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Biomedical subjects

Akihiko Okayama

Publications and source records attributed to Akihiko Okayama.

At least 19 recordsLinked to original sources
PubMed2006

A novel hypothyroid dwarfism due to the missense mutation Arg479Cys of the thyroid peroxidase gene in the mouse.

Recently, we found a novel dwarf mutation in an ICR closed colony. This mutation was governed by a single autosomal recessive gene. In novel dwarf mice, plasma levels of the thyroid hormones, T3 and T4, were reduced; however, TSH was elevated. Their thyroid glands showed a diffuse goiter exhibiting colloid deficiency and abnormal follicle epithelium. The dwarfism was improved by adding thyroid hormone in the diet. Gene mapping revealed that the dwarf mutation was closely linked to the thyroid peroxidase (Tpo) gene on chromosome 12. Sequencing of the Tpo gene of the dwarf mice demonstrated a C to T substitution at position 1508 causing an amino acid change from arginine (Arg) to cysteine (Cys) at codon 479 (Arg479Cys). Western blotting revealed that TPO protein of the dwarf mice was detected in a microsomal fraction of thyroid tissue, but peroxidase activity was not detected. These findings suggested that the dwarf mutation caused a primary congenital hypothyroidism by TPO deficiency, resulting in a defect of thyroid hormone synthesis.

Animals↗
PubMed2006

Patterns of serum type 1 and type 2 immune markers in healthy carriers of HTLV-I.

Type 1 immunity appears to be diminished in healthy Japanese carriers of human T-lymphotropic virus type I (HTLV-I), but type 2 status remains undetermined. To further examine the subclinical effect of HTLV-I on host immunity, we measured serum antibodies to the Epstein-Barr virus (EBV) in 415 healthy Japanese adults to broadly characterize type 1 status. Levels of the type 2 biomarkers total immunoglobulin E (IgE), soluble CD23 (sCD23), and soluble CD30 (sCD30) were assessed in 167, 142, and 135 of these subjects, respectively. We analyzed the association of HTLV-I with levels of each serum marker using linear and logistic regression. Altered EBV antibody profiles that are consistent with deficient type 1 immunity were more prevalent in HTLV-I carriers than non-carriers (odds ratio (OR) = 2.8, 95% confidence interval (CI) = 1.5-5.3). Carriers also had 45% lower total IgE levels (P = 0.04) than non-carriers. In contrast, HTLV-I infection was not significantly associated with elevated levels of sCD23 or sCD30. These observations are contrary to our expectation of elevated type 2 biomarkers among carriers. We conclude that in this population, healthy carriers of HTLV-I may have subclinical deficiencies in both type 1 and type 2 immunity, and that type 1 and type 2 immunity are not necessarily reciprocal in persons with subclinical immune dysregulation.

Adult↗
PubMed2006

[18F]fluorodeoxyglucose positron emission tomography is a useful tool to diagnose the early stage of Takayasu's arteritis and to evaluate the activity of the disease.

Takayasu's arteritis (TA) is a rare disease that can be difficult to diagnose in its early stage. A young woman with a fever and neck pain was thought to have TA, although computed tomographic angiography did not show any specific changes of the arteries. [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) was performed to detect the source of the inflammation. Specific accumulation of [(18)F]FDG-6-phosphate in the thoracic aorta and its direct branches was observed, leading to a diagnosis of TA. [(18)F]FDG-PET is therefore considered to be useful for the diagnosis of early-stage TA.

Adolescent↗
PubMed2006

Coexistent Anaplastic and Differentiated Thyroid Carcinoma.

The aim of the present study was to clarify the underlying molecules that might contribute to the highly aggressive behavior of anaplastic thyroid carcinoma. We selected 5 cases of anaplastic thyroid carcinoma that had a differentiated area to determine differences in the molecules of undifferentiated and differentiated cancer cells. We immunohistochemically examined the localization of nuclear antigen (Ki-67), proliferating cell nuclear antigen (PCNA), p53, apoptotic protease-activating factor-1 (Apaf-1), CD26, galectin-3, E-cadherin, and CD147. We found an increased Ki-67, PCNA, and p53 labeling indices; decreased levels of Apaf-1, CD26, galectin-3, and E-cadherin; and overexpression of CD147 in the undifferentiated area compared with the differentiated area. These findings indicate high proliferative properties, suppression of apoptosis, disruption of cell-cell interaction, and induction of matrix metalloproteinases in the undifferentiated areas. Thus the molecules examined might be useful for evaluating the aggressive nature of this tumor and the prognosis.

Journal Article↗
PubMed2006

Coexistent anaplastic and differentiated thyroid carcinoma: an immunohistochemical study.

The aim of the present study was to clarify the underlying molecules that might contribute to the highly aggressive behavior of anaplastic thyroid carcinoma. We selected 5 cases of anaplastic thyroid carcinoma that had a differentiated area to determine differences in the molecules of undifferentiated and differentiated cancer cells. We immunohistochemically examined the localization of nuclear antigen (Ki-67), proliferating cell nuclear antigen (PCNA), p53, apoptotic protease-activating factor-1 (Apaf-1), CD26, galectin-3, E-cadherin, and CD147. We found increased Ki-67, PCNA, and p53 labeling indices; decreased levels of Apaf-1, CD26, galectin-3, and E-cadherin; and overexpression of CD147 in the undifferentiated area compared with the differentiated area. These findings indicate high proliferative properties, suppression of apoptosis, disruption of cell-cell interaction, and induction of matrix metalloproteinases in the undifferentiated areas. Thus the molecules examined might be useful for evaluating the aggressive nature of this tumor and the prognosis.

Biomarkers, Tumor↗
PubMed2005

Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms.

BACKGROUND: Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia (ATL) after a long latent period. Among accessory genes encoded by HTLV-I, the tax gene is thought to play a central role in oncogenesis. However, Tax expression is disrupted by several mechanims including genetic changes of the tax gene, deletion/hypermethylation of 5'-LTR. To clarify the role of epigenetic changes, we analyzed DNA methylation and histone modification in the whole HTLV-I provirus genome. RESULTS: The gag, pol and env genes of HTLV-I provirus were more methylated than pX region, whereas methylation of 5'-LTR was variable and 3'-LTR was not methylated at all. In ATL cell lines, complete DNA methylation of 5'-LTR was associated with transcriptional silencing of viral genes. HTLV-I provirus was more methylated in primary ATL cells than in carrier state, indicating the association with disease progression. In seroconvertors, DNA methylation was already observed in internal sequences of provirus just after seroconversion. Taken together, it is speculated that DNA methylation first occurs in the gag, pol and env regions and then extends in the 5' and 3' directions in vivo, and when 5'-LTR becomes methylated, viral transcription is silenced. Analysis of histone modification in the HTLV-I provirus showed that the methylated provirus was associated with hypoacetylation. However, the tax gene transcript could not be detected in fresh ATL cells regardless of hyperacetylated histone H3 in 5'-LTR. The transcription rapidly recovered after in vitro culture in such ATL cells. CONCLUSION: These results showed that epigenetic changes of provirus facilitated ATL cells to evade host immune system by suppressing viral gene transcription. In addition, this study shows the presence of another reversible mechanism that suppresses the tax gene transcription without DNA methylation and hypoacetylated histone.

Carrier State↗
PubMed2005

Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir.

Adult T-cell leukemia (ATL), an aggressive malignancy of CD4+ T cells associated with human T-cell leukemia virus type I (HTLV-I) infection, carries a very poor prognosis because of the resistance of leukemic cells to any conventional regimen, including chemotherapy. We examined the effect of ritonavir, an HIV protease inhibitor, on HTLV-I-infected T-cell lines and primary ATL cells and found that it induced apoptosis and inhibited transcriptional activation of NF-kappaB in these cells. Furthermore, ritonavir inhibited expression of Bcl-xL, survivin, c-Myc, and cyclin D2, the targets of NF-kappaB. In nonobese diabetic/severe combined immunodeficient (NOD/SCID)/gammacnull (NOG) mice, ritonavir very efficiently prevented tumor growth and leukemic infiltration in various organs of NOG mice at the same dose used for treatment of patients with AIDS. Our data indicate that ritonavir has potent anti-NF-kappaB and antitumor effects and might be clinically applicable for treatment of ATL. These results would provide a new concept and novel platform for new drug development of leukemia and solid cancer as well.

Adult↗
PubMed2005

Dual targeting of transformed and untransformed HTLV-1-infected T cells by DHMEQ, a potent and selective inhibitor of NF-kappaB, as a strategy for chemoprevention and therapy of adult T-cell leukemia.

Human T-cell leukemia virus type I (HTLV-1) causes adult T-cell leukemia (ATL), a fatal T-cell leukemia resistant to chemotherapy, after more than 50 years of clinical latency from transmission through breast-feeding. Polyclonal expansion of virus-infected T cells predisposes them to transformation. Constitutive activation of nuclear factor-kappaB (NF-kappaB) in the leukemic cells is essential for their growth and survival. Blocking NF-kappaB has been shown to be a potential strategy to treat ATL. We tested this approach using a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), and also examined its application to chemoprevention by selective purging of the HTLV-1-infected cells. DHMEQ inhibited NF-kappaB activation in primary ATL cells and cell lines derived from them and induced apoptotic cell death. NF-kappaB inhibition down-regulated expression of genes involved in antiapoptosis or cell-cycle progression. DHMEQ protected severe combined immunodeficiency (SCID) mice inoculated with HTLV-1-transformed cells from death. In addition, DHMEQ selectively targeted HTLV-1-infected cells in the peripheral blood of virus carriers in vitro, resulting in a decreased number of infected cells. We conclude that NF-kappaB is a potential molecular target for treatment and prevention of ATL. As a potent NF-kappaB inhibitor, DHMEQ is a promising compound allowing the translation of this strategy into clinical medicine.

Animals↗
PubMed2005

Preferential selection of human T-cell leukemia virus type I provirus integration sites in leukemic versus carrier states.

Human T-cell leukemia virus type I (HTLV-I) is a causative agent of neoplastic disease, adult T-cell leukemia (ATL). Although the encoding viral proteins play an important role in oncogenesis, the role of the HTLV-I proviral integration site remains unsolved. We determined the integration sites of HTLV-I proviruses in ATL cells and HTLV-I-infected cells in asymptomatic carriers. In carrier and ATL cells, HTLV-I provirus was integrated into the transcriptional unit at frequencies of 26.8% (15/56) and 33.9% (20/59), respectively, which were equivalent to the frequency calculated based on random integration (33.2%). In addition, HTLV-I provirus was prone to integration near the transcriptional start sites in leukemic cells (P = .006), and the transcriptional direction of the provirus was in accordance with that of integrated cellular genes in 70% of cases. More importantly, the integration sites in the carrier cells favored the alphoid repetitive sequences (11/56; 20%) whereas in leukemic cells they disfavored these sequences (2/59; 3.4%). Taken together, during natural course from carrier to onset of ATL, HTLV-I-infected cells with integration sites favorable for viral gene transcription are susceptible to malignant transformation due to increased viral gene expression.

Base Sequence↗
PubMed2005

The clonal expansion of human T lymphotropic virus type 1-infected T cells: a comparison between seroconverters and long-term carriers.

BACKGROUND: The clonal expansion of human T lymphotropic virus type 1 (HTLV-1)-infected T cells is considered to be important for the maintenance of infection. However, the process by which the clonality of HTLV-1-infected T cells is established is not understood. METHODS: HTLV-1 clonality in 4 adult seroconverters was analyzed by inverse long polymerase chain reaction (PCR) followed by cloning of the PCR products and evaluation of restriction fragment-length polymorphism. The results were compared with those for 8 long-term HTLV-1 carriers. RESULTS: The clonality of HTLV-1-infected T cells in the seroconverters arose stochastically and was variable 3-5 years after seroconversion. On the basis of the frequency with which clones of cells infected with unique HTLV-1 provirus integration sites appeared, it was clear that the seroconverters had a greater number of unique clones with fewer infected cells than did the long-term carriers. CONCLUSIONS: The clonality of the HTLV-1-infected T cells in the adult seroconverters, who had been newly infected via HTLV-1-carrier spouses, was more heterogeneous and less stable than that of the HTLV-1-infected T cells in long-term carriers, who were more likely to have been infected during infancy. The mechanism for the selective maintenance of certain clones in asymptomatic HTLV-1 carriers likely plays a role in the initiation of leukemogenesis.

Aged↗
PubMed2005

Telomerase activity and telomere length as prognostic factors of adult T-cell leukemia.

For the oncogenesis of many malignancies, it is crucial to prevent the shortening of the telomeres by the action of telomerase. In this study, clinical data and disease outcomes were analyzed in conjunction with the telomerase activity (TA) and telomere length (TL) of peripheral blood mononuclear cells. The study was carried out in 22 patients with adult T-cell leukemia (ATL) (7 chronic and 15 acute types) and in 13 asymptomatic human T-lymphotropic virus type 1 (HTLV-1) carriers. The mean values of TA in acute and chronic type patients were 13.8 and 1.6 total product generated (TPG) units, respectively, as determined by telomeric repeat amplification assays. The mean TA values in HTLV-1 carriers and healthy volunteers were 1.8 and 0.7 TPG, respectively. The mean TA value in acute type patients was significantly higher than in the three other subject groups. The mean TL values in patients with acute and chronic types were 5.39 and 4.38 Kb, respectively, while the mean TL values in HTLV-1 carriers and healthy volunteers were 7.69 and 7.06 Kb, respectively. The mean TL values in all ATL patients and in non-ATL subjects were 5.2 and 7.3 Kb, respectively. The former value is significantly shorter than the latter (p < 0.01). Neither TA nor TL of ATL cells showed any significant association with the number of ATL cells, serum soluble interleukin-2 receptor, or serum lactate dehydrogenase in the peripheral blood of acute type patients. This suggests that the levels of TA and TL did not reflect the ATL tumor load. The median survival period of acute ATL patients with high TA and shortened TL was 0.47 years, however, which was significantly shorter than that of acute ATL patients with low TA and normal TL (4.21 years) (p < 0.002). These data suggest that high TA and shortened TL were associated with poorer prognosis, and that TA and TL may be novel markers for the prognosis of ATL patients.

Adult↗
PubMed2005

[Natural history of human T-lymphotropic virus type 1 (HTLV-1) infection].

The natural history of human T-lymphotropic virus type-1 (HTLV-1) infection has been difficult to be clarified, because only a small proportion of HTLV-1 carriers develop adult T-cell leukemia(ATL) after a long incubation period. We have performed a long-term follow-up study of HTLV-1 carriers for 17 years. Based on the findings of this study and other studies, the natural history of HTLV-1 carriers is hypothesized as follows. The major routes of infection of this virus are from mother to child, between spouses, and through blood products. The target of HTLV-1 infection is CD4 positive peripheral blood mononuclear cells (PBMCs). The number of infected cells is supposed to be increased just after the infection, then decreased in a year. The number of infected cells does not change thereafter during more than 10 years. In 90% of newly infected people, this level is low or medium ranging from less than 0.05% to 5% of PBMCs infected; however, approximately 10% of newly infected people develop into carriers with many number of infected cells as more than 5% of PBMCs infected. Clonal expansion of infected cells is likely to be contributing to the maintenance of the HTLV-1 infection. Replication of certain clones among many infected cells may be accelerated by the expression of Tax protein and some of them develop to have a phenotype to avoid immune surveillance. Finally, some of these clones, which acquired the accumulation of genomic abnormality, develop the pre-leukemic state. The increased number of certain T-cells due to HTLV-1 infection may also cause imbalance of the immune system, resulting in immune dysfunction or inflammatory diseases like myelopathy and uveitis. Therefore, it seems to be important to find ways to prevent HTLV-1 associated diseases among the carriers especially those with many infected cells.

Adult↗
PubMed2004

Overexpression of a cell adhesion molecule, TSLC1, as a possible molecular marker for acute-type adult T-cell leukemia.

Adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) infection, occurs in 2% to 4% of the HTLV-1 carriers with a long latent period, suggesting that additional alterations participate in the development of ATL. To characterize and identify novel markers of ATL, we examined the expression profiles of more than 12 000 genes in 8 cases of acute-type ATL using microarray. One hundred ninety-two genes containing interleukin 2 (IL-2) receptor alpha were up-regulated more than 2-fold compared with CD4(+) and CD4(+)CD45RO(+) T cells, and tumor suppressor in lung cancer 1 (TSLC1), caveolin 1, and prostaglandin D2 synthase showed increased expression of more than 30-fold. TSLC1 is a cell adhesion molecule originally identified as a tumor suppressor in the lung but lacks its expression in normal or activated T cells. We confirmed ectopic expression of the TSLC1 in all acute-type ATL cells and in 7 of 10 ATL- or HTLV-1-infected T-cell lines. Introduction of TSLC1 into a human ATL cell line ED enhanced both self-aggregation and adhesion ability to vascular endothelial cells. These results suggested that the ectopic expression of TSLC1 could provide a novel marker for acute-type ATL and may participate in tissue invasion, a characteristic feature of the malignant ATL cells.

Adult↗
PubMed2004

Persistent paradox of natural history of human T lymphotropic virus type I: parallel analyses of Japanese and Jamaican carriers.

Human T lymphotropic virus type I (HTLV-I) is endemic in southern Japan and the Caribbean, but the incidence of HTLV-I-associated diseases varies across geographic areas. We compared markers of disease pathogenesis among 51 age- and sex-matched HTLV-I carrier pairs from Japan and Jamaica. The mean antibody titer (P=.03) and detection of anti-Tax antibody (P=.002) were higher in Jamaican subjects than in Japanese subjects, but provirus load was similar between the 2 groups (P=.26). The correlation between antibody titer and provirus load was more prominent among Jamaican subjects than among Japanese subjects (P=.06). These findings underscore the differences in host immune response to HTLV-I infection in 2 populations.

Adult↗
PubMed2004

Serologic assessment of type 1 and type 2 immunity in healthy Japanese adults.

We assessed the informativeness of several serologic biomarkers of immune function using serum specimens collected in the Miyazaki Cohort Study from subjects who were seronegative for anti-human T-cell lymphotrophic virus I and anti-hepatitis C virus. To broadly characterize type 1 immune status, we measured EBV antibody titers, because titer profiles associated with cellular immune suppression are well described. We also tested for three type 2 biomarkers: total serum IgE, soluble CD23, and soluble CD30. Nonreactivity to a tuberculin purified protein derivative (PPD) skin test is indicative of diminished delayed-type hypersensitivity (type 1) responsiveness in the study population due to a history of tuberculosis exposure or Bacillus Calmette-Guérin vaccination. We therefore evaluated the serologic markers as predictors of PPD nonreactivity using logistic regression. Subjects whose EBV antibody profiles were consistent with deficient type 1 immunity were more than thrice as likely to be PPD nonreactive as persons with "normal" antibody titers. Elevated total IgE was also strongly associated with PPD nonreactivity (odds ratio 3.4, 95% confidence interval 1.2-9.9); elevated soluble CD23 had a weaker, but positive, odds ratio, whereas soluble CD30 levels were not predictive of PPD status. Therefore, PPD nonreactivity is associated, in this population, with a pattern of serum biomarkers that is indicative of diminished type 1 and elevated type 2 immunity. We conclude that, with the exception of soluble CD30, the serologic markers are informative for the characterization of type 1/type 2 immune status using archived sera from study populations of healthy adults.

Adult↗
PubMed2003

Rapid tumor formation of human T-cell leukemia virus type 1-infected cell lines in novel NOD-SCID/gammac(null) mice: suppression by an inhibitor against NF-kappaB.

We established a novel experimental model for human T-cell leukemia virus type 1 (HTLV-1)-induced tumor using NOD-SCID/gammac(null) (NOG) mice. This model is very useful for investigating the mechanism of tumorigenesis and malignant cell growth of adult T-cell leukemia (ATL)/lymphoma, which still remains unclear. Nine HTLV-1-infected cell lines were inoculated subcutaneously in the postauricular region of NOG mice. As early as 2 to 3 weeks after inoculation, seven cell lines produced a visible tumor while two transformed cell lines failed to do so. Five of seven lines produced a progressively growing large tumor with leukemic infiltration of the cells in various organs that eventually killed the animals. Leukemic cell lines formed soft tumors, whereas some transformed cell lines developed into hemorrhagic hard tumors in NOG mice. One of the leukemic cell lines, ED-40515(-), was unable to produce visible tumors in NOD-SCID mice with a common gamma-chain after 2 weeks. In vivo NF-kappaB DNA binding activity of the ED-40515(-) cell line was higher and the NF-kappaB components were changed compared to cells in vitro. Bay 11-7082, a specific and effective NF-kappaB inhibitor, prevented tumor growth at the sites of the primary region and leukemic infiltration in various organs of NOG mice. This in vivo model of ATL could provide a novel system for use in clarifying the mechanism of growth of HTLV-1-infected cells as well as for the development of new drugs against ATL.

Animals↗