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David Hamilton

Publications and source records attributed to David Hamilton.

17 recordsLinked to original sources
PubMed2007

Structure-based identification of novel human gamma-glutamylcysteine synthetase inhibitors.

Glutathione depletion represents a potentially important strategy to sensitize tumors to cytotoxic drugs. l-Buthionine-(R,S)-sulfoximine (l-BSO) has been studied in both preclinical and early clinical trials, but limitation on its access has led to a search for alternatives. Using a 3D molecular model of human gamma-glutamylcysteine synthetase (gamma-GCS(H)), the major subunit of the rate-limiting GSH synthetic enzyme, we virtually screened the National Cancer Institute chemical database to identify compounds that could bind to and potentially inhibit gamma-GCS(H). We identified 51 test chemicals, all with structures very distinct from l-BSO. We subjected these compounds to biological assays measuring gamma-GCS(H) inhibition and glutathione (GSH) depletion. Among 10 novel gamma -GCS inhibitors identified, 4 compounds depleted glutathione in cells, and 2 with related structures sensitized tumor cells to melphalan treatment. This work validates the use of model-based database mining and identified inhibitors of gamma-GCS(H) with novel chemical structures.

Antineoplastic Agents↗
PubMed2006

Extraction and retrieval of potassium from water hyacinth (Eichhornia crassipes).

Studies were carried out on extraction and retrieval of potassium from water hyacinth (Eichhornia crassipes). The stem and leaf were subjected to 13 treatments. The highest rate of K removal following HCl treatment was 69.7% K. Most effective removal of suspended organic substances, Ca2+ and Mg2+ were achieved at pH approximately 13, when 88.0% of K remained in filtrate. Maximum K in precipitate following this step was achieved with tartaric acid additions at n(C4H6O6)/n(K+) of 1.72 when precipitating at 4 degrees C for 3h, which resulted in 72.3% of K removal from the solution. Over the entire process, 44.3% of K in the dried stem-leaf sample of water hyacinth was retrieved in the form of KC4H5O6. This process demonstrated the potential for use of water hyacinth as a resource of potassium to produce potassium salts and provide a valuable end use for the plant, which could be highly invasive in aquatic ecosystems.

Eichhornia↗
PubMed2006

Discrimination between parkinsonian syndrome and essential tremor using artificial neural network classification of quantified DaTSCAN data.

BACKGROUND: In the semi-quantitative assessment of DaTSCAN images, it has been suggested that the ratio of tracer accumulation in the putamen to that in the caudate nucleus may be helpful and could allow parkinsonian syndromes progression to be assessed. Separation of ratio values has been reported when early Parkinson's disease is compared with essential tremor. The separation is lost, however, when the Parkinson's disease is not early stage. OBJECTIVES: To evaluate whether a two-stage analysis can differentiate between parkinsonian syndromes, of various stages, and essential tremor, and whether such a two-stage analysis can be undertaken in a single step using artificial neural networks (ANNs). METHODS: Data from 18 patients were analysed. Quantification was undertaken by manually drawing irregular regions of interest (ROIs): over each caudate nucleus and putamen and over an occipital cortex area near the posterior edge of the brain. A two-stage analysis was undertaken and was repeated, in a single step, using an ANN. RESULTS: The first stage, of the two-stage analysis, identified 12 patients with non-early parkinsonian syndromes. The remaining six patients were then successfully classified into early parkinsonian syndromes and essential tremor. The ANN analysis successfully discriminated parkinsonian syndromes from essential tremor, in all patients, in a single step. CONCLUSIONS: The two-stage process provides a method for classifying early disease without being compromised by the noise from non-early disease. The results of the single stage ANN analysis were very definite and it may be considered to have potential in the quantification of DaTSCAN images for clinical use.

Adult↗
PubMed2006

The Scottish Medical Journal--the first fifty years.

The Scottish Medical Journal has been published for half a century and its pages reveal not only the steady changes in Scottish medical care and careers, but also reflect the attitudes of the times. The Journal has survived a number of crises. Recent changes, both at the Journal and in Scottish politics, leave it well placed for an expanded and important place in Scottish medicine.

History, 20th Century↗
PubMed2005

Evidence, economics, and emotions: the case for temozolomide.

Temozolomide, given as part of first line therapy in the treatment of grade IV astrocytoma, has been shown to improve survival in the short term. The financial cost of the treatment is considerable in New Zealand. This drug provides a good example in the field of oncology of a modern expensive pharmaceutical being a clear improvement over its cheaper predecessors, but it raises the question of what price should be paid to prolong survival in an incurable illness?

Antineoplastic Agents, Alkylating↗
PubMed2005

Cystic fibrosis birth rates in Canada: a decreasing trend since the onset of genetic testing.

OBJECTIVE: To estimate cystic fibrosis (CF) birth rates in Canada from 1971 to 2000 and to assess the population impact of genetic testing in families with a history of CF, after identification of the CF transmembrane conductance regulator gene in 1989. STUDY DESIGN: Age-at-diagnosis data were obtained from the Canadian Cystic Fibrosis Foundation Patient Data Registry and Canadian births for the corresponding years from Canadian Vital Statistics. Estimates of the CF birth rate in each year were based on a nonparametric model that allows the birth rate to vary across the years and adjusts for censoring of currently undiagnosed patients. RESULTS: The overall CF birth rate from 1971-1987 was 1/2714 with no increasing or decreasing trend. Beginning in 1988, 1 year before identification of the CF transmembrane conductance regulator gene, estimated CF birth rates followed a linear decline to an estimated rate of 1/3608 in 2000. CF birth rates may have stabilized in the last few years, but further decline may occur with implementation of carrier screening in the general population. CONCLUSIONS: These results demonstrate the temporal association of genetic testing and declining CF birth rates in Canada. They may assist in decisions relating to the allocation of resources for prenatal and neonatal CF screening programs.

Birth Rate↗
PubMed2005

TLK-199 (Telik).

Telik Inc is developing TLK-199, an intravenous inhibitor of glutathione S-transferase P1-1, for the potential prevention of myelosuppression in blood diseases, namely myelodysplastic syndrome.

Animals↗
PubMed2005

Anthracyclines.

Explore the source record for details and available documents.

Anthracyclines↗
PubMed2004

A cell-based system to identify and characterize the molecular mechanism of drug-metabolizing enzyme (DME) modulators.

Many naturally occurred or synthetic compounds can modulate the body's drug-metabolizing enzymes to enhance carcinogen detoxification, and some have demonstrated remarkable cancer prevention effects. Understanding the molecular mechanism behind each candidate agent is critically important in designing rational cancer chemoprevention strategies. In this work, we have employed a set of molecular mechanism-based assays and characterized eight classes of known drug-metabolizing enzyme (DME) modulators in a cellular system. Examination of mRNA and protein levels of representative phase I and phase II enzymes validated the results obtained in our cell-based system. Our data confirmed that the antioxidant ethoxyquin (EQ) and the isothiolcyanate sulfurophane (SFP) exclusively activate the antioxidant response element (ARE), and thus represent monofunctional inducers. We were also able to reclassify some compounds, and to use the system to identify structure-activity relationships among structurally related but different compounds. Finally, this cell-based system permitted us to identify a potential novel mechanism for cross-talk between the ARE and the xenobiotic response element (XRE)-mediated pathways.

Animals↗
PubMed2004

Glutathione analogues in cancer treatment.

Glutathione is an important intracellular antioxidant and redox potential regulator that plays a vital role in drug detoxification and elimination and in cellular protection from damage by free radicals, peroxides, and toxins. Molecular alterations reported in many of the components of the glutathione system in various tumors and cancer cell lines can lead to increased survival and enhanced chemotherapy drug resistance. Several glutathione analogues that target this system have been developed and used experimentally and clinically in an attempt to improve cancer chemotherapy. These compounds include glutathione-S-transferase inhibitors and prodrugs, glyoxalase I inhibitors, and S-nitrosoglutathione. Work with these analogues has shown promising results, although lack of tumor specificity is a potential problem. Continuing development and optimization of glutathione analogues will lead to more specific targeting of this system in cancer treatment, allowing an increased therapeutic response.

Glutathione↗
PubMed2003

A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production.

Gamma-glutamylcysteine synthetase (gamma-GCS) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis: the adenosine triphosphate (ATP)-dependent ligation of glutamate and cysteine. gamma-GCS consists of a catalytic (gamma-GCSH) and modifier (gamma-GCSL) subunit. Hereditary deficiency of gamma-GCS has been reported in a small number of patients and is associated with low erythrocyte levels of gamma-GCS and GSH leading to hemolytic anemia. Here we report a novel gamma-GCSH mutation, isolated from the cDNA of 2 related patients diagnosed with gamma-GCS deficiency. Each was found to be homozygous for a C>T missense mutation at nucleotide 379, encoding for a predicted Arg127Cys amino acid change. Computerized structure modeling identified that the mutated amino acid lies within a cleft on the protein surface of gamma-GCSH, and the border of this cleft was shown to contain Cys249, an evolutionarily conserved residue that has been proven to lie near the binding site of gamma-GCSH. Transfection studies showed that the mutation is associated with decreased GSH production, and binding studies using purified recombinant protein showed that the mutant protein has markedly decreased enzymatic activity compared to wild type.

Amino Acid Substitution↗
PubMed2003

Perspectives on preventing adolescent substance use and misuse.

This article reviews different theoretical models concerning the prevention of substance use by adolescents. The models differ in their concepts and in their assumptions. Because the models describe different parts of the substance use problem, they can be combined to provide the basis for the design of information-based prevention programs. For example, in order to understand adolescent development, identity models or attachment models can be used. To understand adolescent norm changes, cultural models or peer system models can be applied. To understand how adolescents cope in specific situations where alcohol and other drugs are available, models that include concepts like self-esteem, drug expectations, existing norms, and perceived control of substance use can be employed. All preventive programs need to be pretested as well as evaluated both during and postprogram. The models mentioned may be used as frameworks in an evaluation, i.e., the variables and the assumptions in the models can be used as hypotheses to establish whether the desired results are achieved as a consequence of the selected strategies and techniques in the preventive program. A greater knowledge of the social and psychological processes preventing substance use will put us in a better position to influence and understand adolescent substance use in the future.

Adaptation, Psychological↗
PubMedDate not supplied

Evaluation of drug use prevention programs directed at adolescents.

The aim of this article is to present a theoretical model of how to undertake evaluations of prevention programs directed at adolescents. Based on the results from metaanalyses of outcome studies of school-based programs, this article concludes that interactive programs tend to be more effective than not only those mainly intended to increase factual knowledge about tobacco, alcohol, and illegal drugs, but also those initiatives aimed at influencing adolescents' attitudes toward those substances. The interactive strategy corresponds to problem-based learning or the interactive educational approach, now widely popular in educational circles. These outcome studies have provided us with important knowledge. However, there are relatively few evaluation investigations that analyze in substantive detail the process by which adolescents change their alcohol, tobacco, and illegal drug-use behavior, and alter their perceptions about these substances. In an ongoing intervention study based on an interaction framework, involving all youngsters in the ninth grade (15-16 year olds, n = 300, undertaken in year 2001-2002) in the Aland Islands, Finland, the students' perceptions regarding the risks involved in illegal drug use could not be altered. Neither was it possible to decrease the alcohol or tobacco consumption during this school year. However, what did occur was that a number of expectations regarding alcohol were changed, which, in turn, might influence the patterns of alcohol use by the target group. The ways students in the Alands celebrate the end of junior high school are culturally embedded, and this may explain the lack of success in decreasing their alcohol consumption and tobacco use at the end of the ninth grade. Based on the analysis, a combination of outcome and process evaluations is recommended in order to reach a better understanding of how school prevention programs may achieve the desired goals.

Adolescent↗
PubMedDate not supplied

Medium-term and long-term priorities in ecological studies.

Research priorities in ecology and environmental sciences for the future are formulated. The priorities for both fundamental and applied ecology are proposed. The list of priorities includes 50 items. The priorities are relevant to terrestrial, aquatic, and general ecology. The list of priorities is helpful when grant proposals are being prepared, evaluated, and selected for funding.

Ecology↗