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Biomedical subjects

S Mukai

Publications and source records attributed to S Mukai.

At least 37 records · Page 2Linked to original sources
PubMed2000

Cross-presentation of tumor antigens to effector T cells is sufficient to mediate effective immunotherapy of established intracranial tumors.

The systemic adoptive transfer of tumor-sensitized T cells, activated ex vivo, can eliminate established intracranial tumors. Regression of MHC class II negative MCA 205 fibrosarcomas occurs optimally following adoptive transfer of both CD4 and CD8 tumor-sensitized T cells, indicating an important function for tumor-infiltrating APC. Here, we demonstrate that during an effector response, indirect presentation of tumor Ags to transferred T cells is sufficient to mediate intracranial tumor regression. BALB/c --> CB6F1 (H-2bxd) bone marrow chimeras were challenged with the MCA 205 fibrosarcoma (H-2b). The tumor grew progressively in the H-2b-tolerant chimeras and stimulated an immune response in tumor-draining lymph nodes. Tumor-sensitized lymph node T cells were activated ex vivo with anti-CD3 and IL-2, then adoptively transferred to sublethally irradiated BALB/c or C57BL/6 recipients bearing established intracranial MCA 205 tumors. The transferred T cells eradicated MCA 205 tumors in BALB/c recipients and demonstrated tumor specificity, but had no therapeutic efficacy in the C57BL/6 recipients. These data establish that tumor-associated host cell constituents provide sufficient Ag presentation to drive effector T cell function in the complete absence of direct tumor recognition. This effector mechanism has an evident capacity to remain operative in circumstances of immune escape, where the tumor does not express the relevant MHC molecules, and may have importance even at times when direct CTL recognition also remains operative.

Adoptive Transfer↗
PubMed2000

2-5A antisense telomerase RNA therapy for intracranial malignant gliomas.

Malignant gliomas are the most common intracranial tumors and are considered incurable. Therefore, exploration of novel therapeutic modalities is essential. Telomerase is a ribonucleoprotein enzyme that is detected in the vast majority of malignant gliomas but not in normal brain tissues. We, therefore, hypothesized that telomerase inhibition could be a very promising approach for the targeted therapy of malignant gliomas. Thus, 2-5A (5'-phosphorylated 2'-5'-linked oligoadenylate)-linked antisense against human telomerase RNA component (2-5A-anti-hTER) was investigated for its antitumor effect on an intracranial malignant glioma model. 2-5A is a mediator of one pathway of IFN actions by activating RNase L, resulting in RNA degradation. By linking 2-5A to antisense, RNase L degrades the targeted RNA specifically and effectively. Prior to the experiments using intracranial tumor models in nude mice, we modified the in vitro and in vivo treatment modality of 2-5A-anti-hTER using a cationic liposome to enhance the effect of 2-5A-anti-hTER. Here we demonstrate that 2-5A-anti-hTER complexed with a cationic liposome reduced the viability of five malignant glioma cell lines to 20-43% within 4 days but did not influence the viability of cultured astrocytes lacking telomerase. Furthermore, treatment of intracranial malignant gliomas in nude mice with 2-5A-anti-hTER was therapeutically effective compared with the control (P < 0.01). These findings clearly suggest the therapeutic potentiality of 2-5A-anti-hTER as a novel approach for the treatment of intracranial malignant gliomas.

Adenine Nucleotides↗
PubMed2000

Reduced ventricular response irregularity is associated with increased mortality in patients with chronic atrial fibrillation.

BACKGROUND-Variations in the ventricular response interval (VRI) during atrial fibrillation (AF) may be reduced in patients with adverse clinical outcomes. The properties of VRI dynamics associated with prognosis remain undetermined. METHODS AND RESULTS-In 107 patients with chronic AF (age, 64+/-9 years), we analyzed a 24-hour ambulatory ECG for VRI variability (SD, SD of successive differences, and SD of 5-minute averages) and VRI irregularity (Shannon entropy of histogram, symbolic dynamics, and approximate entropy of beat-to-beat and minute-to-minute fluctuations [ApEn(b-b) and ApEn(m-m)]). During a follow-up period of 33+/-16 months, 18 patients died (17%), 9 from cardiac causes, 7 from fatal strokes, and 2 from malignancies. Reductions in all VRI variability and irregularity measures were associated with an increased risk for cardiac death but not for fatal stroke. A significant association with cardiac death was also found for ejection fraction (relative risk, 1.10; 95% confidence interval [CI], 1.04 to 1.17, per 1% decrement) and ischemic AF (relative risk, 6.52; 95% CI, 1.62 to 26. 3). After adjustment for these clinical variables, all irregularity measures except symbolic dynamics had predictive value (relative risks [95% CIs] per 1SD decrement: Shannon entropy of histogram, 2. 03 [1.14 to 3.61]; ApEn(b-b), 1.72 [1.14 to 2.60]; and ApEn(m-m), 1. 90 [1.03 to 3.52]); however, the predictive power of variability measures was no longer significant. When the patients were stratified with the 33rd and 67th percentile values of ApEn(b-b) (1. 83 and 1.94, respectively), the 5-year cardiac mortality rates for the upper, middle, and lower tertiles were 0%, 13%, and 43%, respectively (log-rank test, P=0.04). CONCLUSIONS-Reduced VRI irregularity in a 24-hour ambulatory ECG has an independent prognostic value for cardiac mortality during long-term follow-up in patients with chronic AF.

Adult↗
PubMed2000

The mammalian peroxin Pex5pL, the longer isoform of the mobile peroxisome targeting signal (PTS) type 1 transporter, translocates the Pex7p.PTS2 protein complex into peroxisomes via its initial docking site, Pex14p.

In mammals, two isoforms of the peroxisome targeting signal (PTS) type 1 receptor Pex5p, i.e. Pex5pS and Pex5pL with an internal 37-amino acid insertion, have previously been identified. Expression of either type of Pex5p complements the impaired PTS1 import in Chinese hamster ovary pex5 mutants, but only Pex5pL can rescue the PTS2 import defect noted in a subgroup of pex5 mutants such as ZP105. In this work, we found that Pex5pL directly interacts with the PTS2 receptor Pex7p, carrying its cargo PTS2 protein in the cytosol. Pex5pL, but not Pex5pS, mediated the binding of PTS2 protein to Pex14p by translocating Pex7p, demonstrating that Pex5pL plays a pivotal role in peroxisomal PTS2 import. Pex5p was localized mostly in the cytosol in wild-type CHO-K1 and Pex14p-deficient mutant cells, whereas it accumulated in the peroxisomal remnants in cell mutants defective in Pex13p or the RING family peroxins such as Pex2p and Pex12p. Furthermore, overexpression of Pex14p, but not Pex10p, Pex12p, or Pex13p, caused accumulation of Pex5p in peroxisomal membranes, with concomitant interference with PTS1 and PTS2 import. Therefore, Pex5p carrying the cargoes most likely docks with the initial site (Pex14p) in a putative import machinery, subsequently translocating to other components such as Pex13p, Pex2p, Pex10p, and Pex12p.

Animals↗
PubMed2000

Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-gamma agonists through induction of apoptosis.

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptors superfamily, have an important regulatory role in adipogenesis and inflammation. PPAR-gamma ligands induce terminal differentiation and growth inhibition of human breast cancer cells and prostatic cancer cells. In this study, we demonstrated that PPAR-gamma, but not PPAR-alpha, was expressed in human lung cancer cell lines by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. We also found that the synthetic PPAR-gamma agonist thiazolidinedione compounds (troglitazone) and the endogenous PPAR-gamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), inhibited the growth of human lung cancer cells through the induction of apoptosis. However, PPAR-alpha agonist (bezafibrate) and other prostanoids (PGE(2), PGF(2alpha)) did not induce apoptosis. These findings suggest that PPAR-gamma may play an important role in the pathogenesis of lung cancer and that PPAR-gamma agonist may be useful therapeutic agents in the treatment of human lung cancer.

Apoptosis↗
PubMed2000

Selective inhibition of cyclooxygenase-2 with antisense oligodeoxynucleotide restricts induction of rat adjuvant-induced arthritis.

The effects of cyclooxygenase (COX)-2 antisense oligodeoxynucleotide (ODN) in induction of adjuvant-induced arthritis were investigated. Female Lewis rats were injected with Mycobacterium butyricum intradermally at the base of tails to induce arthritis. Synthetic 18 mer phosphorothioate ODNs corresponding to the translation initiation site of rat COX-2 mRNA were prepared. The antisense (AS), sense (S), and "scrambled" (Sc) ODNs were intraperitoneally administered. Arthropathy was evaluated with arthritis score, paw edema, and histological examination. Expression of COX-1 and -2 protein and mRNA were examined with immunostaining and reverse-transcription polymerase chain reaction, respectively. COX-2 AS ODN significantly suppressed induction of arthritis in a dose-dependent manner without severe adverse effects, whereas S and Sc ODNs did not show significant inhibitory effects. COX-2 mRNA and protein expression were also suppressed only by COX-2 AS ODN without any alteration of COX-1 expression. These data suggest that selective inhibition of COX-2 with AS ODN may have a therapeutic potency in the treatment of rheumatoid arthritis.

Animals↗
PubMed2000

Reliable and cost-effective system for surgical stent graft insertion.

For intraoperative stented graft implantation, we use a half-inch translucent soft polyvinyl tube as a sheath and an obturator from a two-stage venous cannula as a pushing rod. Ten centimeters of any kind of graft can be used for the stent graft itself. The stent we used was a self-expandable Gianturco double Z stent and was sutured inside the graft.

Aortic Dissection↗
PubMed2000

The expansion of the hypopharynx by correction of glosso-larynx.

The width of the hypopharynx and oropharynx before and after the operation correction of glosso-larynx (CGL) was compared by cranial X-ray film. After the operation, the hyoid bone was seen to have moved downward, and the cranial bone was observed to have rotated forward. As a result, the hypopharynx and the oropharynx were expanded. Expansion of the hypopharynx resulted in the decreased resistance of flow decreased and the increased in airflow.

Airway Resistance↗
PubMed2000

Functions of the uvula and Z-pharyngoplasty.

UPPP includes uvulotomy. The uvula works as the pilot for eating and swallowing. We performed an operation which left the uvula intact and opened the pharynx by Z-opening the palate, Z-pharyngoplasty (ZPP). Twenty-four patients were studied before and after ZPP. The results of the operations were satisfactory. No patients complained of symptoms after uvulectomy. As for the changes indicated by sleep monitoring, minimum SaO2 increased significantly (P = 0.0026), pulse rate decreased significantly (P = 0.0144), apnea index decreased significantly (P = 0.0392), snoring decreased (P = 0.064), and the amount of hours of sleep when SaO2 was over 95% increased (P = 0.0690) after ZPP.

Adult↗
PubMed2000

Activin, inhibin, and follistatin in zebrafish ovary: expression and role in oocyte maturation.

Activins, inhibins, and follistatins are important regulators of mammalian reproduction. However, their roles in lower vertebrates are poorly understood. In this study, we examined the expression of activin A, inhibin A, and follistatins in the zebrafish ovary and determined their role in final oocyte maturation. Using reverse transcription-polymerase chain reaction with primers specific for activin/inhibin beta(A) subunit and for follistatins, we detected DNA fragments of the expected size, which, upon sequencing, conformed to activin/inhibin beta(A) and follistatin. Western blot analysis using an antibody against activin/inhibin beta(A) subunit revealed two bands with sizes similar to those of activin A and inhibin A. The expression of follistatins was also confirmed by Western blot analysis. These results suggest that activin A, an inhibin A-like molecule, and follistatins are expressed in the zebrafish ovary. In cultured zebrafish follicles, activin A and inhibin A both induced final oocyte maturation in a dose-dependent manner. The effects of activin A and inhibin A were blocked by their binding protein, follistatin-288. Interestingly, follistatin-288 also inhibited final oocyte maturation induced by gonadotropin and by maturation-inducing hormone (MIH), suggesting that activin A and/or inhibin A may be local regulators mediating gonadotropin- and MIH-induced final oocyte maturation. Taken together, these findings suggest that activin A and inhibin A are paracrine regulators of ovarian functions in fish.

Activins↗
PubMed2000

Dynamic regulation of middle cerebral artery blood flow velocity in aging and hypertension.

BACKGROUND AND PURPOSE: Although aging and hypertension may predispose hypertensive elderly subjects to cerebral hypoperfusion during orthostatic stress, their effects on the acute cerebral autoregulatory response to hypotension are not known. METHODS: Continuous middle cerebral artery blood flow velocity (BFV) (transcranial Doppler ultrasound) and mean arterial pressure (MAP, Finapres) were measured in response to (1) acute hypotension during standing, (2) steady-state sitting and standing, and (3) hypercarbia during CO(2) rebreathing in 10 healthy young subjects (age 24+/-1 years), 10 healthy elderly subjects (age 72+/-3 years), and 10 previously treated hypertensive elderly (age 72+/-2 years) subjects. CO(2) reactivity was computed as the slope of cerebrovascular conductance (CVC=BFV/MAP) versus end-expiratory CO(2). Coherence, transfer magnitudes, and phases between low-frequency MAP and BFV signals were computed from their autospectra during 5 minutes of sitting and standing. RESULTS: MAP fell to a similar extent in all groups by an average of 21 to 26 mm Hg (22% to 26%) within 30 seconds of standing. Mean BFV also fell in all subjects but significantly less in the older subjects (-4.7+/-0. 7 cm/s in hypertensives and -5.3+/-1.2 cm/s in normotensives, P=NS) compared with younger subjects (-10.1+/-1.1 cm/s, P<0.05). CO(2) reactivity was greater in the young subjects (0.19+/-0.01) compared with normotensive (0.14+/-0.01, P<0.05) and hypertensive elderly subjects (0.11+/-0.02, P<0.05) (P=NS between elderly groups). Fewer hypertensive subjects had coherence between MAP and BFV signals; for subjects with coherence, there were no significant group differences in phase or transfer magnitudes in either sitting or standing positions. CONCLUSIONS: Despite reduced CO(2) reactivity, elderly normotensive and previously treated hypertensive subjects retain cerebral autoregulatory capacity in response to acute orthostatic hypotension.

Adult↗
PubMed2000

PSK and OK-432-induced immunomodulation of inducible nitric oxide (NO) synthase gene expression in mouse peritoneal polymorphonuclear leukocytes and NO-mediated cytotoxicity.

We investigated whether PSK (a polysaccharide from the mycelia of Coriolus versicolor) or OK-432 (a streptococcal preparation) can up-regulate inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO) production in mouse peritoneal polymorphonuclear leukocytes (PMNs). Six hrs after intraperitoneal injection of mice with PSK (2,500 microg/mouse) or OK-432 (100 microg/mouse), mouse peritoneal PMNs were restimulated with PSK (500 microg/ml) or OK-432 (10 microg/ml) plus 100 U/ml of mouse interferon-gamma (IFN-gamma) in vitro. Northern blot analysis showed strong synergism between both PSK and OK-432 and IFN-gamma for the induction of iNOS gene expression. NO production by PMNs was increased up to 20 microM (2 microM/10(6) PMNs/24 hrs) as measured by the Griess reagent method when PMNs were restimulated with PSK or OK-432 plus IFN-gamma for 24 hrs, although tumor cell killing was not detected. NO concentrations of more than 80 microM were required for P815 tumor cell killing. These results suggest that PMNs produce NO after stimulation with PSK or OK-432 in combination with IFN-gamma and may regulate the immune system in vivo, although the NO production induced by these agents is insufficient for tumor cell killing in vitro.

Adjuvants, Immunologic↗
PubMed2000

[Changes in the shape of choanal openings and airflow rates during development].

The shape of the choanal openings were examined in 173 babies aged zero to six months using digital video fiberscope inserted via nose. A numerical analysis and the fluid mechanics were then calculated for each recorded choanal opening. The choanal openings in one month old babies were a flat oval shape. Vertical development was faster than that of horizontal development, and the choanal openings changed from a flat oval to a round and finally a vertical oval shapes as the babies aged from two to four months. Both the air resistance and airflow ratio in the choanae can be calculated by Navier-Stoke's equation, if the choanae are assumed to be an oval tube. Using this equation, it was calculated that the air resistance ratio was one to five and the airflow ratio increased five times from neonates to six month old babies.

Humans↗
PubMed1999

Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy.

The systemic transfer of ex vivo-activated tumor-sensitized T lymphocytes can mediate immunologically specific regression of established tumors. However, it has not been conclusively established whether the infiltration of systemically transferred T cells into metastases is required for their effector function. In this study, T cells from lymph nodes draining the murine fibrosarcoma MCA 205 cells were activated ex vivo with anti-CD3 monoclonal antibody and interleukin-2. During the final 24 h of culture, the T cells were treated with pertussis toxin (PTX) to inhibit signaling through G protein-coupled chemokine receptors required for diapedesis. Systemically transferred PTX-treated cells did not have any therapeutic efficacy against 3-day established pulmonary metastases. This lack of efficacy correlated with their failure to infiltrate the tumor parenchyma. However, PTX-treated cells responded to tumor antigen stimulation with IFN-gamma secretion in vitro. More importantly, PTX-treated effector T cells prevented tumor growth when they were admixed with tumor cells and inoculated s.c. These results demonstrate that systemically transferred tumor-reactive T lymphocytes need to infiltrate the tumor parenchyma through the endothelium to initiate tumor regression, but PTX-sensitive proteins are not required for either antigen recognition or effector functions.

Animals↗
PubMed1999

TAK-778, a novel synthetic 3-benzothiepin derivative, promotes chondrogenesis in vitro and in vivo.

TAK-778, a novel synthetic 3-benzothiepin derivative, stimulates the formation of cartilaginous nodules in mouse chondroprogenitor-like ATDC5 cells in vitro in association with upregulation of the gene expression of transforming growth factor-beta(2), but not bone morphogenetic protein-4 and insulin-like growth factor-I. One-shot injection of the TAK-778-containing sustained-release microcapsules accelerated the repair process of the full thickness defects of articular cartilage in rabbit knees. Our in vitro and in vivo results indicate that TAK-778 may be a therapeutically useful synthetic agent for articular cartilage repair.

Animals↗
PubMed1999

DNA mismatch repair deficiency in curatively resected sextuple primary cancers in different organs: a molecular case report.

A male patient synchronously or metachronously underwent six curative resections after diagnoses of cancers in the rectum, urinary bladder, stomach, colon, liver and lung. Five cancers, excluding early colon cancer, were analyzed for instability in seven microsatellite markers and in transforming growth factor beta type II receptor, insulin-like growth factor II receptor and BAX. All analyzed cancers had replication errors and instability in at least one target gene. These results suggest that abnormal DNA mismatch repair system plays a major role in the occurrence of multiple primary cancers in this case.

Adenocarcinoma↗
PubMed1999

The peroxin Pex14p. cDNA cloning by functional complementation on a Chinese hamster ovary cell mutant, characterization, and functional analysis.

Rat cDNA encoding a 376-amino acid peroxin was isolated by functional complementation of a peroxisome-deficient Chinese hamster ovary cell mutant, ZP110, of complementation group 14 (CG14). The primary sequence showed 28 and 24% amino acid identity with the yeast Pex14p from Hansenula polymorpha and Saccharomyces cerevisiae, respectively; therefore, we termed this cDNA rat PEX14 (RnPEX14). Human and Chinese hamster Pex14p showed 96 and 94% identity to rat Pex14p, except that both Pex14p comprised 377 amino acids. Pex14p was characterized as an integral membrane protein of peroxisomes, exposing its N- and C-terminal parts to the cytosol. Pex14p interacts with both Pex5p and Pex7p, the receptors for peroxisome targeting signal type 1 (PTS1) and PTS2, respectively, together with the receptors' cargoes, PTS1 and PTS2 proteins. Mutation in PEX14 from ZP161, the same CG as ZP110, was determined by reverse transcription-PCR as follows. A 133-base pair deletion at nucleotide residues 37-169 in one allele created a termination codon at 40-42; in addition to this mutation, 103 base pairs were deleted at positions 385-487, resulting in the second termination immediately downstream the second deletion site in the other allele. Neither of these two mutant forms of Pex14p restored peroxisome biogenesis in ZP110 and ZP161, thereby demonstrating PEX14 to be responsible for peroxisome deficiency in CG14.

Amino Acid Sequence↗