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The article focuses on the work of scientist J. B. S. Haldane with geneticist R. A. Fisher and geneticist Sewall Wright regarding the population genetics and the study of evolution on a mathematical basis. Topics discussed include natural selection with genetics, several assumption of Mendelian inheritance and reconciliation of Darwin's evolution.

The colorectal cell line HCA-7 expresses surface human leucocyte antigen-A*0201 (HLA-A*0201), but lacks expression of HLA-A*0101 whilst the normal B-cell line (EVA-1224), derived from the same individual, expresses both surface HLA-A1 and HLA-A2. Amplification refractory mutation system-polymerase chain reaction analysis, using sequence-specific primers, suggested that HCA-7 has a mutation in a 7 base pair (bp) cytosine repeat sequence located at the beginning of Exon 4 (bp 621–627). Cloning and sequencing revealed HCA-7 to have eight cytosine residues in this repeat sequence. In contrast, EVA-1224 contained only 7 cytosines. Analysis of the mRNA for HLA-A*010 using reverse trancriptase-polymerase chain reaction (RT-PCR), with an allele-specific 5′ primer in exon 2 (bp 253–271) and a series of 3′ primers in exons 3, 4 and 7 and in the 3′untranslated region, revealed that HCA-7 contained a shortened message terminating in the region of the exon 3/4 boundary. The insertion of an extra cytosine in this region, which is only two bases from the exon 3/4 splice site, is presumed to lead to a splicing defect between exons 3 and 4 resulting in the lack of expression of a functional HLA-A*0101 product. HCA-7 is mismatch repair (MMR) defective due to lack of expression of hMLH1 resulting from hypermethylation of the promoter region. The consequential increase in errors in single-nucleotide repeat stretches of DNA can account for the HLA-A*0101 mutation. This has probably then been selected for in the tumour to enable escape from immune attack against an HLA-A*0101-restricted tumour-specific determinant that has also arisen as a result of the tumour being MMR defective. [ABSTRACT FROM AUTHOR]

Focuses on several studies about prostate cancer presented during the Prostate Cancer Charitable Trust 2004 Forum. Presentation of a somatic evolutionary perspective on cancer process; Developments on mouse model based on the knowledge of somatic genetic and epigenetic changes occurring in human cancers; Details on the study about the role of integrins in controlling attachment of epithelial cells to extracellular matrix.

Provides information related to prostate cancer. Sources of materials and prostate cancer models; Genetic changes in prostate cancer; Cancer prevention.

Profiles Rose Payne, a pioneer in the field of human histocompatibility and immunogenetics research. Family background; Educational attainment; Career history; Awards and achievements; Contribution to human histocompatibility system; Death.

The article throws light on the familial adenomatous polyposis (FAP) and its gene, adenomatous polyposis coli (APC). FAP is described as an inherited colorectal cancer with the development of several adenomatous polyps in the colons and rectum, starting in the early teens. The overall data clearly indicate that interference with cellular attachment, and the consequent derangement of cellular architecture and an associated encouragement of independent growth, are key early steps in the development of colorectal adenomas and carcinomas.

Presents an introductory statement to the December 1989 issue of the journal, "Immunology."

Examines the status of the Human Genome Project research in Europe and calls for a coordinated genome program. Contributions of European countries to genome project; Funding for program from European Community (EC) and individual countries; United Kingdom's national genome program; Support for genome program in other countries; EC support; the Human Genome Organisation's (HUGO's) role in genome research.

The article presents a report documenting the additions and revisions to the nomenclature of HLA specificities. It states that a number of HLA gene fragments have been reported and named which includes HLA-T previously known as HLA-16 and HLA-V previously known as HLA-75. It further discusses the conditions for acceptance of new genes and allele sequences for official names. It also presents lists of the serological specificities or antigens associated with the alleles.

The article reports that World Health Organization Nomenclature Committee for factor of the human leukocyte antigen (HLA) system has decided to publish an interim report listing updated tables of alleles including those assigned since the publication of the last full report in 2002 (1). There are required conditions for acceptance of new sequences for official names. Where a sequence is obtained from cDNA, or where polymerase chain reaction products are subcloned prior to sequencing, several clones should have been sequenced.

Presents an interim report of the World Health Organization Nomenclature Committee for Factors of the HLA System which lists updated tables of alleles. Naming of additional alleles; Serological specificities associated with alleles; Extension of HLA allele names; IMGT/HLA Sequence Database.

Two monoclonal antibodies, TAL-l85 and TAL-3C3. specific for human Ia α-chain subunits have been produced by fusing P3/NSJ/l-Ag4-l mouse myeloma cells with spleen cells from a BA LB/c mouse immunized with purified α-chains. Specificity for the α-chain subunits was initially established using a solid-phase radioimmunoassay. Indirect binding assays demonstrated that TAL-1B5 bound strongly to all human B lymphoblastoid lines tested and to CLLs, but only weakly to PBL-B cells and not to PBL-T cells or the T-cell lines Molt 4 and HSB-2. TAL-3C3 bound only weakly to B lymphoblastoid lines and not to CLLs or PBL-B cells. From 125 I cell surface-labelled lysates TAL-1B5 immunoprecipitated a 33,000(α):28,000(β) Ia dimer, but TAL-3C3 failed to immunoprecipitate cell surface molecules. Under denaturing conditions, however. both TAL-lB5 and TAL-3C3 immunoprecipitated the 33,000 2-chain subunit. Competitive inhibition studies demonstrated that both monoclonal antibodies recognize the same or spatially related a-chain antigenic determinants with some slight cross-reactivity against β-chains. 2D-NEPHGE/SDS-PAGE analysis of TAL-l85 immunoprecipitates from [35S)-methionine biosynthetically labelled cells revealed the presence of a number of α-chain spots in association with β-chain products of three previously described loci (β-I, β-2, β-3) suggesting that this antibody recognizes an antigenic site common to those human Ia s-chains so far identified. [ABSTRACT FROM AUTHOR]

The WHO Nomenclature Committee for Factors of the HLA System met during the 15th International Histocompatibility and Immunogenetics Workshop in Buzios, Brazil in September 2008. This update is an extract of the main report that documents the additions and revisions to the nomenclature of human leukocyte antigen (HLA) specificities following the principles established in previous reports. [ABSTRACT FROM AUTHOR]

Background:Myofibroblasts have an important role in regulating the normal colorectal stem cell niche. While the activation of myofibroblasts in primary colorectal cancers has been previously described, myofibroblast activation in lymph node metastases has not been described before.Methods:Paraffin-embedded lymph node sections from patients with macrometastases, micrometastases and isolated tumour cells were stained to identify myofibroblasts and to characterise the distribution of different cell types in tumour-containing lymph nodes. The extent of myofibroblast presence was quantified and compared with the size of the metastasis and degree of proliferation and differentiation of the cancer cells.Results:We show substantial activation of myofibroblasts in the presence of colorectal metastases in lymph nodes, which is intimately associated with glandular structures, both in micro- and macrometastases. The degree of activation is positively associated with the size of the metastases and the proportion of Ki67+ve cancer cells, and negatively associated with the degree of enterocyte differentiation as measured by CK20 expression.Conclusion:The substantial activation of myofibroblasts in tumour-containing lymph nodes strongly suggests that these metastatic cancer cells are still significantly dependent on their microenvironment. Further understanding of these epithelial-mesenchymal interactions could lead to the development of new therapies in metastatic disease. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is (CRC) one of the commonest cancers and its therapy is still based on few drugs. Currently, no biological criteria are used to choose the most effective of the established drugs for treatment.Methods: A panel of 77 CRC cell lines was tested for sensitivity to 5-fluorouracil (5FU) using the SRB assay. The responses were grouped into three categories and correlated with genetic changes in the cell lines.Results: The strongest and most clearcut correlation was between 5-fluorouracil response and replication error status (mismatch repair deficiency). All the other significant correlations (loss of heterozygosity for DCC and mutations in TGFbIIR) are secondary to the association with replication error status.Interpretation and Conclusion: Our findings validate previous analyses based mainly on clinical data, and indicate that replication error status could be a useful guide to 5-fluorouracil-based CRC therapy. Essentially, all previously described correlations with 5FU response are secondary to the association with replication error status. [ABSTRACT FROM AUTHOR]

Background: The effect of glycoengineering a membrane specific anti-carcinoembryonic antigen (CEA) (this paper uses the original term CEA for the formally designated CEACAM5) antibody (PR1A3) on its ability to enhance killing of colorectal cancer (CRC) cell lines by human immune effector cells was assessed. In vivo efficacy of the antibody was also tested.Methods: The antibody was modified using EBNA cells cotransfected with beta-1,4-N-acetylglucosaminyltransferase III and the humanised hPR1A3 antibody genes.Results: The resulting alteration of the Fc segment glycosylation pattern enhances the antibody's binding affinity to the FcgammaRIIIa receptor on human immune effector cells but does not alter the antibody's binding capacity. Antibody-dependent cellular cytotoxicity (ADCC) is inhibited in the presence of anti-FcgammaRIII blocking antibodies. This glycovariant of hPR1A3 enhances ADCC 10-fold relative to the parent unmodified antibody using either unfractionated peripheral blood mononuclear or natural killer (NK) cells and CEA-positive CRC cells as targets. NK cells are far more potent in eliciting ADCC than either freshly isolated monocytes or granulocytes. Flow cytometry and automated fluorescent microscopy have been used to show that both versions of hPR1A3 can induce antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages. However, the glycovariant antibody did not mediate enhanced ADCP. This may be explained by the relatively low expression of FcgammaRIIIa on cultured macrophages. In vivo studies show the efficacy of glycoengineered humanised IgG1 PR1A3 in significantly improving survival in a CRC metastatic murine model.Conclusion: The greatly enhanced in vitro ADCC activity of the glycoengineered version of hPR1A3 is likely to be clinically beneficial. [ABSTRACT FROM AUTHOR]

We have developed an automated, highly sensitive and specific method for identifying and enumerating circulating tumour cells (CTCs) in the blood. Blood samples from 10 prostate, 25 colorectal and 4 ovarian cancer patients were analysed. Eleven healthy donors and seven men with elevated serum prostate-specific antigen (PSA) levels but no evidence of malignancy served as controls. Spiking experiments with cancer cell lines were performed to estimate recovery yield. Isolation was performed either by density gradient centrifugation or by filtration, and the CTCs were labelled with monoclonal antibodies against cytokeratins 7/8 and either AUA1 (against EpCam) or anti-PSA. The slides were analysed with the Ikoniscope robotic fluorescence microscope imaging system. Spiking experiments showed that less than one epithelial cell per millilitre of blood could be detected, and that fluorescence in situ hybridisation (FISH) could identify chromosomal abnormalities in these cells. No positive cells were detected in the 11 healthy control samples. Circulating tumour cells were detected in 23 out of 25 colorectal, 10 out of 10 prostate and 4 out of 4 ovarian cancer patients. Five samples (three colorectal and two ovarian) were analysed by FISH for chromosomes 7 and 8 combined and all had significantly more than four dots per cell. We have demonstrated an Ikoniscope based relatively simple and rapid procedure for the clear-cut identification of CTCs. The method has considerable promise for screening, early detection of recurrence and evaluation of treatment response for a wide variety of carcinomas. [ABSTRACT FROM AUTHOR]

CD45 is a haemopoietic tyrosine phosphatase, crucial for lymphocyte signalling. Two polymorphisms (C77G and A138G), which alter CD45 isoform expression, are associated with autoimmune and infectious diseases. Using HapMap data, we show that there is substantial linkage disequilibrium across the CD45 gene (PTPRC), with similar patterns in different populations. Employing a set of single nucleotide polymorphisms, correlated with a substantial proportion of variation across this gene, we tested for association with type 1 diabetes, Graves’ disease in a Japanese population, hepatitis C in UK population and tuberculin response in a Chinese population. A limited number of common haplotypes was found. Most 138G alleles are present on only one haplotype, which is associated with Graves’ disease, supporting previous data that A138G is a functionally important CD45 polymorphism. [ABSTRACT FROM AUTHOR]

The distribution of carcinoembryonic antigen (CEA) in colorectal cancer (CRC) differs from that in normal colorectal tissue, being found on all borders of the cell membrane and hence enabling access to intravenous antibody, making CEA a good target for antibody-based therapy. The distinctive anti-CEA antibody, PR1A3, binds only membrane-bound CEA. Humanised PR1A3 (hPR1A3) was assessed both in vitro cytotoxicity and binding assays with colorectal cancer cell lines expressing varying levels of CEA. Human peripheral blood mononuclear cells (PBMCs) and purified natural killer (NK) cells were used as effectors. The in vitro assays demonstrated hPR1A3 CEA-specific binding and antibody-dependent and CEA-specific killing of human colorectal cancer cell lines by human PBMCs. The effect increased with increasing concentration of antibody and surface CEA, and was lost by using the parent murine IgG1 PR1A3. Killing was also blocked by antibody to the Fc-gammaIIIA receptor. Purified human NK cells were effective at much lower effector:target ratios than unfractionated PBMCs, indicating that NK cells were the main mediators of hPR1A3-based CEA-specific killing. The results support the development of hPR1A3 for therapy of colorectal cancer. [ABSTRACT FROM AUTHOR]

Aims: To characterise a specific and sensitive marker of Barrett's metaplasia (BM). Methods: Cases of normal oesophageal squamous mucosa (11 fresh endoscopic biopsies and 10 formalin fixed, paraffin embedded tissue blocks), BM (11 biopsies and 11 tissue blocks), and normal gastric body mucosa (five biopsies and five tissue blocks) were analysed using reverse transcriptase PCR, Western blotting, and immunohistochemistry for EpCAM, and reverse transcriptase PCR for gpA33. Results: Strong EpCAM mRNA expression was detected in all the BM cases, in contrast to weak expression in all the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Strong gpA33 mRNA expression was detected in all the BM cases, in contrast to weak expression in a quarter of the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Western blotting showed EpCAM protein expression in all the BM cases and in none of the normal gastric or oesophageal mucosal samples tested. Immunohistochemistry showed strong EpCAM protein expression in BM and complete absence of expression in normal oesophageal squamous epithelium. Scattered EpCAM expressing cells were found in the gland bases of normal gastric body mucosa. Conclusions: EpCAM protein and gpA33 mRNA expressions are specific and sensitive markers of BM. [ABSTRACT FROM AUTHOR]

Presents information on a study which determined the toxicity, clinical and immune responses to the murine monoclonal anti-carcinoembryonic antigen antibody in patients with advanced colorectal cancer. Characteristics of patients included in the study; Cytokine production during peripheral blood mononuclear cell stimulation in vitro; Results and discussion.

The molecular pathogenesis of Barren's metaplasia (BM) of the esophagus is poorly understood. The change to an intestinal phenotype occurs on a background of esophagitis due to repulsing acid and bile. CDX1, an important regulator of normal intestinal development, was studied as a potential key molecule in the pathogenesis of BM. CDXI mRNA and protein were universally expressed in all samples of BM tested but not in normal esophageal squamous or gastric body epithelial. This tissue-specific expression was attributable to the methylation status of the CDX1 promoter. Conjugated bile salts and the inflammatory cytokines TNF-a and IL-1fi were all found to increase CDX1 mRNA expression in vitro. These effects were primarily mediated by NF-acB signaling but only occurred when the CDXI promoter was unmethylated or partially methylated. The data suggest that CDXI is a key molecule linking etiological agents of BM to the development of an intestinal phenotype. Although the initial trigger for CDX1 promoter de- methylation is not yet identified, it seems likely that demethylation of its promoter may be the key to the induction and maintenance of CDX1 expression and so of the BM phenotype. [ABSTRACT FROM AUTHOR]

The expression of homeobox protein CDX1 is lost or reduced in a significant proportion of colorectal carcinomas (CRCs) but the underlying mechanism for this is unclear. Researchers have demonstrated absence of CDX1 messenger RNA (mRNA) expression in 7 of 37 CRC cell lines and shown that all 7 cell lines have a methylated CDX1 promoter. Twenty-five cell lines showed both CDX1 mRNA expression and an unmethylated CDX1 promoter. The five remaining cell lines had a partially methylated CDX1 promoter and all expressed CDX1 mRNA, when treated with the demethylating agent, deoxycytidine, these five cell lines all showed increased CDX1 expression. No mutations were found in the promoter and coding regions of CDX1.

Examines clinically diagnosed patients with colorectal polyposis. Identification of germ-line adenomatous polyposis coli (APC) mutation; Use of standard mutation techniques; Mapping of the detected APC deletions using a set of polymorphic markers.

Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JPS) are both characterized by the presence of hamartomatous polyps and increased risk of malignancy in the gastrointestinal tract. Mutations of the LKB1 and SMAD4 genes have been shown recently to cause a number of PJS and JPS cases respectively, but there remains considerable uncharacterized genetic heterogeneity in these syndromes, particularly JPS. The mouse homologue of CDX2 has been shown to give rise to a phenotype which includes hamartomatous-like polyps in the colon and is therefore a good candidate for JPS and PJS cases which are not accounted for by the SMAD4 andLKB1 genes. By analogy with SMAD4, CDX2 is also a candidate for somatic mutation in sporadic colorectal cancer. We have screened 37 JPS families/cases without known SMAD4 mutations, 10 Peutz-Jeghers cases without known LKB1 mutations and 49 sporadic colorectal cancers for mutations in CDX2. Although polymorphic variants and rare variants of unlikely significance were detected, no pathogenic CDX2 mutations were found in any case of JPS or PJS, or in any of the sporadic cancers. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to a letter from Blumenthal and colleagues that states contradiction on a statement about antibodies to carcinoembryonic antigen.

Introduction: The adenoma-carcinoma sequence is well established. Understanding the molecular pathology of the adenoma is therefore important. There is great controversy within the field. The Vogelstein group champion the "top down" theory: colorectal adenomas arise and grow across the mucosal surface, and down into the crypts, whereas other studies, including our own, propose 'bottom up' spread. Methods: Serial sections of 40 small (< 3 mm) sporadic colorectal adenomas were stained with H&E, and for MIB-1 and β catenin. 11 early adenomas were Feulgen stained and microdissected. In addition, we examined the flat mucosa of 3 patients who had undergone colectomies for familial adenomatous polyposis (FAP) and also specimens from an XO/XY individual with FAP, the latter using in situ hybridisation for the Y chromosome. Results: In the earliest sporadic adenomas there were crypts entirely filled with adenomatous epithelium, which showed proliferative activity and nuclear Iocalisation of catenin. There was a sharp cut off beh,veen crypt epithelial cells showing nuclear β catenin and surface cells with no membrane staining. In slightly larger lesions, adenomatous spread from above was seen. Microdissected adenomas showed multiple fission events, with proliferation equally distributed throughout. In FAP tissue, numerous isolated monocryptal adenomas, which were clonal in origin, were seen. Examination of adenomas in the XO/XY individual showed no instances of XY or XO adenomatous epithelium growing down into crypts of the other genotype. Conclusions: Both sporadic and FAP adenomas start as a unicryptal adenomas, and grow initially by crypt fission—a "bottom up" pattern. Later, in sporadic adenomas, there is evidence of growth down into adjacent crypts—"top-down". [ABSTRACT FROM AUTHOR]