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Biomedical subjects

N E Morrison

Publications and source records attributed to N E Morrison.

At least 19 recordsLinked to original sources
PubMed2006

Peptide phage display: opportunities for development of personalized anti-cancer strategies.

Personalized medicine is critical for cancer patients, because (1) cancer is a highly heterogeneous disease with major molecular differences in the expression and distribution of tumor cell surface markers among patients with the same type and grade of cancer, (2) cellular mutations tend to accumulate as cancer progresses, further increasing tumor heterogeneity, and (3) currently used cancer therapies often are toxic to normal cells, causing severe side effects rarely seen in other diseases. To prevent side effects and to improve effectiveness, cytotoxic therapies should be targeted and each patient should be profiled for the presence of cancer targets before the therapy is administered. Phage display technology utilizes combinatorial libraries of proteins expressed on phage particles that can be selected for specific binding to cancer cells. Such cancer-specific molecules can be used in a variety of applications, including identification of cell-specific targeting molecules; identification of cell surface biomarkers; profiling of specimens obtained from individual cancer patients, and the design of peptide-based anti-cancer therapeutics for personalized treatments. This review is focused on peptide phage display strategies that target cell surfaces because many biomarkers important in cancer are differentially expressed molecules located on the outside of the cell membranes.

Antineoplastic Agents↗
PubMed2003

Molecular markers of glial tumors: current targeting strategies.

Diagnosis and therapy for malignant gliomas represents one of the most challenging problems in clinical oncology. Current treatment of malignant glioma is multimodal, involving surgical resection, radiotherapy and chemotherapy. Even with these combined therapies, patients usually die within 1 to 2 years after onset of symptoms. Clearly, improved strategies for selective delivery of therapeutic agents to gliomas are needed to combat these devastating and usually fatal cancers. This review summarizes current knowledge concerning targetable molecular markers on the surface of glial tumor cells and tumor vasculature. Such markers are altered or up-regulated in gliomas compared to normal tissues, or they might be glioma-restricted. These markers include growth factor receptors, cell-surface adhesion molecules, and membrane-type matrix metalloproteinases. Current approaches that utilize growth factor peptides and peptide/antibodies identified via phage display technology as carrier ligands for targeting malignant gliomas are discussed.

Biomarkers, Tumor↗
PubMed2000

Body composition of growing and adult cats as measured by use of dual energy X-ray absorptiometry.

BACKGROUND AND PURPOSE: Total body scans were performed on 89 domestic cats of various ages, using dual energy x-ray absorptiometry (DEXA) to determine body composition, including fat, lean, and bone mineral content. Bone mineral density results from scans also are presented. METHODS: This cross sectional study included data for cats from a closed colony and from privately owned cats. Data were grouped by age and were analyzed by sex and reproductive status to provide information as to the rate of growth of the individual components of body composition. RESULTS: The results indicate that the rate of accretion of bone mineral, fat, and lean tissue differs throughout maturation and by sex. Regressions are provided to highlight age- and sex-related differences. CONCLUSIONS: The results of this study emphasize the benefits of examining the growth of each component of body composition when studying the effects of nutrition, disease processes, or therapeutic interventions.

Absorptiometry, Photon↗
PubMed1999

Alterations in the growth hormone/insulin-like growth factor I pathways in feline GM1 gangliosidosis.

Cats affected with feline GM1 gangliosidosis, an autosomal, recessively inherited, lysosomal enzymopathy, have progressive neurological dysfunction, premature thymic involution, stunted growth, and premature death. Although increased membrane GM1 gangliosides can result in increased apoptosis of thymocytes, there is not a direct correlation between thymocyte surface GM1 and thymic apoptosis in vivo, suggesting that other factors may be important to the pathogenesis of thymic involution in affected cats. Because GH and insulin-like growth factor I (IGF-I) are important hormonal peptides supporting thymic function and affecting growth throughout the body, particularly in the prepubescent period, several components of the GH/IGF-I pathway were compared in GM1 mutant and normal age-matched cats. GM1 mutant cat serum IGF-I concentrations were reduced significantly compared with those in normal cats by 150 days of age, and GM1 mutant cats had no peripubertal increase in serum IGF-I. Additionally, IGF-binding protein-3 was reduced, and IGF-binding protein-2 was elevated significantly in GM1 mutant cats more than 200 days of age. Liver IGF-I messenger RNA and pituitary GH messenger RNA both were reduced significantly in GM1 mutant cats. After stimulation by exogenous recombinant canine GH, serum IGF-I levels increased significantly in GM1 mutant cats, indicating that GH/IGF-I signaling pathways within the liver remain intact and suggesting that alterations are external to the liver.

Aging↗
PubMed1998

Evaluation of GM1 ganglioside-mediated apoptosis in feline thymocytes.

Cats with inherited GM1 gangliosidosis (GM1 mutant cats) have premature thymic involution characterized by decreased total thymocytes primarily affecting the CD4+ CD8+ subpopulation. While GM1 mutant cats have increased cell surface GM1 gangliosides, as determined by cholera toxin B binding, on both thymocytes and peripheral lymph node cells only thymocytes show increased apoptosis. To determine if GM1 gangliosides can increase the occurrence of apoptosis in feline thymocytes directly, we added exogenous GM1 ganglioside (GM1) to feline thymocyte primary cultures and compared the results to apoptotic changes seen in untreated cells or in cells treated with dexamethasone (Dex), a known inducer of thymocyte apoptosis in other species. Incorporation of exogenous GM1 into thymocyte cytoplasmic membranes was confirmed by flow cytometric analyses of cholera toxin B labelling. Apoptosis in feline thymocytes was analyzed by electron microscopy, spectrophotometric evaluation of DNA fragmentation, flow cytometric enumeration of apoptotic nuclei, and gel electrophoretic analysis of degraded DNA. Alterations in percentages of thymocyte immunophenotype following GM1 incorporation were determined by flow cytometric analyses of labelled cell surface markers for feline CD4 and CD8. Because in vitro addition of GM1 gangliosides has been reported in other species to decrease surface expression of CD4 on both thymocytes and peripheral lymphocytes, we evaluated GM1-associated down-regulation of CD4 on the surface of feline thymocytes and peripheral lymph node cells by flow cytometry. Additionally, we compared the apoptotic response of the more mature peripheral lymph node cells to the less mature thymocytes. Our results indicate that incorporation of exogenous GM1 into feline thymocyte cell membranes produces a dose-dependent increase of apoptotic cell death. Although, CD4 expression on both feline thymocyte and lymph node cell membranes was abruptly decreased after introducing exogenous GM1, enhanced apoptotic death was observed only in thymocytes, not in lymph node cells at the same GM1 concentration. Enhancement of thymocyte apoptosis appears to be age-related since cells derived from cats <3 months of age were more vulnerable than those from cats >3 months of age.

Aging↗
PubMed1998

Thymic alterations in feline GM1 gangliosidosis.

GM1 gangliosidosis is an inherited metabolic disease characterized by progressive neurological deterioration with premature death seen in children and numerous animals, including cats. We have observed that thymuses from affected cats greater than seven months of age (GM1 mutant cats) show marked thymic reduction compared to age-matched normal cats. The studies reported here were done to describe alterations in the thymus prior to (less then 90 days of age) and during the development of mild (90 to 210 days of age) to severe (greater than 210 days of age) progressive neurologic disease and to explore the pathogenesis of the thymic abnormality. Although histologic examination of the thymus from GM1 affected cats less than 210 days of age showed no significant differences from age-matched control cats, thymuses from GM1 mutant cats greater than 210 days of age were significantly reduced in size (approximately 3-fold). Histologic sections of lymph nodes, adrenal glands, and spleens from GM1 gangliosidosis-affected cats showed no significant differences. Flow cytometric analyses showed a marked decrease in the percentage of immature CD4+CD8+ thymocytes (p < 0.001) and significantly increased CD4-CD8+ cells (p < 0.01) in GM1 mutant cats greater than 210 days of age when compared to normal age matched cats. Co-labelling with CD4, CD8, and CD5 indicated an increase in the percentage of GM1 mutant cat thymocytes at this age which were CD5high, suggesting the presence of more mature cells. Cytometric analyses of subpopulations of peripheral lymphocytes indicated an increase in CD4-CD8+ cells (p < 0.05) with concurrent decreases in CD4+CD8- and CD4-CD8- cells (which were not significant). Similar analyses of thymocyte and lymphocyte subpopulations from cats < 210 days of age showed no significant differences between GM1 mutant and normal cells. GM1 mutant cats at all ages had increased surface binding of Cholera toxin B on thymocytes, indicating increased surface GM1 ganglioside expression. Increases were highly significant in GM1 mutant cats greater than 210 days of age. In situ labelling for apoptosis was increased in GM1 mutant cats between 90 to 200 days of age when thymic masses were within normal limits. In GM1 mutant cats over 200 days of age, decreased labelling was observed when thymic mass was reduced and the CD4+CD8+ subpopulation, known to be very susceptible to apoptosis, was significantly decreased. These data describe premature thymic involution in feline GM1 gangliosidosis and suggest that increased surface GM1 gangliosides alters thymocyte development in these cats.

Adrenal Glands↗
PubMed1996

Effect of locally injected medications on healing of pad wounds in dogs.

OBJECTIVE: To ascertain the effects of locally injected immunostimulant and tripeptide-copper complex (TCC) on improving healing of pad wounds. DESIGN: Wounds in pads of large dogs were injected with either medication or physiologic saline solution (controls). Healing was evaluated. ANIMALS: 12 mature English Pointers. PROCEDURE: Full-thickness 6 x 8-mm wounds in metatarsal and third and fourth digital pads were injected with immunostimulant or TCC at 0, 3, and 6 days after wounding. Wounds on control dogs were injected with physiologic saline solution. Using planimetric measurements at 0, 3, 6, 14, and 21 days, rates of healing were evaluated. Biopsy of the digital pad wounds at 3, 6, and 14 days was used to evaluate collagen content by hydroxyproline analysis. Biopsy specimens were also evaluated for type-I and type-III collagen, using Sirius red differential staining. RESULTS: Effect on healing rate and hydroxyproline content was best during the first week for immunostimulant. Immunostimulant- and TCC-injected wounds had more type-I collagen than did controls at 6 days; TCC-injected wounds had the most type-I collagen. At 14 days, the amount of type-I collagen in TCC-injected wounds was significantly greater than that in other wounds. CONCLUSIONS: Tested medications had positive effects on healing of pad wounds. CLINICAL RELEVANCE: Intralesional injection of medications helps ensure their presence for enhancement of wound healing. The benefit could be lost with topical use in a bandage if the bandage is lost or becomes wet.

Adjuvants, Immunologic↗
PubMed1994

Differences in binding affinities of human PTH(1-84) do not alter biological potency: a comparison between chemically synthesized hormone, natural and mutant forms.

The purpose of this study was to evaluate receptor binding affinities and biological properties in vitro and in vivo of various recombinant hPTH(1-84) forms representing the natural hormone and a mutagenized hPTH form, [Gln26]hPTH(1-84) (QPTH), after expression in E. coli and Saccharomyces cerevisiae. In LLC-PK1 cells stably transformed with the rat PTH/PTHrP receptor, chemically synthesized hPTH(1-84) and QPTH showed a reduced binding affinity (apparent Kd 18 and 23 nM, respectively) than the recombinant, hPTH(1-84) (apparent Kd 9.5 nM). All recombinant hPTH forms showed a similar potency to stimulate cellular cAMP production (EC50 1.5 nM) and significantly better than chemically synthesized hPTH (EC50 5.7 nM). All hormone forms showed an about equipotent activity in causing elevation in serum calcium, increased excretion of urine phosphate, and cAMP. Thus, the natural recombinant PTH forms showed higher binding affinities and adenylate cyclase activation potencies in LLC-PK1 cells, but the reduced receptor binding affinity exerted by QPTH did not transcend differences in cAMP generation and in vivo biological activities.

Animals↗
PubMed1990

Squamous cell carcinomas often produce more than a single bone resorption-stimulating factor: role of interleukin-1 alpha*.

Several cultured human squamous cell carcinoma cell lines (SCC-4, SCC-12B2, SCC-12F2, EC-GI-10, and BEN) and one normal keratinocyte line (Epy-1) were investigated for the production of bone resorption-stimulating activity (BRSA). Conditioned medium (CM) from each of the six cell lines stimulated bone resorption in neonatal mouse calvariae in culture. The BRSA of SCC-12F2 and EC-GI-10 was inhibited completely by antibody to interleukin-1 alpha (IL-1 alpha), whereas the BRSA in CM from the BEN, SCC-4, SCC-12B2, and Epy-1 cell lines was only partially inhibited by anti-IL-1 alpha. Addition of indomethacin to the calvarial cultures also partially inhibited the BRSA from EC-GI-10, SCC-4, SCC-12B2, and Epy-1 cells; the BRSA from BEN and SCC-12F2 cells was inhibited completely by indomethacin. cAMP production by calvariae was determined after a 60-min incubation with CM. CM from EC-GI-10, BEN, SCC-4, and Epy-1 stimulated cAMP production by bone. Preincubation of CM from BEN, EC-GI-10, SCC-4, and Epy-1 cells with two antisera against PTH-related protein [PTHrP; one specific for two PTHrP-(1-141), the other recognizing both PTHrP-(1-40) and PTHrP-(1-141)] completely inhibited the cAMP-stimulating activity. Using specific enzyme-linked immunosorbent assays for IL-1 alpha and IL-1 beta, IL-1 alpha was measured in CM of the SCC-4, SCC-12B2, SCC-12F2, and Epy-1 cell lines. IL-1 beta was undetectable (less than 0.1 ng/ml) in CM from all cell lines. Our findings indicate that the BRSA secreted by SCC-12F2 cells can be accounted for largely or entirely by IL-1 alpha, while the activity produced by SCC-12B2 includes IL-1 alpha and another unknown factor(s). The BRSA produced by EC-GI-10, BEN, SCC-4, and Epy-1 cells includes both IL-1 alpha and PTHrP. We conclude that IL-1 alpha may be a more prevalent and biologically significant component of the BRSA produced by SCCs than previously recognized.

Animals↗
PubMed1989

The effects of thionapthene-2-carboxylic acid-lysine on the hypercalcemia of malignancy in the rat.

Thionapthene-2-carboxylic acid (TNCA) was previously shown to lower serum calcium concentrations in hypercalcemic rats: however, oral administration of TNCA may cause gastric irritation. We have assessed thionapthene-2-carboxylic acid lysine salt (TNLY) for its effects on serum calcium concentration and survival in rats bearing the hypercalcemic Leydig cell tumor. TNLY (0.6-1.8 mmol/kg/day) produced a marked and prolonged dose-related decrease in serum calcium concentration. At the highest dose of 1.8 mmol/kg/day, hypocalcemia occurred. Effects were sustained for 96 hours or longer. In tumor-bearing rats that were not yet hypercalcemic, pretreatment with TNLY (0.9 mmol/kg/day) did not induce hypocalcemia and the onset of hypercalcemia was prevented. Neither TNLY nor dichloromethylene diphosphonate (CL2MDP), a potent inhibitor of bone resorption, significantly prolonged overall survival. We concluded that TNLY is a potent antihypercalcemic agent that warrants further testing for use in the treatment of hypercalcemic disorders.

Animals↗
PubMed1988

Skeletal contribution of cyclic adenosine monophosphate in response to parathyroid hormone and calcitonin in vivo in the rat.

Cyclic adenosine monophosphate (cAMP) is thought to be a second messenger for the actions of both parathyroid hormone (PTH) and calcitonin (CT). We examined the release of cAMP from rat bone in vivo after administration of synthetic rat PTH-(1-34) (rPTH), synthetic human PTH-(1-34) (hPTH), or synthetic human CT (hCT). Blood from the venous effluent of the femoral bone of rats (bone blood) was drawn at 5 and 10 minutes after the administration of hormones. The cAMP content of the bone blood was then compared to the cAMP content of arterial blood. In both kidney-clamped and non-kidney-clamped rats, hCT led to a significantly greater concentration of cAMP in the bone blood than in the arterial blood. We interpret this to be due to bone production and release of cAMP. Neither hPTH nor rPTH produced a significantly greater amount of cAMP in the bone blood than in arterial blood. These data do not preclude the possibility that there was a production of cAMP within the bone tissue itself after PTH but suggest that there was no release of cAMP from the bone into the bone blood.

Animals↗
PubMed1988

Clofazimine analogues active against a clofazimine-resistant organism.

Clofazimine analogues active against a strain of Mycobacterium smegmatis 607 made resistant to the antileprosy agent have been synthesized. Activity (i.e., less than or equal to 2 micrograms/mL causing complete inhibition of growth) requires that there be a basic nitrogen in the "rimino" side chain and that the spacer distance between this nitrogen and the imino nitrogen be at least three carbon atoms. The nitrogen may be primary, secondary, or tertiary and may be part of an open chain or enclosed in a ring compound. Provided that the criteria of basicity and spacer distance are satisfied, all are active in vitro against both the sensitive and resistant strains. Substitution elsewhere in the molecule had little effect on the activity. The compounds have been shown to have growth inhibitory activity against human-derived Mycobacterium leprae in murine macrophages in culture.

Animals↗
PubMed1984

2-Acetylpyridine thiosemicarbazones and Mycobacterium leprae.

Four 2-acetylpyridine thiosemicarbazones were tested in mice against Mycobacterium leprae by the kinetic method and found to be nearly inactive in a dosage of 0.05% in the diet. At the same dosage, thiacetazone, as a positive control, exhibited its expected activity.

Animals↗
PubMed1983

Fernandez and Mitsuda reactivity in guinea pigs sensitized with heat-killed Mycobacterium leprae: persistence and specificity of skin reactivity to soluble and particulate antigens.

Guinea pigs were sensitized with 500 micrograms dry weight of heat-killed Mycobacterium leprae, M. tuberculosis H37Rv, M. vaccae, or M. nonchromogenicum suspended in saline. Significant Fernandez (peak swelling at 48 hr) and Mitsuda (peaking at 21 days) reactions were observed when all four groups of animals were skin tested with 10 micrograms of the homologous whole-cell antigen (WCA) preparations one month after sensitization. Some of the guinea pigs were given a booster injection of the homologous suspension three months later and were then retested with the four WCA preparations. The Fernandez (rather than the Mitsuda) reactivity was enhanced by the second immunization and was still substantial when tested eight months after boosting. The Mitsuda-type responses observed 12 months after the primary sensitization peaked earlier than in the first- and four-month tests, regardless of the vaccinating organism. The M. leprae-sensitized guinea pigs produced larger Fernandez skin reactions than those seen in the other three groups of sensitized animals, but there was substantial crossreactivity between M. leprae and M. tuberculosis antigens, as well as somewhat lesser responsiveness in the M. vaccae- or M. nonchromogenicum-sensitized animals skin tested with lepromin. The present study indicates that saline suspensions of heat-killed M. leprae induced a highly persistent state of lepromin hypersensitivity which was quantitatively superior to that observed in animals sensitized with the three other mycobacteria.

Animals↗
PubMed1982

Correlations between structure and antimycobacterial activity in a series of 2-acetylpyridine thiosemicarbazones.

The antimycobacterial activity of a new series of 2-acetylpyridine thiosemicarbazones was determined in vitro using Mycobacterium smegmatis ATCC 607. The resulting log minimal inhibitory concentration (mumol l-1) values were plotted against the partition coefficient (log P) values for each compound, and fell on a parabolic distribution curve having a log P opt of 3.0. Compounds having partition coefficients outside the range 2.0 to 4.0 were inactive against M. smegmatis. When similar assays were carried out using M. tuberculosis, M. kansasii, M. marinum, M. simiae, M. avium and M. intracellulare, a similar series of parabolic activity curves were obtained having log P opt values around 4.0. The significance of this shift in the log P opt value obtained using the slow-growing pathogenic mycobacteria compared to that observed with the rapid-growing M. smegmatis is discussed in relation to the structures of the variable substituents of these new 2-acetylpyridine thiosemicarbazone compounds.

Anti-Bacterial Agents↗
PubMed1982

Activity of 2-acetylpyridine and 2-acetylquinoline thiosemicarbazones tested in vitro in combination with other antituberculous drugs.

Determinations of minimal inhibitory concentrations (MIC) were carried out using three new 2-acetylpyridine and two new 2-acetylquinoline thiosemicarbazones tested against Mycobacterium tuberculosis, M. kansasii, M. simiae, M. avium, and M. intracellulare. Two of the compounds (Compounds L and 3I) exhibited MIC less than or equal to 5 micrograms per ml for all of the test organisms, except for M. simiae, which was resistant to most antituberculous drugs. The other thiosemicarbazones (Compounds 3L, 2N, 3G, and 2H) were relatively inactive against the nontuberculous mycobacteria. Rifampin, amikacin, and clofazimine were active when tested singly or in combination with Compounds L and 3I. Addition of compound 3I to a mixture of rifampin, amikacin, and clofazimine resulted in combination MIC of less than 0.6 microgram/ml against all of the nontuberculous mycobacteria, suggesting that combinations of this type may be suitable for the treatment of infections caused by these highly drug-resistant organisms.

Antitubercular Agents↗
PubMed1981

Antimycobacterial activity of 2-acetylpyridine thiosemicarbazones in relation to their antileprosy activity.

Antimycobacterial assays were carried out on sixteen 2-acetylpyridine thiosemicarbazones using a number of culturable mycobacteria in vitro. The resulting MIC determinations were plotted against the lipophilicity (log P) values for the various test compounds. Plots of log MIC vs log P values conformed to a parabolic regression curve having a log Pmax of 4.0 for the slow-growing mycobacteria and 3.0 for the rapid grower, M. smegmatis. Ten thiosemicarbazone compounds covering a log P range of 1.0 to 4.5 were tested for their antileprosy activity in M. leprae-inoculated mouse foot pads. The resulting activity curve had a log Pmax of 2.0. The significance of these findings is discussed in terms of the role played by limiting diffusional factors within the tissue so far as the penetration of these thiosemicarbazones into the intracellular environment is concerned.

Animals↗