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Biomedical subjects

Tomoyuki Masuda

Publications and source records attributed to Tomoyuki Masuda.

At least 19 recordsLinked to original sources
PubMed2006

Aberrant maspin expression in human endometrial cancer.

Maspin, a mammary serine protease inhibitor, was originally reported as a tumor suppressor gene in breast cancer. The purpose of the present study was to examine maspin expression and evaluate its clinicopathological significance in endometrial cancer. We examined maspin expression immunohistochemically in 41 cases with endometrioid adenocarcinoma. DNA methylation status at the maspin promoter region was determined by the methylation-specific polymerase chain reaction method. Aberrant maspin expression was observed in 27 (66%) of 41 endometrioid adenocarcinomas but not in normal endometrial glands. Maspin immunoreactivity of the tumor cells varied in incidence and density among tumors. Positive staining was correlated significantly with the presence of squamous differentiation (presence vs absence = 11/11 [100%] vs 16/30 [53%], P < 0.05), and nuclear subcellular localization of maspin protein was also significantly associated with squamous differentiation (nuclear positive vs nuclear negative = 6/11 [54%] vs 2/30 [6.7%], P < 0.05). An inverse correlation between their immunoreactivity and methylation status was observed (P < 0.01). Three of the four cell lines established from endometrioid adenocarcinomas overexpressed maspin mRNA and its protein product. In a maspin-negative cell line, maspin expression was induced by treatment with 5-aza-2'-deoxycytidine, a DNA demethylating agent. There was no significant correlation between maspin expression and any clinicopathlogical data. These findings suggest that maspin induced by DNA demethylation at the promoter region may contribute to squamous differentiation of tumor cells in endometrioid adenocarcinomas.

Adenocarcinoma↗
PubMed2006

Klinefelter's syndrome associated with systemic lupus erythematosus and autoimmune hepatitis.

Klinefelter's syndrome (KFS) tends to be associated with immunological disorders. We describe a 37-year-old man who presented signs of testicular atrophy and decreased body hair. He showed pancytopenia and elevated levels of liver enzymes. Chromosome analysis revealed 47XXY karyotype; therefore, he was diagnosed with KFS, with systemic lupus erythematosus and autoimmune hepatitis. Treatment with a high dose of methylprednisolone and methyltestosterone improved thrombocytopenia and symptoms, suggesting that methyltestosterone may have a clinical benefit in the treatment of KFS with a low level of testosterone accompanying immunological disorders.

Adult↗
PubMed2006

Protective effect of hepatocyte growth factor against degeneration of the retinal pigment epithelium and photoreceptor in sodium iodate-injected rats.

PURPOSE: To investigate the possible protective effect of hepatocyte growth factor (HGF) against degeneration of photoreceptors and retinal pigment epithelium (RPE) in vivo. METHODS: Sprague-Dawley (SD) rats received an intravitreal injection of HGF in the right eye. The left eye was injected with vehicle as a control. Two days after the intravitreal injections, rats were administered 40 mg/kg of sodium iodate (NaIO3) intravenously. Scotopic ERGs were elicited by different stimulus intensities with a maximum luminance of 0.84 log cds/m2. To evaluate RPE function, the azide response was evoked by intravenous injection of 0.1 mg sodium azide. These electrophysiological measurements were conducted on days 4, 7, 14, and 28 after the NaIO3 injections. After recording ERGs or azide response, animals were sacrificed for quantification of the histological change and immunohistochemical analysis using antibodies against RPE 65. RESULTS: The threshold for the scotopic b-wave was significantly lower in HGF-treated eyes than in untreated control eyes (p < 0.005), and maximum b-wave amplitudes (Vbmax) were significantly larger in HGF-treated eyes (p < 0.05) across all experimental time points after NaIO3 injection. Azide response amplitudes were significantly larger in the HGF-treated eyes than in the untreated eyes (p < 0.05). The structure of the outer retina was preserved to a greater degree in the HGF-treated eyes than in the untreated eyes (p < 0.05). Immunohistochemical analysis demonstrated that irregular alignment of the outer nuclear layer was confined to the retinal area that was not stained with RPE 65. CONCLUSIONS: Our results indicated that an intravitreal injection of HGF provided significant protection against degeneration of the photoreceptor and RPE induced by systemic administration of NaIO3. This suggests that HGF could be used as a therapeutic agent for degeneration of photoreceptors as well as RPE.

Animals↗
PubMed2006

Interferon-gamma down-regulates expression of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats.

Interferon-gamma (IFN-gamma) is a potent cytokine that exerts antiproliferative and antifibrogenic effects on hepatic stellate cells (HSCs). Although therapeutic application of IFN-gamma for chronic liver diseases is anticipated, the responses of activated HSCs to IFN-gamma have not been fully elucidated. To seek unknown molecules and pathways that might be responsive to IFN-gamma treatment in activated HSCs, we examined global protein expression profiles using two-dimensional gel electrophoresis combined with peptide mass fingerprint. We identified 76 increased and 59 decreased spots (>3-fold increase or decrease, total 135 spots). Database analysis suggested that the following four pathways were involved in alteration of HSCs toward a quiescent phenotype in response to IFN-gamma: i) down-regulation of the TGF-beta and PDGF signaling pathways; ii) reorganization of intermediate filaments; iii) up-regulation of fatty acid metabolism; iv) decreased expression of TNF-alpha converting enzyme (TACE)/a disintegrin and metalloproteinase 17 (ADAM17), which is responsible for shedding of the proinflammatory cytokine TNF-alpha. We confirmed down-regulation of both ADAM17 expression and soluble TNF-alpha secretion by Western blotting and real-time PCR. TNF-alpha mRNA/protein expression was not altered by IFN-gamma treatment. Our data suggest that IFN-gamma stimulation suppresses the activated phenotype of HSCs in vitro through multiple pathways. Of these pathways, down-regulation of ADAM17 expression may play a role in blocking the auto-activation mechanism of cultured HSCs through activation of the TNF-alpha signaling and shedding pathways.

ADAM Proteins↗
PubMed2006

Mutations of the epidermal growth factor receptor gene in gastrointestinal tract tumor cell lines.

The epidermal growth factor receptor (EGFR) is commonly overexpressed in many human tumors including gastrointestinal tract tumors. Gefitinib is a selective inhibitor of EGFR tyrosine kinase, and blocks several signal transduction pathways including those involved in tumor cell proliferation, angiogenesis and metastasis. Recent mutational and biological studies have suggested that mutations in the tyrosine kinase domain of the EGFR gene are well correlated with the response to gefitinib, and that these mutations are frequently observed in non-small cell lung cancers affecting women, East Asians and non-smokers. This led us to speculate that EGFR gene mutations may occur frequently in gastrointestinal tract carcinomas (GITCs) because overexpression is observed in these tumor types. To investigate EGFR mutations in GICTs, we studied 11 esophageal, 6 gastric, and 12 colorectal cancer cell lines. We found a missense mutation in a gastric cancer cell line, and 10 single nucleotide polymorphisms. The occurrence of rare mutations in the tyrosine kinase domain of the EGFR gene suggests that gefitinib is unlikely to be reliable as single-drug therapy for GITCs.

Adenocarcinoma↗
PubMed2005

Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone: a case report.

The anti-arrhythmic agent amiodarone (AD) is associated with numerous adverse effects, but serious liver disease is rare. The improved safety of administration of daily low doses of AD has already been established and this regimen is used for long-term medication. Nevertheless, asymptomatic continuous liver injury by AD may increase the risk of step-wise progression of non-alcoholic fatty liver disease. We present an autopsy case of AD-induced liver cirrhosis in a patient who had been treated with a low dose of AD (200 mg/d) daily for 84 mo. The patient was a 85-year-old male with a history of ischemic heart disease. Seven years after initiation of treatment with AD, he was admitted with cardiac congestion. The total dose of AD was 528 g. Mild elevation of serum aminotransferase and hepatomegaly were present. Liver biopsy specimens revealed cirrhosis, and under electron microscopy numerous lysosomes with electron-dense, whorled, lamellar inclusions characteristic of a secondary phospholipidosis were observed. Initially, withdrawal of AD led to a slight improvement of serum aminotransferase levels, but unfortunately his general condition deteriorated and he died from complications of pneumonia and renal failure. Long-term administration of daily low doses of AD carries the risk of progression to irreversible liver injury. Therefore, periodic examination of liver function and/or liver biopsy is required for the management of patients receiving long-term treatment with AD.

Aged↗
PubMed2005

Chemorepulsion and cell adhesion molecules in patterning initial trajectories of sensory axons.

Research in the past decade has advanced our knowledge of the key role that diffusible cues play in axonal guidance during development. In higher vertebrates, dorsal root ganglion (DRG) neurons extend axons centrally to the spinal cord through the dorsal root entry zone and peripherally to muscle and skin targets. In this review, we focus on the role of proximate "non-target" tissues in the initial stages of DRG axonal growth. In the early stages of development, "non-target" tissues including the dermamyotome, the notochord, and the ventral spinal cord exert chemorepulsion for DRG axons. We describe how semaphorin 3A, chondroitin sulfate proteogrycans, and cell adhesion molecules participate in chemorepulsion and the way they provide spatio-temporal specificity to chemorepulsion. Axon chemorepulsion may act not only to shape DRG axonal trajectories but it also affects a variety of other axonal projections in the peripheral and central nervous system.

Axons↗
PubMed2005

Consensus JH gene probes with conjugated 3'-minor groove binder for monitoring minimal residual disease in acute lymphoblastic leukemia.

Several approaches for the detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) have shown the importance of determining the level of MRD precisely. In the present study, we tested a new real-time quantitative polymerase chain reaction (RQ-PCR) strategy with minor groove binder (MGB) technology for immunoglobulin heavy chain gene rearrangements by positioning a MGB probe at the germline JH segments and one of the primers at the downstream introns in combination with an allele-specific oligonucleotide (ASO) primer complementary to the VH-DH or DH-JH junctional region. A MGB probe forms extremely stable duplexes with single-stranded DNA targets, allowing the use of shorter probes for hybridization-based assays. Therefore, it shows positional flexibility. We have designed two novel consensus MGB JH germline probes for analyzing all of the germline rearrangements registered in the V BASE database, and demonstrated that the MRD was detectable with the probes in 17 cases of childhood ALL. The actual copy number for the targets and dynamic changes before and after treatment were almost identical between the JH MGB probe and conventional non-MGB probes in each patient. MGB technology will undoubtedly contribute to MRD-PCR studies of childhood ALL.

Base Sequence↗
PubMed2005

Epigenetic status and aberrant expression of the maspin gene in human hepato-biliary tract carcinomas.

We examined expression of maspin and the epigenetic status of its gene in 40 primary hepato-biliary tract carcinomas and 11 cell lines originating from hepato-pancreatico-biliary tract carcinomas. Aberrant maspin expression was frequently observed immunohistochemically in biliary tract carcinomas (22/25, 88%) but not in hepatocellular carcinomas (HCCs) (0/15, 0%). Aberrant maspin expression by five pancreatico-biliary tract carcinoma cell lines was closely associated with demethylation at the maspin promoter. Five of six HCC cell lines were maspin-negative and exhibited extensive hypomethylation and hypoacetylation at the maspin promoter. Treatment with 5-aza-2'-deoxycytidine did not activate maspin expression in these five maspin-negative HCC cell lines, whereas treatment with Trichostatin A (TSA) activated maspin expression in two of them. Treatment with TSA increased histone acetylation in some HCC cell lines. These results suggest that aberrant maspin expression in biliary tract carcinomas is closely associated with demethylation at the promoter region, but that some HCC cell lines additionally require histone acetylation. In addition, the fact that maspin-negative HCC cell lines remain after treatment with TSA suggests the existence of other repressive factors controlling maspin expression.

Acetylation↗
PubMed2005

Functional changes in rod and cone pathways after photoreceptor loss in light-damaged rats.

PURPOSE: To determine the functional changes in the rod and cone pathways after photoreceptor loss by continuous light exposure. METHODS: Fifty-four male Sprague-Dawley rats were exposed to diffuse fluorescent light of 2000 lux for 24 or 48 hr. Two weeks after the light exposure, full-field scotopic and photopic electroretinograms (ERGs) were elicited by different stimulus intensities with a maximum luminance of 0.84 log cd-s/m2. The amplitudes of the a- and b-waves of the scotopic ERGs and the b-wave of the photopic ERGs were measured. The animals were sacrificed after the ERG recordings, and the number of surviving rod and cone nuclei in the outer nuclear layer was counted. RESULTS: The logarithm (log) of the amplitudes of the maximum rod a-wave (rod Va(max)) and b-wave (rod Vb(max)) was reduced monotonically with a decrease in the rod nucleus counts (p < 0.0001). The regression line for the rod Va(max) decrease was significantly steeper than that for the rod Vb(max) (p < 0.005). The maximum b-wave amplitudes of the photopic ERGs (cone Vb(max)) were significantly correlated with the number of cone nuclei in a log-linear fashion. The slopes of the regression lines for the rod Vb(max) and cone Vb(max) were 0.0067 and 0.0140, respectively, which indicates that the amplitude of the cone b-wave was more severely affected than that of the rod b-waves by light-induced photoreceptor degeneration (p < 0.005). CONCLUSIONS: The amplitudes of the rod and cone ERGs were correlated with rod and cone nuclei counts in a log-linear fashion in light-damaged rats. The functional loss from the photoreceptor death had a greater effect on the cone pathway than on the rod pathway when the retinal function was assessed by the b-wave.

Animals↗
PubMed2005

Identification and characterization of a novel member of murine semaphorin family.

The semaphorin gene family contains a large number of secreted type or transmembrane type proteins, and some of them function as the repulsive and attractive cues of axon guidance during development. Here we report a novel member of murine class 3 semaphorin genes, semaphorin 3G (Sema3G), mapped on chromosome 14. In adulthood, Sema3G is mainly expressed in the lung and kidney, and a little in the brain. Interestingly, in the adult rodent brain Sema3G is expressed only in the granular layer of the cerebellum, as determined by Northern blot and in situ hybridization analyses. We also found that Sema3G binds Neuropilin-2, but not Neuropilin-1, and induces the repulsion of sympathetic axons, but not dorsal root ganglion axons, indicating that Sema3G utilizes Neuropilin-2 as a receptor to repel specific types of axons.

Animals↗
PubMed2005

Distinguishing between proliferating nodal lymphoid blasts in chronic myelogenous leukemia and non-Hodgkin lymphoma: report of three cases and detection of a bcr/abl fusion signal by single-cell analysis.

Lymph node biopsies were analyzed from three patients with chronic myelogenous leukemia (CML) showing nodal blast proliferation. Immunohistochemically, the blasts from all three patients had an immature marker profile with a T-blast population (cCD3+, CD4-, CD7+, CD8-, CD99+, terminal deoxynucleotidyl transferase +) and a hematopoietic progenitor cell marker (CD34). In two patients, the blasts also expressed myeloid lineage specificity (naphthol AS-D chloroacetate esterase activity and myeloperoxidase positivity). However, it was difficult to distinguish between blast proliferation in CML and non-Hodgkin lymphoma from these immunohistopathological findings alone. Subsequently, bcr gene rearrangement and bcr/abl mRNA expression were detected by Southern blot and reverse transcription-polymerase chain reaction analysis of the lymph nodes. Fluorescence in situ hybridization (FISH) analysis of lymph node touch smears also disclosed bcr/abl gene fusion signals in the blasts of all patients, confirming that the blasts were derived from Philadelphia chromosome-positive CML. Accurate discrimination between the proliferating nodal blasts of CML and non-Hodgkin lymphoma is essential for determining subsequent therapy. FISH analysis of bcr/abl in single-cell blast preparations is an efficient tool that allows rapid, accurate cytopathological diagnosis of extramedullary blast-phase CML and its discrimination from non-Hodgkin lymphoma.

12E7 Antigen↗
PubMed2005

Expression of human telomerase reverse transcriptase splice variants is well correlated with low telomerase activity in osteosarcoma cell lines.

The human telomerase reverse transcriptase (hTERT) gene is a catalytic subunit of telomerase that plays an important role in maintaining telomere length. Recently, post-transcriptional (alternative splicing) and epigenetic (promoter methylation) mechanisms affecting expression of the hTERT gene have been reported as negative regulators of telomerase activity (TA). To elucidate the significance of the telomere maintenance mechanism (TMM) in osteosarcoma (OS), we examined hTERT mRNA/protein expression and methylation status in 16 OS cell lines and compared them with TA. Five (31%) of 16 OS cell lines expressed both full-length and splice variants of hTERT mRNA/protein, and 3 (19%) exhibited only full-length hTERT mRNA/protein. No hTERT mRNA/protein expression was observed in 8 cell lines (50%). TA in OS cell lines exhibiting full-length hTERT mRNA/protein without any splice variants was higher than in cell lines expressing splice variants. The promoters of the 16 OS cell lines were relatively hypermethylated, but no inverse relationship between frequency of methyl-CpG sites and hTERT expression was observed. Treatment with a demethylating agent induced hTERT mRNA/protein in only one cell line. These results suggest that the epigenetic mechanism might contribute to the regulation of the hTERT gene in a small subset of OSs, and that alternative splicing might be involved in controlling the TA of OS cell lines, thereby contributing to their TMM.

Alternative Splicing↗
PubMed2005

Infrequent mutation of the human envoplakin gene is closely linked to the tylosis oesophageal cancer locus in sporadic oesophageal squamous cell carcinomas.

Envoplakin (EVPL) is a member of the desmosomal plaque proteins attached to desmosomal cadherin and keratin filaments. The EVPL gene has been mapped to the tylosis oesophageal cancer (TOC) locus on chromosome 17q25, where it has been demonstrated to be frequently deleted in both familial and sporadic forms of oesophageal squamous cell carcinoma (OSC). In this study, we examined EVPL gene mutations in 10 OSC cell lines and 20 sporadic OSCs using reverse transcription-polymerase chain reaction single-strand conformational analysis (RT-PCR SSCP) followed by direct sequencing. We observed one somatic mutation (GCG to ACG at codon 1104, Ala to Thr: 1/20, 5%) in the central rod domain and 5 intragenic polymorphic sites, where frequent loss of heterozygosity (LOH) (63%) was detected. No mutations were detected in the OSC cell lines. The rate of EVPL gene mutation was quite low in contrast to the frequency of LOH on the TOC locus in sporadic OSCs, and the high incidence of oesophageal cancer development in tylosis families. Our results suggest that EVPL might not be the target gene responsible for OSC, despite its strong candidacy in terms of character and localization.

Alleles↗
PubMed2004

Solid variant of aneurysmal bone cyst of the cervical spine.

STUDY DESIGN: A case of the solid variant of aneurysmal bone cyst affecting the posterior component of the fourth cervical vertebra is reported. Imaging studies showed an expansile destructive lesion. After curettage, autologous iliac bone grafting with posterior fusion was performed. There was no sign of local recurrence 2 years after surgery. OBJECTIVES: To emphasize the occurrence of the solid variant of aneurysmal bone cyst in the cervical spine. SUMMARY OF BACKGROUND DATA: The solid variant of aneurysmal bone cyst is rare, and only 12 cases occurring in the vertebrae, including 3 in the cervical vertebrae, have been reported. The condition is difficult to diagnose radiologically before biopsy or surgery. METHODS: A 9-year-old girl presented with pain in the nape of the neck without any neurologic deficit. She was found to have the solid variant of aneurysmal bone cyst in the posterior component of the fourth cervical vertebra, which had destroyed the lamina and spinous process. Part of the posterior aspect of the C4 vertebral body was also involved. Curettage of the lesion was performed, and the defect in the posterior component of the vertebra was reconstructed using an autologous iliac bone graft with posterior fusion using a halo vest. RESULTS: Magnetic resonance imaging disclosed a homogeneous low intensity mass at the lamina, spinous process, and vertebral body of C4 on T1-weighted images. The mass showed heterogeneous high signal intensity on Gd-enhanced images. Histologically, the resected specimen showed predominant fibroblastic proliferation, with minor foci of reactive osteoid formation and an area of osteoclast-like giant cells. Neither cellular atypia nor mitotic figures were evident. There was no sign of local recurrence 2 years after surgery. CONCLUSIONS: The solid variant of aneurysmal bone cyst should be included in the differential diagnosis of any lytic expansile lesion of the spine, even though it is a destructive lesion. Gd-enhanced magnetic resonance imaging may be helpful for distinguishing the solid variant from conventional aneurysmal bone cyst.

Bone Cysts, Aneurysmal↗
PubMed2004

Disruption of cell-type-specific methylation at the Maspin gene promoter is frequently involved in undifferentiated thyroid cancers.

Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but the biological significance of DNA hypomethylation in carcinogenesis is less understood. The expression of Maspin (mammary serpin) in differentiated normal cells is regulated by epigenetic modifications in a cell-type-specific manner. Paradoxical Maspin expression due to epigenetic modification has been addressed in several cancer cell types. To elucidate the role of the Maspin gene in thyroid cancer, we studied methylation status in the promoter region and its expression in six human undifferentiated thyroid cancer cell lines and in specimens from 92 primary thyroid tumors, consisting of six follicular adenomas, 56 well-differentiated thyroid cancers (WDTCs), 17 poorly differentiated thyroid cancers (PDTCs) and 13 undifferentiated thyroid cancers (UDTCs). Three of the six cell lines overexpressed Maspin mRNA and its protein product, but the remaining three did not. The methylation status at the promoter region was inversely correlated with Maspin expression. In Maspin-negative cell lines, Maspin expression was induced by treatment with 5-aza-2'-deoxycytidine, a DNA demethylating agent. Immunoreactivity for Maspin protein was frequently detected in UDTCs (8/13, 62%) and PDTCs (7/17, 41%). Immunoreactivity for Maspin was diffusely positive in UDTCs, and was restricted to dedifferentiated components of the tumor in PDTCs. Positive immunoreactivity was infrequent in WDTCs (1/56, 2%), and all follicular adenomas and normal thyroid glands were completely negative. Their methylation status evaluated by the methylation-specific PCR method showed a good inverse correlation with their immunoreactivity in surgically resected specimens. Our data suggest that overexpression of Maspin by DNA hypomethylation is closely associated with morphological dedifferentiation in thyroid cancers.

Adenoma↗
PubMed2004

Developmental regulation of notochord-derived repulsion for dorsal root ganglion axons.

During the initial stages of development, the notochord provides repulsive signals for dorsal root ganglion (DRG) axons via semaphorin 3A/neuropilin-1, axonin-1/SC2, and other unknown repulsive molecules. The notochord is known to produce aggrecan, one of the chondroitin sulfate proteoglycans (CSPGs). We report here that adding aggrecan to the culture medium cannot only induce DRG growth cone collapse, but also inhibit DRG axonal growth. Using cocultures composed of tissues derived from chick embryos or neuropilin-1-deficient mice treated with chondroitinase ABC, we show the direct evidence that CSPGs are involved in notochord-derived repulsion for DRG axons. At later developmental stages, CSPGs are involved in perinotochordal sheath-derived axon repulsion, but not in notochord core-derived repulsion. We further demonstrate that TAG-1/axonin-1/SC2 is not involved in mediating repulsive activities by CSPGs, but is required for notochord core-derived axon repulsion. Thus, notochord-derived multiple axon repulsions act in a spatiotemporal-specific manner to shape the initial trajectories of DRG axons.

Aggrecans↗