ABSTRACT
Feeding behaviors can be modified via homeostatic and hedonic mechanisms. Homeostasis, while primarily concerned with maintaining energy balance via food consumption and energy expenditure, can alter food reward and motivation in response to food deprivation. Alternatively, reward and motivation of food is also driven by its palatability or hedonic nature, and this process can be augmented by opioid receptor activation. The present study examined sex differences in the motivational properties of sucrose pellets through manipulation of homeostatic and hedonic processes via acute food deprivation and acute systemic administration of morphine, respectively. The results showed that regardless of sex, systemic injections of morphine did not alter the motivation to obtain a sucrose pellet on a progressive ratio schedule of reinforcement but does significantly increase consumption of sucrose pellets when freely available. Male and female rats demonstrated similar increased consumption of sucrose pellets under free feeding conditions following acute (24-hours) food deprivation, compared to the non-deprived conditions. Overall, the findings from these experiments indicate that female rats work harder in order to obtain a sucrose pellet (under a Progressive Ratio (PR) schedule of reinforcement) and consume more sucrose pellets than males. However, while acute morphine administration causes similar increases on feeding in males and females, it does not alter motivation as measured by breakpoint on a PR schedule of reinforcement.
Subject(s)
Feeding Behavior/psychology , Homeostasis , Motivation , Philosophy , Sex Characteristics , Animals , Conditioning, Operant/drug effects , Conditioning, Operant/physiology , Dietary Sucrose , Feeding Behavior/drug effects , Feeding Behavior/physiology , Female , Homeostasis/drug effects , Homeostasis/physiology , Male , Morphine/pharmacology , Motivation/drug effects , Motivation/physiology , Narcotics/pharmacology , Rats, Sprague-DawleyABSTRACT
The purpose of this study was to investigate whether detectable protein biomarker overexpression is a prerequisite for the presence of increased gene copy number or activating mutations and responsiveness to the epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib in patients with lung adenocarcinomas. EGFR status was prospectively analyzed in tumor biopsy samples by three methods: protein expression (n = 117) by standardized immunohistochemistry (IHC), gene copy number (n = 97) by fluorescent in situ hybridization (FISH), and mutation analysis by sequencing (n = 126). Fifty-nine percent of the samples were positive by IHC, 40% were positive by FISH, and 13.5% contained activating kinase domain mutations. Thirty-four percent of the FISH-positive and 27% of the mutant samples were also IHC-negative. All EGFR mutant patients had major clinical responses (five complete response and five partial response) to gefitinib or erlotinib treatment, although three of these tumors were IHC-negative and four were FISH-negative. In a retrospective analysis of samples from nine patients with excellent therapeutic responses (three complete response, five partial response, one stable disease) to erlotinib or gefitinib, mutations were identified in eight cases, but IHC was negative in four of these tumors. These results indicate that molecular diagnostic methods appear to be most important for the identification of lung adenocarcinoma patients who may benefit from EGFR inhibitor treatments.
Subject(s)
Adenocarcinoma/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , Gene Dosage , Lung Neoplasms/genetics , Mutation/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Base Sequence , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , DNA Mutational Analysis , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Erlotinib Hydrochloride , Female , Gefitinib , Genotype , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Male , Middle Aged , Molecular Sequence Data , Quinazolines/pharmacology , Quinazolines/therapeutic use , Treatment OutcomeABSTRACT
Revolution in biotechnology made possible to identify those gene errors, which via their encoded proteins (mostly kinase enzymes) are key players in tumor development, growth and progression, and could be considered as molecular targets in tumor diagnosis and therapy. Activity of EGFR (epidermal growth factor receptor), an outstanding representative of the regulatory cell surface receptors, can be inhibited by drugs proved for clinical use. In the past year many groups observed that those lung adenocarcinoma cells, which contain activating mutation in the tyrosine kinase domain of EGFR show remarkable sensitivity to anti-EGFR compounds. The basis of the effective therapy is the identification of the mutations. The clinical advantage of EGFR is an example from the coming age of tumor chemotherapy, when the presence of molecular targets will guide the therapeutic choice.