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1.
Curr Oncol ; 23(4): 241-9, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27536174

RESUMO

OBJECTIVES: The purpose of the present study was to calculate the proportion of cancers in Canada attributable to tobacco smoking (ts), alcohol use (au), excess weight (ew), and physical inactivity (pia); to explore variation in the proportions of those risk factors (rfs) over time by sex and province; to estimate the economic burden of cancer attributable to the 4 rfs; and to calculate the potential reduction in cancers and economic burden if all provinces achieved rf prevalence rates equivalent to the best in Canada. METHODS: We used a previously developed approach based on population-attributable fractions (pafs) to estimate the cancer-related economic burden associated with the four rfs. Sex-specific relative risk and age- and sex-specific prevalence data were used in the modelling. The economic burden was adjusted for potential double counting of cases and costs. RESULTS: In Canada, 27.7% of incident cancer cases [95% confidence interval (ci): 22.6% to 32.9%] in 2013 [47,000 of 170,000 (95% ci: 38,400-55,900)] were attributable to the four rfs: ts, 15.2% (95% ci: 13.7% to 16.9%); ew, 5.1% (95% ci: 3.8% to 6.4%); au, 3.9% (95% ci: 2.4% to 5.3%); and pia, 3.5% (95% ci: 2.7% to 4.3%). The annual economic burden attributable to the 47,000 total cancers was $9.6 billion (95% ci: $7.8 billion to $11.3 billion): consisting of $1.7 billion in direct and $8.0 billion in indirect costs. Applying the lowest rf rates to each province would result in an annual reduction of 6204 cancers (13.2% of the potentially avoidable cancers) and a reduction in economic burden of $1.2 billion. CONCLUSIONS: Despite substantial reductions in the prevalence and intensity of ts, ts remains the dominant risk factor from the perspective of cancer prevention in Canada, although ew and au are becoming increasingly important rfs.

2.
Clin Exp Immunol ; 117(1): 12-8, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10403910

RESUMO

Previous studies using isolated complement proteins have shown that more C4A than C4B binds to certain types of immune complexes. However, the in vivo binding of the C4 isoforms to an immune complex has not been investigated in detail and may differ from events when measured with the isolated proteins. We report here the binding of C4A and C4B to an immune complex of bovine serum albumin (BSA) anti-BSA as it occurs in serum. We found that when using the isolated C4 proteins more C4A than C4B bound to the complex, but in serum similar amounts of C4A and C4B were found to bind. Furthermore, these results were not explainable by a difference in activity between isoforms. In an attempt to explain these results a number of unexpected observations were noted. First C4A, but not C4B, bound specifically to a yet unidentified 38-kD serum protein. Second, when both covalent and non-covalent binding was assessed, we found that as serum concentration increased there followed a concomitant decrease in covalent binding and C4B was more affected than C4A. The potential biological significance of these findings is discussed.


Assuntos
Complexo Antígeno-Anticorpo/sangue , Complemento C4a/metabolismo , Complemento C4b/metabolismo , Animais , Ligação Competitiva , Bovinos , Humanos , Microesferas , Soroalbumina Bovina/imunologia
3.
Clin Exp Immunol ; 110(2): 310-6, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9367418

RESUMO

Complement-dependent clearance of immune complexes in humans is dependent on the activation and binding of the early components of the classical complement cascade. This prevents immune complex precipitation and promotes binding of the complexes by the C4b/C3b complement receptor CR1 (CD35) found on erythrocytes. The fourth component of human complement is encoded by two closely linked genes within the MHC. These genes give rise to the isotypic forms C4A and C4B, and recent studies suggest that CR1 binds activated C4A (C4Ab) to a greater extent than activated C4B (C4Bb). To study this difference in a more quantitative way the binding reactions between CR1 and C4Ab- and C4Bb-coated immune complexes and between CR1 and soluble dimers of C4Ab (C4Ab2) and C4Bb (C4Bb2) were analysed using the native receptor on human erythrocytes. The binding reaction between immune complexes with equivalent amounts of covalently bound C4Ab or C4Bb and erythrocyte CR1 showed a two-fold higher binding of complexes coated with C4A. Furthermore, erythrocyte CR1 bound C4Ab2 with an apparent four-fold higher affinity (Kd approximately 1.4 x 10(-7) M) than C4Bb2 (Kd approximately 4.8 x 10(-7) M), indicating a preferential binding of CR1 for C4A.


Assuntos
Complemento C4a/metabolismo , Complemento C4b/metabolismo , Eritrócitos/imunologia , Receptores de Complemento 3b/metabolismo , Complexo Antígeno-Anticorpo/imunologia , Complemento C4a/imunologia , Complemento C4b/imunologia , Eritrócitos/metabolismo , Humanos , Ligação Proteica , Ensaio Radioligante , Receptores de Complemento 3b/imunologia
4.
Mol Immunol ; 31(10): 761-9, 1994 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7518568

RESUMO

Human C4A and C4B have different functions that may stem from their ability to bind hydroxyl or free amino groups on complement activating surfaces. Previous studies suggest that C4B binds to hydroxyl or amino groups whereas C4A binds to free amino groups on acceptor molecules. Comparison of the derived amino acid sequences of C4A and C4B has shown that differences exist between them at positions 1101, 1102, 1105 and 1106. These residues appear to be involved in the binding specificity of C4B. Less is known about the corresponding residues of C4A. It has been suggested that the aspartic acid of C4A at position 1106 is involved in amide bond formation by serving as a catalytic residue for the reaction or by promoting an increased interaction with amino nucleophilic groups. To examine the functional role of residues 1101-1106, we studied the effects of the C4A site-specific antipeptide mAb, AII-1 in assays dependent on the covalent binding properties of C4A; the C4 mediated inhibition of hemolysis and the C4 mediated inhibition of immune precipitation. This study shows that mAb AII-1 has no effect on C4-mediated hemolysis or its ability to inhibit the rate of immune precipitate formation. The lack of interference by AII-1 in these assays could not be explained by low affinity interaction between antibody and C4A showing that mAb AII-1 does not affect the covalent binding activity of C4A. Furthermore, results from epitope mapping studies show that AII-1 binds to Leu1105 and Asp1106 suggesting that these residues are not critical for amide bond formation by C4A.


Assuntos
Complemento C4a/química , Hemólise/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais , Complexo Antígeno-Anticorpo/metabolismo , Sítios de Ligação de Anticorpos , Eletroforese em Gel de Poliacrilamida , Epitopos , Citometria de Fluxo , Cobaias , Humanos , Dados de Sequência Molecular , Testes de Precipitina , Ligação Proteica
5.
J Biol Chem ; 269(10): 7696-701, 1994 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-8125996

RESUMO

The complement receptor CR1 (CD35) is a transmembrane protein composed in its extracellular portion of short consensus repeats (SCR 1-30) organized into four long homologous repeats (LHR-A, LHR-B, LHR-C, and LHR-D). Each LHR, except LHR-D, contains a binding site for C3b and/or C4b within its first four SCR. The binding reaction between CR1 and soluble dimers of C4b (C4b2) was analyzed using the native receptor on human erythrocytes and full-length recombinant CR1 expressed in stably transfected Chinese hamster ovary (CHO) cells. CR1 mutants expressed similarly were used to determine the SCR of LHR-A required for C4b2 binding and the potential of C3b binding sites in CR1 to bind C4b2. Erythrocyte CR1, CHO cells expressing full-length recombinant CR1 (ABCD), constructs ACD, and SCR(1-4)D each bound C4b2 with similar affinities (Kd, approximately 4 x 10(-7) M). Construct SCR(1-2)D bound C4b2 with lower affinity (Kd, 1.4 x 10(-6) M) indicating that SCR(1-4) are required for a fully functional C4b2 binding site. Construct SCR(15-18)D, which contains a C3b site, also bound C4b2 with lower affinity (Kd 1.2 x 10(-6) M) than its binding to C3b dimers. Constructs SCR(15-16)D and D did not bind C4b2. Each CR1 construct that bound C4b2 functioned as a cofactor for factor I-mediated cleavage to C4d.


Assuntos
Proteínas de Transporte/metabolismo , Complemento C4b/metabolismo , Proteínas Inativadoras do Complemento , Glicoproteínas , Receptores de Complemento 3b/metabolismo , Animais , Ligação Competitiva , Células CHO , Cricetinae , Eritrócitos/metabolismo , Humanos , Cinética , Proteínas Recombinantes/metabolismo
6.
Cytometry ; 14(3): 271-5, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-7682493

RESUMO

Flow cytometry (FCM) is useful for measuring DNA content as related to cell cycle position. We have extended this technology by developing a method that measures cellular DNA content using propidium iodide after permeabilization with lysolecithin. This technique maintains cell integrity such that high quality mRNA can be isolated from a sorted population. Unfixed MDA-468 cells, a human breast cancer cell line, were temporarily permeabilized with lysolecithin. A range of lysolecithin concentrations were studied in order to optimize DNA staining but minimize alterations in cell size and integrity. Cells permeabilized with lysolecithin in PBS, were stained with propidium iodide (50 micrograms/ml) in the presence of 1% bovine serum albumin, 1 mM Na2EDTA in PBS. The optimal concentration (4 micrograms lysolecithin/ml) combined staining approximately 90% of the cells for DNA, with minimal effects on cell size. Subsequently, the cells were assayed for DNA content as a measure of cell cycle position. MDA-468 cells identified as being in G1 were sorted and collected. From these, high quality mRNA could be isolated, as judged by its ability to be in vitro translated into protein of a wide range of molecular weights. This technique should be useful for molecular studies requiring discrete cell populations based on DNA content and/or cell cycle position.


Assuntos
Separação Celular/métodos , DNA/análise , Citometria de Fluxo/métodos , RNA Mensageiro/isolamento & purificação , Neoplasias da Mama/patologia , Ciclo Celular , Humanos , Lisofosfatidilcolinas , Propídio , RNA Mensageiro/análise , Coloração e Rotulagem , Células Tumorais Cultivadas
7.
J Immunol ; 147(9): 3018-23, 1991 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-1919003

RESUMO

The C4A and C4B isotypes of human C4 show certain functional differences that stem from their relative preference for transacylation to amino (-NH2) vs hydroxyl (-OH) nucleophiles, respectively, on complement-activating surfaces. Comparison of amino acid sequences of the alpha-chain fragment of C4, C4d, has shown C4A- and C4B-specific sequences at residues 1101-1106 are the only consistent structural difference between isotype, i.e., Pro, Cys, Pro, Val, Leu, Asp in C4A and Leu, Ser, Pro, Val Ile, His in C4B. These residues may be responsible either in part or entirely for properties associated with isotype. To examine the functional role of residues 1101-1106 in C4B-mediated hemolysis, whole serum or immunopurified human C4 with allotypes, A3B1, A3, B2B1, or B1 were preincubated in the presence or absence of an antipeptide mAb (BII-1) specific for amino acid residues 1101-1105 of C4B. Sensitized sheep E and C4-deficient guinea pig serum was then added and lysis measured by absorbance at 415 nm. Our results show lysis of antibody-sensitized sheep E is inhibited by antibody and C4B2B1, C4B1, or C4A3B1 but not antibody and C4A3. The interference of hemolysis by BII-1 could not be explained by inhibition of activation of C4B or inhibition of C3 or C5 convertase activity. Furthermore, results from uptake experiments show that BII-1 interferes with the covalent binding activity of C4B, indicating residues 1101-1105 play a role in the covalent binding reaction of C4B to the target E-antibody complex.


Assuntos
Ativação do Complemento , Complemento C4b/imunologia , Sequência de Aminoácidos , Anticorpos/metabolismo , Anticorpos Monoclonais/imunologia , Complemento C1s/metabolismo , Convertases de Complemento C3-C5/metabolismo , Complemento C4b/química , Hemólise , Humanos , Técnicas In Vitro , Isoenzimas/metabolismo , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/imunologia
8.
J Immunol Methods ; 142(1): 121-6, 1991 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-1919016

RESUMO

An indirect cellular enzyme immunoassay for the detection of the serologically defined male-specific antigen, SDMA, was developed using mouse spermatozoa as the target. Serum from B6 female mice injected with male spleen cells was used as the source of SDMA-specific antibody. Our results indicate that the assay is highly reliable (96% accurate) with an intra- and interassay coefficient of variation less than 12%. Since this assay is non-subjective and simple to perform it provides a useful alternative to the complement-dependent cytotoxicity assay for detection of SDMA.


Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Antígeno H-Y/análise , Espermatozoides/imunologia , Animais , Estudos de Avaliação como Assunto , Feminino , Técnicas In Vitro , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Baço/imunologia
9.
Complement Inflamm ; 8(1): 33-42, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-2049934

RESUMO

Comparison of amino acid sequences of the alpha-chain fragment of human C4, C4d, has shown C4A- and C4B-specific sequences at residues 1101-1106 in which the aspartic acid-histidine substitution at position 1106 may be related to the amide and ester bond forming properties of these molecules. Peptides containing twelve amino acid residues of the C4A- or C4B-specific sequences were synthesized and injected into female Balb/c mice. Serum from 2 mice, one immunized with the C4A-specific peptide and the other with the C4B-specific peptide, gave strong isotype-specific responses in an enzyme-linked immunosorbent assay against affinity-purified C4A3 and C4B2B1. Spleen cells from these mice were fused with the mouse myeloma SP2/0-Ag 14, and two cloned cell lines, AII-1 and BII-1, were established from hybrids. Enzyme-linked immunosorbent assay and western blotting of monoclonal antibodies AII-1 and BII-1 show that the former reacts with the C4A but not with the C4B alpha-chain and the latter with C4B but not with the C4A alpha-chain. Furthermore, immunoblotting of C4 allelic variants showed that AII-1 reacted with all C4A allotypes tested, including A6, A4, A3 and A2, whereas BII-1 reacted with all C4B allotypes tested, including B5, B3, B2, and B1.


Assuntos
Anticorpos Monoclonais , Complemento C4a/análise , Complemento C4b/análise , Fragmentos de Peptídeos/análise , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos/imunologia , Western Blotting , Complemento C4a/imunologia , Complemento C4b/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Immunoblotting , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/imunologia
10.
Cell Immunol ; 120(1): 42-60, 1989 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-2522830

RESUMO

Expression of certain autologous lymphocyte-activating antigenic determinants on the developing embryo is known to provide a stimulus for maternal anti-fetal autoproliferative responses. If left unregulated these responses could exert negative influences on the reproductive process by converting to autoaggressive forms of immune reactivity. In normal circumstances, immunological reactions of this nature are therefore likely to be under the control of pregnancy-associated immunoregulatory elements found within the maternal/fetal environment. In the present investigation we describe a naturally occurring splenic inhibitory cell type devoid of conventional T, B, and macrophage surface markers associated with syngeneic murine pregnancy that is capable of exerting potent immunosuppressive effects on an in vitro expression of fetal/newborn T cell autoreactivity, namely the autologous mixed lymphocyte reaction (AMLR). Maternal spleen cells inhibitory for AMLR were found to be highly resistant to cytotoxic pretreatment with a panel of conventional antisera directed against T cell-specific antigenic determinants. The non-T nature of the natural splenic suppressor cell was further indicated by experiments showing that purified spleen T cells had no inhibitory activity. Pregnancy spleen cell populations that were effectively depleted of macrophages retained full ability to inhibit AMLR. Maternal suppressor activity could be localized to the spleen cell population bearing receptors for the B cell-specific lectin, soybean agglutinin (SBA). A panel of monoclonal antibodies prepared against enriched populations of suppressor cells was screened and selected for specific reactivity using an ELISA against glutaraldehyde-fixed SBA+ spleen cell subpopulations from pregnant versus virgin animals. Several of the monoclonals developed against suppressor-enriched spleen cell populations from isopregnant as well as allopregnant animals were effective in reducing or eliminating suppressor cell activity following cytotoxic pretreatment in the presence of complement. The novel set of anti-suppressor monoclonal antibodies described here should prove useful in furthering the isolation and characterization of pregnancy-associated suppressor cells and in determining their relationship to natural suppressor cell populations described in other systems.


Assuntos
Anticorpos Monoclonais/imunologia , Ativação Linfocitária , Prenhez/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Feminino , Teste de Cultura Mista de Linfócitos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Gravidez , Receptores de Complemento/fisiologia , Receptores Fc/fisiologia , Receptores Mitogênicos/metabolismo , Baço/imunologia
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