UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proinflammatory cytokines such as interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-alpha) and IL-1beta are considered to be involved in the pathogenesis of multiple myeloma (MM). In the present study, we examined a G/C polymorphism at position -174 in the promoter region of IL-6, a biallelic polymorphism at position -308 in the promoter region of TNF-alpha, the TaqI restriction fragment length polymorphism in exon 5 of IL-1beta and a variable number of identical tandem repeat polymorphisms in intron 2 of IL-1 receptor antagonist (IL-1Ra) genes. The alleles of these loci are known to influence the level of production of the cytokines and the IL-1Ra. Seventy-three patients with MM, 27 with monoclonal gammopathy of undetermined significance (MGUS) and 129 healthy individuals were included. No difference was found between patients and healthy controls or between MM and MGUS patients in the distributions of genotypes and frequencies of alleles of the IL-6 (-174), TNF-alpha (-308), IL-1beta TaqI and IL-1Ra gene polymorphisms. No associations between the polymorphisms at the loci under study and clinical factors such as age, sex, clinical stage at onset and M-protein type were observed. Our results indicate that the cytokine (IL-6, TNF-alpha and IL-1beta) and IL-Ra gene polymorphisms do not confer susceptibility to the development of MM.
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PMID:Interleukin 6, tumour necrosis factor alpha, interleukin 1beta and interleukin 1 receptor antagonist promoter or coding gene polymorphisms in multiple myeloma. 1116 13

A monoclonal antibody (mAb), named TE-4F 10, was produced by fusing P3X-Ag8 myeloma cells with splenocytes of BALB/c mice immunized with a rat medullary thymic epithelial cell (TEC) line, (TE-R 2.5), previously established in our Institute. Flow cytometry showed that 85-95% TE-R 2.5 cells expressed the TE-4F10 antigen. The mAb immunoprecipitated a 29 kDa molecule from the TE-R2.5 cell lysate. Immunohistochemical analysis using single and double staining of the thymus with anti-cytokeratin (CK) mAb, showed that TE- 4F10 mAb selectively stains a subpopulation of medullary TEC. Hematopoietic and lymphoid cells were negative. The expression of the TE-4F10 antigen on TE-R 2.5 cells in vitro was significantly upregulated by interleukin 1 (IL-1) and tumor necrosis factor (TNFalpha). Other cytokines IL-4, IL-6, IL-10 and granulocyte - macrophage colony stimulating factor (GM-CSF) showed lesser stimulation on its expression, whereas interferon gamma (IFN) and dexamethasone were without significant effect. The TE-R 2.5 cell line strongly bound and induced apoptosis of a rat / mouse thymocyte heterohybridoma (BWRT8), phenotypically alphabetaTCRhiCD4hiCD8lo. TE-4F10 mAb significantly inhibited binding (40-50%) of both BWRT8 cells and the BWRT8 - MDP.1 subclone to TE-R 2.5 cells. The inhibition was enhanced when TEC were stimulated with IL-1 + TNFalpha. The mAb also significantly blocked apoptosis of BWRT8 but did not modulate cell death of the BWRT8 - MDP.1 subclone, which was resistant to TEC-induced apoptosis. These findings indicate that the TE-4F10 antigen might be selectively involved in adhesion and selection processes in the medullary thymic microenvironment. The mAb of the same characteristics has not been described so far.
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PMID:Biochemical and functional characterization of a molecule expressed by a subset of thymic medullary epithelial cells. 1129 58

This study examines the effects of an IL-6-producing murine multiple myeloma cell line on trabecular and cortical mouse bone, and evaluates the efficacy of interleukin-1 receptor antagonist (IL-1ra) in mitigating bone destruction. Six-week-old BALB/c mice were assigned to two groups: normal controls and myeloma animals (5 x 10(7) MPC-11 cells on day 0). Myeloma animals were further assigned to three unique groups: MPC-11 only; MPC-11 treated with hyaluronic acid (HA); and MPC-11 + IL-1ra/HA (100 mg/kg). Disease development was assessed at 14 and 21 days via spleen, liver, and proximal tibia histology; histomorphometry at the femoral middiaphysis; and long bone composition and mechanical testing. Histologic analysis revealed marked myeloma infiltration into organs and bone marrow and gross bone resorption of the proximal tibia. IL-1ra tended to decrease bone resorption at the proximal tibia; however, it had no effect on quantitatively measured bone parameters. Whole femur and tibia, and tibial epiphysis, percent mineralization was decreased (3.0%, 2.9%, and 6.3%, respectively) in all MPC-11 groups. The presence of myeloma did not affect long bone stiffness, strength, or length over the 3 week study. The percent of the femoral endosteal perimeter showing excessive resorption ( approximately 60%) in the MPC-11 groups increased significantly after 21 days. MPC-11 cell presence caused no change in bone formation or morphology. Normal growth mechanisms were not impacted, as the bones lengthened and increased in size and mass despite the presence of myeloma. IL-1 does not appear to be a primary factor in in vivo bone destruction caused by the MPC-11 cell line. These findings reveal the stochastic nature of bone lesions in multiple myeloma and suggest that IL-1 is not a cytokine critical to this disease pathology.
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PMID:Effect of MPC-11 myeloma and MPC-11 + IL-1 receptor antagonist treatment on mouse bone properties. 1179 72

A number of haematological and non-haematological malignancies can be successfully treated using high-dose chemotherapy +/- irradiation followed by haematopoietic progenitor cell transplantation. Post transplant, thrombocytopenia and neutropenia always occur and patients require platelet transfusions. It may be possible to reduce the period of thrombocytopenia by re-infusion of ex vivo expanded megakaryocyte progenitors (MP), derived from the progenitor cell graft. We have investigated the expansion of MP from CD34+ enriched cells from normal bone marrow (NBM) and peripheral blood (PB) and remission BM or PB samples from patients with haematological malignancies. CD34+ cells were cultured in serum-free medium supplemented with thrombopoietin (TPO), interleukin 1 (IL-1), IL-6 and stem cell factor (SCF) for 7 d, then cell proliferation was assessed by flow cytometry using lineage-specific markers. It was possible to significantly expand the number of MP cells from all sources. There were no major differences in yields of MP from normal BM or PB, or BM from multiple myeloma and non-Hodgkin's lymphoma patients. However, expansion of MP in acute myeloid leukaemia samples was lower than all other samples and the number of megakaryocyte colony-forming units was reduced. Several cytokine combinations were evaluated to optimize MP expansion from NBM. Equivalent yields of MP were obtained using TPO and one of IL-1, IL-3, granulocyte-macrophage colony-stimulating factor or SCF, suggesting that large cytokine combinations are not necessary for this procedure. It should be possible to scale up the culture conditions described to produce effective MP doses for clinical transplantation.
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PMID:Ex vivo expansion of megakaryocyte progenitor cells from normal bone marrow and peripheral blood and from patients with haematological malignancies. 1188 1

C-reactive protein (CRP) is a nonspecific but sensitive marker of inflammation. Interleukin-6 (IL-6), IL-1, and tumor necrosis factor alpha induce the synthesis of CRP in hepatocytes. Increased CRP level is considered to be an important risk factor for atherosclerosis, myocardial infarction, peripheral vascular disease, and ischemic stroke. It is positively correlated with weight loss, anorexia-cachexia syndrome, extent of disease, and recurrence in advanced cancer. Its role as a predictor of survival has been shown in multiple myeloma, melanoma, lymphoma, ovarian, renal, pancreatic, and gastrointestinal tumors. Measurement of CRP is simple, cheap, and routine and provides valuable information in palliative care.
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PMID:The role of C-reactive protein as a prognostic indicator in advanced cancer. 1193 16

Myelomatous bone disease affects about 90% patients with multiple myeloma and solitary myeloma as well. In initial stage it is manifested as osteopenia with osteoporosis or osteolytic foci, pathologic fractures followed by neurologic complications. Ethiopathogenitically a role is played by cytokine interactions with local chemokines produced by myeloma cells and activated stromal and hemopoietic cells (osteoblasts, monocytes, macrophages) resp. From the TNF-alpha family glycoprotein complexes are liberated (RANK-L), which support activation and proliferation or are inhibitory (osteoprotegerins). Similarly in the family TGF-beta several izotypes of antiinflammatory cytokines are known (the most important is TGF-beta 1 and the morphogenetic protein-2), which have a fibrotizing effect in bones, because the produced osteoid is insufficiently mineralized. The effect is a pathologic remodelation of the skeleton. In the diagnosis of multiple myeloma the immunological knowledge is used in the initial diagnosis (immunophenotypization, follow up of TNF-alpha, TGF-beta 1, IL-1, IL-6 etc). Important are also biochemistry values of increased osteoresorption (changes of calcium, parathormone, excretion of collagen fission products, osteocalcin, the bone alkaline phosphatase). In the following part the authors inform about favourable results of long-term treatment with bisphosphonates (Bonefos, Ibandronate) in combination with anti-tumor chemotherapy in 364 patients. During a 15 years observation period median survival of 94 months with a 35% probability of 10 year survival was achieved with a significant decrease of bone complications in 58% compared to 14% in the placebo group.
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PMID:[Bone changes in multiple myeloma--current etiopathogenic, diagnostic and therapeutic aspects]. 1219 8

Bone marrow (BM) fibrosis could occur secondarily to several clinical disorders: hematological and nonhematological. Clinical presentation of fibrosis could occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome and myeloma. The pathophysiology underlying BM fibrosis remains unclear despite intensive study, with a corresponding lack of specific therapy. This review discusses new insights in the role of substance P, cytokines and fibronectin in the development of BM fibrosis. Substance P is a neuropeptide that possesses pleiotropic properties, e.g. neurotransmission and immune/hematopoietic modulation and is linked to BM fibrosis. Cytokines and growth factors, in particular those associated with fibrogenic properties, e.g. TGF-beta, IL-1 and platelet-derived growth factor, are linked to BM fibrosis. Extracellular matrix proteins are increased in patients with BM fibrosis. Fibronectin in the sera of patients with BM fibrosis is complexed to substance P. Fibronectin appears to protect substance P from degradation by endogenous peptidases. This review describes the preliminary findings on the colocalization of substance P and fibronectin in the BM of patients with fibrosis. These data are reviewed in the context of published reports with particular focus on the relevant cytokines. A more detailed understanding of intra- and intercellular mechanisms in BM fibrosis may lead to effective therapy.
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PMID:Substance p-fibronectin-cytokine interactions in myeloproliferative disorders with bone marrow fibrosis. 1248 16

Bisphosphonates are endogenous pyrophosphate analogs in which a carbon atom replaces the central atom of oxygen. They are indicated in non-neoplastic diseases including osteoporosis, corticosteroid-induced bone loss, Paget disease, and in cancer-related diseases such as neoplastic hypercalcemia, multiple myeloma and bone metastases secondary to breast and prostate cancer. There is now extensive in vitro evidence suggesting a direct antitumor effect of bisphosphonates at different levels of action. Some new in vitro and in vivo studies support the cytostatic effects of bisphosphonates on tumor cells, and the effects on the regulation of cell growth, apoptosis, angiogenesis, cell adhesion, and invasion, with particular attention to biological properties. Well designed clinical trials are necessary to investigate whether the antitumor potential of bisphosphonates may be clinically relevant. On the basis of their effects on macrophages, we may divide bisphosphonates into two distinct categories: aminobisphosphonates, which sensitize macrophages to an inflammatory stimulus inducing an acute-phase response, and non-aminobisphosphonates that can be metabolized into macrophages and that may inhibit the inflammatory response of macrophages. There is evidence of aminobisphosphonate-induced pro-inflammatory response, in particular, related to modifications of the cytokine network. Several in vivo studies have demonstrated an acute-phase reaction after the first administration of aminobisphosphonates, with a significant increase in the main pro-inflammatory cytokines. However, a peculiar aspect concerning the action of non-aminobisphosphonates seems to be an anti-inflammatory activity caused by the inhibition of the release of inflammatory mediators from activated macrophages, such as interleukin (IL)-6, tumor necrosis factor-alpha and IL-1. The inhibition of inflammatory responses is demonstrated in both in vivo and in vitro models. This activity suggests the use of non-aminobisphosphonates in several inflammatory diseases characterized by macrophage-mediated production of acute-phase cytokines, as prevention of erosions in rheumatoid arthritis, and of loosening of joint prostheses, as well as possibly in osteoarthritis, ankylosing spondylitis, myelofibrosis, and hypertrophic pulmonary osteoarthropathy.
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PMID:Bisphosphonate effects in cancer and inflammatory diseases: in vitro and in vivo modulation of cytokine activities. 1524 2

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

Thalidomide was developed in the 1950s as a sedative drug and withdrawn in 1961 because of its teratogenic effects, but has been rediscovered as an immuno-modifying drug. It has been administered successfully for the treatment of erythema nodosum leprosum, aphthous ulceration in HIV disease, inflammatory bowel diseases, and multiple myeloma. So far, investigations into the mode of action of thalidomide have focused on lymphocytes and vascular endothelial cells and have shown that this agent inhibits the production of tumor necrosis factor (TNF)-alpha and is an inhibitor of tumor angiogenesis. Recently, other immunological effects of this drug have been gaining attention, including attenuation of neutrophil activation and inhibition of myelo-proliferative responses. In autoimmune diseases, inflammation is characterized by an influx of granulocytes, and the association of granulocytes with gastrointestinal ulcer formation or rheumatic arthritis has been well documented. The suppressive effect of thalidomide on the activation of the nuclear transcription factor NF-(kappa)B may explain these effects of thalidomide. NF-(kappa)B is retained in the cytoplasm with I(kappa)B(alpha), and is activated by a wide variety of inflammatory stimuli including TNF, IL-1 and endotoxin followed by its translocation to the nucleus. Constitutive activation of NF-(kappa)B has been detected in various inflammatory diseases, while angiogenesis and organogenesis also require NF-(kappa)B activation. Thalidomide, on the other hand, has been shown to selectively suppress NF-(kappa)B activation induced by inflammatory mediators. NF-(kappa)B is known to be located downstream of proliferative and/or survival signaling induced by growth factors, which regulate anti-apoptotic genes. Myeloid cells in vitro, however, have been found to proceed to apoptosis as the result of the treatment with thalidomide and subsequent inactivation of NF-(kappa)B. These findings are consistent with clinical symptoms that showed the recovery from leukocytosis and/or neutrophilia after the administration of thalidomide. These findings shed new light on the anti-inflammatory properties of thalidomide and suggested that they may inhibit granulocyte-mediated tissue injury.
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PMID:Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation. 1572 33

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