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Biomedical subjects

K Arai

Publications and source records attributed to K Arai.

At least 163 records · Page 9Linked to original sources
PubMed2000

[Two cases of advanced gastric cancer responding to TS-1: a novel oral formation of 5-fluorouracil].

TS-1, a novel oral formation of 5-fluorouracil, consists of 1 M tegafur (5-FU), 0.4 M CDHP and 1 M Oxo. The response rate in the late phase II study was reported as 49% in the patients with advanced gastric cancer. We report two patients with metastases from gastric cancer who markedly responded to TS-1. CASE 1: A 74-year-old man who suffered abdominal tumor was admitted to our hospital. Computed tomography (CT) showed advanced gastric cancer with huge liver metastases and extensive lymph node metastases. After 120 mg of TS-1 was orally administered for 12 weeks, CT showed a 77% reduction in the liver metastases. No serious adverse reactions were observed. CASE 2: A 66-year-old man had undergone a curative distal gastrectomy with D2 lymphadenectomy. One year later, CT showed enlargement of paraaortic lymph nodes due to cancer recurrence. There were no metastatic lesions in the other organs. After 100 mg of TS-1 was orally administered for 4 weeks, CT revealed that almost complete reduction of the metastatic nodes was obtained. Adverse reactions at grade 2 for leucopenia and anemia were observed. In conclusion, TS-1 was effective and well tolerable for patients with advanced gastric cancer.

Administration, Oral↗
PubMed2000

[Two patients with liver metastasis from gastric cancer who responded remarkably to combined therapy of 5'-DFUR and PSK].

Two patients with liver metastasis from gastric cancer who responded remarkably to a combined therapy of 5'-DFUR and PSK are reported. The first patient had liver metastases 8 months postoperatively. Her AFP level was 513 ng/ml and CEA was 30 ng/ml. After the combined therapy, all liver metastases showed a calcified change. Tumor markers of AFP and CEA decreased remarkably to the normal level within 3 weeks after the therapy. The patient had no relapse as of December 1999. The second patient with liver metastases was treated using the same combined therapy for 14 days preoperatively. The size of liver metastases had decreased remarkably by the time of the operation. A small metastasis of S8 (0.5 x 0.5 cm) was resected. No other liver metastasis was detected by intraoperative ultrasonography. The patient had no relapse as of February 2000. It is reported that PSK produces several cytokines which induce thymidine phosphorylase expression. The present report suggests that the upregulation of PyNPase might enhance the antitumor effect of 5'-DFUR.

Aged↗
PubMed1999

Cyclic AMP inhibits the activity of c-Jun N-terminal kinase (JNKp46) but not JNKp55 and ERK2 in human helper T lymphocytes.

The cyclic AMP (cAMP) elevating agent PGE(2) and dibutyryl cyclic AMP (dBcAMP) affect T cell functions. Using human helper T cell clones, we examined effects of cAMP on c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), which are assumed to play a role in T cell regulation. When we analyzed the effects of dBcAMP on activities of mitogen-activated protein kinase (MAPK) family members ERK2, JNKp55 and JNKp46, dBcAMP did not inhibit the activities of ERK2 and JNKp55 induced by PMA/A23187 stimulation. JNKp46 activity was, however, inhibited by dBcAMP. JNK phosphorylates c-Jun on Ser-63 and Ser-73, the result being induction of its transcriptional activity. We found that dBcAMP inhibited the phosphorylation of c-Jun Ser-63 induced by PMA/A23187 stimulation. We suggest a different mechanism of regulation of JNKp55 and JNKp46 activities and that JNKp46 is a specific c-Jun kinase by which the activity of c-Jun is regulated in T lymphocytes.

Antibodies↗
PubMed1999

The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression.

Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide into sphingosine and fatty acid. A deficiency in human AC activity leads to the lysosomal storage disorder, Farber disease (FD). The human AC gene (HGMW-approved symbol ASAH) was cloned and characterized, revealing an organization similar to that of the murine AC gene. The human gene spans about 30 kb in length and contains 14 exons ranging in size from 46 to 1201 bp. The exon/intron junctions were determined and found to follow the GT-AG rule. The putative promoter region had a GC content over 60%, lacked a TATA box, and contained several sequences matching transcription factor binding sites, including nine SP-1 sites, one AP-1 site, and three CACC boxes. The promoter activity of a 475-bp fragment from within this region was demonstrated by chloramphenicol acyltransferase assays. Northern blotting revealed variable expression of the human AC RNA; i.e., expression of the major 2.4-kb transcript was high in heart and kidney, followed by lung and placenta, but low in pancreas, liver, brain, and skeletal muscle. Two minor AC transcripts of 1.7 and 1.2 kb also were detected in heart and skeletal muscle. The human AC gene was mapped to the chromosomal region 8p21.3-p22 by in situ hybridization and FISH analyses, syntenic with the mouse chromosomal location. Finally, three new missense mutations, E138V, R254G, and P362R, were identified in the human AC gene from FD patients. Mutant AC cDNAs containing these point mutations were constructed and examined using the FLAG-tagged expression system. Although the levels of protein expression for these mutant ACs were about equivalent to that of the controls, their enzymatic activity was markedly reduced, confirming their authenticity.

3T3 Cells↗
PubMed1999

A 2-Mb sequence-ready contig map and a novel immunoglobulin superfamily gene IGSF4 in the LOH region of chromosome 11q23.2.

Human chromosome 11q23.2 has been proposed to contain a tumor suppressor gene(s) whose deletion has been associated with cancer of the lung and breast and with neuroblastoma. To analyze the genomic structure and to isolate a candidate tumor suppressor gene from this region, we constructed a 2-Mb sequence-ready contig map using bacteriophage P1 (P1), bacterial artificial chromosome (BAC), and P1-derived artificial chromosome (PAC). The map comprises a contig of 24 overlapping P1, BAC, and PAC clones. To isolate gene fragments from the region, we performed direct cDNA library screening, exon trapping, EST mapping, and genomic sequencing using the P1, BAC, and PAC clones. Sequence analysis of 5 clones, which spans 23% (458,738 bp) of the region, and extensive gene scanning along the entire region revealed that the region is extraordinarily scarce in genes, but we identified one ubiquitously expressed novel gene and one testis-specific gene fragment. The novel gene, which we call IGSF4 (immunoglobulin superfamily 4), is transcribed into a 1.6- or 4.4-kb RNA encoding a 442-amino-acid protein. It shares strong homology with mouse IGSF-B12 and cell adhesion molecules NCAM1 and NCAM2 within their Ig-like C2-type domains. The IGSF4 gene, a novel gene that is shown to be located in the common loss of heterozygosity region, possesses a number of interesting features and may be good candidate for a tumor suppressor gene.

Amino Acid Sequence↗
PubMed1999

CDC7 kinase complex as a molecular switch for DNA replication.

Cdc7 kinase and its activator Dbf4 protein, originally identified in budding yeast Saccharomyces cerevisiae, are widely conserved in eukaryotes including fission yeast and human. Dbf4-related activators bind and stimulate kinase activity of Cdc7-like catalytic subunit. Its kinase activity is cell cycle-regulated, mainly through availability of the activation subunit whose level increases at G1/S boundary and is maintained at a high level throughout S phase. MCM2 protein is among physiologically important substrates. Genetic studies in fission yeast indicate that Cdc7-related kinase complex also functions in meiosis, uninduced mutagenesis, DNA replication checkpoint signaling and maintenance of chromatin structures during S phase.

Animals↗
PubMed1999

Matrix metalloproteinase-9 production, a newly identified function of mast cell progenitors, is downregulated by c-kit receptor activation.

Mast cell precursors invade from the peripheral blood into local tissues where they differentiate to their mature phenotypes. However, the mechanism of this migration process has been unclear. We clearly demonstrated here the production and release of matrix metalloproteinase-9 (MMP-9), a matrix-degrading enzyme necessary for leukocyte transmigration, by interleukin-3-dependent mouse mast cell progenitors: bone marrow-derived cultured mast cells and IC-2 mast cells. Because several interleukin-3-independent mast cell lines with active mutations in the c-kit gene did not release MMP-9, the possible involvement of c-kit receptor activation in downregulation of MMP-9 production was predicted. c-kit receptor activation by stem cell factor led to a significant decrease in MMP-9 production of cultured mast cells and IC-2 mast cells transfected with the c-kit gene. Thus, the present results suggest that mast cell precursors are able to produce MMP-9, which may be essential for mast cell migration into tissues, and that stem cell factor may downregulate the MMP-9 production, resulting in engagement of mast cells to matrix components.

Animals↗
PubMed1999

Ca(2+)/Calmodulin-dependent protein kinase cascade in Caenorhabditis elegans. Implication in transcriptional activation.

We have recently demonstrated that Caenorhabditis elegans Ca(2+)/calmodulin-dependent protein kinase kinase (CeCaM-KK) can activate mammalian CaM-kinase IV in vitro (Tokumitsu, H., Takahashi, N., Eto, K., Yano, S., Soderling, T.R., and Muramatsu, M. (1999) J. Biol. Chem. 274, 15803-15810). In the present study, we have identified and cloned a target CaM-kinase for CaM-KK in C. elegans, CeCaM-kinase I (CeCaM-KI), which has approximately 60% identity to mammalian CaM-KI. CeCaM-KI has 348 amino acid residues with an apparent molecular mass of 40 kDa, which is activated by CeCaM-KK through phosphorylation of Thr(179) in a Ca(2+)/CaM-dependent manner, resulting in a 30-fold decrease in the K(m) of CeCaM-KI for its peptide substrate. Unlike mammalian CaM-KI, CeCaM-KI is mainly localized in the nucleus of transfected cells because the NH(2)-terminal six residues ((2)PLFKRR(7)) contain a functional nuclear localization signal. We have also demonstrated that CeCaM-KK and CeCaM-KI reconstituted a signaling pathway that mediates Ca(2+)-dependent phosphorylation of cAMP response element-binding protein (CREB) and CRE-dependent transcriptional activation in transfected cells, consistent with nuclear localization of CeCaM-KI. These results suggest that the CaM-KK/CaM-KI cascade is conserved in C. elegans and is functionally operated both in vitro and in intact cells, and it may be involved in Ca(2+)-dependent nuclear events such as transcriptional activation through phosphorylation of CREB.

Amino Acid Sequence↗
PubMed1999

An electrochemiluminescence flow-through cell and its applications to sensitive immunoassay using N-(aminobutyl)-N-ethylisoluminol.

An electrochemiluminescence (ECL) flow-through cell with a carbon fiber electrode for ECL detection was developed, and a flow injection analysis system containing the cell was established. N-(aminobutyl)-N-ethylisoluminol (ABEI), an ECL reagent, was determined by this system. A straight-line calibration curve for ABEI (r = 0.999) was obtained from 6 fmol to 25 pmol. The detection limit of ABEI was 6 fmol (S/N = 2) and the relative standard deviation was 1.7% at 1.5 pmol (n = 10). The system was used for immunoassay of human immunogloblin G (hIgG) with ABEI-labeled anti-hIgG. A calibration curve of hIgG was obtained from 80 pg/mL to 1.3 ng/mL. The detection limit of hIgG was 80 pg/mL (S/N = 2), and the relative standard deviation was 1.8% at 0.5 ng/mL (n = 10). Sensitivity and accuracy for sera samples were found to considerably exceed those of the conventional methods, such as single-radial immunodiffusion and nepherometric immunoassay. The present system should prove useful for immunoassay.

Electrochemistry↗
PubMed1999

Serial lectin affinity chromatography demonstrates altered asparagine-linked sugar-chain structures of prostate-specific antigen in human prostate carcinoma.

Differences between prostate carcinoma (PCA) and benign prostatic hyperplasia (BPH) in asparagine (N)-linked sugar-chain structures of prostate-specific antigen (PSA) were investigated using serial lectin affinity chromatography. The amounts of PSA passing through columns of concanavalin A (Con A), phytohaemagglutinin E4 (PHA-E4) and PHA-L4 were significantly greater for PCA-derived PSA than BPH. We propose that the sugar moiety structure of PSA which is increased in PCA is a multiantennary complex type with branched N-acetylglucosamine beta(1->4) mannose. We suggest that N-linked sugar chains in PSA are altered during oncogenesis in the human prostate and may serve as diagnostic tools for PCA.

Aged↗
PubMed1999

Two independent calcineurin-binding regions in the N-terminal domain of murine NF-ATx1 recruit calcineurin to murine NF-ATx1.

Intracellular calcium regulates events controlling nuclear translocation of nuclear factor of activated T cells (NF-AT). Calcium-dependent phosphatase calcineurin (CN) plays a central role in this process. Structural and functional analyses of the N-terminal domain of murine NF-ATx1, a member of the NF-AT family, have defined two distinct CN binding regions (CNBRs), CNBR1 and CNBR2, which are located in the region preceding the SP boxes of serine/proline-rich sequences and the region between the SP boxes and Rel similarity domain, respectively. The binding of murine NF-ATx1 (mNF-ATx1) to CN was abolished by deletion of these two regions, yet was unaffected by the individual deletion. In contrast, the nuclear translocation of mNF-ATx1 was much reduced when only CNBR2 was removed. Luciferase assay revealed that both regions are required for mNF-ATx1-dependent activation of the murine IL-2 promoter. Most importantly, recombinant CNBR2 bound CN with a higher affinity, and when expressed in Jurkat cells, it functioned as a dominant negative mutant that prevented the transcription driven by exogenous mNF-ATx1, probably by interfering with the function of CN. We propose that activation of mNF-ATx1 can be modulated through two distinct CN target regions. Our findings provide a new opportunity for pharmacological intervention with Ca2+-dependent signaling events.

Animals↗
PubMed1999

Corticotropin-releasing factor receptor type 1 mediates emotional stress-induced inhibition of food intake and behavioral changes in rats.

We investigated whether corticotropin-releasing factor (CRF) receptor type 1 (CRFR1) is involved in emotional stress-induced inhibition of food intake and behavioral changes in rats. The inhibition of food intake and increase in locomotor activity induced by emotional stress using a communication box were reversed by both intracerebroventricular injection of alpha-helical CRF (9-41), a non-selective CRF receptor antagonist, and intraperitoneal injection of a selective non-peptidic CRFR1 antagonist. These results suggest that CRFR1 mediates at least in part the emotional stress-induced inhibition of feeding behavior and increase in locomotor activity.

Animals↗
PubMed1999

Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Histiocyte Society.

The familial form of hemophagocytic lymphohistiocytosis (HLH) is a lethal disorder. Although the prognosis for Epstein-Barr virus-associated HLH (EBV-HLH) remains uncertain, numerous reports indicate that it can also be fatal in a substantial proportion of cases. We therefore assessed the potential of immunochemotherapy with a core combination of steroids and etoposide to control EBV-HLH in 17 infants and children who met stringent diagnostic criteria for this reactive disorder of the mononuclear phagocyte system. Treatment of life-threatening emergencies was left to the discretion of participating investigators and typically included either intravenous Ig or cyclosporin A (CSA). Five patients (29%) entered complete remission during the induction phase (1 to 2 months), whereas 10 others (57%) required additional treatment to achieve this status. In 2 cases, immunochemotherapy was ineffective, prompting allogeneic bone marrow transplantation. Severe but reversible myelosuppression was a common finding; adverse late sequelae were limited to epileptic activity in one child and chronic EBV infection in 2 others. Fourteen of the 17 patients treated with immunochemotherapy have maintained their complete responses for 4+ to 39+ months (median, 15+ months), suggesting a low probability of disease recurrence. These results provide a new perspective on EBV-HLH, showing effective control (and perhaps cure) of the majority of EBV-HLH cases without bone marrow transplantation, using steroids and etoposide, with or without immunomodulatory agents.

Child↗
PubMed1999

Constitutive activation of JAK2 confers murine interleukin-3-independent survival and proliferation of BA/F3 cells.

The Janus tyrosine kinase 2 (JAK2) plays an essential role of cytokine receptor signaling, including that of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. We reported earlier that the activation of JAK2 is essential for all the examined signals induced by human GM-CSF through the box1 region of betac, such as promotion of cell survival and proliferation. To elucidate the role of JAK2 in cell survival and proliferation, we generated an artificial activation system by constructing a chimeric molecule (beta/JAK2) consisting of betac extracellular and transmembrane regions fused with JAK2, and we analyzed various signaling events in interleukin-3-dependent mouse pro-B cell, BA/F3. The beta/JAK2 was constitutively phosphorylated in the absence of human GM-CSF and murine interleukin-3, and this led to proliferation and cell survival. Western blot analysis showed that STAT5, Shc, and SHP-2 were not phosphorylated in the cells, and the consistent activation of beta-casein and c-fos promoters was not enhanced. In contrast, c-myc transcription was constitutively activated. We propose that the activation of beta/JAK2 suffices for survival and proliferation and that the activation of STAT5 and mitogen-activated protein kinase cascade is not required for these activities in BA/F3 cells.

Animals↗
PubMed1999

Endoscopic lithotripsy with the holmium:YAG laser.

BACKGROUND AND OBJECTIVE: The holmium:YAG (Ho:YAG) laser can be used not only for soft tissue but also for hard tissue such as urinary calculi. The objective of this study was to assess the usefulness of the Ho:YAG laser for endoscopic lithotripsy in patients with urinary tract stone. STUDY DESIGN/MATERIASL AND METHODS: Of 102 procedures performed among 96 patients, 88 were transurethral ureterolithotripsy (TUL), seven were percutaneous nephrolithotripsy, and seven were transurethral cystolithotripsy. Six patients had bilateral stones. The fragments were reduced as much as possible with the Ho:YAG laser. RESULTS: The efficacy rate of the 102 lithotripsy procedures was 93%. With respect to the effect of TUL, the efficacy rates of 40 procedures for the proximal ureter, 18 procedures for the midureter, and 30 procedures for the distal ureter were 85%, 94%, and 100%, respectively. CONCLUSION: The Ho:YAG laser produced a sufficiently strong lithotripsy force on all stones. The results of this study indicate that lithotripsy of urinary tract stones with the Ho:YAG laser can achieve a clinical outcome equivalent to or exceeding that of pulsed dye laser lithotripsy. The Ho:YAG laser is a multipurpose laser and thus is a cost effective and very useful means for endoscopic lithotripsy of urinary tract stones.

Adolescent↗
PubMed1999

Experimental study on vascularized island pedicle bone graft: bony fusion between the graft and the recipient floor.

To evaluate the process of bony fusion between the recipient floor and the bone graft, where a muscle sleeve has been interposed, an experimental model for a vascularized island pedicle bone graft was prepared using rats. The proximal two thirds of the tibia pedicled with the popliteal artery and vein was collected to be used as a vascularized bone. This was onlay grafted to the femur of the same limb in such a manner that the muscle sleeve was interposed between the bone graft and the recipient floor. The animals subjected to this procedure were designated as the vascularized island pedicle bone graft group (hereafter called group V, n = 32). In another group, vascular pedicles were interrupted by ligation and the animals were subjected to nonvascularized bone graft (hereafter called group N, n = 32). In the third group, an appropriate amount of bone chips was transplanted throughout the length of the grafted floor; then the animals were subjected to additional vascularized island pedicle bone graft (hereafter called group B, n = 13). In groups V and B, the vascularized bone graft formed new bone at the site where the bone graft faced the recipient floor 6 weeks after surgery. Hypertrophy of the bone graft was noted. Bony fusion at the section where a muscle sleeve had been interposed was recognized only in group B. Chondrocytes were found around the free bone graft, suggesting chondrocyte participation in osteogenesis. In group N, the bone graft had been absorbed and no bony fusion was recognized between the bone graft and recipient floor in any of the samples. These findings imply that it is important to minimize the size of the muscle sleeve attached to the vascularized island pedicle bone graft and add free bone chips around the grafted bone to assure bony fusion between a vascularized bone graft and the recipient floor in clinical practice.

Animals↗