Biomedical subjects
Publications and source records attributed to Yuichi Ono.
A 64-year-old man underwent aortic valve replacement for aortic regurgitation. The aortic valve was perforated in the noncoronary cusp. Pathological findings showed that the perforation probably occurred due to infective endocarditis. However, the patient had no obvious inflammatory signs preoperatively, to suggest latent infective endocarditis.
A 46-year-old male had a cardiac stab injury resulting in cardiac tamponade as a result of a suicide attempt using a bodkin, a sharply pointed instrument for making holes. The patient was transferred to our hospital about 12 hours after the injury. Pericardiotomy at the emergency operation revealed the penetration of the right ventricle and the hole was repaired following removal of the bodkin. Postoperative course was uneventful.
Delta-Notch signaling plays an essential role in cell fate determination in many tissue types, including the central nervous system. Although the signaling mechanism of Notch has been extensively studied, the behaviors of its ligands are not well understood. In the present study, we found that, in the developing neural tube, Dll1(Delta-like 1) was mainly localized on the processes extending from nascent neurons toward both the pia and the ventricle and accumulated at apical termini, where adherens junctions (AJs) were formed. To understand the mechanism of Dll1 localization, we searched for binding proteins for Dll1 and identified a scaffolding molecule, MAGI1. In the developing spinal cord, MAGI1 mRNA was highly expressed in the ventricular zone, where Dll1 mRNA was expressed. MAGI1 protein accumulated at the AJs formed around the termini of apically extending processes and was partially colocalized with Dll1. MAGI1 bound not only to Dll1 but also to N-cadherin-beta-catenin complexes. In cultured AJ-forming fibroblasts, MAGI1 was localized at AJs, and Dll1 was recruited to these AJs through binding to MAGI1. In addition, Dll1 was stabilized on the cell surface by MAGI1. Taken together, these results suggest that Dll1 is presented on the surface of AJs formed at the apical termini of processes through interaction with MAGI1 to activate Notch on neighboring cells in the developing central nervous system.
We used PCR-based cDNA subtraction to screen for genes up-regulated during mouse hair morphogenesis. One gene selected was predominantly expressed at the tip of developing hair follicles and encoded a protein characterized by the presence of twelve tandem repeats of approximately 120 amino acids and a novel N-terminal domain containing an Arg-Gly-Asp cell-adhesive motif. Immunohistochemistry demonstrated that the protein encoded by this gene, named QBRICK, was localized at the basement membrane zone of embryonic epidermis and hair follicles, in which it was more enriched at the tip rather than the stalk region. Cell adhesion assays showed that QBRICK was active in mediating cell-substratum adhesion through integrins containing alphav or alpha8 chain, but not integrin alpha5beta1. Immunohistochemistry showed that QBRICK colocalized with alphav-containing integrins in the interfollicular region, but with the alpha8-containing integrin at the tip region of developing hair follicles. These results, together, indicate that QBRICK is an adhesive ligand of basement membrane distinctively recognized by cells in the embryonic skin and hair follicles through different types of integrins directed to the Arg-Gly-Asp motif.
Postmitotic neural precursors are generated in the ventricular zone (VZ) of the developing neural tube and immediately migrate to the mantle layer (ML) where they differentiate into mature neurons. Although the regulation of neuronal differentiation and migration has extensively been studied, the behavior of the early postmitotic precursors migrating toward the ML is largely unknown. In this study, we have identified Neph3 as a specific marker for early postmitotic neural precursors in the VZ of the developing spinal cord. Analysis of Neph3 localization by immunofluorescence and immunoelectron microscopy revealed that early neural precursors in the VZ possessed not only pia-connected processes but also ones that reached the ventricle. This apical extension of processes was confirmed by analyzing another early postmitotic marker, Dll1 mRNA, which was actively transported toward the ventricle and accumulated at the termini of the processes. Furthermore, adherens junctions (AJs) were formed around the apical end of processes extending from Neph3- and Dll1 mRNA-positive postmitotic precursors. Taken together, these observations suggest that migrating early postmitotic neural precursors in the VZ of the developing spinal cord form a neuroepithelial cell-like bipolar morphology and communicate with their neighboring cells through AJs.
We screened for genes specifically expressed in the mesenchymes of developing hair follicles using representational differential analysis; one gene identified was MAEG, which encodes a protein consisting of five EGF-like repeats, a linker segment containing a cell-adhesive Arg-Gly-Asp (RGD) motif, and a MAM domain. Immunohistochemistry showed that MAEG protein was localized at the basement membrane of embryonic skin and developing hair follicles, while MAEG expression diminished at the tip of the hair bud. A recombinant MAEG fragment containing the RGD motif was active in mediating adhesion of keratinocytes to the substratum in an RGD-dependent manner. One of the adhesion receptors recognizing the RGD motif was found to be the alpha8beta1 integrin, the expression of which was detected in the placode close to MAEG-positive mesenchymal cells, but later became restricted to the tip of the developing hair bud. Given its localized expression at the basement membrane in developing hair follicles and the RGD-dependent cell-adhesive activity, MAEG may play a role as a mediator regulating epithelial-mesenchymal interaction through binding to RGD-binding integrins including alpha8beta1 during hair follicle development.
Severe circulatory failure after cardiovascular surgery is occasionally difficult to treat and the mortality risk is high. Systemic inflammatory response syndrome (SIRS) is one of the complications resulting in circulatory failure and, continuous hemodiafiltration (CHDF) seems to be a potentially effective treatment to improve the critical condition by removing proinflammatory cytokines. We present two recent cases of SIRS with critical circulatory failure which were successfully treated by CHDF after operation for thoracic aortic dissection.
During development, neuronal identity is determined by a combination of numerous transcription factors. However, the mechanisms of synergistic action of these factors in transcriptional regulation and subsequent cell fate specification are largely unknown. In this study, we identified a novel gene, Corl1, encoding a nuclear protein with homology to the Ski oncoprotein. Corl1 was highly selectively expressed in the central nervous system (CNS). In the embryonic CNS, Corl1 was expressed in a certain subset of postmitotic neurons generated posterior to the midbrain-hindbrain border. In the developing spinal cord, Corl1 was selectively expressed in the dorsal horn interneurons where a homeodomain transcription factor, Lbx1, is required for proper specification. Corl1 was localized in a nuclear dot-like structure and interacted with general transcriptional corepressors. In addition, Corl1 showed transcriptional repression activity in the GAL4-fusion system, indicating its involvement in the regulation of transcriptional repression. Furthermore, Corl1 interacted with Lbx1 and cooperatively repressed transcription, suggesting that it acts as a transcriptional corepressor for Lbx1 in regulating cell fate determination in the dorsal spinal cord. Corl1 corepressor activity did not depend on Gro/TLE activity, and Gro/TLE also functioned as a corepressor for Lbx1. Thus, Lbx1 can select two independent partners, Corl1 and Gro/TLE, as corepressors. Identification of a novel transcriptional corepressor with neuronal subtype-restricted expression might provide insights into the mechanisms of cell fate determination in neurons.
The signal transduction of the cAMP/cAMP-dependent protein kinase [protein kinase A (PKA)] pathway through multiple receptors is critical for many processes in all cell types. In T cells, the engagement of both the TCR-CD3 complex and the CD28 co-stimulatory molecule also induces cAMP, and subsequently activates PKA. It is believed that elevation of cAMP levels in T cells is inhibitory of IL-2 production and T cell proliferation. However, the function and detailed signal transduction mechanisms of the cAMP/PKA pathway in naive T(h) cells are less well understood. In this study, we show that calcitonin gene-related peptide (CGRP) down-regulates IL-2 and IFN-gamma production and up-regulates IL-4 production to promote T(h)2 differentiation by moderate activation of the cAMP/PKA pathway via the CGRP receptor in the presence of a CD3/CD28 co-stimulation signal. The IL-4 production and transcriptional activation of T(h)2 cytokine mRNAs were also reproduced by the addition of a cAMP analogue, dibutyryl-cAMP, in CD3/CD28-stimulated naive T(h) cells. More interestingly, cAMP/PKA activation in naive T(h) cells stimulated with anti-CD3 plus anti-CD28 mAb is essential for inducing IL-4 production and promoting T(h)2 differentiation; in addition, NF-AT is a downstream effector of the cAMP/PKA signaling pathway. These findings indicate that the cAMP/PKA pathway transduces the critical activation signal to T(h)2 polarization by a CD3/CD28 co-stimulation signal and a PKA activating reagent.
Neuronal differentiation is regulated by many basic-helix-loop-helix (bHLH) family transcriptional activators and repressors, and the balance of activity between these factors is important for the differentiation process. Here, we report the identification of a novel transcriptional repressor, designated Helt. Helt encoded a Hey-related bHLH protein containing the bHLH and Orange domains. Helt could homodimerize, and heterodimerize with Hes5 or Hey2. Both the bHLH and Orange domains were involved in the homodimerization. In contrast, only the bHLH domain was required for the heterodimerization with Hey2, whereas only the Orange domain mediated the interaction between Helt and Hes5. Thus, Helt has two dimerization domains, and these domains independently select a partner. Identification of preferred recognition sequences by CASTing experiments revealed that Helt bound to the E box, which was distinct from the Hes1 optimal sequence around the E box core. Not only the core sequence but also sequences flanking the E box were essential for the recognition by Helt and Hes1. Furthermore, Helt repressed transcription from an artificial promoter through binding to the optimal E box elements, as well as transcription from its own promoter. Using in situ hybridization and immunohistochemistry, Helt expression in embryos was investigated. Helt was mainly expressed in undifferentiated neural progenitors in some of the developing brain regions, including the mesencephalon and diencephalon, at the neurogenesis stage. These results suggest that Helt acts as a transcriptional repressor to regulate neuronal differentiation and/or identity.
We performed high-throughput in situ hybridization screening of sections of mouse epidermis using an equalized skin cDNA library as probes and identified a novel gene giving rise to two splicing variants, both of which are expressed in the spinous layer. This gene was mapped between two genes encoding keratinocyte-related peptides, suprabasin and keratinocyte differentiation-associated protein (Kdap), on human chromosome 19q13.1. These gene products appeared to carry functional signal sequences. We then designated these two splicing variants as dermokine-alpha and -beta. Northern blotting and quantitative RT-PCR revealed that dermokine-alpha/-beta, suprabasin, and Kdap were highly expressed in stratified epithelia. In mouse embryonic development, dermokine-alpha/-beta began to be expressed during the period of stratification. Also, in differentiating primary cultured human keratinocytes, transcription of dermokine-alpha/-beta, suprabasin, and Kdap was induced. These findings indicated that dermokine-alpha/-beta, suprabasin, and Kdap are secreted from the spinous layer of the stratified epithelia and that these genes form a novel gene complex on the chromosome.
BACKGROUND: The endometrial stromal sarcoma (ESS) is a rare neoplasm of the uterine origin. Intracardiac metastasis from the low-grade ESS is an extremely rare event. A case of a patient who successfully underwent surgical extraction of metastatic tumors of the low-grade ESS in the right ventricle is described in the present report. CASE: A 48-year-old woman was considered recurrence of the low-grade ESS 4 years after the initial operation for this disease. The CT scanning and magnetic resonance imaging demonstrated solid masses in the pelvis, the lungs, the inferior vena cava, and the right ventricle. The chemotherapy was effective against the recurrent tumors except for intracardiac site. Although she had no symptoms of right-sided heart failure, surgical resection of the intracardiac masses was successfully performed. Pathological examination confirmed intracardiac recurrent low-grade ESS. CONCLUSION: Surgical approach to intracardiac metastasis of the low-grade ESS is considered viable because of an excellent long-term prognosis in this disease and the likelihood of fatal heart failure or sudden death in untreated cases.
The patient was a 60-year-old women who had undergone left modified radical mastectomy on April 7, 1999, and was treated with chemo- and hormonal therapy of UFT and TAM. Two years and 6 months later, she showed multiple lung metastases. Because 5'-DFUR + MPA therapy was not effective, weekly docetaxel (TXT) + adriamycin (ADM) was carried out, and definite improvement in the lung and lymph nodes metastases was observed. It is suggested that this combination therapy may be useful for advanced recurrent breast cancer patients with multiple lung metastases.
The patient was a 70-year-old man who had sigmoid colon cancer with multiple lung and paraaortic lymph node metastases. Sigmoidectomy was performed on August 3, 2001. After the operation, combined l-Leucovorin (LV) + 5-fluorouracil (5-FU) was carried out. As a result, lung and lymph node metastases were reduced markedly and CEA level decreased. It is suggested that this combination therapy may be useful for advanced colon cancer patients.
Activating transcription factor (ATF) 3, a member of the ATF/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (ATF/CREB) family of transcription factors, is induced by a wide range of stress stimuli. Although the ATF3 homodimer is known to repress transcription of several genes, its precise biological roles are still unclear. In this study, we investigated the functional role of ATF3 in doxorubicin (DOX=adriamycin)-treated neonatal rat cardiac myocytes. DOX rapidly activated JNK and c-Jun and induced ATF3 at both mRNA and protein level. Adenovirus-mediated expression of ATF3 protected cardiomyocytes from DOX-induced apoptosis, as determined by flow cytometry, cell viability, and TUNEL assay. It was further shown that p53, one of the apoptosis-inducing transcription factors, was downregulated in the ATF3-overexpressing cardiomyocytes. These results strongly suggest that ATF3 may function as a cytoprotective transcription factor in DOX-treated cardiac myocytes, at least in part, owing to downregulation of p53. ATF3 may be a novel therapeutic target that protects cardiac myocytes from DOX-induced apoptosis.
This retrospective study was designed to investigate the detailed clinical features of benign oral diseases. A total of 792 patients with benign oral lesions were treated at Kitasato University Hospital over a 27-year period. Benign oral lesions were classified into nine groups as follows: epithelial proliferating lesions (n = 234); fibroma-like lesions (n = 150); cysts and cyst-like lesions of the minor salivary glands (n = 140); ranulas (n = 64); angiomas (n = 62); inflammation/ulcer/granulation lesions (n = 56); pyogenic granulomas (n = 44); pleomorphic adenomas (n = 23); and others (n = 19). The characteristics of all these benign oral lesions are summarized. We believe that these characteristics will be helpful for physicians in their daily clinical examinations.
Tight junctions (TJs) consist of transmembrane proteins and many peripheral membrane proteins. To further characterize the molecular organization of TJs, we attempted here to screen for novel TJ proteins by the fluorescence localization-based expression cloning method. We identified a novel peripheral membrane protein at TJs and named it junction-enriched and -associated protein (JEAP). JEAP consists of 882 amino acids with a calculated molecular weight of 98,444. JEAP contained a polyglutamic acid repeat at the N-terminal region, a coiled-coil domain at the middle region, and a consensus motif for binding to PDZ domains at the C-terminal region. Exogenously expressed JEAP co-localized with ZO-1 and occludin at TJs in polarized Madin-Darby canine kidney cells, but not with claudin-1, JAM, or ZO-1 in L cells. Endogenous JEAP localized at TJs of exocrine cells including pancreas, submandibular gland, lacrimal gland, parotid gland, and sublingual gland, but not at TJs of epithelial cells of small intestine or endothelial cells of blood vessels. The present results indicate that JEAP is a novel component of TJs, which is specifically expressed in exocrine cells.