Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been demonstrated previously that the degree of glycosylation of a molecule may alter its pharmacokinetic properties and, in the case of an antibody, its metabolism and other biological properties. Transfectomas producing aglycosylated chimeric B72.3(gamma 1) pancarcinoma monoclonal antibody (mAb) were developed by introduction of the eukaryotic expression construct pECMgpB72.3 HuG1-agly, into SP2/0 murine myeloma cells producing the chimeric kappa chain of mAb B72.3. After cell cloning, one subclone with the highest binding to the TAG-72-positive human colon carcinoma was designated mAb aGcB72.3, and its biological and biochemical properties were compared with those of the chimeric B72.3(gamma 1), designated mAb cB72.3. Polyacrylamide gel electrophoresis showed that under non-reducing conditions, the molecular masses of the aGcB72.3 and cB72.3 mAbs were 162 kDa and 166 kDa respectively. The heavy chain of mAb aGcB72.3 had a slightly faster mobility than that of cB72.3, while the mobility of the light chains of the two chimeric mAbs was similar. No difference was observed in the isoelectric points of either chimeric mAb. Liquid competition radioimmunoassays demonstrated that the aGcB72.3 and cB72.3 mAbs have comparable binding properties to TAG-72. These studies demonstrate that aglycosylation of the chimeric IgG1 mAb B72.3 at the CH2 domain, as has been shown for other mAbs [Dorai H., Mueller B., Reisfeld R. A., Gillies S. D. (1991) Hybridoma 10:211; Morrison S. L., Oi V. T. (1989) Adv Immunol 44:65], eliminates antibody-dependent cell-mediated cytotoxicity activity, but does not substantially alter affinity or plasma clearance in mice. These studies also demonstrate for the first time (a) no difference in plasma clearance of an aglycosylated and a chimeric mAb in a primate after i.v. inoculation; (b) a difference (P less than or equal to 0.05) in mice in the more rapid peritoneal clearance of a chimeric mAb versus an aglycosylated chimeric mAb; (c) higher (0.05 less than or equal to P less than or equal to 0.1) tumor: liver ratios at 24, 72 and 168 h using 111In-labeled aglycosylated chimeric mAb versus chimeric mAb. Since the liver is the major site of metastatic spread for most carcinomas, slight differences in tumor to normal liver ratios may be important in diagnostic applications. These studies thus indicate that comparative analyses of a novel recombinant construct (i.e., aglycosylated) and its standard chimeric counterpart require documentation in more than one system and are necessary if one is ultimately to define optimal recombinant/chimeric constructs for diagnosis and therapy in humans.
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PMID:Comparative biological properties of a recombinant chimeric anti-carcinoma mAb and a recombinant aglycosylated variant. 163 52

In the present study, we demonstrate that the PKC-activating phorbol ester PMA selectively induced IgA synthesis by PP B cells. PKC activation triggered neither B cell proliferation nor the switching rate of IgA- to IgA+ cells. Together with the fact that the rate of IgA secretion by the myeloma cell line MOPC 315 was not altered by PMA, the data demonstrate that activation of PKC enhances IgA secretion by promoting terminal differentiation of IgA-committed B cells into IgA-secreting plasma cells.
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PMID:Role for protein kinase C activation in IgA B cell terminal differentiation. 195 71

The performed clinical analysis covered 80 patients with multiple myeloma, treated at Hematological Clinic of PMA in the years from 1974 to 1984. The following prognostic factors were analyzed: age, sex, living place, clinical advancement period of the disease, functional state according to Karnofsky (Karnofsky's index), monoclonal protein type, the concentration of urea, creatinine, calcium in blood serum, hemoglobin concentration as well as the neoplastic tumour mass. These factors were considered to indicate poor prognosis: severe anemia, hypercalcemia, renal failure, and Karnofsky's index being below 70 points.
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PMID:[Retrospective analysis of patients with multiple myeloma; clinical characteristics and prognostic factors]. 209 6

In a recent report, a construction containing the alpha chain-variable region (V alpha) coding sequence of a cDNA clone derived from a diphtheria toxoid-specific human T cell (P28), fused to a human immunoglobulin kappa light chain constant region (Ck), was used stably to transfect a murine myeloma cell. In the present study, these transfected cells were employed as an immunogen to raise a mAb, termed 1C5V alpha, specific both for the V alpha Ck chimeric protein secreted by the transfectant and the P28 T cell antigen receptor-V alpha region. mAb 1C5V alpha specifically immunoprecipitates the V alpha Ck protein as a family of 32-35 kDa bands present in the 35S-methionine-labeled culture supernatant from the transfected cells. It specifically binds clone P28. Surface molecules recognized by mAb 1C5V alpha are physically linked to the CD3 molecules since cell treatment with either 1C5V alpha or anti-CD3 mAbs caused the simultaneous down-regulation of the CD3/TCR molecular complex. This link is further supported by immunoprecipitation experiments. Thus, both the 1C5V alpha and the anti-CD3 mAbs precipitate the 16-28 kDa CD3 molecules and the disulfide-linked form of P28 TCR from 125I-labeled P28 T cells. Studies performed in order to define whether a stimulus directly acting on the TCR-V alpha region may trigger the intracellular events observed during human T cell activation showed that (a) mAb 1C5V alpha efficiently triggers the phospholipase C transduction pathway revealed by an accelerated phosphoinositides turn-over and an increased production of phosphorylated derivatives of inositol phosphates; (b) mAb 1C5V alpha induces an up-regulation of IL2R mRNA, accompanied by a slight increase of IL2 and IFN alpha mRNA transcripts evidently amplified in the presence of PMA; (c) soluble mAb 1C5V alpha is strongly mitogenic together with PMA. These results provide the first evidence for the structural authenticity of a secreted water-soluble chimeric form of the variable region of a human TCR alpha chain. They further demonstrate that such chimeric proteins may be valuable tool to further dissect the various functional structure of the human TCR.
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PMID:A human TCR-Ig chimeric protein used to generate a TCR alpha chain variable region-specific mAb. 214 29

Human C-reactive protein (CRP) is an acute phase reactant that is opsonic and an activator of macrophage tumoricidal function. CRP also activates the classical C cascade. These activities suggest that CRP might interact with monocytes/macrophages via specific receptors in a manner analogous to the interaction of IgG with FcR. With the use of radio-labeled human CRP, we have observed specific binding of CRP to human blood monocytes and the human monocytic cell line U-937. Binding was saturable at a pathophysiologic concentration of CRP, with an estimated KD of 9.5 x 10(-8) M and 3.6 x 10(5) binding sites/cell. Specific binding was inhibited by polyclonal human IgG as well as an IgG1 myeloma. In the converse experiment, CRP failed to inhibit specific [125I]IgG binding. The mAb IV.3, which inhibits binding of IgG immune complexes to FcRII, did not inhibit CRP binding. A 100-fold excess of phosphorylcholine or the phosphorylcholine binding peptide of CRP (residues 47-63) failed to inhibit binding. Although human rIFN-gamma and PMA increased FcRI expression, these reagents had no affect on CRP receptor expression. A single membrane protein of 38 to 41 kDa from U-937 cells was chemically cross-linked to [125I]CRP; the cross-linking was inhibited by human IgG1 but not the IV.3 mAb. Furthermore, two membrane proteins with a Mr of 38 to 40 kDa and 58 to 60 kDa were isolated by CRP ligand-affinity chromatography. These proteins were of a distinct size from those isolated for FcRI from an IgG ligand matrix. These studies demonstrate specific binding of human CRP to a human monocytic cell line via receptors that are distinct from the IgG FcR and implicate CRP in nonspecific, preimmune host defense reaction mediated by cells of the monocytic lineage.
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PMID:Characterization and isolation of a C-reactive protein receptor from the human monocytic cell line U-937. 215 64

The production of interleukin 2 (IL-2) by peripheral blood mononuclear cells (PBMC) was studied in 15 normal controls (NC) and 29 patients with multiple myeloma (MM), including 19 patients with active disease (i.e. diagnosis, relapse) and 10 with inactive disease (i.e. complete remission and off-treatment plateau). IL-2 was produced after stimulation of PBMC with PHA alone or with PHA and PMA. The role of suppressor factors/cells on IL-2 production was evaluated using indomethacin and irradiation of PBMC. T cells and T cell subsets (i.e. helper/suppressor T cells) were defined using standard monoclonal antibodies (T3, T4, T8). The production of IL-2 in active MM was similar to that of NC, using either PHA or PHA and PMA. However, a constant defect of prostaglandin-mediated suppressor cells was observed in patients in plateau, with a significant increase of IL-2 production in comparison to that of NC or active MM. IL-2 is an essential factor involved in T cell proliferation. Recent data demonstrate that it plays a role in B cell proliferation and differentiation into antibody-secreting cells. Suppression of antibody synthesis is a major feature of active (but not inactive) MM. The fact that IL-2 production was not affected in MM, in spite of an imbalance of some T cell subsets, is of major interest.
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PMID:Production of interleukin 2 in multiple myeloma. 348 31

Four human B cell lines with a mature phenotype (immunoglobulin secretion and expression of membrane markers associated with maturation) were cultured in the presence of phorbol ester (PMA), dimethyl sulphoxide (DMSO) and two conditioned media. PMA and DMSO led to changes in phenotype which suggested the cells were being activated, whilst the conditioned media resulted in increased immunoglobulin secretion, accompanied by phenotypic changes more consistent with maturation towards the plasma cell stage. The four cell lines, which had different origins (EBV-transformed normal B cell, Burkitt's lymphoma, prolymphocytic leukaemia and multiple myeloma) responded differently to the culture stimuli. These differences suggest that the changes associated with transformation affect the way in which these cells respond to agents which stimulate activation and maturation.
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PMID:Responses of 'mature' human B lymphocyte lines to inducers of maturation and activation. 349

The immunoreactivity of paraffin embedded bone marrow biopsies (BMB) was studied following a one step 20-hour-fixation-decalcification in Lowy formalin mercuric chlorid acid solution which permits excellent histological stainings. Antibodies reactive with myeloid, megakaryocytic, erythroid cells, T and B lymphocytes, mastocytes and metastatic cells were compared. Nearly all antibodies working on paraffin sections were demonstrated on Lowy FMA fixed BMB. Special care was taken to define an optimal working dilution. Trypsinization was not necessary. A slide microwave pre-treatment appeared essential before testing CD20 L26, CD8, CD3, CD34, MB1 Kappa and Lambda antibodies. It was suitable for UCHL1, LN2, CD30 antibodies. The same fixative allowed an m RNA Kappa or Lambda in myeloma and EBER 1 EBV RNAs in HIV lymphoma visualization by in situ hybridization. The safety handling of the toxic mercuric chloride component is discussed.
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PMID:Bone marrow one step fixation-decalcification in Lowy FMA solution: an immunohistological and in situ hybridization study. 754 Jul 53

The baculovirus expression system has been used for the production of a variety of proteins, including antibodies. Two single-gene constructs encoding single-chain immunoglobulins have recently been developed. The antibody employed was monoclonal antibody (MAb) CC49 which reacts with the pancarcinoma antigen, tumor associated glycoprotein, TAG-72. One, single-chain construct designated SCA delta CLCH1 (SCIg), consists of the CC49 sFv covalently joined to the human Fc (gamma 1) through the hinge region. The other, SCA delta CLCH1-IL-2 (SCIg-IL-2), has a human IL-2 molecule attached to the carboxyl end of the SCIg. These constructs have been used to test the feasibility of producing biologically active antibodies using the baculovirus expression system. Both constructs have been successfully expressed in insect cells and purified. The baculovirus recombinant single-chain antibodies have been designated, bV-SCA delta CLCH1 (bV-SCIg) and bV-SCA delta CLCH1-IL-2 (bV-SCIg-IL-2) they have been shown to be secreted in the culture supernatant as dimeric molecules of approximately 115 kDa and 140 kDa, respectively. The specificity and antibody dependent cellular cytolytic activity of the baculovirus recombinant single-chain antibodies were shown to be similar to that of the myeloma derived molecules. Glycosylation analysis showed that baculovirus derived proteins were N-glycosylated, but carried few if any high mannose residues. The biological activity of the IL-2 moiety was retained in bV-SCIg-IL-2, as evidenced by its stimulatory effect on the proliferation of the IL-2 dependent cell line HT-2. The observation that a significantly shorter time is required to develop baculovirus recombinant molecules as compared to myeloma derived molecules and that insect cells express single chain MAbs at acceptable levels may have implications for the production of these molecules for clinical use.
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PMID:Baculovirus expression of a functional single-chain immunoglobulin and its IL-2 fusion protein. 759 24

Lap18 is a highly conserved cytosolic protein that is expressed in dividing cells. Data from a number of studies show that a range of cell lines and mitogen-stimulated normal cells cultured in PMA phosphorylate and subsequently down-regulate Lap18. This has been found to be associated with growth arrest, although it is not clear that these events are causally related. In the present study we confirm that the HL60 promyelocytic leukemia and K562 erythroleukemia cell lines, when cultured with PMA, behave in this manner. This was not the case for any of five mouse plasmacytoma cell lines and six lines derived from patients with multiple myeloma or plasma cell leukemia. All of these lines contain Lap18, although the level of this protein in the mouse but not the human plasmacytoma cell-line cells is relatively low. All the neoplastic plasma cell-line cells phosphorylate Lap18 on culture with PMA, but this does not induce growth arrest nor result in down-regulation of Lap18 expression. Further experiments are required to test whether there is a mechanistic relationship between the continued growth of plasmacytoma cell lines and their failure to down-regulate Lap18 on culture in PMA.
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PMID:Persistent growth of BALB/C mouse plasmacytoma and human myeloma cell lines in the presence of phorbol myristate acetate is associated with continued expression of Lap18 (stathmin). 775 Sep 26


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