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Biomedical subjects

H Osada

Publications and source records attributed to H Osada.

At least 145 records · Page 8Linked to original sources
PubMed1997

LIM-only protein Lmo2 forms a protein complex with erythroid transcription factor GATA-1.

The LIM-only protein Lmo2, originally identified as an oncogenic protein in human T cell leukemia, is essential for erythropoiesis. A possible role for Lmo2 in transcription during erythropoiesis has been investigated. Direct interaction of Lmo2 was observed in vitro and in vivo with the zinc finger transcription factor GATA-1, as well as with the basic helix-loop-helix (bHLH) transcription factor Tall. By using mammalian two-hybrid analysis, E47/Tall/Lmo2/GATA-1 protein complex could be demonstrated. Thus, a molecular link exists between three proteins crucial for erythropoiesis. This data suggest that variations in amounts of complexes involving Lmo2, Tall, and GATA-1 could be important for erythroid differentiation.

Adaptor Proteins, Signal Transducing↗
PubMed1997

[Lung cancer].

Explore the source record for details and available documents.

Biomarkers, Tumor↗
PubMed1997

[Development of new antitumor reagents which block the cell cycle progression].

Most tumor cells have abnormalities in the cell-cycle regulation system. Cyclin-dependent kinases (cdk) are major regulatory molecules for the cell cycle control. Therefore, cell cycle inhibitors, especially cdk-inhibitors, may be a promising new type of antitumor drug. In this review, low-molecular-weight cell-cycle inhibitors isolated from mainly microorganisms are described. As the activation of cdk is caused by the association with cyclins as well as by their phosphorylation and dephosphorylation, kinase inhibitors and phosphatase inhibitors are also candidates for cell cycle inhibitors.

Antibiotics, Antineoplastic↗
PubMed1997

[Resection of multiple thymoma: a case report].

A 74-year-old male, who had been treated for hypertension at the out-patient clinic, was admitted to our hospital because of an abnormal shadow on a chest radiograph. After diagnosis of thymoma by needle biopsy surgery was carried out on July 6, 1995, when an extended thymectomy along with removal of the entire tumor was done. During the surgery it was noticed that there was not one, but two independent tumors located in the anterior mediastinum, the upper left portion was growing from the level of the crania to the left brachiocephalic vein, whereas the lower right portion was growing towards the right thoracic cavity in front of the pericardium. Both tumors were encapsulated firmly, and connected to each other by scantly loose connective tissues. There was no continuity or sarring between the two tumors. Histologically both were diagnosed to be lymphocytic thymoma. We believe that this case is a good example of multiple thymomas and provides evidence of the potential multicentricity of thymoma. It is possible that extended thymectomy may be seeded for a complete resection of thymomas.

Aged↗
PubMed1996

Molecular analysis of the FHIT gene at 3p14.2 in lung cancer cell lines.

Chromosome 3p is frequently deleted in various cancers including examples in the lung. A novel gene, termed FHIT, was recently isolated from the fragile site at 3p14.2, with aberrant transcripts being reported in lung cancer tumor specimens. To avoid overlooking tumor-specific altered transcripts due to contaminating normal cells in primary tumors, FHIT alterations were examined in 41 lung cancer cell lines in the present study. Lack of detectable expression or exclusive expression of aberrantly spliced transcripts, often accompanied by intragenic homozygous deletions, were observed in 7 of 24 non-small cell lung cancers (29%) but in 0 of 17 small cell lung cancers (0%). Extensive reverse transcription-PCR-single-strand conformation polymorphism analysis revealed polymorphisms and alternative splicing but failed to identify point mutations. These results suggest distinct mechanisms for FHIT alterations in lung tumorigenesis and that further studies of this interesting gene are warranted.

Acid Anhydride Hydrolases↗
PubMed1996

Somatic in vivo alterations of the JV18-1 gene at 18q21 in human lung cancers.

The chromosome region 18q21 is frequently deleted in lung cancers. Recent identification of JV18-1 at this locus led us to examine whether or not it might also be altered in lung cancers, as is the case for the closely related DPC4 tumor suppressor gene. A missense somatic mutation and a 9-bp in-frame deletion were detected in the highly conserved region of JV18-1 among 57 lung cancer specimens taken directly from patients. The total alterations in JV18-1 and DPC4, however, are not sufficient to account for all 18q21 deletions in lung cancers. These findings suggest that although JV18-1 and DPC4 may play roles in a limited fraction of lung cancers, another tumor suppressor gene may also exist in this chromosome region.

Carcinoma, Non-Small-Cell Lung↗
PubMed1996

Subcellular localization and protein interaction of the human LIMK2 gene expressing alternative transcripts with tissue-specific regulation.

In our efforts to explore possible roles of proteins with a LIM domain, which is a cysteine-rich Zinc-binding motif, in differentiation and oncogenesis in the lung, we have cloned a human LIMK2 gene and identified two alternative transcripts, LIMK2a and LIMK2b, which are probably due to variation in transcriptional initiation. The former encodes a protein containing two LIM domains, a PDZ domain, and a kinase domain, while the latter has only one and half LIM domains. The predominance of the two transcripts appears to be regulated in a tissue-specific manner. Alteration of the regulation is also observed in some cancer cell lines. Transfection studies have shown an association of 63-kDa and 58-kDa proteins with the LIMK2a and LIMK2b protein; the former is distributed in the cytoplasm and nucleus and the latter occurs mainly in the cytoplasm and is scarcely translocated to the nucleus. In contrast, a truncated LIMK2-Kinase has a nuclear location, not showing the protein association.

Alternative Splicing↗
PubMed1996

Isolation and characterization of the gene encoding an aminopeptidase involved in the selective toxicity of ascamycin toward Xanthomonas campestris pv. citri.

An aminopeptidase gene named XAP has been isolated from Xanthomonas campestris pv. citri, a plant pathogenic bacterium. The bacterium is one of the rare micro-organisms susceptible to ascamycin, an aminoacyl nucleoside antibiotic that inhibits protein synthesis. Sequence analysis reveals that the gene encodes a 311 amino acid protein with a calculated molecular mass of 35134 Da and approx. 50% identity for amino acids to the proline iminopeptidase from Neisseria gonorrhoeae. The XAP gene product, Xap, expressed in Escherichia coli has proline iminopeptidase activity as well as ascamycin dealanylating activity in vitro.

Adenosine↗
PubMed1996

The multidrug resistance-associated protein (MRP) subfamily (Yrs1/Yor1) of Saccharomyces cerevisiae is important for the tolerance to a broad range of organic anions.

We have cloned and characterized a Saccharomyces cerevisiae gene YRS1 that complements the phenotype of the mutant sensitive to the anionic drug reveromycin A. The YRS1 gene, which is identical to the recently identified YOR1 gene, encodes a protein with extensive homology to the human multidrug resistance-associated protein (MRP) and the yeast cadmium factor (Ycf1). A chromosomal deletion of YRS1 lead to viable Deltayrs1 cells, which exhibited hypersensitivity to reveromycin A. Elevation of the YRS1 gene dosage in wild type cells conferred increased resistance to reveromycin A. By analyzing the effect of YRS1 disruption and overexpression it was demonstrated that Yrs1 is involved in the detoxification of a wide range of the organic anions that contain carboxyl group(s) but none of the other type of toxic compounds examined. Fluorescence-activated cell sorter analysis indicated the increased accumulation of the anionic fluorescent compound rhodamine B in Deltayrs1 cells. The expression of YRS1 was induced strikingly by reveromycin A. These results suggest that Yrs1 is a multispecific organic anion transporter important for tolerance against toxic environmental organic anions. Yrs1 had an overlapping specificity with Ycf1 in the resistance to cadmium.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Somatic in vivo alterations of the DPC4 gene at 18q21 in human lung cancers.

The chromosome region 18q21 has been shown to be frequently deleted in lung cancers. Recent identification at this locus of DPC4, a gene whose inactivation has been suggested to play a role in pancreatic carcinogenesis, prompted as to examine whether it might also be altered in lung cancers. Two missense and 2-bp frameshift somatic mutations in DPC4 were detected among 42 lung cancer specimens taken directly from patients. DPC4 mutations, however, were not present in all lung cancers carrying l8q21 deletions. These findings suggest that DPC4 may play a role in a limited fraction of lung cancers and that another tumor suppressor gene may also exist in this chromosome region.

Base Sequence↗
PubMed1996

Aberrant hypermethylation at the bcl-2 locus at 18q21 in human lung cancers.

Accumulating evidence suggests that altered DNA methylation may play a role in the oncogenesis of human neoplasms, including lung cancer. The presence of aberrant hypermthylations at 3p, 9p, 11p, ad 17p, which are known to be hot spots for allele loss in lung cancers, is suggested to be a reflection of the existence of tumor suppressor genes in these chromosomal regions. In the present study, we investigated the methylation status of the Rb locus at 13q14 as well as that of the bcl-2 locus at 18q21 in 134 lung cancer specimens, representing all major histological subtypes. As a result, 18q21 was identified to be the fifth chromosomal region affected by frequent tumor-specific aberrant hypermethylation in lung cancers. The occurrence of aberrant hypermethylation at the bcl-2 locus at 18q21 was restricted to non-small cell lung cancers, and among non-small cell lung cancers, such epigenetic aberrations were observed most frequently in adenocarcinomas without any association with bcl-2 expression. Interestingly, allelic loss at the bcl-2 locus was also seen in 40% (7 of 17 informative cases) of adenocarcinomas; this frequency was also the highest among values for the various histological subtypes of lung cancers. These results suggest that aberrant hypermethylation at the bcl-2 locus may be a reflection of a putative tumor suppressor gene residing at 18q21, and aberrant hypermethylation might play a role in its inactivation. In contrast, altered methylation status of the Rb locus appears to be quite rare in lung cancers, if present at all.

Adenocarcinoma↗
PubMed1996

Allelic-expression imbalance of the insulin-like growth factor 2 gene in hepatocellular carcinoma and underlying disease.

It has been well documented that the liver is an exceptional organ in which the monoallelic expression of insulin-like growth factor 2 (IGF2) due to genomic imprinting is relaxed during the postnatal period, resulting in biallelic expression thereafter. In the present study, changes in the status of genomic imprinting were examined in 15 hepatocellular carcinomas (HCCs) as well as in 29 liver biopsies of chronic hepatitis or liver cirrhosis without clinical evidence of HCC, following screening for heterozygotes with an ApaI polymorphism in IGF2 in 34 HCCs and 80 such non-HCC cases. Extreme allelic-expression imbalance, leading to restoration of monoallelic IGF2 expression, was observed in 15 (100%) of 15 informative HCCs for the polymorphism with this monoallelic IGF2 expression appearing to be non-random from the paternal allele. Interestingly, the same allelic-expression imbalance was also present in a significant fraction of noncancerous liver specimens of patients with underlying disease known to be associated with HCC development. In contrast, the status of genomic imprinting of H19, another gene closely mapped at 11p15 under opposite imprinting, was strictly maintained in seven (100%) of seven cases informative for an RsaI polymorphism of H19. Together with the previous reports on altered genomic imprinting of IGF2 and H19 in embryonal lesions such as Wilms tumors as well as in lung cancers, the results suggest that perturbations of imprinting status occur as locus and tumor-type specific events in the development of human cancers.

Alleles↗
PubMed1996

Selective maternal-allele loss in human lung cancers of the maternally expressed p57KIP2 gene at 11p15.5.

Genomic imprinting at 11p15 is suggested to play a role in certain pediatric tumors such as Wilms' tumor, based on the findings of selective maternal loss of this chromosomal region. Although the allele loss at 11p15 is also frequent in a number of cancers of adults including lung, breast, and bladder cancers, possible involvement of genomic imprinting in these tumors has not been investigated extensively. p57KIP2, a newly described member of the p21 cyclin-dependent kinase (CDK) inhibitor family which is thought to negatively regulate the cell cycle at the G1 checkpoint, has been mapped to 11p15. In the present study, we searched for somatic p57KIP2 mutations in lung cancer, but failed to find such alterations. Interestingly, however, we found that the p57KIP2 gene is imprinted with maternal expression and that the maternal alleles had been selectively lost in 11 of 13 (85%) lung cancer cases carrying 11p15 deletions, this being a significant bias (p=0.01). These data provide the first evidence that genomic imprinting may play a role in the oncogenesis of not only rare pediatric tumors but also this common cancer of adults, suggesting that the imprinted p57KIP2 CDK inhibitor gene is a potential target for maternally biased 11p15 deletions.

Adult↗
PubMed1996

Direct measurement of oscillatory generation of superoxide anions by single phagocytes.

Phagocytic cells such as neutrophils generate superoxide anions (O2-) within phagocytic vacuoles for killing and digesting microorganisms. Here we report the simultaneous observation of morphological changes and O2- generation in single phagocytic cells during phagocytosis. Point stimulation of a cell by contact with an opsonized microelectrode at the cell surface induced significant deformation to engulf the electrode, and also induced the O2- generation which was measured by the electrode. Periodic fluctuations in the magnitude of the O2- generation were observed in the time course. These oscillations may be caused by metabolic regulation of the formation of NADPH, which is the substrate for the O2- generation

Anions↗
PubMed1996

Phorbol-ester-stimulated human lymphoid cell lines produce a plasminogen activator modulator inducing cell-bound urokinase-type plasminogen activator in malignant tumor cell lines.

The importance of cell-associated plasminogen activation in tumor invasion and metastasis is becoming increasingly evident. To clarify the modulators of cell-associated plasminogen activation in malignant states, we have recently established an assay system utilizing endogenous plasminogen activators on the cell surface. In the present study using the assay system, we found that the conditioned medium from phorbol 12-myristate 13-acetate (PMA)-stimulated human lymphoid cell lines, HUT 78 and Raji, strongly enhanced plasminogen activator (PA) activity on the surface of human malignant tumor cell lines (WI-38 VAI3 2RA, A431, A549 and HT-1080). The enhancing effect was inhibited by the addition of actinomycin D. By gel filtration, the active substances in PMA-stimulated HUT 78- and Raji-conditioned media were eluted in similar fractions corresponding to molecular weights of 60 to 80 kDa. The active substance was heat-labile. The enhanced PA activities were completely inhibited by anti-urokinase-type plasminogen activator (uPA) IgG. Moreover, the active substance was found to increase in cell-bound uPA antigen. These findings suggest that a population of activated lymphocytes produces a plasminogen activator modulator that induces uPA on the surface of malignant tumor cells.

Cell Line↗
PubMed1996

Pulmonary, vascular responses in rats exposed to chronic hypobaric hypoxia at two different altitude levels.

High altitude hypoxia is known to cause pulmonary hypertension in humans. Altitudes of 5500 m and 4000 m above sea level are considered to be the upper limits for short-term human survival and long-term human residence, respectively. To study the effects of hypobaric-hypoxic environments on pulmonary vascular beds, the physiologic and morphometric differences occurring in the pulmonary arteries of rats at the equivalent of these two altitude levels were compared. One hundred and ninety male rats were housed in a double-roomed mechanical chamber and subjected for 12 weeks to hypobaric-hypoxic environments equivalent to an altitude level of 5500 m or 4000 m. After 6-8 weeks, mean pulmonary arterial pressure (PAPm) was significantly higher in rats at the 5500 m level than in those at 4000 m. The external diameter of muscular arteries (M) and of partially muscular arteries (PM) in the lungs of rats at 8 and 12 weeks, and those of nonmuscular arteries (NM) around the alveolar sacs at 2 and 8 weeks were each significantly less in rats exposed to the 5500 m level than in those at 4000 m. At 4 weeks, the ratio of medial thickness to external diameter for M and PM around the alveolar ducts and alveolar sacs were greater in rats exposed to the 5500 m level than in those at 4000 m. Erythrocyte count, hemoglobin and hematocrit tests showed polycythemic patterns during the initial hypobaric period in both 5500 m-, and 4000 m-level rats. However, from 4 to 12 weeks, the hematologic values of the 4000 m-level rats declined progressively toward the upper end of the normal range. This study suggests (i) that elevated PAPm in rats exposed to hypobaric-hypoxic environments results from structural remodeling of all M, PM and NM within the lobule, and (ii) that an environment equivalent to the 5500 m level causes more severe pulmonary vascular changes than one equivalent to the 4000 m level. The hematologic results suggest that rats exposed to the equivalent of the upper limit for long-term human residence can acquire acclimatization, but not those exposed to the equivalent of the upper limit for short-term human survival.

Altitude Sickness↗