Molecular determinants of gastrointestinal and liver cancers: role of bile acid activated nuclear receptors

Invasion and metastasis are critical determinants of gastrointestinal and liver cancers morbidity. Genes and molecules participating in these steps (e.g. growth factors and their receptors, cell cycle regulators, cell adhesion molecules, matrix degrading enzymes) have been progressively clarified. Activated Wnt signaling pathway has been found in these tumors. Mutations in one of the DNA mismatch repair genes, alterations in epigenetics, such as aberrant DNA methylation and histone modifications are associated with the progression of gastrointestinal and control liver neoplasies. Bile acids (BAs), the main constituents of bile, activate a family of nuclear receptors (NRs) that control critical steps in bile acid homeostasis, endo- and xenobiotics detoxification, glucose, lipid metabolism and innate immunity. BAs activated NRs are misregulated in gastrointestinal and liver cancers. The present review provides an overview on the molecular determinants involved in gastrointestinal and liver cancers and focuses on the role of BAs activated NRs in the pathogenesis of these tumors.     

Copper deficiency elicits glial and neuronal response typical of neurodegenerative disorders

Dysregulation of copper homeostasis has been associated with neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and prion diseases. The investigation of the role of abnormal copper level in the development of neuropathological damage is essential for the understanding of pathogenetic mechanisms of these neurodegenerative disorders. Using a mouse model of perinatally induced copper deficiency, the present study analysed the response of neuronal and glial cells to copper deficiency from infancy to young adult age. In mice born and maintained after weaning on copper-deficient diet, copper measurements indicated that at 6-8 weeks the copper levels in the brain were decreased by about 80% with respect to controls. In the brain of copper-deficient mice, microglial and astrocytic activation was observed, mostly in the cerebral cortex and thalamus. In addition, small vacuolated globoid cells confined to the subgranular zone of the dentate gyrus were found in the third postnatal week, and larger vacuolar profiles, identified as neuronal vacuoles, were observed in layer V of the cortex after the fourth week. The spatial distribution and temporal onset of vacuolation appeared to be unrelated to those of activated microglia and astrocytes. Nitrotyrosine-positivity was found to reflect the distribution of vacuoles in the cortex. The specific histopathological features here reported, as well as the severity of neurological deficits observed in this murine model of copper deficiency, strongly suggest that some hallmarks of neurodegenerative disorders could be mediated by multifactorial pathogenetic mechanisms that include copper dysregulation.     

Personality changes in Alzheimer's disease

BACKGROUND: Assessment of personality changes in patients with dementia has received little systematic investigation, although caregivers report personality modifications in every phase of dementia. METHODS: A group of 52 patients with probable Alzheimer's disease (AD) vs. a group of fifteen control subjects were selected for these personality tests before and after the manifestation of dementia using an Italian version of Brooks and McKinaly's Personality Inventory (PI). RESULTS: After the onset of AD, a significant shift from positive to negative characteristics in PI was observed in 12 of 18 bipolar pairs of adjectives constituting the instrument and the total mean PI score decreased significantly (p < 0.001), indicating a substantial worsening of personality profile. In the control group however, evaluated before and after retirement, personality traits and total mean PI score did not show a significant change. The association of personality traits and total PI score with demographic, cognitive and functional characteristics of AD patients was calculated. CONCLUSION: Personality changes have been depicted to be influenced by severity of cognitive, functional and behavioural complaints rather than age, sex, education and disease duration. These first applications of the Italian version of PI confirmed that personality modifications make a consistent aspect of the phenomenology of AD although in the negative direction. Further studies are needed to understand the nature of personality changes in dementia and the utility of PI to investigate these changes.