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Biomedical subjects

T Nakatani

Publications and source records attributed to T Nakatani.

At least 19 recordsLinked to original sources
PubMed1999

Hepatocellular carcinoma in an orthotopic mouse model metastasizes intrahepatically in cirrhotic but not in normal liver.

Prognosis of hepatocellular carcinoma (HCC) still remains poor mainly because of intrahepatic metastasis. In the majority of cases, HCC is found in conjunction with liver cirrhosis. It is, therefore, of great importance to investigate the invasive and metastatic behavior of HCC in cirrhotic liver. To examine this, a liver cirrhosis model was produced by injecting thioacetamide i.p. into mice. Murine HCC cells were labeled with the fluorescent carbocyanine dye, DiI, and implanted directly under the capsule of cirrhotic and normal livers of syngeneic mice. DiI-labeled HCC cells in the liver were observed under fluorescent and confocal microscopy. Histological analysis of cirrhotic and normal livers revealed that implanted HCC cells migrated to and invaded the adjacent periportal regions, but not the adjacent centrolobular areas. This characteristic behavior of HCC was more evident in cirrhotic liver than in normal liver. Furthermore, intrahepatic metastasis to unimplanted hepatic lobes was observed in cirrhotic liver as early as 7 days after implantation, while it was not detected in normal liver even 4 weeks later. Thus, an orthotopic animal model for HCC with cirrhosis described here may be suitable for investigating the invasive and metastatic behavior of HCC. Importantly, labeling tumor cells with a fluorescent dye before orthotopic implantation may be a convenient and useful method to investigate the invasive and metastatic behavior of various types of cancer.

Animals↗
PubMed1999

Lipid A directly inhibits IL-4 production by murine Th2 cells but does not inhibit IFN-gamma production by Th1 cells.

Lipopolysaccharide (LPS) is known to be an immunopotentiator but its effect on cytokine production by Th1 and Th2 cells is unknown. We found that high amounts of LPS, its lipid A moiety, and a lipid A analog all induced a decrease in IL-4 production and an increase in IFN-gamma production when given to keyhole limpet hemocyanin (KLH)-restimulated lymph node cells prepared from KLH-primed mice. Lipid A was similarly found to inhibit IL-4 production by purified CD4+ T cells and Th2 clones activated with immobilized anti-CD3epsilon and anti-CD28 antibodies, suggesting that the inhibition is not indirectly mediated through effects on antigen-presenting cells. No inhibitory effect of lipid A was observed on IFN-gamma production by a Th1 clone. Production of both IL-4 by the Th2 clones and IFN-gamma by the Th1 clone were inhibited by the immunosuppressive agent cyclosporin A. These findings indicate that lipid A can directly inhibit IL-4 production by CD4+ T cells without inhibiting the production of IFN-gamma. Lipid A may therefore become a useful tool to study the intracellular events that differentiate Th1 and Th2 cells.

Animals↗
PubMed1999

Contribution of the renal medulla to enhanced ketogenesis with Ringer's acetate administration during hepatic inflow occlusion.

We have reported that the administration of Ringer's acetate solution (AR) maintains plasma ketone body concentrations even during hepatic ischemia due to enhanced ketogenesis in the kidney. In this study we tried to clarify which part of the kidney, cortex or medulla, contributes to the enhanced ketogenesis. During 20 minutes of hepatic inflow occlusion, AR or Ringer's lactate solution (LR) was administered. Ketone body concentrations in arterial and renal venous blood and renal cortical and medullary tissue were measured enzymatically. Results are expressed as means +/- SEM. At 20 minutes of hepatic inflow occlusion, arterial ketone body concentrations decreased to 38% of preischemic values with the LR infusion but increased under AR administration and were four times higher than that with LR. The renal arteriovenous difference in ketone body concentration was 16 +/- 14 micromol/ml before hepatic inflow occlusion and -52 +/- 14 with AR administration, indicating that renal ketogenesis occurred during hepatic ischemia. Total ketone body concentrations in the renal cortex and medulla were 56 +/- 6 and 61 +/- 5 micromol/g, respectively with LR, but increased to 186 +/- 29 and 248 +/- 25 micromol/g, respectively during AR administration. The concentration in the medulla was higher (p = 0. 12) than that in the cortex but did not reach statistical difference. Renal ketogenesis increases during hepatic inflow occlusion with AR administration. It is likely that the enhancement of ketogenesis takes place predominantly in the medulla of the kidney.

Analysis of Variance↗
PubMed1999

Antitumor effect of electrochemotherapy on colorectal carcinoma in an orthotopic mouse model.

Electropermeabilization was shown to markedly increase the sensitivity of murine colorectal carcinoma (CRC) cells to bleomycin (BLM), resulting in more than 2,500-fold higher susceptibility to BLM. Subsequent in vivo electrochemotherapy with BLM revealed profound antitumor effects on subcutaneous CRC tumors. Furthermore, when electrochemotherapy with BLM was employed for the treatment of orthotopic CRC tumors in mice, significantly prolonged survival priods were observed. These results indicate the feasibility of electrochemotherapy with BLM for the treatment of CRC and demonstrate that electrochemotherapy can be translated from the treatment of cutaneous and subcutaneous tumors to the treatment of internal cancers including CRC.

Animals↗
PubMed1998

Comparison of carcinoembryonic antigen promoter regions isolated from human colorectal carcinoma and normal adjacent mucosa to induce strong tumor-selective gene expression.

To establish in vivo gene therapy against cancer, it is requisite to induce strong, cancer cell-selective expression of a therapeutic gene. Comparison of the promoter activity of 5' flanking regions of the carcinoembryonic antigen (CEA) gene isolated from various origins is therefore of considerable interest. The 5' flanking region of the CEA gene between -135 and +69 bp upstream from the transcriptional start site, which is recognized as the core promoter region, was isolated from CEA-producing human colorectal carcinoma (CRC), normal adjacent mucosa, CEA-producing cell lines and CEA-non-producing cell lines. No mutations were observed by single-strand conformation polymorphism in the CEA promoter regions. Subsequent sequence analysis revealed that there were no mutations in the CEA promoter regions isolated from CEA-producing CRC and normal adjacent mucosa. Furthermore, nuclear extracts prepared from CEA-producing human CRC cells could equally bind to both the CEA promoter fragments isolated from CEA-producing CRC and normal mucosa. Both CEA promoter regions could direct 5- to 20-fold higher expression of a luciferase reporter gene in CEA-producing cells than in CEA-non-producing cells. Therefore, we suggest that the use of either CEA promoter region isolated from CRC or normal mucosa is equally effective to induce strong, CEA-producing cancer-selective expression of a therapeutic gene.

Base Sequence↗
PubMed1998

Restricted Zn2+ availability affects the antizyme-dependent ornithine decarboxylase degradation pathway in isolated primary cultured rat hepatocytes.

We previously reported that lack of Zn2+ decreased ornithine decarboxylase (ODC) activity without any change in ODC messenger RNA levels and the half-life of ODC activity being about 2-fold more rapid in primary cultured adult rat hepatocytes, suggesting that lack of Zn2+ decreased ODC activity mainly by degrading the enzyme. The present investigations showed that the chelator, diethylenetriamine penta-acetic acid (DTPA), increased the ratio of ODC-antizyme complex to total ODC (about 2-fold) and caused a decrease in antizyme inhibitor, a protein inhibitor of ODC antizyme (about 50%). These results indicate that a restricted Zn2+ availability affects the antizyme-dependent ODC degradation pathway and consequently decreases ODC activity in primary cultured rat hepatocytes.

Animals↗
PubMed1998

Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives.

Various N-sulfonylamino acid derivatives were synthesized and evaluated for their in vitro and in vivo activities to inhibit type IV collagenase (MMP-9 and MMP-2). When the amino acid residue and the sulfonamide moiety were modified, their inhibitory activities were greatly affected by the structure of the sulfonamide moiety. A series of aryl sulfonamide derivatives containing biaryl, tetrazole, amide, and triple bond were found to be potent and highly selective inhibitors of MMP-9 and MMP-2. In addition, these compounds were orally active in animal models of tumor growth and metastasis. These results revealed the potential of the N-sulfonylamino acid derivatives as a new type of candidate drug for the treatment of cancer.

Administration, Oral↗
PubMed1998

Posterior sinus node artery and accessory atrioventricular node artery arising by a common origin: a case report.

We describe herein a rare and hitherto not reported variation, found in a Japanese male cadaver, in which a posterior sinus node (SN) artery and an accessory atrioventricular node (AN) artery originate from a common trunk branching from the posterior segment of the circumflex artery. After arising in this manner, the posterior SN artery passed in a clockwise direction around the posterior, lateral, and finally anterior wall of the left atrium to the sinus venosus, giving off a branch to the SN from posteriorly. The accessory AN artery coursed in a counterclockwise direction on the posterior wall of the left atrium as far as the crux of the heart, where it bent anterosuperiorly and continued within the interatrial septum. It entered the AN from superiorly and, crossing deep to the principal AN artery, reached the inferior and superficial portion of this node. It could be considered that the accessory AN artery in this study is a modified version of arteries entering and coursing in the interatrial septum, as exemplified by Kugel's anastomotic artery.

Aged↗
PubMed1998

Anomalous triad of a left-sided inferior vena cava, a retroesophageal right subclavian artery, and bilateral superficial brachial arteries in one individual.

We report a rare case of three major vascular variations in the same individual, two within the thorax and abdomen and one within the upper extremity. The observations were made in a cadaver of a 74-year-old Japanese woman. A single left-sided inferior vena cava was observed that began from the confluence of the left and right common iliac veins and ascended vertically to the left side of the abdominal aorta. After receiving the left renal vein, it passed obliquely upward anterior to the abdominal aorta, reaching the right side of the aorta, and then ascended vertically to the right atrium, following its normal course. The retroesophageal right subclavian artery was also present; it arose from the arch of the aorta as the last branch, passing obliquely between the esophagus and the vertebral column. Thus the right recurrent laryngeal nerve was not formed. Additionally, bilateral superficial brachial arteries were observed. They arose from the axillary artery, crossed over the medial root of the median nerve, coursed down the arm, and divided into the radial and ulnar arteries in the cubital fossa. Although each variation is not rare by itself, the triad of events is rare and important to clinicians, anatomists, and medical students.

Aged↗
PubMed1998

Bilateral four-headed biceps brachii muscles: the median nerve and brachial artery passing through a tunnel formed by a muscle slip from the accessory head.

Bilateral four-headed biceps brachii muscles were observed in the dissected cadaver of a 95-year-old Japanese woman. The third head on both sides originated from the humerus at the insertion of the coracobrachialis and inserted into the distal part of the biceps brachii and the proximal part of the common biceps tendon on the ipsilateral side. The fourth head on both sides arose from a thin fibrous origin from the intertubercular sulcus and the insertion of the pectoralis major, and inserted into the confluence of the biceps brachii and the third head. This anomaly is relatively rare. Moreover, the left third head gave off a muscle slip into the posterior fascia of the pronator teres, forming a tunnel. The median nerve and the brachial artery passed through the tunnel, where the nerve and artery seemed to be compressed. The possible production of clinical symptoms, given the anatomy, is discussed.

Aged↗
PubMed1998

Vascular endothelial growth factor tightly regulates in vivo development of murine hepatocellular carcinoma cells.

Angiogenesis is essential for the development of a solid tumor, including hepatocellular carcinoma (HCC). HCC is a well-known hypervascular tumor. Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic factors. Its role has not been clarified in vivo in HCC development. We used a self-contained, tetracycline-regulated retroviral vector system to elucidate the effect of VEGF on murine HCC development in a xenograft experimental model. By delivering the VEGF gene within the retroviral vector and under the control of a tetracycline-regulated promoter, we were able to manipulate VEGF expression in vivo tumor by providing tetracycline in the drinking water. Overexpression of VEGF showed a marked increase in tumor development accompanied by augmentation of neovascularization. The degree of tumor enlargement corresponded to the level of VEGF gene expression. Suppression of VEGF led to a decrease in tumor growth at the established tumor size, whether relatively small or large. The level of VEGF expression did not alter the proliferation of HCC cells in vitro. In a double-chamber chemoinvasion assay, the in vitro invasion activity of VEGF-transduced cells was not changed. In the presence of endothelial cells (EC), however, VEGF-transduced cells showed a marked increase in their in vitro invasion activity. These results suggested that VEGF plays a critical role in the development of HCC in cooperation with EC

Animals↗
PubMed1998

Superficial ulnar artery originating from the brachial artery and its clinical importance.

We found a left superficial ulnar artery in the cadaver of a Japanese woman. This anomalous vessel originated from the brachial artery at a site 55 mm distal to the inferior border of the teres major muscle and medial to the median nerve, ran downward and medially superficial to the forearm flexor muscles, and then downward to enter the hand. It formed superficial and deep palmar arches with the radial artery. The clinical importance of the anomalous ulnar artery is discussed.

Aged↗
PubMed1998

B-cell lymphoma of mucosa-associated lymphoid tissue of the thymus: a report of two cases with a background of Sjögren's syndrome and monoclonal gammopathy.

Two rare cases of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arising in the thymus are reported. Both patients (a 61-year-old man and a 75-year-old woman) were suffering from Sjögren's syndrome and immunoglobulin (Ig)A kappa monoclonal gammopathy. Mixed IgA-IgG cryoglobulinemia was also present in the male case. Tumor cells expressed IgA and kappa antibody reactive proteins identical with serum IgA kappa M. Moreover, we could demonstrate rearrangements of the immunoglobulin heavy and light chain genes, which supported the monoclonal origin of tumor cells. Immunological abnormalities improved after thymectomy in one case in which the tumor cells were confined to the thymus, but not the other with regional lymph node involvement, suggesting a causal role for the tumor. MALT lymphomas of the thymus thus appear to be associated with immunological disorders such as Sjögren's syndrome or monoclonal gammopathy.

Aged↗
PubMed1998

Overlapping epitopes of friend murine leukemia virus gag-encoded leader sequence recognized by single cytotoxic T-lymphocyte clones.

The leader signal sequence of the non-structural gag-encoded glycoprotein precursor, Pr75gag, of Friend murine leukemia virus (F-MuLV) contains overlapping epitopes, SIVLCCLCL (p71-79) and CCLCLTVFL (p75 83) that activate Friend virus (FV)-induced tumor (FBL-3)-specific cytotoxic T-lymphocytes (CTL) (Kondo et al., J. Virol., 69, 1995, 6735-6741; Chen et al., J. Virol., 70, 1996, 7773-7782). It was investigated whether these two peptides are recognized by a single CTL clone or by individual clones with different specificities. The results show that both hydrophobic and cysteine-containing peptides are bound to H-2Db class I major histocompatibility complex (MHC) molecules and cross-recognized by a single CTL clone as well as bulk-cultured CTL from the spleens of mice immunized with FBL-3. The peptide p71-79 was effective for sensitizing target cells to lysis by CTL in the concentration of common antigenic peptides. Moreover, peptide p75-83 was 1000-fold more potent than the peptide p71-79. Specific cytotoxicity assays with variant peptides with alanine- and serine-substitutions suggested a highly complex function of the disulfide bond-forming peptides potentially sensitive to small sequence differences. The dominance of CTL responses to the transmembrane region is discussed in light of the high affinity of a novel hydrophobic peptide to compete with other peptides for binding to MHC molecules.

Amino Acid Sequence↗