Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell surface structures related to differentiation, activation and "homing" were identified on the leukemic cell clone in blood of 64 patients with a monoclonal B-cell lymphoproliferative disorder. Patients were selected with regard to clinical signs and symptoms of the disease. 39 patients had progressive chronic lymphocytic leukemia of B-cell type (B-CLL): 16 with lymph node enlargement and 14 with progressive lymphocytosis as the most prominent symptom, respectively. 1 patient had an isolated splenomegaly and 8 had symptoms from enlarged lymph nodes, lymphocytosis and/or splenomegaly. 25 patients had an isolated monoclonal B-cell lymphocytosis in blood and bone-marrow but no other signs or symptoms of the disease. The lymphocytosis in these patients was considered to be of "undetermined significance" and the term B-cell lymphocytosis of undetermined significance (B-MLUS) was used. Patients with a prominent lymphadenopathy and/or splenomegaly had CD22+ leukemic cells while in patients with a progressive lymphocytosis the B-cell clone expressed Leu-8. Thus, CD22 might be related to the homing capacity of B lymphocytes for lymphnodes and spleen, while Leu-8 might define a circulating B-cell subset. In B-MLUS about 50% of the monoclonal B cells co-expressed Leu8 which is consistent with a more differentiated phenotype compared to B-CLL with progressive lymphocytosis. The CD22 expression was mostly low in B-MLUS although a few patients showed high values. The expression of receptors for growth factors (CD23, CD25, CD71) was higher in B-CLL compared to B-MLUS patients (p less than 0.001), which is consistent with a difference in lymphocyte activation stage and/or response to growth factors.
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PMID:Clonal cell surface structures related to differentiation, activation and homing in B-cell chronic lymphocytic leukemia and monoclonal lymphocytosis of undetermined significance. 226 61

We present the clinical and immunological features of a rare case of chronic lymphoid leukaemia with lymphoplasmacytoid morphology. The patient was first admitted suffering from weakness, pallor, dyspnoea, marked splenomegaly, hepatomegaly and systemic lymphadenopathy and panhypogammaglobulinaemia. White blood cell count revealed important leukocytosis (220 x 10(9) WBC/l) with 2% neutrophils and 98% lymphoid cells showing lymphoplasmacytoid features, while lymphoid cells of identical morphology severely infiltrated the bone marrow and lymph nodes. The disease, initially controlled by non aggressive chemotherapy over a period of 30 months, later evolved to a clinical and haematological picture suggestive of Richter's syndrome. Immunophenotyping of the leukaemic cells demonstrated a monoclonal expansion of B-cells bearing surface markers of typical CLL (CD5, CD19, CD20, CD21, CD22, CD23, CD24, CD40 and low density IgM+IgD/kappa) and also the CD11c and CD38 antigens. A proportion of these cells expressed activation markers (CD25, CD69 and CD71). Following in vitro activation with TPA or PWM, the cells responded by weak incorporation of 3H-TdR but failed to secrete immunoglobulins. These findings confirm the broad morphological, phenotypical and clinical spectrum of chronic lymphoid leukaemias.
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PMID:Monoclonal expansion of immunoglobulin not-secreting CD5+ CD11c+ CD38+ B-cells in a rare case of chronic lymphoplasmacytoid leukaemia. 797 Dec 44

Gallium-67 (67Ga) accumulates in malignant tissues via the transferrin receptor without need for a monoclonal antibody and emits cytotoxic low-energy electrons. In this study we investigated the feasibility, pharmacokinetics, toxicity and preliminary efficiency of high-dose 67Ga injected intravenously (i.v.) in patients with acute leukaemia not responding to conventional therapy. Twelve doses of 36-105 mCi of Gallium67 citrate were administered as a push injection to eight patients with resistant leukaemia in a pilot study. All five patients with acute myeloid leukaemia (AML) and three patients with acute lymphoblastic leukaemia (ALL) had resistant disease or resistant relapse. No (sub)acute toxicity was observed. Independent of the administered dose, whole-blood radioactivity levels 10 min after administration measured only 1.25 +/- 1.39 microCi ml-1, indicating a large volume of distribution. Urine excretion in the first 24 h ranged from 18% to 51.5% (median 29.5%) of the administered dose. Cellular uptake of 67Ga was less than in previous in vitro studies. Whole-body radiation dose was estimated to be 0.25 +/- 0.03 cGy mCi-1. Red marrow dose was estimated to be between 0.18 +/- 0.02 and 0.97 +/- 0.12 cGy mCi-1. One definite response was observed in an ALL patient with disappearance of skin lesions, normalisation of the enlarged spleen and profound leucopenia. Three other patients showed transient reductions in white blood cell counts without disappearance of blasts from the peripheral blood. We conclude that high-dose i.v. 67Ga can be safely administered but that the uptake of 67Ga in blast cells must increase to make 67Ga therapeutically useful in patients with relapsed leukaemia.
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PMID:High-dose gallium-67 therapy in patients with relapsed acute leukaemia: a feasibility study. 851 74

Recombinant human erythropoietin (EPO; epoetin) has been shown to be effective in improving anemia in a proportion of cancer patients. The response rate is approximately 60%, but varies considerably according to baseline hematocrit and transfusion needs, as well as the response criteria used. Response is not greatly influenced by the type of tumor, except in situations of major marrow involvement and limited residual hematopoiesis, or in the presence of specific mechanisms of anemia, such as hemolysis, splenomegaly, bleeding, hemodilution, or ineffective erythropoiesis. Stem cell damage by previous therapy as well as marrow suppression by current intensive chemotherapy can impair response. Besides its intensity, the type of chemotherapy may not be critical, although patients undergoing platinum-based chemotherapy may respond faster than those receiving non-platinum regimens. Complications, such as infections, bleeding, or nutritional deficiencies, may have a major negative impact on outcome. An important response-limiting factor is functional iron deficiency (ie, an imbalance between iron needs in the erythropoietic marrow and iron supply), which depends on the level of iron stores and its rate of mobilization. Functional iron deficiency is best monitored by the percentage of hypochromic red blood cells, and oral or intravenous iron supplements should be given when this percentage increases above 10%. All these factors explain why the response rate to epoetin is only approximately 60%. Therefore, it would be interesting to develop models that could help predict response to epoetin to help select the most appropriate cancer patients for this therapy. Few baseline parameters have been shown to be highly predictive of response in patients with solid tumors, although most studies in patients with myeloma or lymphoma have indicated that patients with a low baseline serum EPO level will respond better. Early changes after 2 to 4 weeks of treatment are also of great interest. Among these early changes, increments of soluble transferrin receptor, reticulocytes, and hemoglobin, as well as the persistence of elevated ferritin or EPO levels, have all shown some predictive value. Combination of baseline serum EPO and the 2-week increment of soluble transferrin receptor or hemoglobin may provide the best prediction of response.
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PMID:Prediction of response to optimize outcome of treatment with erythropoietin. 967 27

The anaemia associated with cancer can be effectively treated with recombinant human erythropoietin (rHuEpo) in about 60% of the patients. However, the response rate varies according to treatment modalities as well as the response criteria used. A number of disease- or chemotherapy-related factors determines the probability of response. Several specific mechanisms of anaemia, such as haemolysis, splenomegaly, bleeding, haemodilution, or ineffective erythropoiesis can seriously interfere with response. However, the type of tumor, in particular haematologic versus non-haematologic, is not critical, except in situations of major marrow involvement and limited residual haematopoiesis. Stem cell damage by previous therapy, reflected by low platelet counts or high transfusion needs, will impair response. In addition, marrow suppression by current intensive chemotherapy will also have a negative impact. Besides its intensity, the type of chemotherapy may not be critical, although patients undergoing platinum-based chemotherapy may respond faster than those receiving non-platinum regimens. Complications such as infections, bleeding or nutritional deficiencies may have a major negative impact on outcome. An important response-limiting factor is functional iron deficiency, i.e. an imbalance between iron needs in the erythropoietic marrow and iron supply, which depends on the level of iron stores and its rate of mobilisation. Therefore, oral or preferably intravenous iron supplements should be given when serum ferritin is below 40-100 micrograms/l, reflecting the absence of iron stores, or when the percentage of hypochromic red cells rises above 10%, indicating functional iron deficiency even in the presence of adequate storage iron. Because up to 40% of the patients will not respond to rHuEpo, it is of utmost importance to develop models that could help predict response to rHuEpo and thus select the most appropriate cancer patients for this therapy. Most studies of patients with myeloma or lymphoma have indicated that patients with a low baseline serum Epo level will respond better, but this is not true of patients with solid tumors. Also of considerable interest are early changes of erythropoietic parameters after 2 to 4 weeks of treatment, including increments of serum transferrin receptor (sTfR), reticulocytes and haemoglobin, as well as the persistence of elevated ferritin or Epo levels. Combination of baseline serum Epo and the 2-week increment of sTfR or haemoglobin may provide the best prediction of response.
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PMID:Prediction of response to treatment with recombinant human erythropoietin in anaemia associated with cancer. 978 36

The major goal of this study was to evaluate the effects of tumor necrosis factor-alpha (TNF-alpha), delivered as pGL1-TNF-alpha, on hematological variables, as well as C6 tumor growth in athymic mice treated with and without radiation. pGL1-TNF-alpha was administered intratumorally at low to high doses (15, 150 and 450 microg) in all three phases of this study. In phase A, pGL1-TNF-alpha expression within tumors was dose dependent and transient, with highest levels seen at 18 h after injection, whereas no TNF-alpha protein was detected in plasma. Low erythrocyte counts, hemoglobin, and hematocrit were associated with tumor presence, but the reduction in these variables was most striking in the group receiving 450 microg of pGL1-TNF-alpha, the group that also exhibited thrombocytopenia at 72 h. In phase B, treatment with pGL1-TNF-alpha at 15 or 150 microg resulted in the greatest degree of splenomegaly, increased spontaneous blastogenesis by splenocytes, and high leukocyte and lymphocyte numbers in the spleen. In these same two groups, flow cytometry analyses of spleen cells showed that high levels of natural killer (panNK+) cells, B (CD19+) lymphocytes, and cells expressing the CD71 and CD25 activation markers were present (p < 0.05). An enhancing effect was also noted in some of the measurements with parental plasmid p WS4 and tumor presence. In phase C, the slowest tumor progression was observed in the groups receiving 15 and 150 microg pGL1-TNF-alpha together with radiation; tumor volumes were 51 and 43% smaller, respectively, than for PBS-injected controls by the end of the study. Collectively, these results show that localized treatment with pGL1-TNF-alpha is hematologically nontoxic at low doses and support the premise that activation of lymphocytes may contribute to the antitumor effects of radiation against a highly aggressive brain tumor.
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PMID:Lymphocyte activation with localized pGL1-TNF-alpha gene therapy in a glioma model. 1181 46

The recombinant congenic mouse strains AcB55 and AcB61 are extremely resistant to malaria (Plasmodium chabaudi AS) despite the presence of susceptibility alleles at the known Char1/Char2 resistance loci. Resistance in AcB55 and AcB61 is controlled by a locus on chromosome 3 (Char4) shown to be allelic with or tightly linked to a loss-of-function mutation in pyruvate kinase (Pklr). AcB55 and AcB61 show important splenomegaly prior to infection caused by the expansion of the red pulp, and display histological signs of extramedullary erythropoiesis in the liver. Examination of splenic cell populations by flow cytometry demonstrates elevated numbers of TER119-positive erythroid precursor cells (>30% of total spleen cells), while RNA expression studies show elevated expression of erythrocyte-specific transcripts such as globin, transferrin receptor, and Nramp2/Slc11a2 in the spleen of both strains. Hematological profiling in both strains is consistent with the presence of anemia as evidenced by low total erythrocyte counts, decreased hemoglobin, as well as abnormally high numbers of circulating reticulocytes (15-20%). These results strongly suggest that the mutant Pklr allele (Pklr(269A)) of AcB55/61 strains causes hemolytic anemia compensated by constitutive erythropoiesis, which in turn protects the mice against P. chabaudi infection. The possible molecular basis of the Pklr protective effect is discussed and is under current investigation in these two strains.
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PMID:Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model. 1502 38

Proinflammatory effects caused by oligodeoxynucleotides (ODN) include cytokine production, splenomegaly and infiltration of mononuclear cells into tissues. Presence of one or more CpG motifs in an ODN sequence confers potency for proinflammatory properties. The objective of this research was to characterize the proinflammatory effects produced by CpG containing ODN as compared to non-CpG ODN using gene array analysis. Female CD-1 mice were administered equipotent dose regimens of a CpG ODN (ISIS 12449, 4 mg/kg sc, single or repeat dose for 7 d) or a non-CpG ODN (ISIS 2302, 50 mg/kg sc, q2d for 1 or 3 weeks) and tissues (liver and peripheral blood leukocytes) were harvested for immunohistochemical analysis or gene array analysis. Splenomegaly, a marker of ODN-induced inflammation, was greatest (3-fold above control) with ISIS 12449 when given at multiple doses. Immunohistochemical staining identified mainly monocytes/macrophages as the immune cell infiltrates in the liver following ISIS 12449 or ISIS 2302 treatment. Gene analysis of liver tissue indicated enhanced expression of chemokines (MIG, MIP-2beta, MCP-1, IL-1beta, CCR3), cell surface markers (CD14, CD18, CD86, CD11c, P-selectin), intracellular markers (NF-kappaBp65, MyD88, Survivin) and markers of cell proliferation (PCNA, Ki-67, CD71) was produced with ISIS 12449 or ISIS 2302. Although CpG and non-CpG containing ODN produced similar gene expression profiles, notable differences were observed to suggest that their mechanisms of immune modulation are not completely overlapping. MIG and MIP 1beta were identified as potential biomarker for immune stimulation that may be used to further study the species specificity, sequence/structure dependence and time course of proinflammatory ODN and antisense inhibitors used as therapeutics.
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PMID:CpG and Non-CpG oligodeoxynucleotides induce differential proinflammatory gene expression profiles in liver and peripheral blood leukocytes in mice. 1895 86

Conventional chemotherapy for cancer has limited specificity for cancer cells. Here, we investigate the possibility of improving the selectivity of chemotherapy by coadministering targeted biological modifier peptides. We show that the 22-amino acid metal-binding transporter domain (MBD) derived from insulin-like growth factor-binding protein-3 selectively targets cancer cells. The rate of MBD uptake by cells was measured using a panel of 54 human cancer cell lines and correlated with MBD cross-linking to cell surface transferrin receptor, caveolin 1, and integrin beta. Gene array data show that MBD uptake correlates with the expression of genes associated with cellular stress-coping mechanisms commonly upregulated in cancer (nuclear factor-kappaB, Hsp-70B). MBD-tagged peptides designed to inhibit such mechanisms have cytotoxic effects on a broad range of human cancer cell lines. The discriminant validity of these peptides as potential cotherapeutic agents was investigated by comparing their cytotoxicity to cancer cell lines versus normal human cell counterparts. Synergies between these peptides and marginally cytotoxic levels of 5-fluorouracil were demonstrated. Biodistribution data from in-vivo experiments in mice and rats confirm that MBD-tagged peptides and proteins preferably localize to specific tissues, such as kidney and pancreas. Intracardial injection of CCRF-CEM T-cell leukemia or MDA-MB-435 cells into Rag-2 mice establishes disseminated disease within 7 days. Twenty-five-day subcutaneous administration of a three-peptide cocktail (3 mg/kg) in combination with 5-fluorouracil in Rag-2 mice with established CCRF-CEM leukemia significantly reduces splenomegaly and bone marrow cancer cell burden. In a similar experiment using MDA-MB-435 cells, MBD-tagged peptides reduced human cell burden in bone marrow. Taken together, these data suggest that MBD-tagged molecules can be used as highly selective chemosensitizers in the treatment of hematological and disseminated malignancies.
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PMID:The metal-binding domain of IGFBP-3 selectively delivers therapeutic molecules into cancer cells. 1934 98

Individuals with beta-thalassemia develop progressive systemic iron overload, resulting in high morbidity and mortality. These complications are caused by labile plasma iron, which is taken up by parenchymal cells in a dysregulated manner; in contrast, erythropoiesis depends on transferrin-bound iron uptake via the transferrin receptor. We hypothesized that the ineffective erythropoiesis and anemia observed in beta-thalassemia might be ameliorated by increasing the amount of circulating transferrin. We tested the ability of transferrin injections to modulate iron metabolism and erythropoiesis in Hbb(th1/th1) mice, an experimental model of beta-thalassemia. Injected transferrin reversed or markedly improved the thalassemia phenotype in these mice. Specifically, transferrin injections normalized labile plasma iron concentrations, increased hepcidin expression, normalized red blood cell survival and increased hemoglobin production; this treatment concomitantly decreased reticulocytosis, erythropoietin abundance and splenomegaly. These results indicate that transferrin is a limiting factor contributing to anemia in these mice and suggest that transferrin therapy might be beneficial in human beta-thalassemia.
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PMID:Transferrin therapy ameliorates disease in beta-thalassemic mice. 2009 32


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