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Biomedical subjects

Yoshiro Niitsu

Publications and source records attributed to Yoshiro Niitsu.

At least 73 records · Page 4Linked to original sources
PubMed2004

[Successful treatment with antiviral agents for human herpesvirus type 6 encephalitis following reduced intensity stem cell transplantation in a patient with myelodysplastic syndrome].

We report here a patient who suffered from PCR-confirmed human herpesvirus type 6 (HHV-6) encephalitis following reduced intensity stem cell transplantation (RIST) from her HLA-matched sibling donor. A 66-year-old woman with MDS-RA underwent RIST from her HLA-matched brother. Engraftment was favorable and grade 2 GVHD (skin and intestine) was observed with good response to 60 mg of prednisolone. On day 162, she developed fever, headache, diplopia, disorientation and abnormal neurological findings including cervical stiffness and nystagmus. An analysis of cerebrospinal fluid (CSF) revealed 80 cells/microl, a glucose level of 50 mg/dl and a protein level of 97 mg/dl on day 162. Although computed tomography (CT) of the brain and electroencephalography (EEG) were nonspecific, HHV-6 was detected in the CSF using polymerase chain reaction (PCR) techniques and the patient was diagnosed as having encephalitis due to local reactivation of HHV-6. Administration of ganciclovir (GCV) and acyclovir (ACV) were started from day 162. Treatment with antiviral agents was effective, with total resolution of her symptoms and the DNA of this virus disappeared from the CSF after 23 days of treatment. This case shows that HHV-6 infection has to be considered in patients with neurological symptoms following stem cell transplantation, and suggests the necessity of PCR for HHV-6 virus from the CSF.

Acyclovir↗
PubMed2004

[Tumor suppressor gene p53 and molecular targeting therapy].

p53 is a molecule which is activated upon a DNA stress, such as gamma irradiation, UV, hypoxia, virus infection, and DNA damage, leading protection of cells by inducing target genes. The molecules activated by p53 induce apoptosis, cell cycle arrest, and DNA repair to conserve genome. In order to kill cancer cells, many strategies targeting p53 have been reported. Preclinical studies have demonstrated that overexpression of wt-p53 by adenovirus vector is capable of inducing apoptosis in cancers. Furthermore, restoration of mt-p53 into wild type by compound has been under development. In this review, clinical application of molecular targeting therapy for p53 is discussed.

Apoptosis↗
PubMed2004

[A case of metastatic liver tumor from colorectal carcinoma--continued arterial infusion chemotherapy through a microcatheter located in replaced right hepatic artery].

The patient was a 78-year-old male with a history of colon cancer. After surgical resection of colon cancer, he suffered a multiple liver metastasis. We treated him by arterial infusion chemotherapy with the catheter edge embedded at the common hepatic artery. For a long period, the lesions were defined as partial response on WHO-criteria, but a wide area of the common hepatic artery was shrunk. After changing the treatment to systemic intravenous chemotherapy, the metastatic lesions began to enlarge. Then, we somehow were able to put a microcatheter into the replaced right hepatic artery (rRHA), and could restart arterial infusion chemotherapy. We continued this procedure for over a year without any complication.

Adenocarcinoma↗
PubMed2004

[Inhibition of relapse in leukemia by using molecular targeting therapy].

Leukemias are generally chemosensitive, and a majority of leukemia patients undergo remission. However, since chemotherapy after remission generally causes gross systemic toxicity, patients cannot be administered enough anti-cancer drugs to be completely cured; thus, the rate of long-term disease-free survival remains low. Improved survival requires new strategies to prevent relapse. Molecular targeting therapies are remarkably specific and have been demonstrated to cause no gross systemic toxicity. Molecular targeting drugs for leukemia such as all-trans retinoic acid and imatinib are presently being used in clinical settings, and many other molecular targeting drugs are being evaluated in phase I/II clinical trials. This review presents an overview of some of these drugs.

Benzamides↗
PubMed2004

[Second hematologic response and disappearance of the ABL gene mutant clone by cessation of imatinib in a CML patient with resistance to imatinib].

A seventy-six year old female patient with chronic myelogenous leukemia (CML), (chronic phase), was treated with imatinib and obtained a major cytogenetic response after 6 months of treatment. However, resistance to imatinib appeared 9 months later due to an ABL gene point mutation, and the patient's platelet count and BCR/ABL positive rate had remarkably increased. We discontinued imatinib and used IFNalpha or hydroxyurea, resulting in the disappearance of the ABL gene mutation clone. After that, we obtained a secondary hematologic response with the administration of imatinib.

Aged↗
PubMed2003

Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors.

Two controversial issues regarding p53 are whether it is involved in apoptosis induction of tumor cells by a histone deacetylase (HDAC) inhibitor and, given that p53 is indeed involved, which genes of acetylated p53 targets are responsible for giving rise to apoptotic death. We, in the present study, first confirmed that some substantial extent of apoptotic cell death was seen when p53-deficient cells (KATO-III) were transfected with wild-type p53 and treated with sodium butyrate (SB) or trichostatin A. By Western blotting, using specific antibodies, we then demonstrated that residues 320, 373, and 382 lysines of p53 were acetylated in KATO-III cells transfected with wild-type p53 (KATO-III/p53) treated with a HDAC inhibitor. However, as revealed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining, only those KATO-III cells transfected with K320R p53 or K373R p53 became insensitive to the HDAC inhibitor, suggesting that these two residues of p53 may be essential for HDAC inhibitor-induced apoptosis, whereas others such as K382R p53 may not. Furthermore, reverse transcription-PCR demonstrated that among various p53-related proapoptotic genes, expression of PIG3 and NOXA were clearly enhanced by SB treatment in KATO-III/p53 cells but not in KATO-III/K320R or KATO-III/K373R cells. Finally, we revealed that apoptosis could be evoked by SB even in cells where p53 mutations occur at residues other than 320 lysine or 373 lysine (TMK-1 and HSC-39 cells) and that this apoptosis was significantly, although not totally, suppressed by the anti-p53 antisense. It was, therefore, concluded that acetylation of the p53 molecule at residues 320 and 373, giving rise to up-regulation of PIG3 and NOXA, is one of the mechanisms for induction of apoptosis by HDAC inhibitors in cancer cells.

Acetylation↗
PubMed2003

Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity.

PURPOSE: Neovascularization is known to be one of the major characteristics of human hepatocellular carcinoma (HCC). Angiogenin (ANG), originally discovered in a human colon cancer cell line, is a liver-derived polypeptide that shows strong angiogenic activity in vivo. However, the role of ANG on the development of HCC remains unknown. The present study was designed to examine the implication of ANG in the neovascularization of human HCC. EXPERIMENTAL DESIGN: Forty-one HCC patients who had undergone conventional celiac angiography were used in this study. ANG protein expression and microvessel density (MVD) in HCC specimens obtained by liver biopsy or surgical resection were examined by immunohistochemistry, and the levels were quantified by the KS-400 image analyzing system. ANG mRNA expression in liver tissues was evaluated by in situ hybridization. Serum ANG concentrations were measured by an ELISA. Survival rates were calculated using the Kaplan-Meier method. RESULTS: Immunohistochemistry and in situ hybridization showed greater increments of ANG protein expression and mRNA expression, respectively, in HCC tissues than in the surrounding nontumorous tissues. MVD within tumorous tissues increased according to dedifferentiation of the histological grade of HCC, showing a significant correlation (r = 0.877, P = 0.0009) with ANG expression levels. Mean +/- SD serum ANG levels of healthy subjects and chronic hepatitis (CH) patients were 362.3 +/- 84.1 ng/ml and 331.9 +/- 133.8 ng/ml, respectively, with no significant difference. Serum ANG levels of liver cirrhosis patients (242.4 +/- 126.9 ng/ml) were lower than those of healthy subjects or CH patients and decreased as the fibrosis grade advanced. In HCC patients, despite the cirrhotic background, serum ANG levels increased as the tumor vascularity increased (197.8 +/- 64.9 ng/ml for hypovascular, 326.7 +/- 148.6 ng/ml for hypervascular, and 405.0 +/- 121.3 ng/ml for very hypervascular), in good accordance with histological grading, and significantly decreased (P = 0.015) after successful treatment with transcatheter arterial embolization or percutaneous ethanol injection. HCC patients were conventionally divided into two groups according to the serum level of ANG, those with values higher than the mean level (332.9 +/- 143.8 ng/ml) and those with values lower than the mean,; the 5-year survival rate of the latter group was determined to be significantly higher than that in the former group. CONCLUSIONS: These results suggest that ANG is one of the neovascularization defining factors of HCC. Thus, measuring serum ANG may assist in monitoring the disease, and targeting ANG may provide a new strategy for treating advanced HCC.

Adult↗
PubMed2003

Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia.

Bone-marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML). We postulate that the drug resistance is induced by the attachment of very late antigen (VLA)-4 on leukemic cells to fibronectin on bone-marrow stromal cells. We found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA-4 and fibronectin. This resistance was negated by VLA-4-specific antibodies. In a mouse model of MRD, we achieved a 100% survival rate by combining VLA-4-specific antibodies and cytosine arabinoside (AraC), whereas AraC alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA-4-negative patients and 44.4% for 15 VLA-4-positive patients. Thus, the interaction between VLA-4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow MRD and AML prognosis.

Animals↗
PubMed2003

Reversal of multiple drug resistance in cholangiocarcinoma by the glutathione S-transferase-pi-specific inhibitor O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-D-phenylglycine ethylester.

Cholangiocarcinoma is markedly resistant to chemotherapy and has a dismal prognosis, but its mechanism of drug resistance is unknown. This study examines whether glutathione S-transferase-pi (GSTP1-1) is involved in resistance to anticancer drugs in cholangiocarcinoma and whether GSTP1-1-specific inhibitors can overcome this resistance. First, immunohistochemical examination disclosed strong staining of all our 17 cholangiocarcinoma specimens for GSTP1-1, irrespective of histological type. Transfection of the GSTP1-1 antisense expression vector into a human cholangiocarcinoma cell line (HuCCT1) apparently decreased its intracellular GSTP1-1 concentration, and the sensitivity of transfectants to adriamycin (ADR), cisplatin, and alkylating agents such as melphalan and 4-hydroxyperoxycyclophosphamide (4-HC) was increased significantly, compared with that of mock transfectants. We next synthesized GSTP1-1-specific inhibitors by elongating the carbon chain of the ethylester at the N-terminal of gamma-glutamyl-S-benzylcysteinyl-phenylglycyl diethylester and performed a pharmacokinetic study on them. Of six GSTP1-1 inhibitors tested, O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-d-phenylglycine ethylester (C16C2) showed the smallest volume of central compartment and smallest volume of distribution at steady state and the second smallest clearance, being the most effective inhibitor in vivo. The IC50 value of ADR or 4-HC for HuCCT1 cells decreased greater by treatment with C16C2 in a dose-dependent manner, paralleling the decrease in GSTP1-1 activity, than that of ADR or 4-HC alone. The antitumor activity of ADR or cyclophosphamide was clearly enhanced by combination therapy with C16C2 in a xenograft model. In conclusion, our results demonstrated that GSTP1-1 is a resistance factor for anticancer drugs in cholangiocarcinoma and that C16C2, a GSTP1-1-specific inhibitor, is a potent agent against the resistance.

Animals↗
PubMed2003

Changes in N-glycosylation of human stromal cells by telomerase expression.

It was established that remarkable changes in the N-glycosylation are induced in immortalized cancer cells. Whether changes were induced in human stromal cells immortalized by transfection with the human telomerase catalytic subunit (hTert) cDNA was examined by lectin blot analysis. Morphological appearance and growth rate of the gene-transfected stromal cells were not changed significantly. However, lectin blot analysis of membrane glycoprotein samples showed that bindings of Ricinus communis agglutinin-I (RCA-I) and of leuko-agglutinating phytohemagglutinin to glycoprotein bands increase significantly in the gene-transfected cells. No lectin binding was observed when blotted filters were treated with diplococcal beta-1,4-galactosidase or N-glycanase prior to incubation with RCA-I. In contrast, no changes in Coomassie brilliant blue-staining and in binding of concanavalin A were obtained between the primary and gene-transfected stromal cells. These results indicate that the highly branched N-glycosylation with augmented galactosylation is induced in human stromal cells immortalized by the telomerase expression.

Bone Marrow Cells↗
PubMed2003

Thrombopoietin concentrations in peripheral blood correlated with platelet numbers in two patients with thrombocytopenia by chronic graft-versus-host disease.

Thrombocytopenia is well known to be one of the clinical manifestations of chronic graft-versus-host disease (cGVHD). However, there exist cases in which the cause of thrombocytopenia has been unexplained. Recently, thrombopoietin (TPO) from bone marrow (BM) stromal cells and transforming growth factor (TGF)-beta from platelets and megakaryocytes have been identified as strong positive and negative regulators of megakaryopoiesis in vivo. We hypothesized that the decreased TPO production from BM could be one of the causes of thrombocytopenia in the patients with cGVHD. In the present study, therefore, TPO and TGF-beta concentrations in peripheral blood (PB) and BM were measured serially in two patients with acute leukemia who had received fully matched stem cell transplantation from relatives and subsequently developed extensive cGVHD with thrombocytopenia. The results showed that platelet numbers correlated well with the TPO concentrations, which were consistently higher in BM than in PB. The difference in TPO concentrations between BM and PB was decreased when the platelet levels were low, indicating that the amount of TPO production from BM decreased throughout the duration of thrombocytopenia. TGF-beta concentrations were normal during all periods in which measurements were carried out. Thus, our results suggest that one mechanism of thrombocytopenia in patients with cGVHD is low TPO production by BM cells.

Adult↗
PubMed2003

Inhibition of type I procollagen production by tRNAVal CTE-HSP47 ribozyme.

BACKGROUND: Fibrosis characteristically occurs in the advanced stages of chronic inflammatory diseases, occasionally as the primary lesion, and frequently determines the disease prognosis. Fibrotic lesions consist mostly of collagen, and therefore it may be possible to prevent or treat fibrosis by inhibiting collagen production. Of the currently available therapeutic approaches, however, none is sufficiently effective and specific for inhibition of collagen. Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that has been reported to play a pivotal role in secretion of procollagen molecules. Therefore, we have tried to suppress its function to inhibit these various types of collagen. METHODS: We have developed a novel type of ribozyme by ligating a hammerhead sequence to a tRNA(Val) promoter to facilitate displacing the ribozyme from nucleus to cytoplasm and to constitutive transport element, a binding motif of helicase which unwinds mRNA to render the target sequence on the mRNA accessible to the ribozyme. RESULTS: The ribozyme thus constructed showed strong activity to cleave HSP47 mRNA and suppress the secretion of type I procollagen in the human primary fibroblast. CONCLUSION: We suggest applicability of this ribozyme as a new modality for antifibrosis therapy.

Antisense Elements (Genetics)↗
PubMed2003

Pre-administration of angiopoietin-1 followed by VEGF induces functional and mature vascular formation in a rabbit ischemic model.

BACKGROUND: Angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF) play important roles in vascular formation and maturation, suggesting that the combination of these two would be a promising therapy for ischemia. However, it remains unclear what the best schedule of administration of these cytokines might be. METHODS: Six experimental groups were used to prepare the rabbit ischemic hindlimb model following naked plasmid intramuscular administration as follows: empty vector (C), single gene (Ang1, A; VEGF, V), Ang-1 followed by VEGF (A - V), co-administration of Ang1 and VEGF (A + V), and VEGF followed by Ang1 (V - A). RESULTS: Thirty days after gene administration, A - V showed a significantly increased blood pressure and blood-flow recovery in the ischemic limb compared with the control group. Histological findings by alpha-smooth muscle-actin (alpha-SMA) staining revealed that the two combination groups had more mature vessels as compared with the control group. Significantly, A - V revealed the highest density of alpha-SMA-positive vessels compared with VEGF alone or Ang1 alone. Angiographic assessment revealed that A - V had a greater increased arterial diameter compared with VEGF alone. Edema, one of the major adverse effects induced by VEGF, was not found in A - V throughout the experiments, while VEGF alone and V - A showed severe edema induced by VEGF. CONCLUSIONS: The pre-administration of Ang1 followed by VEGF resulted in an improvement of hemodynamic status, an increased number of vessels covered with alpha-actin-positive mural cells, and prevention of VEGF-mediated edema. Thus, priming by Ang1 gene administration would be beneficial for therapeutic angiogenesis in VEGF gene therapy.

Angiography↗
PubMed2003

Cyclic platelet and leukocyte count oscillation in chronic myelocytic leukemia regulated by the negative feedback of transforming growth factor beta.

We report a case of chronic myelocytic leukemia (CML) with cyclic oscillation of platelet and leukocyte counts and attempt to elucidate the oscillatory mechanism from the standpoint of cytokine regulation of hematopoiesis. A 57-year-old woman with a diagnosis of CML exhibited platelet and white blood cell (WBC) count fluctuations of a cyclic nature. The average duration of the cycles was about 8 weeks. The patient suffered from headache, fatigue, and malaise at the peak of the cycle. The peak thrombopoietin concentration in peripheral blood coincided with a period of decrease in platelet numbers. The change in transforming growth factor beta (TGF-beta) level paralleled that of the platelet numbers. A progenitor cell assay revealed the suppression of trilineage colony formation in the presence of plasma from the blood cell peak point, and this suppression was completely blocked when the plasma was incubated with an anti-TGF-beta antibody. From these findings, we concluded that the cyclic oscillation of the platelet, WBC, and reticulocyte counts had been induced by excess negative feedback to megakaryopoiesis by TGF-beta.

Antibodies, Monoclonal↗
PubMed2003

Fatality caused by self-bloodletting in a patient with factitious anemia.

Death by bloodletting among patients with factitious anemia has never been reported to our knowledge. We report the first known case. A 25-year-old woman with severe iron deficiency anemia confessed her habit of bloodletting at her first visit to our hospital, in March 1998. We prescribed oral iron and referred her to a psychiatrist. The diagnosis was borderline personality disorder. The psychiatrist began counseling the patient and prescribed a major tranquilizer. The patient's method of bloodletting was to insert an 18-gauge needle without syringe into her vein after inducing congestion in her arm. This method was considered to involve risk of death, because once the patient fell into a faint caused by blood loss, the bloodletting could not be stopped. Although we attempted to persuade the patient to stop bloodletting by this method, she died after self-bloodletting in September 1999. It is not known whether the death was intentional suicide or an accident.

Adult↗
PubMed2003

C(H)OP refractory chronic lymphocytic leukemia patients in whom salvage chemotherapy chosen by evaluating multiple chemotherapeutic drug-resistant factors was remarkably effective.

It is well known that the expression of anticancer drug-resistant factors is elevated in patients with primary refractory or relapsed chronic lymphocytic leukemia (CLL) who have been treated with chemotherapy. We report here two C(H)OP refractory patients with CLL in whom salvage chemotherapy chosen by evaluating anticancer drug-resistant factors (glutathione-S-transferase-Pi [GST-Pi], glycoprotein [GP]-170, multidrug resistance-associated protein [MRP], and lung resistance protein [LRP]) was remarkably effective. A 71-year-old male patient was refractory to induction therapy with cyclophosphamide, vincristine, and prednisone (COP), and his leukemic cells at diagnosis displayed overexpression of GST-Pi and GP-170. A 74-year-old female patient's condition had been stable; she had received ten courses of COP over 9 years. However, because systemic lymphadenopathies recurred, she was treated with chemotherapy consisting of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) or dexamethasone, etoposide, ifosphamide, and carboplatin (DeVIC). However, she did not respond at all, and her leukemic cells at recurrence displayed overexpression of GST-Pi. Therefore, we chose for these patients a salvage therapy consisting of dexamethasone and high-dose cytosine arabinoside (Ara C), to which neither GST-Pi nor GP-170 show any drug resistance. In both patients, this salvage therapy proved effective.

ATP Binding Cassette Transporter, Subfamily B↗