Biomedical subjects
G R Jones
Publications and source records attributed to G R Jones.
Tumorigenicity and oncogene expression in pediatric cancers.
Cytogenetic and epidemiological studies of pediatric cancers have implicated a loss of genetic information in the development of these tumors. In contrast, other studies have shown that activation of endogenous oncogenes is a common event in these cancer cells. The technique of somatic cell hybridization provides a model for investigating the interaction between loss of genetic elements and oncogene activation in pediatric cancers. A variety of human-human cell hybrids were formed between a tumorigenic adult carcinoma and representative tumorigenic pediatric cell lines. All hybrid cells were completely suppressed for tumor-forming ability when assayed in nu/nu (nude) mice. When the expression of the N-myc, c-myc, and sis oncogenes and tumorigenicity were examined in the same hybrid cells, no correlation was found, suggesting that the expression of these oncogenes in these hybrid cells did not appear to be controlled by putative "tumor suppressor" genes. Thus, tumorigenicity behaves as a recessive genetic trait in pediatric cancers. Furthermore, different genetic elements may be lost during tumor development of adult cancers as opposed to pediatric cancers.
Percutaneous ultrasound-guided esophagostomy.
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The interaction between heparin and antithrombin III: a comparison of two different heparin-dye conjugates.
The interactions of antithrombin III with two heparin-dye conjugates have been compared using their fluorescence anisotropy. The first, heparin labelled with 5-isothiocyanatofluorescein, where the dye was mostly bound to unsulphated glucosamine residues, exhibited binding which was characteristic of heparin with a low affinity for antithrombin III. The second, heparin labelled with a reactive naphthalene dye (DENMT), showed similar binding character. However, when the heparin was treated with an amino group blocking agent prior to labelling with DENMT, the resultant heparin-dye conjugate showed binding behaviour, the strength of which was consistent with heparin molecules having both high and low affinity for antithrombin III. Heparin molecules with a high affinity for antithrombin III did not possess free amino groups. The implications of these findings are discussed with regard to the reliability of the data obtained using heparin-fluorescein conjugates.
Introduction of a normal human chromosome 11 into a Wilms' tumor cell line controls its tumorigenic expression.
The development of Wilms' tumor, a pediatric nephroblastoma, has been associated with a deletion in the p13 region of chromosome 11. The structure and function or functions of this deleted genetic material are unknown. The role of this deletion in the process of malignant transformation was investigated by introducing a normal human chromosome 11 into a Wilms' tumor cell line by means of the microcell transfer technique. These variant cells, derived by microcell hybridization, expressed similar transformed traits in culture as the parental cell line. Furthermore, expression of several proto-oncogenes by the parental cells was unaffected by the introduction of this chromosome. However, the ability of these cells to form tumors in nude mice was completely suppressed. Transfer of other chromosomes, namely X and 13, had no effect on the tumorigenicity of the Wilms' tumor cells. These studies provide support for the existence of genetic information on chromosome 11 which can control the malignant expression of Wilms' tumor cells.
Improved detection of metastatic Ewing's sarcoma with the use of bone marrow scintigraphy.
Prognosis in Ewing's sarcoma is inversely related to the extent of the disease at the time of presentation. The most common sites of metastases are the lungs and skeleton. Bone marrow metastases may be present but clinically silent. We report the use of Technetium (Tc)-99m bone marrow scintigraphy to detect sites of marrow involvement by metastatic Ewing's sarcoma. This method of evaluation allowed identification of sites of involvement by Ewing's sarcoma that were not available by any other method of evaluation. In several instances, information provided by this method was pivotal in the management of these patients. Based on this small series of patients, bone marrow scintigraphy appears to be a sensitive modality in the detection of metastatic disease in patients with Ewing's sarcoma. Better understanding of the role of bone marrow scanning and its correlation with other diagnostic procedures in Ewing's sarcoma will require further study.
Transient blastemia in phenotypically normal newborns.
Two normal appearing infants presented in the newborn period with elevated white blood cell counts and immature blast cells. Initial bone marrow karyotype analysis showed trisomy of chromosome 21 in all metaphases. In both patients blastemia spontaneously resolved and percentage of trisomy 21 cells decreased. One infant required multiple exchange transfusions and pericardiotomy. The other patient had undifferentiated blasts and continued to have subtle hematopoietic abnormalities greater than 2 years later. Both children have had normal growth and development. The clinical course of these patients emphasizes the need for aggressive supportive care without use of cytotoxic drugs in phenotypically normal newborns with blastemia showing trisomy 21.
Dysbaric osteonecrosis (caisson disease of bone): are active oxygen species and the endocrine system responsible, and can control of the production of free radicals and their reaction products confer protection?
The development of osteonecrosis after exposure to altered air pressures is consistent with cellular injury brought about by active oxygen species. The syndrome is considered to arise as a result of an unusual combination of circumstances in which hyperoxia itself, together with the additive responses of the endocrine system to hyperoxia, hypothermia and exertion, each appear to play a part; the net result is thought to increase the mitochondrial generation of superoxide. It is suggested that effective prophylaxis may be possible primarily by establishing a nutritional status that is adequate to ensure that the functional activities of radical-scavenging systems are not hampered by deficiencies either of essential trace elements or of vitamin E. Pharmacological pretreatments designed both to decrease excessive levels of superoxide through increased catalysis of anionic dismutation and to attenuate enzyme-dependent peroxidation may provide an additional line of defence.
The anti-sickling drug lawsone (2-OH-1,4-naphthoquinone) protects sickled cells against membrane damage.
The ability of an anti-sickling drug lawsone, 2-OH-1,4-naphthoquinone, and two related compounds to inhibit the haematoporphyrin-sensitised photohaemolysis of normal and sickle cell erythrocytes has been investigated. The compounds appear to protect the erythrocyte membranes by reaction with transient oxidative species. Differential effects between normal and sickle cells are shown and these are attributed to the different membrane composition of irreversibly sickled erythrocytes. This report describes a possible basis for the decreased formation of irreversibly sickled cells in the presence of lawsone.
A comparison of the strength of binding of antithrombin III, protamine and poly(L-lysine) to heparin samples of different anticoagulant activities.
The limiting concentrations, i.e., those concentrations of sodium chloride required to completely disrupt the complexes of heparin with antithrombin III, protamine and poly(L-lysine), were determined using fluorescence techniques, in order to compare the binding strengths of these complexes. From the limiting salt concentration values, poly(L-lysine) always exhibited stronger binding to heparin of a particular anticoagulant potency (degree of sulphation) than did protamine. The binding strengths of both complexes decreased as the degree of sulphation of the heparin participating in the complex was reduced. In contrast, the limiting salt concentration values for complexes formed between antithrombin III and heparin did not change with either the degree of sulphation or the biological potency of the heparin samples. A low-potency heparin simply contained a smaller number of molecules which possessed the intact antithrombin III binding site (thus being fully 'anticoagulant active') than a high-potency sample. Low-affinity heparin did not contain these binding sites and thus showed a low affinity for antithrombin III. High-potency heparin, being highly sulphated, possessed a higher affinity for protamine and poly(L-lysine) than for antithrombin III. However, after partial N-desulphation of heparin, the subsequent heparin-protamine complex was more weakly bound than a significant proportion of the corresponding heparin-antithrombin III complexes. These in vitro findings may have particular relevance in relation to the clinical condition termed 'heparin rebound'.
In vitro neutralization of heparin in plasma prior to the activated partial thromboplastin time test: an assessment of four heparin antagonists and two anion exchange resins.
This study was carried out to investigate the effects on the activated partial thromboplastin time test (APTT) when heparin in plasma was neutralized with protamine, Polybrene(R), poly-DL-lysine, or heparin neutralizing activity (HNA) extracted from platelets; or removed by means of the anion exchange resins TEAE cellulose or ECTEOLA cellulose. The effect on the APTT of adding the polycations protamine, Polybrene or poly-DL-lysine to citrated plasma was examined. The formation of heparin/polycation complexes was studied by means of their light scattering properties. The low yields of platelet HNA obtained excluded this from practical use as an in vitro heparin antagonist. ECTEOLA cellulose was unable to remove plasma heparin at levels as low as 1 U/ml by the technique employed. TEAE cellulose was able to efficiently remove at least 40 U of heparin from 1 ml of plasma but also caused a non-specific prolongation of the APTT. The polycations protamine, Polybrene, and poly-DL-lysine, possessed clot promoting activity at low concentrations and acted as anticoagulants in their own right at higher concentrations. At a plasma heparin concentration of 4 U/ml, protamine was the most efficient neutralizer of heparin, while at 10 U/ml, Polybrene was the most effective in this respect. It was concluded that care must be taken in the interpretation of the APTT after heparin neutralization or removal as heparin antagonist induced non-specific effects may be present.
Urinary polyamine excretion by tumor-bearing and tumor-free mice exposed to cyclophosphamide, 5-fluorouracil and 6-mercaptopurine.
The effects of cytostatic treatment on urinary polyamine excretion have been investigated in tumor-bearing (either Ehrlich carcinoma of S 180 sarcoma) and in tumor-free mice. The animals were exposed to single or multiple treatment with various doses of cyclophosphamide, 5-fluorouracil, or 6-mercaptopurine. Treatment invariably enhanced polyamine excretion dependent on dose and effectiveness of the cytostatic drug. The most pronounced increases were observed in the excretion of spermine and putrescine, with peak excretion usually occurring after 1-2 and 3-4 days, respectively. The urinary excretion of spermidine was relatively modest in untreated mice, but the increases observed following drug treatment were high in proportion. Significant differences in urinary polyamine excretion were observed between tumor-free and tumor-bearing animals following treatment with all cytostatic agents. Peak values were invariably higher in tumor-bearing mice even in those with small, barely detectable tumors. After discontinuation of treatment polyamine excretion returned to normal values and stabilized in groups in which regression predominated, whereas in those groups of animals which showed little or no tumor regression urinary polyamine levels gradually increased again during a 2-week observation period.
Free radicals in immunological killing: the case of tumor necrotising factor (TNF).
There is now considerable evidence that in many circumstances free radical activity constitutes not only an early but also an essential event in the causation of cell death in vivo. It is proposed that the cytotoxic effect of TNF against tumours may be exerted in like manner, by stimulating the generation of hydroxyl radicals which leads in turn to an upset of energy metabolism, and hence to cell death. Simple experimental protocols are indicated for testing the proposal at various stages.
Effects of Bacteroides asaccharolyticus cells and B. fragilis surface components on serum opsonisation and phagocytosis.
The effect of Bacteroides asaccharolyticus on the opsonisation and phagocytosis of gram-positive and gram-negative bacteria by human polymorphonuclear leukocytes (PMNL) was investigated. Uptake of most isolates of staphylococci, streptococci and clostridia by PMNL after opsonisation with serum treated with B. asaccharolyticus was largely unimpaired. The same treatment of serum before opsonisation of isolates of Pseudomonas, Enterobacter, Klebsiella and Gardnerella resulted in the uptake by PMNL varying with individual isolates; a large reduction occurred with some and none with others. Treatment of serum with B. fragilis lipopolysaccharide before opsonisation of Proteus mirabilis produced a marked reduction in uptake, whereas treatment with B. fragilis capsular polysaccharide had little effect.
Metastatic follicular carcinoma of the thyroid presenting with thyrotoxic induced impaired control of diabetes mellitus.
We report a patient with pulmonary and bony metastases due to follicular carcinoma of the thyroid, occurring 12 years after the initial diagnosis. This was brought to light by worsening diabetic control due to thyrotoxicosis from functioning malignant thyroid tissue. Following radio-active iodine therapy, she remains well with good control of her diabetes.
The effect of short term intensive insulin therapy in non-insulin-dependent diabetics who had failed on sulphonylurea therapy.
To determine the effect of short term intensive insulin therapy in non-insulin-dependent diabetes mellitus (NIDDM) we studied 10 patients who had been on maximal doses of sulphonylurea therapy, with a glycosylated haemoglobin value persistently above the normal range. All patients were non-ketonuric, had negative islet cell antibodies, and had been on sulphonylureas for a mean duration of 5.6 yr. Patients were maintained at euglycaemia (plasma glucose 4-7 mmol/l) for 24 hr using an open-loop intravenous insulin regimen, and then underwent a standard 75 g oral glucose tolerance test (OGTT). This was repeated after 3 months of treatment with insulin. Mean fasting plasma glucose and glycosylated haemoglobin were 10.1 mmol/l and 12.2% respectively before, and 7.1 mmol/l (p less than 0.001) and 8.4% (p less than 0.001) after treatment. There was no significant change in body weight. Plasma insulin and C-peptide responses to 75 g OGTT did not change significantly, but the total amount of intravenously infused insulin required for 24-hr euglycaemia fell from a mean value of 138 u before treatment to 87 u (p less than 0.001) at the end of insulin therapy. Remission, with glycosylated haemoglobin in the normal range for more than 3 months after stopping insulin, was observed in 5 out of the 10 patients. All 5 who failed to achieve remission had markedly blunted maximal insulin responses of less than 10 mu/l on both OGTT's. Our study shows that insulin treatment in NIDDM appears to exercise a beneficial effect by lowering insulin resistance. We suggest that this may be of advantage early on in patients with NIDDM in preserving B-cell reserve.
Cancer therapy: phenothiazines in an unexpected role.
Four lines of evidence (clinical findings, epidemiology, inhibition of tumor growth together with prolongation of survival time, and mechanism of action) which suggest that certain phenothiazines, particularly chlorpromazine, possess a range of anti-neoplastic activities in man and in rodents which has not been generally recognised are reviewed and discussed. Chlorpromazine interferes with energy production in sensitive tumours; the mode of action appears to correspond to autooxidative cellular injury, a common form of cell death.