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Biomedical subjects

I Miyoshi

Publications and source records attributed to I Miyoshi.

At least 19 recordsLinked to original sources
PubMed2006

Bridging necrosis and reticulin bridging fibrosis induced by intrahepatic involvement of acute biphenotypic leukemia.

A 47-year-old Japanese woman was diagnosed as having acute biphenotypic leukemia with association of t(9;22)(q34;q11). Cholestatic liver dysfunction arose, and she died of cachexia and intracranial hemorrhage. Autopsy showed unusual hepatic fibrosis. In the liver, bridging infiltration, bridging necrosis and bridging fibrosis by leukemic cells were seen. It seemed that the degree of fibrosis was associated with the number of aggregates of infiltrating leukemic cells. The fibrotic foci were predominantly composed of reticulin and collagen fibers, and distortion of the lobules was observed. Immunohistochemically, dense bundles of alpha-smooth muscle actin (ASMA)-positive stromal cells, namely activated hepatic stellate cells (HSCs), were observed in the immature fibrotic foci as well as along the sinusoids densely infiltrated by leukemic cells. No cells positive for TGF-beta1 or PDGF-BB were identified. In conclusion, extensive intrahepatic involvement by neoplastic cells in adult acute biphenotypic leukemia may cause the unusual "disorganized" hepatic fibrosis.

Becaplermin↗
PubMed2001

Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: associated mutations develop motor neuron disease.

Some cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding cytosolic, copper-zinc superoxide dismutase (SOD1). We report here that rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. As in the human disease and transgenic ALS mice, pathological analysis demonstrates selective loss of motor neurons in the spinal cords of these transgenic rats. In spinal cord tissues, this is accompanied by activation of apoptotic genes known to be activated by mutant SOD1 protein in vitro and in vivo. These animals provide additional support for the proposition that motor neuron death in SOD1-related ALS reflects one or more acquired, neurotoxic properties of the mutant SOD1 protein. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies).

Amino Acid Substitution↗
PubMed2001

Intranuclear localization of the transcription coadaptor CBP/p300 and the transcription factor RBP-Jk in relation to EBNA-2 and -5 in B lymphocytes.

We have studied the expression and the localization of the cellular proteins CBP/p300 and RBP-Jk in in vitro EBV-infected human B lymphocytes in relation to the EBNA-2 and EBNA-5 proteins. We found that the level of CBP/p300 was elevated drastically by EBV infection and also after activation by CD40 ligation. Thus the increase in CBP/p300 expression in the EBV-infected cells is related to the virus-induced activation and proliferation of the cells. EBNA-2 and RBP-Jk colocalized in the nucleoplasm, which is in accordance with their functional interaction. We confirmed earlier reports about the presence and colocalization of EBNA-5 and CBP in the nuclear POD bodies. On the other hand, neither EBNA-2 nor p300 was detected in the PODs. The expression of these two proteins overlapped in some distinct dots of the nucleoplasm. Taken together, the different patterns of CBP and p300 expression and their different localization in relation to the PML bodies and two EBV-encoded proteins in the B cells may provide some clue to their distinct functional roles.

B-Lymphocytes↗
PubMed2001

Green fluorescent protein-transgenic rat: a tool for organ transplantation research.

The purpose of this study is to evaluate green fluorescent protein (GFP) transgenic rats for use as a tool for organ transplantation research. The GFP gene construct was designed to express ubiquitously. By flow cytometry, the cells obtained from the bone marrow, spleen, and peripheral blood of the GFP transgenic rats consisted of 77, 91, and 75% GFP-positive cells, respectively. To examine cell migration of GFP-positive cells after organ transplantation, pancreas graft with or without spleen transplantation, heart graft with or without lung transplantation, auxiliary liver and small bowel transplantation were also performed from GFP transgenic rat to LEW (RT1(1)) rats under a 2-week course of 0.64 mg/kg tacrolimus administration. GFP-positive donor cells were detected in the fully allogenic LEW rats after organ transplantation. These results showed that GFP transgenic rat is a useful tool for organ transplantation research such as cell migration study after organ transplantation without donor cell staining.

Animals↗
PubMed2001

Distribution of various calcium channel alpha(1) subunits in murine DRG neurons and antinociceptive effect of omega-conotoxin SVIB in mice.

Immunohistological study revealed the differential localization of subtypes of voltage-dependent calcium channels in the dorsal root ganglion neurons. Intrathecal injection of omega-conotoxin SVIB, an analogue of omega-conotoxin GVIA, which acts on N-type voltage-dependent calcium channels, significantly shortened the licking time in the late phase of a formalin test.

Animals↗
PubMed2001

Detection of human herpesvirus 6 and JC virus in progressive multifocal leukoencephalopathy complicating follicular lymphoma.

Progressive multifocal leukoencephalopathy (PML), a demyelinating infectious disease caused by JC virus (JCV), occurs almost exclusively in immunocompromised patients usually with malignant diseases. We report here a Japanese female with follicular lymphoma who subsequently developed PML. In addition to JCV, human herpesvirus 6 (HHV-6) was detected in the affected brain lesions of the patient by polymerase chain reaction and by in situ hybridization. HHV-6, recognized as a neurotropic virus, is known to be reactivated during immunosuppression and can cause fatal complications such as encephalitis/encephalopathy. It is likely that impaired immunity associated with lymphoma and the additional immunosuppression following cytopenia-inducing chemotherapies predisposed the patient to reactivated HHV-6 infection. Although it remains to be clarified whether HHV-6 plays an important role as a co-agent with JCV in causing demyelination of the brain, our observation alerts physicians to the possible association of HHV-6 with the pathogenesis of PML.

Adult↗
PubMed2001

Characterization of 5-HT2A receptor desensitization and the effect of cycloheximide on it in C6 cells.

Effect of prolonged pretreatment with serotonin (5-HT) on 5-HT2A receptor desensitization was examined by the measurement of intracellular calcium ([Ca2+]i) mobilization in C6 cells. 5-HT-induced desensitization of [Ca2+]i mobilization was in a time and dose dependent manner and reached a plateau after 3 hr. After 1 and 3 hr 5-HT pretreatment, 5-HT concentration in the medium little changed. 5-HT pretreatment with cycloheximide, a protein synthesis inhibitor, produced an enhancement of the desensitization for 3 and 6 hr pretreatment. However, 5-HT pretreatment for 3 and 6 hr caused no marked change in the 5-HT2A receptor mRNA level or Galphaq/11 protein in this study, suggesting that 5-HT may decrease 5-HT-induced [Ca2+]i mobilization independent of 5-HT2A receptor mRNA or G-proteins. Endothelin-1-induced [Ca2+]i mobilization did not alter after 5-HT and/or cycloheximide pretreatment. These results showed that activation of the 5-HT2A receptor induced homologous desensitization and pretreatment with 5-HT and/or cycloheximide did not change the efficacy of the second messenger pathway from Gq to a [Ca2+]i rise.

Animals↗
PubMed2001

BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19).

Translocation t(15;19)(q13;p13.1) defines a lethal midline carcinoma arising adjacent to respiratory tract in young people. To characterize molecular alterations responsible for the distinctly aggressive biological behavior of this cancer, we mapped the chromosome 15 and 19 translocation breakpoints by fluorescence in situ hybridization (FISH) and Southern blotting. To evaluate preliminarily the frequency, anatomical distribution, and histological features of t(15;19) cancer, we developed a FISH assay for paraffin sections. Our findings reveal a novel oncogenic mechanism in which the chromosome 19 translocation breakpoint interrupts the coding sequence of a bromodomain gene, BRD4. These studies implicate BRD4 as a potential partner in a t(15;19)-associated fusion oncogene. In addition, we localized the chromosome 15 breakpoint to a 9-kb region in each of two cases, thereby identifying several candidate oncogenes which might represent the BRD4 fusion partner. FISH evaluation of 13 pediatric carcinomas revealed t(15;19) in one of four sinonasal carcinomas, whereas this translocation was not detected in thymic (n = 3), mucoepidermoid (n = 3), laryngeal (n = 2), or nasopharyngeal (n = 1) carcinomas. Our studies shed light on the oncogenic mechanism underlying t(15;19) and provide further evidence that this highly lethal cancer arises from respiratory mucosa.

Adolescent↗
PubMed2001

Targeting oncogenesis by introduction of a 5.2-kbp segment of the 5' regulatory region of the human thyrotropin beta-subunit gene.

We produced transgenic mice carrying a fusion gene (TTP-5) consisting of a 5.2-kbp segment of the 5' flanking sequence of the human thyrotropin beta-subunit (TSH beta) gene linked to the simian virus 40 large T antigen (SVT) gene. These mice developed pituitary tumors 6 months after birth and wasted away. With the 5.2-kbp TSH beta 5' flanking region governing SVT expression, SVT mRNA was present in the pituitary and testis but not in other tissues, as detected by the reverse transcriptase-polymerase chain reaction. Histological and immunohistochemical analyses showed that the pituitary tumors of the transgenic mice were composed of moderately differentiated pituitary cells that expressed TSH, growth hormone, and prolactin. These results indicate that the 5.2-kbp segment of the human TSH beta 5' regulatory region is sufficient to drive expression of SVT and induce tumorigenesis of hormone-producing pituitary cells in transgenic mice.

Animals↗
PubMed2001

Suppression of thymic development by the dominant-negative form of Gads.

Gads, a hematopoietic-lineage-specific Grb2 family member, is involved in the signaling mediated by the TCR through its interactions with SLP-76 and LAT. Here, we generated transgenic mice expressing Grf40-dSH2, an SH2-deleted dominant-negative form of Gads, which is driven by the lck proximal promoter. The total number of thymocytes was profoundly reduced in the transgenic mice, whereas in the double-negative (CD4(-)CD8(-)) thymocyte subset, in particular the CD25(+)CD44(-) pre-T cell population, it was significantly increased. However, CD5 expression, which is mediated by pre-TCR stimulation, was significantly suppressed on the CD4(-)CD8(-) thymocytes of the transgenic mice. Furthermore, the SLP-76-dependent signaling was markedly suppressed as well. These data suggest that Gads plays an important role in the pre-TCR as well as TCR signaling in thymocytes.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Morphologic and molecular analysis of estrogen-induced pituitary tumorigenesis in targeted disruption of transforming growth factor-beta receptor type II and/or p27 mice.

The critical genes and products involved in estrogen-induced tumorigenesis of the pituitary gland were investigated in heterozygous transforming growth factor-beta (TGF-beta) receptor type II and p27 knockout mouse models. Tgfbr2(+/-), p27(+/-); Tgfbr2(+/-), and p27(+/-) mice and C57BL/6J wild-type mice received sc implantation of estrogen or placebo pellets for 16 or 25 wk, after which the mice were sacrificed and their pituitary glands removed for examination. The bromodeoxyuridine labeling indexes in tissue from both the anterior and intermediate pituitary lobes from p27 (+/-) and Tgfbr2(+/-); p27(+/-) mice were significantly higher than those from wild-type and Tgfbr2(+/-) mice after treatment with estrogen for 16 wk. Pituitary tumorigenesis was significantly accelerated in Tgfbr2(+/-), p27(+/-), and Tgfbr2(+/-); p27(+/-) mice compared with wild-type mice after treatment with estrogen for 16 wk. Pituitary tumorigenesis was not accelerated in Tgfbr2(+/-); p27(+/-) mice compared with Tgfbr2(+/-) or p27(+/-) mice. Expression of TGF-beta receptor type II mRNA was lower in the pituitary gland of Tgfbr2(+/-) mice than in wild-type mice before estrogen treatment and was significantly reduced after treatment. Pituitary tumorigenesis is accelerated in mice with severe TGF-beta resistance, and greatly accelerated in mice with TGF-beta resistance combined with decreased p27 expression compared with wild-type mice. Both the TGF-beta receptor type II gene and p27 gene and their products are involved in estrogen-induced tumorigenesis.

Animals↗
PubMed2001

Rescue of a transgenic mouse line by transplantation of a frozen-thawed ovary obtained postmortem.

During the course of breeding valuable mutant or transgenic mice, deaths sometimes occur due to sudden-onset disease or accident. We previously showed that mice can be rescued by transplantation of ovaries taken up to 2 h after death from dead mice remaining at conditions of constant temperature (22 +/- 2 degrees C) and humidity (55% +/- 5%). To extend the flexibility of transplantation, we assessed whether it is possible to cryopreserve ovaries taken from dead mice within 2 h after death. Fertile transgenic mice used as donors were euthanized by cervical dislocation and left for 2 h after death. The cryopreservation was based on Sztein's method with a controlled-rate freezer or on Rall and Fahy's method without a controlled-rate freezer. The recipient mice were nontransgenic littermates of the donor mice, and after transplantation of the frozen-thawed ovaries, they were mated with proven-fertile males. Polymerase chain reaction (PCR) analysis confirmed that the progeny carried the transgene. We show here that by using both of the described methods, it is possible to cryopreserve the ovaries taken from dead mice within 2 h after death and that the mice into which the cryopreserved ovaries are transplanted are fertile.

Animals↗
PubMed2000

Constitutional t(3;11)(p21;q23) in a family, including one member with lymphoma: establishment of novel cell lines with this translocation.

We describe a family with an inherited constitutional chromosome translocation (3;11) (p21;q23). Of three proven translocation carriers, one had duodenal malignant lymphoma (B-cell diffuse lymphoma, medium-sized cell type). The t(3;11)(p21;q23) was detected not only in hematopoietic cells including the patient's lymphoma cells, non-pathological bone marrow, and phytohemagglutinin-stimulated peripheral blood, but also in fibroblasts of the skin. We have successfully established an Epstein-Barr virus-transformed B-cell line and a Herpesvirus saimiri-transformed T-cell line from the patient, and found that both cell lines also carried this translocation. The patient's asymptomatic mother and sister had the same chromosomal abnormality. Chromosomal abnormalities of the 11q23 band occur frequently in various hematopoietic malignant disorders, and 3q21 has been linked to the pathogenesis of several solid tumors including carcinomas of the kidney, lung, and breast. Although 11q23 is known to recombine with many different chromosomal segments, t(3;11)(p21;q23) has not been reported to our knowledge. Further assessment is warranted to clarify if this constitutional translocation predisposes to certain malignancies. Our cell lines carrying the novel chromosome translocation would be useful for the molecular analysis of the rearranged genes involving both 3p21 and 11q23.

Adult↗