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Biomedical subjects

Fumihiko Kimura

Publications and source records attributed to Fumihiko Kimura.

At least 19 recordsLinked to original sources

1. Molecular target drug discovery.

Cancer is caused by genetic abnormalities: activation of oncogenes and functional inactivation of tumor-suppressor genes. Direct correction of these abnormalities should be the essential treatment for cancer; however, we have not developed any techniques to effectively fix the genome to date. Molecular biological analyses have demonstrated the cancer function of abnormal gene products, activated signal transduction pathways, and cancer-specific cell surface antigens. Molecular target drugs have been designed to suppress these molecules, important for maintaining cancer status, at stages of mRNA and protein. Some targets contributing to cancer progression are even within host cells such as angiogenic factor receptors. Differing from conventional chemotherapeutic agents screened and developed with cytotoxicity to tumor cells, molecular target drugs show higher specificity for cancer and sometimes simply stabilize the tumor. The effect of such drugs depends on the expression and functional importance of the target in cancer, and prediction of the effect using molecular techniques such as DNA microarray may be necessary for appropriate use.

Antibodies, Monoclonal↗

Myeloid/NK cell precursor acute leukemia lost both CD13 and CD33 at first diagnosis.

It has been reported that malignancies of natural killer (NK) cell precursors, which are present in both myeloid and lymphoid antigens, are characterized by immature lymphoblastoid morphology with CD7+, CD33+ and CD56+ phenotype. Here, we report a 18-year-old man who was diagnosed with CD33- and CD13- NK cell precursor acute leukemia at first diagnosis. Following a 3-year remission state, he had a relapse as a testicular tumor and CD33+ myeloid/NK cell precursor acute leukemia after allogenic BMT. This case suggests that myeloid antigens are not necessary for diagnosis of myeloid/NK cell precursor acute leukemia.

Adolescent↗

MmTRA1b/phospholipid scramblase 1 gene expression is a new prognostic factor for acute myelogenous leukemia.

We previously found that expression of the Mm-1 cell-derived transplantability-associated gene 1b (MmTRA1b)/phospholipid scramblase 1 gene was markedly induced during the granulocytic differentiation of human myeloid leukemia cells. To evaluate the role of MmTRA1b expression in human myeloid leukemia, we investigated the relative levels of MmTRA1b transcripts in 81 patients with acute myelogenous leukemia (AML) by the reverse transcriptase polymerase chain reaction. The expression of MmTRA1b in AML-M1, -M5a and -M5b was significantly lower than that in normal bone marrow cells. The levels of MmTRA1b expression in AML-M2 and -M4 varied among patients. Higher MmTRA1b mRNA levels were associated with significantly longer overall survival in AML, especially in AML-M4 patients, independent of chromosomal aberrations such as t(8;21) and inv(16). The present results suggest that the MmTRA1b mRNA level is a new prognostic factor for AML, especially the AML-M4 subtype.

Adult↗

Methimazole-induced aplastic anemia caused by hypocellular bone marrow with plasmacytosis.

Aplastic anemia is a rare but severe complication of methimazole (MMI) treatment for Graves' disease. We present a case of a 53-year-old Japanese female who had been treated with 30 mg/d of MMI for 30 days for Graves' disease and was subsequently admitted to the Japan Self Defense Forces (JSDF) Central Hospital with a mild sore throat and high-grade fever that began the previous day. The patient had a reduced white blood cell count (WBC) count of 0.9 x 10(3) per microliter with severe granulocytopenia and increased lymphocytes, a platelet count of 49 x 10(3) per microliter, and hemoglobin of 10.6 g/dL. Bone marrow (BM) aspirates showed hypocellular bone marrow with plasmacytosis. Because of poor recovery of her peripheral blood values after withdrawal of MMI, she was given transfusions of platelets and erythrocytes thereafter. This is the second report of plasmacytosis in bone marrow of MMI-induced aplastic anemia, and suggests that immunogenic mechanisms may cause this rare complication.

Anemia, Aplastic↗

Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid.

The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-L-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals. Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM.

Antioxidants↗

[Emergence and decrement of Ph-negative clone with trisomy 8 in CML during imatinib therapy].

An increase in the presence of the Ph-negative, trisomy 8 clone has been reported in chronic myelogenous leukemia (CML) under imatinib therapy, but any impact of the clone on patient prognosis remains uncertain. We report here on a 42-year-old male with CML who received imatinib after failure of interferon-alpha therapy. A chromosomal analysis revealed 18/20 trisomy 8 in bone marrow at 10 months of imatinib administration. Continuing imatinib at 300 mg daily resulted in a decrease in the number of trisomy 8 clones as well as the disappearance of Ph clone. Furthermore, the patient's pancytopenia was gradually improved. Imatinib therapy could be continued even with the emergence of trisomy 8.

Adult↗

[Ethylene glycol poisoning complicated by central nervous system abnormalities].

We report a case of ethylene glycol (EG) poisoning complicated by central nervous system abnormalities. A long-distance truck driver aged 36 year old ingested 200ml of EG in a suicidal attempt. He was referred to our hospital from another hospital because of vomiting and altered mental status. On arrival at our hospital, he had low level of consciousness (Glasgow Coma Scale: E3V4M5), miosis, and external ophthalmoplegia. Laboratory analysis revealed a severe metabolic acidosis with wide anion gap. Many crystals were detected in the urinary sediment. After admission, acute oliguric renal failure required continuous hemodialysis for 6 days. Despite the treatment, the level of consciousness did not improve. The CT scan of the brain obtained on the fourth day revealed low density areas in the bilateral basal ganglia, mid brain and pons. The renal biopsy showed tubular oxalate deposits. After 12 days, the volume of urination increased. At the same time the mental status gradually recovered. He was discharged on 36 days after admission without any sequelae.

Adult↗

Development of service-oriented products based on the inverse manufacturing concept.

To achieve sustainability, resource consumption and waste generation must be drastically decreased. For societal acceptance, preservation of both quality of life and corporate profits are essential. One promising approach is to shift the source of value from the amount of product sold to the quality of services the product provides. This paper describes the need for redesigning recycling systems from a manufacturing perspective and then discusses the possibility of this "servicification" of products, describing our experience with prototype development. We discuss development of product prototypes and their business, using consumer facsimile machines as an example of "service-oriented products". Traditional thought presumes that only products comprising new materials and components are valuable. Consideration of a service-oriented product can serve as a stimulus to revise this mode of thought and to control delivery and quality of disposed products. This paper also provides a life cycle simulation of the developed service-oriented business. Simulation results indicate that service-oriented business can potentially reduce environmental impact while extending business opportunities from the viewpoint of whole product life cycles.

Commerce↗

Cloning and characterization of a novel RING-B-box-coiled-coil protein with apoptotic function.

We have identified a novel RING-B-box-coiled-coil (RBCC) protein (MAIR for macrophage-derived apoptosis-inducing RBCC protein) that consists of an N-terminal RING finger, followed by a B-box zinc finger, a coiled-coil domain, and a B30.2 domain. MAIR mRNA was expressed widely in mouse tissues and was induced by macrophage colony-stimulating factor in murine peritoneal and bone marrow macrophages. MAIR protein initially showed a granular distribution predominantly in the cytoplasm. The addition of zinc to transfectants containing MAIR cDNA as part of a heavy metal-inducible vector caused apoptosis of the cells characterized by cell fragmentation; a reduction in mitochondrial membrane potential; activation of caspase-7, -8, and -9, but not caspase-3; and DNA degradation. We also found that the RING finger and coiled-coil domains were required for MAIR activity by analysis with deletion mutants.

Amino Acid Sequence↗

[Two cases of effective weekly paclitaxel administration and concurrent radiation for metastatic breast cancer].

We report two cases in which weekly paclitaxel (TXL) administration and concurrent radiation was effective for metastatic breast cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication. Case 1: A 50-year-old woman was found to have atelectasis of the middle lobe after treatment for brain metastasis. She was diagnosed with hilar, mediastinal and supraclavicular lymph nodes metastases. She received weekly TXL administration and concurrent radiation to the mediastinum and supraclavicular fossa. The metastatic lymph nodes had disappeared one month after the treatment. Case 2: A 31-year-old woman was diagnosed with advanced breast cancer with lung, pleural, bone and orbital metastases. She received weekly TXL administration and concurrent radiation to the orbit. The lung and pleural metastases had disappeared and the orbital metastasis was decreased by 75% one month after the treatment, and the case was assessed as a partial response. Leukopenia and other major adverse effects were not observed in either of the two cases.

Adult↗

[A case of effective weekly paclitaxel administration for metastatic gastric cancer].

We report a case of long-term effectiveness of weekly paclitaxel (TXL) administration for metastatic gastric cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. A 61-year-old man was diagnosed as having gastric cancer with multiple liver metastases. He was treated with FP therapy and irinotecan/cisplatin administration and both therapies were assessed to result in progressive disease. We attempted weekly TXL administration and assessed a long period of no change after 6 courses. The treatment is ongoing. The toxic events were peripheral neuropathy and alopecia (grade 2), with no episodes of leukopenia, nausea and vomiting. The patient's quality of life was fair during the treatment. Weekly TXL administration is a useful treatment for metastatic gastric cancer.

Antineoplastic Agents, Phytogenic↗

[Management of patients with hepatic metastases from gastric carcinoma].

Many studies have reported the benefit of hepatic resection for metastatic tumors from colorectal cancer. However, the significance of hepatic resection for gastric metastasis has been controversial. Peritoneal metastases were recognized in 40% of gastric cancer patients with liver metastases, and metastatic lesions in both lobes of the liver were seen in 60% of patients. Resection with curability B was performed in only 10% of the all gastric cancer patients with liver metastases. However, the overall 5-year survival rate of curability B resection was more than 30%, suggesting that it is worth while treating metastases of gastric cancer to the liver. Both synchronous and metachronous metastases are indications for hepatectomy. If there is only one liver metastasis, with no peritoneal and paraaortic lymph node metastases, curability B resection can be performed. Although there is no consensus on the method of hepatectomy, wedge resection is satisfactory. As systemic chemotherapy, S-1 + cisplatin results in a response rate of 50% in patients with metastases to the liver. As arterial infusion chemotherapy, the 5-fluorouracil-doxorubicin-mitomycin (FAM) regimen yields a response rate of more than 70% including 15% complete response rate. FAM is thus a superior regimen, but care must be taken to prevent complications resulting from intraarterial infusion of outside the vas due to deviation of the catheter.

Hepatectomy↗

[Weekly paclitaxel therapy for metastatic breast cancer].

We treated 12 patients with metastatic breast cancer with weekly paclitaxel therapy. Paclitaxel was administrated by 1 hour infusion at a dose of 80 mg/m2 after short premedication every week on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. All patients had received prior metastatic chemotherapy, and prior anthracycline therapy was done in 66.7% of the patients. Partial responses were observed in 66.7% of the patients and progressive disease in 33.3%. The response rate was 66.7%. Responses were observed in 62.5% of the patients with prior anthracycline therapy. Grade 3/4 leukopenia and neutropenia occurred in 25% of the patients, respectively, and no grade 3/4 peripheral neuropathy was observed. Dyspnea occurred in 25% of the patients and was grade 3 in 16.7%. Dyspnea is thought to be one of the adverse events requiring caution with weekly paclitaxel administration. Weekly paclitaxel therapy is effective and well tolerated in patients with metastatic breast cancer.

Aged↗