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Biomedical subjects

A M Taylor

Publications and source records attributed to A M Taylor.

At least 145 records · Page 8Linked to original sources
PubMed1990

Inhibition of sulphate incorporation by chondrocytes in intact cartilage by hyaluronate from foetal cartilage.

A number of regulators are available in cartilage to effect the local control of matrix production by chondrocytes. A cartilage slice assay has been used in this study to investigate the influence of such regulators (extracted from foetal cartilage) on intact cartilage. A net inhibition of sulphation was found, rather than stimulation as reported for extracts rich in the somatomedin-like, cartilage derived factor (CDF). Inhibition was due, to a high molecular weight component identified as hyaluronic acid (based on enzyme sensitivity, chromatographic behaviour and temperature stability). Its inhibition of sulphation in intact cartilage was more profound than that produced by commercially available umbilical cord hyaluronate. We conclude that foetal cartilage hyaluronate is a far more potent inhibitor of sulphation than hyaluronate from other sources, suppressing sulphation even in the presence of a somatomedin-like activator and in intact cartilage, which responds poorly to commercial hyaluronate.

Animals↗
PubMed1990

Rearrangement of the same chromosome regions in different SV40 transformed human skin keratinocyte lines is associated with tumourigenicity.

Twelve different human keratinocyte strains were transformed with recombinant plasmid pSV6-1 which contained an origin defective SV40 genome. When injected into athymic nude mice lines produced either squamous cell carcinomas (SCC) in all animals, SCC in some animals and epidermal cysts in others, or epidermal cysts only in all the animals. The tumourigenic capacity of the lines could be correlated with the chromosomal changes present initially in the transformed cells. Lines which produced SCC in all the animals within a short period of time all showed simultaneous loss of part of chromosomes 3p, 8p and 11p in one homologue. Lines which were not tumourigenic did not show these simultaneously appearing rearrangements. These specific rearrangements are acquired in vitro and the time taken for a recognisable tumour to appear is related to the proportion of such cells in the line. The rearrangement of the same chromosome regions in different tumourigenic cell lines suggests that genes in these regions are important in the development of squamous cell carcinoma, possibly by loss of heterozygosity, at particular loci.

Animals↗
PubMed1990

Sensitivity to ionising radiation of transformed human cells containing mutant ras genes.

Measurement of colony forming ability following exposure to gamma-rays has been performed on human retinoblasts transformed with either adenovirus 5 or 12 early region 1 DNA, adenovirus early region 1A plus activated N- or H-ras DNA or SV40 DNA. In contrast to recently reported results (M.D. Sklar, 1988, Science, 239, 645-647), we found no general correlation between transformation with activated ras and increased radiation resistance. Similarly, there was no correlation between D0 values and the level of expression of ras p21 in transformed human retinoblasts as determined by liquid competition assay. Indeed, cell lines with very similar D0 values had ras contents varying by up to one hundred fold. Cell lines transformed with SV40 DNA were generally less sensitive to ionising radiation than adenovirus and/or ras transformants, but even so the variation in sensitivity within these encompassed the whole spectrum of values obtained for the ras transformants. It may be interesting to note, however, that two out of the three ras transformants which were least sensitive to gamma-rays were cell lines expressing the highest levels of p21.

Adenovirus Early Proteins↗
PubMed1989

Cultured skin keratinocytes from both normal individuals and basal cell naevus syndrome patients are more resistant to gamma-rays and UV light compared with cultured skin fibroblasts.

Measurement of colony-forming ability following exposure to gamma-rays was performed on cultured skin keratinocytes and skin fibroblasts obtained from normal individuals, basal cell naevus syndrome patients (BCNS) and ataxia telangiectasia (A-T) patients. The most striking observation was the radiation resistance of 8/8 keratinocyte strains compared with fibroblasts whether from BCNS patients or normals. The single A-T keratinocyte cell strain showed the same radiosensitivity as A-T fibroblast cell strains. The differential survival of keratinocytes and fibroblasts was also observed following exposure to 254 nm UV light. The survival curves of SV40 immortalized keratinocytes and retinoblasts derived from normal individuals or BCNS patients showed large shoulder regions following exposure to gamma-rays or 254 nm UV light. An increased D37 rather than an increased D0 was therefore the feature of such curves. This contrasted with the SV40 immortalized A-T keratinocytes or fibroblasts which showed a minimal shoulder effect and an increased D0. No difference in survival was observed between BCNS and normal cells following exposure to either UV or gamma-rays.

Ataxia Telangiectasia↗
PubMed1989

Increased radiosensitivity and the basic defect in ataxia telangiectasia.

Various cellular defects have been found in ataxia telangiectasia (A-T) cells including increased radiosensitivity, increased sensitivity to various chemical agents, a probable DNA repair defect and a defect in DNA synthesis. How these different features are related to each other is at present unknown. It has been suggested that there is a defect in A-T that acts in tissue differentiation as well as during growth and in the mature adult. This hypothesis is supported by the observations, for example, of an immature thymus present in patients, the production of alpha-fetoprotein, which results in a high serum level, and ovarian dysgenesis. A gene for A-T has recently been localized to chromosome region 11q22-23, a site involved in chromosomes translocations in some non-lymphoid leukaemias. At the chromosomal level the spontaneous abnormalities in A-T include, first, an increased frequency of cells showing chromosome translocations involving immune system genes that normally undergo rearrangement to form a functional product; secondly, the formation of telometric dicentrics in both lymphocytes and fibroblasts; and thirdly formation of long-lived chromosome damage following exposure to ionizing radiation and radiomimetic drugs. The gene defect underlying this disorder is unknown and distinguishing between primary and secondary effects of the mutant gene is difficult. We consider alternative models for retention of translocation T cells. First, it is possible that there is a defect in recognition of site-specific damage leading to retention of translocation cells that might otherwise be removed. Secondly, a feature common to the production of illegitimate T-cell receptor gene rearrangements and to formation of telomeric dicentric chromosomes in A-T cells is an increased period of time available for chromosome interchange, possibly due to a site-specific defect in strand break repair. It is possible that this defect may also prevent chromosome restitution following exposure of cells to ionizing radiation.

Ataxia Telangiectasia↗
PubMed1989

Relationship between insulin, insulin-like growth factor I, and dehydroepiandrosterone sulfate concentrations during childhood, puberty, and adult life.

The relationships between plasma insulin, insulin-like growth factor I (IGF-I) and dehydroepiandrosterone sulfate (DHEAS) concentrations in normal subjects have not been defined. We performed iv glucose tolerance tests on 102 normal subjects, aged 5-20 yr. The subjects were divided into 4 groups according to pubertal stage (Tanner): A, stage 1 (n = 22); B, stages 2 and 3 (n = 17); C, stages 4 and 5 (n = 20); and D, adult, greater than 17 yr (n = 43). The basal plasma IGF-I and insulin concentrations and incremental 0-60 min insulin areas in response to glucose rose significantly throughout puberty (P less than 0.001 for all parameters) and declined to prepubertal levels by the third decade of life. There was a strong positive correlation between log fasting plasma insulin vs. log plasma IGF-I (r = 0.625; P less than 0.001) and log incremental 0-60 min insulin areas vs. log plasma IGF-I (r = 0.572; P less than 0.001). Plasma DHEAS concentrations were measured in groups A-C (n = 59); these also rose throughout puberty. There was strong correlations between log plasma DHEAS and log basal or stimulated (incremental 0-60 min areas) insulin responses (P less than 0.001). To assess the relationship between plasma DHEAS and insulin before puberty, we analyzed the data from group A separately. Plasma DHEAS concentrations tended to be higher in children 9 yr of age or older than in those less than 9 yr old, whereas basal and stimulated plasma insulin levels were similar. We found no correlation between log plasma insulin (fasting or stimulated responses) and log plasma DHEAS concentrations in group A (P greater than 0.05). In conclusion, we found a strong relationship between plasma insulin and IGF-I throughout childhood and puberty and during adult life. This finding suggests that insulin may be important for normal growth during childhood. There was no correlation between plasma insulin and DHEAS concentrations in prepubertal children, which suggests that adrenarche does not influence insulin levels.

Adolescent↗
PubMed1989

A monoclonal antibody to human insulin-like growth factor-I: characterization, use in radioimmunoassay and effect on the biological activities of the growth factor.

A monoclonal antibody (BPL-M23) to insulin-like growth factor-I (IGF-I) was obtained following immunization of BALB/c mice with human IGF-I conjugated to ovalbumin. The affinity constant of BPL-M23 for IGF-I was 10.5 litres/nmol and the cross-reactivities of IGF-II, multiplication-stimulating activity III-2 and insulin were 0.8, 0.03 and less than 0.0001% respectively. Porcine, bovine, ovine and rabbit sera, but not rat or mouse sera, showed substantial reactivity with the antibody. Comparison of radioimmunoassay analyses of 54 human serum samples from normal subjects and acromegalic and GH-deficient patients using BPL-M23 and a polyclonal rabbit antiserum (R557A) to human IGF-I showed a high correlation, indicating the usefulness of the monoclonal antibody in radioimmunoassay. Monoclonal antibody BPL-M23 was capable of abolishing the sulphation, mitogenic and insulin-like activities of IGF-I in in-vitro bioassays, suggesting that these activities may rely upon the same receptor-binding site which is near to the antibody-binding site.

Animals↗
PubMed1988

Insulin like growth factor-I, protein kinase-C, calcium and cyclic AMP: partners in the regulation of chondrocyte mitogenesis and metabolism.

The possible role of protein kinase-C (PKC), calcium and cyclic AMP (cAMP) in mediating the metabolic and mitogenic effects of insulin-like growth factor-I (IGF-I) on chondrocytes was investigated using a PKC activator (phorbol ester 12,13-dibutyrate, PDBU), a PKC inhibitor (compound H7), a calcium channel blocker, (verapamil) and a cAMP analogue (dibutyryl cAMP). IGF-I and PDBU stimulated sulphate and thymidine incorporation by chondrocytes. Both of these effects were inhibited by compound H7. Verapamil inhibited IGF-I- and PDBU-stimulated sulphate incorporation, but contrastingly stimulated basal and enhanced IGF-I and PDBU stimulation of thymidine incorporation. Dibutyryl cAMP increased basal and IGF-I-stimulated sulphate incorporation but inhibited but inhibited both basal and IGF-I stimulation of thymidine incorporation. These results suggest a harmonic overlap between the activities of PKC and cAMP-dependent PKA enzyme systems, and calcium balance in the mitogenic and metabolic process of the chondrocyte.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1988

Structure and evolution of the horse zeta globin locus.

The equine zeta globin gene locus consists of an intact 5' gene and a truncated 3' pseudogene (psi zeta) that has only 5' control sequences and a first exon and intron. Nevertheless, the psi zeta gene has retained almost perfect homology with its neighbour, presumably by gene conversion. The first introns of both zeta and psi zeta genes contain a number of degenerate tandem repeats of a 14 base-pair sequence that has been found in the zeta genes of goats and humans and that is related to a family of human minisatellite sequences. Comparisons of sequences flanking the zeta and psi zeta genes reveal areas of considerable interspecies homology, which can be explained by a zeta gene duplication that pre-dated the mammalian radiation.

Animals↗
PubMed1988

Breakage of the T cell receptor alpha chain locus in non malignant clones from patients with ataxia telangiectasia.

Patients with ataxia telangiectasia (A-T) develop specific chromosome translocations, which may confer a proliferative advantage, resulting in the appearance of large clones in the peripheral blood lymphocytes. These lymphocytes are not malignant. Using in situ hybridisation techniques we have investigated a consistent 14q11 translocation breakpoint observed in a t(X;14)(q28;q11) translocation clone from each of two different patients and a t(14;14)(q11;q32) clone from a third patient. In all cases the chromosome translocation involved breakage within the alpha chain locus of the T cell receptor (TCR alpha), between the variable and constant regions, at 14q11. Chromosome rearrangement involving breakage within TCR alpha can therefore precede the development of malignancy. Further chromosomal rearrangement may be required in these patients, for progression to the leukaemic state.

Ataxia Telangiectasia↗
PubMed1988

Characterization of a novel nuclear envelope protein restricted to certain cell types.

The monoclonal antibody AGF2.3 identifies a nuclear envelope protein that is restricted to certain cell types. In particular, this antigen shows a reduced level of expression during haemopoietic cell maturation. In this study, we have examined the relationship of this protein to known nuclear envelope proteins that have a similar molecular mass. Antigen extraction and immunoelectron microscope studies revealed that the AGF2.3 protein is an integral membrane protein present at both the inner and outer aspects of the nuclear envelope. The protein is not associated with nuclear pores and therefore is distinct from pore complex proteins. The AGF2.3 protein does not have ATPase activity. Therefore, this protein is also distinct from a myosin heavy chain-like ATPase that is associated with the nuclear envelope. The AGF2.3 antibody identifies a novel nuclear envelope protein. Further studies of the biochemical nature of the AGF2.3 protein should provide insight into novel cellular processes at the nuclear envelope relating to the lineage or maturation status of cells.

Antibodies, Monoclonal↗
PubMed1988

Somatomedin-C/IGF-I measured by radioimmunoassay and somatomedin bioactivity in adolescents with insulin dependent diabetes compared with puberty matched controls.

Plasma concentrations of insulin like growth factor-I in the adolescent diabetic remain controversial. IGF-I levels were determined by radioimmunoassay in 81 insulin dependent adolescent diabetics (49 boys and 32 girls) and compared with 75 puberty stage matched normal controls. Plasma somatomedin bioactivity was determined by cartilage bioassay in a smaller group of 10 normal and 25 diabetic subjects. IGF-I concentrations increased in the normals during puberty and there were no observed differences between the sexes. (P1, 0.77 +/- 0.08; P2, 1.33 +/- 0.2; P3, 1.59 +/- 0.16; P4, 1.76 +/- 0.16; P5, 2.24 +/- 0.09). IGF-I also increased in the diabetics reaching a peak level at stage three in both girls and boys. Combining the data from both sexes the diabetics had significantly lower levels of IGF-I compared to controls at stages; (P1, 0.67 +/- 0.05, ns. P2, 0.92 +/- 0.1, p less than 0.05; P3, 1.16 +/- 0.09, p less than 0.01; P4, 0.73 +/- 0.11, p less than 0.001; P5, 1.13 +/- 0.11, p less than 0.001). Plasma somatomedin bioactivity was elevated in the normals but inhibitory responses were observed in all but two of the diabetic subjects, highlighting the presence of inhibitory factors in diabetic plasma. HbA1C levels rose in the diabetics during puberty, however using covariance analysis there was no relationship between IGF-I and HbA1C when changes relating to puberty were excluded. The importance of controlling for pubertal stage as opposed to age is noted when assessing IGF-I status in the diabetic adolescent.

Adolescent↗
PubMed1987

A comparison of fresh and cultured T lymphocytes from patients with ataxia telangiectasia using T-cell subset markers and chromosome translocations.

Ataxia telangiectasia (A-T) is an autosomal recessive disorder in which patients show an unusual predisposition to lymphoid malignancies including T-cell leukaemia. We compare here the surface phenotypes of fresh and cultured A-T T cells. A total of 17 T-cell cultures from 8 A-T patients are compared with each other and with 5 T-cell cultures from normal individuals. The large, cytogenetically abnormal t(14;14) and t(X;14) clones in 2 of the patients both occurred only in the CD8+ population of T lymphocytes. There was no difference in the rate of growth of A-T T cells in vitro compared with those from normal individuals, although many of the original characteristics of the T cells were lost, including the cytogenetically abnormal clones seen in fresh A-T lymphocytes.

Adolescent↗
PubMed1987

Ultrastructural organisation of the projection from the superior colliculus to the ventral lateral geniculate nucleus of the rat.

Retinorecipient regions of the ventral lateral geniculate nucleus of the thalamus and the superior colliculus of the midbrain are linked by reciprocal axonal projections. In this study we have investigated the ultrastructural characteristics, the distribution, and the postsynaptic targets of the terminals of axons projecting to the ventral lateral geniculate nucleus from the superior colliculus. Horseradish peroxidase was injected into the superior colliculi of adult albino rats, and the Hanker-Yates method was used to visualize anterogradely and retrogradely transported peroxidase in the ventral lateral geniculate nuclei 24 hours following the injection. Labelled terminals were found in the lateral and ventrolateral parts of the external division of the ipsilateral ventral lateral geniculate nucleus. The labelled terminals were confined to areas of simple, nonglomerular neuropil. They were 0.45-1.5 micron in diameter; contained small, dark mitochondria and spherical synaptic vesicles; and established Gray type I (asymmetrical) synaptic contacts with the dendritic shafts, dendritic spines, and occasionally cell bodies of cells with the ultrastructural characteristics of projection cells. A few labelled terminals established synaptic contact with retrogradely labelled cells. Thus, in the rat, the projection from the superior colliculus gives rise to a uniform population of axon terminals in the nonglomerular neuropil of the lateral portion of the ventral lateral geniculate nucleus, which synapse with, and are probably excitatory to, geniculocollicular and other projection cells.

Animals↗
PubMed1987

Growth of large chromosomally abnormal T cell clones in ataxia telangiectasia patients is associated with translocation at 14q11. A model for other T cell neoplasia.

Human T cell malignancies often show chromosome breaks at 14q11, within the alpha chain locus of the human T cell antigen receptor, with translocation of the distal portion of 14 to one of several sites. In patients with ataxia telangiectasia (A-T) the majority of T cell chromosome translocations associated with this disorder appear to occur at the sites of the T cell antigen receptor genes 7p14, 7q35, and 14q11 and may result in clone formation. In three large proliferating A-T T cell clones we have observed (including one which became malignant) and in most T cell tumours reported, the clonal chromosome exchange involves one breakpoint at 14q11 with the second breakpoint occurring in a gene not involved in the immunoglobulin supergene family. Our observations on A-T patients confirm the suggestion that chromosome exchanges involving either t(7;14)(p14;q11), t(7;14)(q35;q11), inv(7)(p14q35), or t(7;7)(p14;q35) confer only a small proliferative advantage on T cells in vivo without the capacity for malignant transformation and that the potential for malignant change is not a feature of all these rearrangements, but is restricted to cells or clones with other chromosome exchanges.

Ataxia Telangiectasia↗
PubMed1987

The breakpoint of an inversion of chromosome 14 in a T-cell leukemia: sequences downstream of the immunoglobulin heavy chain locus are implicated in tumorigenesis.

T-cell tumors are characterized by inversions or translocations of chromosome 14. The breakpoints of these karyotypic abnormalities occur in chromosome bands 14q11 and 14q32--the same bands in which the T-cell receptor (TCR) alpha-chain and immunoglobulin heavy chain genes have been mapped, respectively. Patients with ataxia-telangiectasia are particularly prone to development of T-cell chronic lymphocytic leukemia with such chromosomal abnormalities. We now describe DNA rearrangements of the TCR alpha-chain gene in an ataxia-telangiectasia-associated leukemia containing both a normal and an inverted chromosome 14. The normal chromosome 14 has undergone a productive join of TCR alpha-chain variable (V alpha) and joining (J alpha) gene segments. The other allele of the TCR alpha-chain gene features a DNA rearrangement, about 50 kilobases from the TCR alpha-chain constant (C alpha) gene, that represents the breakpoint of the chromosome 14 inversion; this breakpoint is comprised of a TCR J alpha segment (from 14q11) fused to sequences derived from 14q32 but on the centromeric side of C mu. These results imply that 14q32 sequences located at an undetermined distance downstream of the immunoglobulin C mu locus can contribute to the development of T-cell tumors.

Ataxia Telangiectasia↗
PubMed1987

Oxygen toxicity and chromosomal breakage in ataxia telangiectasia.

Toxic effects of ionizing radiation and elevated O2 levels (hyperoxia) are both thought to be mediated by oxidizing free radicals. In view of the reported hypersensitivity of ataxia telangiectasia (A-T) cells to the clastogenic effect of ionizing radiation, the chromosomal sensitivity of A-T cells to hyperoxic culture conditions was investigated in unirradiated and G0-irradiated A-T lymphocyte cultures. Unlike Fanconi's anaemia lymphocytes, which tend to respond to oxygen, especially after treatment with mitomycin C, both non-irradiated and G0-irradiated A-T lymphocytes failed to show an effect. We conclude that the excessive spontaneous and radiation-induced chromosomal breakage in A-T does not result from a deficiency in the cellular defences against the clastogenic effect of hyperoxia.

Ataxia Telangiectasia↗