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Biomedical subjects

J A Lawrence

Publications and source records attributed to J A Lawrence.

At least 19 recordsLinked to original sources
PubMed2000

Progress in cancer chemoprevention: development of diet-derived chemopreventive agents.

Because of their safety and the fact that they are not perceived as "medicine," food-derived products are highly interesting for development as chemopreventive agents that may find widespread, long-term use in populations at normal risk. Numerous diet-derived agents are included among the >40 promising agents and agent combinations that are being evaluated clinically as chemopreventive agents for major cancer targets including breast, prostate, colon and lung. Examples include green and black tea polyphenols, soy isoflavones, Bowman-Birk soy protease inhibitor, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol, vitamin D, vitamin E, selenium and calcium. Many food-derived agents are extracts, containing multiple compounds or classes of compounds. For developing such agents, the National Cancer Institute (NCI) has advocated codevelopment of a single or a few putative active compounds that are contained in the food-derived agent. The active compounds provide mechanistic and pharmacologic data that may be used to characterize the chemopreventive potential of the extract, and these compounds may find use as chemopreventives in higher risk subjects (patients with precancers or previous cancers). Other critical aspects to developing the food-derived products are careful analysis and definition of the extract to ensure reproducibility (e.g., growth conditions, chromatographic characteristics or composition), and basic science studies to confirm epidemiologic findings associating the food product with cancer prevention.

Biomarkers↗
PubMed2000

Clinical development of estrogen modulators for breast cancer chemoprevention in premenopausal vs. postmenopausal women.

Tamoxifen has proven to be beneficial in the chemoprevention of breast cancer in women at increased risk for the disease. Other compounds that mediate the estrogen pathway remain to be tested for clinical efficacy. The mechanism of action, efficacy, and dose response of the estrogen modulators is determined by the hormonal milieu of the host which should be considered in the early clinical trials for dose range finding studies and surrogate endpoint biomarker (SEB) evaluation. This review presents the hormonal effects to consider in the clinical testing of an agent in premenopausal vs. postmenopausal cohorts. Recommended SEBs that may be evaluated in Phase I/II clinical trials of estrogen modulators for breast cancer chemoprevention are presented.

Aromatase Inhibitors↗
PubMed1999

Behavioural analysis of the acute and chronic effects of MDMA treatment in the rat.

RATIONALE: A variety of animal models have shown MDMA (3,4-methylenedioxymethamphetamine) to be a selective 5-HT neurotoxin, though little is known of the long-term behavioural effects of the pathophysiology. The widespread recreational use of MDMA thus raises concerns over the long-term functional sequelae in humans. OBJECTIVE: This study was designed to explore both the acute- and post-treatment consequences of a 3-day neurotoxic exposure to MDMA in the rat, using a variety of behavioural paradigms. METHODS: Following training to pretreatment performance criteria, animals were treated twice daily with ascending doses of MDMA (10, 15, 20 mg/kg) over 3 days. Body temperature, locomotor activity, skilled paw-reaching ability and performance of the delayed non-match to place (DNMTP) procedure was assessed daily during this period and on an intermittent schedule over the following 16 days. Finally, post mortem biochemical analyses of [3H] citalopram binding and monoamine levels were performed. RESULTS: During the MDMA treatment period, an acute 5-HT-like syndrome was observed which showed evidence of tolerance. Once drug treatment ceased the syndrome abated completely. During the post-treatment phase, a selective, delay-dependent, deficit in DNMTP performance developed. Post-mortem analysis confirmed reductions in markers of 5-HT function, in cortex, hippocampus and striatum. CONCLUSIONS: These results confirm that acutely MDMA exposure elicits a classical 5-HT syndrome. In the long-term, exposure results in 5-HT neurotoxicity and a lasting cognitive impairment. These results have significant implications for the prediction that use of MDMA in humans could have deleterious long-term neuropsychological/psychiatric consequences.

Animals↗
PubMed1999

Progress in cancer chemoprevention.

More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets. A few have been in vanguard, large-scale intervention trials--for example, the studies of tamoxifen and fenretinide in breast, 13-cis-retinoic acid in head and neck, vitamin E and selenium in prostate, and calcium in colon. These and other agents are currently in phase II chemoprevention trials to establish the scope of their chemopreventive efficacy and to develop intermediate biomarkers as surrogate end points for cancer incidence in future studies. In this group are fenretinide, 2-difluoromethylornithine, and oltipraz. Nonsteroidal anti-inflammatories (NSAID) are also in this group because of their colon cancer chemopreventive effects in clinical intervention, epidemiological, and animal studies. New agents are continually considered for development as chemopreventive drugs. Preventive strategies with antiandrogens are evolving for prostate cancer. Anti-inflammatories that selectively inhibit inducible cyclooxygenase (COX)-2 are being investigated in colon as alternatives to the NSAID, which inhibit both COX-1 and COX-2 and derive their toxicity from COX-1 inhibition. Newer retinoids with reduced toxicity, increased efficacy, or both (e.g., 9-cis-retinoic acid) are being investigated. Promising chemopreventive drugs are also being developed from dietary substances (e.g., green and black tea polyphenols, soy isoflavones, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol). Basic and translational research necessary to progress in chemopreventive agent development includes, for example, (1) molecular and genomic biomarkers that can be used for risk assessment and as surrogate end points in clinical studies, (2) animal carcinogenesis models that mimic human disease (including transgenic and gene knockout mice), and (3) novel agent treatment regimens (e.g., local delivery to cancer targets, agent combinations, and pharmacodynamically guided dosing).

Animals↗
PubMed1998

Solid-phase extraction method with high-performance liquid chromatography and electrochemical detection for the quantitative analysis of oxycodone in human plasma.

A sensitive and reproducible solid-phase extraction (SPE) method for the quantification of oxycodone in human plasma was developed. Varian Certify SPE cartridges containing both C8 and benzoic acid functional groups were the most suitable for the extraction of oxycodone and codeine (internal standard), with consistently high (> or =80%) and reproducible recoveries. The elution mobile phase consisted of 1.2 ml of butyl chloride-isopropanol (80:20, v/v) containing 2% ammonia. The quantification limit for oxycodone was 5.3 pmol on-column. Within-day and inter-day coefficients of variation were 1.2% and 6.8% respectively for 284 nM oxycodone and 9.5% and 6.2% respectively for 28.4 nM oxycodone using 0.5-ml plasma aliquots.

Analgesics, Opioid↗
PubMed1998

A high-risk lesion for invasive breast cancer, ductal carcinoma in situ, exhibits frequent overexpression of retinoid X receptor.

The development of prevention strategies for breast cancer will require a molecular map of carcinogenesis. We have investigated gene expression patterns in premalignant and early carcinomatous human breast lesions that confer to the patient varying risks for developing invasive breast cancer. The relative expression levels of one of the retinoid receptors, retinoid X receptor (RXR), was determined by in situ hybridization to 58 biopsy specimens; RXR mRNA grain density over each lesion was compared to that over the normal ductal/lobular units in each section. Overexpression of RXR mRNA was observed in 66% of noncomedo ductal carcinoma in situ (DCIS), which confer a >8-fold increase in breast cancer risk, and 88% of comedo DCIS lesions, which are associated with a yet higher risk. In contrast, only 8% of lesions that confer little or no increase in breast cancer risk overexpressed RXR mRNA (P = 0.0008). Limited in situ hybridization data using retinoic acid receptor (RAR) riboprobes showed overexpression of RAR alpha, but not RAR beta or -gamma, in only a modest percentage (36%) of cases, suggesting that all members of the retinoid receptor superfamily are not similarly regulated. Immunohistochemistry performed on 52 DCIS specimens for alpha, beta, and gamma isoforms of RXR confirmed its overexpression at the protein level and implicate RXR alpha as the predominant overexpressed form. The data indicate that RXR overexpression is associated with an increased risk for the development of invasive breast cancer in human breast lesions and suggest the hypothesis that it is causally involved in breast oncogenesis. The implications for retinoid chemoprevention are discussed.

Biomarkers, Tumor↗
PubMed1997

Immunisation of smallholder dairy cattle against anaplasmosis and babesiosis in Malawi.

A field study was conducted in the Southern Region of Malawi to evaluate the possible benefits of immunisation of improved dairy cattle against Anaplasma marginale, Babesia bigemina and Babesia bovis. Friesian crossbred heifers were immunised when they were being reared on Government farms. They were then issued to smallholder farmers, together with unvaccinated controls, where many of them were exposed to heavy tick infestation. Vaccination was shown to provide a significant degree of protection against babesiosis on the smallholder farms; 15/32 unvaccinated controls developed clinical disease as compared to only 3/28 vaccinates.

Anaplasma↗
PubMed1997

Identification of compounds with preferential inhibitory activity against low-Nm23-expressing human breast carcinoma and melanoma cell lines.

We have used the COMPARE computer algorithm and Nm23 expression as a marker of tumor metastatic potential to examine the in vitro antiproliferative activity of chemotherapeutic drugs on human breast carcinoma and melanoma cell lines. None of 171 compounds in clinical use or under development and only 40 of 30,000 repository compounds exhibited preferential growth inhibition of low-Nm23-expressing, metastatically aggressive cell lines with a Pearson correlation coefficient of < or = -0.64. Characterization of one compound, NSC 645306, is presented including in vivo activity in a hollow fiber assay. The data demonstrate a novel approach to drug identification for aggressive human tumors.

Algorithms↗
PubMed1997

Conventional vaccines for tick-borne haemoparasitic diseases of sheep and goats.

Of the many tick-borne haemoparasites of sheep and goats, three may be controlled by vaccination. A live virulent blood vaccine for Cowdria ruminantium infection (heartwater) is used widely in southern Africa in an infection and treatment procedure. A live vaccine for Babesia ovis attenuated by passage in splenectomised sheep has been used extensively in Bulgaria with good results. A live vaccine for Theileria hirci, consisting of schizonts propagated in a lymphoid cell culture and attenuated by passage, has been used successfully in the Middle East.

Anaplasmosis↗
PubMed1997

The small heat shock protein hsp27 increases invasiveness but decreases motility of breast cancer cells.

The small heat shock protein hsp27 is often expressed at high levels in clinical breast tumors; however, its biological role in this disease still remains unclear. Several laboratories have recently shown that hsp27 expression is associated with aggressive tumor behavior. We hypothesized that hsp27 may influence the metastatic tumor process since this is part of tumor 'aggressiveness'. Therefore, we stably transfected breast cancer cell lines with sense (MDA-MB-231) and antisense (MDA-MB-435) hsp27 constructs, respectively, and examined various cellular aspects associated with the metastatic process. We found that hsp27-overexpressing clones lost their protrusive morphology, but exhibited higher membrane ruffling as compared to low expressing cells. hsp27 overexpression also resulted in decreased cell motility, but invasiveness, adhesion, and growth in Matrigel were all significantly increased. Conversely, antisense suppression of hsp27 expression resulted in increased cell motility, but decreased in vitro invasiveness. The direct correlation of hsp27 levels with metastasis was confirmed by an in vivo assay measuring the number of lung metastases in mice injected with hsp27-transfected cells. Thus, we conclude that hsp27 overexpression may influence the invasive and metastatic potential of human breast cancer cells.

Animals↗
PubMed1996

Mechanisms of tumor invasion and metastasis.

Metastasis is the cascade of events involved in the transition of a malignancy from a localized tumor to the establishment of a distant foci. In this review we define the known stages and the factors involved. The multiplicity of steps involved allows many opportunities for therapeutic intervention. Current research has focused on interruption of a step or a series of steps to limit the spread of cancer. With emphasis on the urologic malignancies, we outline the research thus far accomplished in the field of metastasis.

Animals↗
PubMed1996

Integrated tick and tick-borne disease control trials in crossbred dairy cattle in Malawi.

Crossbred dairy heifers on a farm in an East Coast fever (ECF) endemic area in Malawi were immunised against Theileria parva, Anaplasma spp., Babesia bigemina, Babesia bovis and Cowdria ruminantium. They were treated at infrequent intervals with chlorfenvinphos to limit infestation with adult ticks, without providing complete tick control. In one trial, which tested a threshold dipping regimen, 20 heifers were dipped only once in 6 months to control a flush of Boophilus microplus. Unimmunised controls showed serological evidence of exposure to T. parva and B. bigemina, and one died of ECF, but there were no incidents of tick-borne disease in the immunised group. In a second trial, which tested a strategic dipping regimen, 107 animals were dipped 9 times over a 6 month period. Despite heavy challenge by B. bovis and moderate challenge by B. bigemina and Anaplasma spp. demonstrated serologically, there was only a single clinical case of babesiosis. The observations provide encouragement for the introduction of integrated tick and tick-borne disease control programmes in improved cattle in ECF endemic areas.

Administration, Topical↗
PubMed1996

Nurses' representations of the positive and negative features of nursing.

Nurses' representations of their work are defined as their cognitive 'work spaces', a theoretical concept derived from Newell & Simon's (1977) problem-solving model and Lewin's (1935) concept of interacting positive and negative valences. Using a structural equation modelling technique, a network of positive and negative features in nurses' work spaces is described in patterns of response to a questionnaire eliciting nurses' ratings of their professional opportunities and difficulties. The modelling technique revealed the dominance of positive over negative features, and the overall significance of social recognition for encouraging nurses to remain in nursing. Comparative analyses revealed that dominant features of work space representations did not differ for nurses from four city and country hospitals, nor in relation to positions in the nursing hierarchy. The importance of understanding the perceptions of nurses is discussed in relation to changes and development in nursing as a profession.

Adult↗
PubMed1996

Malignant melanoma metastatic to the gastrointestinal tract.

Malignant melanoma, a common malignancy whose prevalence is increasing, represents 1-3% of cancers in the United States [1]. At autopsy, metastatic deposits to the gut are frequently found, but less than 9% of melanoma patients are diagnosed with gastrointestinal metastases while living [2]. Modern management includes aggressive surgical therapy to prolong survival and to palliate the disease [3]. Therefore, imaging of metastatic melanoma is clinically important to detect extent and determine whether the patient would benefit by surgery. Gastrointestinal metastases may manifest as mucosal or submucosal masses, serosal implants, or carcinomatosis [4]. They arise more commonly in the mesentery or distal small bowel than the proximal gastrointestinal tract or colon. The purpose of this essay is to illustrate the appearance of melanoma metastatic to the gastrointestinal tract on luminal contrast studies and on CT and to emphasize the importance of early investigation of gastrointestinal symptoms in a patient with a history of malignant melanoma.

Adult↗
PubMed1996

Field observations on the duration of immunity in cattle after vaccination against Anaplasma and Babesia species.

In an outbreak of Babesia bovis in a large herd of Friesian x Malawi Zebu cattle, which occurred after an interruption of intensive dipping, clinical or fatal babesiosis occurred in 54/299 (18.1%) animals which had never been vaccinated, as compared to 9/153 (5.9%) vaccinated animals. Eight of the nine affected vaccinates had been vaccinated more than 27 months previously. Sera were collected every 3-4 months from 33 Friesian x Malawi Zebu heifers maintained with intensive dipping and vaccinated with trivalent B. bovis, Babesia bigemina and Anaplasma centrale vaccine. After 2 years, 25% had become seronegative for B. bovis by indirect immunofluorescence, as compared to 97% for B. bigemina and 46% for A. centrale. Because of the evidence that immunity following vaccination against B. bovis declines after 2 years in the absence of tick challenge, it is recommended that tick control should be relaxed after immunity has been established, in order to save acaricide, reinforce immunity and avoid any need for revaccination.

Anaplasma↗
PubMed1996

Improving the specificity of indirect immunofluorescence for the serological diagnosis of bovine anaplasmosis.

Fluorescing inclusion appendages were detected consistently in preparations of Anaplasma centrale and Anaplasma marginale when they were used as antigen in indirect immunofluorescence serological tests for the diagnosis of anaplasmosis in cattle. The presence of the inclusion appendages made it possible to confirm the specificity of the immunofluorescent reaction and to determine end-points with accuracy.

Anaplasmosis↗