Biomedical subjects

Stephen L Brown

Publications and source records attributed to Stephen L Brown.

29 records · Page 2Linked to original sources

PubMed2004

A quantitative method for measuring gene expression magnitude and volume delivered by gene therapy vectors.

This study describes a quantitative method to measure the magnitude and distribution of gene expression following local delivery of an adenoviral vector containing the human sodium iodide symporter (hNIS) reporter gene into the canine prostate. Following systemic administration of Na(99m)TcO(4), autoradiographs of prostate sections depicting hNIS-dependent (99m)TcO(4)(-) uptake were digitized and stacked to produce a three-dimensional reconstruction of gene expression. Frequency histograms reflecting hNIS gene expression magnitude and volume were used to quantify hNIS function. The method demonstrated submillimeter resolution allowing for precise measurements of gene expression magnitude and volume in vivo. The method developed here could be applied to other reporter gene systems in which the readout can be digitized from thin tissue sections.

Adenoviridae↗

PubMed2004

The relationship between anxiety, smoking, and gambling in electronic gaming machine players.

Given higher reported rates of smoking in populations under treatment for problem gambling, in a sample of 81 Electronic Gaming Machine players, this study considered whether: 1) there were relationships between tobacco dependency and problem gambling, and 2) a common mechanism such as negative affect was involved. The untreated sample comprised eighty-one Electronic Gaming Machine players that completed the South Oaks Gambling Screen, the Tobacco Dependence Scale and the State-Trait Anxiety Inventory. There was a relationship between smoking status and scores on the South Oaks Gambling Screen, and negative affect contributed to both gambling problems and tobacco dependence. It was suggested that gambling problems and tobacco dependence have similar characteristics. The data has implications for treatment and anti-smoking legislation in gaming venues.

Adult↗

PubMed2004

Gene therapy strategies to improve the effectiveness of cancer radiotherapy.

Having the ability to alter the genetic makeup of a cancer cell by gene transfer is a potentially powerful strategy for treating human cancer. However, a low efficiency of gene delivery in vivo and poor tumour specificity has prevented the widespread implementation of this technology in the clinic. Despite these formidable obstacles, the first successful application of gene therapy in the treatment of cancer may occur when it is combined with local modalities such as radiation therapy. A small number of gene therapy strategies have been evaluated in clinical trials in combination with external beam radiation therapy. The combined therapy has been well-tolerated and has not exacerbated the side effects of radiation therapy. Gene transfer and tumour cell destruction has been demonstrated in vivo. Although the results await confirmation in larger, prospective Phase III trials, there is suggestive evidence that the combined therapies may be demonstrating better than expected antitumour activity. Our vast knowledge of the molecular defects that drive the cancer process, coupled with our expanding understanding of the genes responsible for tumour cell radioresistance, have spawned the development of rational, targeted gene therapies designed to increase tumour cell radiosensitivity. Here, the results of the clinical trials conducted so far will be reviewed, followed by a description of new approaches under development at present.

Adenoviridae↗

PubMed2004

Modification of radiation injury by ramipril, inhibitor of angiotensin-converting enzyme, on optic neuropathy in the rat.

Inhibitors of angiotensin-converting enzyme (ACE) have been used to reduce radiation-induced normal tissue injury. The present study was carried out to determine whether ramipril, one of the inhibitors of ACE, would ameliorate radiation-induced brain damage, using a well-characterized optic neuropathy model in the rat, one of the most critical and radiosensitive structures in the brain. The brains of adult Fischer rats were irradiated stereotactically with 30 Gy using a single collimated beam. Six months after irradiation and 1.5 mg/kg day(-1) ramipril (started 2 weeks after irradiation), rats were assessed for optic nerve damage functionally, using visual evoked potential, and histologically. Results show that ramipril conferred significant modification of radiation injury, since rats receiving radiation alone showed a threefold lengthening in the mean peak latency in the visual evoked potential, whereas 75% of rats receiving radiation followed by ramipril had evoked potentials that resembled those of normal untreated control rats. The histology of irradiated and ramipril-treated optic nerves appeared nearly normal, while there was significant demyelination in both optic nerves of irradiated rats. The study represents the first demonstration of prophylaxis of radiation injury by a carboxyl-containing ACE inhibitor, providing a pharmacological strategy designed to reduce radiation-induced normal tissue damage.

Administration, Oral↗

PubMed2004

Gene therapy strategies to enhance the effectiveness of cancer radiotherapy.

Altering the genetic makeup of a cancer cell by gene transfer is a potentially powerful strategy for treating human cancer. However, a low efficiency of gene delivery in vivo and poor tumor specificity has prevented the widespread implementation of this technology in the clinic. Despite these formidable obstacles, the first successful application of gene therapy in the treatment of cancer could occur when it is combined with local modalities such as radiation therapy. A small number of gene therapy strategies have been evaluated in clinical trials in combination with external-beam radiation therapy. Combined therapy has been well tolerated and has not exacerbated the side effects of radiation therapy. Gene transfer and tumor cell destruction have been demonstrated in vivo. Although the results await confirmation in larger, prospective phase III trials, there is suggestive evidence that combined therapies may be demonstrating better than expected antitumor activity. The vast knowledge of the molecular defects that drive the cancer process, coupled with expanding the understanding of the genes responsible for tumor cell radioresistance, have led to the development of rational, targeted gene therapies designed to increase tumor cell radiosensitivity. Results of the clinical trials conducted to date are reviewed, followed by a description of new approaches currently under development.

Clinical Trials as Topic↗

PubMed2003

Risk-mitigating beliefs, risk estimates, and self-reported speeding in a sample of Australian drivers.

PROBLEM: Research suggests that people who engage in risk-taking behaviors often hold specific beliefs that can mitigate or reduce their perceptions of risk associated with those behaviors. METHOD: A scale was developed (Speeding Risk Belief Scale (SRBS)) to assess beliefs about speeding-related risk and predict self-reported speeding in a random-digit telephone survey of 800 South Australian drivers between the ages of 16 and 50. RESULTS: The scale was internally consistent, and path analyses showed it to be associated with self-reported speeding, both directly and indirectly through participants' estimates of speeding-related risk. DISCUSSION: Origins of risk-mitigating beliefs and the extent to which they may be causally linked with speeding are discussed, and recommendations are made for future research. IMPACT ON INDUSTRY: This research has strong implications for the conduct of countermeasure campaigns that disseminate information on speeding-related risk.

Accidents, Traffic↗

PubMed2003

GENIS: gene expression of sodium iodide symporter for noninvasive imaging of gene therapy vectors and quantification of gene expression in vivo.

With the goal of optimizing adenovirus-mediated suicide gene therapy for prostate cancer, we have developed a method based on the human sodium iodide symporter (hNIS) that allows for noninvasive monitoring of adenoviral vectors and quantification of gene expression magnitude and volume within the prostate. A replication-competent adenovirus (Ad5-yCD/mutTK(SR39)rep-hNIS) coexpressing a therapeutic yeast cytosine deaminase (yCD)/mutant herpes simplex virus thymidine kinase (mutTK(SR39)) fusion gene and the hNIS gene was developed. Ad5-yCD/mutTK(SR39)rep-hNIS and a replication-defective hNIS adenovirus (rAd-CMV-FLhNIS) were injected into contralateral lobes of the dog prostate and hNIS activity was monitored in live animals following administration of Na(99m)TcO(4) using gamma camera scintigraphy. Despite the close proximity of the urinary bladder, (99m)TcO(4)(-) uptake was readily detected in the prostate using viral dose levels (10(10) to 10(12) viral particles) that have been safely administered to humans. Due to its rapid clearance and short physical half-life (6 h), it was possible to obtain daily measurements of (99m)TcO(4)(-) uptake in vivo, allowing for dynamic monitoring of reporter gene expression within the prostate as well as biodistribution throughout the body. High-resolution autoradiography of prostate sections coupled with 3D reconstruction of gene expression demonstrated that the magnitude and volume of gene expression could be quantified with submillimeter resolution. Implementation of the GENIS (gene expression of Na/I symporter) technology in the clinic will facilitate optimization of future human gene therapy trials.

Adenoviridae↗

PubMed2003

Arsenic trioxide enhances radiation response of 9L glioma in the rat brain.

Arsenic trioxide (ATO) at low doses induces leukemia cells to undergo apoptosis and at higher doses causes blood flow to solid tumors to shut down. To determine whether a potential synergistic interaction exists between ATO at the non-toxic dose level in the rat and radiation, the present study was carried out with orthotopic 9L malignant gliomas growing in the brains of rats. Animals died within 50 days of treatment when 12-day-old 9L gliomas growing in the brain of Fischer rats were treated with either the drug alone (8 mg/kg) or radiation alone (25 Gy). In contrast, the overall tumor cure rate exceeded 50% at a follow-up time of 120 days after the combined treatment with radiation and ATO. Long-term surviving animals showed no clinical or disproportionately enhanced histopathological changes in the brain parenchyma. Early changes in tumor physiology showed that the vascular leakage of FITC-dextran conjugates was apparent within 8 h of drug administration. Last, the use of diffusion magnetic resonance imaging as an early surrogate marker of therapeutic efficacy corroborated the effects of drug with and without radiation on brain histology and animal survival.

Animals↗

PubMed2002

Synergistic interaction with arsenic trioxide and fractionated radiation in locally advanced murine tumor.

We have shown previously that arsenic trioxide (ATO) preferentially shutsdown tumor blood flow, leading to pronounced cell death in the central part of the solid tumor with a minimal effect on the surrounding normal tissues. On the basis of the histopathological and tumor perfusion studies, we hypothesized that the tumor control rate of locally advanced solid tumors would increase after the combined treatment of ATO and radiation relative to either radiation or ATO alone. The antitumor action and quantitative tumor perfusion studies were carried out with locally advanced methylcholanthrene-induced fibrosarcoma grown in BALB/c mice. The s.c. methylcholanthrene-induced fibrosarcoma leg tumors were treated with ATO alone (10 mg/kg), radiation alone (30 Gy), or drug plus radiation together. Radiation alone and drug alone delayed the growth of the tumor by a few days compared with untreated tumors. In contrast, when radiation and drug were given together, the tumor growth delay was longer than 1 month, resulting local tumor cure of 55%. The fractionated radiation combined with ATO showed a similar pronounced tumor growth delay relative to the drug alone or radiation alone. Sustained reduction in tumor blood flow after the combined treatment measured using a rubidium uptake method paralleled enhanced tumor response. There was an immediate 10-fold increase in the production of tumor necrosis factor-alpha in the tumor tissue after the drug treatment, concomitant with the onset of prompt reduction of the tumor blood flow. The present results indicate that tumor response was better with combined treatment than with either treatment alone, suggesting that ATO has potential as an adjuvant to radiotherapy.

Animals↗

PubMed2002

Noninvasive detection of radiation-induced optic neuropathy by manganese-enhanced MRI.

Available imaging techniques have a limited ability to detect radiation-induced injury of the normal brain. In particular, there is no noninvasive method available for detection of structural or functional neuronal damage induced by radiation. This study was designed to determine whether MRI enhanced using the neuronal track tracer MnCl(2) can detect radiation-induced optic neuropathy. A single dose of radiation (35 Gy) was delivered to produce optic neuropathy in Fischer 344 rats by using a stereotactic method with a 6-mm dorsoventral secondary collimator. At 6 months after irradiation, MRI was performed in 1-mm sections using a 7-T magnetic field with the neuronal tracer MnCl(2) injected into the vitreous of the eye 24 h prior to imaging. The rats were then killed humanely for a histological study with hematoxylin and eosin, glial fibrillary acidic protein (Gfap) for the detection of astrocytic activity, Luxol Fast Blue/Periodic Acid Schiff (LFB/PAS) for the detection of myelinization status, and Bielschowski silver stain for axon status. In nonirradiated control animals, T1-weighted MRI with manganese vitreous injection revealed an optic nerve track that was brightly enhanced from the orbit to the optic chiasm. In the irradiated animals, there was clear evidence of the damage at the optic chiasm and optic nerves, with loss of axon and demyelinization within the site of irradiation upon histological examination. T1-weighted MRI with manganese vitreous injection showed an enhancing optic nerve posterior to the orbit. However, this enhancement disappeared at the site of irradiation. The area of loss of manganese contrast on the MRI scan correlated well with the area of histological abnormality showing axonal degeneration and demyelinization. Radiation-induced optic neuropathy was thus detected noninvasively by MRI with the antegrade neuronal tracer manganese, which exhibited negative contrast enhancement by causing loss of signal. This study represents the first demonstration of MR imaging of radiation-induced neuronal damage and could provide a means to explore the biological and functional integrity of neuronal pathways.

Animals↗

PubMed2002

Preventive mental health education for functioning adults: stress, coping and mental health courses at the University of Maryland.

Three fifteen-week courses at the University of Maryland are described. These courses explore diverse cognitive-behavioral skills that facilitate coping, are preventive in nature, and are suitable for learning by healthy individuals in educational settings. Initial results, previously reported, are encouraging and suggest the possibilities that similar courses might be offered in other university, community or workplace settings.

Adaptation, Psychological↗