Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nearly one-half of all hypercalcemic patients with lymphoma present with inappropriately elevated circulating concentrations of the active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D3). However, the cellular source of the vitamin D hormone in lymphomas remains unclear. To address this, we report the case of a 75-year-old man with hypercalcemia associated with raised circulating concentrations of 1,25(OH)2D3 and suppressed parathyroid hormone (PTH) levels. Positron emission tomographic (PET) and computed tomographic (CT) imaging revealed the presence of a large lymphoma that was confined to the spleen; subsequent pathological analysis showed that this was an intermediate grade B-cell lymphoma. After surgical removal of the spleen, serum calcium and 1,25(OH)2D3 levels became normalized within 24 h. Immunolocalization of the vitamin D-activating enzyme 25-hydroxyvitamin D3-1alpha-hydroxylase (la-hydroxylase) in sections of resected spleen showed that staining was negative in the lymphoma cells but positive in neighboring macrophages. This case study indicates that the hypercalcemia associated with lymphomas may be due, in some instances, to excessive extrarenal production of 1,25(OH)2D3. Furthermore, by using immunohistochemistry to assess the distribution of la-hydroxylase, we have been able to show for the first time that tissue macrophages, rather than actual tumor cells, are the most likely ectopic source of this enzyme. Based on this case study, we propose that the abnormal synthesis of 1,25(OH)2D3 associated with some lymphomas is because of paracrine regulation of tumor-associated macrophages.
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PMID:Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages. 1261 44

Acute tumor lysis syndrome (TLS) is a catastrophic complication of the treatment of certain neoplastic disorders. It most commonly occurs in association with hematologic malignancies and manifests a few hours to a few days after initiation of specific chemotherapy. Acute spontaneous TLS has been described in leukemia and lymphoma and in some patients with solid tumors prior to institution of therapy. The findings that may be seen in acute TLS include hyperphosphatemia, hypocalcemia, hyperuricemia, hyperkalemia, and acute oliguric or anuric renal failure due to uric acid precipitation within the tubules (acute uric acid nephropathy) and to calcium phosphate deposition in the renal parenchyma and vessels. We report here a case of acute spontaneous TLS (high grade B-cell lymphoma of the right colon) in which serum uric acid concentration attained exceptionally high levels (36.7 mg/dL). The patient underwent acute oliguric renal failure soon after right colectomy. He was treated by means of a large infusion of saline. The renal function recovered in such a rapid way that no dialysis treatment was required. In conclusion the present case report has two peculiarities: that of being one of the rare examples of spontaneous TLS, and that of showing an exceptionally severe hyperuricemia, probably the highest ever reported in the literature. The administration of a large volume of saline was able to ensure a complete recovery of renal function. Therefore, hydration with saline remains the keystone in the prevention and treatment of acute TLS.
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PMID:[An exceptionally severe hyperuricemia in acute renal failure caused by spontaneous tumor lysis syndrome (TLS)]. 1463 69

This study investigated the role of several chemokines and their receptors on malignant B lymphocytes recovered from 13 patients with chronic lymphocytic leukemia (CLL), 9 with hairy cell leukemia (HCL), 5 with mantle cell lymphoma (MCL), 5 with marginal zone B-cell lymphoma (MZL), 6 with small lymphocytic lymphoma (SLL), and 5 with follicular cell lymphoma (FCL). Flow cytometry analysis demonstrated that CXCR4 and CXCR5 were expressed on all malignant and normal B cells. Considering CC receptors, CCR1 was expressed in 70% of patients with CLL and 40% of those with HCL but was lacking in patients with MCL, MZL, SLL, and normal B cells. CCR2 showed a heterogeneous pattern of expression. CCR3 was found in almost all patients with CLL and in the majority of those with HCL, whereas it was usually lacking in patients with MZL and SLL and in healthy subjects. CCR5 was expressed in patients with HCL and MCL. Migration assays showed that different chemokines, mainly CXCL12 and CXCL13, are able to trigger migration of malignant B lymphocytes. Some of these chemokines induce calcium mobilization. These data indicate that different patterns of chemokine receptor expression identify different malignant B-cell subsets and that these receptors are functional and might play a role in malignant B-cell circulation.
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PMID:Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas. 1500 69

Purging of neoplastic cells for autologous stem cell transplantation is usually done in vivo by administering chemotherapy and/or other agents before harvesting. It is also possible to decrease malignant cells counts directly in the cell harvest. In this study, we ascertained the effect of anti-CD20 monoclonal antibody and rituximab administration on peripheral blood hematopoietic stem cells. Five samples of stem cell harvests from different patients with B cell lymphoma were obtained. Each sample was divided in two tubes with calcium gluconate (20 mEq/50 microl). Rituximab (1 mg/600,000 mononuclear cells) was added to one of the tubes. Using flow cytometry, CD19, CD20 (B cell markers), and CD95 (apoptosis marker), expression was measured at baseline and 24 h after the addition of rituximab. A one-sided t-test with equal variances was used to analyze the results. Immediately after rituximab addition, CD20 expression became null. No significant difference in variation of CD19 expression was detected after the addition of rituximab (-3.64% control vs. 0.63% rituximab, p = 0.69). Mean variations of percentage of CD95 expression were 2.9% (controls) and 10.52% (rituximab tubes) (p = 0.06). We conclude that rituximab is capable of initiating apoptosis in vitro. We found no decrease in the CD19+ cell count, used as a surrogate marker for CD20+ cells, meaning that, at least in 24 h, apoptosis activation is not capable of decreasing CD20+ cell numbers. In vitro purging of peripheral blood stem cells harvests with rituximab could be part of a broader therapeutic strategy to be offered to lymphoproliferative disorder patients.
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PMID:Induction of apoptosis and effect on CD20+ using rituximab on autologous peripheral blood stem cell harvests from patients with B cell lymphomas. 1518 35

Rituxan, a chimeric anti-CD20 antibody, is the first antibody approved for immunotherapy in non-Hodgkin's B-cell lymphoma and other B-cell lymphoproliferative disorders. Additionally, efficacy of Rituxan treatment has been reported in nonmalignant autoimmune diseases such as rheumatoid arthritis. Crosslinking of CD20 molecules by Rituxan induces therapeutic B-cell depletion. CD20 is a B-lymphocyte specific integral membrane protein, proposed to function as a store-operated calcium channel, which is activated upon receptor-stimulated calcium depletion of intracellular stores. Crosslinking of CD20 by antibodies has been reported to induce a redistribution of CD20 molecules to specialized microdomains at the plasma membrane known as lipid rafts. Here, we report that in the absence of Rituxan, CD20 exhibits a low affinity to lipid rafts. However, binding of Rituxan significantly increases the affinity of CD20 for lipid rafts resulting in its redistribution to a fraction resistant to Triton X-100 solubilization. Furthermore, we demonstrate that disturbing the raft integrity by cholesterol extraction results in dissociation of CD20 from a Triton X-100 resistant fraction followed by complete inhibition of Rituxan-induced calcium entry and apoptosis. The integrity of lipid rafts seems to play a crucial role for CD20-induced caspase activation. These data show, for the first time, that Rituxan-induced translocation of CD20 to lipid rafts is important for increased intracellular Ca(2+) levels and downstream apoptotic signalling.
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PMID:Rituxan (anti-CD20 antibody)-induced translocation of CD20 into lipid rafts is crucial for calcium influx and apoptosis. 1573 Mar 89

SLP65 represents a critical component in (pre-) B cell receptor signal transduction but is compromised in a subset of pre-B cell-derived acute lymphoblastic leukemia. Based on these findings, we investigated (i.) whether SLP65-deficiency also occurs in mature B cell-derived lymphoma and (ii.) whether SLP65-deficient B cell lymphoma cells use an alternative B cell receptor signaling pathway in the absence of SLP65. Indeed, expression of SLP65 protein was also missing in a fraction of B cell lymphoma cases. While SLP65 is essential for B cell receptor-induced Ca2+ mobilization in normal B cells, B cell receptor engagement in SLP65-deficient as compared to SLP65-reconstituted B cell lymphoma cells resulted in an accelerated yet shortlived Ca2+-signal. B cell receptor engagement of SLP65-deficient lymphoma cells involves SRC kinase activation, which is critical for B cell receptor-dependent Ca2+-mobilisation in the absence but not in the presence of SLP65. As shown by RNA interference, the SRC kinase LYN is required for B cell receptor-induced Ca2+ release in SLP65-deficient B cell lymphoma cells but dispensable after SLP65-reconstitution. B cell receptor engagement in SLP65-deficient B cell lymphoma cells also resulted in tyrosine-phosphorylation of the proliferation- and survival-related MAPK1 and STAT5 molecules, which was sensitive to silencing of the SRC kinase LYN. Inhibition of SRC kinase activity resulted in growth arrest and cell death specifically in SLP65-deficient lymphoma cells. These findings indicate that LYN can short-circuit conventional B cell receptor signaling in SLP65-deficient B cell lymphoma cells and thereby promote activation of survival and proliferation-related molecules.
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PMID:The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells. 1656 84

B lymphocyte stimulator (BLyS) is crucial for B-cell survival, and the biological effects of BLyS are mediated by three cell surface receptors designated B cell-activating factor receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antibody (BCMA). Increased expression of BLyS and its receptors has been identified in numerous B-cell malignancies. We generated a fusion toxin designated rGel/BLyS for receptor-mediated delivery of the recombinant gelonin (rGel) toxin to neoplastic B cells, and we characterized its activity against various B-cell tumor lines. Three mantle cell lymphoma (MCL) cell lines (JeKo-1, Mino, and SP53) and two diffuse large B-cell lymphoma (DLBCL) cell lines (SUDHL-6 and OCI-Ly3) expressing all three distinct BLyS receptors were found to be the most sensitive to the fusion toxin (IC(50) = 2-5 pmol/L and 0.001-5 nmol/L for MCL and DLBCL, respectively). The rGel/BLyS fusion toxin showed specific binding to cells expressing BLyS receptors and rapid internalization of the rGel component into target cells. The cytotoxic effects of rGel/BLyS were inhibited by pretreatment with free BLyS or with soluble BAFF-R, TACI, and BCMA decoy receptors. This suggests that the cytotoxic effects of the fusion toxin are mediated through BLyS receptors. The rGel/BLyS fusion toxin inhibited MCL cell growth through induction of apoptosis associated with caspase-3 activation and poly (ADP-ribose) polymerase cleavage. Our results suggest that BLyS has the potential to serve as an excellent targeting ligand for the specific delivery of cytotoxic molecules to neoplastic B cells expressing the BLyS receptors, and that the rGel/BLyS fusion toxin may be an excellent candidate for the treatment of B-cell malignancies especially MCL and DLBCL.
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PMID:The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA. 1726 61

Adequate amounts of nutrients such as folate, vitamin A, iron, selenium and calcium are essential for general health including prevention of cancer. Yet, excess amounts of vitamin A, folate, and iron may also promote cancer. This study sought to determine whether adults who had completed initial treatments for B-cell lymphoma from 1 to 3 years earlier were consuming recommended amounts of these key nutrients and their interests in nutritional education. We surveyed 141 patients undergoing follow-up in the Lymphoma/Myeloma Clinic at The University of Texas M. D. Anderson Cancer Center using a validated food frequency questionnaire and supplemental questionnaire regarding nutritional interest. Nutrient intakes were estimated based on national databases of average content in foods and compared with recommended guidelines. One hundred forty-one participants returned complete questionnaires, but errors limited some nutrient estimates to 134 participants. Participants' mean age was 50, 55% were male, and 80% were non-Hispanic whites. Most participants (94%) were consuming either inadequate or excessive amounts of one or more of these key nutrients. Half of the participants were interested in receiving nutritional education. These findings are of concern because of their potential impact upon recovery and maintenance of general health and possibly cancer-related pathways after treatment.
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PMID:Patients previously treated for lymphoma consume inadequate or excessive amounts of five key nutrients. 1776 Nov 31

Emerging evidence indicates that in addition to their well-characterized role in antigen presentation, MHC II molecules transmit signals that induce death of APCs. Appropriately timed APC death is important for prevention of autoimmunity. Though the exact mechanism of MHC II-mediated cell death signaling is unknown, the response appears independent of caspase activation and does not involve Fas-FasL interaction. Here we investigated MHC II structural requirements for mediation of cell death signaling in a murine B cell lymphoma. We found that neither the transmembrane spanning regions nor the cytoplasmic tails of MHC II, which are required for MHC II-mediated cAMP production and PKC activation, are required for the death response. However, mutations in the connecting peptide region of MHC II alpha chain (alphaCP), but not the beta chain (betaCP), resulted in significant impairment of the death response. The alphaCP mutant was also unable to mediate calcium mobilization responses, and did not associate with Igalpha/beta. Knock-down of Igbeta by shRNA eliminated the MHC II-mediated calcium response but not cell death. We propose that MHC II mediates cell death signaling via association with an undefined cell surface protein(s), whose interaction is partially dependent on alphaCP region.
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PMID:MHC class II structural requirements for the association with Igalpha/beta, and signaling of calcium mobilization and cell death. 1819 17

The mechanisms leading to mucus accumulation in equine inflammatory airway disease (IAD) and recurrent airway obstruction (RAO) are unclear. In airways of human patients with asthma and/or chronic obstructive pulmonary disease as well as in animal models of these diseases, associations of mucus hyperproduction with increased calcium-activated chloride channel 1 (CLCA1), epidermal growth factor receptor (EGFR), mucin 5AC (MUC5AC), B-cell lymphoma 2 (Bcl-2), interleukin (IL)-13 and interferon (IFN)-gamma expression have been reported. We hypothesized that increased mucus accumulation in RAO and IAD are associated with alterations in inflammatory cytokine (IL-13 and IFN-gamma) and epithelial gene (CLCA1, EGFR, Bcl-2 and MUC5AC) profiles. Therefore, mRNA expression of these genes in cell pellets extracted from bronchoalveolar lavage fluid (BALF) and bronchial epithelial brushing (BEB) was compared between 11 clinically healthy (Control group), 7 IAD- and 12 RAO-affected horses by reverse transcription polymerase chain reaction. We also performed arterial blood gas analysis, endoscopic scoring of mucus accumulation in the trachea and cytology of tracheo-bronchial secretions (TBS) and of BALF. Tracheal mucus accumulation, along with TBS and BALF neutrophils were significantly increased and arterial pO(2) was decreased in RAO-affected horses compared to the Control group. IL-13 in BALF samples was significantly lower in the RAO group. None of the other genes' relative mRNA levels displayed significant differences between groups. Our findings suggest that mucus production in equine RAO is induced by pathways independent of IL-13, CLCA1, EGFR, MUC5AC and Bcl-2 up-regulation.
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PMID:Increased mucus accumulation in horses chronically affected with recurrent airway obstruction is not associated with up-regulation of CLCA1, EGFR, MUC5AC, Bcl-2, IL-13 and INF-gamma expression. 1859 57


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