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Biomedical subjects

T Otsuki

Publications and source records attributed to T Otsuki.

At least 55 records · Page 3Linked to original sources
PubMed2000

Autologous peripheral blood stem cell transplantation for adults with B-lineage acute lymphoblastic leukemia: a pilot study.

We conducted a pilot study on autologous peripheral blood stem cell transplantation (PBSCT) for 11 adults with B-lineage acute lymphoblastic leukemia (ALL) in first complete remission (CR) or even in those with more advanced stages. All patients achieved CR by induction therapy, of whom 10 were treated with anthracycline, vincristine and prednisolone-based regimens. After consolidation therapy, all patients except one received high-dose cytarabine followed by granulocyte colony-stimulating factor (G-CSF) administration to collect PBSCs. Ten patients received busulfan 4 mg/kg for 4 days, etoposide 20 mg/kg for 3 days and ranimustine 200 mg/m2 for 2 days as a conditioning regimen. One received a regimen consisting of etoposide, cyclophosphamide and total body irradiation. From day 1, G-CSF was given intravenously, and no additional chemotherapy was administered. At the median follow-up time of 30.8 months, four of six patients with standard-risk B-lineage ALL survived within the range of 19.7 to 85.4 months without relapse. In contrast, only one of five with high-risk B-lineage ALL survived for 36.3 months without relapse. Autologous PBSCT as post-remission therapy may prolong CR in adults with standard-risk B-lineage ALL.

Adolescent↗
PubMed2000

Expression of cell cycle regulator genes in KB, a human squamous cell carcinoma cell line, after irradiation.

DNA damage induced by irradiation causes overexpression of the p53 gene, and subsequently the upregulation of p53 downstream genes involved in cell cycle modification. Irradiated malignant cells which possess wild-type p53 have been known to undergo G1 arrest due to p21/Cip1/Waf1 upregulation. Other p53 downstream genes related to the modification of the cell cycle such as gadd45 may cause G2 arrest. Many of the genes which regulate the cell cycle progression have been identified, including the G1 phase specific ink4 family of cyclin-dependent kinase inhibitors (CDK-I), another group of CDK-Is, which affect the cyclin-CDK complexes ubiquitously, and S/G2 accelerator genes. The sequential changes in these cell cycle regulator genes after irradiation has not been clarified. We analyzed the appearance of the apoptotic fraction and cell cycle perturbation after irradiation using KB, a human squamous cell carcinoma line derived from oral floor, and examined the alteration of gene expression for cell cycle regulator genes. The KB cells proceeded to undergo apoptosis in a time and dose dependent manner after irradiation and showed G2 arrest accompanied by upregulation of p53, ubiquitous CDK-Is, and S and G2 accelerator genes.

Apoptosis↗
PubMed2000

Expression levels of estrogen receptor-alpha, estrogen receptor-beta, coactivators, and corepressors in breast cancer.

Recent studies have indicated that a complex machinery of transactivation of target genes by estrogen or antiestrogen through estrogen receptor (ER) exists. However, the substantial roles of ER-beta, coactivators, and corepressors in the development and progression of breast cancer remain to be elucidated. To obtain some clue to these roles, we screened the expression levels of ER-alpha, ER-beta, coactivators (SRC-1, TIF2, AIB1, CBP, and P/CAF) and corepressors (N-CoR and SMRT) in 6 normal mammary glands, 6 intraductal carcinomas, 22 invasive ductal carcinomas, and 7 breast cancer cell lines using a multiplex reverse transcription-PCR. ER-alpha mRNA expression levels significantly correlated with ER-alpha protein levels measured by enzyme immunoassay in the breast cancer tissues and cell lines. A significant correlation of expression levels was observed between ER-alpha and TIF2, AIB1, P/CAF, and N-CoR, and between ER-beta and AIB1 and CBP in the tissue samples. A significant correlation was also observed between ER-alpha and ER-beta and between ER-beta and CBP in the cell lines. The expression levels of ER-alpha, TIF2, and CBP were significantly higher in the intraductal carcinomas than those in the normal mammary glands. In addition, the expression levels of ER-alpha and N-CoR were significantly higher in the intraductal carcinomas than those in the invasive ductal carcinomas. These findings suggest a positive correlation of expression levels among ER-alpha and cofactors and among ER-beta and cofactors, an up-regulation of expression levels of ER-alpha and cofactors during the development of intraductal carcinomas from normal mammary glands, and a decrease in their expression levels during the progression of breast cancer.

Breast↗
PubMed2000

Cellular biological differences between human myeloma cell lines KMS-12-PE and KMS-12-BM established from a single patient.

To clarify cellular biological varieties of myeloma cells, biological differences were analyzed between 2 human myeloma cell lines, KMS-12-PE and KMS-12-BM, derived from pleural effusion and bone marrow, respectively, of a single patient. Although both lines were considered to be derived from the same clone because both had the same chromosomal marker and immunoglobulin H rearrangement, several biological differences were noted. CD11a and CD20 were highly expressed in the KMS-12-BM line, whereas the KMS-12-PE line showed a higher expression of CD7 and CD95/Fas. Although growth was stimulated in KMS-12-BM by interleukin-6 and interferon-alpha, it was inhibited in KMS-12-PE. In addition, apoptosis inhibitors Bcl-2 and Bcl-X(L) were highly expressed in KMS-12-BM cells. Because KMS-12-PE was cultivated 2 months before KMS-12-BM, these differences might be related to their origin (pleural effusion and bone marrow) or the phases of disease progression. However, these biological differences may help clarify myeloma cell biology and lead to improvement in treatment for myeloma patients.

Antigens, Surface↗
PubMed2000

Expression and production of interleukin 10 in human myeloma cell lines.

Recent investigations of the cytokine network surrounding myeloma cells have disclosed the importance of gp130-related cytokines including interleukin (IL)-6 for myeloma cell survival and proliferation, identification of IL-10 as a growth factor for myeloma cells, the close relationship between IL-10 and the receptors for gp130-related cytokines, and the growth enhancement effect of IL-11 and IL-7 on myeloma cells. In this study, IL-10 production was observed in three out of seven human myeloma cell lines examined and five (including three producing lines) out of 10 lines exhibited mRNA expression of IL-10. The IL-10 mRNA expression was also enhanced in approximately one third of primary specimens, whereas the IL-10 receptor (R) expression was not changed compared with that of normal component marrow controls. However, reverse transcription-polymerase chain reaction (RT-PCR) assay of various cytokines and their receptors showed no particular association with IL-10-producing myeloma lines compared with non-producing lines. Supplementing exogenous IL-10 or neutralization of the IL-10 signal by anti-IL-10 monoclonal antibody (mAb) in a culture conditions did not significantly affect myeloma cell growth regardless of expression of IL-10 or its receptor (IL-10R). However, supplement of anti-IL-10 mAb caused upregulation of certain genes such as IL-11, leukaemia inhibitory factor receptor (LIFR) and syndecan-1 in IL-10R-expressing cell lines. These findings indicate that the cytokine network surrounding myeloma cells is complicated and variable. In addition, IL-10 may modify this network and the cellular biological properties of myeloma cells rather than cell proliferation.

Actins↗
PubMed1999

SNX5, a new member of the sorting nexin family, binds to the Fanconi anemia complementation group A protein.

The function of the Fanconi anemia complementation group A (FANCA) protein remains unclear. To investigate possible protein-protein interactions, we performed yeast two-hybrid screening using a FANCA fragment as bait. Sorting nexin 5 (SNX5), a new member of the human SNX family, was identified as a putative FANCA-binding protein. The interaction between FANCA and SNX5 was confirmed by immunoprecipitation studies. All members of the SNX family have a characteristic amino acid region termed the phox homology (PX) domain. Deletion mutant analysis indicated that the PX domain is not required for binding to FANCA. The SNX proteins are thought to play an important role in receptor trafficking between organelles. We found that overexpression of SNX5 increased FANCA protein levels. Northern blot analysis of SNX5 showed the presence of alternatively spliced transcripts and different expression patterns in various human cancer cell lines and normal tissues. Further studies are needed to elucidate the functional significance of FANCA and SNX5 binding; however, we speculate that FANCA may affect SNX5 traffic with cell surface receptors.

Alternative Splicing↗
PubMed1999

Proper name anomia after left temporal lobectomy: a patient study.

A patient with a selective deficit in retrieving proper names after left temporal lobectomy is reported. He showed proper name anomia in conversation, in response to photographs, and in verbal descriptions, despite being able to provide semantic information about the people he was unable to name. This report provides evidence that the rostral part of the left temporal lobe plays a crucial role in processing proper names without involvement of other verbal functions.

Anomia↗
PubMed1999

Tumor necrosis factor-alpha and CD95 ligation suppress erythropoiesis in Fanconi anemia C gene knockout mice.

Fanconi anemia (FA) is a genetic syndrome predisposing to hematopoietic failure. Little is known about the pathophysiology of FA, except that tumor necrosis factor-alpha (TNF-alpha) is overexpressed in patients. FA group C (Fac) gene knockout mice have been developed in order to model the human disease, but the mice do not spontaneously exhibit aplasia. To investigate secondary influences on hematopoiesis in the Fac-null mice, we studied the sensitivity of hematopoietic progenitor cells (HPC) to death receptor triggering by TNF-alpha and Fas receptor (CD95) ligation. Previously we had found that overexpression of a human FAC transgene protects hematopoietic progenitors from Fas-mediated apoptosis (Wang et al., 1998, Cancer Res 58:3538-3541). In the present experiments with Fac-null mice, growth of erythroid burst-forming units (BFU-E) was significantly inhibited by TNF-alpha and CD95 ligation. Flow cytometric analysis revealed that CD95 was induced more readily in the Fac-null CD34+ cell fraction. Apoptosis induced by TNF-alpha alone or with CD95 ligation also occurred more frequently in null mouse HPC. We then bred null mice against transgenic mice overexpressing TNF-alpha (at serum levels in the range of 100 pg/ml). Resultant Fac-null mice that overexpressed TNF-alpha not only yielded decreased numbers of BFU-E but also expressed higher levels of CD95 in the CD34+ fraction. We conclude that mutation in the Fac protein induces heightened sensitivity to TNF-alpha and Fas receptor ligation, results that may explain the mechanism of anemia in FA-C patients.

Animals↗
PubMed1999

Quantitative evaluation of gait pattern in patients with osteoarthrosis of the knee before and after total knee arthroplasty. Gait analysis using a pressure measuring system.

Using a pressure measuring system, we quantitatively evaluated gait pattern in patients with osteoarthrosis (OA) of the knee before and after total knee arthroplasty (TKA). In the OA group, the stance time was longer, and the average vertical component of the floor reaction force (AVF) was lower than the values in normal age-matched subjects. These gait parameters correlated with the clinical score. These results suggest that changes in the gait parameters reflect gait patterns that reduce load on the knee. The center of pressure (COP) under the foot was correlated with the axial alignment of the lower limb in the mid-stance phase. In the TKA group, the clinical scores and gait parameters were improved 12 months after surgery compared with the preoperative values. The COP in the mid-stance phase moved inward after the TKA. However, in patients examined more than 2 years after a TKA, stance time and AVF did not reach normal levels, despite the patients' good clinical scores. These findings indicate that the gait pattern before surgery continues although pain on walking is reduced early after a TKA. Gait evaluation with a simple pressure measuring system revealed the changes in gait that are difficult to define by subjective clinical assessment.

Aged↗
PubMed1999

Medroxyprogesterone acetate inhibits interleukin 6 secretion from KPL-4 human breast cancer cells both in vitro and in vivo: a possible mechanism of the anticachectic effect.

Interleukin 6 (IL-6) is a multifunctional cytokine. Recent reports suggest that circulating IL-6 secreted from tumour cells plays an important role in cancer-induced cachexia. Medroxyprogesterone acetate (MPA) has been used as an endocrine therapeutic agent for patients with breast cancer. It has been suggested that MPA decreases serum IL-6 levels and preserves the bodyweight of patients with advanced breast cancer. However, the mechanisms of action responsible for the anticachectic effect of MPA have not been elucidated. Therefore, the effects of MPA on IL-6 secretion were studied both in vitro and in vivo using a human breast cancer cell line, KPL-4, which secretes IL-6 into medium and induces cachexia when injected into female nude mice. MPA (10-1000 nM) dose-dependently decreased basal IL-6 secretion into medium, and also suppressed tumour necrosis factor (TNF-alpha)-induced IL-6 secretion. Both basal and TNF-alpha-induced IL-6 mRNA levels were dose-dependently lowered by MPA. Moreover, intramuscular injections of MPA (100 mg kg(-1) twice a week) into nude mice bearing KPL-4 transplanted tumours significantly decreased serum IL-6 levels without affecting tumour growth and preserved the bodyweight of recipient mice. These findings suggest that suppression of IL-6 secretion from tumour cells, at least in part, causes the anticachectic effect of MPA.

Animals↗
PubMed1999

Isolation and characterization of a new human breast cancer cell line, KPL-4, expressing the Erb B family receptors and interleukin-6.

A new human breast cancer cell line, KPL-4, was recently isolated from the malignant pleural effusion of a breast cancer patient with an inflammatory skin metastasis. This cell line can be cultured under serum-free conditions and is tumorigenic in female athymic nude mice. Flow cytometric analysis revealed the expression of Erb B-1, -2 and -3. Dot blot hybridization showed a 15-fold amplification of the erb B-2. Reverse transcription-polymerase chain reaction analysis showed a detectable level of mRNA expression of all the Erb B family receptors. In addition, all the receptors were autophosphorylated under a serum-supplemented condition. Unexpectedly, transplanted KPL-4 tumours induced cachexia of recipient mice. A high concentration of interleukin-6 (IL-6) was detected in both the culture medium and the serum of mice. The weight of tumours significantly correlated with the serum IL-6 level. The antiproliferative effect of a humanized anti-Erb B-2 monoclonal antibody, rhuMAbHER2, was investigated. This antibody significantly inhibited the growth of KPL-4 cells in vitro but modestly in vivo. Loss of mouse body weight was partly reversed by rhuMAbHER2. These findings suggest that KPL-4 cells may be useful in the development of new strategies against breast cancer overexpressing the Erb B family receptors and against IL-6-induced cachexia.

Animals↗
PubMed1999

Serum levels of soluble Fas ligand in patients with silicosis.

Certain patients with silicosis have been reported to exhibit immunological abnormalities such as the appearance of antinuclear antibodies and the occurrence of autoimmune diseases. Fas ligand (FasL) is a type II membrane protein which induces apoptosis by binding to its membrane receptor, Fas. FasL is converted to a soluble form by a metalloproteinase-like enzyme. We have already found serum soluble Fas (sFas) levels in silicosis patients as well as in patients with systemic lupus erythematosus (SLE) to be significantly higher than those in healthy volunteers. To examine further the role of the Fas/FasL system in silica-induced immunological abnormalities, we investigated serum soluble FasL (sFasL) levels in silicosis patients with no clinical symptoms of autoimmune diseases, using ELISA for sFasL. Although the serum sFasL levels in patients with SLE were significantly higher than those in healthy volunteers and showed a slight positive correlation with serum sFas levels, those in silicosis patients exhibited no significant difference from those in healthy volunteers, and there was no correlation with serum sFas levels. However, sFasL levels were elevated in silicosis patients with slight dyspnoea or normal PCO2 among various clinical parameters of silicosis. It may be speculated that the immunological disturbances presented by the abnormalities of apoptosis-related molecules in silicosis patients do not occur with a similar degree of respiratory involvement. Further studies are required to clarify which kinds of factors are involved in silicosis patients who exhibit immunological abnormalities.

Adult↗
PubMed1999

Expression of vascular endothelial growth factor (VEGF) family members in breast cancer.

Vascular endothelial growth factor (VEGF)-A is known to play an important role in tumor angiogenesis. Three additional members of the VEGF family, VEGF-B, -C and -D, have recently been discovered. VEGF-C and VEGF-D are ligands for VEGF receptor-3, which is expressed in the endothelium of lymphatic vessels. The expression of VEGF-C is known to be associated with the development of lymphatic vessels. Therefore, it is conceivable that VEGF-C and VEGF-D might play a role in the development of lymphatic vessels in solid tumors. To obtain some clue as to this role, we developed a semi-quantitative reverse transcription-polymerase chain reaction method to investigate the mRNA expression levels of each VEGF family member in breast cancer. All the VEGF family members were expressed at different levels in seven human breast cancer cell lines explored. Although VEGF-A and VEGF-B expressions were detected in both node-positive and node-negative breast tumors, VEGF-C expression was detected only in node-positive tumors. VEGF-D expression was detected only in an inflammatory breast cancer and a tumor which developed an inflammatory skin metastasis. These findings suggest a possible relationship between the expression level of VEGF-C and/or VEGF-D and the development of lymphatic tumor spread.

Adult↗
PubMed1999

Dose-related effects of single focal irradiation in the medial temporal lobe structures in rats--magnetic resonance imaging and histological study.

The dose-related effects of single focal irradiation on the medial temporal lobe in rats were investigated by sequential magnetic resonance imaging and histological examination. Irradiation of 200 Gy as a maximum dose using 4 mm collimators with a gamma unit created an area of necrosis consistently at the target site within 2 weeks after irradiation. Irradiation of 100 Gy caused necrosis within 10 weeks, and 75 Gy caused necrosis within one year. Irradiation of less than 50 Gy did not induce necrosis consistently, although a restricted area of necrosis was created in the medial temporal structures including the intraparenchymal portion of the optic tract. 75 Gy may be the optimum dose for creating necrosis consistently in the medial temporal lobe structures. However, careful dose planning considering both dose-time and dose-volume relationships in necrosis development is necessary to avoid injury to vulnerable neural structures such as the optic tract when applying radiosurgical techniques to treat functional brain disorders in medial temporal lobe structures such as temporal lobe epilepsy.

Amygdala↗
PubMed1999

Surgical treatment of intractable epilepsy originating from the primary sensory area of the hand--case report.

A 14-year-old right-handed girl presented with intractable epilepsy originating from the primary sensory area of the hand, manifesting as sensory partial seizures in the left hand with secondary generalization. Neurological examination showed no abnormal findings. Magnetic resonance imaging, magnetoencephalography, and cortical stimulation using chronic subdural electrodes demonstrated a lesion located in the primary sensory cortex of the hand, in which the ictal onset zone was identified by 24-hour intracranial electroencephalographic recording. Surgical resection of the lesion and multiple subpial transections of the adjacent cortices were performed. The histological diagnosis was dysembryoplastic neuroepithelial tumor (DNT). She was completely free of seizures without permanent sensory deficits postoperatively. DNT located in the primary sensory hand area may be resectable without causing postoperative sensory deficits, if accurate functional mapping and surgical resection are performed.

Adolescent↗
PubMed1999

Evaluation of cases with silicosis using the parameters related to Fas-mediated apoptosis.

To establish a new clinical index for immunological abnormalities occurring in silicosis, several clinical parameters related to Fas-mediated apoptosis; i.e., membrane Fas expression on peripheral blood lymphocytes (mFas), serum soluble Fas levels (sFas), serum soluble Fas ligand levels (sFasL), and soluble/membrane Fas mRNA expression ratios (s/mFas ExR) in peripheral blood mononuclear cells (PBMC) were investigated. Fifty-eight silicosis patients with no clinical symptoms of autoimmune diseases were the subjects of this study. Factor analysis was performed using 12 clinical parameters including four parameters related to Fas-mediated apoptosis. Two common factors were identified. Factor 1 which consisted of the following parameters; duration of exposure, symptomatic dyspnea, PO2, PCO2, and A-aDO2, should be designated as the respiratory factor for cases with silicosis. The parameters of factor 2 were serum IgG, sFas with high factor loading, titer of ANA, sFasL, and s/mFas ExR. These parameters of factor 2 are indicative of the immunological disorders occurring in silicosis cases. Some cases exhibited abnormalities in parameters of factor 2 but not factor 1. The factor analysis clearly demonstrated that the parameters related to Fas-mediated apoptosis should be the most beneficial for predicting the pre-clinical status of complicated autoimmune diseases in silicosis.

Aged↗
PubMed1999

Man-made mineral fibers induce apoptosis of human peripheral blood mononuclear cells similarly to chrysotile B.

The aim of this study was to investigate whether man-made mineral fibers (MMMF) induce apoptosis of human peripheral blood mononuclear cells (PBMC), as we recently demonstrated for chrysotile B. In vitro cultivation of PBMC with various MMMF as well as chrysotile B clearly produced apoptotic cells. The alteration of the expression for apoptosis related genes at the mRNA level during in vitro cultures of PBMC with various MMMF revealed upregulation of Flice and Apaf-1 genes and down regulation of TNF receptor 1 and Bid genes. These results indicate that MMMF induce apoptosis of PBMC in a similar manner to chrysotile B. However, the process may be mediated not only by the Fas-related apoptotic pathway but also a mitochondrial pathway. Thus, one should be aware that respiratory and immunological abnormalities may occur in workers who are exposed to MMMFs.

Adult↗