Biomedical subjects

Junichi Tsukada

Publications and source records attributed to Junichi Tsukada.

At least 19 recordsLinked to original sources

PubMed2006

[Hormone therapy for breast cancer].

Breast cancer is a hormone responsive disease, and its proliferation and progression correlate with estrogen. Estrogen binds to estrogen receptor and induces various target genes, thus promoting proliferation of breast cancer cells. Therefore, the strategy of endocrine therapy is the blockade of estrogen action. We can use a luteinizing hormone releasing hormone agonist and aromatase inhibitor as an interruptor of supply, tamoxifen as an inhibitor of estrogen receptor, and medroxyprogesterone acetate with an anti-estrogen action. In this article, we review endocrine therapy for breast cancer patients based on recent clinical trials.

Aromatase Inhibitors↗

PubMed2006

[A medical economic benefit of outpatient with cancer chemotherapy].

Recently, there is a worldwide tendency to decrease medical costs, and a medical insurance revolution, such as a diagnosis procedure combination system, has also been put forward in Japan. It is important to consider medical management healthily by shortening hospital stays and cutting the cost of admission therapies. In this background, outpatients' chemotherapy takes notice because of the improvement in quality of life, discovery of new drugs without severe adverse effects, use-effectiveness of hospital beds and medical cost-effectiveness. Cancer patients suffer from not only a major burden of the diseases such as their physical and mental state, but also an economic impact. In this article, we review the medical cost-benefit for outpatients undergoing cancer chemotherapy.

Ambulatory Care↗

PubMed2006

[Chemotherapy for lung cancer patients].

The number of lung cancer-related deaths has increased since the 1960 and has become the leading cause of cancer-related death in Japan. It is anticipated that the number will double in the next 20 years. Chemotherapy is a hopeful systemic therapy because of distant metastases due to lung cancer. Platinum based doublets remain the standard of care for the first-line treatment of metastatic NSCLC. As salvage chemotherapy for patients, the effectiveness of docetaxel has been confirmed. The standard chemotherapy for extensive SCLC is the combination of cisplatin and irinotecan or etoposide. Recently, randomized trials have shown that platinum-based chemotherapy has the potential to improve survival among patients with completely resected NSCLC. Recent advances in molecular biology and genetics have created new molecular targeted therapies for lung cancer. New anti-cancer agents, including gefitinib, erlotinib, bevacizumab, pemetrexed and amrubicin, are being developed currently.

Antineoplastic Agents, Phytogenic↗

PubMed2006

Growth suppression of human mast cells expressing constitutively active c-kit receptors by JNK inhibitor SP600125.

Activation of c-jun N-terminal kinase (JNK) through c-kit-mediated phosphatidylinositol 3 (PI3) and Src kinase pathways plays an important role in cell proliferation and survival in mast cells. Gain-of-function mutations in c-kit are found in several human neoplasms. Constitutive activation of c-kit has been observed in human mastocytosis and gastrointestinal stromal tumor. In the present study, we demonstrate that an anthrapyrazole SP600125, a reversible ATP-competitive inhibitor of JNK inhibits proliferation of human HMC-1 showed constitutive activation of JNK/c-Jun, and the inhibitory effect of SP600125 on cell proliferation was associated with cell cycle arrest at the G1 phase and apoptosis accompanied by the cleavage of caspase-3 and PARP. Caspase-3 inhibitor Z-DEVD-FMK almost completely inhibited SP600125-induced apoptosis of HMC-1 cells. In contrast, caspase-9 inhibitor Z-LEHD-FMK failed to block SP600125-induced apoptosis. Following Sp600125 treatment, down-regulation of cyclin D3 protein expression, but not p53 was also observed. Thus, JNK/c-Jun is essential for proliferation and survival of HMC-1 cells. The results obtained from the present study suggest the possibility that JNK/c-Jun may be a therapeutic target in diseases associated with mutations in the catalytic domain of c-kit.

Anthracenes↗

PubMed2006

[What do cancer chemotherapy outpatients want?--results of a questionnaire survey].

We conducted a questionnaire survey to evaluate patients at the cancer chemotherapy center of the university of occupational and environmental health hospital from January to March 2006. Thirty-three (61.1%) and 5 (9.2%) of 54 patients wished to receive chemotherapy on an outpatient basis and as inpatients, respectively. Among the reasons for wishing to be treated as outpatients were the following: Keeping in touch with family, not wanting to be hospitalized, a desire to work, and the wish to continue hobbies, at 45.5 (15/33), 36.4 (12/33), 24.2 (8/33), and 24.2 (8/33), respectively. Twenty-four (44.4%) patients voiced concerns about chemotherapy at an outpatient clinic in terms of associated adverse events, feeling bad about causing trouble to their family, and the desire to have consultations at night or on holidays. Thirty-eight (70.4%) patients wished to have chemotherapy within 3 hours, and 42 (77.7%) of them requested improvements in the examinations, time, duration of chemotherapy, and the effect of chemotherapy. These findings indicate that a major part of patients wish to receive cancer chemotherapy at an outpatient clinic within 3 hours. However, they also have serious reservations about any associate adverse events. We therefore need to improve the overall environment for cancer chemotherapy patients in order to allow them to feel safe when undergoing such treatments.

Ambulatory Care↗

PubMed2005

[Out-patient treatment for cancer patients at cancer chemotherapy centers in university hospitals].

At present, one-third of people die of cancer and the number is still increasing in Japan. A safe and effective treatment system is critically required. Recently, the discovery of new drugs and the development of medical oncology promotes out-patient treatment for cancer patients. Out-patient treatment in the cancer chemotherapy center of the University of Occupational and Environmental Health Hospital has been started, and many chemotherapy regimens were verified in this center. Not only different organ-specific chemotherapies but also summarizing the oncology team are necessary for performance of the mission. We describe in this review the characteristics of the cancer chemotherapy center.

Ambulatory Care↗

PubMed2005

Glucocorticoid inhibits the human pro-interleukin lbeta gene (ILIB) by decreasing DNA binding of transactivators to the signal-responsive enhancer.

Elucidating the role of glucocorticoid in regulating gene expression is crucial to developing effective strategies against inflammatory diseases such as arthritis. In this report we demonstrate that glucocorticoid inhibits transcription directed by the IL-lbeta gene (IL1B) upstream induction sequence (UIS) enhancer, and to a much lesser extent by the tissue-specific basal promoter. Within the enhancer, three transcription factor binding sites, previously demonstrated by us to be important for the induction of IL1B by lipopolysaccharide, are now shown to be directly inhibited by the synthetic glucocorticoid, dexamethasone. We also previously showed that one of these sites could bind a novel STAT-like factor, while the other two bound heterodimers containing NF-IL6(C/EBPbeta). Although it has been reported by others that NF-IL6 homodimers can interact with glucocorticoid receptor (GR) to enhance transcription of the alpha1-acid glycoprotein gene, it now appears that glucocorticoid represses DNA binding of NF-IL6 heterodimers as well as the novel STAT-like factor to the critical sites within the IL1B UIS. Thus, GR likely disrupts the DNA binding capability of critical IL1B factors via transrepression.

Binding Sites↗

PubMed2005

Reduced expression of human mismatch repair genes in adult T-cell leukemia.

In this study, we investigated the expression of six human DNA mismatch repair (MMR) genes, human MutS homologues 2 (hMSH2), 3 (hMSH3), and 6 (hMSH6), human MutL homologue 1 (hMLH1), human post-meiotic segregations 1 (hPMS1) and 2 (hPMS2), in primary leukemic cells obtained from 11 patients with acute-type adult T-cell leukemia (ATL) by using reverse transcription-polymerase chain reaction (RT-PCR). In contrast to normal peripheral lymphocytes, all primary ATL samples had reduced or loss of expression of two or more MMR genes, and the expression of several MMR genes was simultaneously suppressed in each ATL patient. Abnormal expression of hMSH2, hMSH3, hMSH6, hMLH1, and hPMS1 was observed more frequently than that of hPMS2. In particular, expression of hMSH2 and hPMS1 was reduced in all cases. Western blot analysis further showed reduced expression of both hMSH2 and hPMS1 proteins in all five cases examined. In three out of the 5 cases, both of the two proteins were undetectable. Interestingly, methylation-specific PCR indicated methylation of hPMS1 promoter in all of four ATL cases examined. hPMS1 expression, but not hMSH2 expression, was restored by treatment with a DNA demethylation agent, 5-aza-2'-deoxycytidine, suggesting that methylation plays a crucial role in inhibition of the hPMS1 gene expression in ATL. Our results demonstrate that defect of both human MutS and human MutL systems in primary ATL cells.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Constitutive tyrosine and serine phosphorylation of STAT4 in T-cells transformed with HTLV-I.

STAT4 is a critical mediator of IL-12-stimulated gene regulation in T-helper type 1 (Th1) cell. IL-12 activates the Janus family tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693. The p38 mitogen-activated protein kinase (MAPK) signaling pathway is also activated in response to IL-12, followed by phosphorylation of STAT4 on serine 721, which is required for STAT4 full transcriptional activity. In the present study, we demonstrated constitutive activation of STAT4 in HTLV-I-transformed T-cell lines MT-2, MT-4 and HUT102 by immunoprecipitation, Western blotting and electrophoretic mobility shift assay (EMSA). In HTLV-I-transformed T-cell lines, STAT4 was constitutively phosphorylated not only on tyrosine 693 but also on serine 721, and formed a heterodimer with STAT3. Constitutive phosphorylation of its upstream activators, JAK2, Tyk2 and p38 MAPK was also observed in the cells. EMSA and transient transfection studies further showed that the high-affinity sis-inducible element (hSIE) preferentially binds the STAT3/STAT4 heterodimer and is constitutively transactivated in MT-2 cells in the absence of exogenous cytokine stimulation. When STAT4 expression vector was cotransfected along with STAT3 expression vector into MT-2 cells, STAT4 significantly synergized with STAT3 to transactivate hSIE, showing the functional importance of heterodimer formation between STAT4 and STAT3.

Blotting, Western↗

PubMed2005

[Generalized erythema triggered by a rapid decrease of basophils in chronic myeloid leukemia treated with imatinib].

A 57-year-old woman with chronic myeloid leukemia showing severe basophilia (WBC 17.1 X 10(9)/L, basophils 23%) was treated with 400mg imatinib in June 2003. A high basophil count (WBC 10.6 X 10(9)/L, basophils 31%) was still observed after 1 week of therapy. After 9 days of therapy, she developed generalized pruritic skin erythema, chills and high fever. After terminating imatinib treatment, prednisolone therapy was initiated. The rash quickly disappeared. Four days after withdrawal of imatinib, leukocyte count was 13.0 X 10(9)/L with 3% of basophils, suggesting the possibility that rapid decrease in basophils following imatinib therapy may induce severe cutaneous reactions.

Antineoplastic Agents↗

PubMed2005

[Angioimmunoblastic T-cell lymphoma accompanied by pure red cell aplasia].

A 71-year-old woman was admitted in December 2002 because of lymphadenopathy, hepatosplenomegaly and pleural effusion. She had severe anemia with hemoglobin 5.9 g/dl and a reticulocyte count of 1% per hundred. Direct/indirect Coombs tests and anti-double stranded DNA antibody were positive, her serum CH50 level was reduced and an increase in serum LDH isoenzyme 3 was observed. Bone marrow aspiration showed an almost total absence of erythroblasts and no pathological cell proliferation. The diagnosis of angioimmunoblastic T-cell lymphoma (AILT) was made based on the lymph node histological findings. Proliferation of arborizing small vessels with hyperplastic endothelium and infiltration of atypical T-lymphocytes were observed. After combination chemotherapy (THP-COP), remission was achieved in both the pure red cell aplasia (PRCA) and AILT. Remission was also accompanied by normalization of the Coombs tests, suggesting that autoimmune mechanisms in AILT may contribute to the development of PRCA.

Aged↗

PubMed2004

Macrophage inflammatory protein-1alpha induces hypercalcemia in adult T-cell leukemia.

UNLABELLED: Hypercalcemia is observed in >80% of ATL. Serum MIP-1alpha levels were elevated in all 24 ATL with hypercalcemia but undetectable in all 10 patients with humoral hypercalcemia of malignancy with solid tumors and in 34 of 37 ATL without hypercalcemia. We propose that serum MIP-1alpha is a clinical hallmark for hypercalcemia in ATL. INTRODUCTION: High serum cytokines levels are not always associated with hypercalcemia in patients with adult T-cell leukemia (ATL), suggesting that other factors are involved in the pathogenesis of ATL patients with hypercalcemia. This study was designed to determine the role of macrophage inflammatory protein-1alpha (MIP-1alpha), a chemokine recently described as an osteoclast stimulatory factor, in ATL-associated hypercalcemia. MATERIALS AND METHODS: We measured serum interleukin (IL)-1beta, IL-6, TNF-alpha, parathyroid hormone-related protein (PTHrP), and MIP-1alpha levels in ATL patients by enzyme-linked immunosorbent assays. FACScan was used to measure the expression of RANKL on ATL cells. Osteoclast formation in cocultures of ATL cells and peripheral blood mononuclear cells (PBMCs) was evaluated by TRACP staining. RESULTS: High serum MIP-1alpha levels were noted in all 24 ATL patients with hypercalcemia and in 3 of 37 ATL patients without hypercalcemia. The elevated levels of MIP-1alpha and calcium in ATL patients decreased after effective chemotherapy, emphasizing the role of MIP-1alpha in ATL hypercalcemia. ATL cells spontaneously produced MIP-1alpha. MIP-1alpha significantly enhanced human monocyte (precursor cells of osteoclasts) migration and induced RANKL expression on ATL cells. ATL cell-induced osteoclast formation from PBMCs was inhibited by anti-MIP-1alpha antibody and osteoprotegerin. CONCLUSION: Our results suggest that MIP-1alpha can induce RANKL on ATL cells in autocrine fashion and that RANKL seems to mediate the hypercalcemic effect of MIP-1alpha in ATL. We propose that MIP-1alpha is the clinical hallmark of hypercalcemia in ATL and could be a potentially useful therapeutic target.

Carrier Proteins↗

PubMed2004

Imatinib mesylate-sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: report of two cases.

Although imatinib mesylate has shown encouraging activity in chronic myelogenous leukemia (CML), disease progression during therapy has been observed, manifested by clonal expansion of imatinib mesylate-resistant leukemia cells. On the other hand, myelosuppression related to treatment of imatinib mesylate is often managed with temporary interruption of treatment or dose reduction. We here report two CML patients who had imatinib mesylate-sensitive blast crisis (BC) immediately after discontinuation of imatinib mesylate therapy. The patients discontinued therapy because of neutropenia. Although there was no evidence of blastic phase during therapy, BC occurred 2 weeks after the withdrawal of treatment in both cases. Interestingly, additional chromosomal abnormalities were detected following the withdrawal of imatinib mesylate and disappeared by re-introduction of this agent. The same doses of imatinib mesylate was still effective and remission was sustained with imatinib mesylate alone again. Our report suggests the possibility that withdrawal of imatinib mesylate may lead to proliferation of blast clones even in patients showing good responses to imatinib mesylate without signs of disease progression.

Aged↗

PubMed2004

Transcriptional regulation of multidrug resistance-1 gene by interleukin-2 in lymphocytes.

P-glycoprotein, encoded by the multidrug resistance (MDR)-1 gene, expels various drugs from cells resulting in drug resistance. However, its functional relevance to lymphocytes and the regulatory mechanism remain unclear. Although MDR-1 is known to be induced by various cytotoxic stimuli, it is poorly understood whether the activation stimuli such as cytokines induce MDR-1 transcription. We investigated the transcriptional regulation of MDR-1 in lymphocytes by activation stimuli, particularly by interleukin (IL)-2. IL-2 induced translocation of YB-1, a specific transcriptional factor for MDR-1, from the cytoplasm into nucleus of lymphocytes in a dose-dependent manner and resulted in the sequential events; transcription of MDR-1, expression of P-glycoprotein on the cell surface, and excretion of the intracellular dexamethasone added in vitro. Transfection of YB-1 anti-sense oligonucleotides inhibited P-glycoprotein expression induced by IL-2. Cyclosporin A, a competitive inhibitor of P-glycoprotein, recovered intracellular dexamethasone levels in lymphocytes. We provide the first evidence that IL-2, a representative lymphocyte-activation stimulus, induces YB-1 activation followed by P-glycoprotein expression in lymphocytes. Our findings imply that lymphocytes activation by IL-2 in vivo, in the context of the pathogenesis of autoimmune diseases, results in P-glycoprotein-mediated multidrug resistance, and that P-glycoprotein could be an important target for the treatment of refractory autoimmune diseases.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

[Remission induction of refractory diffuse large B-cell lymphoma with allogeneic peripheral blood stem cell transplantation followed by interferon-alpha and donor lymphocyte infusion].

Graft-versus-lymphoma (GVL) effect has been described in patients with malignant lymphoma after allogeneic stem cell transplantation (alloSCT). The effect of interferon-alpha (IFN-alpha) on the GVL effect still remains unclear. Here we report on a 29-year-old woman with refractory diffuse large B-cell lymphoma (DLBL). Her clinical findings included multiple masses in the liver, stomach, bilateral kidneys, thyroid, vertebral bones and a bulky mediastinal mass. Since the patient did not respond to various combination chemotherapies and further developed superior vena cava syndrome, allogeneic peripheral blood stem cell transplantation (PBSCT) from a HLA-identical brother was carried out after a myeloablative TBI/CY-based conditioning regimen. DLIs have been also performed every 4 weeks since day +14. As a result, the lymphoma masses showed a partial response. In order to enhance the GVL effect, IFN-alpha was further given at a maximum of 3 MU four times per week. Although the patient only experienced graft-versus-host disease of the skin (grade II) even after both DLIs and IFN, complete clinical remission was observed. 200 days after transplantation, the patient is still disease-free and in good condition. This report suggests the curative potential of IFN-alpha combined with DLI after allogeneic SCT in refractory DLBL.

Adult↗

PubMed2004

[Registration of hematological disorders by the Kyushu Hematology Organization for Treatment (K-HOT) Study Group].

The Kyushu Hematology Organization for Treatment (K-HOT) Study Group was organized in 1999 to study hematological disorders diagnosed in the participating institutions in the Kyushu district. We registered all new patients with hematological disorders and from February 2000 to the end of 2003, a total of 2908 patients had been registered. They include non-Hodgkin's lymphoma in 803 patients, leukemia in 556, multiple myeloma (MM) in 276, myelodysplastic syndrome in 273, and adult T-cell leukemia/lymphoma (ATL) in 269 followed in a decreasing order by idiopathic thrombocytopenic purpura, aplastic anemia, and other benign hematological disorders and myeloproliferative disorders. The annual incidence of MM is estimated to be much higher than that previously reported. It is also confirmed that ATL is still one of the frequently encountered lymphoid malignancies in the Kyushu district.

Female↗

PubMed2003

Primary bilateral adrenal intravascular large B-cell lymphoma associated with adrenal failure.

We report a rare case of bilateral primary adrenal non-Hodgkin's lymphoma with adrenal failure. A 66-year-old woman developed symptoms of adrenal failure. The cause of adrenal failure was suspected to be malignant lymphoma based on the high levels of serum soluble interleukin-2 receptor and LDH. Bilateral adrenalectomy was performed and pathological examination showed intravascular large B-cell lymphoma (IVL). Although complete remission was achieved, recurrence occurred three months later with brain metastases. IVL should be suspected in patients with bilateral adrenal tumors who present with rapidly progressive adrenal failure.

Adrenal Gland Neoplasms↗

PubMed2002

Autocrine induction of the human pro-IL-1beta gene promoter by IL-1beta in monocytes.

IL-1beta is produced primarily by activated monocytes/macrophages. We report in this study that IL-1beta induces the human pro-IL-1beta (IL1B) gene promoter in human THP-1 monocytic cells. The -131 to +12 minimal IL1B promoter was induced by IL-1beta in a dose-dependent manner. The promoter possesses two important transcription factor binding motifs, one for an ETS family transcription factor Spi-1 (PU.1), and the other a binding site for NF-IL6 (CCAAT/enhancer binding protein beta). Autocrine promoter activity was completely inhibited by mutation of the Spi-1 site. Mutation of the NF-IL6 binding motif caused partial loss of activity. EMSAs using THP-1 cell nuclear extracts indicated that IL-1beta significantly induced Spi-1 binding to its target site within the IL1B promoter that was maximal at 1 h after stimulation, correlating with the kinetics of IL-1beta induction. The importance of Spi-1 was supported by our observation that Spi-1-deficient EL4 thymocytes exhibited IL-1beta-induced activity only after transfection with a Spi-1 expression vector. Moreover, TNFR-associated factor 6 also required Spi-1 to activate the promoter. Transfection studies using Spi-1 mutant constructs showed that the TATA-binding protein binding and glutamine-rich domains of Spi-1 were important for IL-1beta induction, whereas LPS induction required the proline, glutamic acid, serine, and threonine-rich domain containing serine 148 as well as the TATA-binding protein and glutamine-rich domains. We conclude that the IL1B promoter is an IL-1beta-responsive sequence as a result of its ability to bind Spi-1 in response to IL-1beta.

Autocrine Communication↗