Search PubMed⌕ Search

Biomedical subjects

Shigeo Mori

Publications and source records attributed to Shigeo Mori.

At least 37 records · Page 2Linked to original sources
PubMed2004

Altered expression of ARPP protein in skeletal muscles of patients with muscular dystrophy, congenital myopathy and spinal muscular atrophy.

OBJECTIVES: Ankyrin-repeated protein with PEST and a proline-rich region (ARPP) is a recently identified protein with 4 ankyrin-repeated motifs in its central portion. Type 1 myofibers of skeletal muscle express high levels of ARPP. Recently, we have found that ARPP expression was induced in mouse denervated skeletal muscle. This led us to hypothesize that ARPP expression might be induced in skeletal muscle under some pathological conditions. METHODS: In this study, we performed immunohistochemical analysis of ARPP expression in biopsy specimens of muscle tissue from 15 patients with muscular dystrophies (MDs), 13 with congenital myopathies and 11 with spinal muscular atrophies (SMAs). RESULTS: The ARPP expression levels of all the specimens from MD patients appeared to be lower than control muscle levels. In contrast, the specimens from the 13 patients with congenital myopathies were all ARPP positive. We also found increased numbers of ARPP-positive myofibers in patients with congenital myopathies, and these myofibers co-expressed the slow myosin heavy chain. Indeed, it has been reported that type 1 myofibers are predominant in patients with congenital myopathies, suggesting that increased numbers of ARPP-positive myofibers in such patients may be associated with increased numbers of type 1 fibers. In patients with SMAs, we found that ARPP-positive myofibers tended to be distributed in groups. As grouped myofibers have been reported to result from the process of denervation, innervation and subsequent denervation of re-innervated myofibers, the grouped ARPP-positive myofibers in SMA patients may result from denervation of the motor units. CONCLUSIONS: These findings suggest that evaluation of ARPP may be helpful for the histological diagnosis of muscle diseases.

Adult↗
PubMed2004

Durable response but prolonged cytopenia after cladribine treatment in relapsed patients with indolent non-Hodgkin's lymphomas: results of a Japanese phase II study.

We conducted a phase II study to evaluate the efficacy and safety of cladribine (2-chlorodeoxyadenosine [2-CdA]) for patients with refractory or relapsed indolent B-cell lymphoma or mycosis fungoides. Forty-five patients were enrolled, and 43 patients, including 34 with follicular lymphoma, were eligible. 2-CdA was given by continuous intravenous infusion at a dose of 0.09 mg/kg daily for 7 consecutive days, and this schedule was repeated every 4 weeks up to a maximum of 6 cycles. The overall and complete response rates were 58.1% (25/43; 90% confidence interval, 44.5%-70.9%) and 14.0% (6/43), respectively. The disease progression-free proportions of all 43 eligible and all 25 responding patients at 2 years were 30.3% and 48.1%, respectively. Neutropenia and thrombocytopenia of grade 3 or 4 were observed in 53.3% and 37.8% of patients, respectively, with prolonged cytopenia observed in patients with increased numbers of treatment cycles. Nonhematologic toxicities of grade 3 or greater included diarrhea, arrhythmia, malaise, and gastrointestinal bleeding in 1 patient each, an increase in glutamic-pyruvic transaminase level in 2 patients, and infection in 5 patients. Two treatment-related deaths were observed. Four patients developed myelodysplastic syndrome (MDS) at 13 months to 2 years after completion of the 2-CdA treatments. 2-CdA is an active agent with acceptable toxicity for refractory or relapsed indolent lymphoma; however, prolonged myelosuppression and the potential development of MDS should be carefully monitored.

Adult↗
PubMed2004

Vestibulo-ocular reflex and gravity in fish.

An otolith organ on ground behave as a detector of both gravity and linear acceleration, and play an important role in controlling posture and eye movement for tilt of the head or translational motion. On the other hand, a gravitational acceleration ingredient to an otolith organ disappears in microgravity environment. However, linear acceleration can be received by otolith organ and produce a sensation that is different from that on Earth. It is suggested that in microgravity signal from the otolith organ may cause abnormality of posture control and eye movement. We examined function of otolith organ in goldfish revealed from analysis of eye movement induced by linear acceleration. We analyzed vertical eye movements from video images frame by frame. In normal fish, leftward lateral acceleration induced downward eye rotation in the left eye and upward eye rotation in the right eye. Acceleration from caudal to rostra1 evoked downward eye rotation in both eyes. When the direction of acceleration was shifted 15 degrees left, the responses in the left eye disappeared. These results suggested that otolith organs in each side transmitted different signals.

Acceleration↗
PubMed2004

Eye movements of goldfish depending on the relationship between acceleration vector and otolith organ.

Prior experiments demonstrated that the acceleration deviating 15 degrees to the right (left) from the longitudinal body axis could not produce vertical eye movement in left (right) eye of the goldfish. From these results, we expected that vertical eye movement of goldfish for the acceleration perpendicular to the longitudinal body axis might different between right and left eye. However, in this experiments, there were no clear difference in magnitude of vertical eye movements for the acceleration shifted 15 degrees around the left-right body axis. On the other hand, the response of right eye was larger than that of left eye for the acceleration applied from left to right of the body. These results suggest that stimulation from medial to lateral and lateral to medial of the otolith organ has different effect on vertical eye movement in each eye of goldfish.

Acceleration↗
PubMed2003

Mice lacking a transcriptional corepressor Tob are predisposed to cancer.

tob is a member of antiproliferative family genes. Mice lacking tob are prone to spontaneous formation of tumors. The occurrence rate of diethylnitrosamine-induced liver tumors is higher in tob(-/-) mice than in wild-type mice. tob(-/-)p53(-/-) mice show accelerated tumor formation in comparison with single null mice. Expression of cyclin D1 mRNA is increased in the absence of Tob and is reduced by Tob. Tob acts as a transcriptional corepressor and suppresses the cyclin D1 promoter activity through an interaction with histone deacetylase. Levels of tob mRNA are often decreased in human cancers, implicating tob in cancer development.

Animals↗
PubMed2003

IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist.

IL-17 is a T cell-derived, proinflammatory cytokine that is suspected to be involved in the development of various inflammatory diseases. Although there are elevated levels of IL-17 in synovial fluid of patients with rheumatoid arthritis, the pathogenic role of IL-17 in the development of rheumatoid arthritis remains to be elucidated. In this report, the effects of IL-17 deficiency were examined in IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice that spontaneously develop an inflammatory and destructive arthritis due to unopposed excess IL-1 signaling. IL-17 expression is greatly enhanced in IL-1Ra(-/-) mice, suggesting that IL-17 activity is involved in the pathogenesis of arthritis in these mice. Indeed, the spontaneous development of arthritis did not occur in IL-1Ra(-/-) mice also deficient in IL-17. The proliferative response of ovalbumin-specific T cells from DO11.10 mice against ovalbumin cocultured with antigen-presenting cells from either IL-1Ra(-/-) mice or wild-type mice was reduced by IL-17 deficiency, indicating insufficient T cell activation. Cross-linking OX40, a cosignaling molecule on CD4(+) T cells that plays an important role in T cell antigen-presenting cell interaction, with anti-OX40 Ab accelerated the production of IL-17 induced by CD3 stimulation. Because OX40 is induced by IL-1 signaling, IL-17 induction is likely to be downstream of IL-1 through activation of OX40. These observations suggest that IL-17 plays a crucial role in T cell activation, downstream of IL-1, causing the development of autoimmune arthritis.

Animals↗
PubMed2003

Distortion of autocrine transforming growth factor beta signal accelerates malignant potential by enhancing cell growth as well as PAI-1 and VEGF production in human hepatocellular carcinoma cells.

Resistance to growth inhibitory effects of transforming growth factor (TGF)-beta is a frequent consequence of malignant transformation. On the other hand, serum concentrations of TGF-beta, plasminogen activator inhibitor type 1 (PAI-1), and vascular endothelial growth factor (VEGF) are elevated as tumor progresses. The molecular mechanism of autocrine TGF-beta signaling and its effects on PAI-1 and VEGF production in human hepatocellular carcinoma (HCC) is unknown. TGF-beta signaling involves TGF-beta type I receptor-mediated phosphorylation of serine residues within the conserved SSXS motif at the C-terminus of Smad2 and Smad3. To investigate the involvement of autocrine TGF-beta signal in cell growth, PAI-1 and VEGF production of HCC, we made stable transfectants of human HCC line (HuH-7 cells) to express a mutant Smad2(3S-A), in which serine residues of SSXS motif were changed to alanine. The transfectants demonstrated an impaired Smad2 signaling. Along with the resistance to growth inhibition by TGF-beta, forced expression of Smad2(3S-A) induced endogenous TGF-beta secretion. Moreover, this increased TGF-beta enhanced ligand-dependent signaling through the activated Smad3 and Smad4 complex, and transcriptional activities of PAI-1 and VEGF genes. In conclusion, distortion of autocrine TGF-beta signals in human HCC accelerates their malignant potential by enhancing cell growth as well as PAI-1 and VEGF production.

Amino Acid Motifs↗
PubMed2003

A tetraspanin-family protein, T-cell acute lymphoblastic leukemia-associated antigen 1, is induced by the Ewing's sarcoma-Wilms' tumor 1 fusion protein of desmoplastic small round-cell tumor.

Recurrent chromosomal translocations in neoplasms often generate hybrid genes that play critical roles in tumorigenesis. Desmoplastic small round-cell tumor (DSRCT) is an aggressive malignancy associated with the chromosomal translocation t(11;22)(p13;q12). This translocation generates a chimeric transcription factor, EWS-WT1, which consists of the transcriptional activation domain of the Ewing's sarcoma (EWS) protein and the DNA binding domain of the Wilms' tumor 1 (WT1) protein. One of the splice variants, EWS-WT1(-KTS) lacks three amino acid residues (Lys-Thr-Ser) in the DNA binding domain and transforms NIH3T3 cells. Therefore, it is likely that aberrant gene expression caused by EWS-WT1(-KTS) is involved in the malignant phenotype of DSRCT. Microarray analysis of 9600 human genes revealed that a gene encoding a tetraspanin-family protein, T-cell acute lymphoblastic leukemia-associated antigen 1 (TALLA-1), was induced in EWS-WT1(-KTS)-expressing cell clones. This induction was EWS-WT1(-KTS)-specific, and more importantly, TALLA-1 protein was expressed in the three independent cases of DSRCT. Tetraspanin-family genes encode transmembrane proteins that regulate various cell processes such as cell adhesion, migration and metastasis. Our findings provide a novel insight into the malignant phenotype of DSRCT, suggesting that TALLA-1 is a useful marker for diagnosis and a potential target for the therapy of DSRCT.

Carcinoma, Small Cell↗
PubMed2003

Detection of germinal center B-cell lymphoma in archival specimens: critical evaluation of Bcl-6 protein expression in diffuse large B-cell lymphoma of the tonsil.

Expression of Bcl-6 and CD10, markers for the tumor of the germinal center (GC) B-cell derivation, has been studied in primary diffuse large B-cell lymphomas (DLBCLs) of the lymph node, gastrointestinal tract, and mediastinum. In these studies, the coexpression rate of CD10 and Bcl-6 was relatively constant at 30% approximately 40%, but the frequency of Bcl-6+ tumors varied from 55% to 100%, raising doubts about the usefulness of Bcl-6 expression in identifying the tumor of GC B-cell derivation. Because the expression of Bcl-6 in tumors of non-GC B-cell origin has recently been reported, we critically evaluated the expression of Bcl-6 and CD10 in primary DLBCLs of the tonsil, a relatively common tumor in Japan and Korea. The cases (n = 51) represented a consecutive series for any recent 2-year period at several teaching hospitals in Korea and Japan. Formalin-fixed, paraffin-embedded specimens were used for immunostaining. Staining for Bcl-6 and CD10 was positive in 44 (86%) and 22 cases (45%), respectively. However, among those positive for Bcl-6 (>10% Bcl-6+ tumor cells), 2 basic patterns were recognized: uniform and nonuniform. The uniform pattern was characterized by a dense population (>75%) and a consistent density in any given area, resembling the staining pattern observed in GC or follicular lymphoma (FL) (the "GC/FL" pattern). In contrast, the nonuniform pattern exhibited a varying density from area to area, as well as a less-dense population (<75%). The uniform pattern was observed in 26 cases (51%). All but 1 (95%) of the CD10+ tumors coexpressed Bcl-6, with most (82%) displaying the uniform pattern. We conclude that tumors showing a uniform pattern of Bcl-6 expression should be distinguished from those showing a nonuniform pattern, because the former most likely represent tumors of GC B-cell derivation and the latter most likely represent tumors of non-GC derivation. GC B-cell lymphoma thus defined accounted for 51% of tonsillar DLBCL, a proportion comparable to that of the nodal DLBCL. CD10 expression correlated with the "GC/FL" pattern, but appeared to be not essential for the identification of GC B-cell lymphoma. This study suggests that a significant proportion of tonsillar DLBCLs in Asia is of GC B-cell origin rather than of mucosa-associated lymphoid tissue origin. This finding may have significance for clinical management of these lymphomas.

Adolescent↗
PubMed2003

Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy.

Cardiac ankyrin repeat protein (CARP), which is structurally characterized by the presence of four ankyrin repeat motifs in its central region, is believed to be localized in the nucleus and to participate in the regulation of cardiac-specific gene expression in cardiomyocytes. However, we recently found that CARP was induced in skeletal muscle by denervation, leading us to speculate that CARP may be induced under some pathological conditions. In the present study, we immunohistochemically analyzed the expression of CARP in 11 cases of spinal muscular atrophy (SMA) and 14 cases of congenital myopathy. In SMA, CARP was expressed selectively in severely atrophic myofibers, suggesting that CARP expression may reflect the status of muscle atrophy. Furthermore, in the congenital myopathies, the expression patterns of CARP were distinct among the subtypes, which included nemaline myopathy, myotubular myopathy, central core disease, and congenital fiber type disproportion. Although CARP was preferentially expressed in severely damaged myofibers in nemaline myopathy, it was not detected in central core disease. These findings suggest that immunohistochemical evaluation of CARP may be helpful in the diagnosis of SMA and the congenital myopathies.

Biomarkers↗
PubMed2003

p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts.

Hepatic stellate cells (HSCs) spontaneously transdifferentiate into myofibroblast (MFB)-phenotype on plastic dishes. This response recapitulates the features of activation in vivo. Transforming growth factor beta (TGF-beta) plays a prominent role in stimulating liver fibrogenesis by MFBs. In quiescent HSCs, TGF-beta signaling involves TGF-beta type I receptor (TbetaRI)-mediated phosphorylation of serine residues within the conserved SSXS motif at the C-terminus of Smad2 and Smad3. The middle linker regions of Smad2 and Smad3 also are phosphorylated by mitogen-activated protein kinase (MAPK). This study elucidates the change of Smad3-mediated signals during the transdifferentiation process. By using antibodies highly specific to the phosphorylated C-terminal region and the phosphorylated linker region of Smad3, we found that TGF-beta-dependent Smad3 phosphorylation at the C-terminal region decreased, but that the phosphorylation at the linker region increased in the process of transdifferentiation. TGF-beta activated the p38 MAPK pathway, further leading to Smad3 phosphorylation at the linker region in the cultured MFBs, irrespective of Smad2. The phosphorylation promoted hetero-complex formation and nuclear translocation of Smad3 and Smad4. Once combined with TbetaRI-phosphorylated Smad2, the Smad3 and Smad4 complex bound to plasminogen activator inhibitor-type I promoter could enhance the transcription. In addition, Smad3 phosphorylation mediated by the activated TbetaRI was impaired severely in MFBs during chronic liver injury, whereas Smad3 phosphorylation at the linker region was remarkably induced by p38 MAPK pathway. In conclusion, p38 MAPK-dependent Smad3 phosphorylation promoted extracellular matrix production in MFBs both in vitro and in vivo.

Active Transport, Cell Nucleus↗
PubMed2003

Intermittent hypoxia improves endurance performance and submaximal exercise efficiency.

The purpose of the present study was to elucidate the influence of intermittent hypobaric hypoxia at rest on endurance performance and cardiorespiratory and hematological adaptations in trained endurance athletes. Twelve trained male endurance runners were assigned to either a hypoxic group (n = 6) or a control group (n = 6). The subjects in the hypoxic group were exposed to a simulated altitude of 4500 m for 90 min, three times a week for 3 weeks. The measurements of 3000 m running time, running time to exhaustion, and cardiorespiratory parameters during maximal exercise test and resting hematological status were performed before (Pre) and after 3 weeks of intermittent hypoxic exposure (Post). These measurements were repeated after the cessation of intermittent hypoxia for 3 weeks (Re). In the control group, the same parameters were determined at Pre, Post, and Re for the subjects not exposed to intermittent hypoxia. The athletes in both groups continued their normal training together at sea level throughout the experiment. In the hypoxic group, the 3000 m running time and running time to exhaustion during maximal exercise test improved. Neither cardiorespiratory parameters to maximal exercise nor resting hematological parameters were changed in either group at Post, whereas oxygen uptake (.V(O2)) during submaximal exercise decreased significantly in the hypoxic group. After cessation of intermittent hypoxia for 3 weeks, the improved 3000 m running time and running time to exhaustion tended to decline, and the decreased .V(O2) during submaximal exercise returned to Pre level. These results suggest that intermittent hypoxia at rest could improve endurance performance and submaximal exercise efficiency at sea level in trained endurance athletes, but these improvements are not maintained after the cessation of intermittent hypoxia for 3 weeks.

Adaptation, Physiological↗
PubMed2003

Cardiac-restricted ankyrin-repeated protein is differentially induced in duchenne and congenital muscular dystrophy.

Cardiac ankyrin-repeated protein (CARP) has been shown to associate with a transcription factor, YB-1, that may activate expression of the ventricular myosin light chain-2 gene during cardiogenesis. CARP is induced in the adult hypertrophic heart subjected to pressure overload, suggesting that CARP may play important functional roles in both embryonic and adult hearts. Although CARP expression was initially believed to be restricted to the heart, we found recently that CARP is induced strongly in human fetal skeletal muscle and in experimentally denervated skeletal muscle, leading us to speculate that CARP may also play important roles in skeletal muscle. In the present study, we found that in rats initially damaged by a single injection of bupivacaine, CARP expression was induced strongly in regenerating muscles with a peak 3 days after the injection, followed by down-regulation to undetectable levels after 28 days. Although CARP was coexpressed with embryonic myosin heavy chain (MHC) in regenerating myofibers, CARP expression persisted even after down-regulation of embryonic MHC expression, whereas it began to decrease before the onset of slow or fast MHC expression, suggesting that CARP is expressed at a specific differentiation stage during muscle regeneration. We analyzed the expression of CARP in muscle biopsy specimens from 14 patients with muscular dystrophy (MD) and detected high expression of CARP in 13 of the 14 cases. CARP-positive myofibers were detected more often in congenital muscular dystrophy (CMD) than in Duchenne muscular dystrophy (DMD). We found that CARP was expressed exclusively, and at a high level, in small regenerating myofibers that express embryonic MHC in DMD, which suggested that CARP could be used as a marker of muscle regeneration in DMD. On the other hand, in CMD, expression of CARP was not limited to regenerating fibers, being detectable in myofibers expressing embryonic MHC and those expressing mature-type MHC. These findings suggest that the differentiation stage of CARP-positive myofibers in DMD and CMD may differ.

Animals↗
PubMed2003

[A case of anaplastic large cell lymphoma associated with Epstein-Barr virus infection, representing clinicopathological features of malignant histiocytosis].

An 82-year-old woman was admitted with fever and anorexia. Aggravated pancytopenia and liver dysfunction suggested the presence of disseminated intravascular coagulation. The serum ferritin level increased to 9,100 ng/ml. Bone marrow aspiration showed an increase of histiocytes with phagocytosis and a diagnosis of hemophagocytic syndrome was made. Symptomatic therapy was performed because of her deteriorated general condition. She died of multiple organ failure, 32 days after admission. Autopsy revealed swollen lymph nodes with proliferation of large neoplastic cells containing rich cytoplasm and pleomorphic and multi-segmented large nuclei. The immunophenotype of the neoplastic cells was LCA-, CD3-, CD5-, CD 20-, CD79a-, UCHL1-, MT1-, CD15-, p80-. Neoplastic cells were positive for CD30, mainly in Golgi apparati, and also positive for EBV-encoded small nonpolyadenylated RNAs (EBER). This case was diagnosed as anaplastic large cell lymphoma (ALCL) associated with hemophagocytic syndrome. It was estimated that Epstein-Barr virus had played an important role in the development of ALCL in the present case.

Aged↗