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Biomedical subjects

W F Bodmer

Publications and source records attributed to W F Bodmer.

At least 109 records · Page 6Linked to original sources
PubMed1995

Failure of programmed cell death and differentiation as causes of tumors: some simple mathematical models.

Most models of tumorigenesis assume that the tumor grows by increased cell division. In these models, it is generally supposed that daughter cells behave as do their parents, and cell numbers have clear potential for exponential growth. We have constructed simple mathematical models of tumorigenesis through failure of programmed cell death (PCD) or differentiation. These models do not assume that descendant cells behave as their parents do. The models predict that exponential growth in cell numbers does sometimes occur, usually when stem cells fail to die or differentiate. At other times, exponential growth does not occur: instead, the number of cells in the population reaches a new, higher equilibrium. This behavior is predicted when fully differentiated cells fail to undergo PCD. When cells of intermediate differentiation fail to die or to differentiate further, the values of growth parameters determine whether growth is exponential or leads to a new equilibrium. The predictions of the model are sensitive to small differences in growth parameters. Failure of PCD and differentiation, leading to a new equilibrium number of cells, may explain many aspects of tumor behavior--for example, early premalignant lesions such as cervical intraepithelial neoplasia, the fact that some tumors very rarely become malignant, the observation of plateaux in the growth of some solid tumors, and, finally, long lag phases of growth until mutations arise that eventually result in exponential growth.

Apoptosis↗
PubMed1995

The HLA system and the analysis of multifactorial genetic disease.

The human leukocyte antigen (HLA) system comprises closely linked genes controlling highly polymorphic proteins involved in the presentation of peptides to the T-cell receptor. Specific alleles at HLA loci are associated with diseases, often those suspected to be of autoimmune aetiology. Many of these associations result from linkage disequilibrium between the HLA gene studied and other HLA genes or non-HLA genes close by. Owing to its high level of polymorphism and its candidate role in many diseases, HLA was the first system used in many techniques of genetic mapping, such as affected-sib-pair analysis and association (linkage disequilibrium) studies. Much remains unknown about the reasons why diseases are associated with HLA. Experience gained from HLA has, however, shown how other loci involved in complex traits can be identified by studying families with multiple affected cases or sib pairs, followed by linkage-disequilibrium mapping and then analysis of candidate genes.

Autoimmune Diseases↗
PubMed1995

The HLA-A,B,C genotype of the class I negative cell line Daudi reveals novel HLA-A and -B alleles.

Daudi, a lymphoblastoid B cell line derived from an African Burkitt lymphoma does not express HLA-A,B,C antigens at the cell surface. Although HLA-A,B,C heavy chains are made normally they do not assemble into functional molecules because beta 2-microglobulin is absent. Previous serological analysis of somatic cell hybrids indicated that the HLA haplotypes of Daudi encoded HLA-A1, A10(A26), B17, and B16(38) antigens. Here we describe the application of molecular methods: ARMS-PCR, cDNA cloning and sequencing, immunoprecipitation and gel electrophoresis, to define the class I genotype of the Daudi cell line which is HLA-A*0102, A*6601, B*5801, B*5802, Cw*0302 and Cw*0602. With the exception of the B38 antigen, which is not a product of the alleles defined, the genotype is consistent with the serological description. Two previously undiscovered alleles emerged from this analysis: A*0102 and B*5802. The A*0102 allele differs from A*0101 by 5 nucleotide substitutions within exon 2 where it has a motif shared with A*30 alleles; the B*5802 allele differs from B*5801 by 3 substitutions in exon 3 where it has a motif shared with B*14 alleles. Subtyping HLA-A1 alleles showed A*0102 was well represented amongst individuals typed serologically as A1 in an African population but was absent from caucasoids. B*5802 has been found in a second individual. Thus the novel A and B alleles are not specific to the Daudi tumor. Overall, this analysis of a single East African cell illustrates the power of molecular methods to define new class I HLA alleles in non-caucasoid populations.

Africa, Eastern↗
PubMed1994

Beta 2-microglobulin gene mutations: a study of established colorectal cell lines and fresh tumors.

The technique of single-strand conformation polymorphism (SSCP) was used to screen a series of 37 established colorectal cell lines, 22 fresh tumor samples, and 22 normal DNA samples for mutations in the beta 2-microglobulin gene. Exon 1 (including the leader peptide sequence) and exon 2 were screened separately. Six of 37 colorectal cell lines and 1 of 22 fresh tumors were shown to contain mutations, whereas no mutations were detected in the normal DNA samples. Sequencing of these mutations showed that an 8-bp CT repeat in the leader peptide sequence was particularly variable, since 3 of the cell lines and one fresh tumor sample have deletions in this region. In the related cell lines, DLD-1 and HCT-15, two similar mutations were identified, a C-->A substitution in codon 10 and a G-->T mutation in the splice sequence of intron 1. Expression of beta 2-microglobulin was examined using a series of monoclonal antibodies in an ELISA system. Reduced expression correlated with a mutation in one allele of beta 2-microglobulin, whereas loss of expression was seen in instances where a line was homozygous for a mutation or heterozygous for two mutations.

Amino Acid Sequence↗
PubMed1994

An epitope on carcinoembryonic antigen defined by the clinically relevant antibody PR1A3.

The monoclonal antibody PR1A3 has been used successfully for in vivo imaging of colorectal cancers, and several properties associated with this antibody, including minimal reactions of the antibody with circulating antigen in patients' sera, differentiate it from anti-carcinoembryonic antigen (CEA) antibodies used in similar studies. However, the antigen bound by PR1A3 was identified as CEA by analysis of somatic cell hybrids and by antigen expression from yeast artificial chromosomes, cosmids, and cDNA clones. The molecular weight, presence of a glycosyl-phosphatidylinositol anchor, elevation of surface expression by gamma-interferon, and N-terminal amino acid sequence all confirmed the antigen identification as CEA. A series of biliary glycoprotein-CEA hybrid proteins was produced which demonstrated that the epitope bound by the antibody was at the site of membrane attachment and involved parts of the glycosyl-phosphatidylinositol anchor and the B3 domain of CEA to form a conformational epitope. Access to this epitope, although possible when the antigen was on the cell surface, appeared to be blocked when CEA was released from the cell. The nature and location of the epitope on CEA are proposed to be responsible for the unique properties of the antibody.

Animals↗
PubMed1994

Intron splice acceptor site sequence variation in the hereditary non-polyposis colorectal cancer gene hMSH2.

Common but weakly penetrant mutations of certain genes may confer an increased susceptibility to colorectal cancer and account for a proportion of 'sporadic' cases. We analysed DNA from 111 colorectal cancer cases and 114 controls for a specific candidate sequence variation in the hereditary non-polyposis colorectal cancer gene hMSH2. The variant sequence was found in a quarter of individuals, and there was no difference between cancer cases and controls, according to age of development of cancer or presence of family history. It thus appears that this particular sequence variation is a polymorphism rather than a mutation which increases cancer susceptibility.

Adolescent↗
PubMed1994

Cancer genetics.

The fundamental ideas on the causes of cancer have been known for some time. They can now be interpreted in terms of the notion that cancer is essentially a genetic disease at the cellular level. The aim of this introductory article is to provide a brief overview of these ideas and the evidence for them, as well as some of the implications for future approaches to the prevention, early detection and treatment of cancer.

Family↗