Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphocyte egress from the vascular compartment into the lymph node (LN) parenchyma occurs at the postcapillary venules, termed high endothelial venules (HEVs). Lymphocyte adhesion and migration through the HEVs is a receptor-mediated, energy-dependent, process. The aim of this study was to investigate the role of MHC Class II antigen expression on lymphocyte-HEV interaction in normal (CBA) and autoimmune (MRL/l) mice. Using the HEV binding assay, lymphocyte adhesion to LN sections pretreated with monoclonal antibody (MAb; 10-2.16) was decreased compared to diluent (mean of the differences +/- standard deviation; xd +/- SD: 0.749 +/- 0.22, P less than 0.0075)- and myeloma immunoglobulin-pretreated controls (xd = 0.462 +/- 0.13, P less than 0.005). Similar inhibition of binding was found in MRL/l LN sections pretreated with MAb 10-2.16. Binding inhibition was concentration dependent, but total inhibition was never achieved. Several other anti-Ia MAb's were used, but failed to inhibit lymphocyte attachment. Lymphocyte binding to control sections treated with MAb's against MHC Class I antigen, plasminogen activator (PAM-3), anti-thrombin III (AT-IIIm), and MECA-325 antigen was not significantly different from diluent controls. LN cell suspensions pretreated with MAb 10-2.16 bound normally to LN sections. By contrast, MAb to lymphocyte homing receptor (MEL-14) inhibited lymphocyte adhesion. The role of Class II antigens in lymphocyte-HEV interactions is discussed.
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PMID:Anti-Ia monoclonal antibody (10-2.16) inhibits lymphocyte-high endothelial venule (HEV) interaction. 318 Feb 28

Immunoglobulin light chain amyloidosis (AL) is characterized by a clonal expansion of plasma cells within the bone marrow. Gene expression analysis was used to identify a unique molecular profile for AL using enriched plasma cells (CD138+) from the bone marrow of 24 patients with AL and 28 patients with multiple myeloma (MM) and 6 healthy controls. Class prediction analysis (PAM) revealed a subset of 12 genes, which included TNFRSF7 (CD27), SDF-1, and PSMA2, that distinguished between these 2 groups with an estimated and observed accuracy of classification of 92%. This model was validated with an independent dataset of 11 patients with AL and 12 patients with MM with 87% accuracy. Differential expression for the most discriminant genes in the 12-gene subset was validated using quantitative real-time polymerase chain reaction and protein expression analysis, which upheld the observations from the micro-array expression data. Functional analyses using a novel network mapping software revealed a number of potentially significant pathways that were dysregulated in patients with AL, with those regulating proliferation, apoptosis, cell signaling, chemotaxis, and migration being substantially represented. This study provides new insight into the molecular profile of clonal plasma cells and its functional relevance in the pathogenesis of light chain amyloidosis.
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PMID:Functional gene expression analysis of clonal plasma cells identifies a unique molecular profile for light chain amyloidosis. 1538 84

Melphalan (L-PAM) has been an integral part of multiple myeloma (MM) treatment as a conditioning regimen before stem cell transplant (SCT). After initial response, most treated patients experience relapse with an aggressive phenotype. Increased glutathione (GSH) in MM may mediate resistance to L-PAM. We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L-PAM activity (inducing 2-4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices <1.0). In MM cell lines, BSO significantly (P<0.05) depleted GSH, increased L-PAM-induced single-strand DNA breaks, mitochondrial depolarization, caspase cleavage and apoptosis. L-PAM depleted GSH, but GSH rapidly recovered in a L-PAM-resistant MM cell line unless also treated with BSO. Treatment with N-acetylcysteine antagonized BSO+L-PAM cytotoxicity without increasing GSH. In human MM xenografted into beige-nude-xid mice, BSO significantly depleted MM intracellular GSH and significantly increased apoptosis compared with L-PAM alone. BSO+L-PAM achieved complete responses (CRs) in three MM xenograft models including maintained CRs >100 days, and significantly increased the median event-free survival relative to L-PAM alone. Combining BSO with L-PAM warrants clinical testing in advanced MM.
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PMID:The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma. 2503