[Show abstract][Hide abstract] ABSTRACT: Breast cancer is the most commonly diagnosed cancer among women worldwide. High breast cancer incidence and mortality rates, especially in obese patients, emphasize the need for a better biological understanding of this disease. Previous studies provide substantial evidence for a vital role of the local extracellular environment in multiple steps of tumor progression, including proliferation and invasion. Current evidence supports the role of adipocytes as an endocrine organ, which produces steroid hormones, pro-inflammatory cytokines and adipokines, such as leptin. To further define the role of the mammary microenvironment on tumorigenesis, we have developed an adipose-tumor epithelial cell co-culture system designed to reproduce the in vivo mammary environment. We validate this model through use of coherent anti-Stokes Raman scattering (CARS) microscopy, a label-free vibrational imaging technique. CARS analysis demonstrates the sustained viability of the adipocytes, and that mammary cancer cell morphology parallels that of tumors in vivo. Also, characterized was the influence of mammary adipose tissue on tumor cell growth and migration. Adipose tissue co-cultured with mammary tumor epithelial cells, in the absence of any serum or supplemental growth factors, resulted in substantial increases in growth and migration of tumor cells. In conclusion, this novel co-culture system provides an ideal model to study epithelial-stromal interactions in the mammary gland. Understanding the relationship between adipose tissue, the most abundant and least studied component of the breast stroma and tumor epithelial cells is critical to clarifying the influence of obesity on the development, progression and prognosis of breast cancer.
International Journal of Cancer 06/2012; · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Germination and carbohydrate concentrations were determined in excised dormant and afterripened wild oat (Avena fatua L. line M73) embryos cultured on N6 medium with and without 88 mM fructose (Fru). Without Fru dormant embryos began to germinate after approximately 2 weeks, and the germination rate was greater at 12 than 16°C. With addition of Fru 80% of dormant embryos germinated in 3 days. More than 80% of afterripened embryos germinated within 1 day on N6 with or without additional sugars. Therefore, relative to afterripened embryos, true embryo dormancy exists in line M73. Concentrations of starch and soluble sugars were initially similar in dormant and afterripened embryos. Culturing dormant and afterripened embryos on medium with Fru resulted in concentrations of glucose (Glu), sucrose (Sue), Fru and maltose (Mal) that were the same or higher than the initial levels. The concentration of starch in embryos initially increased slightly then remained constant or declined, except in dormant embryos on Fru-amended medium, where starch accumulated to 34 μg Glu equivalents (mg fresh weight)-1 at 52 h. Raffinose (Raf) and stachyose (Stach) concentrations declined over time in all embryos. Carbohydrate concentrations in afterripened embryos on medium without Fru decreased to nearly undetectable levels by 52 h. Soluble sugar concentrations in dormant embryos on medium without Fru also declined by 52 h, but changes were not as extensive as those in afterripened embryos without Fru. In 52 h Raf and Stach were nearly depleted in all afterripened embryos, and in dormant embryos cultured on Fru-containing medium but not in dormant embryos without Fru. The concentration of Stach in dormant embryos without Fru declined 60% at 12 to 18 days coinciding with the potential for germination. The results demonstrate that a decline in Stach concentration is associated with the potential for germination of dormant (D) excised embryos. The mechanism of dormancy-breaking associated with the Raf family oligosaccharides remains to be determined.
Physiologia Plantarum 06/2008; 85(3):461 - 466. · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is an epidemic in the US and an established risk factor for breast cancer incidence and morbidity. In obese patients breast cancer is commonly more aggressive and associated with poor prognosis. The goal of our research is to develop safe and efficient novel therapies to treat aggressive breast tumors, like those in obese patients. To enhance drug uptake we intend to develop electro-endocrine therapy, an electrically mediated hormone (endocrine) delivery system. In this study, we optimize parameters for electrical pulses and tamoxifen (anti-hormone drug) dosages in an in vitro model of breast cancer, as these parameters vary for each cell type. For this purpose, MCF-7 human breast adenocarcinoma cells were used. Results of our experiments show that treatment of electroporation combined with tamoxifen has an enhanced effect on suppressing tumor cell growth compared to tamoxifen treatment alone. The long-term goal is to translate application of this method to clinical practice.
Journal of Electrostatics 01/2008; · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Conventional breast cancer treatments, such as surgery (the Gold Standard), radiation therapy and chemotherapy serve most of the patients while they do not serve all of them. They are expensive and have extensive side effects, both near term and long term. Affordable, alternate treatments are needed to treat aggressive and drug resistant breast cancer tumors. We propose the use of electrical pulses to enhance the therapeutic molecule uptake in breast cancer patients. In order to better understand uptake processes of malignant tissues, it is necessary to investigate uptake in normal tissues as a reference. In this research, we studied the different electroporation characteristics of malignant breast cancer cell lines, MCF-7 and CRl 1743 compared to the non-malignant breast cancer cell lines MCF- 10. We applied 200V/cm, 10-40ms pulses and studied their effect on viability and other phenomena. Considering that approximately one million incidences of breast cancers are estimated in the world, with ~200,000 in the US and ~320,000 in the Europe, and the rest in the rest of the world, inexpensive, less toxic, existing alternative treatments need to be developed and implemented for clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Obesity has become a major health problem in children and adults and is associated with increased breast cancer incidence and mortality The epidemic of childhood obesity is recent and little information exists regarding its association with mammary tumongenesis Towards better understanding this relationship we have developed and characterized a new rat model of childhood onset Diet Induced Obesity (DIO) and breast cancer We have shown that young female rats fed a high fat Western Style diet have a 24-fold higher body fat mass and elevated serum comorbidity factors as compared to Chow fed Lean rats When these animals are treated with the carcinogen MNU mammary tumors appear sooner and in greater numbers in Obese rats We determined via histology that tumors from Obese rats are of a more invasive type compared to tumors from Lean rats This is in accord with the association between human obesity and breast cancer mortality This new model parallels the onset of obesity as it occurs in humans and therefore provides an excellent system to study the underlying mechanisms of obesity and mammary tumor formation and progression Our long-term goals are to exploit this model to better understand adipocyte-epithelial interactions during mammary tumongenesis identify and validate novel molecular therapeutic targets and to establish biomarkers for cancer prevention and prognosis
[Show abstract][Hide abstract] ABSTRACT: Nonstructural carbohydrates were determined in both embryo and endosperm of dormant (nongerminating) and afterripened (germinating) intact caryopses of wild oat (Avena fatua L.). No changes in endosperm starch or soluble sugar were observed at the onset of germination (18 h). No changes in glucose, fructose, sucrose or starch within dormant or afterripened embryos correlated with onset of visual germination. In afterripened embryos, depletion of raffinose (18 h), stachyose (18 h) and galactose (24 h) was correlated with germination. In contrast, raffinose-family oligosaccharide levels in dormant embryos remained constant for 7 days following imbibition. Germination of isolated dormant embryos on 88 mM galactose-containing media was accompanied by decreased endogenous levels of raffinose and stachyose. Isolated embryos from dormant caryopses incorporated 14C from 14C-fructose into both raffinose and stachyose during 24 h of imbibition. In contrast, no 14C incorporation into stachyose was observed in embryos from afterripened caryopses. No 14C incorporation into raffinose was observed at 18 and 24 h. When in vitro activities of galactosidase were measured, no temporal differences between dormant or afterripened caryopses were detected in either embryo or endosperm tissue. Although the mechanism associated with differences in utilization of raffinose and stachyose is yet unidentified, alterations in raffinose-family oligosaccharide metabolism in the embryo appear to be a unique prerequisite for afterripening-induced germination.
Physiologia Plantarum 04/2006; 88(2):221 - 228. · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 1. The magnitude of physostigmine-induced hypothermia increased with decreasing environmental temperature. 2. The hypothermic response was accompanied by significant changes in plasma levels of corticosterone, glucose and fatty acids. 3. Central cholinergic mediation appears to be a significant component of physostigmine-induced hypothermia and neuroendocrine changes at moderate temperature. 4. At lower ambient temperatures cholinergic blockers produced less antagonism of physostigmine-induced effects. 5. The decreased effectiveness of cholinergic blockers at low environmental temperatures and the increased plasma fatty acid levels under almost all conditions studied may be of importance in considering long term therapy with cholinergic agonists.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 02/1991; 15(6):873-84. · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effects of environmental temperature on body temperature and neuroendocrine parameters were evaluated following a single acute dose (60 micrograms/kg) of soman. Plasma levels of corticosterone, glucose, and free fatty acids, as well as acetylcholinesterase activity in plasma, erythrocytes, and brain were determined over a 96-hr time course in rats maintained at 23-25, 14-16, and 3-5 degrees C. Considerable inhibition of plasma and erythrocyte acetylcholine hydrolysis activity was observed after administration of soman at all three environmental temperatures. The degree of hypothermia in all soman-treated rats in each environment tested was associated with the amount of brain acetylcholinesterase inhibition. In animals maintained at 23-25 and 14-16 degrees C, changes in plasma corticosterone levels were influenced by central acetylcholine hydrolysis. Hyperglycemia was found only in rats with greater than 45% brain inhibition regardless of environmental temperature. However, the plasma concentration of glucose over the 96 hr test period varied in relation to the hydrolysis of acetylcholine in soman-treated rats. Recovery of plasma acetylcholinesterase was more rapid at lower environmental temperatures. A greater inhibition of central acetylcholinesterase was found in soman-treated rats exposed to 3-5 degrees C. Soman may be more toxic at low environmental temperatures.
Fundamental and Applied Toxicology 06/1990; 14(4):696-705.
[Show abstract][Hide abstract] ABSTRACT: The anorectic actions of amphetamine have been known for over forty years, yet the precise relationship(s) between the enantiomeric forms of the drug and anorexia is not clearly understood. Previous studies have utilized primarily racemic amphetamine or its d-isomer in the analysis of feeding behavior. In the present investigation, a detailed examination of the effects of single and repeated equiactive doses of d- and l-amphetamine on food consumption by adult male rats was undertaken with emphasis on aspects of tolerance development. Weight loss and pattern of daily food intake differed depending upon the isomer, dose, and degree of tolerance. Two types of tolerance were seen with both isomers, an initial tolerance with a decrease in efficacy between days 1 and 2, and a later gradual decrease in efficacy over 12 days of repeated dosage. Rats tolerant to the anorectic effects of d-amphetamine were only minimally affected when challenged with an equiactive anorectic dose of l-amphetamine, while rats tolerant to the anorectic effects of l-amphetamine showed a significantly depressed food intake and modified eating pattern when challenged with an equiactive dose of d-amphetamine. Therefore two-way cross tolerance, as previously assumed, does not completely exist between low equiactive doses of d- and l-amphetamine.
Pharmacology Biochemistry and Behavior 06/1989; 33(1):181-8. · 2.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 1. Hypothermia was found to be related to both the dose of physostigmine and the environmental temperature. 2. Plasma corticosterone levels were elevated above controls regardless of dose of physostigmine or environmental temperature. 3. Plasma free fatty acid levels appeared to be inversely related to physostigmine-induced hypothermia. 4. A hyperglycemic response was observed under all experimental conditions at 0.5 hours and 1.0 hour post injection. 5. Significant inhibition of brain acetylcholinesterase was observed, whereas, plasma and erythrocyte acetylcholinesterase activity was inconsistent.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 02/1988; 12(6):935-49. · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the present study, the relationship between central catecholamine levels and the anorexia induced by Walker 256 carcinoma was investigated. Results indicate that the anorexia is not due to depletion of central catecholamines. Tumor bearing rats sacrificed at night, when spontaneous food intake is selectively depressed, showed increased norepinephrine levels in the hypothalamus, cortex and hippocampus and increased dopamine levels in the striatum, midbrain, and cortex. Increased nighttime hypothalamic norepinephrine levels were positively correlated with the magnitude of spontaneous food intake in tumor rats.
Life Sciences 07/1985; 36(23):2223-31. · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of brain serotonin levels in Walker 256 tumor induced anorexia was investigated. Total and free plasma tryptophan, regional brain serotonin and 5-hydroxyindoleacetic acid were determined at night, and their relationship to nocturnal anorexia assessed by linear regression analysis. No significant difference in tryptophan, serotonin, or 5-hydroxyindoleacetic acid levels was detected between pair fed and tumor bearing rats exhibiting a 20% reduction of nighttime food intake. Tumor bearing rats with a 40% reduction in food intake had higher nighttime plasma free tryptophan and regional 5-hydroxyindoleacetic acid levels than their pair fed malnourished controls. These results indicate that increased plasma free tryptophan and elevated serotonin metabolism may not be the initial dysfunction responsible for nocturnal anorexia. However, it may contribute to the decreasing nocturnal food intake in severely anorexic tumor rats.
Life Sciences 05/1983; 32(16):1819-25. · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The enantiomers of 3,4-(methylenedioxy)amphetamine (MDA), p-methoxyamphetamine (PMA), and N-Me-MDA (MDMA), along with their alpha, alpha-dimethylated derivatives, were evaluated for an effect on the release of [3H]serotonin from rat whole brain synaptosomes. The amphetamine isomers were all potent in inducing the release of [3H]serotonin at bath concentrations of 1 and 10 micrometers but were inactive at 0.1 micrometers. No significant difference in isomer potency was observed at the 10 micrometers concentration. However, at 1 micrometer the (+) isomer of MDMA was more effective in inducing release than was the (-) isomer. Since it is the (+) isomer which is clinically active, this result suggests that transmitter release may play a role in the biological activity of MDMA. By contrast, the alpha, alpha-dimethyl compounds were not effective in releasing serotonin, even at the highest bath concentration.
Journal of Medicinal Chemistry 06/1982; 25(5):530-5. · 5.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A new stimulant compound, 1,2-dihydro-2-naphthalenamine (2-amino-1,2-dihydronaphthalene, 2-ADN), was prepared as an analogue of amphetamine and of 2-aminotetralin. The optical isomers of 2-ADN were obtained by chemical resolution, and the absolute configuration was determined to be R-(+) and S-(-). Preliminary pharmacological evaluation revealed that racemic 2-ADN is approximately one-fourth as potent as (+)-amphetamine as a stimulant in mice. The S-(-) isomer of 2-ADN was found to be solely responsible for the stimulant effects of the racemate. Both reserpine and alpha-methyl-p-tyrosine antagonized the stimulation produced by 2-ADN.
Journal of Medicinal Chemistry 06/1982; 25(5):535-8. · 5.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Based on the known biological activity of a variety of guanidine-containing agents, several N-substituted 3,4-dihydroquinazolines were synthesized. These compounds can be considered to be rigid analogues of phenylguanidines. In anesthetized rats the compounds decreased blood pressure and were antagonists of the pressor response to norepinephrine.
Journal of Medicinal Chemistry 12/1980; 23(11):1261-4. · 5.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is an established risk factor for breast cancer incidence and mortality. However, the mechanism that links obesity to tumorigenesis is not well understood. Here we combined nonlinear optical imaging technologies with an early-onset diet-induced obesity breast cancer animal model to evaluate the impact of obesity on the composition of mammary gland and tumor stroma. Using coherent anti-Stokes Raman scattering and second harmonic generation on the same platform, we simultaneously imaged mammary adipocytes, blood capillaries, collagen fibrils, and tumor cells without any labeling. We observed that obesity increases the size of lipid droplets of adipocytes in mammary gland and collagen content in mammary tumor stroma, respectively. Such impacts of obesity on mammary gland and tumor stroma could not be analyzed using standard two-dimensional histologic evaluation. Given the importance of mammary stroma to the growth and migration of tumor cells, our observation provides the first imaging evidence that supports the relationship between obesity and breast cancer risk.