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Biomedical subjects

E Webb

Publications and source records attributed to E Webb.

At least 19 recordsLinked to original sources
PubMed1990

An E mu-v-abl transgene elicits plasmacytomas in concert with an activated myc gene.

To clarify how the v-abl oncogene of Abelson murine leukemia virus contributes to lymphoid tumorigenesis, we introduced the gene linked to an immunoglobulin heavy chain enhancer (E mu) into the mouse germline. Although lymphoid development was not detectably affected in young E mu-v-abl mice, three transgenic lines shared a high predisposition to develop clonal plasmacytomas that secreted IgA or IgG. The unexpected absence of pre-B lymphomas suggests that Abelson virus generates such tumors by infecting an early lymphoid progenitor cell that has not yet activated the heavy chain enhancer. Most plasmacytomas bore a rearranged c-myc gene, apparently as a result of spontaneous translocation to the Igh locus. Moreover, progeny of a cross with analogous E mu-myc mice rapidly developed oligoclonal plasmacytomas. Thus, the collusion of v-abl with c-myc is stage specific, efficiently transforming plasma cells but not pre-B cells or B cells.

Abelson murine leukemia virus↗
PubMed1990

Effect of mitochondrial inhibitors on adenosinetriphosphate levels in Plasmodium falciparum.

1. The effects of mitochondrial inhibitors on the ATP levels of intraerythrocytic Plasmodium falciparum have been studied. 2. Changes in parasite ATP or ADP levels with time in response to various mitochondrial inhibitors appear quite complex; ATP levels may be initially depressed and then elevated above normal, but the nature of the response depends upon the stage in the intraerythrocytic cycle and in some cases upon the concentration of the inhibitor used. 3. After ca 2 hr incubation of cultures with inhibitors ATP levels appear to be stabilized and are similar to those of untreated parasites. However, ADP levels of trophozoites show significant increases after a 2 hr incubation with inhibitors, particularly with oligomycin and to a lesser extent with antimycin A; increases in ADP levels however were not observed in ring-stages of the parasite. 4. Inhibition of red cell and parasite glycolysis leads to rapid decreases in parasite ATP levels which are not significantly affected by oligomycin. Incubation of in vitro cultures with oligomycin can result in a decreased, rather than increased rate of lactate production with a concomitant appearance of pyruvate in the growth medium. 5. This investigation would indicate that if there is a mitochondrial contribution to the parasite ATP pool it is relatively small, and that a short-fall in this contribution is quickly compensated for by ATP from other source(s), although this is not necessarily met by increased glycolysis.

Adenosine Diphosphate↗
PubMed1989

N-myc transgene promotes B lymphoid proliferation, elicits lymphomas and reveals cross-regulation with c-myc.

To assess the impact of constitutive N-myc expression on lymphocytes, we generated lines of transgenic mice bearing the murine N-myc oncogene coupled to the immunoglobulin heavy chain enhancer (E mu). As in mice carrying an analogous c-myc construct, E mu-N-myc mice exhibit a limited overgrowth of cycling pre-B cells and eventually succumb to clonal B lymphoid tumours. The endogenous N-myc and c-myc alleles are silent in both E mu-N-myc and E mu-myc lymphomas, suggesting that these genes are subject to auto- and cross-regulation. The regulatory interaction and the similar biological effects of N-myc and c-myc imply that the two genes perform interchangeable functions in the promotion of cell proliferation.

Animals↗
PubMed1989

A bcr-v-abl oncogene induces lymphomas in transgenic mice.

In chronic myeloid leukemia and some cases of acute lymphoblastic leukemia, a 9;22 chromosome translocation has fused most of the c-abl oncogene to a gene designated bcr. To explore in vivo the biological effects of the chimeric gene, we introduced a facsimile of the translocation product, a bcr-v-abl gene, into the mouse germ line under the control of the immunoglobulin heavy-chain enhancer or a retroviral long terminal repeat. Some transgenic mice bearing either construct developed clonal lymphoid tumors. T lymphomas predominated, but some pre-B lymphomas developed. The transgenes were expressed in the tumors but not detectably in the lymphoid tissues of nontumorous transgenic animals, implying that transcription is activated by a low-frequency somatic event. These results demonstrate that bcr-v-abl is tumorigenic in vivo and provide a new animal model for lymphomagenesis.

Animals↗
PubMed1989

Lymphomagenesis in Emu-myc transgenic mice does not require transgene rearrangement or mutation of myc exon 1.

In most human Burkitt's lymphomas, translocation of the myc oncogene to an immunoglobulin locus is associated with loss of myc exon 1 or with mutations near its 3' border, a region where myc transcription is attenuated and translation of a larger myc polypeptide initiates. Emu-myc transgenic mice, which bear the three myc exons coupled to an immunoglobulin enhancer, provide a model for the development of such lymphomas, because their lymphomagenesis appears to require events other than expression of the transgene. To determine whether myc rearrangement or exon 1 mutation is a necessary tumorigenic event, we examined the transgene structure and myc exon 1 sequences in Emu-myc B lymphoid tumours. Southern blots revealed no transgene rearrangements in 20 of the lymphomas, and only two tumours showed amplification (2 to 5-fold). To search for exon 1 alterations, the exon 1 mRNA region was amplified from five tumours by polymerase chain reaction and sequenced, but no mutations were found. Hence, neither excision nor mutation of exon 1 is necessary to render myc tumorigenic. The sequence analysis across the exon 1-exon 2 boundary unexpectedly revealed an ambiguity in myc splicing that predicts a variant form of the larger myc polypeptide lacking a single amino acid residue.

Amino Acid Sequence↗
PubMed1988

Expression of multiple homeobox genes within diverse mammalian haemopoietic lineages.

Several mouse and human genes encoding the DNA-binding homeobox domain are implicated here in haematopoiesis, a differentiation process maintained throughout life. Four homeobox cDNA clones were isolated from bone marrow and spleen of adult mice and two from the human leukaemia cell line K562. They derive from the Hox 1.1, Hox 2.3, Hox 6.1 genes and two previously undescribed genes, one of a type (paired) not found before in vertebrates. A survey of 36 cell lines of the lymphoid, myeloid and erythroid lineages revealed that certain homeobox transcripts were almost ubiquitous, while others were restricted to certain lineages or even particular cell lines. The expression pattern altered in a myeloid and an erythroid line induced to terminal differentiation, and in novel lines that had switched from a lymphoid to a myeloid phenotype. Altogether, the haemopoietic compartment may contain up to 20 homeobox transcripts. In one myeloid leukaemia, DNA rearrangement has perturbed expression. These findings suggest that homeobox genes may influence developmental decisions within the haemopoietic system.

Animals↗
PubMed1987

Arachidonic acid-induced inflammation: inhibition by dual inhibitor of arachidonic acid metabolism, SK&F 86002.

The antiinflammatory activity of the structurally novel dual inhibitor of arachidonic acid metabolism, SK&F 86002 was evaluated using arachidonic acid-induced edema and inflammatory cell infiltration. Histological examination demonstrated extensive subcutaneous edema and neutrophil (PMN) accumulation in perivascular and interstitial locations one hour after application of arachidonic acid to the ear. SK&F 86002 and, to a lesser extent, phenidone demonstrated potent inhibition of this inflammatory response following oral and topical administration. Nordihydroguaiaretic acid (NDGA) displayed only topical activity. The selective cyclooxygenase inhibitors ibuprofen and naproxen were either inactive or stimulated ear swelling. Histological evaluation of the lesion in drug-treated animals revealed that SK&F 86002 impaired edema formation and caused a significant reduction in numbers of infiltrating neutrophils. Using arachidonic acid-induced peritoneal exudation, a reduction in the cellular infiltrate was observed after oral treatment with SK&F 86002 or phenidone, but not with naproxen. Taken together, these data illustrate the potent antiinflammatory effects of SK&F 86002 and support the suggestion that 5-lipoxygenase products play a significant role in both the edematous and cellular phases of arachidonic acid-induced inflammation.

Animals↗
PubMed1987

Effect of supplementary vitamins and iron on malaria indices in rural Gambian children.

The effect of a combined supplement of iron, thiamine, riboflavin and vitamin C on malarial incidence in 5 to 14-year-old children was tested in a malnourished rural community in a region of The Gambia noted for high prevalence of malaria during the rainy season. 190 children, divided into 2 matched groups, received either the supplement or a matching placebo for 3 months. No significant difference in malarial incidence was observed between the 2 groups, despite a major improvement in biochemical indices of nutrient status in the supplemented group, especially for riboflavin and vitamin C. Severity of episodes was also similar between groups, but in subjects who developed parasitaemias there was a trend towards higher parasite counts in those receiving the active supplement. Nutritional interventions in malarious areas may have adverse effects on malaria, and the increase in parasitaemia was compatible with the hypothesis that a small but significant reduction in defences had occurred. However, the absence of increases in the incidence of proven malaria cases and their severity must also be taken into account, in order to make a balanced assessment of the possible increase in risk. Further investigations are needed to measure the risk in benefit rates, and to consider the effects of individual nutrients in isolation.

Adolescent↗
PubMed1985

Variant (6;15) translocations in murine plasmacytomas involve a chromosome 15 locus at least 72 kb from the c-myc oncogene.

The variant (6;15) translocations in murine plasmacytomas join the myc oncogene-bearing band of chromosome 15 and the immunoglobulin kappa band of chromosome 6. We recently cloned a region from chromosome 15 linked to C kappa and have now used probes from that region to define the major locus of plasmacytoma variant translocations, which we denote pvt-1. In five of nine plasmacytomas we analysed, the 6;15 translocation resulted from reciprocal recombination between the C kappa locus and a 4.5-kb region of pvt-1. Moreover, nearby we located the region shown by others to have undergone a complex (15;12;6) translocation in plasmacytoma PC7183. All the chromosome 6 breakpoints fell between 1 and 3 kb 5' to C kappa but only two were near J kappa genes. Thus the J kappa -C kappa region appears to be a recombination 'hot spot' in lymphocytes, but the breaks are unlikely to be mediated via V/J recombination enzymes. Comparison of a cloned 108-kb region across pvt-1 and another of 52 kb across c-myc established that the pvt-1 breakpoints lie at least 72 kb from the c-myc promoters. Since c-myc is expressed at a substantial level, the 6;15 translocation apparently activates c-myc. Activation may occur directly, at a remarkable distance along the chromosome, or indirectly, via a putative pvt-1 gene product.

Animals↗
PubMed1985

Effects of a multivitamin and iron supplement on running performance in Gambian children.

Forty boys and girls between 11 and 14.5 years with evidence of subclinical vitamin deficiencies were allocated to two groups to receive, twice weekly, either a placebo or a multivitamin and iron supplement. Prior to supplementation and on two subsequent occasions about 5 weeks apart, the children performed an exercise regimen on a treadmill during which expired air was collected and heart rate monitored. The supplement resulted in marked improvements in riboflavin and vitamin C status and checked the decline in iron stores seen in the unsupplemented children. During the study the running performance of unsupplemented children deteriorated, and markedly so in a subgroup with initially poor nutrient status. The vitamin and iron supplement prevented this deterioration so as to produce a significant reduction in the energy cost of treadmill running in the more malnourished subgroup, relative to the changes seen in children receiving no supplement.

Adolescent↗
PubMed1976

General and specific effects of amino acid starvation on the formation of undermodified Escherichia coli phenylalanine tRNA.

The heterogeneity of undermodified phenylalanine tRNA produced in relaxed control E. coli during amino acid starvation was investigated. Examination of the RPC-5 elution profiles of tRNAPhe prepared from non-starved cells and cells starved of a variety of amino acids, including some known to be involved in the formation of modified bases revealed that: (1) only one species of fully modified tRNAPhe appears to occur in cells grown in enriched medium; (2) at least two chromatographically unique isoacceptor species are observed in addition to the normal tRNAPhe in starved cells; (3) the unique, undermodified species of tRNAPhe from leucine-starved cells, known to be deficient in dihydrouridine, pseudouridine, 2-thiomethyl-N6-(delta2-isopentenyl) adenosine and 3-(3-amino-3-carboxypropyl) uridine, co-elute with the unique species produced in cells starved of histidine or arginine or treated with puromycin or chloramphenicol; (4) additional unique species of tRNAPhe can be detected in methyl- and sulfur-deficient tRNA from methionine- and cysteine-starved cells; (5) analysis of phenoxyacetylated tRNA revealed that the chromatographically unique and normal species from starved cells contain subspecies deficient in 3-(3-amino-3-carboxypropyl) uridine; and (6) using phenoxyacetylation as a means of effecting the resolution of undermodified subspecies, a total of at least ten chromatographically unique subspecies of rRNAPhe were detected in an organism that appears to posses only one gene for tRNAPhe. Taken together, the results support the view that there are both general and specific effects of amino acid starvation on the post-transcriptional modification of tRNA.

Amino Acids↗
PubMed1976

Unique phenylalanine transfer ribonucleic acids in relaxed control Escherichia coli: genetic origin and some functional properties.

Inhibition of protein synthesis in relaxed control E. coli results in the formation of chromatographically unique isoacceptor species of phenylalanine tRNA. The genetic origin and some functional properties of the major unique species of tRNA (Phe) produced during leucine starvation were investigated. RNA:DNA hybridization analyses revealed that the normally occurring and major unique species of tRNA (Phe) are generated from DNA sequences which are identical or closely related and that there may be only one such sequence in the E. coli chromosome. Results from 32P pulse-chase experiments revealed that the unique tRNA (Phe) can be converted to a chromatographically normal form upon resumption of cell growth in fully supplemented medium. These findings, taken with earlier results which indicate that the unique species is not derived from preexisting, normally occurring species, indicate that the unique tRNA(Phe) is a modification-deficient form of the normal species. Comparative studies of the unique and normal phenylalanine tRNAs revealed that the unique species is aminoacylated at a much lower rate than the normal species and is only about 60% as efficient in a tRNA-dependent, poly(U)-directed protein synthesizing system.

Binding Sites↗