Bromodomain and extraterminal domain (BET) protein inhibition hinders glioblastoma progression by inducing autophagy-dependent differentiation

Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant primary brain tumor, and it is characterized by a high recurrence incidence and poor prognosis due to the presence of a highly heterogeneous mass of stem cells with self-renewal capacity and stemness maintenance ability. In recent years, the epigenetic landscape of GBM has been explored and many epigenetic alterations have been investigated. Among the investigated epigenetic abnormalities, the bromodomain and extra-terminal domain (BET) chromatin readers have been found to be significantly overexpressed in GBM. In this work, we investigated the effects of BET protein inhibition on GBM cell reprogramming. We found that the pan-BET pharmacological inhibitor JQ1 was able to promote a differentiation program in GBM cells, thus impairing cell proliferation and enhancing the toxicity of the drug Temozolomide (TMZ). Notably, the pro-differentiation capability of JQ1 was prevented in autophagy-defective models, suggesting that autophagy activation is necessary for BET protein activity in regulating glioma cell fate. Given the growing interest in epigenetic therapy, our results further support the possibility of introducing a BET-based approach in GBM clinical management

A hybrid solution proposal for precast tunnel segments

The construction of underground structures is playing a relevant role in modern society. As a result of noticeable tunnel boring machine (TBM) evolution, mechanized excavation methods are gaining increased market shares. TBM driven tunnels are generally used in combination with precast concrete segments as the main support system for reducing or minimizing surface disturbances during construction and to fulfill the project requirements with regards to quality, construction times, budget and safety. Within this framework optimization approaches strongly focused on these process parameters, rather than the general structural performance of the segments. However, improving the performance by using conventional reinforcement, High Performance Fiber Reinforced Concretes (HPFRCs) or a combination of such enables a possible reduction of the lining thickness or the amount of reinforcement. To this aim, this paper presents a new hybrid solution for precast tunnel segments with a reduced thickness, which leads to new perspectives in reducing the total amount of concrete, in decreasing the volume of disposal materials from the boring process as well as to minimize the TBM size. A parametric numerical study is developed for evaluating the effectiveness of proposed hybrid solution. The latter is based on high strength reinforced concrete in combination with HPFRC at the longitudinal joints, whose geometric configuration is properly modified to maximize the segment's bearing capacity

NGF Modulates Cholesterol Metabolism and Stimulates ApoE Secretion in Glial Cells Conferring Neuroprotection against Oxidative Stress

Cholesterol plays a crucial role in the brain, where its metabolism is particularly regulated by astrocytic activity. Indeed, adult neurons suppress their own cholesterol biosynthesis and import this sterol through ApoE‐rich particles secreted from astrocytes. Recent evidence suggests that nerve growth factor (NGF) may exert neurotrophic activity by influencing cell metabolism. Nevertheless, the effect of NGF on glial cholesterol homeostasis has still not been elucidated. Thus, the aim of this project is to assess whether NGF could influence cholesterol metabolism in glial cells. To reach this objective, the U373 astrocyte‐derived cell line was used as an experimental model. Immunoblot and ELISA analysis showed that proteins and enzymes belonging to the cholesterol metabolism network were increased upon NGF treatment in glial cells. Furthermore, NGF significantly increased ApoE secretion and the amount of extracellular cholesterol in the culture medium. Co‐culture and U373‐ conditioned medium experiments demonstrated that NGF treatment efficiently counteracted rotenone‐mediated cytotoxicity in N1E‐115 neuronal cells. Conversely, neuroprotection mediated by NGF treatment was suppressed when N1E‐115 were co‐cultured with ApoE‐silenced U373 cells. Taken together, these data suggest that NGF controls cholesterol homeostasis in glial cells. More importantly, NGF exerts neuroprotection against oxidative stress, which is likely associated with the induction of glial ApoE secretion

Bromodomain and Extra-Terminal Proteins in Brain Physiology and Pathology: BET-ing on Epigenetic Regulation

BET proteins function as histone code readers of acetylated lysins that determine the positive regulation in transcription of genes involved in cell cycle progression, differentiation, inflammation, and many other pathways. In recent years, thanks to the development of BET inhibitors, interest in this protein family has risen for its relevance in brain development and function. For example, experimental evidence has shown that BET modulation affects neuronal activity and the expression of genes involved in learning and memory. In addition, BET inhibition strongly suppresses molecular pathways related to neuroinflammation. These observations suggest that BET modulation may play a critical role in the onset and during the development of diverse neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s disease, fragile X syndrome, and Rett syndrome. In this review article, we summarize the most recent evidence regarding the involvement of BET proteins in brain physiology and pathology, as well as their pharmacological potential as targets for therapeutic purposes

Relation between pulmonary function and 10-year risk for cardiovascular disease among healthy men and women in Italy: the Moli-sani Project.

BACKGROUND: Pulmonary dysfunction could influence the onset and the evolution of cardiovascular disorders. This study evaluated whether pulmonary dysfunction based on spirometry, plethysmography and carbon monoxide diffusion test is associated with the estimated risk of cardiovascular disease in 10 years. DESIGN: We performed a cross-sectional general population-based cohort study. METHODS: The Moli-sani Project is a population-based cohort study of subjects aged ≥35 years, randomly recruited from the general population in Italy. Cardiovascular risk in 10 years was predicted by the CUORE score which provides an estimate of the probability of a first coronary or cerebrovascular event in the next 10 years, based on a risk equation derived from Italian cohorts. Out of 12,933 subjects with high-quality flow/volume manoeuvre, 8,132 subjects had suitable plethysmography and 3,422 carbon monoxide diffusion (carbon monoxide alveolar diffusion test [DLCO]). RESULTS: In multivariate analyses, reduced pulmonary function expressed by forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and total lung capacity (TLC) were inversely associated with CUORE score both in men and in women, independently of other risk factors such as age, height, smoking habits, total cigarettes exposure (pack-years), pulmonary disease, body mass index, social status and physical activity. In contrast, there was no association between FEV1/FVC ratio, residual volume, DLCO and CUORE risk score. CONCLUSIONS: In both genders from an adult general Italian population, pulmonary function decline is associated with increased cardiovascular risk. These results suggest that pulmonary monitoring could be useful to more accurately predict cardiovascular risk

Total dietary antioxidant capacity and lung function in an Italian population: a favorable role in premenopausal/never smoker women

BACKGROUND/OBJECTIVES: Antioxidant-rich foods may favorably influence lung function. We examined possible associations between the total dietary antioxidant capacity (TAC) and pulmonary function in a healthy Italian population. SUBJECTS/METHODS: Until May 2009, 22,300 persons were randomly recruited from the general population in the Moli-sani project. A sample only including healthy women (5824) and men (5848) was analyzed. TAC was measured in foods by three different assays and the ferric reducing-antioxidant power (FRAP) assay was selected as the better indicator of dietary TAC. The European Investigation into Cancer and Nutrition Food Frequency Questionnaire was used for dietary assessment. The association between quintiles of dietary FRAP and pulmonary indexes was assessed using analysis of variance separately for men and women. RESULTS: After adjustment for confounders, women in the highest quintile of FRAP intake had +39 ml forced expiratory volume in the first second (FEV(1)) and +54 ml forced vital capacity, compared with those in the lowest quintile (P for trend ≤0.006). Stratified analysis showed that this relationship only occurred in women who were premenopausal/never smokers. In this subgroup, the observed effect of higher FRAP intake on FEV(1) was equivalent to an improvement in pulmonary age of 3.3 years. In men, all significant associations between pulmonary function and TAC were lost after adjustment for confounding. CONCLUSIONS: Dietary TAC may have a favorable role in respiratory health, particularly in premenopausal/never smoker women

The Moli-sani project: computerized ECG database in a population-based cohort study.

Abstract Computerized electrocardiogram (ECG) acquisition and interpretation may be extremely useful in handling analysis of data from large cohort studies and exploit research on the use of ECG data as prognostic markers for cardiovascular disease. The Moli-sani project (http://www.moli-sani.org) is a population-based cohort study aiming at evaluating the risk factors linked to chronic-degenerative disease with particular regard to cardiovascular disease and cancer and intermediate metabolic phenotypes such as hypertension, diabetes, dyslipidemia, obesity, and metabolic syndrome. Between March 2005 and April 2010, 24 325 people aged 35 years or older, living in the Molise region (Italy), were randomly recruited. A follow-up based on linkage with hospital discharge records and mortality regional registry and reexamination of the cohort is ongoing and will be repeated at prefixed times. Each subject was administered questionnaires on personal and medical history, food consumption, quality of life (FS36), and psychometry. Plasma serum, cellular pellet, and urinary spots were stored in liquid nitrogen. Subjects were measured blood pressure, weight, height, and waist and hip circumferences, and underwent spirometry to evaluate pulmonary diffusion capacity, gas diffusion, and pulmonary volumes. Standard 12-lead resting ECG was performed by a Cardiette ar2100-view electrocardiograph and tracings stored in digital standard communication protocol format for subsequent analysis. The digital ECG database of the Moli-sani project is currently being used to assess the association between physiologic variables and pathophyiosiologic conditions and parameters derived from the ECG signal. This computerized ECG database represents a unique opportunity to identify and assess prognostic factors associated with cardiovascular and metabolic diseases

Nutrition knowledge is associated with higher adherence to Mediterranean diet and lower prevalence of obesity. Results from the Moli-sani study.

A Mediterranean dietary pattern has been associated with reducing the risk of cardiovascular and chronic disease. The aim of this study was to evaluate the role of nutrition knowledge in determining possible differences among dietary patterns in a general population from a Mediterranean region. We conducted a cross-sectional study on a subsample of 744 subjects enrolled in the population-based cohort of the Moli-sani Project. A 92-item questionnaire on nutrition knowledge was elaborated, validated and administered. Dietary information were obtained from the EPIC food frequency questionnaire and adherence to a Mediterranean dietary pattern was evaluated both by the a priori Greek Mediterranean diet score and the a posteriori approach obtained by principal component analysis. Nutrition knowledge was significantly associated with higher adherence to a Mediterranean dietary pattern. The odds of having higher adherence to a Mediterranean dietary pattern increased with greater nutrition knowledge. The odds ratio of being obese significantly decreased with increasing nutrition knowledge levels. The results showed that nutrition knowledge was significantly associated with higher adherence to a Mediterranean dietary pattern and with lower prevalence of obesity in a Southern Italian region with Mediterranean diet tradition independently from education and other socioeconomic factors

Total dietary antioxidant capacity and lung function in an Italian population: a favorable role in premenopausal/never smoker women

Background/Objectives: Antioxidant-rich foods may favorably influence lung function. We examined possible associations between the total dietary antioxidant capacity (TAC) and pulmonary function in a healthy Italian population. Subjects/Methods: Until May 2009, 22 300 persons were randomly recruited from the general population in the Moli-sani project. A sample only including healthy women (5824) and men (5848) was analyzed. TAC was measured in foods by three different assays and the ferric reducing-antioxidant power (FRAP) assay was selected as the better indicator of dietary TAC. The European Investigation into Cancer and Nutrition Food Frequency Questionnaire was used for dietary assessment. The association between quintiles of dietary FRAP and pulmonary indexes was assessed using analysis of variance separately for men and women. Results: After adjustment for confounders, women in the highest quintile of FRAP intake had +39 ml forced expiratory volume in the first second (FEV 1) and +54 ml forced vital capacity, compared with those in the lowest quintile (P for trend ≤ 0.006). Stratified analysis showed that this relationship only occurred in women who were premenopausal/never smokers. In this subgroup, the observed effect of higher FRAP intake on FEV 1 was equivalent to an improvement in pulmonary age of 3.3 years. In men, all significant associations between pulmonary function and TAC were lost after adjustment for confounding. Conclusions: Dietary TAC may have a favorable role in respiratory health, particularly in premenopausal/never smoker women. © 2012 Macmillan Publishers Limited All rights reserved