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D W Bell

Publications and source records attributed to D W Bell.

At least 37 records · Page 2Linked to original sources
PubMed1998

Identification and mapping of human histone acetylation modifier gene homologues.

The products of histone acetyltransferase and deacetyltransferase genes regulate histone acetylation in eukaryotes, thereby regulating access of transcription factors to chromatin and modulating gene expression. Histone acetylation modifiers have been found to participate as cofactors in diverse mammalian transcriptional complexes involved in regulation of cellular proliferation and differentiation. A role for histone acetylase has been implicated in leukemias and developmental disorders. To gain insight into a role of additional potential histone acetylation modifier genes in human disease, we identified six histone acetyl-transferase or deacetyltransferase homologues using the dbEST database, and we mapped, using high-resolution FISH, a total of five family members to 1p34.3, 6q21-q22, 5q31, 3p24, and 17q21. We then identified human genetic disorders for which candidate genes are not yet known and that have been mapped to the same chromosomal regions as the histone acetylation modifiers. This analysis may help identify new candidate genes for human diseases that involve disturbances of histone acetylation.

Acetyltransferases↗
PubMed1998

Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/canalicular multispecific organic anion transporter-related transporter.

Multidrug resistance-associated protein (MRP) and canalicular multispecific organic anion transporter (cMOAT) are closely related mammalian ATP-binding cassette transporters that export organic anions from cells. Transfection studies have established that MRP confers resistance to natural product cytotoxic agents, and recent evidence suggests the possibility that cMOAT may contribute to cytotoxic drug resistance as well. Based upon the potential importance of these transporters in clinical drug resistance and their important physiological roles in the export of the amphiphilic products of phase I and phase II metabolism, we sought to identify other MRP-related transporters. Using a degenerate PCR approach, we isolated a cDNA that encodes a novel ATP-binding cassette transporter, which we designated MOAT-B. The MOAT-B gene was mapped using fluorescence in situ hybridization to chromosome band 13q32. Comparison of the MOAT-B predicted protein with other transporters revealed that it is most closely related to MRP, cMOAT, and the yeast organic anion transporter YCF1. Although MOAT-B is closely related to these transporters, it is distinguished by the absence of a approximately 200 amino acid NH2-terminal hydrophobic extension that is present in MRP and cMOAT and which is predicted to encode several transmembrane spanning segments. In addition, the MOAT-B tissue distribution is distinct from MRP and cMOAT. In contrast to MRP, which is widely expressed in tissues, including liver, and cMOAT, the expression of which is largely restricted to liver, the MOAT-B transcript is widely expressed, with particularly high levels in prostate, but is barely detectable in liver. These data indicate that MOAT-B is a ubiquitously expressed transporter that is closely related to MRP and cMOAT and raise the possibility that it may be an organic anion pump relevant to cellular detoxification.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Amplification of the ATP-binding cassette 2 transporter gene is functionally linked with enhanced efflux of estramustine in ovarian carcinoma cells.

An estramustine-resistant human ovarian carcinoma cell line, SKEM, was generated to explore resistance mechanisms associated with this agent. Cytogenetic analysis revealed that SKEM cells have a homogeneously staining region (hsr) at chromosome 9q34. Microdissection of the hsr, followed by fluorescence in situ hybridization to SKEM and normal metaphase spreads, confirmed that the amplified region was derived from sequences from 9q34. In situ hybridization with a probe specific for ABC2, a gene located at 9q34 that encodes an ATP-binding cassette 2 (ABC2) transporter, indicated that this gene is amplified approximately 6-fold in the estramustine-resistant cells. Southern analysis confirmed that ABC2 was amplified in SKEM, and Northern analysis indicated that the ABC2 transcript was overexpressed approximately 5-fold. The ABC1 gene located at 9q22-31 was not amplified in the resistant cells, and mRNA levels of several other ABC transporter genes were unaltered. Consistent with the concept that increased ABC2 expression contributes to the resistant phenotype, we observed that the rate of efflux of dansylated estramustine was increased in SKEM compared with control cells. In addition, antisense treatment directed toward ABC2 mRNA sensitized the resistant cells to estramustine. Together, these results suggest that amplification and overexpression of ABC2 contributes to estramustine resistance and provides the first indication of a potential cellular function for this product.

ATP-Binding Cassette Transporters↗
PubMed1998

Genomic locations of ANX11 and ANX13 and the evolutionary genetics of human annexins.

We have reconstructed a molecular genetic history of human annexins to chronicle their origins and dispersal throughout the genome. This involved the completion of chromosomal mapping, determination of ancestral relationships, and estimation of gene duplication dates. Fluorescence in situ hybridization localized human annexin XI (ANX11) to 10q22.3-q23.1 and annexin XIII (ANX13) to 8q24.1-q24.2. Orthologous annexins showed minor rate variation when calibrated to species separation times given by the fossil record, but paralogous subfamilies have diverged at fivefold variable rates. The rates and extents of sequence divergence were used to predict a mean separation time of 450 million years between vertebrate annexins, although their common ancestor may have emanated from invertebrate stock. Annexins XIII and VII formed a phylogenetically early clade, and annexins II and VIa were the most divergent members of two distinct clades. ANX6 may have been created by tandem duplication about 500 million years ago (Mya) and duplicated again to form ANX5 400 Mya, whereas ANX4 and ANX8 are proposed to be sequential duplication products from annexin XI. Vertebrate annexins thus proliferated via a cascade of gene duplications in higher metazoa to form at least three diverging groups of ubiquitous and structurally related genes. These can be distinguished by their dispersed genomic locations as well as their individual patterns of expression and partially differentiated functions.

Annexins↗
PubMed1997

Immunisation coverage in Christchurch in a birth cohort. Christchurch Immunisation Coordination Committee.

AIM: To ascertain the immunisation status of a birth cohort of infants at 8 months of age. METHODS: Data on all children born in Christchurch in June, July and August 1995 were matched with immunisation benefit claim information for the 6-week, 3-month and 5-month immunisation events. Those not listed as receiving all three immunisations by the age of 8 months were traced to ascertain their immunisation status. RESULTS: Immunisation status was established for 933 (93.1%) of the cohort of 1002 infants. Of these, 95% had received all three immunisations that were scheduled up to 5 months of age. This represents a coverage of at least 88.2% of the entire cohort. It was probable that many of those not traced would also have been fully immunised. Using a conservative estimate of coverage among this group, we calculated that 93% of the entire cohort had been fully immunised by the age of 8 months. CONCLUSION: There was a high immunisation coverage rate in Christchurch. This is in contrast to a commonly held view that children in New Zealand have a poor immunisation record. There was no evidence of a significant anti-immunisation stance among Christchurch parents. Immunisation data relevant to specific, defined populations can identify individual children and groups of children who may require assistance beyond general practitioner recall to achieve appropriate immunisation. The tracking process also allowed for immunisation reminders to be personally delivered and included some facilitation for achieving further immunisation. We suggest that a pilot programme, using a centralised register based on birth data, feeding into existing immunisation delivery and recall systems, and using tracking methods similar to those used in our study, should be the next step in addressing immunisation coverage surveillance and immunisation coordination in Christchurch.

Birth Certificates↗
PubMed1997

Multiple regions of allelic loss from chromosome arm 6q in malignant mesothelioma.

Our previous cytogenetic studies of malignant mesotheliomas (MMs) revealed losses from 6q15-21 in approximately 40% of cases, suggestive of recurrent loss of function of a putative tumor suppressor gene(s) located in this chromosome region. To more precisely define the critical region of molecular genetic loss within 6q, we have constructed a high-resolution deletion map of this chromosome arm in 46 MMs. We analyzed 32 microsatellite markers to detect loss of heterozygosity in tumor DNAs. Allelic losses from 6q were observed in a high percentage (61%) of cases. Partial deletions of 6q were identified in 11 cases, and these were used to define four nonoverlapping regions of chromosomal loss: a region involving 6q14-21 (approximately 9 cM; 7 of 11 cases with partial deletions), a region within 6q16.3-21 (approximately 8 cM; 9 cases), a region within 6q21-23.2 (approximately 10 cM; 8 cases), and a distal region located at 6q25 (approximately 13 cM; 9 cases). Most cases exhibited losses from more than one of these regions. We conclude from these data that genomic losses involving 6q in MM are more frequent than previously recognized cytogenetically and that the deletions fall into four discrete locations, suggesting the existence of multiple tumor suppressor loci in 6q that may contribute to the pathogenesis of this malignancy.

Alleles↗
PubMed1997

Detection of DNA gains and losses in primary endometrial carcinomas by comparative genomic hybridization.

Comparative genomic hybridization (CGH) was used in a retrospective analysis of chromosomal imbalances in frozen primary tumor specimens from 14 endometrial carcinoma patients. Chromosome changes were detected in nine cases (64%), and tumor stage and grade tended to parallel the degree of genomic imbalances. Gain of the entire long arm of chromosome 1 was observed in six cases (43%), three of which displayed only this chromosome change. Other common sites of copy number increases included 8q21-->qter (4 cases), 10p15 (4 cases), 10q11-->q24 (3 cases), and 13q21-->qter (3 cases, each with stage III disease). Two of the tumors with gains of chromosome 10 involved the whole chromosome, and this was the sole abnormality in one case. DNA amplification at 5p14-->p15 was identified in one specimen, a stage III tumor having numerous imbalances. DNA microsatellite analysis revealed multiple replication errors (RER), indicative of the RER+ phenotype, in four of 13 (31%) cases evaluated. The RER+ phenotype was observed in four of six stage la tumors but in none of seven stage Ib or stage III tumors. Multiple genomic imbalances detected by CGH were not observed in RER+ tumors but were detected in five of nine tumors without the RER+ phenotype. These investigations demonstrate the feasibility of CGH for the retrospective assessment of chromosomal changes in endometrial carcinoma specimens. Moreover, these data suggest that the etiologies in tumors with and without the RER+ phenotype may differ.

Aged↗
PubMed1997

Combined chromosome microdissection and comparative genomic hybridization detect multiple sites of amplification DNA in a human lung carcinoma cell line.

Chromosome microdissection-fluorescence in situ hybridization and comparative genomic hybridization (CGH) were performed in parallel to identify the native location of amplified DNA in a human non-small cell lung cancer (NSCLC) cell line exhibiting a homogeneously staining region (hsr) and double minutes (dmin). The native locations of microdissected DNA from the hsr and dmin were 7p12-13 and 8q24, respectively. Southern analysis revealed coamplification of EGFR (7p12) and MYC (8q24). CGH detected amplification of DNA not only from 7p12-13 and 8q24, but also from 9p24 and 10q22.

Blotting, Southern↗
PubMed1997

Advances in the analysis of chromosome alterations in human lung carcinomas.

A review of chromosomal analyses of human lung carcinomas is presented. Karyotypic studies have revealed multiple cytogenetic changes in most small cell lung carcinomas (SCLCs) and non-small cell lung carcinomas (NSCLCs). In SCLCs, losses from 3p, 5q, 13q, and 17p predominate; double minutes associated with amplification of members of the MYC oncogene family may be common late in disease. In NSCLCs, deletions of 3p, 9p, and 17p, +7, i(5)(p10), and i(8)(q10) often are reported. The recurrent deletions encompass sites of tumor suppressor genes commonly inactivated in lung carcinomas, such as CDKN2 (9p21), RB1 (13q14), and TP53 (17p13). Despite technical advances in cell culture, the rate of successful karyotypic analysis of lung carcinomas has remained low. Alternative molecular cytogenetic methods to assess chromosome changes in lung cancer, particularly comparative genomic hybridization (CGH) analysis, are discussed. Initial CGH studies confirm the existence of many of the karyotypic imbalances identified earlier in lung cancer and have revealed several recurrent abnormalities, such as 10q- in SCLC, that had not been recognized previously. The further application of such molecular cytogenetic approaches should enable investigators to define more precisely the spectrum and clinical implications of chromosome alterations in lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed1996

The human GATA-6 gene: structure, chromosomal location, and regulation of expression by tissue-specific and mitogen-responsive signals.

GATA factors constitute a family of transcriptional regulatory proteins expressed with distinct developmental and tissue-specific profiles and thought to regulate cell-restricted programs of gene expression. Here we describe the molecular cloning, chromosomal location, and transcription of the human GATA-6 gene. The GATA-6 cDNA encodes a predicted 449-amino-acid protein, which is highly conserved among vertebrates, and includes the two adjacent zinc-finger/basic domains characteristic of the GATA factor family. GATA-6 maps to human chromosome 18q11.1-q11.2 by fluorescence in situ hybridization. The gene is transcribed in a pattern overlapping that of GATA-4. Transcripts for both of these genes are prominent in heart, pancreas, and ovary, but only GATA-6 mRNA is found in lung and liver. GATA-6 transcripts are also detected in cultures of human and rat vascular smooth muscle cells (VSMCs). In VSMCs, GATA-6 transcripts are down- regulated when quiescent cultures are stimulated to proliferate in response to mitogen activation. These data demonstrate that GATA-6 is subject to both tissue-specific and mitogen-responsive regulatory signals. GATA-6 is a prime candidate for a gene that might regulate the differentiative state of VSMCs.

Amino Acid Sequence↗
PubMed1996

A genetic, physical, and comparative map of rat chromosome 10.

A map of rat Chromosome (Chr) 10 was generated from 21 markers, mostly of conserved structural genes, by linkage analysis and fluorescence in situ hybridization. The study emphasizes the proximal third of the chromosome which, until now, has been relatively devoid of markers. Based on comparative analysis, our data suggest that genes on rat Chr 10 are conserved on mouse Chr 11, 16, 17 and human Chr 16, 5, and 17.

Animals↗
PubMed1995

Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas.

The AKT2 gene is one of the human homologues of v-akt, the transduced oncogene of the AKT8 virus, which induces lymphomas in mice. In previous studies, AKT2, which codes for a serine-threonine protein kinase, was shown to be amplified and overexpressed in some human ovarian carcinoma cell lines and amplified in primary tumors of the ovary. To confirm and extend these findings, we conducted a large-scale, multicenter study of AKT2 alterations in ovarian and breast cancer. Southern-blot analysis demonstrated AKT2 amplification in 16 of 132 (12.1%) ovarian carcinomas and in 3 of 106 (2.8%) breast carcinomas. No AKT2 alteration was detected in 24 benign or borderline tumors. Northern-blot analysis revealed overexpression of AKT2 in 3 of 25 fresh ovarian carcinomas which were negative for AKT2 amplification. The difference in the incidence of AKT2 alterations in ovarian and breast cancer suggests a specific role for this gene in ovarian oncogenesis. No significant association was found between AKT2 amplification and amplification of the proto-oncogenes MYC and ERBB2, suggesting that amplification of AKT2 defines an independent subset of breast and ovarian cancers. Ovarian cancer patients with AKT2 alterations appear to have a poor prognosis. Amplification of AKT2 was especially frequent in undifferentiated tumors (4 of 8, p = 0.019), suggesting that AKT2 alterations may be associated with tumor aggressiveness.

Adenocarcinoma↗
PubMed1995

A microdissection library of the rat renal carcinoma gene region.

Predisposition to hereditary renal carcinoma in the Eker rat involves a mutation of a putative tumor suppressor gene within chromosome band 10q12. We describe the identification of three unique polymorphic sequences in the vicinity of this locus following the microdissection, construction and characterization of a region-specific DNA library for rat chromosome band 10q12.

Animals↗
PubMed1995

Chromosomal localization of a gene, GF1, encoding a novel zinc finger protein reveals a new syntenic region between man and rodents.

The Gfi1 gene encodes a zinc finger protein which binds DNA and is involved in transcriptional regulation. Gfi1 was assigned to the central portion of mouse Chr 5 by interspecific backcross mapping and to human chromosome band 1p22 and rat chromosome band 14p22 by fluorescence in situ hybridization (FISH). Comparative mapping data presented here describes a new syntenic region between man and rodents.

Animals↗
PubMed1994

p16 alterations and deletion mapping of 9p21-p22 in malignant mesothelioma.

To determine whether p16 is altered in human malignant mesothelioma (MM), molecular analysis of multiple 9p loci was performed on 40 cell lines and 23 primary tumors from 42 MM patients. We identified homozygous deletions of p16 in 34 (85%) cell lines and a point mutation in 1 line. Down-regulation of p16 was observed in 4 of the remaining cell lines, 1 of which displayed a DNA rearrangement of p16. Homozygous deletions of p16 were identified in 5 of 23 (22%) primary tumors; no mutations or rearrangements were found in these specimens. Four cell lines displayed a single homozygous deletion proximal to or distal to p16; 4 others had 2 nonoverlapping deletions, one involving p16 and the other involving a region proximal to this locus. These data indicate that alterations of p16 are a common occurrence in MM cell lines and, to a lesser extent, in primary tumors. Furthermore, deletions of 9p21-p22 outside of the p16 locus may reflect the involvement of other putative tumor suppressor genes that could also contribute to the pathogenesis of some MMs.

Base Sequence↗
PubMed1994

Chromosomal localization of the genes encoding the kinetochore proteins CENPE and CENPF to human chromosomes 4q24-->q25 and 1q32-->q41, respectively, by fluorescence in situ hybridization.

CENPE and CENPF are human kinetochore proteins of 312 and approximately 400 kDa, respectively. As part of an effort to characterize the functions of these two proteins, we have used their respective cDNAs to map their human chromosomal locations by fluorescence in situ hybridization. The gene that encodes CENPE, a kinetochore-associated motor protein that is postulated to segregate chromosomes during mitosis, maps to chromosome 4q24-->q25. The CENPF gene, which encodes a structural protein of the kinetochore, maps to chromosome 1q32-->q41 within close proximity to the genetic locus that is linked to Van der Woude syndrome.

Chromosomal Proteins, Non-Histone↗
PubMed1994

Home traction in the management of femoral fractures in children.

Fracture of the femur in children is a common problem which can be managed in a variety of ways. We treated such fractures in children up to the age of 13 by immobilization in a Thomas splint, after reduction, if necessary, and traction in hospital. After a short period, traction was continued at home using a mobile frame with the Thomas splint. The results of such home traction were assessed in terms of both healing of the fracture and any complications and of the parental attitudes to treatment at home. It was found that traction at home was an acceptable method for the management of such fractures. Results were comparable to other methods of treatment and parental satisfaction was very high, providing there was adequate surveillance by the district nurse and immediate access to advice. The cost-savings of such a treatment are significant.

Adolescent↗