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)

Microsporidia (M), representatives of the phylum Microspora, make a world-wide distributed group of intracellular protists, parasitic in the vast number of hosts, from Protozoa to Primates. In their morpho-functional organization, both very primitive and extremely specialized features are seen definitely combined. Data available on RNA and DNA sequences suggest that M may be the most ancient eukaryotes. By the present, as many as 13 microsporidian species have been recognized as opportunistic pathogens in AIDS and transplant patients. Information about structural, transport and regulatory proteins of M, as well as on their enzymes is scarce, though it could serve as a basis for understanding pathogenicity of M and indicate some possible sites of relevant suppressive therapy. The present study persuaded two main goals: 1) to examine two ways of antigen preparation (from the infected organ and from the purified spores) and to evaluate their relation to the yield of the resulting antibodies; 2) to identify and localize new proteins with the help of the obtained antibodies by means of IFA, IEM and WB. Mice were immunized: 1) with dissolved proteins of heavily loaded with parasites fat bodies isolated from crickets Gryllus bimaculatus infected with Nosema grylli, and 2) with proteins of the purified spores of N. grylli. As a result two antisera were obtained. Antiserum 1 reacted predominantly with spore walls on IFA slides and ultrathin sections (IEM). It also reacted with a broad spectrum of parasite and host cell proteins on WB. Antiserum 2 recognized polar filaments and walls of discharged spores in IFA and IEM tests. It did not react with undischarged spores or fat bodies of uninfected crickets and gave a comparatively weak reaction with those of the infected hosts. Hybridization of spleen cells of immune mice with murine myeloma cells resulted in several hybridoma clones. They produced Mabs, 5 of which were tested by IFA, IEM and WB. Mab 1BF3 recognized 55 kDa protein connected with polar filaments as it was clearly suggested by IEM and IFA. Mab 1BD9 recognized 25, 34, 43 kDa proteins from the fraction of membrane bound proteins of spore walls, the sites of their interaction with antigens being marked with uneven fluorescence (IFA) and by gold precipitates on spore walls (IEM). Mab 1BB9 reacted with 36, 45, 65 and 75 kDa proteins, which belong mainly to the fraction of membrane-bound spore proteins, and gave a weak fluorescence associated with spores. Mab 2AB3 recognized 44 and 60 kDa proteins from the fraction of soluble spore proteins, and Mab 2AD4 acknowledged a single protein of 55 kDa from the same fraction. The obtained antibodies add to the existing microsporidian antibody bank and can be used for further work of isolation, description and sequencing the microsporidian proteins in order to understand eventually their functions.
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PMID:Analysis of antibodies raised against soluble and membrane bound proteins of Nosema grylli (Microspora) spores. 1121 49

In the present study, we examined the effect of soluble CD4 (sCD4) on host resistance and delayed-type hypersensitivity (DTH) response to Cryptococcus neoformans using a novel mutant mouse that exhibits a defect in the expression of membrane-bound CD4 but secretes high levels of sCD4 in the serum. In these mice, host resistance to this pathogen was impaired as indicated by an increased number of live pathogens in the lung. To elucidate the mechanism of immunodeficiency, three different sets of experiments were conducted. First, administration of anti-CD4 mAb restored the attenuated host defense. Second, in CD4 gene-disrupted (CD4KO) mice, host resistance was not attenuated compared to control mice. Third, implantation of sCD4 gene-transfected myeloma cells rendered the CD4KO mice susceptible to this infection, while similar treatment with mock-transfected cells did not show such an effect. These results indicated that immunodeficiency in the mutant mice was attributed to the circulating sCD4 rather than to the lack of CD4+ T cells. In addition, DTH response to C. neoformans evaluated by footpad swelling was reduced in the mutant mice compared to that in the control, and the reduced response was restored by the administration of anti-CD4 mAb. Finally, serum levels of IFN-gamma, IL-12 and IL-18 in the mutant mice were significantly reduced, while there was no difference in Th2 cytokines, such as IL-4 and IL-10. Considered collectively, our results demonstrated that sCD4 could directly prevent host resistance and DTH response to C. neoformans through interference with the production of Th1-type cytokines.
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PMID:Circulating soluble CD4 directly prevents host resistance and delayed-type hypersensitivity response to Cryptococcus neoformans in mice. 1122 Jun 77

More than 35 years ago, study of an unknown immunoglobulin (Ig) in the serum from a myeloma patient led to the discovery of IgD. Subsequently, the finding that it also exists as a membrane-bound Ig stimulated a large number of studies during the 70s. Then, the interest on IgD shrank, largely because of the lack of known function of secretory IgD (secIgD) and of a stagnating knowledge of the functions of surface IgD. In the recent years, very significant advances followed the tremendous accumulation of data on the physiology of the B cell receptor, of which IgD is the major component, on the role of secIgD in normal and diseased individuals. This review, which is focused on human IgD but integrates data in the mouse and other species when needed, summarizes present data on the structure, synthesis and functions of both membrane and secIgD, IgD receptors and the involvement of IgD in various diseases, especially the hyperIgD syndrome.
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PMID:Structural and functional properties of membrane and secreted IgD. 1128 92

Receptor activator of nuclear factor kappaB (RANK) is a membrane-bound tumor necrosis factor receptor homologue that mediates signals obligatory for osteoclastogenesis as well as osteoclast activation and survival in vivo. The present study was undertaken to evaluate the efficacy of a soluble murine RANK-human immunoglobulin fusion protein (muRANK.Fc) as a bone resorption inhibitor in vitro and in vivo. The in vitro studies demonstrated the ability of muRANK.Fc to inhibit human parathyroid hormone-related protein (PTHrP)-induced resorption in fetal rat long bone cultures. Short-term administration of muRANK.Fc to normal growing mice resulted in a complete disappearance of osteoclasts from metaphyses of long bones associated with a pronounced increase in calcified trabeculae and bone radiodensity. In a model of humoral hypercalcemia of malignancy in which PTHrP secreted by s.c. xenografts of human lung cancer in nude mice induces extensive osteolysis and severe hypercalcemia, daily administration of muRANK.Fc from time of tumor implantation profoundly inhibited osteoclastic bone resorption and prevented hypercalcemia. muRANK.Fc had no effect on tumor production of PTHrP, because there was no significant difference between circulating human PTHrP levels in muRANK.Fc-treated and vehicle-treated tumor-bearing mice. Moreover, even when treatment was initiated after hypercalcemia was established, muRANK.Fc significantly attenuated further increases in blood ionized calcium. These data demonstrate the potent antiresorptive effects of muRANK.Fc in vivo as well as highlight the potential utility of disrupting RANK signaling as a novel therapeutic approach in humoral hypercalcemia of malignancy and possibly multiple myeloma and skeletal metastases associated with osteolysis.
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PMID:Therapeutic efficacy of a soluble receptor activator of nuclear factor kappaB-IgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy. 1128 33

Specific modified substrate-analogous amino acids and peptides have been used as affinity ligands in the affinity chromatography of proteases. Alanine methyl ketone-Sepharose (AMK-Sepharose) is introduced as affinity support for the purification of a bacterial alanyl aminopeptidase (AAP) from a membrane protein extract and Arginine-Agarose as support for the preparation of a membrane-bound proteinase of myeloma cells (MP-1). Peptidyl methyl ketones as affinity ligands have been used to separate subtilisin enzymes and the cysteine proteases cathepsin B, L, and S. As a new type of ligands, spacer-bound peptidyl chloromethyl ketones are presented for a specific and oriented immobilization of proteinases. Oriented-immobilized cathepsin B was used to isolate antibodies against this enzyme.
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PMID:Purification of soluble and membrane-bound proteases with substrate-analogous inhibitors by affinity chromatography. 1169 97

Study of the network of cytokines has helped identify cell growth factors in multiple myeloma. Plasma cells themselves may produce autocrine interleukin 6 (IL-6) while IL-6 production by bone marrow stromal cells may operate a paracrine mechanism. Involvement of IL-6 in multiple myeloma is indicated by its ability to induce the differentiation of myeloma plasmablasts into mature malignant plasma cells. Differential diagnosis between multiple myeloma and monoclonal gammopathies of undetermined significance (MGUS) is generally based on clinical and laboratory parameters. Nevertheless, evaluation of the serum level of IL-6, C reactive protein, soluble IL-6 receptor, soluble IL-2 receptor together with the activity exerted by IL-3 and IL-4 on some cellular subsets constitutes an additional element in the differential diagnosis of border-line cases. Serum levels of IL-6, soluble IL-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R) and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels correlate with the duration of survival, as high values at the time of diagnosis correlate with short duration of survival.
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PMID:Interleukin-6 and the network of several cytokines in multiple myeloma: an overview of clinical and experimental data. 1174 46

Because many studies have focused on growth factors in multiple myeloma, the study of the cytokine network appears to be useful for this purpose. Interleukin-6 (IL-6) and IL-2 with their soluble receptors (IL-3, IL-4, IL-10, and IL-11) have been examined. Plasma cells may produce IL-6 by an autocrine mechanism whereas a paracrine mechanism is believed to be involved in the production of IL-6 by bone marrow stromal cells through an interaction between adhesion molecules present on myeloma plasma cells and their respective receptors that are present on bone marrow stromal cells. In addition, control over production of IL-6 may be exerted by other ILs such as IL-1beta and IL-10. Among target cells, the growth of normal and myeloma plasma cells is supported by IL-6, which also induces the differentiation of myeloma plasmablastic cells into mature plasma cells. This last action also is shared by IL-3, IL-4, and, most likely, IL-8. Evaluation of the serum level of IL-6, C reactive protein, soluble IL-6 receptor (sIL-6R), and soluble IL-2 receptor (sIL-2R), together with the activity exerted by IL-3 and IL-4 on some cellular subsets, may constitute an additional element in the differential diagnosis of borderline cases. However, the concomitant evaluation of all immunologic parameters could be more useful than the value of a single IL. Serum levels of IL-6, sIL-6R, sIL-2R, and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells, are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels are believed to be correlated with the duration of disease-free survival because a high serum level at the time of diagnosis is believed to be correlated with a short duration of survival. However, some laboratory parameters may express the same prognostic value as high beta(2) microglobulin and lactate dehydrogenase (LDH) serum levels together with a high plasma cell labeling index are correlated with disease activity. Furthermore, if the evaluation is performed at the time of diagnosis, high values of these parameters are correlated with a short disease-free survival. A correlation between laboratory parameters and the serum level of several cytokines was demonstrated. Hence, the real advantage of the prognostic evaluation of cytokines is reserved for patients who do not exhibit uniform results with regard to beta(2) microglobulin and LDH serum levels, or, better, for borderline cases. With regard to the differential diagnosis, all immunologic parameters should be evaluated concomitantly rather than separately to confer a real prognostic value to results. Furthermore, a particular relation was found between a high sIL-6R serum level and a poor response to chemotherapy, therefore suggesting the possibility of identifying in advance a subset of patients with a high risk of treatment failure, as has already been demonstrated in other hematologic malignancies.Finally, the majority of studies indicate that interferons are used mainly in the immunotherapy for multiple myeloma, whereas many clinical trials should still be required for the evaluation of the effectiveness of anti-I-L6 antibodies or antiidiotypic vaccines in reference to the eligible patients for these particular therapies.
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PMID:A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. 1273 43

Summary The ratio of osteoprotegerin [OPG, tumour necrosis factor receptor superfamily, member 11b (TNFRSF11B)] to receptor activator of nuclear factor kappaB ligand [RANKL, tumour necrosis factor (ligand) superfamily, member 11 (TNFSF11)] in bone is critical for the regulation of bone remodelling. Myeloma cells can home to bone, triggering increased RANKL and decreased OPG expression by stromal cells, leading to osteolysis. Whether myeloma cells contribute directly to the pool of RANKL or OPG in bone has been contentious. Here we provide evidence of RANKL expression by reverse transcription polymerase chain reaction and in situ hybridization, demonstrating transcripts encoding both the membrane-bound and secreted forms of RANKL in five human multiple myeloma cell lines (LP-1, NCI-H929, OPM-2, RPMI8226, U266) and myeloma cells purified from bone marrow aspirates of myeloma patients. We demonstrated that RANKL encoding mRNAs are translated to protein by antibody detection of RANKL. In vitro assays showed that myeloma cells induced bone marrow derived mononuclear cells to differentiate into adherent tartrate-resistant acid phosphatase positive multinucleated cells, indicative of the formation of functional osteoclasts. This differentiation could also be achieved with passaged myeloma media alone, implicating secreted products. Finally, we provide evidence that the differentiation observed is at least in part the result of myeloma cell expression of RANKL. We therefore conclude that myeloma cells can directly contribute to the pool of RANKL in bone.
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PMID:Myeloma cells can directly contribute to the pool of RANKL in bone bypassing the classic stromal and osteoblast pathway of osteoclast stimulation. 1523 39

Multiple myeloma has recently been found to induce considerable imbalance in the newly identified system of osteoprotegerin (OPG), receptor activator of nuclear factor KB ligand (RANKL) and RANK. The binding of RANKL to RANK on the surface of osteoclastic precursors in the presence of m-CSF activates the signalling pathways for differentiation and proliferation of an osteoclastic line. OPG is a decoy circulating receptor for RANKL which blocks its binding to RANK. There are at least three mechanisms by which myeloma cells affects the OPG/ RANKL/RANK system: 1: The adhesion between the myeloma / stromal cells and the osteoblastic precursors stimulates the system by increasing the production of RANKL. 2: Some myeloma lines produce independently membrane-bound or free RANKL. 3: The normal and mutated plasma cells bind, degrade and block the OPG production from the stromal cells. The OPG/RANKL/RANK system is the latest therapeutic target in the treatment of myeloma bone disease. The first results from the application of a synthetic analogue of OPG, as well as of RANKL antagonists or RANK inhibitors show decrease of the number of osteoclasts, osteolytic lesions and M-gradient.
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PMID:Bone lesions in multiple myeloma--the OPG/RANK-ligand system. 1581 51

Malignant plasma cells in multiple myeloma home to the bone marrow (BM), accumulate in different niches and, in late disease, migrate from the BM into blood. These migratory events involve cell trafficking across extracellular matrix (ECM)-rich basement membranes and interstitial tissues. Metalloproteinases (MMP) degrade ECM and facilitate tumour cell invasion. The chemokine CXCL12 is expressed in the BM, and it was previously shown that it triggers myeloma cell migration and activation. In the present work we show that CXCL12 promotes myeloma cell invasion across Matrigel-reconstituted basement membranes and type I collagen gels. MMP-9 activity was required for invasion through Matrigel towards CXCL12, whereas TIMP-1, a MMP-9 inhibitor that we found to be expressed by myeloma and BM stromal cells, impaired the invasion. In addition, we show that the membrane-bound MT1-MMP metalloproteinase is expressed by myeloma cells and contributes to CXCL12-promoted myeloma cell invasion across Matrigel. Increase in MT1-MMP expression, as well as induction of its membrane polarization by CXCL12 in myeloma cells, might represent potential mechanisms contributing to this invasion. CXCL12-promoted invasion across type I collagen involved metalloproteinases different from MT1-MMP. These data indicate that CXCL12 could contribute to myeloma cell trafficking in the BM involving MMP-9 and MT1-MMP activities.
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PMID:Role of metalloproteinases MMP-9 and MT1-MMP in CXCL12-promoted myeloma cell invasion across basement membranes. 1627 22


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