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Biomedical subjects

J F Miller

Publications and source records attributed to J F Miller.

At least 415 records · Page 23Linked to original sources
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Human but not ovine isolates of Bordetella parapertussis are highly clonal as determined by PCR-based RAPD fingerprinting.

The DNA fingerprints of 170 human isolates and ten ovine isolates of Bordetella parapertussis were examined by arbitrarily-primed PCR/RAPD with 29 primers. Based on this technique, all the human isolates appear highly genetically homogeneous. The ovine isolates could be distinguished from human isolates and they showed diversity among themselves. Therefore, human isolates of B. parapertussis are a highly clonal group adapted to infect humans and they are distinct from polymorphic ovine isolates.

Animals↗
PubMedDate not supplied

Antibody-directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase A1: in vitro and in vivo studies with prodrugs of methotrexate and the thymidylate synthase inhibitors GW1031 and GW1843.

Antibody-directed enzyme prodrug therapy (ADEPT) is a technique to increase antitumor selectivity in cancer chemotherapy. Our approach to this technology has been to design a mutant of human carboxypeptidase A (hCPA1-T268G) which is capable of hydrolyzing in vivo stable prodrugs of MTX and targeting this enzyme to tumors on an Ep-CAM1-specific antibody, ING1. Through the use of this >99% human enzyme which is capable of catalyzing a completely nonhuman reaction, we hope to increase ADEPT selectivity while decreasing overall immunogenicity of the enzyme-antibody conjugate. In the current report, prodrugs of the thymidylate synthase inhibitors GW1031 and GW1843 and the dihydrofolate reductase inhibitor methotrexate were studied for their wild-type and mutant hCPA enzyme hydrolysis, their in vivo stability, and their use in therapy. Prodrugs with high kcat/Km ratios for mutated versus wild-type hCPA1 were examined in vitro for their stability in human pancreatic juice, and in vivo for their stability in mouse plasma and tissues. In addition, targeting and in vivo enzyme activity studies were performed with an ING1 antibody conjugate of the mutant enzyme (ING1-hCPA1-T268G). Finally, in vivo therapy studies were performed with LS174T tumors to demonstrate proof of principle. Results indicate that prodrugs can be synthesized that are selective and efficient substrates of hCPA1-T268G and not substrates of the endogenous CPA activities; this leads to excellent in vivo stability for these compounds. In vivo conjugate targeting studies showed that the antibody-enzyme conjugate was targeted to the tumor and enzyme was initially active in vivo at the site. Unfortunately therapeutic studies did not demonstrate tumor reduction. Experiments to determine reasons for the lack of antitumor activity showed that the enzyme activity decreased as a result of enzyme instability. The results offer encouragement for additional novel mutant enzyme improvements and additional in vivo studies on this unique approach to ADEPT.

Adenocarcinoma↗
PubMedDate not supplied

Development of atherosclerosis in genetically hyperlipidemic rabbits during chronic fish-oil ingestion.

The evidence for a reduction in cardiovascular mortality from fish oil is based on epidemiologic observations. To test whether fish-oil supplementation influences the development of atherosclerosis, we treated Watanabe heritable hyperlipidemic rabbits (WHHL), an inbred strain that spontaneously develops atherosclerosis, with 2.5 ml of MaxEPA fish-oil concentrate daily and compared them to a control group fed unsupplemented rabbit chow. Serial cholesterol and triglyceride levels were monitored as were plasma lipid hydroperoxides. The animals were given fish oil from the time of weaning until 1 year of age, when they were sacrificed and their aortas were compared for the extent of atherosclerosis. No significant differences in the cholesterol or triglyceride levels were noted between the two groups. Fatty acid hydroperoxide levels were also similar and were noted to increase from weaning (1.0 +/- 0.7 microM) to the time of sacrifice (1.8 +/- 1.5 microM, p less than 0.01). Fish oil had no influence on the extent of aortic atherosclerosis (25% +/- 14% surface area for controls vs. 28% +/- 19% for treated, p = NS), plaque thickness, or plaque volume after 1 year. We conclude that fish oil does not reduce the levels of serum cholesterol, lipid hydroperoxides, or aortic atherosclerosis in WHHL rabbits. The hypothesis that fish oil protects against atherosclerosis was not supported by this study.

Animals↗
PubMedDate not supplied

Antigen perception by T lymphocytes. Influence of the major histocompatibility complex.

There is considerable evidence that T cell activation to soluble antigens occurs only if this is processed by macrophages and displayed appropriately on the plasma membrane in association with products of the genes of the major histocompatibility complex. The genes responsible differ according to the antigens involved. For cytotoxicity, targets and killer T cells must share K or D region gene products. For delayed type hypersensitivity to fowl gammaglobulin in mice, I-A identity is necessary; for dinitrofluorobenzene, identity at either the I, K or D region is sufficient. Experiments using three different approaches do not support the notion that these genetic constraints are due to the necessity for the T cell and stimulator cell to match an identical gene product or "cell interaction molecule." Rather they favour the hypothesis that activated T cells recognize antigen and products of genes of the major histocompatibility complex. The implications of the results are discussed in terms of the mode of action of immune responsiveness (Ir) genes and of the possible parallel evolution of T cell receptors for antigen and gene products of the major histocompatibility complex.

Animals↗
PubMedDate not supplied

Three decades of T-ology.

Tremendous progress has been achieved in our understanding of thymus function in the last 3 decades. Distinct T cell subsets have been characterized and shown to have an essential role in initiating and in regulating a variety of immune responses. The ontogenetic events which lead to their intrathymic differentiation have been mapped and have allowed studies on the selection of the T cell repertoire. The major histocompatibility complex and associated antigenic peptides play a major role in T cell selection and antigen activation. The T cell receptor for antigen and the genes which code for it have recently been identified. Future studies should allow some insight into how to activate specific T cells more effectively for vaccination purposes and how to switch them off to induce tolerance to transplanted tissues.

Animals↗
PubMedDate not supplied

Development of an instrument to measure hope.

The purpose of this study was to develop an instrument to measure hope in adults and to evaluate its psychometric properties. A 40-item Miller Hope Scale (MHS) was developed based on critical elements of hope revealed in a comprehensive review of the literature and on an exploratory study of hope in persons who survived a critical illness. The instrument was critiqued by measurement and content experts, and content validity was established. The MHS was pretested on 75 subjects. The refined instrument was next evaluated using 522 healthy adults. The intent was to establish norms on the instrument before using it on ill subjects. The range of scores on the MHS is 40 to 200, with high scores indicating high hope. Mean hope score for this healthy sample was 164.46 (SD = 16.31). A leptokurtic curve, skewed to the left, was noted in these responses. As expected, the instrument detected high hope in individuals who were screened to have no physical or mental health problems. The internal consistency alpha coefficient was .93 with a 2-week test-retest reliability of .82. Criterion-related construct validity was established by correlating the MHS to the Psychological Well-Being Scale, r = .71, the Existential Well-Being Scale, r = .82, and a 1-item hope self-assessment, r = .69. Divergent validity with the Hopelessness Scale was established, r = -.54. Maximum likelihood factor analysis with oblimin rotation resulted in a three-factor solution: I, Satisfaction with Self, Others, and Life; II, Avoidance of Hope Threats; and III, Anticipation of a Future.

Adolescent↗