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Biomedical subjects

K Mitani

Publications and source records attributed to K Mitani.

At least 73 records · Page 4Linked to original sources
PubMed1998

The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transforming growth factor-beta-mediated growth inhibition of myeloid cells.

The t(3;21)(q26;q22) chromosomal translocation associated with blastic crisis of chronic myelogenous leukemia results in the formation of the AML1/Evi-1 chimeric protein, which is thought to play a causative role in leukemic transformation of hematopoietic cells. Here we show that AML1/Evi-1 represses growth-inhibitory signaling by transforming growth factor-beta (TGF-beta) in 32Dcl3 myeloid cells. The activity of AML1/Evi-1 to repress TGF-beta signaling depends on the two separate regions of the Evi-1 portion, one of which is the first zinc finger domain. AML1/Evi-1 interacts with Smad3, an intracellular mediator of TGF-beta signaling, through the first zinc finger domain, and represses the Smad3 activity, as Evi-1 does. We also show that suppression of endogenous Evi-1 in leukemic cells carrying inv(3) restores TGF-beta responsiveness. Taken together, AML1/Evi-1 acts as an inhibitor of TGF-beta signaling by interfering with Smad3 through the Evi-1 portion, and both AML1/Evi-1 and Evi-1 repress TGF-beta-mediated growth suppression in hematopoietic cells. Thus, AML1/Evi-1 may contribute to leukemogenesis by specifically blocking growth-inhibitory signaling of TGF-beta in the t(3;21) leukemia.

Animals↗
PubMed1998

TLE, the human homolog of groucho, interacts with AML1 and acts as a repressor of AML1-induced transactivation.

The AML1 gene encodes DNA-binding proteins that contain the Runt domain and is found at the breakpoints of some translocations associated with leukemias. It has been reported that AML1 plays pivotal roles in myeloid differentiation, probably through the transcriptional regulation of various hematopoietic genes. Here we demonstrate the physical and the functional interaction between AML1 and TLE1 (transducin-like Enhancer of split) human homolog of Groucho that is known to be a corepressor of Hairy-related proteins. TLE1 binds to AML1 through the Runt domain and the C terminus of AML1 that includes the VWRPY motif. The interaction is mainly mediated by the SP domain of TLE1. Moreover, TLE1 inhibits AML1-induced transactivation of the target promoters through the C terminus of AML1. These results suggest that TLE1 acts as a repressor of AML1 and provide important insights into the mechanism of the negative regulation of the AML1 functions in hematopoiesis and leukemogenesis.

Animals↗
PubMed1998

The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting Smad3.

Evi-1 encodes a zinc-finger protein that may be involved in leukaemic transformation of haematopoietic cells. Evi-1 has two zinc-finger domains, one with seven repeats of a zinc-finger motif and one with three repeats, and it has characteristics of a transcriptional regulator. Although Evi-1 is thought to be able to promote growth and to block differentiation in some cell types, its biological functions are poorly understood. Here we study the mechanisms that underlie oncogenesis induced by Evi-1 by investigating whether Evi-1 perturbs signalling through transforming growth factor-beta (TGF-beta), one of the most studied growth-regulatory factors, which inhibits proliferation of a wide range of cell types. We show that Evi-1 represses TGF-beta signalling and antagonizes the growth-inhibitory effects of TGF-beta. Two separate regions of Evi-1 are responsible for this repression; one of these regions is the first zinc-finger domain. Through this domain, Evi-1 interacts with Smad3, an intracellular mediator of TGF-beta signalling, thereby suppressing the transcriptional activity of Smad3. These results define a new function of Evi-1 as a repressor of signalling through TGF-beta.

Animals↗
PubMed1998

Cerebrospinal fluid homovanillic acid levels are not reduced in early corticobasal degeneration.

To investigate the contribution of nigral degeneration to the development of parkinsonism in the early stages of corticobasal degeneration (CBD), we measured the cerebrospinal fluid (CSF) levels of homovanillic acid (HVA) in patients with early CBD (n = 5), and compared the levels with those in patients with early Parkinson's disease (n = 11) and in normal subjects (n = 13). The mean CSF HVA level in the early CBD group (33.1 +/- 6.0 ng/ml) did not differ significantly from that in the control group (37.1 +/- 12.7 ng/ml), whereas that in the early Parkinson's disease group (19.0 +/- 7.6 ng/ml) was reduced significantly (P < 0.001). This result suggests that neuronal cell loss in the substantia nigra and presynaptic nigrostriatal dopaminergic neuron dysfunction are mild in the early stages of CBD.

Aged↗
PubMed1998

The AML1/ETO(MTG8) and AML1/Evi-1 leukemia-associated chimeric oncoproteins accumulate PEBP2beta(CBFbeta) in the nucleus more efficiently than wild-type AML1.

AML1, a gene on chromosome 21 encoding a transcription factor, is disrupted in the (8;21)(q22;q22) and (3;21)(q26;q22) chromosomal translocations associated with myelogenous leukemias; as a result, chimeric proteins AML1/ETO(MTG8) and AML1/Evi-1 are generated, respectively. To clarify the roles of AML1/ETO(MTG8) and AML1/Evi-1 in leukemogenesis, we investigated subcellular localization of these chimeric proteins by immunofluorescence labeling and subcellular fractionation of COS-7 cells that express these chimeric proteins. AML1/ETO(MTG8) and AML1/Evi-1 are nuclear proteins, as is wild-type AML1. Polyomavirus enhancer binding protein (PEBP)2beta(core binding factor [CBF]beta), a heterodimerizing partner of AML1 that is located mainly in the cytoplasm, was translocated into the nucleus with dependence on the runt domain of AML1/ETO(MTG8) or AML1/Evi-1 when coexpressed with these chimeric proteins. When a comparable amount of wild-type AML1 or the chimeric proteins was coexpressed with PEBP2beta(CBFbeta), more of the cells expressing the chimeric proteins showed the nuclear accumulation of PEBP2beta(CBFbeta), as compared with the cells expressing wild-type AML1. We also showed that the chimeric proteins associate with PEBP2beta(CBFbeta) more effectively than wild-type AML1. These data suggest that the chimeric proteins are able to accumulate PEBP2beta(CBFbeta) in the nucleus more efficiently than wild-type AML1, probably because of the higher affinities of the chimeric proteins for PEBP2beta(CBFbeta) than that of wild-type AML1. These effects of the chimeric proteins on the cellular distribution of PEBP2beta(CBFbeta) possibly cause the dominant negative properties of the chimeric proteins over wild-type AML1 and account for one of the mechanisms through which these chimeric proteins contribute to leukemogenesis.

Animals↗
PubMed1998

Overexpression of the MEN/ELL protein, an RNA polymerase II elongation factor, results in transformation of Rat1 cells with dependence on the lysine-rich region.

The MEN gene (also called ELL) encodes an RNA polymerase II elongation factor that has been implicated in t(11;19)(q23;p13.1) translocation in myeloid leukemias. The function of another elongation factor, elongin, is known to be inhibited by VHL tumor suppressor protein in vitro, suggesting the possible relationship of aberrant transcriptional elongation to oncogenesis. We overexpressed the MEN protein in Rat1 fibroblasts to evaluate its transforming activity. MEN-overexpressing cells acquired the capacity for anchorage-independent growth. In addition, the growth factor requirement was decreased in these cells. However, cells expressing a deletion mutant of MEN lacking the lysine-rich region did not exhibit such biological abilities. c-Fos protein expression and AP-1 activity were elevated in the MEN-expressing cells, which might be part of the mechanism responsible for the transformation. The c-fos mRNA, the expression of which is known to be regulated partly at the stage of transcriptional elongation, appeared earlier in the MEN-expressing cells than in cells transfected with an empty vector or the deletion mutant lacking the lysine-rich region after stimulation with epidermal growth factor. The RNA polymerase II elongation factor MEN may play an important role in the regulation of cell proliferation.

3T3 Cells↗
PubMed1998

c-Cbl is tyrosine-phosphorylated by interleukin-4 and enhances mitogenic and survival signals of interleukin-4 receptor by linking with the phosphatidylinositol 3'-kinase pathway.

Interleukin-4 (IL-4) is a cytokine that induces both proliferation and differentiation and suppresses apoptosis of B cells. Although IL-4 has been shown to activate the phosphatidylinositol 3' (PI3)-kinase pathway, the role of PI3 kinase in the IL-4 receptor (IL-4R) signaling remains unclear. In this study, we demonstrated that c-Cbl proto-oncogene product is inducibly phosphorylated on tyrosine residues and is associated with the p85 subunit of PI3-kinase by IL-4 stimulation. Overexpression of c-Cbl enhances the PI3-kinase activity and, at the same time, mitogenic activity and survival of cells in the presence of IL-4. However, these effects of c-Cbl were abolished by wortmannin, a specific inhibitor for the PI3 kinase pathway, or by a point mutation at tyrosine 731 of c-Cbl, which is a major binding site for p85. These results indicate that c-Cbl plays a role in linking IL-4R with the PI3 kinase pathway and thus enhancing the mitogenic and survival signals.

Androstadienes↗
PubMed1998

DNA ploidy, proliferative activities, and immunophenotype of malignant lymphoma: application of flow cytometry.

BACKGROUND: To explore the flow cytometric diagnosis of malignant lymphoma, we examined the deoxyribonucleic acid (DNA) ploidy, proliferative activities, and immunophenotype of surgical biopsy- and fine-needle aspiration (FNA)-derived materials. Our goal was to determine the possibility of making a diagnosis of malignant lymphoma by flow cytometric analysis of FNA-derived materials. METHODS: The DNA ploidy and proliferative indices including the percentage of S-phase fraction (SPF), G2 + M fraction (G2M), and Ki-67-positive fraction (Ki-67) were analyzed on the fresh materials from 84 consecutive patients with suspected malignant lymphoma. Flow cytometric analysis of surface antigens was simultaneously performed. Fourteen of the patients underwent FNA and subsequent surgical biopsy of the same lymph nodes for flow cytometric analysis. RESULTS: The proliferative indices of intermediate-grade non-Hodgkin's lymphomas (NHL) (n = 28) and high-grade NHL (n = 23) were significantly higher than those of the reactive hyperplasia (n = 25). The total for SPF + G2M of 6% was a satisfactory threshold for differentiating these NHL from reactive hyperplasia (sensitivity of 84%, specificity of 88%, and accuracy of 86%). However, low-grade NHL (n = 3) and Hodgkin's lymphoma (HL, n = 5) could not be discriminated by employing this parameter. DNA aneuploidy was seen in 13 of the 28 intermediate-grade NHL and 8 of the 23 high-grade NHL, whereas it was not seen in 25 reactive hyperplasia, 3 low-grade NHL, and 5 HL. The percentage of CD19-positive cells in B-cell NHL or CD3-positive cells in T-cell NHL was significantly higher compared with those for reactive hyperplasia. The percentage of CD16 + CD56-positive cells in natural killer (NK) cell NHL was extremely high, with a mean of 91.8%. Flow cytometric results for FNA-derived materials showed excellent correlation with those for surgical biopsy-derived specimens. CONCLUSIONS: Analyses of DNA ploidy, proliferative activities, and immunophenotype by flow cytometry (FCM) are useful for diagnosing intermediate- and high-grade NHL. Fine-needle aspiration is a less invasive approach than surgical biopsy, and, when combined with FCM, it may have a place in the diagnosis of NHL.

Biopsy, Needle↗
PubMed1998

Plasma concentration of itraconazole in patients receiving chemotherapy for hematological malignancies: the effect of famotidine on the absorption of itraconazole.

Fungal infection is a serious complication in immunocompromised patients, especially those with neutropenia. Itraconazole (ITZ) is expected to be an effective prophylactic agent for fungal infection because it has more activity against Aspergillus species than fluconazole and it is less toxic than amphotericin-B. However, ITZ is available only as an oral capsule, the absorption of which is thought to depend on the presence of acid in the stomach. In this study, the effect of famotidine, an H2-blocker, on the absorption of ITZ was investigated. Patients undergoing chemotherapy for hematological malignancies were enrolled. To minimize the effect of famotidine, the time of ITZ intake was different from that of famotidine intake. The plasma concentrations of ITZ with or without taking famotidine were determined just before and 4 h after ITZ intake. Mean trough and peak concentrations of ITZ without famotidine were 332 ng/ml and 476 ng/ml, respectively. When famotidine was co-administered, the concentrations decreased to 204 ng/ml and 315 ng/ml, respectively. Statistical analyses revealed significant differences between trough concentrations in the presence and absence of famotidine (p = 0.008). There was also a clear tendency toward higher peak concentrations in the plasma concentrations with famotidine (p = 0.06). These findings suggest that famotidine decreases the plasma concentration of ITZ in patients undergoing chemotherapy. Close monitoring of the plasma concentration of ITZ and dose adjustment are required for efficient prophylaxis.

Antifungal Agents↗
PubMed1998

Increased CSF tau protein in corticobasal degeneration.

Using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) method, we measured the concentration of total tau protein in the cerebrospinal fluid (CSF) from nine patients with corticobasal degeneration (CBD) in comparison with 12 normal control subjects in order to assess its diagnostic value. The CSF concentration of tau in patients with CBD (0.69, 0.20 ng/ml; mean, SD) was higher than that in, the normal controls (0.48, 0.14 ng/ml, P = 0.0076 unpaired t test). This increase in CBD patients may reflect widespread tau pathology in CBD, but should be interpreted with reserve as an aid to diagnosis.

Aged↗
PubMed1998

Pre-operative assessment of metastatic parotid tumors.

Metastatic disease to the parotid gland is rare and its diagnosing procedures are not established. We assessed several parameters, including the prior history of malignancy, fine needle aspiration cytology (FNAC) and magnetic resonance (MR) imaging and determined the most useful combinations for diagnosing metastatic parotid tumors. The primary tumors were squamous cell carcinomas of the eyelid, larynx, tonsil and of unknown origin, malignant melanoma of the auricle and small cell lung carcinoma. In three of four patients with parotid lymph node metastasis who underwent MR imaging, rim enhancement of the tumor was observed on gadolinium (Gd)-enhanced fat-suppressed T1-weighted MR images (sensitivity 75%). In the histopathologic examinations, the tumor was encapsulated and massive infiltration of normal lymphocytes was found peripheral to the capsule. These were not seen in the patients with metastasis to the parotid parenchyma via hematogeneous dissemination or with advanced-stage parotid node metastasis. The FNAC diagnosis accorded with the tumor histology in five of six patients (sensitivity 83%). Three of the six patients had a prior history of malignancy in other sites (sensitivity 50%). The triad of FNAC, prior history of malignancy and enhanced MR images was identified as the combination most useful in the diagnosis of metastatic parotid tumors (sensitivity 100%).

Aged↗
PubMed1998

Primary thyroid lymphoma associated with metastatic thyroid tumor: discrimination with US.

We surgically treated a 75-year-old man who suffered from metastatic adenocarcinoma from the colon associated with primary thyroid lymphoma measuring 1 cm maximum in diameter. Radiologic findings were correlated with histopathology of excised specimens. Ultrasonography could discriminate between these two tumors based on the margin characteristics and the lesion echogenicity: the metastatic tumor was shown as an ill-defined hypo to iso echoic mass, while the malignant lymphoma was detected as a well-defined markedly hypoechoic mass. In addition, we could confirm that early-stage primary thyroid lymphoma even as small as 1 cm shows the same radiologic appearance as that of a bulky lymphoma.

Adenocarcinoma↗
PubMed1998

B cell lymphoma-associated hemophagocytic syndrome after PBSCT.

Hemophagocytic syndrome (HPS) associated with T cell lymphoma is well known, but an association with B cell lymphoma is rare. We report a patient who developed subcutaneous non-Hodgkin's lymphoma (NHL) of B cell origin. Autologous peripheral blood stem cell transplantation (PBSCT) was undertaken in her second complete remission (CR), but HPS appeared 5 months after transplantation. The patient deteriorated rapidly and died of metabolic acidosis. Necropsy revealed that she had relapsed B cell NHL involving liver, spleen and bone marrow. B cell NHL after PBSCT, associated with HPS as an initial sign, is rare. We report this case and review the literature.

Adult↗
PubMed1998

Phimosis as a manifestation of chronic graft-versus-host disease after allogeneic bone marrow transplantation.

Chronic GVHD is one of the major complications of BMT, involving a variety of organs, but rarely involving the genitourinary system. We report a patient who simultaneously developed extensive chronic GVHD and phimosis after BMT. From the clinical course and pathological findings, chronic GVHD was considered to be responsible for the phimosis. Despite intensive immunosuppressive therapy, the phimosis persisted. Phimosis is a rare complication after BMT, which may often remain neglected. Possibility of this complication should be considered in patients with chronic GVHD.

Adult↗
PubMed1998

Increased soluble Fas-ligand in sera of bone marrow transplant recipients with acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is a major complication following allogeneic bone marrow transplantation (BMT). Recently, accumulating evidence indicates that the Fas/Fas ligand (FasL) system is implicated in the pathogenesis of aGVHD in murine models. We determined the serum levels of soluble FasL (sFasL) in BMT recipients using an enzyme-linked immunosorbent assay. The serum sFasL was suppressed during the period of myelosuppression following the preparative regimen and subsequently increased with hematopoietic reconstitution after BMT. In patients with aGVHD, the serum sFasL level was significantly higher than in those without aGVHD. In the mixed lymphocyte reaction assay, sFasL in the supernatants was increased with a significant correlation to the level of 3H-thymidine uptake. Our findings suggest that the Fas/FasL system is activated by allogeneic stimulation and may have close correlation to the development of aGVHD in human BMT.

Adolescent↗
PubMed1998

Elevated B-type natriuretic peptide levels after anthracycline administration.

BACKGROUND: Cardiotoxicity leading to congestive heart failure is a complication of the anthracyclines. Biochemical methods to diagnose and monitor cardiac function after anthracycline administration would be most useful. We examined the diagnostic role of B-type natriuretic peptide (BNP), a potent biochemical marker of left ventricular dysfunction, in patients administered anthracyclines. METHODS: Twenty-seven consecutive patients receiving anthracyclines were investigated by serial measurements of BNP levels and other cardiac neurohormones (A-type natriuretic peptide, renin, aldosterone, angiotensin II, norepinephrine, and epinephrine) and myocardial markers (creatine kinase-MB and myosin light chain). Echocardiography was done to assess systolic (ejection fraction) and diastolic (mitral inflow A/E ratio) functions. RESULTS: Of the examined cardiac biochemical markers, BNP levels alone showed marked elevations to abnormal levels after anthracycline administration. Most patients showed transient increases (peak at 3 to 7 days). Patients with persistent elevations showed a poor prognosis. A/E ratio also correlated with increases in BNP levels in selected patients, which may suggest that raised BNP levels are reflective of induced diastolic dysfunction. CONCLUSIONS: Our studies suggest the possible use of BNP levels to assess the cardiac state after anthracycline administration. BNP levels most likely reflect cardiac tolerance to the cardiotoxic agent. Serial BNP profiles also suggest persistent elevations to be associated with potentially decompensatory states in contrast to tolerable transient increases. Diagnosis of degree of cardiac tolerance by response to drug administration may be analogous to use of stress testing (exercise) to help define underlying left ventricular dysfunction.

Adult↗
PubMed1998

Frameshift mutations of the hMSH6 gene in human leukemia cell lines.

Defects in DNA mismatch repair mechanisms, including frameshift mutations of the hMSH6 and hMSH3 genes at their (C)8 and (A)8 tracks, respectively, have been shown to be associated with human malignancies. To clarify the possible involvement of these mutations in hematopoietic malignancies, we screened a total of forty-four human leukemia and lymphoma cell lines for mutations in the hMSH6 and hMSH3 genes, as well as in other genes required for DNA replication or repair, by polymerase chain reaction single-strand conformation polymorphism analysis and sequencing analysis. Frameshift mutations at the (C)8 track of the hMSH6 gene were detected in two cell lines established from lymphoid leukemias. These two cell lines had no wild-type alleles, and both of them showed microsatellite instability. This is the first report that describes mutations and inactivation of the hMSH6 gene in hematological malignancies, suggesting that defects of the hMSH6 gene may be associated with development of hematological malignancies.

Base Sequence↗