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Biomedical subjects

K Kono

Publications and source records attributed to K Kono.

At least 19 recordsLinked to original sources

Evolution of virulence in picornaviruses.

The Picornaviridae encompass many positive-strand RNA viruses, all of which share a generally similar genome design and capsid structure, but which induce quite diverse diseases in humans and other animals. Picornavirus strains of the same serotype have been shown to express different virulence (or pathogenic) phenotypes when studied in animal models, demonstrating that key elements of pathogenesis reside in the viral genome. However, the genetics that determine the virulence phenotype of any picornavirus are poorly understood. Picornaviruses do not have virulence genes per se, but the design ofthe capsid andhow it interacts with the virus receptor expressed on the host cell surface, specific sequences within the nontranslated regions of the viral genome, as well as coding sequences that result in different protein sequences may all have a part in determining the virulence phenotype. Virulence may be better understood as a continuum from an apparent inability to induce disease to the ability to cause severe pathogenic changes. Ultimately, the ability of a picornavirus to induce disease depends upon viral genetics and how they are modulated by the host environment.

Animals↗

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma.

The utilisation of antitumour T cells induced by cancer vaccination with HER-2 peptides or antibodies (Herceptin) against HER-2, as immunotherapy for oesophageal cancer, is a novel and attractive approach. It is important to clarify the frequencies of HER-2 expression and gene amplification in patients with oesophageal squamous cell carcinoma (SCC) and to evaluate the relationship between HER-2 status and HLA haplotype, since the candidates for HER-2 peptide-based vaccination are restricted to a certain HLA haplotype. We determined the frequency of HER-2 expression using the HercepTest for immunohistochemistry and HER-2 gene amplification by fluorescence in situ hybridisation (FISH) assay in oesophageal SCC (n=66). HER-2-positive tumours (1+/2+/3+) analysed by a HercepTest were observed in 30.3% of all the patients and HER-2 gene amplification evaluated by FISH was observed in 11.0% of all the patients, in which all HercepTest (3+) tumours were found to have gene amplification and three of six moderately positive (2+) tumours showed gene amplification. Furthermore, HER-2-positive cells were present more diffusely and were larger within each tumour in the patients who were HercepTest 3+ than those who were HercepTest 1+. Moreover, the survival rate in HER-2-positive group was significantly worse than that in HER-2-negative group. Also, the survival rate in the patients with HER-2 gene amplification was significantly worse than that without HER-2 gene amplification. In addition, oesophageal SCC patients with both HLA-A24-positive and HER-2-positive tumours (1+/2+/3+) accounted for 26% of these cases, and both HLA-A2- and HER-2-positive tumours accounted for 18% of them.

Aged↗

Characterization of an infectious cDNA copy of the genome of a naturally occurring, avirulent coxsackievirus B3 clinical isolate.

Group B coxsackieviruses (CVB) cause numerous diseases, including myocarditis, pancreatitis, aseptic meningitis and possibly type 1 diabetes. To date, infectious cDNA copies of CVB type 3 (CVB3) genomes have all been derived from pathogenic virus strains. An infectious cDNA copy of the well-characterized, non-pathogenic CVB3 strain GA genome was cloned in order to facilitate mapping of the CVB genes that influence expression of a virulence phenotype. Comparison of the sequence of the parental CVB3/GA population, derived by direct RT-PCR-mediated sequence analysis, to that of the infectious CVB3/GA progeny genome demonstrated that an authentic copy was cloned; numerous differences were observed in coding and non-coding sequences relative to other CVB3 strains. Progeny CVB3/GA replicated similarly to the parental strain in three different cell cultures and was avirulent when inoculated into mice, causing neither pancreatitis nor myocarditis. Inoculation of mice with CVB3/GA protected mice completely against myocarditis and pancreatitis induced by cardiovirulent CVB3 challenge. The secondary structure predicted for the CVB3/GA domain II, a region within the 5' non-translated region that is implicated as a key site affecting the expression of a cardiovirulent phenotype, differs from those predicted for cardiovirulent and pancreovirulent CVB3 strains. This is the first report characterizing a cloned CVB3 genome from an avirulent strain.

5' Untranslated Regions↗

Transcranial magnetic stimulation over the cerebellum evokes late potential in the soleus muscle.

Transcranial magnetic stimulation (TMS) with a double cone coil placed over the left lateral side of the basal occiput was able to elicit late electromyographic (EMG) responses at the bilateral soleus muscles (SOL) averaged over 30 stimulation events, with a mean latency of approximately 100 ms. These EMG responses were detected using a low frequency bandpass filter with 0.05 Hz magnetic stimulation on ten healthy subjects in standing posture. As magnetic stimulation over the left basal occiput with a double cone coil can stimulate cerebellar structure, this late response seems to be conducted from the cerebellar structure to the SOL via an as yet unknown descending pathway. Here, we report new late EMG responses in relation to cerebellum or cerebellum related structures.

Adult↗

Cellular immunity to the Her-2/neu protooncogene.

Her-2/neu (HER-2) is a 185-kDa receptor-like glycoprotein that is overexpressed by a variety of tumors such as breast, ovarian, gastric, and colorectal carcinomas. Overexpression of this oncogene is directly associated with malignant transformation of epithelial cells. The frequency of HER-2 overexpression varies among the different types of cancers, but universally represents a marker of poor prognosis. The critical role of HER-2 in epithelial oncogenesis as well as its selective overexpression on malignant tissues makes it an ideal target for immunotherapy. Antibodies and T cells reactive to HER-2 are known to naturally occur in patients with HER-2 positive tumors, confirming the immunogenicity of the molecule. Both antibodies as well as T cells reactive to HER-2 have been utilized for immunotherapy of HER-2 positive tumors. The "humanized" monoclonal antibody Herceptin has been tested in several clinical trials and found to be an effective adjuvant therapy for HER-2 positive breast and ovarian cancer patients. However, the frequency of patients responding to Herceptin is limited and a majority of patients initially responding to Herceptin develop resistance within a year of treatment. The use of vaccination strategies that generate T cell responses with or without accompanying antibody responses may serve to mitigate the problem. Various strategies for generating T cell-mediated responses against HER-2 are currently being examined in animal models or in clinical trials. The potential advantages of the various approaches to immunotherapy, their pitfalls, and the mechanisms by which HER-2 positive tumors can evade immune responses are discussed in this review.

Amino Acid Sequence↗

Thermosensitive polymer-modified liposomes.

Temperature-sensitive liposomes are considered to be a promising tool to achieve site-specific delivery of drugs. These liposomes have been prepared using lipids whose membranes undergo a gel-to-liquid crystalline phase transition a few degrees above physiological temperature. However, recently, temperature-sensitization of liposomes has been attempted using thermosensitive polymers. So far, functional liposomes whose contents release behavior, surface properties, and affinity to cell surface can be controlled in a temperature-dependent manner, have been developed according to this strategy. The design and function of these thermosensitive polymer-modified liposomes have been outlined in this review.

Animals↗

The Y chromosome in the liverwort Marchantia polymorpha has accumulated unique repeat sequences harboring a male-specific gene.

The haploid liverwort Marchantia polymorpha has heteromorphic sex chromosomes, an X chromosome in the female and a Y chromosome in the male. We here report on the repetitive structure of the liverwort Y chromosome through the analysis of male-specific P1-derived artificial chromosome (PAC) clones, pMM4G7 and pMM23-130F12. Several chromosome-specific sequence elements of approximately 70 to 400 nt are combined into larger arrangements, which in turn are assembled into extensive Y chromosome-specific stretches. These repeat sequences contribute 2-3 Mb to the Y chromosome based on the observations of three different approaches: fluorescence in situ hybridization, dot blot hybridization, and the frequency of clones containing the repeat sequences in the genomic library. A novel Y chromosome-specific gene family was found embedded among these repeat sequences. This gene family encodes a putative protein with a RING finger motif and is expressed specifically in male sexual organs. To our knowledge, there have been no other reports for an active Y chromosome-specific gene in plants. The chromosome-specific repeat sequences possibly contribute to determining the identity of the Y chromosome in M. polymorpha as well as to maintaining genes required for male functions, as in mammals such as human.

Amino Acid Sequence↗

Surface fluctuations of normal and superfluid 3He probed by Wigner solid dynamics.

Electron scattering from surface fluctuations on normal and superfluid 3He has been measured by its effect on the linewidth of the low-wave-vector transverse magnetophonon mode of the electron crystal (the Wigner solid) floating on the helium surface. The relaxation rate becomes anomalously low below 70 mK, and reaches a plateau at about 3 times less than its expected value before dropping further at the superfluid transition. The absence of such anomalous behavior on 4He suggests that the effect is specific to liquid 3He.

Journal Article↗

Brain magnetic resonance imaging in 23 patients with mucopolysaccharidoses and the effect of bone marrow transplantation.

A longitudinal study of cranial magnetic resonance imaging (MRI) was carried out in 23 patients with mucopolysaccharidoses (MPS); 1 each of types IH, VI, and VII; 2 of type IS; 10 of type II; and 4 each of types IIIB and IVA. Six types of distinct abnormalities were 1) cribriform changes or spotty changes in the corpus callosum, basal ganglia, and white matter; 2) high-intensity signal in the white matter on T2-weighted image; 3) ventriculomegaly; 4) diffuse cerebral cortical atrophy; 5) spinal cord compression; and 6) megacisterna magna. The cribriform changes that corresponded to dilated perivascular spaces were found in the patients with MPS IS, II, and VI. The patchy and diffuse intensity changes were found in the patient with MPS II and IIIB, respectively. MPS IH and the severe type of MPS II showed marked ventriculomegaly. Marked cerebral atrophy was observed in all MPS IIIB patients and in the severe type of MPS II patients. Spinal cord compression was a feature usually observed in MPS IH, IVA, VI, and VII. Megacisterna magna was frequent in the patients with MPS II (6/10). In two of five patients, the therapeutic effect of bone marrow transplantation (BMT) was remarkable. Both the cribriform changes and the intensity change of the white matter in a MPS VI patient disappeared eight years after the BMT. Slight improvement of cribriform change was noted in one patient with MPS II three years after the BMT. MRS was not sufficient to estimate the accumulation of glycosaminoglycans but was useful for evaluating neuronal damages.

Adolescent↗

MR imaging of a case of a dumbbell-shaped spinal schwannoma with intramedullary and intradural-extramedullary components.

We present here a case of intramedullary- and extramedullary-intradural, dumbbell-shaped schwannoma that developed in the upper thoracic cord in a middle-aged man. Before surgery, the tumor was clearly revealed as a mass with two components, intramedullary and extramedullary, on MRI, and it could be useful for operation. We discuss the possible pathogenesis of this tumor.

Humans↗

Endoscopic findings of radiation esophagitis in concurrent chemoradiotherapy for intrathoracic malignancies.

BACKGROUND AND PURPOSE: The incidence and extent of radiation esophagitis were assessed endoscopically in patients treated with concurrent chemoradiotherapy. PATIENTS AND METHODS: Eighty-two patients who received thoracic radiotherapy for lung, thymic, or esophageal cancer were investigated endoscopically from July 1991 to the end of 1997. Among them, 23 esophageal cancer patients were treated with radiation alone, and the others were treated with concurrent chemoradiotherapy. Esophageal endoscopy was performed during or just after radiotherapy. The presence of radiation esophagitis was assessed and assigned an endoscopic score (i.e. grade 0 for normal, 1 for erythema, 2 for erosion or sloughing, 3 for ulcer, hemorrhage, or stricture). The symptomatic grade was assessed using the RTOG (Radiation Therapy Oncology Group) acute radiation morbidity score. RESULTS: A correlation was seen between endoscopic and RTOG scores. However, even some patients with RTOG grade 0 to 1 had endoscopic grade 3 esophagitis. Endoscopic grade 3 was observed in 16 (27.1%) patients in the concurrent chemoradiotherapy group, whereas it did not occur in any patient in the radiation alone group (P=0.004). CONCLUSIONS: Our results suggest that (1) RTOG score correlates closely to esophageal mucosal damage, and (2) more severe esophagitis occurs in those undergoing concurrent chemoradiotherapy than those undergoing radiotherapy alone [corrected].

Adult↗

Novel gene delivery systems: complexes of fusigenic polymer-modified liposomes and lipoplexes.

We have previously developed the succinylated poly(glycidol)-modified liposome which becomes fusigenic under weakly acidic condition. In this report, we describe that complexation of this pH-sensitive, fusigenic liposome with a lipoplex consisting of 3beta-(N-(N',N'-dimethylaminoethane) carbamoyl)cholesterol, dioleoylphosphatidylethanolamine and plasmid DNA gives efficient gene delivery systems. In this study, we prepared the complexes, which are termed SucPG-complexes, with a positively or negatively charged surface by mixing the lipoplex with varying amounts of the SucPG-modified liposomes. The positively charged SucPG-complexes either bearing or not bearing a cell-specific ligand, transferrin, could transfect HeLa cells efficiently. In contrast, the negatively charged complexes hardly transfected the cells when transferrin was not conjugated to them. However, the negatively charged SucPG complexes bearing transferrin exhibited high transfection ability against HeLa and K562 cells, indicating that this gene delivery was achieved through their binding to the cellular receptors. These transferrin-attached, negatively charged complexes retained the high transfection ability in the presence of serum. Thus, this negatively charged complex may be useful as nonviral vectors in vivo.

Blood↗

Effect of oesophagectomy on monocyte-induced apoptosis of peripheral blood T lymphocytes.

BACKGROUND: Surgical stress has been reported to induce immunosuppression. The mechanisms giving rise to T-cell dysfunction following surgery are still unclear. The cellular mechanisms behind T-cell dysfunction following surgery were investigated, based on the induction of T-cell apoptosis and downregulation of T-cell signalling molecules. METHODS: Peripheral blood T cells were collected and separated before and after surgery in patients who had oesophagectomy, gastrectomy or cholecystectomy, and studied for their ability to produce cytokines, the induction of T-cell apoptosis with terminal deoxynucleotidyl transferase-mediated dUPT-biotin nick end labelling methods, and the expression of T-cell signalling zeta (TCR zeta) molecules with intracellular staining. RESULTS: The increased degree of T-cell apoptosis, downregulation of TCR zeta molecules and impaired cytokine production of T cells were significant on days 1 and 3 after operation in patients who had oesophagectomy, but not after gastrectomy or cholecystectomy. A higher level of T-cell apoptosis was observed in the co-culture with postoperative monocytes than with preoperative monocytes. CONCLUSION: Peripheral blood T cells obtained after oesophagectomy underwent apoptosis that correlated with the downregulation of TCR zeta molecules. Postoperative monocytes induced by surgical stress were able to mediate the T-cell apoptosis.

Aged↗

Interposed colon between remnants of the small intestine exhibits small bowel features in a patient with short bowel syndrome.

We describe herein the case of a 48-year-old man who underwent emergency massive resection of the small intestine due to a strangulated ileus, which led to short bowel syndrome (SBS), as he was left with only 7 cm of jejunum and 8 cm of ileum with ileocecal valve. He then received interposition of a colon segment between the jejunum and ileum remnants isoperistaltically. For 24 months after the operation, he has been able to tolerate oral intake, but still requires partial home parenteral nutritional support during the night on a bimonthly basis. Biochemical and nutritional parameters, including the analysis of minerals and trace elements, indicated that the patient was in relatively good health. Histological examination revealed that the mucosa of the interposed colon showed hypertrophy and hyperplasia of the crypt glands, and cells resembling Paneth cells which are usually seen in the small intestine, suggesting that the colon segment exhibits adaptive changes to the small intestine. Colon interposition may be a useful technique in patients with SBS when the small bowel is too short for the other surgical considerations.

Anastomosis, Surgical↗

Reduction of acetals with samarium diiodide in acetonitrile in the presence of Lewis acids.

Transformation of acetals into ethers by partial reduction using a samarium diiodide-Lewis acids-acetonitrile system is described. The reaction with aromatic acetals occurred in good yields in the presence of aluminum chloride (2 eq) whereas the corresponding aliphatic, vinylic, and alkynyl derivatives did not afford ethers under the same conditions. Beta-elimination to give an enol ether becomes predominant when aliphatic acetals that possess a hydrogen at the 2-position are treated with iodotrimethylsilane in the presence of SmI2 or SmI3.

Acetals↗

S-15183a and b, new sphingosine kinase inhibitors, produced by a fungus.

In the course of our screening for inhibitors of sphingosine kinase, we found two active compounds in a culture broth of a fungus, Zopfiella inermis SANK 15183. The structures of the compounds, named S-15183a and b, were elucidated by a combination of spectroscopic analyses to be new azaphilone-type metabolites. S-15183a and b inhibited sphingosine kinase from rat liver with IC50 values of 2.5 and 1.6 microM, respectively. S-15183a also inhibited endogenous SPH kinase activity in intact platelets.

Blood Platelets↗

Elevated caspase-3 activity in peripheral blood T cells coexists with increased degree of T-cell apoptosis and down-regulation of TCR zeta molecules in patients with gastric cancer.

To evaluate the mechanisms of T-cell dysfunction in patients with gastric cancer, we investigated the caspase activity of T cells, the induction of spontaneous T-cell apoptosis, the expression of T-cell receptor (TCR) zeta molecules, and the ability of T cells to produce cytokines in peripheral blood lymphocytes from patients (n = 22) and healthy controls (n = 14). The caspase-3 activity of T cells was studied as the protease activity of caspase-3 using the cell-permeable substrate of PhiPhiLux G1D2. Flow cytometric analysis was performed with triple staining by annexin V-FITC, propidium iodide, and CD3-R-phycoerythrin-Cy5 for the detection of T-cell apoptosis and with intracellular staining using permeabilized cells for the expression of TCR-zeta molecules. IFN-gamma and tumor necrosis factor alpha production from T cells was evaluated in response to anti-CD3 stimulation. Caspase-3 activity of peripheral blood T cells from patients with advanced disease was significantly increased compared with that from controls [15.5 +/- 3.6 mean fluorescence intensity (MFI) versus 11.5 +/- 3.3 MFI; P = 0.0068]. Parallel to this, the apoptosis of peripheral blood T cells from patients with advanced disease was significantly higher than for those from controls (16.5 +/- 15.5% versus 4.8 +/- 2.7%; P = 0.010). Furthermore, the expression of TCR-zeta molecules in patients with advanced disease was significantly decreased in comparison with that of the controls (41.0 +/- 13.9 MFI versus 56.7 +/- 16.3 MFI; P = 0.014), and this decreased expression coexisted with impaired IFN-gamma (42.4 +/- 43.2 pg/ml versus 1,757.4 +/- 2449.0 pg/ml; P = 0.031) and tumor necrosis factor alpha (682.6 +/- 519.3 pg/ml versus 1,686.0 +/- 1,533.7 pg/ml; P = 0.041) production of T cells. Thus, peripheral blood T cells from gastric cancer patients simultaneously exhibit an elevated caspase-3 activity, an increased degree of T-cell apoptosis, a down-regulation of TCR-zeta molecules, and impaired cytokine production. These observations suggest that induction of T-cell apoptosis coexisting with a down-regulation of TCR-zeta molecules may be responsible for T-cell dysfunction in patients with gastric cancer.

Apoptosis↗