5-Fluorouracil and cisplatin sequential chemotherapy; mechanism of action and clinical application in advanced, unresectable non-small cell lung cancer.
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Adult↗
Biomedical subjects
Y Niho
Publications and source records attributed to Y Niho.
[Inhibitory effects of interleukin (IL) -10 and viral IL-10 (vIL-10) on the functions of monocytes/macrophages].
In this study, we examined the effects of IL-10 and vIL-10 on the production of superoxide anion (O2-) and nitric oxide (NO) by human monocytes and mouse macrophages. At an optimal concentration, human IL-10 (hIL-10) and vIL-10 significantly inhibited the production of interferon (IFN)-gamma by stimulated human peripheral blood mononuclear cells (PBMNCs). They also efficiently inhibited the production of O2- by both unstimulated and IFN-gamma-activated human monocytes. Mouse IL-10 (mIL-10) also significantly inhibited the production of NO by lipopolysaccharide (LPS) and IFN-gamma-stimulated mouse peritoneal macrophages. Moreover, the production of O2- and NO was effectively suppressed whether the IL-10 was added before or together with the stimulus, indicating that this cytokine acts primarily at an early stage of monocyte/macrophage activation by IFN-gamma and LPS. We also examined the effects of IL-4 and transforming growth factor (TGF)-beta on the production of O2- and NO by human monocytes and mouse macrophages, and found that they significantly inhibited both the production of O2- by human monocytes and the production of NO by mouse macrophages. Moreover, a combination of any two of IL-10, IL-4 and TGF-beta caused an additive effect on the inhibition of O2- production by human monocytes. These results indicated that IL-10 suppresses monocyte/macrophage activation either indirectly via an inhibition of the synthesis of IFN-gamma, a potent monocyte/macrophage activator, by PBMNCs, or directly via the deactivation of monocytes/macrophages. Moreover IL-10 may act in concert with IL-4 and TGF-beta to suppress monocyte/macrophage activation in vivo.
Animals↗
[A case of hemophagocytic syndrome manifesting adult Still's disease and acute hepatitis].
We report a 20 year-old woman with hemophagocytic syndrome. In February 1993, she developed high fever, arthralgia, salmon-like pink eruption, leukocytosis and splenomegaly. She was diagnosed as adult Still's disease and successfully treated with intravenous immunoglobulin and oral prednisolone. In September 1993, she was re-admitted to our hospital complaining of general fatigue and low grade fever and treated with oral prednisolone at a daily dose of 15 mg. On October 2, 1993, she suddenly developed high fever and salmon-like pink eruption on her leg followed by the marked increase of serum transaminase and LDH levels (GOT 3,270 IU/l, GPT 1,880 IU/l, LDH 5,480 IU/l) on October 7. Since hepatic failure progressed, we started methylprednisolone pulse therapy and plasmapheresis. However, because of the progression of pancytopenia caused by hemophagocytosis, the treatment with VP-16 was initiated. However, she died of DIC on November 2, 1993. Autopsy revealed submassive necrosis of the hepatocytes with moderate infiltration of histiocytes. She was retrospectively diagnosed as hemophagocytic syndrome whose manifestations are very similar to those in adult Still's disease and acute viral hepatitis.
Acute Disease↗
[A young woman with rheumatoid arthritis who rapidly developed secondary amyloidosis].
A 22-year-old woman, who had been diagnosed as having rheumatoid arthritis (RA) 2 years before, was admitted to our hospital complaining of watery diarrhea (several times/day). She had been treated with low dose prednisolone (PSL) and auranofin in out-patient clinic. On admission, laboratory data showed moderate proteinuria (0.3 g/day) and positive CRP (2.7 mg/dl). Although the activity of RA was controlled by the administration of low dose methotrexate (7.5 mg/week) in addition to PSL, watery diarrhea and proteinuria did not improve. The biopsy of the stomach, rectum and kidney revealed the deposition of AA type amyloid protein, resulting in the diagnosis of secondary amyloidosis. Secondary amyloidosis has been reported as one of the common complications in RA patients, especially in old patients with a long history of RA. To our knowledge, however, there have been few reported cases who developed secondary amyloidosis so early during the course of RA as our case. We should be careful for the development of secondary amyloidosis even in young RA patients with short history of RA, when the disease is active.
Adult↗
Peripheral B lymphocyte repertoire to mitochondrial antigen in primary biliary cirrhosis--positive correlation between the disease activity and the frequency of circulating B lymphocytes specific for pyruvate dehydrogenase complex.
B lymphocytes committed to the production of IgG antibodies (Abs) to mitochondrial antigen such as pyruvate dehydrogenase complex(PDC) were quantitated in the peripheral blood of patients with primary biliary cirrhosis(PBC) using Epstein-Barr virus as a polyclonal activator of human B lymphocytes. B lymphocytes committed to the production of IgG Abs to PDC were found in high frequency in patients with PBC(0.54 +/- 0.16%, mean value +/- SE, of total IgG-producing B lymphocytes) in contrast to type C chronic hepatitis and healthy subjects in which they were less than 0.01%. The frequency of these B lymphocytes specific for PDC increased in parallel to the progression of the Scheuer's stage from I to II (stage I: 0.35 +/- 0.23%, stage II: 1.04 +/- 0.32%), but decreased with further progression to stage IV (stage III: 0.39 +/- 0.21%, stage IV: 0.07 +/- 0.06%). In addition, B lymphocytes specific for PDC decreased in the peripheral blood during the administration of cyclosporin A; this was accompanied by an improvement of lymphocyte infiltration severity in the liver. These data indicate that B lymphocytes specific for PDC are present in the peripheral blood of patients with PBC and their frequency reflects the degree of the lymphocyte infiltration in the liver.
Adult↗
Malignant histiocytosis derived from a common histiocyte clone in a patient with chronic Epstein-Barr virus infection.
Epstein-Barr virus (EBV) has a particular propensity for B lymphocytes, but in a few cases it seems to play a role in histiocytic disorders and EVB DNA has been identified in histiocytes. To determine what kind of cell proliferate clonally, we studied a patient with malignant histiocytosis that developed after chronic EBV infection. Polymerase chain reaction (PCR) for lymphocyte-defined membrane antigen (LYDMA) of EBV, a marker of monoclonality, double stainings of cell markers (B, T lymphocytes; histiocytes), and in situ hybridization for EBV were performed in tissues obtained in 1987 and 1990 before the appearance of malignant histiocytosis and in 1991 after the disease was diagnosed. PCR for LYDMA from multiple samples during the disease showed the same single band, indicating that chronic EBV infection and malignant histiocytosis were caused by the same single virion. We also found a single terminal repeat band of EBV which supports this finding. In the studies of double stainings, EBV was present in histiocytes of the non-neoplastic early stage, and in the neoplastic cells of malignant histiocytosis. The histiocyte, infected with EBV, clonally expanded to result in malignant histiocytosis.
Adolescent↗
In vitro study of deoxymethylspergualin on functions of lymphocytes and bone marrow cells from healthy volunteers.
15-Deoxy-11-O-methylspergualin (MeDSG) is an analogue of 15-deoxyspergualin, which has potent immunosuppressive activity. The present study was designed to evaluate the in vitro effects of MeDSG on the functions of peripheral blood mononuclear cells (PBMC) and bone marrow cells derived from healthy volunteers. MeDSG failed to suppress the proliferation of PBMC stimulated with mitogens. In the allogeneic mixed lymphocyte reaction, MeDSG strongly suppressed both the proliferation of lymphocytes and the generation of alloreactive cytotoxic T lymphocytes, but did not affect the cytolytic activity of the established cytotoxic T lymphocytes. MeDSG had no effect on the cytolytic activity of natural killer cells. Concerning positive hematopoietic regulators, MeDSG had a slight enhancing effect on the release of granulocyte-macrophage colony-stimulating factor and a slight inhibitory effect on the release of interleukin-6 and granulocyte-colony-stimulating factor from PBMC stimulated with mitogens. Significantly, MeDSG completely suppressed the colony formation of bone marrow cells in the presence of granulocyte colony-stimulating factor.
Bone Marrow↗
Relationship of infused CFU-GM and CFU-Mk mobilized by chemotherapy with or without G-CSF to platelet recovery after autologous blood stem cell transplantation.
Although hematologic reconstitution is usually rapid after autologous blood stem cell transplantation (ABSCT), there is an occasional delay in platelet recovery. We studied the hematologic recovery of 27 adult patients with hematologic malignancies who received marrow-ablative chemotherapy and ABSCT to determine whether or not the numbers of infused mononuclear cells (MNC), colony-forming units granulocyte/macrophage (CFU-GM), and colony-forming units megakaryocyte (CFU-Mk) were related to the speed of platelet recovery after ABSCT. Peripheral blood stem cells were collected using chemotherapy-induced mobilization with or without cytokine therapy. While the number of MNC infused did not show a significant correlation with time to platelet recovery as well as granulocyte and reticulocyte recovery, the logarithmic number of CFU-GM-infused did (p < 0.01). We also found a significant correlation between the logarithmic number of CFU-Mk-infused and the time to platelet recovery (p < 0.01). These findings suggest that the number of CFU-GM-infused is a reliable indicator of hematopoietic recovery and that the number of CFU-Mk-infused is no more reliable than CFU-GM for predicting platelet recovery after ABSCT.
Adolescent↗
High-frequency granuloid colony-forming ability of G-CSF receptor possessing CD34 antigen positive human umbilical cord blood hematopoietic progenitors.
The presence of granulocyte colony-stimulating factor receptor (G-CSFR) in CD34+ hematopoietic progenitors is demonstrated by flow cytometry. Cord blood mononuclear cells (MNCs) contain about 1.09 +/- 0.2% CD34+ cells, 0.32 +/- 0.1% CD34+/G-CSFR+ (G-CSFR+) cells, and 0.77 +/- 0.1% CD34+/G-CSFR- (G-CSFR-) cells. The colony-forming ability of G-CSFR+ cells in the presence of G-CSF, granulocyte-macrophage CSF (GM-CSF), interleukin-3 (IL-3), and erythropoietin (Epo) was higher than that of G-CSFR- cells (29.5 vs. 9.8%; p < 0.01). In the fraction of G-CSFR+ cells, the most frequently formed colony type was CFU-G/GM, while burst-forming unit-erythroid (BFU-E) or colony-forming unit-macrophage (CFU-M) were rare. On the other hand, the incidence of BFU-E and CFU-G/GM was similar in the fraction of G-CSFR- cells. This indicates that most granuloid colonies of CD34+ cells were derived from G-CSFR+ cells. These results suggest a lineage commitment for the vast majority of G-CSFR+ hematopoietic progenitors.
Antigens, CD↗
Granulocyte colony-stimulating factor mobilizes primitive hematopoietic stem cells in normal individuals.
We studied the hematopoietic activity of peripheral blood stem cells (PBSC) mobilized by recombinant human granulocyte colony-stimulating factor (G-CSF) using semisolid and long-term culture systems (LTC) in 5 normal individuals. Following 2 or 3 daily subcutaneous injections of G-CSF (filgrastim; 1.5 micrograms/kg), not only committed progenitors including CFU-GM, BFU-E, and CFU-Mix, but also long-term culture initiating cells (LTC-IC) were increased in the peripheral blood. When the cells derived from CFU-GM, BFU-E and CFU-Mix colonies were replated for secondary colony formation, a minor fraction of CFU-GM and CFU-Mix colonies formed after 3 days of G-CSF stimulation in vivo could produce secondary colonies. Moreover, the replating capacity of primary colonies from 5-week-old LTC initiated after 3 days of G-CSF stimulation was increased compared to that from 5-week-old LTC initiated in a 'steady-state'. These observations indicate that G-CSF can mobilize very primitive progenitors (LTC-IC) along with committed progenitors into the circulation and suggest that some of these G-CSF-mobilized progenitors may retain self-renewal capacity.
Adult↗
G-CSF induces tyrosine phosphorylation of the JAK2 protein in the human myeloid G-CSF responsive and proliferative cells, but not in mature neutrophils.
Granulocyte colony-stimulating factor (G-CSF) stimulates a rapid phosphorylation on tyrosines of several proteins of Mr. 130, 100, 90, 70, 44 kd in human myeloid leukemia cell line cells, Kasumi-1, which respond to G-CSF to proliferate in vitro. In HL60 cells, only a 100 kd protein was phosphorylated, and no detectable phosphorylated proteins were observed in neutrophils by the stimulation of G-CSF. Among these proteins, the 130 kd protein was immunoprecipitated by anti- JAK2 serum. While JAK2 is a non receptor tyrosine kinase and is reported to be involved in the signal transduction by various cytokines including growth hormone, erythropoietin, and granulocyte-macrophage colony-stimulating factor/interleukin-3, it is strongly suggested that a signaling pathway that relates to the cell proliferation triggered by G-CSF in immature hematopoietic cells also involves JAK2.
Cell Division↗
[Basic study of hematopoietic stem cells and the clinical application].
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Animals↗
[Optimal administration of 5-FU and cisplatin based on biochemical modulation in the treatment of non-resectable non-small cell lung carcinoma].
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Antineoplastic Combined Chemotherapy Protocols↗
Surface phenotype and Ig heavy-chain gene usage in chronic B-cell leukemias: expression of myelomonocytic surface markers in CD5- chronic B-cell leukemia.
We investigated the surface expression of leukocyte differentiation antigens and the Ig heavy-chain variable region (VH) gene family use in leukemic cells from 26 Japanese patients with chronic B-cell leukemias with special reference to CD5 antigen expression. CD5 was expressed on leukemic cells in 21 of 26 cases (CD5+) but not in 5 cases (CD5-). Myelomonocytic marker, CD13 antigen was expressed on the leukemic cells in all 5 CD5- cases but in none of CD5+ cases. Leukemic cells in CD5- cases also expressed CD11b antigen more frequently than those in CD5+ cases (80% v 11%; P < .01). Another myeloid marker, CD33, was expressed neither on CD5+ nor CD5- leukemic cells. CD22, a restricted B-cell marker, was expressed more frequently on CD5- leukemic cells than on CD5+ leukemic cells (80% v 33%; P < .05). Another restricted B-cell activation marker, CD23, was expressed at similar frequency in both the CD5+ and CD5- groups (67% v 60%). Although CD45RA was expressed on the majority of leukemic B cells, the CD45RA expression level was significantly higher among CD5- cases than CD5+ cases (P < .01). In the analysis of VH gene expressed in chronic B-cell leukemias by polymerase chain reaction amplification, CD5+ cases preferentially used VH4 family members (48%; 10 of 21). CD5- cases, on the other hand, mainly used VH3 family (80%; 4 of 5). Thus, from our present observation of an albeit limited patient population, we have found an association between VH gene family use and CD5 antigen expression in chronic B-cell leukemias. We have also shown the differential expression of myelomonocytic markers in the CD5+ and CD5- chronic B-cell leukemias. These result are in agreement with previous suggestions that CD5 positivity is the hallmark for distinct clinical entity commonly referred to in the literature as chronic lymphocytic leukemia.
Adult↗
Expression of the alpha 2-macroglobulin-encoding gene in rat brain and cultured astrocytes.
The alpha 2-macroglobulin (alpha 2M), a protease inhibitor, is a major acute-phase protein in rats, and is produced in the liver during acute inflammation. Recently, it has been demonstrated that alpha 2M is also produced by cultured astrocytes from newborn rat brain and has neurite-promoting activity. Here, we found that the expression of the alpha 2M gene was significantly enhanced in the brain following intraperitoneal injection of the neurotoxicant, kainic acid (KA), suggesting that alpha 2M acts as an acute-phase protein in the brain, as in the case of the liver, and may be involved in neural repair processes. Expression of alpha 2M in cultured astrocytes was shown to be stimulated by interleukin-6 (IL-6) and/or leukemia inhibitory factor (LIF) in the presence of glucocorticoid. The amount of mRNAs for IL-6 and LIF increased in the brain of KA-injected rats prior to alpha 2M induction. These results strongly suggested that IL-6 and LIF are involved in alpha 2M induction in the brain, as in the case of the liver. Analysis of the cis-acting element(s) and the trans-acting factor(s) suggested that the regulatory mechanism for alpha 2M expression in astrocytes was similar to that in inflamed liver.
Animals↗
Expression of the c-kit ligand and interleukin 6 genes in mouse bone marrow stromal cell lines.
The expression of c-kit ligand and interleukin 6 (IL-6) genes in mouse bone marrow-derived stromal cell lines was examined using quantitative polymerase chain reaction (PCR) analysis based on the design of an internal DNA control. The stromal cells studied included the 14F1.1 endothelial-adipocytes that support long-term hemopoiesis and two additional cell lines (MBA-1, MBA-13) which do not have this function. All the cell lines expressed c-kit ligand gene constitutively, and this expression was not increased by lectins. On the other hand, the expression of the IL-6 gene was markedly induced in all the lines by lipopolysaccharide (LPS) and by phorbol 12-myristate 13 acetate (PMA). The constitutive expression of c-kit ligand in 14F1.1 cells was the lowest among the three cell lines studied and could be increased by stimulation with IL-4. Thus, we observed some quantitative differences among the cell lines in their expression of cytokine genes. However, the unique capacity of 14F1.1 cells to support in vitro hemopoiesis cannot thus far be explained solely on the basis of the ability of these cells to secrete cytokines which are not produced by other stromal cell lines. c-kit ligand may be necessary, but its presence alone is not sufficient for 14F1.1 cells to support prolonged hemopoiesis.
Adipose Tissue↗
Analysis of acute myeloid leukemia cells by flow cytometry, introducing a new light-scattering classification.
A combined flow-cytometric evaluation of light scattering and the immunophenotype of acute myeloid leukemia (AML) cells from 71 newly diagnosed consecutive patients was conducted. Light-scattering characteristic of AML cells examined by flow cytometry and multiple surface markers were also analyzed using the same samples, to enable a comparison with the French-American-British (FAB) classification. Our AML cases could be classified into three light-scattering classification (LSC) types according to their physical properties on flow cytometry. These were type A, where forward light scattering (FSC) of the leukemic cell population was larger than that of lymphocytes, while side light scattering (SSC) was the same or larger than that of lymphocytes but smaller than that of monocytes; type B, where FSC of the leukemic cell population was larger than that of lymphocytes and SSC spread toward that of monocytes; and type C, where both FSC and SSC of the leukemic cell population spread beyond those of monocytes. Although a clear relationship between the FAB classification and LSC classification by the light-scattering profile of AML was not established, we observed the following findings. The majority of cases were classified as type A (58%), while type B comprised 25% and type C comprised 17%. While CD7 expression on AML cells is considered to be an immature characteristic, CD7 was expressed more frequently among LSC type A cases. Furthermore, all but one of the FAB M1 cases were classified as type A. On the other hand, CD7 was not expressed on type C leukemic cells. The percentage of cases in which more than 60% of leukemic cells possessed another immature surface antigen, CD 34ö, was 13/18 (72%) among FAB M1 cases, much higher than among FAB M2 (35%) or FAB M4 (27%) cases. A negative correlation was observed between mature antigen CD33 and CD34 among the FAB M2 cases. The frequency of CD7 expression was 25% among the total cases, and CD7-positive cases were frequent among FAB M1 and M2, but not among FAB M3 cases. These findings concerning LSC and immunophenotyping indicate that the scattergram pattern analysis may contribute towards more precise immunophenotyping, in that it reflects the maturation stage of each AML case.
Acute Disease↗