Biomedical subjects

T Yoshiki

Publications and source records attributed to T Yoshiki.

At least 73 records · Page 4Linked to original sources

PubMed1997

Inhibitory effects of the antiangiogenic agent TNP-470 on establishment and growth of hematogenous metastasis of human pancreatic carcinoma in SCID beige mice in vivo.

Effects on the liver of the antiangiogenesis agent O-(chloroacetyl-carbamoyl) fumagillol (TNP-470) on hematogenous metastasis of a human pancreatic carcinoma cell line were examined. One million PCI-43 cells, a human pancreas carcinoma cell line, were injected into the spleen of SCID beige mice, then TNP-470 at 30 mg/kg was administered subcutaneously every other day. The mice were killed 6 or 10 weeks thereafter and metastatic nodules in the liver were counted and measured microscopically. Metastases were inhibited and an approximately 10% loss of weight was evident in the TNP-470-administered mice. There was no suppression in maximal size of metastatic colonies in mice given the agent for 6 weeks, while inhibition was apparent in mice given the drug for 10 weeks. Suppression of proliferation and an increase in apoptosis were evident in metastatic nodules in the TNP-470-administered groups, following stainings for proliferative cell nuclear antigen and terminal deoxytransferase-mediated dUTP-biotin nick end-labeling, respectively. TNP-470 inhibited the proliferation of human umbilical vein endothelial cells but not PCI-43 in vitro. TNP-470 did not suppress production of vascular endothelial growth factor by PCI-43 cells. Neovascularization in vivo induced by PCI-43 cells was suppressed in the TNP-470-administered mice, using a diffusion chamber placed in subcutaneous tissues of SCID beige mice. These observations suggest that inhibition of angiogenesis is effective in suppressing establishment and subsequent growth of hematogenous micrometastases of pancreatic adenocarcinoma to the liver.

Animals↗

PubMed1997

In vivo retrovirus-mediated herpes simplex virus thymidine kinase gene therapy approach for adult T cell leukemia in a rat model.

We have previously demonstrated that human T-lymphotropic virus type I (HTLV-I) tax-expressing human T cell lines are selectively eliminated in the presence of aciclovir, using a retroviral vector carrying the herpes simplex virus thymidine kinase (HSV TK) gene under the control of the long terminal repeat (LTR) of HTLV-I. Based on these findings in vitro, we investigated whether this system could also be effective in vivo, using a rat model. Following infection of the HTLV-I-transformed and tax-expressing rat T cell line TARS-1 with this retrovirus (LNLTK virus), high levels of HSV TK expression were observed and resulted in increased susceptibility to ganciclovir (GCV). Tumors were generated by subcutaneous injection of TARS-1 in newborn syngeneic WKA/H rats. While the tumors derived from infected TARS-1 cells with control virus, as well as uninfected cells, continued to grow in all the rats with or without administration of GCV, those derived from LNLTK-infected cells exhibited dramatic regression upon GCV treatment. These results indicate that the HTLV-I LTR-HSV TK system also causes selective elimination of HTLV-I-transformed, tax-expressing T cells in vivo. Therefore, our present study may provide a rationale for clinical gene therapy against adult T cell leukemia.

Animals↗

PubMed1997

[Clinical analysis of bladder cancer patients treated by radical cystectomy].

We assessed the treatment outcome of 105 patients with transitional cell carcinoma of the bladder treated by total cystectomy at our university hospital, between 1979 and 1993. The patients consisted of 84 men and 21 women (male to female ratio : 4:1), between 45 and 82 years old (mean, 65.5 years old). The overall cancer-specific survival rate at 3 and 5 years was 76.3% and 68.9%, respectively. The 5-year survival rate was 85.2% for grade 2 and 59.9% for grade 3 tumors with a significant difference in the survival curves between the two groups (p < 0.05). The 5-year survival rate according to pathological stage was 100% for pTa, 75.6% for pT1, 78.4% for pT2, 54.0% for pT3 and 39.8% for pT4. A significant difference was observed between pTa and pT3 (p < 0.05), and between pTa-2 and pT4 (p < 0.05). The 5-year survival rate was 72.3% for patients without lymph node involvement and 11.9% for those with lymph node involvement, the difference being significant (p < 0.01). Nineteen patients who received pre- and/or post-operative chemotherapy did not show a higher 5-year survival rate than those who did not.

Aged↗

PubMed1997

[Endogenous retroviruses in autoimmune diseases].

Endogenous retroviruses (ERVs) and those related genes are thought to be originated from integration of infectious retroviruses to germ cells or evolved from transposable genetic elements. Some of them can make biological effects on activities of hosts, by promoting the expression of flanking genes or producing certain regulatory proteins. If those mechanisms occur on cells in immune networks, immunological dysregulation including autoimmunity will develop. ERVs can also produce proteins serving as auto-antigens, followed by autoimmune responses. In this article, studies up to date on ERVs of animals and humans are shortly reviewed, related to immunological disorders to autoimmune diseases, showing some examples.

Animals↗

PubMed1997

HTLV-I pX transgenic rats: development of cytokine-producing mammary carcinomas and establishment of the pX mammary carcinoma cell lines.

In two lines of transgenic rats (pX rats) from WKAH and F344 strains and carrying the HTLV-I pX gene under control of the mouse H-2Kd promoter, mammary carcinomas developed predominantly in females starting at about 5 months of age. The incidence of the tumor reached about 40% when the rats were 12 months old. Histology of the tumor was undifferentiated carcinoma with massive infiltration of granulocytes into the tumor tissue. Systemic granulocytosis and hepato-splenomegaly due to extramedullary granulocytopoiesis were seen in pX rats and nude mice bearing pX mammary tumor. mRNAs of both pX and host genes, Gro and MIP-2, which are granulocyte chemoattractants of the IL-8 family, were highly expressed in the tumor tissue. Since expression and point mutation of several oncogenes and anti-oncogene, related with mammary carcinomas, were not demonstrated, hitherto unidentified novel oncogenic pathways may be transactivated by the pX transgene in these pX rats. pX mammary carcinoma cell lines, which have similar characteristics to the primary tumor, were established and the cells underwent apoptosis under the serum deprived conditions. The pX rats and the pX mammary carcinomas appear to be suitable models for analyses of HTLV-I pX oncogenesis and immune pathogenesis in vivo and in vitro.

Animals↗

PubMed1997

Models of HTLV-I-induced diseases. Infectious transmission of HTLV-I in inbred rats and HTVL-I env-pX transgenic rats.

To examine the pathogenic roles of HTLV-I in HTLV-I-induced diseases, we developed two models; namely HTLV-I carrier rats and HTLV-I env-pX transgenic rats. Among life long HTLV-I carriers in seven rat strains, only WKAH rats with the RT1k haplotype developed chronic progressive myeloneuropathy, resembling HAM/TSP clinically and histologically in humans, designated as HAM rat disease and after long incubation periods. Apoptosis of myelin forming cells, oligodendrocytes and Schwann cells associated with HTLV-I infection appears to be the primary cause of HAM rat disease. Local activation of the pX gene and TNF alpha gene was evident in these rats. WKAH rats transgenic for HTLV-I env-pX gene were established and at age 5 weeks, swelling of the bilateral ankle joints began to develop and histological features of the affected joints resembled findings in cases of rheumatoid arthritis (RA): high-titers of rheumatoid factors were present in these rats. A series of vascular collagen diseases such as polyarteritis nodosa-like angiitis, polymyositis, myocarditis, and Sjögren's syndrome-like sialodenitis together with RA were present, even in one individual animal. These transgenic rats as well as HAM rats appear to be suitable animal models for elucidating pathogenic mechanisms implicated in HTLV-I-induced diseases and also various demyelinating vascular collagen diseases of unknown etiology.

Animals↗

PubMed1997

HTLV-I induced myeloneuropathy in WKAH rats: apoptosis and local activation of the HTLV-I pX and TNF-alpha genes implicated in the pathogenesis.

To investigate the pathogenesis of HTLV-I associated diseases, we established a rat model for HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in WKAH rats. In the spinal cords of WKAH rats carrying HTLV-I, chronological histopathology revealed the occurrence of apoptotic cell death starting at 9 months after the infection, followed by demyelination, macrophage infiltration, and the activation of astrocytes starting at 12, 15 and 20 months, respectively. Apoptosis of the Schwann cells was also observed in the peripheral nerves of these rats. By RT-PCR, pX mRNA of HTLV-I was selectively expressed in the diseased spinal cords and peripheral nerves, but not in the unaffected cerebra, cerebella, even though provirus DNAs were consistently identified in these tissues. Among several cytokines examined, mRNA expression and production of TNF-alpha were frequently detected in the spinal cord and the cerebrospinal fluid. The collective evidence suggests that the selective activation of HTLV-I, in particular Tax expression, and/or the production of TNF-alpha in target spinal cord and peripheral nerves are causally related to apoptotic death of the oligodendrocytes and Schwann cells, a major pathogenetic pathway of HTLV-I induced myeloneuropathy in the WKAH rat.

Animals↗

PubMed1997

HTLV-I env-pX transgenic rats: prototype animal model for collagen vascular diseases.

To evaluate the function of HTLV-I env-pX gene in vivo, we developed two lines of transgenic rats (env-pX rats) that expressed env-pX gene products, under control of own LTR promotor. In various tissues of the rats, env and pX mRNAs were constitutively expressed, irrespective of age. At age 5 weeks, swelling of the bilateral ankle joints histologically showing synovial lining hyperplasia, severe chronic inflammation, erosion of the joint cartilage, and bone destruction with pannus formation began to develop in these env-pX rats. These histologic features resemble those of rheumatoid arthritis (RA) in man. High titered rheumatoid factors and low anti-dsDNA antibodies and hyper-gamma globulinemia were detected. Necrotizing arteritis resembling polyarteritis nodosa, polymyositis, myocarditis and Sjögren syndrome-like sialoadenitis developed, together with RA-like arthritis even in one individual animal. Thymic atrophy with low body weight was also observed. The evidence indicates that env-pX rats appear to be suitable animal models for elucidating pathogenetic mechanisms involved in not only HTLV-I related diseases but also various collegen vascular and autoimmune diseases of unknown etiology in man.

Aging↗

PubMed1996

Phenotypes correlating to metastatic properties of pancreas adenocarcinoma in vivo: the importance of surface sialyl Lewis(a) antigen.

Metastasis to the liver often occurs in patients during the natural course of pancreatic cancer. Using carcinoma cell lines established from 9 such patients, we examined phenotypes of cell lines to search for correlations with their potential to metastasize to the liver. Anti-asialo GMI-treated nude mice were used. PCI-43, -55, -24 and -6, in this order, had frequent metastases, while PCI-10, -19, -35, -64, and -66 did not. In vitro doubling time, surface expression of sialyl Lewis(a) (SLe(a)), VLA-4/6, LFA-I/3, CEA, E-selectin, VCAM-I, NCAM, Mac-I, HLA-ABC/ DR/DQ, ICAM-I/2, production of interleukin-I alpha, tumor necrosis factor-alpha, and matrix metalloproteinase, as well as susceptibility to cytotoxicity by natural killer cells, were all examined. Expression of surface SLea was significantly associated with metastasis; numbers of metastatic colonies of SLe(a)-positive and -negative cell lines were 21.6 +/- 33.9 and 6.5 +/- 14.3 (p < 0.01), respectively. Moreover, the intensity of surface SLe(a) expression of each PCI line correlated with the number of metastatic colonies in the liver. When anti-SLe(a) monoclonal antibody (MAb) was administered, the development of liver metastasis by PCI-43 cells was significantly repressed, as compared with a control MAb. Although a reverse correlation between surface ICAM-I expression and liver metastasis was noted, the species-restricted function of ICAM-I makes interpretation difficult. Collective evidence indicates that expression of SLe(a) is an important positive mediator in the hematogenous metastasis of pancreas carcinoma.

Adenocarcinoma↗

PubMed1996

Suppression of pancreatic cancer by the dominant negative ras mutant, N116Y.

N116Y, H-ras mutant, possesses dominant negative activity to Ras function. The aim of this study is to assess whether N116Y can inhibit the proliferation of pancreatic cancer cell lines carrying K-ras mutations and cause reversion of the malignant phenotype. We transfected an expression vector of N116Y, pZIP-N116Y, into eight human pancreatic cancer cell lines with K-ras mutations (PCI 10, 19, 24, 35, 43, 55, 64, and 66) by using a lipofection procedure. The growth inhibition activity of N116Y was evaluated by the colony-forming efficiency in selection medium. In order to examine the effect of N116Y on the neoplastic phenotype, we established N116Y-expressing clones and analyzed their growth ability in soft agar and tumorigenicity in nude mice. The growth of the eight pancreatic cancer cell lines was strongly inhibited by the transfection of pZIP-N116Y. Moreover, the N116Y-expressing clones became less spread and lost their anchorage-independent growth ability. Furthermore, they were nontumorigenic in vivo. N116Y significantly inhibits the growth of pancreatic cancer cell lines and causes reversion of the malignant phenotypes. These results suggest that N116Y may be a candidate gene for use in the gene therapy of pancreatic cancer.

Animals↗

PubMed1996

Interleukin (IL)-6 as a pancreas carcinoma-derived vascular permeability regulator in vitro.

The interaction between pancreas adenocarcinoma and vascular endothelial cells in vitro was investigated. Culture media of pancreas carcinoma cells PCI-10, but not PCI-24, induced an augmented albumin permeability across the endothelial monolayer, an event which was blocked by the calmodulin antagonist, W-7. Only marginal inhibitory effects were obtained using protein kinase inhibitors, H-7 and HA-1004. When cytokine production by pancreas carcinoma cells was examined, production of IL-6 in large amounts by PCI-10, but not by PCI-24 cells was evident. As recombinant IL-6 generated a dose-dependent permeability increase, and as this effect was inhibited by W-7, we considered that the enhancement of vascular permeability was mediated by this cytokine. The activity of culture supernatants for enhanced permeability was almost completely absorbed by the addition of an antibody specific for IL-6. Tumor-derived IL-6 as a soluble mediator regulates vascular permeability in vitro, and the production of this factor by pancreas adenocarcinoma cells presumably modulates biologic behavior.

Adenocarcinoma↗

PubMed1996

Human T lymphocyte virus type I-induced myeloneuropathy in rats: implication of local activation of the pX and tumor necrosis factor-alpha genes in pathogenesis.

The pathogenetic roles of human T lymphocyte virus type I (HTLV-I) and cytokines were investigated in HTLV-I-induced myeloneuropathy in Wistar-King-Aptekman-Hokudai rats. In the nervous system, pX messenger RNAs of HTLV-I were selectively expressed in the diseased spinal cord and peripheral nerves but not in the unaffected cerebrum and cerebellum, even though proviral DNAs were consistently identified in these tissues. Among several cytokines examined, mRNA expression and production of tumor necrosis factor (TNF)-alpha in the spinal cord and cerebrospinal fluid correlated positively with the development of spinal cord lesions. The collective evidence strongly suggests that selective activation of HTLV-I, in particular Tax expression and production of TNF-alpha induced by HTLV-I infection in target spinal cord and peripheral nerves, is causally related to apoptotic death of oligodendrocytes and Schwann cells, a major pathogenetic pathway of the HTLV-I-induced myeloneuropathy.

Animals↗

PubMed1996

Effects of monoclonal anticardiolipin antibody on pregnant mice.

OBJECTIVE: To clarify the effects of anticardiolipin antibodies (aCL) on pregnancy. METHODS: Monoclonal aCL obtained from MRL/lpr mice was administered to pregnant BALB/c mice and changes in the outcome of pregnancy were evaluated. RESULTS: The pregnant BALB/c mice injected with monoclonal aCL showed a higher intrauterine fetal death rate than controls, but there were no significant differences in platelet counts. We observed signs of placental infarction only in the placenta of the treated pregnant BALB/c mice. CONCLUSION: The intrauterine fetal deaths may have been due to thrombosis.

Animals↗

PubMed1995

Cytokine-producing mammary carcinomas in transgenic rats carrying the pX gene of human T-lymphotropic virus type I.

In two lines of transgenic rats (pX rats) from WKAH and F344 strains and carrying the human T-lymphotropic virus type I pX gene, undifferentiated mammary carcinomas developed predominantly in females starting at about 5 months of age, and there was massive infiltration of granulocytes in the tumor tissue. The incidence of the tumor reached about 40% when the rats were 12 months old. mRNAs of both pX and host genes Gro and MIP-2, which are granulocyte chemoattractants of the interleukin 8 family, were highly expressed in the tumor tissue. Since expression and point mutation of several oncogenes and the antioncogene were not demonstrated, hitherto unidentified novel oncogenic pathways may be transactivated by the pX transgene in these pX rats.

Animals↗

PubMed1995

E-selectin expression induced by pancreas-carcinoma-derived interleukin-1 alpha results in enhanced adhesion of pancreas-carcinoma cells to endothelial cells.

Cellular adhesion of sialyl-Lewis-a(SLea)-positive pancreas carcinoma to endothelial cells (EC) is augmented by activation of EC via up-regulated E-selectin expression on EC. Co-cultivation of pancreas-carcinoma cells, PCI-24, with human umbilical-vein endothelial cells (HUVEC) for 5 hr at the PCI-to-HUVEC ratio of 1:10 induced E-selectin expression on the endothelial-cell surface, augmenting SLea-positive pancreas-carcinoma cell attachment with HUVEC. Culture supernatants of 6 tested pancreas-carcinoma cell lines contained soluble, E-selectin-inducing factor(s). The E-selectin-inducing effect by the supernatants was blocked by the protein-kinase-C inhibitor, H7. Antibodies against SLea and E-selectin but not SLex or ICAM-1 blocked the increased pancreas-carcinoma-to-endothelial attachment. Paraformaldehyde(PFA)-fixed PCI-24 cells also induced E-selectin on vascular endothelial cells upon direct contact with endothelial cells, indicating the presence of a membrane-bound form. The 6 pancreas-carcinoma lines all produced IL-1 alpha mRNA and protein but not IL-1 beta or TNF-alpha protein and/or mRNA. Absorption of IL-1 alpha from the supernatants by IL-1 alpha-specific antibody almost completely abolished E-selectin-inducing activity. Anti-IL-1 alpha antibody also abolished the E-selectin-inducing activity of PFA-fixed PCI. IL-1 alpha production by PCI cells was up-regulated by TNF-alpha. These observations suggest that substance(s) produced by pancreas-carcinoma cells, in this case, IL-1 alpha, may contribute to pancreas-carcinoma-cell colonization in non-inflamed, distant locations in vivo, by activating vascular endothelial cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1995

Three cases of idiopathic interstitial pneumonia with bullae seen in schoolteachers.

We encountered three patients with chronic interstitial pneumonia with many bullae in the lower lung fields whose lifetime occupation was teaching school. Pathological examination of autopsy lungs of these patients revealed interstitial pneumonia and multiple bullae throughout the lungs, including the lower lobe. Since blackboard chalk has been used as a popular writing material among teachers in Japan, the mineral contents in the lungs of two of the three cases and four control cases with idiopathic interstitial pneumonia (IIP) (whose occupations were not teaching) were analyzed. The amount of deposition of total dust, inorganic dust, non-SiO2 inorganic dust, and calcium was significantly higher in the lungs of two schoolteachers compared with those of the control lungs. The amount of free silica in case 1 and alpha-quartz in case 3 were also significantly higher than in the controls. Two thirds of the chalk produced in Japan is still made from gypsum and involves small amounts of silica and other minerals, in addition to calcium. These findings indicated the deposition of chalk in the lungs of these patients with interstitial pneumonia and multiple bullae.

Blister↗

PubMed1995

Demonstration of fibroblast growth factor receptor-I in human prostate by polymerase chain reaction and immunohistochemistry.

The expression and localization of fibroblast growth factor receptor-1 were investigated in human prostatic tissues with or without benign hyperplasia. Using a polymerase chain reaction method, we were able to demonstrate that prostatic tissues with benign hyperplasia expressed a significantly higher level of fibroblast growth factor receptor-1 mRNA than normal prostatic tissues (P < 0.01 by Anova). Western blot analysis using an antiserum against the receptor gave 2 bands with molecular weights of about 140 kDa and 80 kDa; these correspond to the expected sizes of the long and secreted forms of the fibroblast growth factor receptor-1, respectively. An immunohistochemical study using the same antiserum further demonstrated that the immunoreactive staining occurred mainly in the basal cells of the glandular epithelium and occasionally in the stromal cells. These results suggest that fibroblast growth factors may influence, at least in part, the proliferation of the epithelial cells seen in benign hyperplasia of human prostate.

Adult↗

PubMed1995

A rat model of HTLV-I infection: development of chronic progressive myeloneuropathy in seropositive WKAH rats and related apoptosis.

In seropositive HTLV-I carrier rats of the WKAH strain inoculated with 2 x 10(7) MT-2 cells at 3-6 months of age, chronic progressive myeloneuropathy, tentatively designated as HTLV-I-associated myelopathy (HAM) rat disease, occurred when the rats were 19-23 months old. Clinical and pathological findings were basically identical to those of seronegative HAM rats of the same strain neonatally inoculated with MT-2 cells. It appears that a high dose of MT-2 cells (10(8) cells) is more effective for the induction and acceleration of HAM rat disease. Seronegative and seropositive carriers of other strains (F344, ACI, and LEW), WKAH rats inoculated with HUT-78 (a human T cell line without HTLV-I infection), and untreated WKAH rats at comparable ages did not develop HAM rat disease, thereby indicating that development of this disease is caused by HTLV-I infection and is under strict genetic restriction of the host strain. Chronological examination of HAM rat disease induced by 10(7) MT-2 inoculation into newborn rats showed that the spinal cord lesion began to develop by 12 months of age. T cells were absent in the affected spinal cord throughout the disease process. There was morphological evidence of apoptotic death of oligodendrocytes in the affected spinal cord. Apoptosis was also confirmed by the specific nick end labeling of the nuclear fragmentation in situ, and the apoptotic oligodendrocytes confined to the demyelinating foci, and the number of apoptotic cells positively correlated with severity of the spinal cord lesion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗