Biomedical subjects

S A Lightfoot

Publications and source records attributed to S A Lightfoot.

15 recordsLinked to original sources

PubMed2000

Involvement of capsaicin-sensitive sensory neurons in stress-induced gastroduodenal mucosal injury in rats.

The pathogenesis of stress-induced gastroduodenal mucosal injury is complex and incompletely understood. The aim of this investigation was to examine the involvement of gastric and duodenal capsaicin-sensitive neurons in mucosal damage associated with water-restraint stress (WRS) in rats. Following WRS, gastroduodenal mucosal injury was quantitated by macroscopic and microscopic methods. Calcitonin gene-related peptide (CGRP) content was measured by radioimmunoassay. WRS-induced mucosal erosive injury in the stomach and duodenum (40.9 +/- 4.2 and 5.1 +/- 0.6 mm2, respectively) was reduced significantly (by 88% and 67%, respectively) by acute intragastric capsaicin administration prior to WRS. In contrast, sensory denervation by chronic capsaicin significantly increased the area of gastric injury and duodenal damage. WRS alone caused a significant reduction (by 52% and -35%, respectively) in gastric and duodenal CGRP content, which was prevented by acute capsaicin treatment. The data suggest that gastric and duodenal sensory neurons and CGRP are involved in the pathogenesis of stress-induced mucosal injury to the stomach and duodenum.

Animals↗

PubMed1999

Expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and p53 tumor suppressor in dysplastic progression and adenocarcinoma in Barrett esophagus.

BACKGROUND: Barrett esophagus predisposes individuals to esophageal carcinoma, which develops from intermediate stages of tissue dysplasia primarily in the vicinity of the gastroesophageal junction. Understanding the cellular and molecular events in the progression of Barrett esophagus to adenocarcinoma may contribute to its early diagnosis and treatment. Mutation and overexpression of the tumor suppressor p53 have previously been observed in Barrett high grade dysplasia and adenocarcinoma. The expression of the cyclin-dependent kinase (CdK) inhibitor p21 can be up-regulated by p53, resulting in the down-regulation of cell division at the G(1)/S-phase transition. The current study examined the correlation between the expression of p21 and p53 by quantifying their levels during the progression of dysplasia and adenocarcinoma in Barrett esophageal tissues. METHODS: Barrett esophageal tissue samples that were negative or indefinite for dysplasia, contained dysplasia, and contained adenocarcinoma were examined by immunohistochemistry. Paraffin embedded sections of lining and glandular epithelia were adsorbed with primary murine antibodies against human p21 or p53 followed by horseradish peroxidase secondary antibody. An immunoreactivity score for each primary antibody and section was obtained by multiplying a staining intensity factor by the percent of positively stained cells. RESULTS: Nuclear p21 expression was detectable immunohistochemically in Barrett esophagus that was negative for dysplasia, but it was significantly elevated (P </= 0.05) in tissues scored as indefinite for dysplasia, positive for low grade or high grade dysplasia, and positive for adenocarcinoma. Importantly, p53 expression did not parallel p21 expression. p53 levels were low in the early stages of Barrett dysplasia and were increased in high grade dysplasia and adenocarcinoma. There were no differences in p21 or p53 levels between glandular and lining epithelia in Barrett tissue throughout the histologic stages of neoplastic progression evaluated in this study. CONCLUSIONS: p21 expression in Barrett tissue scored as indefinite for dysplasia or low grade dysplasia was significantly elevated relative to p53 expression. Elevated levels of p21 were also observed in high grade dysplasia and adenocarcinoma, in which they do not appear to be effective in down-regulating cell division. Analysis of p21 and p53 expression may aid in the evaluation of tissue abnormalities in Barrett esophagus.

Adenocarcinoma↗

PubMed1999

Prevention of rat mammary carcinoma utilizing leuprolide as an equivalent to oophorectomy.

A clinical trial is currently under way to examine the effectiveness of leuprolide as a breast cancer chemopreventive agent and contraceptive. This trial, as well as similar proposed studies, is based on the assumption that leuprolide is as effective as surgical castration in preventing the onset of mammary tumors; however, this has not been well documented in the DMBA animal model. We directly compared leuprolide and oophorectomy in this model and examined a combined therapy of leuprolide/bromocriptine. Twenty-seven day old female Sprague-Dawley rats were randomly allocated into one of eight groups. All rats received a 20-mg dose of DMBA at the age of 55 days. Group 1 (n = 10), no treatment; Group 2 (n = 9), leuprolide (100 microg/kg/day) for eight weeks beginning four weeks prior to DMBA; Group 3 (n = 10), oophorectomy four weeks prior to DMBA with replacement estrogen beginning four weeks following DMBA. Estrogen replacement was achieved with a 0.05-mg estradiol tablet releasing 0.833 microg/day over a 60-day period. Group 4 (n = 10), leuprolide (100 microg/kg/day) initiated two weeks prior to DMBA and continuing for two weeks following DMBA; Group 5 (n = 9), oophorectomy two weeks prior to DMBA with 0.05 mg of estradiol in depot form, releasing 0.833 microg/day, beginning four weeks following DMBA and continuing until week 16 of the study; Group 6 (n = 10), leuprolide (100 microg/kg/day) beginning two weeks prior to DMBA and continuing for the duration of the experiment; Group 7 (n = 10), leuprolide (100 microg/kg/day) for eight weeks beginning two weeks prior to DMBA; Group 8 (n = 9), leuprolide (100 microg/kg/day) and bromocriptine (83 microg/day) for eight weeks beginning two weeks prior to DMBA. At nineteen weeks (15 weeks post DMBA), animals were sacrificed and autopsies performed. One hundred percent of untreated animals developed tumors. No animals undergoing oophorectomy four weeks prior to DMBA or receiving leuprolide four weeks prior to and simultaneously with DMBA developed tumors. In animals pretreated two weeks prior to DMBA with leuprolide or oophorectomy, each group had one animal with tumor development. No tumors developed in the animals receiving ongoing injections of leuprolide. However, one tumor developed in those receiving leuprolide for the first eight weeks beginning two weeks prior to DMBA administration. One animal receiving both leuprolide and bromocriptine developed one tumor. We conclude that chemical oophorectomy (with leuprolide) is as effective as surgical oophorectomy in inhibiting DMBA induced carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1998

Expression of peroxisome proliferator activated receptor mRNA in normal and tumorigenic rodent mammary glands.

The peroxisome proliferator activated receptors (PPARs) alpha, beta/delta, and gamma are novel nuclear hormone receptors activated by long chain fatty acids and synthetic ligands and which regulate lipid metabolism. Recent studies have detected PPARgamma mRNA in human mammary tumor cell lines. The current study examined the expression profile of PPAR mRNAs in normal and malignant rodent mammary tissues. Virgin murine mammary glands contained PPAR alpha, beta/delta, and gamma mRNAs based on northern blot analysis. The PPARgamma isoform was predominantly gamma2 based on quantitative PCR analysis. During pregnancy and lactation, the PPARalpha and gamma mRNAs decreased while the PPAR beta/delta mRNA remained relatively unchanged. NMuMG cells, an epithelial line derived from normal murine mammary gland, expressed PPAR alpha, beta/delta, and gamma mRNAs, independent of the presence or absence of compounds modifying PPAR activity. In rats, the physiologic expression pattern of PPARgamma mRNA paralleled the murine model; levels were detected in virgin but not lactating mammary glands. In addition, the PPARgamma mRNA was not detected in several histologically distinct 7,12-dimethylbenz(a)anthracene induced mammary tumors. These findings suggest that PPARs may regulate mammary epithelial and stromal cell function in response to physiologic or pathologic stimuli that profoundly alter lipid metabolism.

Adipocytes↗

PubMed1998

Prevention of DMBA-induced rat mammary carcinomas comparing leuprolide, oophorectomy, and tamoxifen.

Leuprolide, a gonadotropin releasing hormone agonist, is currently being evaluated in a pilot study of premenopausal women for the prevention of breast cancer. However, little data is available regarding the efficacy of leuprolide in experimental animal models of carcinoma when administered prior to the carcinogen. In the present study the capacity of leuprolide to prevent tumor development was evaluated by comparing its pretreatment effects in the DMBA-induced rat mammary carcinoma model to pretreatment with tamoxifen and oophorectomy. Fifty-five day old, female Sprague-Dawley rats were randomly allocated to one of four groups: 1) no treatment; 2) oophorectomy two weeks prior to DMBA; 3) leuprolide, 40 microg/kg/day; and 4) tamoxifen, 10 mg/kg/week. All animals received four 5 mg doses of DMBA for a total dose of 20 mg. Leuprolide and tamoxifen treatments began two weeks prior to DMBA and ended one week after DMBA administration. Animals were assessed weekly to determine palpable tumor onset, number, size, and volume. At the conclusion of the study (16 weeks), autopsies were performed and tumor tissue was collected for confirmation of malignancy. Seventy-eight percent of the untreated rats developed tumors. No tumors developed in the oophorectomy group, while the number of rats with tumors was significantly reduced (p<0.05) with both leuprolide (30%) and tamoxifen (21.9%) compared to controls (77.8%). There were no significant differences in the tumor number for each tumor-bearing rat or in tumor volume between treated and control groups. Using our dosage regimen, 'chemical oophorectomy' with leuprolide was not as effective as surgical oophorectomy in the prevention of chemical carcinogenesis by DMBA but was comparable to the results obtained with tamoxifen.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1998

Global primary blast injury: a rat model.

Blast wave injury from bombs cause a unique but poorly understood spectrum of injuries. Previous blast wave models involved high energy explosives detonated in an open field without the sophisticated monitoring of laboratory equipment. We characterized a rodent model that produces a global blast injury in a safe laboratory environment. Male rats, prospectively randomized to four groups of ten, were anesthetized and subjected to a blast at 2.0 cm, 2.5 cm, or 3.5 cm from the blast nozzle. The control group received no blast. Intensity of the blast (80-120 psi peak pressure, 1-2 msec duration) was controlled by varying the distance of the blast wave generator to the rat. The rats were monitored for three hours following the blast and then euthanized. Bradycardia was an immediate but transient response to blast injury. Mean arterial pressure was bimodal with severe hypotension occurring immediately after the blast and, again, two to three hours later. The characteristic injuries from a blast wave, such as pulmonary hemorrhage with increased lung weight, intestinal serosal hemorrhage, and hemoperitoneum, were found in the rats subjected to the blast pressure wave. In conclusion, our rodent model accurately reproduces the clinical spectrum of injuries seen in blast victims and will provide a powerful tool for studying the pathophysiology and potential treatments of bomb blast victims.

Analysis of Variance↗

PubMed1997

Biological assay for activity and molecular mechanism of retinoids in cervical tumor cells.

The composition and response of the retinoid signaling pathway in a human cell line (CC-1), representative of a low grade cervical carcinoma, were evaluated. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis demonstrated expression of cytoplasmic retinol binding protein, CRBPI, cytoplasmic retinoic acid binding protein, CRABPII, and nuclear retinoic acid receptors, RAR alpha, RARgamma, RXR alpha, and RXRbeta, but not CRABPI or RARbeta. This pattern is similar to that of the ectocervix. Activation of endogenous nuclear receptors was evaluated in a reporter subline of CC-1, called CC-B, containing a reporter gene controlled by a retinoic acid responsive element (RARE) and thymidine kinase promoter. Retinoid treatment of CC-B resulted in dose-dependent increases in reporter gene expression. Retinoids inhibited growth at concentrations greater than 100 nM. 9-cis retinoic acid (1 nM) significantly stimulated growth. Immunohistochemical analysis of CC-B organotypic cultures demonstrated a high level of epidermal growth factor receptor (EGF-R) expression that was decreased by retinoids. The degree of RARE transactivation induced by retinoids significantly correlated with the degree of inhibition of growth (R = -0.96) and EGF-R expression (R = -0.92). The dose-dependent and retinoid-specific responses of CC-1 at the molecular and biological levels demonstrate the utility of this reporter cell line for evaluation of retinoid activities.

Cell Division↗

PubMed1994