Search PubMed⌕ Search

Biomedical subjects

M T Cronin

Publications and source records attributed to M T Cronin.

33 records · Page 2Linked to original sources
PubMed1995

Quantitative structure-activity study of the toxicity of benzonitriles to the ciliate Tetrahymena pyriformis.

The toxicities of 34 benzonitriles to Tetrahymena pyriformis have been measured. Structure-activity relationships indicate that for these compounds different mechanisms of toxic action are taking place dependent on the nature of the substituent. Benzonitrile itself, some halogenated and the toluene derivatives model as non-polar narcotics; more polar substituents model well as polar narcotics; whilst the nitro and aldehyde substituted benzonitriles, and compounds that may be metabolised to benzoquinone are shown to exhibit considerable excess toxicity and, thus, the probability is that they are acting by a specific mechanism of action. After the removal of two outliers, QSAR analysis reveals a significant three parameter equation, and confirms the importance of hydrophobicity and descriptors of reactivity for the comprehension and the prediction of the toxicity of the benzonitriles.

Animals↗
PubMed1994

Light-generated oligonucleotide arrays for rapid DNA sequence analysis.

In many areas of molecular biology there is a need to rapidly extract and analyze genetic information; however, current technologies for DNA sequence analysis are slow and labor intensive. We report here how modern photolithographic techniques can be used to facilitate sequence analysis by generating miniaturized arrays of densely packed oligonucleotide probes. These probe arrays, or DNA chips, can then be applied to parallel DNA hybridization analysis, directly yielding sequence information. In a preliminary experiment, a 1.28 x 1.28 cm array of 256 different octanucleotides was produced in 16 chemical reaction cycles, requiring 4 hr to complete. The hybridization pattern of fluorescently labeled oligonucleotide targets was then detected by epifluorescence microscopy. The fluorescence signals from complementary probes were 5-35 times stronger than those with single or double base-pair hybridization mismatches, demonstrating specificity in the identification of complementary sequences. This method should prove to be a powerful tool for rapid investigations in human genetics and diagnostics, pathogen detection, and DNA molecular recognition.

Base Sequence↗
PubMed1994

Multivariate QSAR analysis of a skin sensitization database.

There is a regulatory requirement for the potential of a new chemical to cause skin sensitization to be assessed. This requirement is presently fulfilled by the use of animal tests. In this study a data base of heterogeneous organic compounds from the guinea pig maximization test has been subjected to multivariate QSAR analysis. The compounds were described both by whole molecule parameters and structural features associated with likely sites of reactivity. Principal component analysis was applied to the data set and although it functions reasonably well to reduce the dimensionality of a large data matrix, it is only moderately useful as a predictive tool when descriptors were chosen rationally. Stepwise discriminant analysis produces a fourteen parameter model, of which twelve were structural features associated with reactivity. This however predicts only 82.6% of compounds correctly after cross validation. There is trend for the linear discriminant analysis model to predict compounds as non sensitizers, suggesting that the parameters incorporated were not wholly suitable for discriminating between the two classes. Another criticism of linear discriminant analysis is that it may be unable to cope with the likely embedded data structure. With this in mind, the structural alerts may be better employed in an expert system, to identify potential hazard, where they will not suffer the limitations of a statistical model.

Animals↗
PubMed1991

IL-6 production by human T lymphocytes. Expression in HTLV-1-infected but not in normal T cells.

IL-6 is an important regulator of humoral and cellular immunity. Although this cytokine is produced by diverse cell types, it is not known whether it is produced by T lymphocytes under physiologic conditions or which agents can induce T cell expression of IL-6. We analyzed the production of IL-6 by human peripheral blood T cells, human thymocytes, and human T cell lines. In pure populations of these cells, stimulated with different combinations of various mitogens and cytokines, IL-6 activity could not be detected. Analysis of purified T-alpha beta and T-gamma delta cells showed that neither T cell subset produced IL-6. Similarly, IL-6 mRNA was not detected in T cell or thymocyte populations for up to 48 h after stimulation. With the use of a PCR assay, IL-6 mRNA in T cells was found to be virtually negligible, and did not change after T cell activation. By in situ hybridization it was shown that the cells expressing IL-6 mRNA after mitogen activation of PBMC do not belong to the T cell lineage. To analyze whether human T cells express IL-6 in vivo, we examined lymphoid tissues by in situ hybridization. In normal human thymus there was no detectable signal for IL-6. Tonsils showed only few positive cells within the parenchyma, but strong expression of IL-6 by epithelial cells in crypts. In contrast to normal lymph node, which contained only rare cells positive for IL-6, a lymph node from a patient with Castleman's disease showed IL-6 expression in cells occupying the marginal sinus and interfollicular areas. Screening of various human T cell lines showed that all cell lines infected with HTLV-1 secrete IL-6 activity and express IL-6 mRNA. In addition, in vitro infection of peripheral blood T cells with HTLV-1 induced de novo synthesis and secretion of IL-6. Furthermore, IL-6 expression in HTLV-1-infected cells was enhanced by stimulation with IL-1 beta or TNF-alpha. In contrast, IL-6 was not detectable in non-infected T cell lines. These studies indicate that IL-6 may not be a physiologic product of human T lymphocytes and that infection of T cells with HTLV-1 results in aberrant expression of this cytokine.

Cell Line↗
PubMed1991

QSAR studies of comparative toxicity in aquatic organisms.

This study investigated the relationships between the toxicities of common organic pollutants to the fathead minnow (Pimephales promelas), to Daphnia magna, to Tetrahymena pyriformis and in the Microtox test, which uses the luminescent bacterium Photobacterium phosphoreum. The toxicity data were compiled from the literature, with the exception of 40 experimentally determined Microtox data. Encouraging correlations are seen, indicating significant relationships between fish toxicities and those to lower organisms. When the toxicities of individual chemical classes are studied, further improvement is often seen in the correlations. Analysis of significant outliers from the inter-species relationships has led to the suggestion that the fathead minnow may be more susceptible to chemicals that are metabolised to reactive intermediates (such as the aldehydes). The fish may, however, be less susceptible to other chemical classes such as ketones and alcohols.

Animals↗
PubMed1986

Effects of epidermal growth factor receptor concentration on tumorigenicity of A431 cells in nude mice.

To test the relationship between the concentration of epidermal growth factor (EGF) receptors and tumor growth in vivo, we measured the rate of growth of several independently isolated A431 cell lines in athymic mice. This series of A431 clonal variants with differing extents of EGF receptor gene amplification and protein expression were implanted into athymic mice and the time to solid tumor formation and rate of growth were measured. Results of these experiments indicate that the degree of gene amplification and concentration of EGF receptors are directly correlated with the growth of these cells as solid tumors in host animals. Complementary DNA hybridization analysis revealed no change in the extent of gene amplification and expression in implanted cells versus excised tumors nor any evidence of further gene rearrangement in vivo. A high concentration of EGF receptors appears to facilitate the growth of tumor cells in vivo and in vitro.

Animals↗
PubMedDate not supplied

Prediction of drug toxicity.

The use of computer-aided methods to predict the toxicity of drugs is described. These methods can assist in the identification of toxic compounds early in the drug development process. Thus, there is potential for these methods to be combined with combinatorial synthesis and library design. Quantitative structure-activity relationships allow for the prediction of individual endpoints, usually for restricted groups of compounds. Expert systems for toxicity prediction are based on a number of methodologies, each with its own strengths and weaknesses. The relative merit of each individual technique and methodology is described. However, more toxicity data are required, both to produce and to validate expert systems. Potential sources of new data include the use of high-throughput screening and microarrays for toxicology.

Computers↗
PubMedDate not supplied

A novel index for the description of molecular linearity.

To investigate the description of molecular shape, a heterogeneous data set of 200 compounds was designed. The compounds included many disparate molecular shapes, and a total of 64 descriptors was calculated including topological indices, surface areas, molecular volumes, measures of molecular dimensions, and ratios of moments of inertia. Cluster analysis on the variables indicated that there are four major categories of steric descriptors, those for molecular bulk, dimensions, and two clusters representing varying aspects of shape. To describe molecular shape more efficiently, a novel linearity index based upon ratios of moments of inertia and the molecular weight is proposed.

Journal Article↗
PubMedDate not supplied

Response-surface analyses for toxicity to Tetrahymena pyriformis: reactive carbonyl-containing aliphatic chemicals.

A response-plane has been developed with Tetrahymena pyriformis population growth impairment toxicity data [log 1/50% growth inhibitory concentration (IGC50)], the 1-octanol/water partition coefficient (log Kow), and the energy of the lowest unoccupied molecular orbital (Elumo). A statistically robust plane [log 1/IGC50 = 0.530 (log Kow) -0.890 (Elumo) -0.271, n = 50, s = 0.295, r2 = 0.855, F = 145] was found for reactive carbonyl-containing aliphatic chemicals. These compounds had a variety of electrophilic mechanisms of action and included aldehydes acting as Schiff-base formers, alpha,beta-unsaturated aldehydes and alpha,beta-unsaturated ketones acting as Michael-type acceptors, and selected alpha-diones acting as selective binders to arganine residues; gamma-diones acting as selective binders to tubulin; and beta-diones with unknown mechanisms of action. Outliers to this model broadly fell into two groups: small reactive molecules (e.g., acrolein) that were more toxic than predicted and molecules in which the reactive center was sterically hindered by an alkyl group (e.g., 2,4-dimethyl-2,6-heptadienal) that were less toxic than predicted.

Animals↗
PubMedDate not supplied

The use of bootstrap resampling to assess the uncertainty of cooper statistics.

The predictive abilities of two-group classification models (CMs) are often expressed in terms of their Cooper statistics. These statistics are often reported without any indication of their uncertainty, making it impossible to judge whether the predicted classifications are significantly better than the predictions made by a different CM, or whether the predictive performance of the CM exceeds predefined performance criteria in a statistically significant way. Bootstrap resampling routines are reported that provide a means of expressing the uncertainty associated with Cooper statistics. The usefulness of the bootstrapping routines is illustrated by constructing 95% confidence intervals for the Cooper statistics of four alternative skin-corrosivity tests (the rat skin transcutaneous electrical resistance assay, EPISKIN, Skin(2) and CORROSITEX), and four two-step sequences in which each in vitro test is used in combination with a physicochemical test for skin corrosion based on pH measurements.

Animal Testing Alternatives↗
PubMedDate not supplied

The use of bootstrap resampling to assess the variability of Draize tissue scores.

The acute dermal and ocular effects of chemicals are generally assessed by performing the Draize skin and eye tests, respectively. Because the animal data obtained in these tests are also used for the development and validation of alternative methods for skin and eye irritation, it is important to assess the inherent variability of the animal data, since this variability places an upper limit on the predictive performance that can be expected of any alternative model. The statistical method of bootstrap resampling was used to estimate the variability arising from the use of different animals and time-points, and the estimates of variability were used to determine the maximal extent to which Draize test tissue scores can be predicted.

Animal Testing Alternatives↗