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Biomedical subjects

M Akiyama

Publications and source records attributed to M Akiyama.

At least 19 recordsLinked to original sources
PubMed1995

Activation of telomerase in human lymphocytes and hematopoietic progenitor cells.

This is the first report describing up-regulation of telomerase activity in human normal cells. Telomerase, a ribonucleoprotein enzyme, has been thought to be involved in maintaining telomere length stability in germline and most cancer cells, but not in normal cells. However, in the present study, we demonstrate that telomerase activity is detectable at low levels in normal human T and B cells, increases by in vitro mitogenic stimulation, increases in hematopoietic progenitor cells upon their proliferation and differentiation, and decreases with aging. Understanding the regulation of telomerase activity in normal cells may provide important insights not only into the mechanisms of normal cellular senescence but also into the mechanisms of telomerase activity deregulation as part of cancer development.

Adolescent↗
PubMed1995

Cytogenetic and immunologic identification of clonal expansion of stem cells into T and B lymphocytes in one Atomic-bomb survivor.

Chromosome aberration frequency in peripheral blood lymphocytes is elevated in radiation-exposed people, and identical karyotypic changes are not infrequently encountered in one blood sample as well as in separate samples from the same donor. Such clonal propagation originates either from a single immature stem cell able to expand and differentiate into several cell types or from a single mature lymphocyte able to expand after antigen stimulation in vivo. In the present study, a total 71 T-lymphocyte and 58 B-lymphocyte colonies were established from one atomic-bomb survivor, who showed a persistent clonal aberration t(4;6), t(5;13) in phytohemagglutinin culture of peripheral lymphocytes. Nearly 10% of the colonies (6 T-lymphocyte and 7 B-lymphocyte colonies) showed the same chromosome abnormality. Southern blot analyses of the T-cell-receptor or Ig heavy-chain gene showed all different rearrangement patterns among T- or B-lymphocyte colonies, respectively. Thus, the chromosome aberration occurred in a precursor cell before differentiation into T and B lineages and was not derived from monoclonal proliferation of mature T or B lymphocytes in the periphery. To confirm the issue, cells from erythroid burst-forming unit (BFU-E) colonies were examined by the chromosome-painting method. Two translocations, one between chromosomes 5 and 13 and the other between chromosomes 4 and one of group C, perfectly consistent with the t(4;6), t(5;13), were found in about 10% of the cells. The results imply that a single stem cell of an adult is capable of generating long-lived myeloid and lymphoid progeny amounting to several percent of the total population of circulating lymphocytes and hematopoietic progenitors.

Aged↗
PubMed1995

Radiation studies.

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Government Agencies↗
PubMed1995

Molecular analysis of the cytokine network involved in cachexia in colon 26 adenocarcinoma-bearing mice.

Two clones, one cachexigenic (clone 20) and the other noncachexigenic (clone 5), from a murine colon adenocarcinoma, colon 26 cells, were used to analyze the involvement of immune reactions as well as the cytokine network in cachexia. Clone 20 induced cachexia in nude and SCID mice as well as in normal BALB/c mice, suggesting that lymphocytes played little, if any, role in the process. Both clones failed to express mRNA of interleukin (IL) 1 alpha, IL-1 beta, IL-6, and tumor necrosis factor alpha in vitro with or without the coculture of NIH3T3 cells or spleen cells. However, IL-6 mRNA was selectively detected at the tumor site of clone 20 but not at that of clone 5-bearing mice. In contrast, tumor necrosis factor alpha mRNA was detected at tumor sites and in spleens of only clone 5-bearing mice, suggesting a potential role of IL-6, but not tumor necrosis factor alpha, in inducing cachexia. Anti-IL-6 antibody partially reversed the weight loss induced by clone 20, whereas the continuous infusion of IL-6 failed to cause weight loss, despite being associated with an elevation of a serum acute phase protein. These results suggest that IL-6 is necessary but not sufficient for the induction of cachexia. Both clones expressed IL-6 mRNA in the presence of IL-1 in vitro, and mice bearing either clone expressed IL-1 beta mRNA at the tumor site. Moreover, IL-1 receptor antagonist (IL-1Ra) mRNA was detected at the tumor site of clone 5-bearing mice but not at that of clone 20-bearing mice, suggesting that IL-1Ra might block IL-1 activity to reduce IL-6 production in clone 5-bearing mice. However, the transfection of clone 20 with IL-1Ra cDNA failed to abolish its capacity to produce IL-6 and to cause cachexia. Collectively, additional factor(s) besides IL-1Ra and IL-1 beta may control IL-6 and some other cachexigenic factor production, thereby causing cachexia in this model.

Adenocarcinoma↗
PubMed1995

The usefulness of severe combined immunodeficiency (SCID) mice to study human carcinogenesis.

In the present study, we engrafted normal colonic epithelial and histologically diagnosed colonic adenomas from a familial adenomatous polyposis (FAP) patient into severe combined immunodeficient (SCID) mice and subsequently examined them histologically and molecular biologically. Successful engraftment and metastasis was observed. The facts that human normal colonic epithelium and adenomatous polyps can take in SCID mice indicates the possibility that this human SCID mouse system will be useful for investigating the dynamics of human carcinogenesis in various tissues.

Adenomatous Polyposis Coli↗
PubMed1995

Preparation of specific antibodies against murine IL-1ra and the establishment of IL-1ra as an endogenous regulator of bacteria-induced fulminant hepatitis in mice.

Blocking monoclonal antibodies (mAbs) specific to mouse interleukin-1 receptor antagonist (IL-1ra) were prepared by immunizing Armenian hamsters with recombinant mouse IL-1ra. A sensitive and specific ELISA against mouse IL-1ra was also established. In Propionibacterium acnes-induced liver injury, P. acnes induced transient increase of serum tumor necrosis factor-alpha levels but not those of IL-1ra, IL-1, and IL-6. However, subsequent lipopolysaccharide (LPS) challenge induced the increase of serum levels of all these cytokines and the peak serum IL-1ra level was more than 20 times as high as serum IL-1 levels. Immunohistochemical analysis demonstrated that IL-1ra was predominantly produced by hepatocytes during the course of the priming phase by P. acnes and eliciting phase by LPS challenge. Furthermore, the administration of a mAb to mouse IL-1ra exacerbates the liver injury induced by P. acnes and sublethal dose of LPS, suggesting a protective role of endogenous IL-1ra in this liver injury model.

Animals↗
PubMed1995

Immune response to fresh meniscal allografts in mice.

To date, no study of allogeneic meniscal transplantation has investigated both the host cellular immune response and the humoral immune response. Using inbred mice, we examined cellular and humoral immunity to meniscal allografts through the mixed lymphocyte culture reaction and a complement-dependent cytotoxicity test. We also examined the histology of an allogeneic meniscus transplanted subcutaneously. The stimulation index of the mixed lymphocyte culture seen after placing fresh meniscal allografts subcutaneously was not significantly higher than when isograft controls were similarly placed. Following placement of the allografts, no specific antibodies were detected in serum throughout the 24-week period after grafting. Although viable fibrochondrocytes in the allogeneic meniscus decreased in number and lymphocyte infiltration around the allogeneic meniscus was noted at Week 2, no remarkable infiltration of lymphocytes into the meniscus was observed. These results indicate that in our experimental mouse model, a fresh meniscus apparently is not sufficiently immunogenic to induce a systemic reaction. Our results suggest that a fresh allogeneic meniscus can be transplanted without any special treatment to decrease its immunogenicity.

Animals↗
PubMed1995

Mutant frequency at the HPRT locus in peripheral blood T-lymphocytes of atomic bomb survivors.

The mutant frequency at the hypoxanthine-guanine phosphoribosyltransferase locus in peripheral blood lymphocytes was measured for 254 atomic bomb survivors (171 exposed and 83 control survivors) by a colony assay using recombinant human interleukin-2. Weak but significant effects were detected for atomic bomb radiation dose and smoking status at the time of examination but not for age and sex. However, the slope of the dose-response curve is quite small, and the smoking effect would not have been significant without the inclusion of data from just three individuals with extremely high mutant frequencies. The weakness of the dose response is at least partly due to the time lapse of 50 years since radiation exposure. Among the 254 survivors, 23 had chromosome aberration data in lymphocytes and the dose response was highly significant. However, the correlation between the mutant frequency and the proportion of cells with aberrations was not significant. It was concluded that the lymphocyte mutation assay is presently not sensitive enough for biological dosimetry of radiation exposure in the survivors.

Adult↗
PubMed1995

Mutation frequency in human blood cells increases with age.

Using either the colony formation assay or flow cytometry, it is feasible to measure the frequency of rare mutant lymphocytes or erythrocytes in human peripheral blood. Accordingly, we have investigated the mutant cell frequencies of the hypoxanthine-guanine phosphoribosyltransferase and T-cell receptor genes in T lymphocytes and of the glycophorin A gene in erythrocytes of several hundred persons aged 0-96 years. The mutant frequency of every one of these genes increased significantly with age. A simple accumulation of mutations in hematopoietic stem cells over time may explain the age-dependent increase in the frequency of glycophorin A mutants. In contrast, a balance between mutant cell generation and loss should be taken into account for the mechanism of the increase of T-cell mutations.

Adolescent↗
PubMed1995

Late effects of radiation on the human immune system: an overview of immune response among the atomic-bomb survivors.

The studies of the late effects of atomic-bomb (A-bomb) radiation on the immune system were started about 20 years after the bombings in 1945. The most remarkable late effects of radiation are the functional and quantitative abnormalities of T and B cells in survivors exposed to high doses (> or = 1.0 Gy). Abnormalities of T-cell immunity include (1) a decreased proportion of CD3+ T cells in peripheral blood lymphocytes, particularly the proportion of CD4+ CD45RA+ naive T cells (study period 1987-91); (2) an increased frequency of CD4- and CD8- (double negative) alpha beta + T cells (1987-91); and (3) functional defects in T-cell responses to mitogens and alloantigens (1974-85). B-cell abnormalities include: (1) a significant increase in the proportion of B cells among peripheral lymphocytes (1987-91); (2) an increase in serum immunoglobulin A levels in females and immunoglobulin M and the incidence of rheumatoid factor in both sexes (1987-89); and (3) an increased level of anti-Epstein-Barr virus antibody titer (1987-90). In contrast, suggestive (0.05 < p < 0.1) or not significant (p > 0.1) dose effects were observed for the number and function of natural killer cells (1983-91), and benign monoclonal gammopathy (1979-87). In addition, studies initiated sooner after the bombing such as the incidence of autoimmune diseases (1958-87), systemic bacterial infections (1954-67), and granulocyte functions (1947-79) also show little dose-effects. Thus, A-bomb radiation induced the alteration of the balance/interaction between the T- and B-cell subsets--specifically, a decrease in the T-cell population and an increase in the B-cell population in the periphery.

Antibody Formation↗
PubMed1995

Pericranial muscle hardness in tension-type headache. A non-invasive measurement method and its clinical application.

Using a new method to measure the hardness of pericranial muscles, the role of muscle factors in tension-type headache was evaluated. In 223 normal healthy subjects, the hardness of trapezius muscles was 82 +/- 15 kPa/cm (mean +/- SD). The muscle hardness in women, 92 +/- 17 kPa/cm, was significantly greater than that in men, 74 +/- 14 kPa/cm (P < 0.01). Trapezius muscles were significantly harder than paraspinal posterior neck muscles measured at the level of the fifth cervical vertebra (71 +/- 13 kPa/cm; n = 26) but a significant correlation in muscle hardness did exist between these two muscle groups (r = 0.89, P < 0.001). Muscle hardness did not show a significant correlation with advancing age, blood pressure or subjective feeling of stiffness in the shoulder. A significant correlation was noted between the muscle hardness measured by the present method and the stiffness scores evaluated by manual palpation. In patients with tension-type headache (n = 60), the hardness of trapezius muscles, 114 +/- 24 kPa/cm (mean +/- SD), was significantly greater than that in normal subjects (P < 0.01). Twenty-six patients (43% of the total) showed significantly high values which exceeded the mean +/- 2 SD (113 kPa/cm) of the normal value, while the remaining patients (57%) constituted a high normal group. The hardness of posterior neck muscles measured in 27 patients (99 +/- 21 kPa/cm) was also significantly greater than that in normal subjects (P < 0.01). There was no significant difference in muscle hardness between episodic tension-type headache and chronic tension-type headache.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Spectrum of in vivo hprt mutations in T lymphocytes from atomic bomb survivors. I. Sequence alterations in cDNA.

Recently, we found an elevated frequency of 6-thioguanine-resistant (TGr) mutations at the hyoxanthine-guanine phosphoribosyltransferase (hprt) gene in T cells of peripheral blood from atomic bomb survivors and a slight, but significant, positive correlation between the frequency of mutation and radiation dose. Southern blot analysis of DNA from TGr mutant T cells of atomic bomb survivors, however, failed to show a significant difference between the control and survivor groups. We here report mutational events at the hprt locus of TGr mutant T cell clones from atomic bomb survivors as found by (i) the multiplex polymerase chain reaction (PCR) and (ii) the reverse transcription (RT)-PCR of cDNA and sequencing. The numbers of independent TGr mutant T cell clones examined were 41 from a control group of 18 individuals who had received less than 0.005 Gy and 50 from an exposed group of 24 individuals who had received more than 1.5 Gy (mean dose 2.45 +/- 0.85 Gy). Gross structural alterations, which were detected by multiplex PCR as a loss of or shift in hprt exon-containing fragments of genomic DNA, were found in 10-15% of the clones from both groups, thus indicating that there was no significant difference between them. The altered sequences in the HPRT cDNAs recovered from both groups were of various types. Similar proportions of base substitutions (approximately 45%), deletions or insertions (approximately 25%) and exon skipping (approximately 20%) were found in both groups, indicating that neither the gross structural alterations in the genomic DNA nor sequence alterations in the hprt cDNA of both groups differ significantly. These results confirm our previous observation that A-bomb-induced HRT- mutant T cells have mostly been eliminated from the peripheral blood over the decades that have elapsed since exposure. Some unique features of the mutational sequence alterations found are also described.

Adult↗
PubMed1995

Somatic-cell mutations as a possible predictor of cancer risk.

The somatic-mutation theory of carcinogenesis has received strong scientific support from results of recent studies on tumor-suppressor genes. We anticipated that people among the high risk for cancer group, either through exposure to various ionizing radiations or by virtue of unique genotypes, would also manifest increased frequencies of somatic mutation. This report presents the results of two somatic-mutation assays--at the erythrocyte glycophorin A (GPA) and lymphocyte T-cell receptor (TCR) genes--in various groups at high risk for cancer development, including atomic-bomb survivors, patients with various cancers, patients administered Thorotrast, and patients with genetic disorders that make them cancer prone. Although neither the GPA-mutation nor the TCR-mutation assay detects gene mutations directly related to carcinogenesis, increased mutation frequencies were detected by both assays in many individuals among the high-risk groups and among cancer patients. We have continued to follow up those individuals who show values of about three times higher than those of the control group. Thus, these assays may prove useful for identifying high-risk cancer groups and for estimating the effects of mutagens. Such information would constitute a valuable data base for epidemiological studies.

Adult↗
PubMed1995

Characterization of hair follicle bulge in human fetal skin: the human fetal bulge is a pool of undifferentiated keratinocytes.

It has been suggested that the bulge of the hair follicle contains a pool of follicular stem cells that may serve as a target site of graft-versus-host disease and as a source of cells with carcinogenic potential. The bulge is prominent in the developing follicle although it is a subtle swelling in the adult follicle. In this paper, we studied the bulge in human fetal skin specimens. Ultrastructurally, the bulge cells, especially the interior cells, have abundant free ribosomes and glycogen particles, but almost no cytoplasmic organelles indicative of differentiation. Immunostaining with several specific anti-keratin antibodies demonstrated that the bulge cells express keratins of both stratified and simple epithelia. Melanocytes and Merkel cells, defined by immunohistochemical and ultrastructural criteria, are seen among bulge cells. Laser confocal microscopy revealed that primitive smooth muscle cells attached directly to the bulge initially at the mid-bulbous hair peg, the stage when the bulge is most prominent. K-laminin and type VII collagen are strongly expressed in the dermoepidermal junction of the bulge and between the matrix area of the bulb and the dermal papilla. Thus, the bulge of human hair follicle is not only an attachment site for arrector pili muscle, but also a pool of keratinocytes that are relatively undifferentiated.

Animals↗
PubMed1995

A novel SCID mouse model for studying spontaneous metastasis of human lung cancer to human tissue.

We established a novel severe combined immunodeficient (SCID) mouse model for the study of human lung cancer metastasis to human lung. Implantation of both human fetal and adult lung tissue into mammary fat pads of SCID mice showed a 100% rate of engraftment, but only fetal lung implants revealed normal morphology of human lung tissue. Using these chimeric mice, we analyzed human lung cancer metastasis to both mouse and human lungs by subcutaneous inoculation of human squamous cell carcinoma and adenocarcinoma cell lines into the mice. In 60 to 70% of SCID mice injected with human-lung squamous-cell carcinoma, RERF-LC-AI, cancer cells were found to have metastasized to both mouse lungs and human fetal lung implants but not to human adult lung implants 80 days after cancer inoculation. Furthermore, human-lung adenocarcinoma cells, RERF-LC-KJ, metastasized to the human lung implants within 90 days in about 40% of SCID mice, whereas there were no metastases to the lungs of the mice. These results demonstrate the potential of this model for the in vivo study of human lung cancer metastasis.

Adenocarcinoma↗