavage pathways for cholic acid biosynthesis in humans, rabbits, and mice. Assay of enzyme activities by high-resolution gas chromatography;-mass spectrometry.

In classic cholic acid biosynthesis, a series of ring modifications of cholesterol precede side chain cleavage and yield 5beta-cholestane-3alpha, 7alpha, 12alpha-triol. Side chain reactions of the triol then proceed either by the mitochondrial 27-hydroxylation pathway or by the microsomal 25-hydroxylation pathway. We have developed specific and precise assay methods to measure the activities of key enzymes in both pathways, 5beta-cholestane-3alpha, 7alpha, 12alpha-triol 25- and 27-hydroxylases and 5beta-cholestane-3alpha, 7alpha, 12alpha, 25-tetrol 23R-, 24R-, 24S- and 27-hydroxylases. The extracts from either the mitochondrial or microsomal incubation mixtures were purified by means of a disposable silica cartridge column, derivatized into trimethylsilyl ethers, and quantified by gas chromatography;-mass spectrometry with selected-ion monitoring in a high resolution mode. Compared with the addition of substrates in acetone, those in 2-hydroxypropyl-beta-cyclodextrin increased mitochondrial triol 27-hydroxylase activity 132% but decreased activities of the enzymes in microsomal 25-hydroxylation pathway (triol 25-hydroxylase and 5beta-cholestane-3alpha, 7alpha, 12alpha, 25-tetrol 23R-, 24R-, 24S- and 27-hydroxylases) 13;-60% in human liver. The enzyme activities in both pathways were generally 2- to 4-times higher in mouse and rabbit livers compared with human liver. In all species, microsomal triol 25-hydroxylase activities were 4- to 11-times larger than mitochondrial triol 27-hydroxylase activities but the activities of tetrol 24S-hydroxylase were similar to triol 27-hydroxylase activities in our assay conditions. The regulation of both pathways in rabbit liver was studied after bile acid synthesis was perturbed. Cholesterol feeding up-regulated enzyme activities involved in both 25- (64;-142%) and 27- (77%) hydroxylation pathways, while bile drainage up-regulated only the enzymes in the 25-hydroxylation pathway (178;-371%). Using these new assays, we demonstrated that the 25- and 27-hydroxylation pathways for cholic acid biosynthesis are more active in mouse and rabbit than human livers and are separately regulated in rabbit liver.

Animals↗
PubMed2000

[Small cell lung cancer associated with anti-Hu antibody-positive paraneoplastic neurologic syndrome].

We report a case of small cell lung cancer with anti-Hu antibody-positive paraneoplastic neurologic syndrome preceded by variable neurological symptoms. A 57-year-old man first noticed a numbness on the inner side of his right leg in April 1998. He was later admitted to a hospital following the development of polyneuropathy, cerebellar dysfunction, and psychological symptoms. Chest plain X-ray films and computed tomographic scans disclosed a mass shadow in the right upper lobe, in addition to enlarged mediastinal lymph nodes. Small cell lung cancer was suspected on the basis of pathologic findings on an enlarged right supraclavicular lymph node and radiologic findings. The patient was referred to our hospital in October 1998. Anti-Hu antibody was detected both in serum and cerebrospinal fluid. Small cell lung cancer (clinical T1N3M0, stage IIIB) with paraneoplastic neurologic syndrome was diagnosed. Three courses of combination chemotherapy (carboplatin and etoposide) were administered with a partial response. However, the patient's neurological symptoms were not alleviated. We discussed the mechanism, clinical symptoms, and treatment of this disease.

Autoantibodies↗
PubMed2000

[A case of nonresectable scirrhous type gastric cancer successfully treated by low-dose cisplatin (CDDP), 5-fluorouracil (5-FU) and pirarubicin (THP)].

There have been few effective chemotherapeutic regimens for scirrhous type gastric cancer. Recently, the usefulness of combined cancer agent chemotherapy based on the concept of biochemical modulation has been reported. For example sequential MTX and 5-FU therapy, low-dose CDDP plus 5-FU, and the like. In this paper, we report the usefulness of low-dose CDDP plus 5-FU therapy in combination with pirarubicin (THP) for inoperable scirrhous type gastric cancer. A 32-year-old man who was suffering from scirrhous type gastric cancer with pyloric stenosis was treated with this regimen. Eight weeks after the start of therapy, his gastric capacity and lumen diameter had clearly increased, and he was taking ordinary meals. Ascites had also completely disappeared. CR has now been continued about 7 months. This regimen is considered to be promising for scirrhous type gastric cancers with a poor prognosis.

Adenocarcinoma, Scirrhous↗
PubMed2000

[Surgical stress and CARS: involvement of T cell loss due to apoptosis].

The term compensatory anti-inflammatory response syndrome(CARS) is the cytokine antagonist cascade which down-regulates the inflammatory cascade that appeared to contribute to the onset of bacterial infection. CARS represents immunosuppression, in which state reduced numbers of T cells in blood were encountered. Here we have determined whether this T cell loss is a consequence of bacterial antigen-mediated activation-induced cell death(AICD). By flowcytometric analysis, less than 0.3% of freshly isolated T cells from healthy volunteers and patients with severe pneumonia were identified as apoptosis. However, during culture, the rate of apoptosis in peripheral blood T cells from patients was 3.0 + 0.9%, and increased further in the presence of anti-CD3(7.4 + 2.1%) and decreased when IL-2 was added(4.4 + 1.3%). In contrast, there were no changes observed in healthy volunteers on addition of anti-CD3. Further, anti-CD3 significantly increased susceptibility to apoptosis of CD45RO+ T cells, but not CD45RA+ T cells from patients. Collectively, these findings demonstrated that bacteria-reactive T cells were more susceptible to AICD, and AICD of CD45RO+ T cells, therefore, provides an explanation for the loss of bacteria-reactive T cells during CARS.

Apoptosis↗
PubMed2000

Induction of apoptosis in human esophageal cancer cells by sequential transfer of the wild-type p53 and E2F-1 genes: involvement of p53 accumulation via ARF-mediated MDM2 down-regulation.

Transcriptional factor E2F-1 as well as tumor suppressor p53 have been shown to cause apoptosis independently in some types of human cancer cells when overexpressed. Here we report that sequential transfer of the wild-type p53 and E2F-1 genes efficiently induces apoptosis in human esophageal cancer cells and that E2F-1 overexpression directly, activates expression of p14 (ARF), which inhibits MDM2-mediated p53 degradation, resulting in the stabilization of p53. Infection of human esophageal cancer cell lines T.Tn and TE8 with adenovirus vector-expressing E2F-1 (Ad-E2F-1) enhanced mRNA and protein expression of ARF and decreased MDM2 protein expression. Transfection of ARF plasmid decreased MDM2 protein expression, which in turn increased p53 protein expression. Infection of T.Tn and TE8 cells first with adenovirus-expressing wild-type p53 (Ad-p53) and then with Ad-E2F-1 resulted in rapid induction of apoptosis; in contrast, simultaneous infection with Ad-E2F-1 and Ad-p53 had no significant antitumor effect. As shown by Western blot analysis, infection with suboptimal concentrations of Ad-E2F-1 induced the accumulation of exogenous p53 transduced by suboptimal concentrations of Ad-p53. Moreover, Ad-E2F-1-mediated ARF expression inhibited the up-regulation of MDM2 by overexpressed p53 in TE8 cells. Thus, overexpression of ectopic E2F-1 protein may stabilize endogenous as well as ectopic p53 protein via the E2F-1/ARF/MDM2/p53 regulatory pathway and, in this way, render cells more sensitive to apoptosis, an outcome that has important implications for the treatment of human esophageal cancers.

Adenoviridae↗
PubMed2000

[Genetic analysis for colorectal cancer: what can we learn from microsatellite research?].

Recent advances in molecular biology have unveiled the mechanisms of carcinogenesis, especially colorectal carcinogenesis. A large body of evidence supports the idea that accumulated genetic changes due to inherited as well as environmental factors underlie colorectal cancer development. Recently, several reports have suggested that aberrant methylation of the CpG island may also play an important role in colorectal carcinogenesis. This genetic information is not yet sufficient but some useful genetic information can be applied clinically. This paper presents the results of intensive study of microsatellite instability in colorectal cancers and some clinically applicable discoveries. Future problems are also discussed.

Colorectal Neoplasms↗
PubMed2000

Establishment of a tightly regulated human cell line for the development of hepatocyte transplantation.

Hepatocyte transplantation (HTX) could be an attractive treatment for patients with liver failure and liver-based metabolic disease. Human primary hepatocytes are ideal in this modality, but the shortage of human livers available for hepatocyte isolation severely limits the use of this form of therapy. A tightly regulated human hepatocyte cell line that grows economically in culture and exhibits differentiated liver functions would be an attractive alternative to the primary human hepatocytes. To test the feasibility, human hepatocytes were immortalized by a retroviral vector expressing simian virus 40 large T antigen and herpes simplex virus-thymidine kinase. A highly differentiated immortal hepatocyte line NKNT-3 was established. NKNT-3 cells grew in chemically defined serum-free medium, retained highly differentiated liver functions, and were sensitivity to ganciclovir as a prodrug. Essentially unlimited availability of NKNT-3 cells may be clinically useful for HTX and bioartificial liver.

Antigens, Viral↗
PubMed2000

Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: a positron emission tomography study.

We measured brain acetylcholinesterase activity in 30 patients with Alzheimer's disease (AD) and 14 age-matched controls by positron emission tomography (PET) and using a carbon 11-labeled acetylcholine analogue. Seven AD patients had repeat PET scans. The k3 values were calculated as an index of acetylcholinesterase activity in a three-compartment analysis using the metabolite corrected arterial input function. Twenty-eight of the 30 AD patients (14 each in the early and late onset subgroups) were retained in the study so as to equalize the range and average severity of cognitive impairment within the early and late onset subgroups. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala in the early onset AD patients, although the k3 values were significantly reduced only in the temporoparietal cortex and amygdala in the late onset AD patients. In the longitudinal study, all 7 repeat AD patients showed further reduction of cortical k3 values in the second PET scans, with a mean interval of 2 years, suggesting a progressive loss of the ascending cholinergic system from the nucleus basalis of Meynert in AD. In 37 AD patients, there was a highly significant correlation between the cortical k3 values and Mini-Mental State Examination scores, supporting the cholinergic hypothesis in AD.

Acetylcholinesterase↗
PubMed2000

[Recombinant adenovirus expressing wild-type p53 is antiagiogenic--implication for lung cancer gene therapy].

Angiogenesis is required for the growth and progression of malignancies. Recent studies have demonstrated that genetic alterations may accompany acquisition of the angiogenic phenotype. Here we demonstrate that the recombinant adenovirus-mediated transfer of the wild-type p53 gene into a mutant p53-expressing human non-small cell lung cancer cell line markedly inhibited the expression of an angiogenic factor, vascular endothelial growth factor (VEGF), and increased the expression of a novel antiangiogenic factor, brain-specific angiogenesis inhibitor 1 (BAI 1), resulting in reduced neovascularization in vivo. These results may explain in part the mechanism of the bystander effect induced by wild-type p53 gene transfer of adjacent tumor cells.

Adenoviridae↗
PubMed2000

[Impending paradoxical embolism visualized by echocardiography combined with pulmonary embolism: a case report].

A 43-year-old man was admitted to our hospital complaining of dyspnea on exertion and dizziness. Transthoracic echocardiography revealed a mobile mass (3.5 x 1.0 cm) attached to the left atrial septum and transesophageal echocardiography showed the mass in the right atrium protruding through the patent foramen ovale into the left atrium. A mobile snake-like thrombus was apparent in the right atrium and right ventricle. The diagnosis was pulmonary embolism with impending paradoxical emboli.

Adult↗
PubMed2000

Effects of mixed administration of glucose and fat emulsion on the liver of rats undergoing hepatopancreatectomy.

To prevent the development of liver failure after simultaneous massive resection of the liver and pancreas, we examined whether fat emulsion could be used as an energy source during postoperative transfusion. Using rats, the following four groups were prepared: the simple laparotomy group (S group), 68% hepatectomy group (H group), 90% pancreatectomy group (P group) and 68% hepatectomy + 90% pancreatectomy group (HP group). A constant total calorie level and transfusion dose were used. Three kinds of transfusions with different glucose-to-fat emulsion caloric ratios, that is: 75% fat emulsion (of the total calorie level) + 25% glucose (75L), 50% fat emulsion + 50% glucose (50L) and 25% fat emulsion + 75% glucose + 1 unit/5 g glucose of insulin (25L), were continuously administered for 48 hours, and the effects of these transfusions on the survival rate and liver were examined. After 75L administration, survival rates in the H group and HP group were significantly lower than those in the S group and P group. After administration of 50L, survival rates did not significantly differ among the four groups. After 25L administration, the survival rate in the HP group was significantly lower than that in other groups. In the HP group, the survival rate after 50L administration was the highest. However, necrosis was observed in a portion of the hepatic lobule, while the blood aspartate aminotransferase (AST) level was increased. After 25L administration, hepatocellular mitochondrial swelling and degeneration were noted in the HP group; furthermore, the blood total protein level was decreased. These results showed that the post-operative administration of fat emulsion at a percentage of 50% of the total calorie level caused partial hepatocellular necrosis in the HP group, but improved the survival rate.

Animals↗
PubMed2000

Conformational analysis of 2-[2-(3-methoxyphenyl) ethyl]phenoxyalkylamines with high 5-HT2 receptor binding affinity.

A conformational analysis of three groups of 2-[2-(3-methoxyphenyl)ethyl]phenoxyalkylamines with high 5-HT2 receptor binding affinity has been performed using the systematic search. Two groups of compounds with different lengths of alkyl chains connecting the amine nitrogen and the central oxygen showed a one order difference in their 5-HT2 receptor binding affinity. The computational analysis of these compounds confirmed the differences in the N--O distances between the two groups, quantitatively. A probable active conformation was proposed based on a superimposition of the stable conformations over a rigid molecule, mianserin. Two hydroxy derivatives in the third group showed a significant difference in their binding affinity depending on the stereochemistry of the hydroxy group. The difference in the energetically favorable order of the stable conformations reasonably explained the relationship between the stereochemistry and the binding activity. A molecular dynamics-based conformational search was also carried out to compare it with the systematic search.

Alkanes↗
PubMed2000

[Tuberculosis in patients with acquired immune deficiency syndrome].

HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. In Japan, the cumulative number of the patients reported is 131 by the end of 1999 with 10 to 20 annual new cases. Most of Japanese cases are advanced AIDS patients with low CD4 number less than 100/microliter. The peak age of Japanese patient is 40 to 60 years old, whereas that of foreigners is 20-30 years old, suggesting that most Japanese cases are recurrent tuberculosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found that, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. We also reported that Mycobacterium tuberculosis stimulates HIV-1 replication by enhancing transcription on the 5' LTR in a macrophage cell line, THP-1, in vitro. In contrast, HIV-1 replication is suppressed by M. tuberculosis infection of monocytes derived macrophages (MDM) or differentiated monocytic THP-1 cells. We observed that HIV-1 5' LTR function was repressed in PMA differentiated THP-1 cells after co-infection with M. tuberculosis. Point mutations in C/EBP-beta binding domains of the HIV-1 LTR negative regulatory element (NRE) abolished promoter repression. Monocyte-derived macrophages and differentiated THP-1 cells increased expression of the 16 kDa inhibitory from of C/EBP-beta after M. tuberculosis coinfection. Bronchoalveolar lavage cells obtained from normal controls and alveolar macrophages from uninflamed lung of tuberculosis patients also expressed the 16 kDa inhibitory form of C/EBP-beta. However, alveolar macrophages from lung segments involved with pulmonary tuberculosis had markedly reduced C/EBP-beta expression. These data suggest that 16 kDa isoform of C/EBP-beta plays an important role for the control of HIV-1 replication in macrophages. We propose derepression of HIV-1 LTR mediated transcription as one mechanism for enhanced HIV-1 replication observed in pulmonary tuberculosis.

AIDS-Related Opportunistic Infections↗