Ovarian cancer, oral contraceptives, and BRCA mutations.
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Contraceptives, Oral↗
Biomedical subjects
B Friedenson
Publications and source records attributed to B Friedenson.
A current perspective on genetic testing for breast and ovarian cancer: the oral contraceptive decision.
A clinician faces a problem in how best to counsel the woman with a family history of breast or ovarian cancer about her options for pregnancy prevention. The physician must guide her as she makes new and complex decisions. Recent data strongly support an amplified effect of the estrogens in oral contraceptives for the woman with a genetic risk for breast cancer. Nonetheless, a woman's immediate need to prevent pregnancy may be much more important to her than worrying about the long-term risk of breast cancer. Another factor is that oral contraceptives prevent ovarian cancer, so the physician may wish to prescribe them to protect her from ovarian cancer. In some genetic backgrounds, however, oral contraceptives not only do not prevent ovarian cancer, but they may raise the risk of breast cancer so significantly that they should not be taken. With other genetic backgrounds, oral contraceptives will protect the woman from ovarian cancer without much effect on her breast cancer risk. When does each of these cancer risks or benefits become significant? The clinician can provide an important benefit to a woman who must prevent pregnancy yet worries about her cancer risk. The physician can help her evaluate the evidence, with its gaps and uncertainties, in the context of her own preferences. To assist in this evaluation, this decision aid provides base-line estimates of the cancer risk that accompanies each of a woman's options. In some cases, genetic testing is likely to provide valuable information as she makes choices about contraception and the risks vs. benefits of different alternatives available to her.
Breast Neoplasms↗
Is mammography indicated for women with defective BRCA genes? Implications of recent scientific advances for the diagnosis, treatment, and prevention of hereditary breast cancer.
About 5% of breast cancer patients have inherited their disease because of a mutation in genes encoding either the BRCA-1 or BRCA-2 proteins. Inheriting one of these mutations confers a 50% to 87% risk of breast cancer. Many physicians faced with such a patient would, at a minimum, suggest increased and earlier screening for breast cancer by routine mammography.[1] Normally, regular mammographic screening combined with appropriate and prompt treatment can reduce mortality from breast cancer by 30% in women aged 50-59 years and by about 14%-18% in women aged 40-49. There are no controlled clinical trials for screening young women who have multiple first-degree relatives developing breast cancer before age 45, or those known to carry BRCA-1 or BRCA-2 mutations. In fact, recent advances point out that BRCA-1 and BRCA-2 gene products are needed to repair radiation damage to DNA.[4,5] Based on this finding, I propose that women with defective BRCA genes are likely to have an inordinate sensitivity to radiation, and this raises a question about the advisability of routinely screening these women by frequent mammography.
Adult↗
A simple general method of exactly comparing different binding activities and antigenic properties of antibodies by obtaining duplicate copies from a single isoelectric focusing gel.
We report a simple general method of exactly comparing different binding activities and/or antigenic properties of antibodies in ascites fluid after fractionation on a single isoelectric focusing gel. Two copies of the gel are made on nitrocellulose: 1 copy is overlaid with the radioiodinated form of one overlay protein and the other copy is overlaid with the radioiodinated form of another. By superimposing X-ray films obtained after radioautography, any 2 binding activities or antigenic properties of antibodies can be compared exactly and in detail. The procedure is simple, highly sensitive, and independent of the molecular weight of the overlay protein. This is accomplished without requiring isolation of the antibodies, denaturing agents, precipitation, chemical fixation or other modification reactions.
Acrylic Resins↗
Changes in intracellular glutathione levels in stimulated and unstimulated lymphocytes in the presence of 2-mercaptoethanol or cysteine.
Certain low m.w. thiol compounds can enhance various in vitro lymphocyte mitogenic responses, whereas reagents that react with sulfhydryl groups are potent cell poisons. The possible targets for thiols and thiol reagents could include membrane and cytoplasmic proteins, some of which may regulate lymphocyte proliferation. As a step toward understanding how lymphocyte proliferation is enhanced in the presence of thiols, we studied the appearance of both protein and non-protein sulfhydryl groups in stimulated lymphocytes. To help clarify the role of the cellular targets for thiols, we studied the time course of appearance of both protein and non-protein sulfhydryl groups as lymphocytes proliferate under various conditions. In the presence of an appropriate concentration of the thiol 2-mercaptoethanol (2-ME), there is a substantial rise in the level of intracellular glutathione for lymphocytes stimulated with the mitogen concanavalin A (Con A). Otherwise, the level of intracellular glutathione declines, even for Con A-stimulated cells, but the presence of 2-ME partially prevents this decline. Increasing the amount of cysteine in the medium to a level that enhances cell proliferation leads to effects similar to those obtained with 2-ME. Thus, apparently one effect of various thiol reducing agents is to enhance the production of glutathione in lymphocyte mitogenesis and to protect against the loss of glutathione that occurs in resting or proliferating lymphocytes.
Animals↗
Loss of an individual idiotype on chemical modification. A strategy for assigning idiotypic determinants.
Two dextran-binding myeloma proteins, J558 and Hdex 24, which possess the same individual idiotype (IdI) were diazotized to low levels (1-3.3 groups per subunit) with 1-[14C]-p-aminobenzoate. Both proteins lost the IdI idiotype under these conditions with most of the label incorporated on the heavy chains of each protein. When the diazotization ws carried out in the presence of the hapten 1-O-methyl-alpha-D-glucopyranoside the loss of idiotypic reactivity could be prevented for J558 but not for Hdex 24. Under these conditions most of the label was incorporated on the light chains of J558, but on the heavy chains of Hdex 24. For J558, these results show that a major determinant of the individual idiotype is within the hypervariable positions of the heavy chain. For Hdex 24 the determinant being modified is on the heavy chain but not involved in hapten binding. These results are consistent with previous work showing that J558 and Hdex 24 differ in amino acid sequence in the D and the J segments of the heavy chain and offer an alternative and complementary strategy for assigning idiotypic determinants.
Amino Acid Sequence↗
Highly active amino-terminal sialoglycopenta-, hexa- and heptapeptides from human erythrocyte NM antigens.
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Animals↗
Free sulfhydryl groups of rabbit secretory IgA.
The reaction of sIgA with 5,5'dithiobis (2-nitrobenzoic acid) or with 14C-iodoacetamide revealed an average of 1 mol -SH per mol sIgA under nondenaturing conditions, whereas an average of 7.5 mol -SH was found under denaturing conditions. These -SH groups were found in both the sIgA-f and sIgA-g subclasses; in the sIgA-g subclass, the free -SH groups were found in the Fab alpha portion but not in the Fc alpha portion of the molecule. To determine whether the noncovalently bound polypeptide chains in sIgA contained free -SH groups, sIgA was alkylated with 14C-iodoacetamide and subjected to gel filtration in 6 M guanidine-HCl. This treatment liberated several different polypeptides that were identified as secretory component (SC), L chain dimers, and L chain monomers; measurement of radioactivity incorporated in each of these noncovalently bound chains showed that SC and the L chain dimers did not contain free -SH groups but that an average of 1 -SH group per L chain monomer was found. Of the covalently bound polypeptide chains, J chain and SC did not have detectable -SH groups, whereas the L chains and alpha-chains had 0.3 and 1.2 mol -SH per mol protein, respectively. The identification of free -SH groups in the Fab portion of the sIgA-g subclass and their preferential localization within only some of the L chains reflect the structural heterogeneity of sIgA; these -SH groups presumably arise during biosynthesis.
Animals↗
Serologic and structural comparisons of rabbit IgA allotypes.
Serologic and structural comparisons of the rabbit IgA-g allotypes revealed that 1) the IgA-g allotypes have multiple allotypic determinant sites, 2) the g74, g76 and g77 allotypic specificities have several allotypic determinants in common whereas g75 molecules do not appear to have allotypic determinants in common with g74, g76 and g77 molecules, 3) the partial amino acid sequence of alpha chain from g75 and g76 Fc2alpha fragments differ by at least one amino acid residue, and 4) the g74 alpha-chains may have the "extra" intradomain disulfide bond in the Calpha2 domain whereas the g75 and g76 alpha chains lack this disulfide bond. Thus, multiple mutational events must have occurred during the evolution of g74, g75 and g77 genes.
Amino Acid Sequence↗
Structural studies of rabbit IgA allotypes: partial amino acid sequences of alpha-chain allotypes controlled by allelic genes at the Calphag locus.
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Alleles↗
Characterization of C-reactive protein and the complement subcomponent C1t as homologous proteins displaying cyclic pentameric symmetry (pentraxins).
Partial amino acid sequences of rabbit C-reactive protein, a peptide derived from human C-reactive protein by cyanogen bromide cleavage, and the C1t subcomponent of the human complement component C1 have been determined. Extensive sequence homology between these proteins establish their evolutionary relationships. In addition, examination of C-reactive proteins by negative-stain electron microscopy revealed that the protein is composed of five subunits arranged in cyclic symmetry. This structure is similar to that reported for both C1t and the amyloid P-component. The extensive structural relationship suggests similar or overlapping functions and the term pentraxin is proposed to describe these homologous proteins.
Amino Acid Sequence↗
Partial amino-acid sequences of human and rabbit C-reactive proteins: homology with immunoglobulins and histocompatibility antigens.
Partial amino-acid sequence analyses of the amino terminus of rabbit C-reactive protein and of a peptide isolated from human C-reactive protein after cyanogen bromide cleavage show an extensive sequence homology between these proteins. Computer analysis detected a distant but significant homology between rabbit C-reactive protein and the CH3 domain of human IgG, In addition, an examination of the limited data available for the amino-acid sequences of human and mouse histocompatibility antigens revealed a similarity between these proteins and C-reactive protein and, therefore, immunoglobulins; These relationships are presented as evidence in support of the hypothesis that C-reactive protein and immunoglobulins share, in addition to functional similarities, a common evolutionary origin with the major histocompatibility antigens.
Amino Acid Sequence↗
A possible difference in the heterogeneity of the heavy and light chains from a rabbit anti-p-azobenzoate antibody preparation.
CNBr cleavage of rabbit heavy (H) chains leads to the formation of a fragment, C-1, which consists of the N-terminal half of the H chain. Fragment C-1 is cleaved at methionyl residues but held together by intrachain S-S bonds so that smaller fragments can be liberated by total reduction and alkylation. In the case of the C-1 fragment from an anti-p-azobenzoate antibody preparation, which has a light (L) chain of markedly restricted heterogeneity, total reduction and alkylation liberated seven major fragments in good yield. The N-terminus of two of these fragments corresponds to position 35 of the H chain but their N-terminal sequences are clearly different. The H chain regions represented by the other fragments implied that they were derived from H chains having different distributions of methionyl residues. This hypothesis was supported by isolating six different antibody components from the antibody preparation by isoelectric focusing and then digesting them with CNBr. Comparison of the products showed that the six components all appeared to behave differently. These results are interpreted as suggesting that the process whereby H and L chains are paired in vivo may not be completely specific and may provide a simple means of generating a significant contribution to antibody diversity.
Alkylation↗
Partial sequence of the variable region of an anti-p-azobenzoate antibody light chain: a one solvent sequenator program.
The partial amino acid sequence of the variable region of a rabbit anti-p-azobenzoate antibody was determined. The sequence determination was facilitated by a modified dimethylallylamine sequencer program in which 1-chlorobutane is used as both the S1 and S3 solvents. To establish the primary structure of virtually the entire light-chain variable region, two different sequencer runs were sufficient: a double cleavage run of 66 cycles on the intact light chain and a single cleavage run of 40 cycles on a peptide isolated from a tryptic digest of the succinylated light chain. Within the limits of the methods used, the light chain appears completely homogeneous. The heavy chains could be more heterogeneous, since the antibody preparation gives at least 18 bands on isoelectric focusing.
Amino Acid Sequence↗
Location of light chain tyrosine peptides from the combining site of a rabbit anti-p-azobenzoate antibody.
Peptic peptides containing a tyrosyl residue from the binding site of a rabbit anti-p-azobenzoate antibody were isolated by means of the paired-iodination procedure. The peptides were from the light chain, and the tyrosyl residue is 29, 30, 31, 32, 32A, 32B, 33 at position 30 in the sequence -Val-Tyr-Asn-Asx-Lys-Gly-Leu- and thus is in the first hypervariable region. The sequence of the N-terminal 40 residues was determined. The major antibody-site peptide isolated was a diiodotyrosyl (DIT) tetrapeptide representing residues 30-32A; the monoiodotyrosyl (MIT) tetrapeptide was also isolated, but in a smaller yield. By isoelectric focusing, the light chain appeared to be homogeneous. No heterogeneity was apparent in the light chain sequencing until position 32B when, in addition to the phenylthiohydantoin derivative of tyrosine present as the major residue, a significant amount of the phenylthiohydantoin derivative of glycine was obtained. The glycine presumably represents a light chain variant population and explains the source of the other antibody-site peptides isolated, i.e. two pentapeptides, apparently of the sequence Tyr-Asn-Asx-Lys-Gly, isolated as the DIT and MIT derivatives. The tetrapeptides must have been derived from the peptic cleavage between Lys 32A and Tyr 32B in the major light chain variant and the pentapeptides from the peptic cleavage between Gly 32B and Leu 33 in the other variant. It is interesting that position 30 is occupied by a tyrosyl residue in five out of twelve other rabbit antibody light chains of known sequence (Margolies, M.N. et al., Proc. Nat. Acad. Sci. US 1975.72: 2180). One light chain is from another rabbit anti-p-azobenzoate antibody in which Tyr 30 is apparently not important in hapten binding although a tyrosyl at position 96 is clearly involved in hapten binding (Roholt, O.A. et al., J. Immunol. 1973.111:1367). The other four of the five light chains are from anti-pneumococcal polysaccharide antibodies in which the role of this tyrosyl residue is not known.
Amino Acid Sequence↗
Constancy of amino-terminal amino-acid sequences of antibodies of defined specificity and shared idiotype from individual inbred mice.
Amino-terminal amino-acid sequences were determined for the heavy (H) chains of anti-p-azophenylarsonate antibodies with shared idiotype, isolated from nine individual A/J mice. Mice chosen for investigation were those producing high titers of antibody with the cross-reactive idiotype. The antibodies were further enriched for the idiotype by isoelectric focusing. The H chains are largely or entirely unblocked at the N-terminus and appear by sequence analysis to be greatly restricted in heterogeneity. All N-terminal sequences were found to be identical. The results suggest that the framework (nonhypervariable) sequence is determined by a germ line gene and is not influenced by somatic processes.
Amino Acid Sequence↗
Existence of VHIII subgroup in rabbit antibody heavy chains.
Sequence analysis of CNBr fragments from the heavy chains of a rabbit anti-p-azobenzoate antibody of restricted heterogeneity has revealed a VHIII-like heavy chain sequence which was present in 6 to 10% of the heavy chain preparation.
Adsorption↗