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)

Labeling of platelets in vivo by 75Se-methionine was performed in premalignant and malignant haematological disorders for evaluation of the kinetics of platelet maturation. The "normal" platelet maturation time (time between the injection of the isotope and maximum radioactivity of separated blood platelets) in eight non-haematological patients showing normal platelet counts was 9.1 days. A shortening of platelet maturation time of 5-7 days was observed in three of four cases with panmyelopathy (high bone marrow cellularity), in three of four cases with malignant lymphatic disorders (multiple myeloma, chronic lymphocytic leukaemia, lymphosarcoma), and in two of four cases with myeloproliferative syndromes. No correlation to the peripheral platelet counts was observed. For explanation of the premature platelet release from the bone marrow a disturbance of the megakaryocyte maturation is suggested.
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PMID:In vivo study of platelet kinetics by 75Se-methionine in different haematological disorders. 57 7

Functional pleiotropy and redundancy are characteristic features of cytokines. Interleukin 6 (IL-6) is a typical example: IL-6 induces cellular differentiation or expression of tissue-specific genes; it is involved in processes such as antibody production in B cells, acute-phase protein synthesis in hepatocytes, megakaryocyte maturation, cytotoxic T cell differentiation, and neural differentiation of PC12 (pheochromocytoma) cells. It promotes growth of myeloma/plasmacytoma cells, T cells, keratinocytes and renal mesangial cells, and it inhibits growth of myeloid leukaemic cell lines and certain carcinoma cell lines. The IL-6 receptor consists of two polypeptide chains, a ligand-binding chain (IL-6R) and a non-ligand-binding, signal-transducing chain (gp130). Interaction of IL-6 with IL-6R triggers the association of gp130 and IL-6R, and the signal can be transduced through gp130. Association of gp130 with IL-6R is involved in the formation of high affinity binding sites. This two-chain model has been shown to be applicable to receptor systems for several other cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-5 and nerve growth factor (NGF). The pleiotropy and redundancy of cytokines may be explained on the basis of this unique receptor system.
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PMID:The molecular biology of interleukin 6 and its receptor. 142 18

Despite major advances in supportive care, neutropenic infections and thrombopenic bleedings remain major lethal treatment- and disease-related complications in patients with malignancy. Moreover, complications of platelet (Plt) and erythrocyte transfusion therapy have become a cause of great concern and shortages of homologous blood products are a constant problem. Suggestions that the application of recombinant human hemopoietins may provide an alternative treatment modality in this patient population is currently being evaluated in clinical trials. Erythropoietin (EPO) has been shown to be effective in the treatment of anemia in patients with bone marrow, infiltrating low-grade non-Hodgkin's lymphoma, multiple myeloma, and in some patients with myelodysplastic syndrome. Preliminary data suggest that subcutaneous administration of EPO results in a higher slope of increasing erythropoietic parameters compared to intravenous administration. Protective effects on normal erythropoiesis have been attributed to EPO in patients receiving chemotherapy. The finding of EPO receptors on megakaryocytes supports the clinical observation of increased Plt production associated with decreased bleeding and transfusion frequencies in a substantial number of patients receiving EPO. Clinical trials with granulocyte-macrophage (GM-CSF) and granulocyte colony stimulating factor (G-CSF) have reached phase III trials. Both factors show high efficacy to shorten or improve neutropenia related to chemotherapy, bone marrow transplant, or underlying disease. Mechanisms responsible for mucosa protection and improved healing of mucositis observed with both factors remain undetermined yet phase I/II evaluation of IL-3 shows multilineage hemopoietic responses including myeloid, erythroid, and megakaryocyte lineages. Possible anti-cancer effects of hemopoietins achieved by direct action or by increased chemotherapy intensity are currently under investigation.
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PMID:Hemopoietins in clinical oncology. 204 61

Multiple myeloma (MM) originates from the malignant clonal expansion of transformed B-lymphocytes (in which c-myc and ras oncogenes are probably involved). MM cells have a hybrid phenotype (with coexpression of the markers for both early and late B-differentiation and, sometimes, of T-lymphocyte, myelomonocyte, erythroid and megakaryocyte markers), which accounts for the association between MM and myeloproliferative disorders and for cytokine production. Interleukin-6 and immunologic control mechanisms regulate proliferation and differentiation into plasma cells secreting a monoclonal component (MC). Overt MM is diagnosed 1-2 years following malignant transformation. At this time, several aneuploid clones with resistant phenotype have been selected, and a small pool of actively cycling cells produces the great bulk (over 90%) of non proliferating tumor cells. The clinical and laboratory signs of MM arise from both tumor proliferation and MC damage to organs and organ systems. Tumor proliferation is mainly responsible for bone disease (since MM cells produce cytokines that activate the osteoclasts), inhibition of hemopoiesis and the appearance of plasma cell tumors. The MC causes renal failure, neurological signs, hemorrhagic manifestations. The prognosis for multiple myeloma is probably best estimated by two parameters, serum beta-2-microglobulin and the bone marrow labeling index. Induction therapy is still based on the use of alkylating agents, melphalan and cyclophosphamide, combined with prednisone. Second line treatment consists of VAD polychemotherapy or high-dose pulsed glucocorticoids. Many investigational approaches have been proposed, but their effectiveness awaits confirmation. In the absence of a curative regimen, much effort should be dedicated to the quality of supportive care. In this respect, bisphosphonates represent a new effective tool for the control of myeloma bone disease.
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PMID:Multiple myeloma. 208 Oct 91

As a result of the striking discrepancy between the substantial amount of information on the role of natural killer (NK) cells derived from in vitro experimentation and the corresponding lack of data demonstrating their physiologic relevance, we have examined the importance of NK cells for the steady state production of hematopoietic stem and progenitor cells in situ. B6D2F1 mice received two 0.2-ml injections of ascites containing anti-NK 1.1 monoclonal antibody (anti-NK) directed to murine NK cells. Another group was treated similarly but received "control" ascites (CA) that was induced solely by injection of a mouse myeloma cell similar to the fusion partner of the NK 1.1 hybridoma. Two days after the last injection, we determined the number and cycling fraction (i.e., percentage of cells in S-phase determined by in vivo hydroxyurea suicide) of femoral stem cells (spleen colony-forming units; CFU-S) and committed granulocyte-macrophage (granulocyte-macrophage colony-forming units; CFU-GM), megakaryocytic (megakaryocyte colony-forming units; CFU-Meg), and erythroid (erythroid burst-forming units; BFU-E and erythroid colony-forming units; CFU-E) progenitor cells. The striking finding was the almost complete abolishment of the proliferation of CFU-Meg in the anti-NK group, resulting in a statistically significant (p less than 0.02) decrease in number to 37% of the CA control. In contrast, the cycling fraction of BFU-E was significantly (p less than 0.05) increased to 205% of the CA control with no increase in number. The number and cycling fraction of CFU-S, CFU-GM, and CFU-E in the anti-NK group were not significantly different from values in the control group. These findings add a novel aspect to the understanding of hematopoietic regulation by providing the first evidence for a differential effect of NK cells on the steady-state proliferation of CFU-Meg and BFU-E in situ.
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PMID:Differential effect of natural killer cells on modulating CFU-Meg and BFU-E proliferation in situ. 280 34

Peripheral blood stem cells (PBSC) from 15 patients with advanced non-Hodgkin's lymphoma (NHL), two patients with chronic lymphocytic leukemia, and two patients with myeloma were collected by continuous-flow leukapheresis after chemotherapy with MIV (mitoxantrone, ifosfamide, and etoposide, five patients) or high-dose cyclophosphamide (14 patients), followed by administration of GM-CSF. Sixteen patients (84%) had persistent marrow involvement at time of inclusion. Results were compared to those obtained in a control group of similar age and disease status in whom collection had been performed after MIV chemotherapy alone. The number of mononuclear cells, granulocyte-macrophage colony-forming units (CFU-GM), CD34+ cells were higher in GM-CSF treated patients with a lower mean number of leukapheresis (3.5 versus 6.4). Among the 19 patients harvested after chemotherapy plus GM-CSF, more progenitor cells were obtained in the cyclophosphamide group than in the MIV group. In all these patients except one, the number of mononuclear cells was sufficient to realize a transplantation. Seventeen patients received intensification with BEAM regimen (8 patients) or cyclophosphamide plus etoposide and total body irradiation (9 patients). Two patients failed to reconstitute correct hematopoiesis and three early toxic deaths occurred for a total of five procedure-related deaths. Nine of these 17 patients are in persistent complete remission with a median post-transplant follow-up of 18 months. Time to reach granulocyte and platelet recovery was not correlated with the number of mononuclear cells, CFU-GM, granulocyte-erythroid-macrophage-megakaryocyte colony-forming units (CFU-GEMM), CD34+ cells, and CD34+ CD33- cells but with the number of previous chemotherapy regimens. PBSC harvesting is achievable after chemotherapy plus GM-CSF in heavily pretreated patients with persistent marrow involvement. Moreover, these cells are able to reconstitute correct hematopoiesis after intensive treatment in these patients.
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PMID:Peripheral blood stem cells harvested after chemotherapy and GM-CSF for treatment intensification in patients with advanced lymphoproliferative diseases. 810 11

Interleukin 11 (IL-11) is a stromal cell-derived cytokine that has multiple effects on hematopoietic and nonhematopoietic systems. In vitro, it enhances the growth of early progenitors and promotes megakaryocytopoiesis and erythropoiesis. In healthy animals, IL-11 administration stimulates megakaryocyte maturation and increases peripheral platelet counts. IL-11 accelerates the recovery of peripheral neutrophil, erythrocyte, and platelet counts in mice that have undergone cytoablative treatment. Therefore, IL-11 may be useful clinically as an agent promoting recovery from hematopoiesis. However, its clinical use in patients with hematological malignancies may be restricted because IL-11 has been reported to stimulate some leukemia and myeloma cells. In the United States, phase I trials have shown that IL-11 accelerates recovery from chemotherapy-induced or bone-marrow transplantation (BMT)-induced thrombocytopenia. In Japan, phase II trials studying the thrombopoietic effect of IL-11 in patients with solid tumors postchemotherapy, in patients undergoing BMT, and in patients with aplastic or refractory anemia are now under way. Recently, thrombopoietin (TPO) has been cloned, and its thrombopoietic effect and accelerating effect on platelet count recovery in thrombopoietic states have been demonstrated in animal models. The physiological effect of TPO is restricted to hematopoiesis; therefore, it may have fewer side effects than IL-11. However, in addition to its hematopoietic effect, IL-11 administration to mice that have undergone cytoablative therapy significantly decreases morbidity and mortality due to chemotherapy-related endogenous infections caused by gut microorganisms. Therefore, IL-11 can be used in patients postchemotherapy and post-BMT not only to promote platelet recovery but also to prevent life-threatening infections. The use of in-vitro-expanded hematopoietic stem cells for BMT or as target cells for gene therapy is one of the most exciting areas in the field of medicine. Since IL-11 can expand hematopoietic progenitor-cell populations when used in combination with other cytokines, it may be useful as an ex vivo hematopoietic progenitor-cell-amplifying agent.
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PMID:Effect of interleukin 11 on normal and pathological thrombopoiesis. 876 27

Prolonged thrombocytopenia resulting from inadequate megakaryocyte (MK) progenitor cell reconstitution is a serious complication of hematopoietic cell-supported high-dose chemotherapy (HDC). In this situation, the infusion of MK progenitors that are expanded ex vivo could be clinically beneficial. In this study we investigated the ability of various growth factor combinations to generate MK progenitors. CD34+ cells derived from bone marrow (BM) and granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (PB) from 17 patients with breast cancer, lymphoma, or myeloma were cultured unpertubed for 10 days in a serum-free liquid culture system that contained recombinant growth factors. Five different growth factors combinations were evaluated: Stem cell factor (SCF), interleukin (IL)-3, IL-6 + G-CSF (combination 1); SCF, megakaryocyte growth and development factor (MGDF) + G-CSF (combination 2); SCF + MGDF (combination 3); MGDF alone (combination 4); and SCF, IL-3, IL-6, G-CSF + MGDF (combination 5). PB CD34+ cells yielded significantly higher numbers of CD41+ MK progenitors than BM CD34+ cells with any of the growth factor regimens assayed. PB CD34+ cells (2x10[5]) at day 0 generated 1.2 to 1.3x10(6) CD41+ cells by day 10 when cultured in the presence of growth factor combinations 1, 2, or 3. In contrast, 2x10(5) BM CD34+ cells produced 5x10(5) CD41+ cells after 9 days in the presence of combination 1, whereas lower numbers of CD41+ cells were generated in cultures with combinations 2 and 3 (2.3x10[5] and 4.2x10[4], respectively). The addition of MGDF to cultures that were grown with combination 1 for 5 days increased the number of CD41+ cells (1.7-fold increase in PB-derived cultures, 1.6-fold increase in BM-derived cultures). Treatment with MGDF alone resulted in higher frequencies of MK progenitors than those obtained in cultures with combined growth factors (79% in PB-derived cultures, 25% in BM-derived cultures), but because total cell growth was attenuated, absolute numbers of MK progenitors were lower (7x10(5) in PB-derived cultures, 7x10(4) in BM). Morphological analysis of immunocytochemically identified megakaryocytic cells revealed mononuclear cells as the predominant cell type in all of the cultures. During the 10-day culture period, PB-derived MK progenitors did not show notable maturation, even under the influence of MGDF, whereas in BM-derived cultures MGDF induced a significant shift to binuclear cells and stage I MK after day 5. Phenotypic analysis of cell surface markers showed that the majority of cultured megakaryocytic cells coexpressed CD34 and platelet glycoproteins (GPs), also indicating an immature stage of development. The ex vivo proliferative activity of CD34+ cells and their potential to develop into the megakaryocytic lineage demonstrated considerably high interpatient variations. There was no correlation between platelet recovery following HDC with hematopoietic cell support and the magnitude of GP+ cell expansion ex vivo, suggesting the feasibilty of MK expansion ex vivo in patients with prolonged thrombocytopenia posttransplantation. In summary, these data indicate that GCSF-mobilized CD34+ PBPCs are more effectively expanded ex vivo into the megakaryocytic lineage than are CD34+ BMPCs. CD34+/GP+ MK progenitors may be an appropiate cell population for transplantion as prophylaxis or treatment of prolonged thrombocytopenia. The efficacy of this procedure will be tested prospectively in a clinical trial.
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PMID:Ex vivo expansion of megakaryocyte progenitors: effect of various growth factor combinations on CD34+ progenitor cells from bone marrow and G-CSF-mobilized peripheral blood. 932 49

Recent observations have underscored the biologic relevance of intratumoral angiogenesis and its potential impact on prognosis. Increased bone marrow angiogenesis has been demonstrated in a variety of hematologic disorders, including multiple myeloma. The extent and prognostic significance of bone marrow angiogenesis in 114 patients with myelofibrosis with myeloid metaplasia (MMM) was investigated. A control group of 44 patients without bone marrow disease, 15 patients with polycythemia vera, and 17 patients with essential thrombocythemia was also studied. Bone marrow microvessel density was assessed by a semiquantitative method, visual microvessel grading, and 2 separate quantitative methods, visual count and computerized image analysis. Angiogenesis estimation by all 3 methods was highly comparable. On visual microvessel grading, a grade 3 or 4 increase in bone marrow angiogenesis was demonstrated in 70% of patients with MMM, 33% of patients with polycythemia vera, 12% of patients with essential thrombocythemia, and 0% of normal controls. In a multivariate analysis, increased angiogenesis in MMM correlated significantly with increased spleen size and was found to be a significant and independent risk factor for overall survival. Increases in marrow angiogenesis correlated with hypercellularity and megakaryocyte clumping. In contrast, these 2 features were inversely proportional to reticulin fibrosis, whereas increases in marrow angiogenesis were independent of reticulin fibrosis. These preliminary findings suggest that neo-angiogenesis is an integral component of the bone marrow stromal reaction in MMM and may provide useful prognostic information and a rationale for the therapeutic investigation of anti-angiogenic agents.
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PMID:Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia. 1107 30

James Homer Wright (1869-1928), the eldest son of a Pittsburgh glass merchant, was educated in Baltimore and practiced pathology in Boston from 1893 until his death in 1928. In 1896, when not quite 27 years old, he assumed directorship of the newly founded Pathology Laboratory at the Massachusetts General Hospital, a post he held for the next 30 years. He is remembered eponymously by the blood cell stain that bears his name and the Homer Wright pseudorosettes of neuroblastoma, but he made many additional contributions to pathology. These include the following: determination of the cellular lineage of multiple myeloma, identification of the megakaryocyte as the cell of origin of blood platelets, recognition of the cell of origin of the neuroblastoma, demonstration of spirochetes in syphilitic aneurysms of the aorta, and clarification of misconceptions about actinomycosis. Additionally, Wright coauthored, with Dr. Frank B. Mallory, the book Pathological Technique, which was a staple of laboratories for >40 years and exemplifies Wright's wide-ranging interests in, and contributions to, practical aspects of pathology including staining, culture and frozen section techniques, photography, and development of the rotary microtome. He received Honorary Doctor of Science Degrees from Harvard University, the University of Maryland (his alma mater), and the University of Missouri. He was the recipient of the Gross prize in 1905 for his publication on actinomycosis and the Boylston Medical Prize in 1908 for his discovery of the origin of platelets, and he was inducted into the American Academy of Arts and Sciences in 1915. Although shy and somewhat austere in the workplace, a different side was shown by his anonymously sending flowers to a young Norwegian opera singer whom he subsequently married. The pathology laboratories of the Massachusetts General Hospital were named the "James Homer Wright Pathology Laboratories" in 1956. Today James Homer Wright is remembered and honored 100 years after his description of the stain that, along with the pseudorosettes of neuroblastoma, carry his name into eternity and ensure his great contributions will never be forgotten.
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PMID:James Homer Wright: a biography of the enigmatic creator of the Wright stain on the occasion of its centennial. 1175 74


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