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Biomedical subjects

Takashi Ishida

Publications and source records attributed to Takashi Ishida.

At least 19 recordsLinked to original sources
PubMed2025

Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.

Decoding the mechanisms governing the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. To explore intrinsic and extrinsic regulation of FL-HSC self-renewal at single-cell resolution, we engineered a culture platform replicating the FL endothelial niche that supports the amplification of serially engraftable HSCs. Leveraging this platform together with single-cell index flow cytometry, live imaging, transplantation assays, and single-cell RNA sequencing, we demonstrate that differentiation latency, cell-division symmetry, and transcriptional signatures of biosynthetic dormancy are distinguishing properties of rare FL-HSCs capable of serial multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and niche-derived signals together facilitate the symmetric self-renewal of FL-HSCs while delaying their active participation in hematopoiesis. Our study also provides a resource for future investigations into intrinsic and extrinsic signaling pathways governing FL-HSC self-renewal.

Hematopoietic Stem Cells↗
PubMed2007

Virtual bronchoscopic navigation system shortens the examination time--feasibility study of virtual bronchoscopic navigation system.

Computed tomography (CT)-guided transbronchial biopsy (TBB) using an ultrathin bronchoscope with simulation by virtual bronchoscopy (VB) is effective for diagnosing small peripheral pulmonary lesions. However, we occasionally lose the proper bronchi to the lesion when a bronchoscope is inserted into peripheral bronchi with severe rotation. To overcome this problem, the virtual bronchoscopic navigation system that can display real-time VB images during TBB procedures in comparison with actual bronchi has been developed. We evaluated the usefulness of the virtual bronchoscopic navigation system for CT-guided TBB using an ultrathin bronchoscope (navigation method) to diagnose small peripheral pulmonary lesions, and compared the results to those with previous method that uses VB images in a simulation (simulation method). We performed CT-guided TBB using an ultrathin bronchoscope for 69 patients with 71 small peripheral pulmonary lesions (mean diameter, 13.7 mm) between November 2002 and November 2005 with the navigation method. CT-guided TBB with the navigation method was performed safely without any serious complications for all patients. Mean time to the initial scan, time to the first biopsy and total examination time were 5.3, 8.5 and 24.5 min, respectively. Fifty lesions (70%) were diagnosed by this procedure. Compared to simulation method, diagnostic sensitivity was higher in the navigation method, but the difference was not significant. However, the time to the first biopsy and total examination time were significantly shorter in the navigation method than in the simulation method (p<0.05). In summary, the virtual bronchoscopic navigation system was safely used, effective for diagnosing small peripheral pulmonary lesions, and useful for shortening the examination time of CT-guided TBB using an ultrathin bronchoscope.

Aged↗
PubMed2006

Clinical significance of a blood eosinophilia in adult T-cell leukemia/lymphoma: a blood eosinophilia is a significant unfavorable prognostic factor.

We investigated the clinical significance of a blood eosinophilia in a cohort of 158 consecutive patients with adult T-cell leukemia/lymphoma (ATLL), and multivariate analysis revealed that a blood eosinophilia was an independent and a significant unfavorable prognostic factor. Interestingly, a blood eosinophilia was independent of serum LDH level, which might reflect the tumor burden. The present study shows that measurement of the blood eosinophil count is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients.

Adult↗
PubMed2006

Twisted growth and organization of cortical microtubules.

In plants, directional cell expansion greatly contributes to the final shape of mature cells, and thus to organ architecture. A particularly interesting mode of cell expansion is helical growth in which the growth axis is continuously tilted either to the right or to the left as the cell grows. Fixed handedness of helical growth raises fundamental questions on the possible origin of left-right asymmetry. Twisting mutants of Arabidopsis thaliana offer unique opportunities to study the cellular basis of helical growth. Most of the twisting mutants with fixed handedness have been shown to have defects in microtubule functions, whereas mutants that twist in non-fixed directions appear to be defective in auxin response or transport. Good correlations have been found between the tilted growth direction and alignment of cortical microtubule arrays in twisting mutants with compromised microtubule functions. The present challenge is to understand how particular array patterns are organized during progression of the interphase in rapidly expanding cells. Molecular and cell biological studies on twisting mutants will lead to better understanding on how wild-type plant cells utilize the microtubule cytoskeleton to initiate and rigorously maintain straight growth.

Microtubules↗
PubMed2006

CCR4 as a novel molecular target for immunotherapy of cancer.

Leukocyte trafficking, which is critically regulated by chemokines and their receptors, shares many of the characteristics of tumor cell infiltration and metastasis. Expression of CC chemokine receptor 4 (CCR4) by tumor cells is associated with skin involvement, but CCR4 also has an important role in normal and tumor immunity. In a subset of patients with CCR4(+) T-cell leukemia/lymphoma, the tumor cells themselves function as regulatory T (Treg) cells, contributing to tumor survival in the face of host antitumor immune responses. In other types of cancers, the chemokines TARC/CCL17 and MDC/CCL22, specific ligands for CCR4 that are produced by tumor cells and the tumor microenvironment, attract CCR4(+) Treg cells to the tumor, where they create a favorable environment for tumor escape from host immune responses. A novel humanized anti-CCR4 monoclonal antibody (mAb) has been developed, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity by increasing its binding affinity to Fc receptor on effector cells. We are now conducting a phase I clinical trial of this anti-CCR4 mAb in patients with CCR4(+) T-cell leukemia/lymphoma in Japan (clinical trials gov. identifier: NCT00355472). Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill the CCR4(+) tumor cells, but also to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.

Humans↗
PubMed2006

Potential for assessing quality of protein structure based on contact number prediction.

We developed a novel knowledge-based residue environment potential for assessing the quality of protein structures in protein structure prediction. The potential uses the contact number of residues in a protein structure and the absolute contact number of residues predicted from its amino acid sequence using a new prediction method based on a support vector regression (SVR). The contact number of an amino acid residue in a protein structure is defined by the number of residues around a given residue. First, the contact number of each residue is predicted using SVR from an amino acid sequence of a target protein. Then, the potential of the protein structure is calculated from the probability distribution of the native contact numbers corresponding to the predicted ones. The performance of this potential is compared with other score functions using decoy structures to identify both native structure from other structures and near-native structures from nonnative structures. This potential improves not only the ability to identify native structures from other structures but also the ability to discriminate near-native structures from nonnative structures.

Algorithms↗
PubMed2006

Clinical significance of serum Th1-, Th2- and regulatory T cells-associated cytokines in adult T-cell leukemia/lymphoma: high interleukin-5 and -10 levels are significant unfavorable prognostic factors.

Patients with adult T-cell leukemia/lymphoma (ATLL) are in a severely immunocompromised state. Therefore, it is assumed that ATLL cells either express particular cytokines or induce their expression in host immune cells, disrupting the balanced production of cytokines and causing the host's immune system to break down. We examined the levels of serum cytokines including T helper type 1- (Th1-) associated cytokines [IFN-gamma, TNF-alpha, and interleukin (IL)-2], Th2-associated cytokines (IL-4, -5 and -6) and regulatory T cell-associated cytokines (IL-10 and TGF-beta1) in 94 ATLL patients, 39 asymptomatic human T-cell lymphotropic virus type-1 (HTLV-1) carriers and 50 healthy adult volunteers, to clarify whether elevated levels of particular cytokines are associated with the prognosis of ATLL patients. On multivariate analysis, high IL-5 and IL-10 levels were independent and significant unfavorable prognostic factors among the ATLL patients. The IL-10 level significantly increased with disease progression at each step from asymptomatic HTLV-1 carrier to ATLL of the indolent variant (chronic and smoldering subtypes) to ATLL of the aggressive variant (acute and lymphoma subtypes). Furthermore, high IL-10 was significantly associated with high lactate dehydrogenase (LDH), indicating that the IL-10 level reflects the tumor burden. The IL-5 level was not associated with disease progression nor LDH. Among ATLL patients with the aggressive variant, high IL-5, but not high IL-10, was an independent and significant unfavorable prognostic factor on multivariate analysis. Measurement of serum IL-5 and IL-10 levels is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients.

Adult↗
PubMed2006

Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege.

Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of inflammatory cells, but the contribution of the abundant nontumor cells to HL pathogenesis is poorly understood. We showed that migratory CD4(+) cells induced by HL cells were hyporesponsive to T-cell receptor stimulation and suppressed the activation/proliferation of the effector CD4(+) T cells in an autologous setting. We further showed that HL cells in the affected lymph nodes were surrounded by a large number of lymphocytes expressing both CC chemokine receptor 4 (CCR4) and FOXP3. These findings indicate that the migratory cells induced by HL cells function as regulatory T (Treg) cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. In addition, we showed that a chimeric anti-CCR4 monoclonal antibody (mAb) could deplete CCR4(+) T cells and inhibit the migration of CD4(+)CD25(+) T cells in vitro. Recognition of the importance of CCR4(+) Treg cells in the pathogenesis of HL will allow rational design of more effective treatments, such as use of an anti-CCR4 mAb, to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.

Adult↗
PubMed2006

Acute sensorineural hearing loss and vertigo in a young adult with congenital plasminogen disorder.

A 19-year-old Japanese man exhibiting acute right sensorineural hearing loss and vertigo was referred to the Jichi Medical School Hospital in June 1994. Although he had no history of recurrent thrombosis and no family history of thrombosis, he had undergone reconstruction of a right foot joint fracture 4 months earlier. Screening studies for plasminogen activity demonstrated 10% of normal plasminogen activity and his plasminogen was diagnosed as "plasminogen Tochigi" by the gene analysis using restriction enzyme Fnu4HI. The patient's hearing returned to normal with administration of heparin, and he was prescribed warfarin for the prevention of thrombosis until October 1995. There was no recurrence of hearing loss during seven years of follow-up. The cause of this patient's hearing loss is believed to be associated with consumption of the already low levels of plasminogen as a result of his surgery as well as congenital plasminogen disorder.

Acute Disease↗
PubMed2006

Polymorphism of egfr Intron1 is associated with susceptibility and severity of asthma.

To clarify the associations of the egfr CA repeat polymorphism with asthma and its severity, we examined 579 Japanese asthmatics and 232 control subjects. The number of CA repeat ranges from 9 to 24. Asthmatic patients had a significantly higher incidence of having shorter alleles (<==16 CA repeats) compared with control subjects (p < 0.05). The most severe asthmatic patients have the highest frequency of short alleles (p < 0.05). In addition, subjects treated with leukotriene modifiers had higher incidence of having shorter allele compared to those without it (p < 0.01). Thus, the egfr CA repeat polymorphism is associated with the susceptibility and the severity of asthma.

Adult↗
PubMed2006

[Constituents relating to anti-oxidative and alpha-glucosidase inhibitory activities in Yacon aerial part extract].

Hot water extract of the aerial part of Yacon (Smallanthus sonchifolia, Compositae) showed potent free radical-scavenging activity and inhibitory effects on lipid peroxidation in rat brain homogenate. The most potent antioxidative activity focused on the 50% MeOH-eluted fraction on DIAION HP-20 column chromatography. The structure of the major component in the fraction was identified as 2,3,5-tricaffeoylaltraric acid (TCAA) based on spectroscopic evidence. The antioxidative activity of TCAA is superior to that of natural antioxidants such as (+/-)-catechin, alpha-tocopherol, and ellagic acid, and TCAA also showed selective maltase-inhibitory activity (IC(50) 49 microg/ml). As the hypoglycemic activity of Yacon extract was described in a previous report, the present results showing that the aerial part of Yacon has strong antioxidative activity may encourage its potential use as a food supplement to prevent type II diabetes.

Animals↗
PubMed2006

A virtual bronchoscopic navigation system for pulmonary peripheral lesions.

STUDY OBJECTIVES: We performed ultrathin bronchoscopy for pulmonary peripheral lesions using a system that displays virtual bronchoscopy (VB) images to the lesion simultaneously with actual images and navigates the bronchoscope to the target bronchus. We then evaluated the system with regard to its usefulness and problems. DESIGN: A pilot study. SETTING: A tertiary teaching hospital. PATIENTS: The subjects were consecutive patients with small pulmonary peripheral lesions (< or = 30 mm). INTERVENTIONS: Using this system, the rotation, advancement, and retreat of VB images were possible, and the bronchus into which the bronchoscope was to be advanced was displayed. VB images were displayed along with actual images, and the ultrathin bronchoscope was advanced to the target bronchus under direct vision. Under CT and radiographic fluoroscopy, a pair of forceps was inserted into the lesion via the bronchoscope. Thin-section CT images were obtained; after confirming the advancement of the bronchoscope into the target bronchus and the arrival of the forceps at the lesion, a biopsy was performed. RESULTS: Study subjects included 37 patients with 38 lesions. VB images to a median of the sixth- (third- to ninth-) order bronchi could be produced. Using this system, the ultrathin bronchoscope could be advanced into the planned route for 36 of the 38 lesions (94.7%). The system was used for a median of 2.6 min, and the median examination time was 24.9 min. The biopsy forceps could be advanced to the lesion in 33 of the 38 lesions (86.8%), and diagnosis was possible for 31 lesions (81.6%). CONCLUSIONS: This navigation system is useful for ultrathin bronchoscopy for pulmonary peripheral lesions.

Adult↗
PubMed2006

Molecular-based haplotype analysis of the beta 2-adrenergic receptor gene (ADRB2) in Japanese asthmatic and non-asthmatic subjects.

BACKGROUND: The beta2-adrenergic receptor gene (ADRB2) is a target molecule of beta2-agonists. Single nucleotide polymorphisms (SNPs) in the ADRB2 are related to the effectiveness of beta2-agonists. However, there are some discrepancies in the results of pharmacogenetic studies of ADRB2 among different ethnic groups. The aims of this study were to determine the ADRB2 haplotypes and diplotypes in Japanese asthmatic and non-asthmatic subjects and to examine their relation to asthma and to compare these results with previous studies done in other ethnic groups. METHODS: Complete sequences for 3 kb promoter and 1.2 kb structural regions of ADRB2 were analyzed in 48 Japanese asthmatics and 100 controls, and haplotypes and diplotypes of SNPs were analyzed. RESULTS: Fifteen SNPs including a novel one in -839 were observed. Allele frequencies for all SNPs were similar between asthmatics and controls. We also identified 42 haplotypes and 54 diplotypes of ADRB2 in a Japanese population. The frequencies were similar between the two groups. They were classified into 17 and 23 types, respectively, according to Drysdale's haplotype-organization system, and a significant ethnic difference was observed between the Japanese and Caucasian populations. CONCLUSIONS: The frequencies of SNPs and ADBR2 haplotypes in Japanese are different from those in Caucasians and African Americans. These divergences might imply the need for independent pharmacogenetic studies for ADBR2 in each ethnic group.

Black or African American↗
PubMed2006

[A case of advanced double cancer of the lung and stomach responding to combination chemotherapy of cisplatin and TS-1].

A 76-year-old male patient was diagnosed with advanced double cancer of the lung and stomach. He had also been suffering from interstitial pneumonitis for several years. He was treated with combination of cisplatin and TS-1. TS-1 (120 mg/body/day) was administered for 21 days from day 1, and cisplatin (60 mg/m(2)) was given on day 8 followed by a 14-days interval. After two courses of chemotherapy,the dose of cisplatin was reduced to 48 mg/m(2) because of grade 1 serum creatinine elevation. The lesions of the lung and stomach were improved significantly without exacerbation of the interstitial pneumonitis.

Aged↗
PubMed2006

[A case of lung tuberculosis showing no chest radiograph findings with recurrent hemoptysis].

A 59-year-old male was referred to our hospital because of hemoptysis. A chest X-ray film and 7 mm-slice CT scan showed no abnormal finding. Bronchoscopy revealed hemorrhage in the right upper bronchus (B1a) Bronchial lavage of the lesion was performed, but Mycobacterium tuberculosis was not detected. Because of repeated hemoptysis, he was admitted to our hospital. Right bronchial artery angiograph showed vascular hyperplasia in the peripheral part of the upper lobal branch, and this lesion was suggested to be a bleeding point. There were no vascular malformations. Thin slice (0.5 mm-thick) CT scan showed mild infiltrative shadow in the right upper lobe. After admission, sputa smear for mycobacteria and PCR for M. tuberculosis became positive, and he was diagnosed as pulmonary tuberculosis. After starting antituberculous chemotherapy, hemoptysis disappeared, and sputa smear and culture for mycobacteria converted to negative. This case suggests that lung tuberculosis should be suspected in patients having hemoptysis, even though they had no chest X-ray film abnormality.

Hemoptysis↗
PubMed2006

[An autopsy case of Aspergillus pneumonia after inhalation of a great deal of dust in a mushroom factory].

A man in his forties with alcoholic liver injury was referred to our hospital because of progressive dyspnea and diffuse infiltrative shadows in both lung fields. Two weeks before admission he had carried a lot of rotten Enoki mushrooms in his factory, and then inhaled a great deal of airborne dust. Serological examination showed extremely elevated beta-D-glucan and positive Aspergillus antigen. Culture of dust collected from the floor of the factory proved to be positive for Aspergillus fumigatus. Aspergillus pneumonia was diagnosed and treatment with anti-fungal drugs was started. In spite of intensive treatment he died of respiratory failure. The autopsy disclosed multiple abscess formation containing hyphae of Aspergillus fumigatus and granulomatous reaction with multinuclear giant cells. However, there was no Aspergillus invasion in other organs. This was a rare case of invasive pulmonary aspergillosis that developed after inhalation of organic dust in a non-immunocompromised host.

Adult↗
PubMed2005

Protection of plasminogen activator inhibitor-1-deficient mice from nasal allergy.

This study was performed to clarify the relationship between fibrinolytic components and the pathology of allergy, particularly that during the development of nasal allergy and nasal tissue changes. Intranasal OVA challenge after sensitization by i.p. administration of OVA induced a higher level of excess subepithelial collagen deposition in wild-type (WT) C57BL/6J mice than in plasminogen activator inhibitor (PAI)-1-deficient (PAI-1(-/-)) mice. The excess PAI-1 induction in the nasal mucosa and higher level of active PAI-1 in the nasal lavage fluid of WT-OVA mice compared with those in WT-control mice suggested that the decrease of proteolytic activity inhibits the removal of subepithelial collagen. The frequency of sneezing, nasal rubbing, nasal hyperresponsiveness, production of specific IgG1 and IgE in the serum, and production of IL-4 and IL-5 in splenocyte culture supernatant increased significantly in WT-OVA mice. In PAI-1(-/-) mice, these reactions were absent, and specific IgG2a in serum and IFN-gamma in splenocyte culture medium increased significantly. Histopathologically, there were marked goblet cell hyperplasia and eosinophil infiltration into the nasal mucosa in WT-OVA mice, but these were absent in PAI-1(-/-) mice. These results indicate that the immune response in WT-OVA mice can be classified as a dominant Th2 response, which would promote collagen deposition. In contrast, the Th2 response in PAI-1(-/-) mice was down-regulated, and the immune response shifted from Th2-dominant reaction to a Th1-dominant one. Taken together, these findings suggest that PAI-1 plays an important role not only in thrombolysis but also in immune response.

Animals↗