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Biomedical subjects

A Slater

Publications and source records attributed to A Slater.

At least 19 recordsLinked to original sources
PubMed1999

Induction of MDR1 gene expression by anthracycline analogues in a human drug resistant leukaemia cell line.

The effects of 4-demethoxydaunorubicin (idarubicin, IDA) and MX2, a new morpholino-anthracycline, on up-regulation of the MDR1 gene in the low-level multidrug resistant (MDR) cell line CEM/A7R were compared at similar concentrations (IC10, IC50 and IC90) over a short time exposure (4 and 24 h). The chemosensitivity of each drug was determined by a 3-day cell growth inhibition assay. Compared with epirubicin (EPI), IDA and MX2 were 17- and eightfold more effective in the CEM/A7R line respectively. No cross-resistance to 5-FU was seen in the CEM/A7R line. Verapamil (5 microM) and PSC 833 (1 microM), which dramatically reversed resistance to EPI in the CEM/A7R line, had no sensitizing effect on the resistance of this line to MX2, but slightly decreased resistance to IDA. The sensitivity to 5-FU was unchanged by these modulators. The induction of MDR1 mRNA expression by IDA, MX2 and 5-FU was analysed by Northern blotting and semiquantitatively assessed by scanning Northern blots on a phosphorimager. The relative level of MDR1 expression was expressed as a ratio of MDR1 mRNA to the internal RNA control glyceraldehyde-3-phosphate dehydrogenase (GAPDH). IDA, MX2 and 5-FU differentially up-regulated MDR1 mRNA in the CEM/A7R line in a dose-dependent manner. Both IDA and MX2 induced MDR1 expression within 4 h. 5-FU up-regulated MDR1 expression only when drug exposure was prolonged to 24 h. Based on MRK 16 binding, flow cytometric analysis of P-glycoprotein (Pgp) expression paralleled the increase in MDR1 mRNA levels. For the three anthracyclines, the increase in MDR1 expression was stable in cells grown in the absence of drug for more than 3 weeks after drug treatment. The induction of MDR1 expression by 5-FU was transient, associated with a rapid decrease in the increased Pgp levels which returned to baseline 72 h after the removal of 5-FU. This study demonstrates that MDR1 expression can be induced by analogues of anthracyclines not pumped by Pgp, and that this induction appears to be stable despite a 3-week drug-free period.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

The plant cell cycle in context.

Biological scientists are eagerly confronting the challenge of understanding the regulatory mechanisms that control the cell division cycle in eukaryotes. New information will have major implications for the treatment of growth-related diseases and cancer in animals. In plants, cell division has a key role in root and shoot growth as well as in the development of vegetative storage organs and reproductive tissues such as flowers and seeds. Many of the strategies for crop improvement, especially those aimed at increasing yield, involve the manipulation of cell division. This review describes, in some detail, the current status of our understanding of the regulation of cell division in eukaryotes and especially in plants. It also features an outline of some preliminary attempts to exploit transgenesis for manipulation of plant cell division.

Amino Acid Sequence↗
PubMed1998

Innate and learned perceptual abilities in the newborn infant.

From research carried out over the last few years, it has become apparent that the visual world of the newborn baby (0-7 days from birth) is highly organised. It is also clear that the newborn infant is an extremely competent learner. These themes are illustrated with respect to two areas of research, face perception and intermodal learning. Evidence is presented suggesting that the human face is "special" in that newborns respond to them as faces, rather than merely collections of stimulus elements. Additional evidence is presented which demonstrates that newborns can form auditory-visual associations after only a short exposure to the stimulation. These lines of evidence suggest that innate capacities, or modules, facilitate and direct early learning in order to allow newborn infants to understand their newly encountered world.

Humans↗
PubMed1998

Engineered human carboxypeptidase B enzymes that hydrolyse hippuryl-L-glutamic acid: reversed-polarity mutants.

Variants of human pancreatic carboxypeptidase B (HCPB), with specificity for hydrolysis of C-terminal glutamic acid and aspartic acid, were prepared by site-directed mutagenesis of the human gene and expressed in the periplasm of Escherichia coli. By changing residues in the lining of the S1' pocket of the enzyme, it was possible to reverse the substrate specificity to give variants able to hydrolyse prior to C-terminal acidic amino acid residues instead of the normal C-terminal basic residues. This was achieved by mutating Asp253 at the base of the S1' specificity pocket, which normally interacts with the basic side-chain of the substrate, to either Lys or Arg. The resulting enzymes had the desired reversed polarity and enzyme activity was improved significantly with further mutations at residue 251. The [G251T,D253K]HCPB double mutant was 100 times more active against hippuryl-L-glutamic acid (hipp-Glu) as substrate than was the single mutant, [D253K]HCPB. Triple mutants, containing additional changes at Ala248, had improved activity against hipp-Glu substrate when position 251 was Asn. These reversed-polarity mutants of a human enzyme have the potential to be used in antibody-directed enzyme prodrug therapy of cancer.

Alanine↗
PubMed1997

Paediatric index of mortality (PIM): a mortality prediction model for children in intensive care.

OBJECTIVE: To develop a logistic regression model that predicts the risk of death for children less than 16 years of age in intensive care, using information collected at the time of admission to the unit. DESIGN: Three prospective cohort studies, from 1988 to 1995, were used to determine the variables for the final model. A fourth cohort study, from 1994 to 1996, collected information from consecutive admissions to all seven dedicated paediatric intensive care units in Australia and one in Britain. RESULTS: 2904 patients were included in the first three parts of the study, which identified ten variables for further evaluation. 5695 children were in the fourth part of the study (including 1412 from the third part); a model that used eight variables was developed on data from four of the units and tested on data from the other four units. The model fitted the test data well (deciles of risk goodness-of-fit test p = 0.40) and discriminated well between death and survival (area under the receiver operating characteristic plot 0.90). The final PIM model used the data from all 5695 children and also fitted well (p = 0.37) and discriminated well (area 0.90). CONCLUSIONS: Scores that use the worst value of their predictor variables in the first 12-24 h should not be used to compare different units: patients mismanaged in a bad unit will have higher scores than similar patients managed in a good unit, and the bad unit's high mortality rate will be incorrectly attributed to its having sicker patients. PIM is a simple model that is based on only eight explanatory variables collected at the time of admission to intensive care. It is accurate enough to be used to describe the risk of mortality in groups of children.

Adolescent↗
PubMed1997

Altered methylation of the human MDR1 promoter is associated with acquired multidrug resistance.

One of the most important forms of drug resistance in acute myeloid leukemia is the multidrug resistance (MDR) phenotype, which is characterized by the expression of the MDR1 gene product, P-glycoprotein. Although a number of factors affect MDR1 gene expression, the genetic events that "switch on" the human MDR1 gene in tumor cells that were previously P-glycoprotein negative have remained elusive. Here, we report evidence that the methylation status of the human MDR1 promoter may serve as a basis for this "switch." Based on Southern analysis using methylation-sensitive and methylation-insensitive restriction enzymes, a tight correlation was found between MDR phenotype and demethylation of the 5' region of the MDR1 gene in a human T cell leukemia cell line. Similar results were obtained from the analysis of P-glycoprotein-positive and P-glycoprotein-negative samples of chronic lymphocytic leukemia. Treatment of the cell lines with the demethylating agent 5'-azadeoxycytidine altered the methylation pattern of the MDR1 promoter in P-glycoprotein-negative cells to resemble that of P-glycoprotein-positive cells and activated the promoter such that MDR1 mRNA was now detectable. Treatment also resulted in an increased resistance to epirubicin and decreased daunomycin accumulation, both of which were reversible by verapamil, a characteristic of the classical MDR phenotype in cells expressing P-glycoprotein. These results suggest that the MDR phenotype may be acquired as a result of changes in methylation of the MDR1 promoter.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Increase in epithelial mast cell numbers in the nasal mucosa of patients with perennial allergic rhinitis.

The aim of the study was to compare the numbers and distribution of mast cells in the nasal mucosa of perennial allergic rhinitis (PAR) patients and controls, as demonstrated by different staining methods for light microscopy. Biopsies of inferior turbinate mucosa were taken from 10 patients with PAR and 10 patients undergoing septoplasty or septorhinoplasty (control group). Sections for light microscopy were stained with azure A. chloroacetate esterase and an ABC immunohistochemical technique using antibody to tryptase. Three times more mast cells were found in the epithelium of PAR patients compared to controls using the immunohistochemical technique (p = 0.0074). This method demonstrated considerably more mast cells than the other stains. The increase in epithelial mast cells is consistent with the migration of mast cells seen in seasonal allergic rhinitis, and this may be important in the phenomenon of nasal priming seen after repeated antigen exposure.

Cell Count↗
PubMed1996

Mucociliary function in patients with nasal polyps.

Patients with nasal polyposis complain of nasal blockage and rhinorrhoea, which may be due to impaired mucociliary clearance. The saccharine clearance time and ciliary beat frequency of samples of ciliated epithelium from patients with nasal polyps was measured. We also studied the effect of fluid from the oedematous stroma of nasal polyps and of histamine and prostaglandin (PG) D2, E2 and F2 alpha on the cilia from normal individuals. Polyp fluid was found to increase ciliary beat frequency. Histamine and PGD2 had no effect, but PGE2 and PGF2 alpha both increased ciliary beat frequency and so may cause the ciliostimulatory effect of polyp fluid. The saccharine clearance time was prolonged in three of nine patients, but ciliary beat frequency was only slightly reduced in one of these. Thus, where mucociliary clearance is reduced, it is likely to be due to abnormalities of mucus rather than impaired ciliary activity.

Cilia↗
PubMed1996

Cyclosporin A and PSC 833 prevent up-regulation of MDR1 expression by anthracyclines in a human multidrug-resistant cell line.

We have previously demonstrated that within 24 h of exposure of the CEM/A7R cell line to epirubicin (EPI), MDR1 gene expression is induced. The aim of the current study was to investigate the role of cyclosporin A (CyA) and PSC 833, two biochemical modulators of the classical multidrug-resistant phenotype, in this model. CEM/A7R cells were exposed to EPI in the presence or absence of various concentrations of CyA or PSC 833. MDR1 expression was assessed using Northern blot analysis and quantitated using a phosphorimager. P-glycoprotein (P-gp) expression was analyzed by the determination of MRK16 binding using flow cytometry. P-gp function was measured in an assay of [3H]daunomycin accumulation. The coincubation of CyA or PSC 833 with EPI prevented the increase in MDR1 gene expression induced by EPI alone. This effect of the two modulators was dose dependent. Neither modulator alone had any significant effect on the expression of MDR1. In these experiments, changes in MDR1 expression correlated with changes in P-gp levels (based on MRK16 binding) and P-gp function. Thus, both PSC 833 and CyA appear to prevent the induction of MDR1 gene expression caused by the short-term exposure of CEM/A7R cells to EPI.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Rapid up-regulation of mdr1 expression by anthracyclines in a classical multidrug-resistant cell line.

Studies were carried out in a variant human multidrug-resistant (MDR) cell line CEM/A7R, which expresses very low levels of mdr1 mRNA and P-glycoprotein (P-gp). The induction of mdr1 RNA expression by three anthracyclines, (doxorubicin, daunorubicin, epirubicin), VP-16 and two vinca alkaloids (vincristine, vinblastine) was semiquantitatively assessed by scanning Northern blots on a phosphorimager. The relative level of mdr1 expression was expressed as ratio of mdr1 to the internal RNA (actin). A significant increase (P < 0.02) in expression of mdr1 was noted within 4 hrs of exposure to 1.5 micrograms ml-1 daunorubicin or epirubicin. Neither vinblastine nor vincristine had any effect on mdr1 levels after an 8 h exposure. With increasing concentrations of daunorubicin or epirubicin in a fixed 24 h time period, mdr1 expression increased, although a biphasic response was seen. Based on MRK 16 binding, an increase in P-gp levels was seen in the CEM/A7R line after a 24 h exposure to 1 microgram ml-1 daunorubicin or epirubicin. The rapid increase in mdr1 expression after a short period of exposure to doxorubicin, daunorubicin or epirubicin suggests that induction of mdr1 expression may have an important role in the development of drug-resistant tumours.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Individual differences in infancy and later IQ.

In recent years it has been demonstrated that cognitive development from infancy to later childhood displays some degree of (correlational) continuity. Studies that have demonstrated this continuity are reviewed, focusing on measures of visual information processing, means-ends problem-solving and other cognitive indices of infant performance. Models of continuity are described and evaluated, and the relevance of the findings and models to the Nature-Nurture issue are considered, with particular attention to the related issues of the role of experience in early life, and the extent to which infant development is canalized. Theoretical and practical applications of the research are discussed.

Child↗
PubMed1995

PCR and non-isotopic labeling techniques for plant virus detection.

PCR technology permits the detection of viruses at levels several orders of magnitude lower than is possible by other methods. This high sensitivity facilitates detection of virus sequences during the early stages of infection of plants and in soil and vector samples. Early detection of beet necrotic yellow vein virus (BNYVV) in Beta vulgaris is an important part of the strategy for prevention of the spread of rhizomania, a commercially significant disease of sugar beet. A diagnostic test for BNYVV has been developed. This test involves amplification of the viral genome by PCR coupled with non-isotopic labeling and detection of specific sequences. The PCR amplification of BNYVV sequences has been optimized with respect to primer design, sample preparation and reaction conditions. Several non-isotopic labeling strategies for signal amplification have been compared. Hybridization with digoxigenin-labelled cDNA permits the most sensitive detection of PCR products and is the most appropriate method for routine diagnosis. These observations are discussed in the context of the application of PCR for detecting a wide range of viruses.

Base Sequence↗
PubMed1995

Cloning novel alfalfa cyclin sequences--a RACE-PCR approach.

Cyclins are a complex group of proteins involved in regulation of the eukaryotic cell division cycle via their interaction with cyclin dependent kinases (Cdks). Cyclin gene sequences have been cloned from a number of plant species, including alfalfa, but the diversity of these genes suggests that there are many plant cyclins which have yet to be characterized. A RACE-PCR strategy has been adopted for cloning cyclin gene sequences expressed during direct somatic embryogenesis in alfalfa. RT-PCR with nested degenerate primers was used to amplify the highly conserved "cyclin box" region of a novel A-like cyclin mRNA sequence expressed after induction of somatic embryogenesis. The sequence of this PCR product was used to design primers for 5'- and 3'-RACE protocols. 5'-RACE using a modified SLIC (single strand ligation to single stranded cDNA) procedure revealed considerable sequence heterogeneity in the N-terminal region of the coding sequence with several closely related sequences apparent. Conventional 3'-RACE generated a single cyclin sequence. The complete coding sequence of one member of this A-like cyclin subgroup has been obtained by this RACE strategy and confirmed by PCR amplification and sequencing of alfalfa genomic DNA.

Amino Acid Sequence↗
PubMed1993

Prednimustine (Sterecyt) versus cyclophosphamide both in combination with methotrexate and 5-fluorouracil in the treatment of advanced breast cancer.

153 women with advanced breast cancer were randomly allocated for treatment with SMF [prednimustine (Sterecyt) + methotrexate + 5-fluorouracil, 83 patients] or CMF (cyclophosphamide+methotrexate+5-fluorouracil, 70 patients). Prednimustine was administered orally 100 mg/m2 daily, for 5 days, and cyclophosphamide was administered orally 100 mg/m2, for 14 days, each, every 4 weeks. Methotrexate was given at a dose of 40 mg/m2 and 5-fluorouracil at 600 mg/m2 on day 1 and 8, every 4 weeks. Leucovorin was used in 39 patients to alleviate mucositis. The two treatment groups were balanced in terms of age, performance status, lymph node status, histology, menopausal status and previous therapy. Response was evaluated in 140 patients. Of 76 patients treated with SMF, 4 had a complete and 21 a partial response (CR+PR = 33%), 40 had no change (NC) and 11 had progressive disease (PD). Of 64 patients treated with CMF, 3 had a complete and 18 a partial response (CR+PR = 33%), 30 had no change (NC) and 13 had progressive disease (PD). Time to treatment failure and survival were similar in both groups. A relationship between haematological and gastrointestinal toxicity and therapeutic efficacy was demonstrated with a superior survival and response rate recorded for patients with such toxicity than in patients without. Haematological toxicity was, in general, mild to moderate with no difference between the two groups. Alopecia (P = 0.008), nausea/vomiting (P = 0.02) and euphoria (P = 0.03) were more common in the CMF-treated group. Diarrhoea was more common in the SMF group (P = 0.03). In conclusion, SMF seems to be as efficient as CMF with regard to response rate, time to treatment failure and survival. However, SMF was tolerated better than CMF.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Form perception at birth: Cohen and Younger (1984) revisited.

Cohen (1988; Cohen & Younger, 1984) has suggested that there is a shift in the perception of form sometime after 6 weeks of age. Prior to this age infants can remember the specific orientations of line segments, but cannot process and remember the angular relations that line segments can make. Experiment 1 used simple line stimuli with newborn infants to test this suggestion. Following habituation to a simple two-line angle the newborns dishabituated to a change of orientation but not to a change in angle, confirming Cohen and Younger's suggestion that orientation is a powerful cue in early shape perception. In Experiments 2 and 3 newborns were familiarized either to an acute or to an obtuse angle that changed its orientation over trials. On subsequent test trials the babies gave strong novelty preferences to a different angle. Alternative interpretations of the results are discussed, but these experimental findings are compatible with the suggestion that newborns can quickly learn to process angular relations, and that rudimentary form perception may not be dependent on a lengthy period of learning and/or maturation for its development.

Attention↗
PubMed1991

Visual processing of stimulus compounds in newborn infants.

An experiment is described in which newborn infants' processing of stimulus compounds was investigated. After familiarization to two alternately presented stimuli which differed in colour and orientation, the newborns showed significant preferences for a stimulus which had a novel colour/orientation combination: the novel stimulus was produced by recombining features of the stimuli used for familiarization. This finding argues against the view that infants initially process separate components, or parts, of visual stimuli and are only able to attend to the correlations between them after about 3 months of age. Rather, the ability to process and remember stimulus compounds is present at birth.

Attention↗
PubMed1990

Size constancy at birth: newborn infants' responses to retinal and real size.

Two experiments are described whose aim was to investigate whether perception of size at birth is determined solely by proximal (retinal) stimulation, or whether newborn babies have the ability to perceive an object's real size across changes in distance. In Experiment 1, preferential looking between pairs of stimuli which varied in real size and viewing distance was found to be solely determined by retinal size, suggesting that changes to proximal stimulation can have profound effects on newborns' looking behavior. However, in Experiment 2 newborns were desensitized to changes in distance (and retinal size) during familiarization trials, and subsequently strongly preferred a different sized object to the familiar one, suggesting that the real size had been perceived as constant across the familiarization trials. These results confirm Granrud's (1987) findings that size constancy is present at birth.

Attention↗