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Biomedical subjects

W Gregory

Publications and source records attributed to W Gregory.

At least 37 records · Page 2Linked to original sources
PubMed1992

Characterization of the signal for rapid internalization of the bovine mannose 6-phosphate/insulin-like growth factor-II receptor.

The signal for rapid internalization of the mannose 6-phosphate/insulin-like growth factor II receptor has been localized to the sequence Tyr-Lys-Tyr-Ser-Lys-Val in positions 24-29 of its 163-residue cytoplasmic tail. Most of the activity of this signal is mediated by the carboxyl 4 amino acids, especially Tyr26 and Val29 (Canfield, W. M., Johnson, K. F., Ye, R. D., Gregory, W. and Kornfeld, S. (1991) J. Biol. Chem. 266, 5682-5688). In this study, we have tested the effect of a series of mutations on the internalization rate of a mutant receptor that contains a 29-amino acid cytoplasmic tail terminating with the 4-amino acid internalization sequence Tyr-Ser-Lys-Val. Replacement of Tyr26 with Phe or Trp gave rise to mutant receptors that were internalized at 10% the wild-type rate, while receptors with Ala, Leu, Ile, Val, or Asn at this position were totally inactive. Val29 could be replaced by other large hydrophobic residues (Phe, Leu, Ile, or Met) with no loss of activity, but the presence of Ala, Gly, Arg, Gln, or Tyr in this position inactivated the signal. Ser27 could be effectively replaced by many different amino acids, but not by Pro or Gly. However, Gly27 could be tolerated if the residues at positions 28 and 29 were also changed. A change in the 2-residue spacing between Tyr26 and Val29 destroyed the signal. These data show that the essential elements of this signal are an aromatic residue, especially a Tyr in the first position, separated from a large hydrophobic residue in the last position by 2 amino acids. The residues in positions 2 and 3 of the signal may have a modulating effect on its activity. The Tyr-Ser-Lys-Val signal could be moved to a more proximal region of the cytoplasmic tail with only a modest loss of activity. In addition, the signal could be effectively replaced by the putative 4-residue signals of seven other receptors and membrane proteins known to undergo rapid endocytosis, including the Tyr-Thr-Arg-Phe sequence of the transferrin receptor, a Type II membrane protein. These results are compatible with the 4-residue signals of this type being interchangeable, even among Type I and Type II membrane proteins.

Amino Acid Sequence↗
PubMed1992

Clinical pharmacokinetics of epirubicin: the importance of liver biochemistry tests.

The influence of liver biochemistry tests on epirubicin pharmacokinetics has been investigated in 52 women with advanced breast cancer, 27 of whom had radiologically proven liver metastases. Patients received epirubicin 12.5-120 mg m-2 given as an i.v. bolus. Epirubicin levels were measured by HPLC following the first cycle of treatment. Epirubicin elimination, expressed as clearance (dose/AUC), in the 22 patients with normal AST and bilirubin was compared with that of 30 patients with a raised AST +/- raised bilirubin. Epirubicin clearance was significantly reduced in the patients with a raised AST, whether their serum bilirubin was normal (22 patients) or elevated (eight patients). In the 30 patients with a raised AST +/- raised bilirubin, epirubicin clearance correlated strongly with the level of AST (r = -0.72) but not with serum bilirubin, alkaline phosphatase, albumin or creatinine. Using a multiple regression analysis, AST was the only one of these biochemical variables predictive of epirubicin clearance (r2 = 0.47, P = 0.0006). We conclude that a raised serum AST is a more sensitive and reliable measure of abnormal epirubicin pharmacokinetics than increased bilirubin. These findings have implications for anthracycline treatment in patients with abnormal liver biochemistry.

Adult↗
PubMed1992

Patterns of survival in patients with advanced Hodgkin's disease (HD) treated in a single centre over 20 years.

A total of 164 consecutive adults with newly confirmed stage IIIB, IVA or IVB Hodgkin's disease (HD) commenced cyclical combination chemotherapy comprising mustine, vinblastine, prednisolone and procarbazine (MVPP) every 6 weeks (145 patients) or minor variants (19) at St Bartholomew's Hospital between 1968 and 1984. The median follow-up period is 14 years. Complete remission (CR) was achieved in 97/164 (59%) and partial remission (PR) in 23/164 (14%) with lesser responses or death being documented in 44. Achievement of CR correlated with stage, serum albumin and serum beta2 microglobulin level at presentation on univariate and multivariate analysis; 55/97 (58%) remain in continuous CR, the median duration of remission not having been reached. Twelve patients died in first remission; there have been 30 recurrences, one occurring after 13 years. Second remission was achieved in 17/30; 6/17 remain in continuous second remission and two have died in second remission. There have been nine second recurrences, third remission being achieved in 6/9. Two continue in third remission, two patients have died in third remission: 82/164 patients are alive with a minimum follow-up of 6 years. Eighty-two patients have died; 66 with evidence of HD, six with second malignancy, one each of haemorrhage and infection, eight of unrelated causes, the cause of death was unknown in one. The overall median survival from presentation is 14 years, being the same for patients in CR and PR with minimal residual abnormality (good partial remission, GPR), and being better for those for whom remission was achieved than those for whom it was not. The median survival following first recurrence is 4 years, being significantly longer for younger patients (less than 50 years). These results emphasise the importance of long-term follow-up to determine the clinical course of HD and are vital for planning experimental chemotherapy at the time of early treatment failure or recurrence.

Adolescent↗
PubMed1992

The pharmacogenetics of chemical carcinogenesis.

The human body is endowed with a large number of xenobiotic chemical metabolizing enzymes, a significant proportion of which are polymorphic and thus render one individual at greater or lesser risk than another of chemically-induced disease. All examples of genetic polymorphism of chemical metabolizing enzymes have been reviewed in relation to their potential to activate and detoxicate procarcinogens and promutagens. Many examples are cited whereby phenotype can act as a carcinogenic risk factor. With the availability of a large amount of DNA sequence data for chemical metabolizing enzymes there has emerged a number of polymerase chain reaction (PCR) strategies aimed at discerning one metabolic phenotype or another. This is seen as a very positive and democratic scientific development, widening the franchise for studies of disease risk. Nevertheless, it is argued that, at these early stages with many laboratory-based scientists scarcely familiar with epidemiological study design, a cautious approach should obtain when interpreting single studies.

Animals↗
PubMed1992

Exertional dyspnea and ventilation in hyperthyroidism.

Dyspnea is recognized to be an important feature in patients with hyperthyroidism at rest and during exercise. However, its etiology is not well-understood. Since dyspnea is thought to be related to the perception of excessive ventilatory effort, we explored the possibility that dyspnea in these patients might be related to an inappropriate ventilatory response to the increased metabolic rate. We studied 11 hyperthyroid patients and 11 age- and sex-matched controls, performing spirometry, lung volumes, mouth pressure measurements, and incremental exercise test. Central drive was estimated by measuring P0.1 and sensation of dyspnea by the Borg scale. We found that hyperthyroid patients (1) have higher ventilation than normal subjects during exercise even when corrected for VCO2 levels; (2) this increased ventilation is secondary to increased central drive which is correlated to the T3ria level (r = 0.85, p less than 0.01); (3) hyperthyroid patients are more dyspneic than controls; and (4) the increased drive can be normalized by beta-blockade. We conclude that the main ventilatory abnormality in hyperthyroid patients is an inappropriate increase in respiratory drive, possibly secondary to increased adrenergic stimulation.

Adult↗
PubMed1991

Localization of the signal for rapid internalization of the bovine cation-independent mannose 6-phosphate/insulin-like growth factor-II receptor to amino acids 24-29 of the cytoplasmic tail.

The signal for the rapid internalization of the cation-independent mannose 6-phosphate/insulin-like growth factor-II receptor has been previously localized to the inner half of the 163-amino acid cytoplasmic tail, including tyrosine 24 and tyrosine 26 (Lobel, P., Fujimoto, K., Ye, R. D., Griffiths, G., and Kornfeld, S. (1989) Cell 57, 787-796). To define this signal more precisely, we generated a series of truncation and substitution mutants and analyzed them for their ability to mediate the endocytosis of extracellular lysosomal enzymes. Mutant receptors containing cytoplasmic domains of 29 or more amino acids functioned normally in endocytosis whereas a mutant receptor with a 28-amino acid cytoplasmic domain was internalized extremely slowly. Alanine scanning of the region between amino acids 19 and 30 identified tyrosine 26 and valine 29 as the most important residues for rapid receptor internalization. Tyrosine 24 and lysine 28 also contributed to the signal while the other amino acids were not critical. The tyrosine residues could be substituted with phenylalanines with no loss of activity, indicating the requirement for an aromatic residue in these positions rather than tyrosine specifically. Conservative substitutions of arginine or histidine for lysine 28 also preserved the internalization signal. These results indicate that the sequence Tyr-Lys-Tyr-Ser-Lys-Val serves as the internalization signal for the mannose 6-phosphate/insulin-like growth factor-II receptor. The crucial elements of this sequence are present in the cytoplasmic tails of a number of other membrane receptors and proteins known to undergo rapid internalization.

Amino Acid Sequence↗
PubMed1990

Gene amplification on chromosome band 11q13 and oestrogen receptor status in breast cancer.

We have analysed DNA from 183 primary breast cancers for amplification or rearrangement of a number of cellular proto-oncogenes, focusing primarily on a cluster of markers on the long arm of chromosome 11. Two of these oncogenes, INT2 and HST1, both of which encode members of the fibroblast growth factor family, are implicated in the generation of virally induced mammary tumours in mice. Here we confirm earlier reports that the q13 region of chromosome 11, in which these genes are tandemly linked, is modestly amplified in approximately 15% of primary human breast cancers. This amplification is confined, with one exception, to cases in which the oestrogen receptor (ER) levels are in excess of 20 fmol/mg protein (P = 0.001). However, DNA amplification does not usually result in detectable expression of either the INT2 or HST1 gene. The data imply that some other gene in the vicinity must contribute to the development of a subset of ER-positive tumours and that assessing the amplification of this region of DNA may be of value in defining a separate category of ER-positive tumour.

Adult↗
PubMed1990

High dose cytosine arabinoside in the initial treatment of adults with acute lymphoblastic leukaemia.

In a study conducted at St Bartholomew's Hospital between 1972 and 1982, using moderately intensive therapy (OPAL/HEAV'D), a low blast count at presentation (less than 10 x 10(9) 1(-1)) and common ALL (C-ALL) phenotype correlated favourably with duration of remission. Fifty-four patients (age range 15-57, median 32) subsequently received a modification of the previous treatment programme which included high-dose ara-C 2 g m-2 b.d. for 6 days as cycle 3 (OPAL + HD ARA-C). CR was achieved in 36/54 (67%) patients, response correlating favourably with younger age (15-30 years vs 31-57 years, P = 0.02). Three patients died in CR. Overall, there was no difference in survival or remission duration between patients who received high dose ara-C and those in the control group. However, in contrast to the early results, there was a reversal in the relevance of the prognostic factors with a trend in favour of high blast count (greater than 10 x 10(9) 1(-1)) and T-cell phenotype in terms of remission duration. Moreover, comparison of duration of remission for the previously defined prognostic groups according to therapy suggests that the prognosis of patients with 'high risk' disease (T, B, null ALL or high blast count) is improved with more intensive therapy. In contrast, those with 'low risk' disease (C-ALL and low blast count) have a better prognosis with less intensive therapy. These observations confirm those of others and allow for individualization of therapy on the basis of pre-treatment variables.

Adolescent↗
PubMed1989

Ligand interactions of the cation-independent mannose 6-phosphate receptor. The stoichiometry of mannose 6-phosphate binding.

The interaction of the bovine cation-independent mannose 6-phosphate receptor with a variety of phosphorylated ligands has been studied using equilibrium dialysis and immobilized receptor to measure ligand binding. The dissociation constants for mannose 6-phosphate, pentamannose phosphate, bovine testes beta-galactosidase, and a high mannose oligosaccharide with two phosphomonoesters were 7 X 10(-6) M, 6 X 10(-6) M, 2 X 10(-8) M, and 2 X 10(-9) M, and the mol of ligand bound/mol of receptor monomer were 2.17, 1.85, 0.9, and 1.0, respectively. We conclude that the cation-independent mannose 6-phosphate receptor has two mannose 6-phosphate-binding sites/polypeptide chain.

Acetylglucosamine↗
PubMed1988

Bone marrow transplantation for chronic myeloid leukaemia in first chronic phase: importance of a graft-versus-leukaemia effect.

We analysed the incidence of graft failure, graft-versus-host disease (GVHD) and relapse of leukaemia in 208 patients undergoing allogeneic bone marrow transplantation (BMT) for chronic myeloid leukaemia in chronic phase in eight transplant centres in Europe and the United States. 106 patients received unmanipulated donor bone marrow (Group 1) and 102 patients received marrow depleted of T-cells by incubation with the monoclonal antibodies Campath-1 or CT-2 and complement (Group 2). The incidence of graft failure was higher and of GVHD was lower in Group 2 than in Group 1. Relapse of leukaemia occurred more frequently in patients in Group 2 than in Group 1 (17 v. 2, P less than 0.001). Multivariate analysis showed that the following factors were associated with an increased risk of relapse: the use of T-cell depletion, the absence of GVHD and a high platelet count at the time of admission for transplant. The findings support the concept that a graft-versus-leukaemia effect mediated by T-lymphocytes is important for cure of leukaemia after BMT.

Adolescent↗
PubMed1987

Failure to preserve fertility in patients with Hodgkin's disease.

The hypothesis that the "down-regulated" gonad is less vulnerable to the effects of cytotoxic chemotherapy for advanced Hodgkin's disease has been investigated. Thirty men and eighteen women were randomly allocated to receive an agonist analogue of gonadotrophin-releasing hormone prior to, and for the duration of, cytotoxic chemotherapy. Buserelin (d-Ser-[TBU]6 LHRH ethylamide) was prescribed in two different dosage schedules to twenty men, and in a single dosage schedule to eight women. A standard gonadotrophin-releasing hormone test (GnRH 100 micrograms) was performed 1 week prior to and on day 1 of each cycle of chemotherapy. In all patients peak luteinizing hormone responses to GnRH were suppressed throughout treatment. The higher of the two dosage schedules used in the men caused more effective suppression of luteinizing hormone, and both regimens led to an initial suppression of peak follicle-stimulating hormone responses to GnRH, which was not maintained. At follow-up assessment up to 3 years from the completion of treatment, all men treated with buserelin were profoundly oligospermic and four of the eight women were amenorrhoeic. All ten male controls were profoundly oligospermic, and six of nine female controls were amenorrhoeic. In the dosages and schedules investigated, buserelin was ineffective in conserving fertility.

Amenorrhea↗