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Biomedical subjects

D Lane

Publications and source records attributed to D Lane.

At least 55 records · Page 3Linked to original sources
PubMed1998

Phase II study of liarozole in advanced non-small cell lung cancer.

The aim of this phase II study was to investigate the efficacy and tolerability of liarozole, a novel benzimidazole derivative, in non-small cell lung cancer (NSCLC). Liarozole 300 mg twice daily orally was evaluated in 14 patients with stage IIIB and IV NSCLC. 8 patients had received prior treatment with chemotherapy and/or radiotherapy. WHO toxicity grading and response criteria were used. Liarozole was well tolerated. Grade 2 toxicities included alopecia (1 patient), dermatological toxicity (5 patients), dry mouth (2 patients) and nausea and vomiting (2 patients). Leukocytosis was seen in 5 patients, including 2 cases with an elevated white cell count pretreatment. Liarozole was discontinued in 1 patient who developed intolerable progressive pruritus associated with an erythematous rash. No objective tumour response was seen, all 14 patients developing progressive disease within 4 months of commencing treatment. Liarozole was well tolerated but was ineffective as single agent therapy in the management of NSCLC. The side-effect profile was compatible with inhibition of retinoic acid degradation.

Administration, Oral↗
PubMed1998

Lipoprotein(a) as a risk predictor for cardiac mortality in patients with acute coronary syndromes.

AIMS: Raised lipoprotein(a) concentrations are considered to be a risk factor for atherothrombotic diseases. We examined whether baseline concentrations were a risk factor for an adverse outcome in patients admitted with acute coronary syndromes. METHODS AND RESULTS: Five hundred and nineteen patients admitted with suspected acute coronary syndromes were studied and followed prospectively for a median of 3 years. The prognostic significance of a baseline lipoprotein(a) concentration of > or = 30 mg x dl(-1) or lower for subsequent cardiac death was assessed in patients with myocardial infarction (266) and unstable angina (197) and compared with other variables in regression models. In patients with myocardial infarction, a baseline lipoprotein(a) concentration of > or =30 mg x dl(-1) was associated with a 62% increase in subsequent cardiac death compared to the lower concentration group (29.8% vs 18.6%, Log rank P=0.04). In a multivariate regression model a baseline lipoprotein(a) concentration of > or = 30 mg x dl(-1) retained its significance as an independent predictor of cardiac death (P=0.037). In patients with unstable angina, baseline concentrations of > or = 7.9 mg x dl(-1) were found to be significant predictors of cardiac death in univariate (P=0.021) and multivariate (P=0.035) regression models. CONCLUSION: Baseline lipoprotein(a) concentrations in patients admitted with acute coronary syndromes are associated with an increased risk of cardiac death. For patients with myocardial infarction a concentration of > or = 30 mg x dl(-1) appears appropriate as a risk discriminator; for patients admitted with unstable angina, however, much lower concentrations of lipoprotein(a) appear to be prognostically important.

Acute Disease↗
PubMed1998

Evaluation of Jump Into Action: a program to reduce the risk of non-insulin dependent diabetes mellitus in school children on the Texas-Mexico border.

Jump Into Action, a school-based non-insulin dependent diabetes mellitus (NIDDM) prevention program, encourages students to eat low-fat foods and exercise regularly to reduce their risks for developing NIDDM. A study was conducted in a school district with a predominately Hispanic enrollment to assess the effectiveness of Jump Into Action in improving fifth-graders' knowledge, self-efficacy, and behaviors regarding NIDDM prevention. Jump Into Action was found effective in increasing knowledge and self-efficacy regarding NIDDM prevention and improving dietary and exercise-related behaviors. These gains were sustained from posttest to follow-up four weeks later.

Child↗
PubMed1998

Simulation applied to health services: opportunities for applying the system dynamics approach.

The aim of this essay is to raise awareness and broaden understanding within the health services community of the system dynamics (SD) simulation approach to policy analysis. The application of simulation in health services is reviewed. A comparison is made between the SD and traditional simulation approaches and is illustrated by considering reductions in waiting times for coronary heart disease treatment. Traditionally, simulation studies have tended to focus on the analysis of localized decisions and therefore on problems orientated towards individual patients. Although these methods are extremely powerful and effective, there is scope for an alternative modelling approach which is based on a more holistic perspective; SD is one such approach. It can assist in the design of robust policies by supporting debate on how the underlying structure might influence the evolutionary behaviour of a system. Using this method we can consider the time variation both of tangibles, such as waiting times and health care costs, and intangibles, such as patient anxiety and the effects of various pressures on purchasing decisions. We propose that SD holds great potential in assisting policy formation in health care.

Computer Simulation↗
PubMed1997

Protein interactions at the carboxyl terminus of p53 result in the induction of its in vitro transactivation potential.

The tumor suppressor protein p53 is a transcription factor frequently inactivated in human cancers. We have studied the DNA binding potential and the transcriptional activity of p53 variants and p53 protein complexes in in vitro transcription assays. p53 specific transcription was measured via introduction of radioactive UTP into G-free cassette transcripts regulated by promoter sequences containing p53 response elements. Latent and activated p53 fractions were prepared from insect cells infected with p53 encoding baculoviruses by chromatography on heparin columns. p53 fractions distinguishable by their specific DNA binding activities and their recognition by monoclonal antibody PAb421 were obtained. Specific DNA binding and binding to PAb421 are mutually exclusive. The C-terminus of p53 can be phosphorylated by casein kinase II, protein kinase C and cyclin dependent kinases. The antibody PAb421 binds within the PKC phosphorylation site of p53 and is able to activate DNA binding of latent p53 in vitro. Activation of p53 by PAb421 also results in enhanced transactivation in vitro. Dephosphorylation of latent p53 with phosphatase 2A does not change these properties. This suggests that a conformational change in the carboxyl terminal domain of p53 controls the transactivation potential of p53.

Animals↗
PubMed1997

Genetic basis of the MbrC "ploidy" phenotype in Escherichia coli.

The mbrC17 mutation in Escherichia coli had been shown to cause conditional growth defects and an increase in the quantity of DNA per cell. The present work was aimed at identifying the mutation. Sequencing showed that the MbrC17 phenotype does not involve glr (murI), as previously suggested. P1 transduction data indicated that the mbrC17 mutation is closely linked to rpoB, and allele exchange showed it to lie within the secE-nusG operon. A single change relative to wild type was found in the secE-nusG region from the mbrC17 strain, a G-->A mutation 23 bp upstream of the secE coding sequence. This mutation causes a two-fold increase in the concentration of secE-nusG mRNA.

Amino Acid Isomerases↗
PubMed1997

Functional IL-2 receptors are expressed by rat lung type II epithelial cells.

Interferon (IFN)-gamma-induced inhibition of type II epithelial cell thymidine incorporation (45% decrease vs. control) was restored by cocultures with mitogen-activated peripheral blood mononuclear cells (PBMC) and conditioned media (CM) from mitogen-activated PBMC. Successive exposure of type II cells to IFN-gamma and interleukin (IL)-2 produced similar alterations in thymidine incorporation. Given that IL-2 is a powerful pleiotropic cytokine produced by lymphoid and myeloid cells, the presence of IL-2 receptors (IL-2R) was assessed in primary cultures of rat type II pneumocytes (TIIP) and the nontransformed alveolar type II epithelial cell line L2. The presence of IL-2R membrane protein on rat type II cells was established by immunodetection assays. The expression of all three murine IL-2R alpha-, beta-, and gamma-chain RNA transcripts in primary TIIP cultures and L2 cells was highlighted by reverse transcriptase-polymerase chain reaction analysis. Overall, these experiments demonstrate, for the first time, that type II epithelial cells can express functional IL-2R, confirming TIIP as a potential "partner" in the lung immune system. Consequently, it can be speculated that TIIP are new cellular targets for lymphokines using (IL-2R) gamma-chain-bearing receptors in lung distal air-spaces.

Animals↗
PubMed1996

Arylamine N-acetyltransferase in erythrocytes of cystic fibrosis patients.

Sulphamethoxazole, a substrate of human arylamine N-acetyltransferase, is used in the treatment of cystic fibrosis patients, who metabolise the drug rapidly. Increased metabolic clearance of sulphamethoxazole has been suggested to account for this rapid metabolism. Arylamine N-acetyltransferase type 1 is expressed in erythrocytes and leucocytes and the activity in erythrocytes is shown to contribute approximately 99% of the activity of arylamine N-acetyltransferase type 1 in blood cells. Arylamine N-acetyltransferase type 1 activity in erythrocytes from 16 adult cystic fibrosis patients and 19 age-matched controls were compared. Although there is a variation in erythrocyte arylamine N-acetyltransferase type 1 activity within each group, no difference was found when the two groups were compared. All individuals from the cystic fibrosis and control groups were investigated for certain allelic variants of the arylamine N-acetyltransferase type 1 gene (NAT1). Only one copy of a mutant NAT1 allele (NAT1*11) was found. The heterozygous NAT1 individual is a cystic fibrosis patient with a low level of erythrocyte arylamine N-acetyltransferase type 1 activity. A second distinct arylamine N-acetyltransferase isozyme, arylamine N-acetyltransferase type 2, is encoded at the multi-allelic NAT2 locus. There was no correlation between erythrocyte arylamine N-acetyltransferase-1 activity and NAT2 alleles present in either the cystic fibrosis or control groups. The distribution of NAT2 alleles was very similar in the two groups. The increased clearance of sulphamethoxazole in cystic fibrosis patients appears unlikely to be due to erythrocyte arylamine N-acetyltransferase type 1 activity or to inheritance of alleles at either the NAT1 or NAT2 loci.

Adolescent↗
PubMed1996

Lung alveolar epithelial cell migration in vitro: modulators and regulation processes.

After acute lung injury, altered bronchioloalveolar epithelia must be repaired quickly in order to restore lung function. During reepithelialization, type II cells initially appear to migrate and spread over a remodeled matrix; then a secondary proliferative phase occurs. It was hypothesized that 1) type II cells can develop locomotion in vitro that is modulated by growth factors, proinflammatory cytokines, and substrate adhesion molecules and 2) migration and proliferation of type II cells can occur as distinctive processes. Chemotaxis assays were elaborated using short term cultures of rat type II pneumocytes. Epidermal growth factor (EGF), transforming growth factor-alpha, laminin, fibronectin were found to be the main attractants for type II cells with respective increases of approximately 8.5-, 10.5-, 8-, and 7-fold in cell migration (P<0.05 vs. control). Laminin induced gradient-dependent and random cell migration. Addition of laminin with EGF had a synergistic effect in promoting cell migration (approximately 30-fold increase over control, P<0.05). Interferon-gamma and interleukin-6 inhibited EGF-induced type II cell migration, whereas tumor necrosis factor-alpha and interleukin-1beta acted as primers for type II cell migration (approximately 1.5-fold increase over control, P<0.05. Type II cells did not need to be in a proliferative phase in order to exhibit motility. New insights regarding the regulatory processes for type II cell migration are especially relevant in our understanding of early events occurring during epithelial repair after acute lung injury.

Adenocarcinoma↗
PubMed1996

Inhibition of dexamethasone-induced cytoskeletal changes in cultured human trabecular meshwork cells by tetrahydrocortisol.

PURPOSE: To determine the cellular mechanism of action of the intraocular pressure (IOP) lowering steroid tetrahydrocortisol (THF). METHODS: Tetrahydrocortisol was evaluated for glucocorticoid antagonist activity using in vitro and in vivo assays. Systemically administered THF was evaluated for its ability to inhibit dexamethasone-induced body weight loss and systemic hypertension in rats. In vitro receptor antagonism was tested using the supernatant fraction of IM9 cells as the source of soluble glucocorticoid receptor in 3H-dexamethasone displacement binding assays. In addition, six different primary human trabecular meshwork (TM) cell lines were cultured for 0 to 14 days in the absence or presence of dexamethasone (10(-7) M) and/or THF (10(-6) to 10(-8) M). The effects of these steroids on the TM cytoskeleton were determined by epifluorescent microscopy and by transmission electron microscopy. RESULTS: Tetrahydrocortisol was unable to inhibit the dexamethasone (DEX)-induced systemic hypertension and decrease in body mass in rats and was unable to displace 3H-DEX from the soluble human glucocorticoid receptor. However, THF inhibited the DEX-induced formation of cross-linked actin networks in cultured human TM cells in a progressive and dose-dependent manner (IC50 = 5.7 x 10(-7) M). Dexamethasone caused changes in the TM cell microtubules that were reversed partially by concomitant treatment with THF. Tetrahydrocortisol alone appeared to increase microfilament bundling in TM cells. CONCLUSIONS: Tetrahydrocortisol was not a glucocorticoid antagonist at the level of the classical glucocorticoid receptor and did not appear to antagonize systemically mediated glucocorticoid activity in the rat. Tetrahydrocortisol inhibited DEX-induced changes in the TM microfilaments and microtubules. These results may explain partially the IOP lowering activity of THF because glucocorticoid-mediated changes in the TM cytoskeleton have been proposed to be involved in the generation of ocular hypertension.

Actins↗
PubMed1995

Prognostic significance of p53 overexpression in primary breast cancer; a novel luminometric immunoassay applicable on steroid receptor cytosols.

A novel quantitative luminometric immunoassay (LIA) has been developed for the measurement of wild-type and mutant p53 protein in extracts from breast tumour tissue. The LIA was found to yield reliable estimates of p53 expression in cytosol samples routinely prepared for steroid receptor analysis as compared with results obtained with immunohistochemical analysis. The LIA was evaluated on 205 primary breast tumour cytosols prepared for steroid receptor analysis and stored frozen at -80 degrees C for 6-8 years, p53 protein being detected in 65% of the samples (range 0.01-23 ng mg-1 protein). Using an arbitrary cut-off value of 0.15 ng mg-1 protein, 30% of the tumours were classified as manifesting p53 overexpression. Significant and independent correlations were found to exist between p53 overexpression and shorter disease-free (P < 0.001) and overall survival (P = 0.039) at a median duration of follow-up of 50 months. p53 overexpression was related to low oestrogen receptor content and high proliferation rate (S-phase fraction). No relationship was found to tumour size or the presence of lymph node metastasis. Three tumours possessed an extremely high p53 content (> 10 ng mg-1 protein), all of which were of medullary or high-grade ductal type, oestrogen and progesterone receptor negative, DNA non-diploid, had S-phase fractions of > 22% and recurred within 1-2 years. In summary, a new sensitive and quantitative LIA suitable for routine analysis of p53 protein in steroid receptor cytosol preparations from breast tumours has been developed to confirm the prognostic importance of p53 protein accumulation in human breast cancer.

Breast Neoplasms↗
PubMed1995

Q-beta replicase-amplified assay for detection of Mycobacterium tuberculosis directly from clinical specimens.

We report the results of a study conducted to evaluate the performance of manual Q-Beta replicase-amplified Mycobacterium tuberculosis complex assay compared with that of culture for detecting M. tuberculosis directly from digested sputum pellets. A total of 261 specimens submitted to three tuberculosis testing laboratories were analyzed. Culture and acid-fast bacillus smear results were provided by the tuberculosis testing laboratories. Of these 261 specimens, 34 (13% prevalence rate) were positive for M. tuberculosis by culture. The samples were digested and decontaminated by the testing laboratories by using their standard digestion and decontamination procedures. An aliquot of the digested and decontaminated pellet was sent to GENE-TRAK. The digested and decontaminated pellet was neutralized by washing it with 0.067 M phosphate buffer (pH 6.8), and the bacteria present in the washed pellet were heat inactivated at 100 degrees C for 15 min. The samples were combined with sample processing buffer containing GuSCN and were treated for 6 min in the GENE-TRAK Sample Processing Instrument to release the nucleic acids. The release rRNA was analyzed in a manual Q-Beta replicase assay format which incorporates elements of sandwich hybridization, reversible target capture, and Q-beta replicase signal amplification technologies. In comparison with culture, the overall assay sensitivity and specificity were 97.1 and 96.5%, respectively. The positive predictive value was 80.5%, and the negative predictive value was 99.5%. After analysis of discrepant results, the assay sensitivity and specificity were 97.3 and 97.8, respectively, and the prevalence rate was 14%. The positive predictive value and the negative predictive value were 87.8 and 99.5%, respectively. The Q-Beta replicase assay is rapid sensitive, semiquantitative, and specific for the direct detection of M. tuberculosis from clinical specimens.

Bacteriological Techniques↗
PubMed1995

Clara cell protein (CC-16) induces a phospholipase A2-mediated inhibition of fibroblast migration in vitro.

Clara cell protein (CC-16, also designated CC-10) is synthesized by the bronchiolar epithelium and has been suggested as an inhibitor of phospholipase A2 (PLA2) activity. Therefore, CC-16 is a candidate for controlling inflammatory events in the lung. Because CC-16 amounts and function may be altered in fibrosing lung diseases in which bronchiolar injury has been reported, it was measured in alveolar fluids and sera. Secretory PLA2 activity in alveolar fluids and the influence of CC-16 on platelet-derived growth factor-induced human fibroblast chemotaxis and cytosolic PLA2 activity were also explored. CC-16 content was decreased in alveolar fluids from idiopathic pulmonary fibrosis (IPF: 1.3 +/- 0.1 mg/L) and bleomycin lung (1.1 +/- 0.2 versus 2.1 +/- 0.2 mg/L in controls, p < 0.05), whereas there was a three- to ninefold increase in secretory PLA2 activity (p < 0.05 versus controls). CC-16 inhibited fibroblast chemotaxis in a dose-dependent manner (90% inhibition at 30 micrograms/ml CC-16). This inhibition was reversed by reducing CC-16. CC-16 was also able to lower fibroblastic cytosolic PLA2 activity by 50% in vitro. In summary, CC-16 is able to inhibit fibroblast chemotaxis in vitro by mechanisms that may be related to a blockage of cytosolic PLA2 activity. It can be postulated that CC-16 deficiency may contribute to fibroblast burden activity in fibrosing lung diseases.

Adult↗
PubMed1994

Induction of the SOS response by IS1 transposase.

We find that IS1 transposase, like that of Tn10, can induce the SOS response when produced at high levels. Most of the activity (> 80%) requires IS1 ends in cis to the transposase gene and depends strictly on the presence of RecBCD function. This implies that processing of transposase-induced cleavages is responsible for generating the response. Induction of the SOS response during growth in a rich medium is seen only when cells approach stationary phase. The end-dependent induction is abolished by mutations in the ends of IS1 that eliminate transposition activity. IS1 ends in identical orientation on the same plasmid are inactive in transposition but stimulate SOS strongly. Even plasmids with a single end can stimulate SOS, probably as a consequence of plasmid dimer formation which places the ends in direct repeat orientation. These results imply that transposase-induced cleavages do not need inversely oriented ends. The system can therefore be used to dissociate cleavage activity from the other reactions of transposition. Induction of SOS by a series of short (67 to 114 bp) IS1-like elements was found to occur in a cyclical pattern as a function of length with a period of 10 to 11 bp. The frequency of cointegration promoted by these elements showed the same helix-phase dependence. These results suggest that transposase molecules bound to the ends of IS1 interact, and that this interaction is needed for the cleavages that initiate transposition.

Base Sequence↗
PubMed1994

Antibody fragments from a 'single pot' phage display library as immunochemical reagents.

The display of repertoires of antibody fragments on the surface of filamentous bacteriophage offers a new way of making antibodies with predefined binding specificities. Here we explored the use of this technology to make immunochemical reagents to a range of antigens by selection from a repertoire of > 10(8) clones made in vitro from human V gene segments. From the same 'single pot' repertoire, phage were isolated with binding activities to each of 18 antigens, including the intracellular proteins p53, elongation factor EF-1 alpha, immunoglobulin binding protein, rhombotin-2 oncogene protein and sex determining region Y protein. Both phage and scFv fragments secreted from infected bacteria were used as monoclonal and polyclonal reagents in Western blots. Furthermore the monoclonal reagents were used for epitope mapping (a new epitope of p53 was identified) and for staining of cells. This shows that antibody reagents for research can be readily derived from 'single pot' phage display libraries.

Amino Acid Sequence↗