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Francois G Roberge - One of the best experts on this subject based on the ideXlab platform.
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humanized antibodies against the alpha Chain of the il 2 receptor and against the Beta Chain shared by the il 2 and il 15 receptors in a monkey uveitis model of autoimmune diseases
Journal of Immunology, 1997Co-Authors: Y Guexcrosier, Chi-chao Chan, J Raber, M S Kriete, J Benichou, R S Pilson, J A Kerwin, Thomas A Waldmann, J Hakimi, Francois G RobergeAbstract:We studied the efficacy and tolerance of humanized Ab interfering with the signal of the IL-2 and IL-15 receptors in a primate model of experimental autoimmune uveoretinitis. The inhibitory effects of humanized anti-Tac (HAT), an anti-IL-2R alpha-Chain Ab, and HuMik Beta1, an Ab directed at the Beta-Chain shared by the receptors of IL-2 and IL-15, were tested in culture on the proliferative response of monkey Con A-blast lymphocytes stimulated with IL-2 or IL-15. Uveitis was induced in cynomolgus monkeys by immunization with human recombinant retinal S-antigen. Treatment was initiated at the first sign of disease and consisted of HAT and HuMik Beta1, alone or in combination, or vehicle control given by i.v. injection twice a week for 4 wk. Disease was evaluated by ocular funduscopy. The results in culture showed a significant dose-dependent inhibition of the IL-2-driven proliferation of lymphocytes by HAT. HuMik Beta1 alone was ineffective against IL-2 stimulation, but had a marked potentiating effect in combination with HAT, independent of IL-15 signaling. IL-15-driven proliferation was inhibited by HuMik Beta1, but not by HAT alone or in combination. In monkeys, experimental autoimmune uveoretinitis evolution was significantly inhibited by HAT treatment. HuMik Beta1 alone had no effect on the disease. However, when used in combination, the two Ab markedly reduced the severity of ocular inflammation. The Ab were well tolerated. Only three monkeys, treated with HAT alone, made an Ab response against the injected Ab.
David E Isenman - One of the best experts on this subject based on the ideXlab platform.
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a single arginine to tryptophan interchange at Beta Chain residue 458 of human complement component c4 accounts for the defect in classical pathway c5 convertase activity of allotype c4a6 implications for the location of a c5 binding site in c4
Journal of Immunology, 1992Co-Authors: Roger O Ebanks, Michael C. Carroll, R D Campbell, M.j. Anderson, A S Jaikaran, David E IsenmanAbstract:In general, C4A allotypes of human C4 show one-fourth to one-third the hemolytic activity of C4B allotypes. An exception to this rule is C4A6 which is almost totally deficient in hemolytic activity. Previous studies have localized the defect in C4A6 to the C5 convertase stage. Of the two critical events required for C5 cleavage, namely formation of a covalent adduct between C3b and the C4b subunit of the C3 convertase (C4b2a), and binding of C5 to this C4b-C3b complex, it is a defect in the latter step that accounts for the aberrant activity of C4A6. DNA sequencing studies described in a companion paper have suggested that the sole C4A6-specific difference was a Trp for Arg replacement at Beta-Chain residue 458. To directly ascertain whether this single substitution was responsible for the hemolytic defect in C4A6, we have used site-directed mutagenesis to introduce this change into both C4A and C4B cDNA expression plasmids. We found that the R to W replacement totally abrogated hemolytic activity. However, irrespective of the amino acid at residue 458, the mutant proteins behaved like their wild-type counterparts with respect to covalent binding to C1-bearing targets, i.e., the C4B recombinants displayed higher binding to sheep and human red cells than did the C4A counterparts. Furthermore, the mutants were able to form covalent C4b-C3b adducts. There was, however, substantially less C5 cleavage produced by cell-bound C4boxy23b complexes made with R458W mutant C4B than with wild-type C4B. These results are consistent with the sole defect in the mutants being at the C5 binding stage and strongly suggest that Arg 458 of the C4 Beta-Chain contributes to the C5 binding site of the molecule.
Chunfang Gao - One of the best experts on this subject based on the ideXlab platform.
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identification alpha 2 hs glycoprotein precursor and tubulin Beta Chain as serology diagnosis biomarker of colorectal cancer
Diagnostic Pathology, 2014Co-Authors: Naijun Fan, Rui Kang, Yan Liu, Hongmei Chen, Chunfang GaoAbstract:Colorectal cancer (CRC) remains a major worldwide cause of cancer-related morbidity and mortality largely due to the insidious onset of the disease. The current clinical procedures utilized for disease diagnosis are invasive, unpleasant, and inconvenient. Hence, the need for simple blood tests that could be used for the early detection is crucial for its ultimate control and prevention. The present work is a case–control study focused on proteomic analysis of serum of healthy volunteers and CRC patients by the ClinProt profiling technology based on mass spectrometry. This approach allowed to identifying a pattern of proteins/peptides able to differentiate the studied populations. Moreover, some of peptides differentially expressed in the serum of patients as compared to healthy volunteers were identified by LTQ Orbitrap XL. A Quick Classifier Algorithm was used to construct the peptidome patterns (m/z 1208, 1467, 1505, 1618, 1656 and 4215) for the identification of CRC from healthy volunteers with accuracy close to 100% (>CEA, P < 0.05). Peaks at m/z 1505 and 1618 were identified as alpha-2-HS-glycoprotein precursor and tubulin Beta Chain, respectively. Alpha-2-HS-glycoprotein precursor and tubulin Beta Chain could be involved in the pathogenesis of CRC and perform as potential serology diagnosis biomarker. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4796578761089186 .
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identification of tubulin Beta Chain thymosin Beta 4 like protein 3 and cytochrome b c1 complex subunit 1 as serological diagnostic biomarkers of gastric cancer
Clinical Biochemistry, 2013Co-Authors: Naijun Fan, Qingyin Liu, Xiuli Wang, Chunfang GaoAbstract:Abstract Objective Despite major advances in its diagnosis and treatment, gastric cancer (GC) remains a major life-threatening disease. Treatment of the disease is further aggravated by the lack of diagnostic biomarkers that can aid in the early detection of GC and promote its favorable prognosis. The present work aims to identify novel diagnostic biomarkers for GC. Design and methods The present work is a case–control study that focuses on proteomic analysis of serum from healthy volunteers and GC patients using ClinProt profiling technology based on mass spectrometry. A pattern of proteins/peptides with the ability to differentiate the studied populations was identified. Deregulated proteins/peptides differentially expressed in the serum of patients compared with healthy volunteers were identified by mass spectroscopy. Results A pattern of proteins/peptides consisting of four protein/peptide peaks at m/z 1467, 1867, 2701, and 2094 was identified. These protein/peptide peaks were able to differentiate the studied populations with close to 100% sensitivity and specificity. Three of the deregulated proteins/peptides at m/z 1867, 2701, and 2094 were identified by mass spectroscopy (LTQ Orbitrap XL) as tubulin Beta Chain, thymosin Beta-4-like protein 3, and cytochrome b–c1 complex subunit 1, respectively. Conclusions The pattern of proteins/peptides identified in the present work shows great potential for GC diagnosis. Deregulated proteins of tubulin Beta Chain, thymosin Beta-4-like protein 3, and cytochrome b–c1 complex subunit 1 may be involved in the pathogenesis of GC and serve as potential serological diagnostic biomarkers.
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tubulin Beta Chain filamin a alpha isoform 1 and cytochrome b c1 complex subunit 1 as serological diagnostic biomarkers of esophageal squamous cell carcinoma a proteomics study
Omics A Journal of Integrative Biology, 2013Co-Authors: Naijun Fan, Chunfang Gao, Xiuli WangAbstract:Abstract Despite the major advances in diagnosis and treatment, esophageal squamous cell carcinoma (ESCC) remains a major life-threatening disease. Early diagnosis is critical for guiding the therapeutic management of ESCC. This case-control study focused on the proteomic analysis of serum of healthy volunteers and ESCC patients using the ClinProt profiling technology based on mass spectrometry. A total of 80 healthy volunteers and 119 ESCC patients were enrolled. We identified a pattern of proteins/peptides (including m/z 1867, 2700, and 2094) and differentiated ESCC patients from healthy volunteers with sensitivity and specificity close to 100%. Using mass spectrometry (LTQ orbitrap XL), tubulin Beta Chain, filamin A alpha isoform 1, and cytochrome b-c1 complex subunit 1 were identified as the three differentially expressed proteins/peptides in the patient serum. These three dysregulated proteins/peptides could be involved in the pathogenesis of ESCC and may serve as putative serological diagnostic biom...
David Danielpour - One of the best experts on this subject based on the ideXlab platform.
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The C-terminus of interferon gamma receptor Beta Chain (IFNγR2) has antiapoptotic activity as a bax inhibitor
Cancer biology & therapy, 2009Co-Authors: Jose A. Gomez, Weiyon Sun, Vivian Gama, Dagmar Hajkova, Tomoyuki Yoshida, Masaru Miyagi, John J. Pink, Mark W. Jackson, David DanielpourAbstract:Bax is a pro-apoptotic protein that mediates intrinsic cell-death signaling. Using a yeast-based functional screening approach, we identified interferon gamma receptor Beta Chain (IFNγR2) as a new Bax suppressor. IFNγR2 is a component of the IFNγ receptor complex along with the IFNγR alpha Chain (IFNγR1). Upon IFNγ binding, a conformational change in the receptor complex occurs that activates the Jak2/STAT1 signaling cascade. We found that the C-terminal region (amino acids 296-337) of IFNγR2 (IFNγR2296-337) contains a novel Bax inhibitory domain. This portion does not contain the Jak2-binding domain; therefore, the antiapoptotic function of IFNγR2 is independent of JAK/STAT signaling. IFNγR2296-337 rescued human cells from apoptosis induced by overexpression of Bax but not Bak. Overexpression of IFNγR2 (wild type and IFNγR2296-337) rescued cells from etoposide and staurosporine, which are known to induce Bax-mediated cell death. Interestingly, IFNγR2 inhibited apoptosis induced by the BH3-only protein Bi...
R D Campbell - One of the best experts on this subject based on the ideXlab platform.
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The coding sequence of the hemolytically inactive C4A6 allotype of human complement component C4 reveals that a single arginine to tryptophan substitution at Beta-Chain residue 458 is the likely cause of the defect.
Journal of immunology (Baltimore Md. : 1950), 1992Co-Authors: M.j. Anderson, Caroline M. Milner, Richard G.h. Cotton, R D CampbellAbstract:The C4A6 allotype of the human complement component C4 is known to be defective in C5 binding within the C5 convertase. To characterize the position and nature of the molecular defect in the C4A6 allotype we have isolated the C4A6 gene from a cosmid genomic DNA library. Direct sequencing of a 4.4-kb region of the gene covering exons 17 to 31 and encoding the C4d fragment and most of the rest of the alpha Chain of C4 revealed that the C4A6 allele encodes the A isotypic residues Pro Cys-Leu Asp at positions 1101, 1102, 1105, and 1106 and the same residues as the C4A3 alpha gene at the polymorphic positions 1054 (Asp), 1157 (Asn), 1182 (Thr), 1188 (Val), 1191 (Leu) and 1267 (Ala). In addition the C4A6 allele was shown to encode a Pro at the previously characterized polymorphic position 707 in the C4a peptide where the C4A3 alpha allele encodes a Leu. The remaining 26 exons of the C4A6 gene were analyzed by detecting nucleotide mismatches in C4A6/C4A3 and C4A6/C4B1 DNA heteroduplexes using the chemical cleavage of mismatch technique. The regions around detected mismatches were sequenced. In total seven nucleotide differences were defined on comparison of the C4A6 and other C4 sequences, of which three were present in exons. Two of these resulted in amino acid changes. One of the amino acid differences is a known polymorphism in C4, a Tyr/Ser substitution at position 328 in the Beta-Chain. The second amino acid difference caused by a C to T transition in the first base of the codon for amino acid residue 458 was the only one shown to be specific to the C4A6 allotype. The C4A6 allotype contains a Trp residue at this position in the Beta-Chain instead of the Arg residue found in all other C4A and C4B allotypes so far characterized. We propose that this Arg to Trp substitution at Beta-Chain residue 458 is responsible for the inability of C4A6 to bind C5 in the C5 convertase.
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a single arginine to tryptophan interchange at Beta Chain residue 458 of human complement component c4 accounts for the defect in classical pathway c5 convertase activity of allotype c4a6 implications for the location of a c5 binding site in c4
Journal of Immunology, 1992Co-Authors: Roger O Ebanks, Michael C. Carroll, R D Campbell, M.j. Anderson, A S Jaikaran, David E IsenmanAbstract:In general, C4A allotypes of human C4 show one-fourth to one-third the hemolytic activity of C4B allotypes. An exception to this rule is C4A6 which is almost totally deficient in hemolytic activity. Previous studies have localized the defect in C4A6 to the C5 convertase stage. Of the two critical events required for C5 cleavage, namely formation of a covalent adduct between C3b and the C4b subunit of the C3 convertase (C4b2a), and binding of C5 to this C4b-C3b complex, it is a defect in the latter step that accounts for the aberrant activity of C4A6. DNA sequencing studies described in a companion paper have suggested that the sole C4A6-specific difference was a Trp for Arg replacement at Beta-Chain residue 458. To directly ascertain whether this single substitution was responsible for the hemolytic defect in C4A6, we have used site-directed mutagenesis to introduce this change into both C4A and C4B cDNA expression plasmids. We found that the R to W replacement totally abrogated hemolytic activity. However, irrespective of the amino acid at residue 458, the mutant proteins behaved like their wild-type counterparts with respect to covalent binding to C1-bearing targets, i.e., the C4B recombinants displayed higher binding to sheep and human red cells than did the C4A counterparts. Furthermore, the mutants were able to form covalent C4b-C3b adducts. There was, however, substantially less C5 cleavage produced by cell-bound C4boxy23b complexes made with R458W mutant C4B than with wild-type C4B. These results are consistent with the sole defect in the mutants being at the C5 binding stage and strongly suggest that Arg 458 of the C4 Beta-Chain contributes to the C5 binding site of the molecule.