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Biomedical subjects

S J Baker

Publications and source records attributed to S J Baker.

At least 19 recordsLinked to original sources
PubMed1992

Mutant p53 can induce tumorigenic conversion of human bronchial epithelial cells and reduce their responsiveness to a negative growth factor, transforming growth factor beta 1.

Loss of normal functions and gain of oncogenic functions when the p53 tumor suppressor gene is mutated are considered critical events in the development of the majority of human cancers. Human bronchial epithelial cells (BEAS-2B) provide an in vitro model system to study growth, differentiation, and neoplastic transformation of progenitor cells of lung carcinoma. When wild-type (WT) or mutant (MT; codon 143Val-Ala) human p53 cDNA was transfected into nontumorigenic BEAS-2B cells, we observed that (i) transfected WT p53 suppresses and MT p53 enhances the colony-forming efficiency of these cells, (ii) MT p53 increases resistance to transforming growth factor beta 1, and (iii) clones of MT p53 transfected BEAS-2B cells are tumorigenic when inoculated into athymic nude mice. These results are consistent with the hypothesis that certain mutations in p53 may function in multistage lung carcinogenesis by reducing the responsiveness of bronchial epithelial cells to negative growth factors.

Animals↗
PubMed1992

Jun is phosphorylated by several protein kinases at the same sites that are modified in serum-stimulated fibroblasts.

c-jun is a member of the family of immediate-early genes whose expression is induced by factors such as serum stimulation, phorbol ester, and differentiation signals. Here we show that increased Jun synthesis after serum stimulation is accompanied by a concomitant increase in phosphorylation. Several serine-threonine kinases were evaluated for their ability to phosphorylate Jun in vitro. p34cdc2, protein kinase C, casein kinase II, and pp44mapk phosphorylated Jun efficiently, whereas cyclic AMP-dependent protein kinase and glycogen synthase kinase III did not. The sites phosphorylated by p34cdc2 were similar to those phosphorylated in vivo after serum induction. The major sites of phosphorylation were mapped to serines 63, 73, and 246. Phosphorylation of full-length Jun with several kinases did not affect the DNA-binding activity of Jun homodimers or Fos-Jun heterodimers. Comparison of the DNA binding and in vitro transcription properties of wild-type and mutated proteins containing either alanine or aspartic acid residues in place of Ser-63, -73, and -246 revealed only minor differences among homodimeric complexes and no differences among Fos-Jun heterodimers. Thus, phosphorylation of Jun did not produce a significant change in dimerization, DNA-binding, or in vitro transcription activity. The regulatory role of phosphorylation in the modulation of Jun function is likely to be considerably more complex than previously suggested.

Blood↗
PubMed1991

Lactic acid recovery profiles following exhaustive arm exercise on a canoeing ergometer.

In this study lactate removal rates were monitored in ten subjects during a 30-min recovery period following exhaustive arm exercise. Each subject experienced three recovery regimens on different occasions in random order. One recovery period consisted of supine rest while the other two were active, one incorporating low intensity arm exercise and the other consisting of low intensity leg exercise. Lactate clearance rates showed a significant difference between the recovery regimens, and a posteriori test indicated a significant difference between leg exercise and arm exercise in the recovery period and also between leg exercise and rest. There was no significant difference in lactate clearance between arm exercise and rest in the recovery period.

Adult↗
PubMed1991

Mutant p53 proteins bind DNA abnormally in vitro.

The p53 gene encodes a phosphoprotein which binds DNA. Many types of tumors contain mutant p53 genes, but the effects of these mutations on the intrinsic properties of p53 are largely unknown. In the present study, we tested the effect of p53 mutations on DNA-binding. Each of 15 different mutant p53 gene products derived from human tumors or mouse transformants bound calf thymus DNA more weakly than did wild-type products. A significant subset of mutant proteins were also found to be underphosphorylated compared to the wild-type protein when produced in a reticulocyte lysate system, but this did not appear to explain the pattern of alterations of DNA-binding. The tested mutations were dispersed over several regions of the p53 gene and included representatives of all four of the evolutionarily conserved domains that are the known 'hot spots' for p53 mutation. The results suggest common pathways by which these various mutations affect the normal function of p53.

DNA↗
PubMed1990

p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis.

Coordinate loss of one copy of the p53 gene and mutation of the remaining copy occur in colorectal carcinomas and in many other human malignancies. However, the prevalence of p53 gene mutations in carcinomas which maintain both parental copies of p53 has not previously been evaluated. Moreover, it is not known whether p53 gene mutations are limited to malignant tumors or whether they can also occur in benign neoplasms. To answer these questions, a total of 58 colorectal tumors have been examined; in each tumor, allelic losses were assessed using restriction fragment length polymorphisms and p53 gene mutations were assessed by sequencing cloned polymerase chain reaction products. The following conclusions emerged: (a) p53 gene mutations occurred but were relatively rare in adenomas, regardless of size and whether the adenomas were derived from patients with familial adenomatous polyposis; (b) In carcinomas as well as in adenomas, p53 gene mutations were infrequently observed in tumors which contain both copies of chromosome 17p (17% of 30 tumors), while tumors which lost one copy of chromosome 17p usually had a mutation in the remaining p53 allele (86% of 28 tumors); (c) p53 gene mutations were found at similar frequencies in primary tumor samples and in cell lines derived from tumors. These and other data suggest that the rate limiting step in p53 inactivation is point mutation and that once a mutation occurs, loss of the remaining wild-type allele rapidly follows. Both mutations and allelic losses generally occur near the transition from benign to malignant growth, and the p53 gene may play a causal role in this progression.

Adenoma↗
PubMed1990

Suppression of human colorectal carcinoma cell growth by wild-type p53.

Mutations of the p53 gene occur commonly in colorectal carcinomas and the wild-type p53 allele is often concomitantly deleted. These findings suggest that the wild-type gene may act as a suppressor of colorectal carcinoma cell growth. To test this hypothesis, wild-type or mutant human p53 genes were transfected into human colorectal carcinoma cell lines. Cells transfected with the wild-type gene formed colonies five- to tenfold less efficiently than those transfected with a mutant p53 gene. In those colonies that did form after wild-type gene transfection, the p53 sequences were found to be deleted or rearranged, or both, and no exogenous p53 messenger RNA expression was observed. In contrast, transfection with the wild-type gene had no apparent effect on the growth of epithelial cells derived from a benign colorectal tumor that had only wild-type p53 alleles. Immunocytochemical techniques demonstrated that carcinoma cells expressing the wild-type gene did not progress through the cell cycle, as evidenced by their failure to incorporate thymidine into DNA. These studies show that the wild-type gene can specifically suppress the growth of human colorectal carcinoma cells in vitro and that an in vivo-derived mutation resulting in a single conservative amino acid substitution in the p53 gene product abrogates this suppressive ability.

Cell Division↗
PubMed1990

p53 functions as a cell cycle control protein in osteosarcomas.

Mutations in the p53 gene have been associated with a wide range of human tumors, including osteosarcomas. Although it has been shown that wild-type p53 can block the ability of E1a and ras to cotransform primary rodent cells, it is poorly understood why inactivation of the p53 gene is important for tumor formation. We show that overexpression of the gene encoding wild-type p53 blocks the growth of osteosarcoma cells. The growth arrest was determined to be due to an inability of the transfected cells to progress into S phase. This suggests that the role of the p53 gene as an antioncogene may be in controlling the cell cycle in a fashion analogous to the check-point control genes in Saccharomyces cerevisiae.

Amino Acid Sequence↗
PubMed1990

Enhanced testosterone secretion in adult rams after establishment of a high-frequency, low-amplitude pattern of LH pulses in the nonbreeding season occurs without changes in the number or binding affinity of testicular LH receptors.

When the LH signal in the ram is changed from one of large and infrequent pulses to one of small and frequent pulses, the testes quickly become more responsive to LH and testosterone secretion is elevated, perhaps because the number and (or) binding affinity of testicular LH receptors have increased. An experiment was undertaken in the nonbreeding season (July) with 10 adult Dorset x Leicester x Suffolk rams that were about 3.5 years of age and 69 +/- 2 kg in body weight. Rams were given injections into the jugular vein of either 5 micrograms NIH-LH-S24 (in 1 ml saline) or vehicle every 80 min for 6 days. LH treatment produced a series of LH pulses that occurred three times more frequently and were 70% less in amplitude than pulses in the control rams, without causing mean LH concentration to increase. Endogenously produced LH pulses were not evident in the treated rams after LH injection began. The modified LH-pulse pattern elevated mean testosterone concentration by 150% (assessed on days 2 and 5), and caused the cumulative testosterone response to LH pulses, estimated by multiplying testosterone-pulse amplitude by frequency per 6 h, to increase progressively by 180% (days -2 through 5). Enhanced testicular steroidogenic activity, presumably due to greater enzymatic activity and cholesterol availability within Leydig cells, was not associated with increases in either the concentration or affinity of LH-binding sites in the testis (assessed on days 3 and 6).

Animals↗
PubMed1990

Mutant p53 DNA clones from human colon carcinomas cooperate with ras in transforming primary rat cells: a comparison of the "hot spot" mutant phenotypes.

The majority of the p53 genes derived from human colorectal carcinomas contain point mutations. A significant number of these mutations occur in or around amino acids 143, 175, 273, or 281. Experiments presented here demonstrate for the first time that p53 DNA clones containing any one of these mutations cooperate with the activated ras oncogene to transform primary rat embryo cells in culture. These transformed cells produce elevated levels of the human p53 protein, which has extended half-lives (1.5-7 h), as compared to the wild-type human p53 protein (20-30 min). The p53 mutant with an alteration at residue 175 (p53-175H) binds tightly to the cellular heat shock protein, hsc70. In contrast, the p53 mutants possessing mutations at either residue 273 or 281 (p53-273H/281G) do not bind detectably to this heat shock protein and generally are less efficient at forming transformed foci in culture. The transformed cell lines are tumorigenic in nude mice. Thus, two classes of p53 mutant proteins can be distinguished: p53-175H, which cooperates with ras efficiently and binds to hsc70, and p53-273H/281G, which has a reduced efficiency of transformed foci formation and does not bind hsc70. This demonstrates that complex formation between mutant p53 and hsc70 is not required for p53-mediated transformation, but rather it facilitates this function, perhaps by ensuring sequestration of the endogenous wild-type p53 protein. The positive effect on cell proliferation by these mutant p53 proteins is consistent with a role for activated p53 mutants in the genesis of colorectal carcinomas.

Animals↗
PubMed1979

A preliminary simulated iron fortification trial in South Indian preschool children.

1. The effect of fortification of food with iron to provide 10 mg elemental Fe/child per d was studied in preschool children maintained on a cereal diet, over a 5-month period. 2. The absorption of 5 mg Fe as ferrous sulphate mixed in one meal was 3.3% of the test dose and when 3.3 mg was given with each of three meals over a 2 d period the corresponding value was 4.8%. 3. The mean absorption of a test dose of ferrous ascorbate studied in twenty-four children midway through the trial was 42%. 4. The only beneficial effect of Fe fortification in this time-period in the experimental group was the prevention of the decrease in packed cell volume which occurred in the control groups.

Child, Preschool↗
PubMed1979

WHO sponsored collaborative studies on nutritional anaemia in India. The effects of ascorbic acid and protein supplementation on the response of pregnant women to iron, pteroylglutamic acid and cyanocobalamin therapy.

1. A study was conducted in two centres in southern and northern India of the effects of the addition of ascorbic acid and protein supplements to iron, pteroyglutamic acid and cyanocobalamin, in the prophylaxis and treatment of anaemia of pregnancy. 2. A dose of 500 mg ascorbic acid/d had no beneficial effect. Women who received 15 g calcium caseinate/d showed a superior haematological response. The reasons for this are unknown, but are more likely attributable to an increased absorption of the supplemental iron than to the correction of a protein deficiency.

Anemia, Hypochromic↗
PubMed1979

WHO sponsored collaborative studies on nutritional anaemia in India. The effect of parenteral iron administration in the control of anaemia of pregnancy.

1. The relative efficacy of oral and parenteral iron administration in the prophylaxis and treatment of Fe-deficiency anaemia of pregnancy has been studied. 2. Intravenous administration of Fe by total dose infusion of Fe dextran was not superior to oral Fe 120 mg/d, 6 d/week for 10-12 weeks. 3. Intramuscular Fe dextran, 100 mg twice per week for 10-12 weeks, produced a significantly greater rise in mean haemoglobin concentration than oral Fe therapy. 4. The superiority of intramuscular Fe as compared with intravenous Fe is probably related to the different handling of the Fe dextran by the reticulo-endothelial system. 5. In spite of the better response to intramuscular Fe dextran, it is not recommended for public health practice because of the risks associated with its use and the much higher cost of the preparation and its delivery.

Administration, Oral↗
PubMed1979

Nutritional anemia: its understanding and control with special reference to the work of the World Health Organization.

Since 1949, the World Health Organization, recognizing the public health importance of nutritional anemia, has sponsored efforts directed towards its understanding and control. During this period, often as a result of the work of the Organization, advances have been made in many areas. Basic understanding of iron, folate and vitamin B12 nutrition, and the various factors which may influence the availability and requirements of these factors, has greatly increased. Surveys in a number of countries have highlighted the widespread prevalence of nutritional anemia, particularly in developing countries. The major factor responsible is a deficiency of iron, whith folate deficiency also playing a role in some population groups, especially in preganant women. There is increasing evidence that anemia adversely affects the health of individuals and may have profound socioeconomic consequences. Control of nutritional anemia is possible by providing the deficient nutrient(s) either as therapeutic supplements or by fortification of commonly used foodstuffs. Some control programs are reviewed and suggestions for further action outlined. The Organization still has an important role to play in this field, encouraging the development of control programs and providing advice and technical assistance ot member countries.

Adolescent↗
PubMed1978

Studies in iron supplementation of preschool children.

1. The effect of daily supplements of 20-30 mg inorganic iron as ferrous sulphate on the growth, activity and haematological status of preschool children was studied for 3.5, 7 and 12 months and compared to that of children who served as controls. All children were given their daily requirements of energy and protein. In addition, they received 5 microgram cyanocobalamin and 200 microgram folic acid. 2. Fe supplementation increased the haemoglobin, serum Fe and percentage saturation of transferrin and reduced the unsaturated Fe-binding capacity significantly compared to corresponding values for the controls. 3. Height and activity were unaffected by Fe supplements. 4. Of the children 45% had haemoglobin values below 110 g/l at the end of 7-12 months of Fe supplementation.

Body Height↗
PubMed1978

Faecal flora of South Indian infants and young children in health and with acute gastroenteritis.

The faecal flora of 29 healthy infants and young children was compared with that of 49 children of similar age and socio-ecomonic status with acute gastroenteritis. In the healthy children the most common organisms in the faeces were bifidobacteria, veillonellae, enterobacteria and enterodocci with anaerobes outnumbering aerobes. Most members of the noraml faecal flora were present in the diarrhoeal stools, but anaerobes were signigicantly reduced in number and enterobacteria were significantly increased, thereby altering the ratio of anaerobes to aerobes. The alterations in the flora were not related to the nature of the aetiological agent or to the severity of the diarrhoea. The changes appeared to be a direct result of the altered colonic environment produced by the diarrhoeal state. In 13 of the 28 patients from whom bacterial pathogens were isolated, the pathogens were the predominant faecal organsims.

Actinomycetaceae↗