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Biomedical subjects

C A Metcalf

Publications and source records attributed to C A Metcalf.

14 recordsLinked to original sources
PubMed2006

Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases.

Vascular endothelial growth factor (VEGF) is the predominant pro-angiogenic cytokine in human malignancy, and its expression correlates with disease recurrence and poor outcomes in patients with colorectal cancer. Recently, expression of vascular endothelial growth factor receptors (VEGFRs) has been observed on tumours of epithelial origin, including those arising in the colon, but the molecular mechanisms governing potential VEGF-driven biologic functioning in these tumours are not well characterised. In this report, we investigated the role of Src family kinases (SFKs) in VEGF-mediated signalling in human colorectal carcinoma (CRC) cell lines. Vascular endothelial growth factor specifically activated SFKs in HT29 and KM12L4 CRC cell lines. Further, VEGF stimulation resulted in enhanced cellular migration, which was effectively blocked by pharmacologic inhibition of VEGFR-1 or Src kinase. Correspondingly, migration studies using siRNA clones with reduced Src expression confirmed the requirement for Src in VEGF-induced migration in these cells. Furthermore, VEGF treatment enhanced VEGFR-1/SFK complex formation and increased tyrosine phosphorylation of focal adhesion kinase, p130 cas and paxillin. Finally, we demonstrate that VEGF-induced migration is not due, at least in part, to VEGF acting as a mitogen. These results suggest that VEGFR-1 promotes migration of tumour cells through a Src-dependent pathway linked to activation of focal adhesion components that regulate this process.

Adenocarcinoma↗
PubMed2005

Protein phosphorylation and signal transduction modulation: chemistry perspectives for small-molecule drug discovery.

Protein phosphorylation has been exploited by Nature in profound ways to control various aspects of cell proliferation, differentiation, metabolism, survival, motility and gene transcription. Cellular signal transduction pathways involve protein kinases, protein phosphatases, and phosphoprotein-interacting domain (e.g., SH2, PTB, WW, FHA, 14-3-3) containing cellular proteins to provide multidimensional, dynamic and reversible regulation of many biological activities. Knowledge of cellular signal transduction pathways has led to the identification of promising therapeutic targets amongst these superfamilies of enzymes and adapter proteins which have been linked to various cancers as well as inflammatory, immune, metabolic and bone diseases. This review focuses on protein kinase, protein phosphatase and phosphoprotein-interacting cellular protein therapeutic targets with an emphasis on small-molecule drug discovery from a chemistry perspective. Noteworthy studies related to molecular genetics, signal transduction pathways, structural biology, and drug design for several of these therapeutic targets are highlighted. Some exemplary proof-of-concept lead compounds, clinical candidates and/or breakthrough medicines are further detailed to illustrate achievements as well as challenges in the generation, optimization and development of small-molecule inhibitors of protein kinases, protein phosphatases or phosphoprotein-interacting domain containing cellular proteins.

Drug Design↗
PubMed1996

Design and baseline characteristics of a hypertension intervention program in a South African village.

The Mamre Hypertension Project was initiated in response to studies indicating that hypertension and cardiovascular disease were prevalent in a rural community of Mamre, located in the Western Cape, South Africa. A survey was done to collect baseline information on the prevalence of hypertension and other cardiovascular disease risk factors. The age-adjusted prevalence of hypertension in people aged 15 years or more was 13.9% in men and 16.3% in women. Of the hypertensive subjects, 27% were not aware of their hypertension, a further 14.4% were not on treatment, and only 16.8% had their blood pressure (BP) controlled at under 140/90 mm Hg. There was a high prevalence of smoking, heavy alcohol use (in men), obesity (in women) and physical inactivity. The survey results will be used to assess the impact of the intervention programme using a before and after design, and are being used to direct interventions. The intervention programme comprises a BP station catering primarily for people with hypertension, and a health education and promotion programme directed at the general community. The BP station screens for hypertension, monitors BP and compliance with medication in hypertensives, and encourages risk factor modification. Health promotion activities include a smoking cessation group and a weight reduction and exercise group. These are run by community volunteers with support from outside consultants. The effects of the programme will be assessed after 4-5 years.

Adolescent↗
PubMed1994

Missed opportunities for immunisation at hospitals in the western Cape--a reappraisal.

Immunisation practices were examined at 6 hospitals in the western Cape during the latter half of 1992 to determine whether these practices had improved subsequent to the February 1991 resolution of the Health Matters Committee (HMC) on immunisation in hospitals, and since a similar study was undertaken in 1990. Exit interviews were conducted with the escorts of all children aged 3-59 months who attended the study hospitals on the days designated for the study. In the second study, 88 of the 311 children studied (28.3%) were in need of immunisation on arrival, but only 12 of the 88 (13.6%) were immunised during the hospital visit. There was no evidence of an increase in requests to see children's Road-to-Health cards (37.1% compared with 35.2% previously). The incidence of missed opportunities for measles immunisation in children aged 6-59 months remained unacceptably high (51.4% compared with 63.7% previously, when a strict definition was used; and 15.7% compared with 18.1% previously, when a lenient definition was used). Health authorities at all levels need to take urgent action to address the problem of missed opportunities for immunisation at hospitals.

Child, Preschool↗
PubMed1993

Attitudes of private general practitioners towards health care in South Africa.

The need for health care reform in South Africa is acknowledged by the government as well as by the non-governmental health sector. There is, however, no unanimity regarding the nature of the envisaged reform. A country-wide postal survey of 700 private sector general practitioners (GPs) from a commercial database of 5,000 was conducted to explore attitudes towards health care. A response rate of 67.4% was obtained. Respondents were mostly male (92%) and urban-based (64%). The median age was 42 years. Most respondents: (i) believed health care to be a right for all citizens; (ii) favoured private or a combination of private and public funding mechanisms with fee-for-service arrangements; (iii) opposed cost-containment measures imposed by funders, e.g. medical aids; and (iv) believed doctors should be responsible for primary care in under-served areas. After sex, age, location (urban versus rural) and GP postgraduate qualification had been controlled for by means of logistic regression techniques, the university at which a respondent's basic degree was obtained emerged as the only independent predictor of attitudes to the following: (i) comprehensive care as a right; (ii) integration of the public and private sectors; (iii) preferred funding source for a future health system; and (iv) preference for fee-for-service remuneration. Both university and gender independently predicted attitudes on GPs' income. Graduates of white, Afrikaans-medium universities were strongly in favour of a privately funded and fee-for-service orientated system. Those who qualified at black universities, on the other hand, favoured public funding with less emphasison fee-for-service.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Smoking policies in the workplace in the western Cape.

A postal survey of workplace smoking restrictions among the member organisations of the Cape Chamber of Industries was carried out in 1989. The response rate was 57.1%. Of the 572 respondent organisations, 66.1% had some smoking restrictions. Large workplaces were more likely to restrict smoking than small workplaces: 42.0% of those with fewer than 10 employees had restrictions, increasing to 90.9% of those with more than 500 employees. Organisations producing manufactured goods (other than engineering) were more likely to have restrictions than non-manufacturing concerns. Smoking was commonly restricted on the factory floor (61.3%) and in warehouses (55.8%), but only 7.4% prohibited smoking in shared offices. The reasons for smoking restrictions stated most frequently were the fire hazard (85.3%) and legislation (66.0%). Only 29.1% stated that health care concerns were an important reason for restrictions, while a further 16.3% stated that health was a minor reason for restrictions. Of the respondents, 48.4% expressed a need for guidance in improving their smoking policies. These results indicate that there is considerable potential for intervention to decrease both active and passive smoking in local workplace settings.

Humans↗
PubMed1991

Peering into the black hole--the quality of black mortality data in Port Elizabeth and the rest of South Africa.

In the year ending 30 June 1989, 26.8% of 5,345 deaths in the Port Elizabeth area were classified as ill-defined. A study was undertaken in an attempt to identify the reasons for the high proportion of such deaths. Copies of all death notifications and death register forms of black people in the area served by the Port Elizabeth City Health Department were collected for a 6-week period. Of the 316 deaths, 154 (48.7%) were certified by medical practitioners at a hospital, 158 (50%) by the police and 4 (1.3%) by private medical practitioners. Of the police-certified deaths 116 (73.4%) were recorded as due to 'natural causes', with the remainder being submitted to autopsy. Of the hospital deaths, 26% were not adequately described in the section for the cause of death on the death certificate. Review of national mortality data for 1985 showed that only 29.9% of ill-defined deaths (in all population groups) were certified by a medical practitioner. The prime source of deaths classified as ill-defined, both in Port Elizabeth and nationally, were those not certified by a medical practitioner. Strategies aimed at minimising the number of deaths certified by the police need to be developed.

Black or African American↗
PubMed1991

An evaluation of an education programme on HIV infection using puppetry and street theatre.

'Puppets Against AIDS' is a novel educational medium being used to try to reduce the spread of HIV infection in South Africa. It involves the use of street theatre employing two-metre-high puppets who act out a story of how one person, who is infected with HIV, passes it onto a series of other people until he eventually dies. The puppet show was evaluated in two phases. The first involved a content analysis of a video recording of the show by a multidisciplinary group, according to a set of criteria for appropriate education on HIV infection. This show was found to be professional and comprehensive in terms of the educational messages provided. Some suggestions were made for improvements. The second phase was a before and after study of the impact on the audience at a series of live shows. The show made a significant contribution to knowledge and intended behaviour in the short term. Overall it was felt that the show does make a valuable contribution, but could be made more effective if incorporated into existing community-based education programmes on HIV infection.

Adult↗
PubMed1990

Knowledge, attitudes and beliefs about AIDS in township school students in Cape Town.

Students (N = 377) from four Cape Town township high schools were surveyed to obtain information on their knowledge of and attitudes towards the acquired immunodeficiency syndrome (AIDS), and on their sexual behaviour. The study was undertaken to provide information for planning an AIDS education intervention. Three-quarters of students reported that they had had sexual intercourse. Most students had heard of AIDS, and the majority of these knew that it was infectious. More than half of the students were confused or lacked knowledge about the modes of transmission. Two-thirds of the students believed AIDS could be prevented, but knowledge of prevention strategies was superficial. Of the sexually active students only 11.4% had ever used a condom, and of all students 39.6% stated that they would use a condom in the future. Two-thirds of the students were not aware that there is no cure for AIDS. Students did not acknowledge that AIDS could affect them directly, and attributed the problem to prostitutes and 'promiscuous' people in 36.4% of responses, and to 'white' people in 23.8% of responses. Students expressed intolerance, fear and rejection of people with AIDS, and only 6.4% would accept an affected person into their class. Almost all the students wanted AIDS education at school, and most of these requested that the school nurse facilitate this education. It is concluded that appropriate AIDS prevention education is urgently required for both high school and junior school students.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Knowledge and beliefs about tuberculosis among non-working women in Ravensmead, Cape Town.

The results of a community-based survey on knowledge and beliefs about tuberculosis in non-working women are presented. The women in the sample showed a very good knowledge of the important aspects of tuberculosis: 90% were aware that it is a problem in their area; 97% knew that it affects the chest; 94% said that it could be fatal; 85% considered it to be infectious and 88% knew that the local clinic provided treatment. Their knowledge of symptoms was good overall but the study revealed misconceptions about the causes and transmission of tuberculosis; 16% indicated that they would not be keen to associate with people with tuberculosis owing to fear of infection. The design effect of cluster sampling was considered in the analysis. The highest design effects (i.e. the most clustering of responses) were found for responses to questions on the causes of tuberculosis and places where treatment could be obtained, possibly reflecting that these beliefs are influenced by neighbourhood contacts. Future tuberculosis education in this group needs to build on existing knowledge and awareness and should focus on changing attitudes such as misconceptions about transmission and the stigmatisation of the disease. Health workers face the challenge of changing behaviour in this community to ensure that people with symptoms present early for screening and that people diagnosed as having tuberculosis comply with treatment.

Adolescent↗
PubMedDate not supplied

Structure-based design and solid-phase parallel synthesis of phosphorylated nonpeptides to explore hydrophobic binding at the Src SH2 domain.

Using a novel, solid-phase parallel synthetic route and a computational docking program, a series of phosphorylated nonpeptides were generated to determine their structure-activity relationships (SAR) for binding at the SH2 domain of pp60src (Src). A functionalized benzoic acid intermediate was attached to solid support via Rink amide linkage, which upon acid cleavage generated the desired benzamide template-based nonpeptides in a facile manner. Compounds were synthesized using a combination of solid- and solution-phase techniques. Purification using reversed-phase, semipreparative HPLC allowed for quantitative SAR studies. Specifically, this work focused on functional group modifications, in a parallel fashion, designed to explore hydrophobic binding at the pY+3 pocket of the Src SH2 domain.

Benzamides↗