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)

A method for purification of the mRNA coding for heavy-chain protein of a mouse G(2a) myeloma (5563) is reported. Complete myeloma protein (H(2)L(2)) specifically binds to the heavy-chain mRNA, and the resultant RNA-protein complex is precipitated with antiserum against 5563 myeloma protein. Cytoplasmic RNA isolated by this method showed two bands of 6.0 x 10(5) and 3.1 x 10(5) molecular weight when analyzed by acrylamide gel electrophoresis. The RNA in the bands contained 1.5% and 8% A-rich regions, respectively. The RNA in each of the bands contained sequences for heavy-chain protein when translated in Xenopus laevis oocytes.
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PMID:Isolation of messenger RNA coding for mouse heavy-chain immunoglobulin. 451 8

Studies on the sera and isolated proteins from 14 patients with gammaG3 multiple myeloma revealed a concentration- and temperature-dependent aggregation which was not encountered in 26 sera from patients with multiple myeloma involving other gammaG subgroups. When the gammaG3 myeloma sera were diluted and characterized by analytical ultracentrifugation, complex formation was minimal. However, when these sera were examined undiluted, marked complex formation was observed. Studies on the isolated proteins, their enzymatic fragments, as well as their heavy and light polypeptide chains localized the aggregating sites to the Fd fragment of the heavy chains. The findings were also documented by acrylamide-gel electrophoresis and capillary tube viscometry.THE HYPERVISCOSITY SYNDROME WAS OBSERVED IN SIX PATIENTS: three with gammaG3 myeloma and three with gammaG1 myeloma. In the latter group extreme protein concentrations appeared essential for the development of the clinical symptoms. The gammaG3 cases, however, because of the aggregation phenomenon, showed the syndrome at relatively low protein concentrations.
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PMID:Aggregation of gamma-G3 proteins: relevance to the hyperviscosity syndrome. 541 87

An antigenic heterogeneity among IgD myeloma proteins was tested by immunoelectrophoresis and double immunodiffusion in agar with four kinds of anti-delta(Fc) antisera produced by immunization with isolated Fc fragments of IgD myeloma proteins. According to antigenicity of the Fc fragment, IgD myeloma proteins were divided into two different groups. Anti-delta(Fc)-T1 (S.T.) antiserum, absorbed with te Y.S. myeloma protein or serum, either gave a faint precipitin line or failed to react against the isolated IgD myeloma proteins or sera. With the papain-digested IgD myeloma proteins and sera, anti-delta(Fc)-T1 antiserum either gave heavy precipitin lines or failed to react. Of twelve papain-digested sera containing IgD myeloma proteins tested, nine (75%) showed positive precipitin lines using anti-delta(Fc)-T1 antiserum. No relationship was found between the two groups of myeloma proteins with respect to IgD levels. SDS polyacrylamide gel electrophoresis of the IgD myeloma proteins (S.T. and Y.S.) showed no difference in the molecular weights of the whole myeloma proteins, and their light and heavy chains. Polyacrylamide gel electrophoresis of the IgD myeloma proteins (S.T. and Y.S.), after treatment with papain, revealed almost the same patterns.
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PMID:Immunochemical studies on heterogeneity of IgD myeloma proteins. 616 63

Spleen cells from BALB/c mice, immunized with SDS-acrylamide gel purified human fibroblast interferon (HuIFN-beta) were fused with mouse myeloma cells. Culture fluids from the resulting hybrid cells were screened for HuIFN-beta specificity by the following tests: a solid-phase RIA using partially purified HuIFN-beta, a protein-transfer RIA using electrophoretically resolved and immobilized HuIFN-beta, and a bioassay which tests residual HuIFN-beta activity in the supernatant following immunoprecipitation. Six HuIFN-beta-specific hybridomas were identified; two were capable of partially neutralizing HuIFN-beta activity. All six antibodies bind to the beta 1-IFN polypeptide synthesized in E. coli cells containing a cloned beta 1-IFN DNA sequence. All six monoclonal antibodies were found to be IgG3/kappa.
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PMID:Monoclonal antibodies directed against human fibroblast interferon: characterization and functional studies. 620 71

Intact rabbit immunoglobulin G molecules (IgGs) and their papain or pepsin fragments were radio-iodinated and injected into HeLa cells. Whole IgGs, Fab2, and Fc fragments were degraded with half-lives of 60-90 h, whereas half-lives of Fab fragments were 110 h. These results indicate that proteolytic cleavage in the hinge region of the IgG molecule is not the rate-limiting step in its intracellular degradation. The hingeless human myeloma protein, Mcg, was degraded at the same rate as bulk human IgG, providing further evidence that the proteolytically susceptible hinge region is not important for intracellular degradation of IgG molecules. SDS acrylamide gel analysis of injected rabbit IgG molecules revealed that heavy and light chains were degraded at the same rate. Injected rabbit IgGs and rabbit IgG fragments were also examined on isoelectric focusing gels. Fab, Fab2, and Fc fragments were degraded without any correlation with respect to isoelectric point. Positively charged rabbit IgGs disappeared more rapidly than their negative counterparts, contrary to the trend reported for normal intracellular proteins. The isoelectric points of two mouse monoclonal antibodies were essentially unchanged after injection into HeLa cells, suggesting that the altered isoelectric profile observed for intact rabbit IgG resulted from degradation and not protein modification. The intracellular distributions of IgG fragments and intact rabbit IgG molecules were determined by autoradiography of thin sections through injected cells. Intact IgG molecules were excluded from HeLa nuclei whereas both Fab and Fc fragments readily entered them. Thus, for some proteins, entry into the nuclear compartment is determined primarily by size.
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PMID:Intracellular distribution and degradation of immunoglobulin G and immunoglobulin G fragments injected into HeLa cells. 640 51

AA-protein was identified by SDS-acrylamide electrophoresis in amyloid fibrils fixed in formalin after isolation from fresh-frozen tissues obtained from patients with familial Mediterranean fever (FMF) amyloidosis and idiopathic AA-amyloidosis and, following deparaffination, rehydration and homogenization of embedded formalin-fixed tissues of old autopsy cases of the hereditary amyloidosis of FMF and amyloidosis acquired in association with tuberculosis, bronchiectasis, and rheumatoid arthritis. That AA-protein is unaltered by formalin was firmly established by agar gel diffusion using specific rabbit anti-AA serum. By contrast, AL proteins could not be demonstrated either in formalin-fixed amyloid fibrils derived from fresh-frozen tissues of a patient with presumably AL-amyloidosis dominated by cardiomegaly and one with AL-kappa amyloidosis or in blocks of cases of familial neuropathic amyloidosis, multiple myeloma, and idiopathic amyloidosis with cardiopathy. AA-protein is not denatured by formalin and retains its typical electrophoretic, chromatographic, and immunologic characteristics even 30 years after fixation and paraffin-embedding.
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PMID:Demonstration of AA-protein in formalin-fixed, paraffin-embedded tissues. 706 12

Unlike other immunoglobulin G (IgG) subclasses, IgG4 antibodies in plasma have been reported to be functionally monovalent. In a previous paper, we showed that the apparent monovalency of circulating IgG4 antibodies is caused by asymmetry of plasma IgG4-a large fraction has two antigen-binding sites resulting in bispecificity. We postulated that the generation of bispecific antibodies was caused by a post-secretion mechanism, involving the exchange of IgG4 half-molecules (i.e. one heavy and one light chain). This hypothesis was based on the observed instability of the inter-heavy chain disulfide bonds of IgG4. To investigate this instability, we constructed IgG4 mutants and analyzed the covalent interaction between the heavy chains by sodium dodecyl sulfate-poly acrylamide gel electrophoresis (SDS-PAGE) under non-reducing conditions. The mutation to serine of one of the hinge cysteines involved in the inter-heavy chain bond formation, Cys226, resulted in a more stable rather than a more labile inter-heavy chain linkage. Moreover, we confirmed that mutating the IgG4 hinge sequence Cys-Pro-Ser-Cys to the IgG1 hinge sequence Cys-Pro-Pro-Cys also markedly stabilizes the covalent interaction between the heavy-chains. These two observations suggested an explanation for the observed instability of the inter-heavy chain disulfide bonds: the formation of an alternative, intra-chain cystine. Obviously, this intra-chain cystine cannot be formed in the mutant where Cys226 is replaced by Ser, and cannot easily be formed in the mutant with the IgG1 hinge sequence (Cys-Pro-Pro-Cys) due to the restricted torsional freedom of prolines. We, therefore, postulate that the lack of a covalent heavy-chain interaction in a subpopulation of IgG4 reflects an equilibrium between inter- and intra-chain cystines. Based upon the published structure of the IgG4-related hinge-deleted IgG1 myeloma protein Mcg, we propose a model for the two forms of IgG4 and for the half-molecule exchange reaction, which might result in the formation of bispecific IgG4 antibodies.
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PMID:The inter-heavy chain disulfide bonds of IgG4 are in equilibrium with intra-chain disulfide bonds. 1148 5

Resurgent interest in covalent target engagement in drug discovery has demonstrated that small molecules containing weakly reactive electrophiles can be safe and effective therapies. Several recently FDA-approved drugs feature an acrylamide functionality to selectively engage cysteine side chains of kinases (Ibrutinib, Afatinib, and Neratinib). Additional electrophilic functionalities whose reactivity is compatible with highly selective target engagement and in vivo application could open new avenues in covalent small molecule discovery. Here, we report the synthesis and evaluation of a library of small molecules containing the 2-chloropropionamide functionality, which we demonstrate is less reactive than typical acrylamide electrophiles. Although many library members do not appear to label proteins in cells, we identified S-CW3554 as selectively labeling protein disulfide isomerase and inhibiting its enzymatic activity. Subsequent profiling of the library against five diverse cancer cell lines showed unique cytotoxicity for S-CW3554 in cells derived from multiple myeloma, a cancer recently reported to be sensitive to PDI inhibition. Our novel PDI inhibitor highlights the potential of 2-chloropropionamides as weak and stereochemically tunable electrophiles for covalent drug discovery.
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PMID:2-Chloropropionamide As a Low-Reactivity Electrophile for Irreversible Small-Molecule Probe Identification. 2861 14


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