Neural structural abnormalities behind altered brain activation in obesity: Evidence from meta-analyses of brain activation and morphometric data.

Obesity represents a risk factor for disability with a major bearing on life expectancy. Neuroimaging techniques are contributing to clarify its neurobiological underpinnings. Here, we explored whether structural brain abnormalities might accompany altered brain activations in obesity. We combined and compared data from brain activation studies for food stimuli and the data reported in structural voxel-based morphometry studies. We found that obese individuals have reduced grey matter density and functional activations in the thalamus and midbrain. A functional connectivity analysis based on these two clusters and its quantitative decoding showed that these regions are part of the reward system functional brain network. Moreover, we found specific grey matter hypo-densities in prefrontal cortex for the obese subjects, regions involved in controlled behaviour. These results support theories of obesity that point to reduced bottom-up reward processes (i.e., the Reward Deficit Theory), but also top-down theories postulating a deficit in cognitive control (i.e., the Inhibitory Control Deficit Theory). The same results also warrant a more systematic exploration of obesity whereby the reward of food and the intentional control over consummatory behaviour is manipulated.

Evaluating Residual Cognition in Advanced Cognitive Impairment: The Residual Cognition Assessment.

BACKGROUND: In nursing homes, most of the patients with dementia are affected by severe cognitive disorder. Care interventions follow an accurate and recurring multidimensional assessment, including cognitive status. There is still a need to develop new performance-based scales for moderate-to-advanced dementia. OBJECTIVES: The development of the Residual Cognition Assessment (RCA) responds to the need to create new scales for global cognitive screening in advanced dementia, with some peculiar features: performance based, brief (<5 m), available without specific training, and suitable for nonverbal patients with minimal distress. METHODS: Two raters have administered the RCA and the Severe Impairment Battery-short version (SIB-S) to 84 participants with MMSE = 0. After 2-3 weeks, the same sample has been retested. The RCA has been also administered to 40 participants with MMSE 1-10 for a comparison. RESULTS: The RCA has exhibited excellent values for test-retest reliability (intraclass correlation [ICC] = 0.956) as well as for inter-rater reliability (ICC = 0.997). The concurrent validity analyzes have shown strong correlations between the RCA and the SIB-S with ρ = 0.807 (p < 0.01), and the RCA and the Clinical Dementia Rating (CDR) with ρ = -0.663 (p < 0.01). Moderate correlation has been found between the RCA and the Functional Assessment Staging Scale with ρ = -0.435 (p < 0.01). The instrument has showed high internal reliability, too (total: α = 0.899). The RCA has low floor effect (2%) with respect to the SIB-S (58%) but shows ceiling effect in the MMSE 1-10 sample (50%). The ROC curve analyses demonstrate that the RCA is acceptably able to discriminate between subjects with CDR 4/5 with an AUC of 0.92. Exploratory factor analysis shows 3 factors, defined as three major degrees of cognitive performance in advanced dementia, indeed hierarchically structured in three possible levels of decline. CONCLUSIONS: The RCA has showed excellent validity and reliability as well as good sensitivity to identify advanced cognitive impairment in dementia, without floor effect. The RCA seems complementary to the MMSE, so advisable when the latter reaches 0. Administration and scoring are simple, and only few minutes are required to assess the patient. The RCA can discriminate at least 3 different major stages in advanced dementias: severe, profound, and late.

Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia.

Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to environmental/occupational exposure to asbestos, characterized by the presence of significant areas of hypoxia. In this study, we firstly explored the expression and the role of transglutaminase 2 (TG2) in MPM cell adaptation to hypoxia. We demonstrated that cells derived from biphasic MPM express the full-length TG2 variant at higher levels than cells derived from epithelioid MPM and normal mesothelium. We observed a significant induction of TG2 expression and activity when cells from biphasic MPM were grown as a monolayer in chronic hypoxia or packed in spheroids, where the presence of a hypoxic core was demonstrated. We described that the hypoxic induction of TG2 was HIF-2 dependent. Importantly, TGM2-v1 silencing caused a marked and significant reduction of MPM cell viability in hypoxic conditions when compared with normoxia. Notably, a TG2-selective irreversible inhibitor that reacts with the intracellular active form of TG2, but not a non-cell-permeable inhibitor, significantly compromised cell viability in MPM spheroids. Understanding the expression and function of TG2 in the adaptation to the hypoxic environment may provide useful information for novel promising therapeutic options for MPM treatment.

KDM6B histone demethylase is an epigenetic regulator of estrogen receptor ß expression in human pleural mesothelioma.

AIM: To assess the correlation between KDM6B and estrogen receptor ß (ERß) expression in malignant pleural mesothelioma (MPM). MATERIALS & METHODS: We evaluated gene expression by in silico analysis of microarray data, real-time PCR and western blot in MPM tumors and cell lines. RESULTS & CONCLUSION: We report a strong positive correlation between the expression of KDM6B and ERß in MPM tumors and cell lines. We describe that, in hypoxia, the HIF2α-KDM6B axis induces an epithelioid morphology and ERß expression in biphasic MPM cells with estrogen receptor-negative phenotype. Reduced histone H3K27 tri-methylation confirms KDM6B activity under hypoxic conditions. Importantly, cells treated during reoxygenation with the selective ERß agonist, KB9520, maintain ERß expression and the less aggressive phenotype acquired in hypoxia.

SIRT1 at the crossroads of AKT1 and ERß in malignant pleural mesothelioma cells.

In this report, we show that malignant pleural mesothelioma (MPM) patients whose tumors express high levels of AKT1 exhibit a significantly worse prognosis, whereas no significant correlation with AKT3 expression is observed. We provide data that establish a phosphorylation independent role of AKT1 in affecting MPM cell shape and anchorage independent cell growth in vitro and highlight the AKT1 isoform-specific nature of these effects.We describe that AKT1 activity is inhibited by the loss of SIRT1-mediated deacetylation and identify, by mass spectrometry, 11 unique proteins that interact with acetylated AKT1.Our data demonstrate a role of the AKT1/SIRT1/FOXM1 axis in the expression of the tumor suppressor ERß. We further demonstrate an inhibitory feedback loop by ERß, activated by the selective agonist KB9520, on this axis both in vitro and in vivo.Our data broaden the current knowledge of ERß and AKT isoform-specific functions that could be valuable in the design of novel and effective therapeutic strategies for MPM.

Intracellular lactate-mediated induction of estrogen receptor beta (ERß) in biphasic malignant pleural mesothelioma cells.

Biphasic malignant pleural mesothelioma (MPM) is the second most common histotype of MPM. It is histologically characterized by the concomitant presence of epithelioid and sarcomatoid features, the latter associated with worse prognosis. In this report we describe that silencing of AKT1 in spindle-shaped biphasic MPM cells promotes the shift toward an epithelioid phenotype. Furthermore, AKT1 silencing resulted in decreased expression of the lactate/H+ symporter MCT4 and its chaperone CD147/Basigin, and in the induction of estrogen receptor ß (ERß) expression. We provide evidence that ERß expression is induced by increased intracellular lactate concentration. Spheroid culturing and tumor growth of ERß negative biphasic MPM in nude mice resulted in the induction of ERß expression and response to the selective agonist KB9520. In both models, the treatment with the ERß agonist results in reduced cell proliferation, decreased expression of MCT4 and CD147/Basigin and increased acetylation and inactivation of AKT1. Collectively, in response to metabolic changes, ERß expression is induced and exerts an anti-tumor effect through selective agonist activation. The possibility to reverse the more aggressive biphasic mesothelioma histotype by targeting ERß with a selective agonist could represent a new effective treatment strategy.