Seismic and thermal precursors of crater collapses and overflows at Stromboli volcano.

Lava overflows are highly hazardous phenomena that can occur at Stromboli. They can destabilize the crater area and the "Sciara del Fuoco" unstable slope, formed by several sector collapses, which can generate potentially tsunamigenic landslides. In this study, we have identified precursors of the October-November 2022 effusive crisis through seismic and thermal camera measurements. We analyzed the lava overflow on October 9, which was preceded by a crater-rim collapse, and the overflow on November 16. In both cases, seismic precursors anticipating the overflow onset have been observed. The analysis of the seismic and thermal data led to the conclusion that the seismic precursors were caused by an escalating degassing process from the eruptive vent, which climaxed with the overflows. Volcano deformation derived from ground-based InSAR and strainmeter data showed that inflation of the crater area accompanied the escalating degassing process up to the beginning of the lava overflows. The inflation of the crater area was especially evident in the October 9 episode, which also showed a longer seismic precursor compared to the November 16 event (58 and 40 min respectively). These results are important for understanding Stromboli's eruptive mechanisms and open a perspective for early warning of potentially dangerous phenomena.

Geophysical precursors of the July-August 2019 paroxysmal eruptive phase and their implications for Stromboli volcano (Italy) monitoring.

Two paroxysmal explosions occurred at Stromboli volcano in the Summer 2019, the first of which, on July 3, caused one fatality and some injuries. Within the 56 days between the two paroxysmal explosions, effusive activity from vents located in the summit area of the volcano occurred. No significant changes in routinely monitored parameters were detected before the paroxysmal explosions. However, we have calculated the polarization and the fractal dimension time series of the seismic signals from November 15, 2018 to September 15, 2019 and we have recognized variations that preceded the paroxysmal activity. In addition, we have defined a new parameter, based on RSAM estimation, related to the Very Long Period events, called VLP size, by means of which we have noticed significant variations through the whole month preceding the paroxysm of July 3. In the short term, we have analyzed the signals of a borehole strainmeter installed on the island, obtaining automatic triggers 10 minutes and 7.5 minutes before the July 3 and the August 28 paroxysms, respectively. The results of this study highlight mid-term seismic precursors of paroxysmal activity and provide valuable evidence for the development of an early warning system for paroxysmal explosions based on strainmeter measurements.

Incretin treatment and atherosclerotic plaque stability: Role of adiponectin/APPL1 signaling pathway.

AIMS: Glucagon like peptide 1 (GLP-1) analogues and dipeptidyl peptidase IV (DPP-4) inhibitors reduce atherosclerosis progression in type 2 diabetes mellitus (T2DM) patients and are associated with morphological and compositional characteristics of stable plaque phenotype. GLP-1 promotes the secretion of adiponectin which exerts anti-inflammatory effects through the adaptor protein PH domain and leucine zipper containing 1 (APPL1). The potential role of APPL1 expression in the evolution of atherosclerotic plaque in TDM2 patients has not previously evaluated. METHODS: The effect of incretin therapy in the regulation of adiponectin/APPL1 signaling was evaluated both on carotid plaques of asymptomatic diabetic (n=71) and non-diabetic patients (n=52), and through in vitro experiments on endothelial cell (EC). RESULTS: Atherosclerotic plaques of T2DM patients showed lower adiponectin and APPL1 levels compared with non-diabetic patients, along with higher oxidative stress, tumor necrosis factor-α (TNF-α), vimentin, and matrix metalloproteinase-9 (MMP-9) levels. Among T2DM subjects, current incretin-users presented higher APPL1 and adiponectin content compared with never incretin-users. Similarly, in vitro observations on endothelial cells co-treated with high-glucose (25mM) and GLP-1 (100nM) showed a greater APPL1 protein expression compared with high-glucose treatment alone. CONCLUSIONS: Our findings suggest a potential role of adiponectin/APPL1 signaling in mediating the effect of incretin in the prevention of atherosclerosis progression or plaque vulnerability in T2DM.

Effect of CArbocisteine in Prevention of exaceRbation of chronic obstructive pulmonary disease (CAPRI study): An observational study.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a chronic and progressive lung disease characterized by irreversible airflow obstruction, airway inflammation, oxidative stress and, often, mucus hypersecretion. The aim of this study is to determine if carbocisteine, a mucolytic and antioxidant agent, administered daily for 12 months, can reduce exacerbation frequency in COPD patients. METHODS: This observational study was conducted in Naples (population approximately 1000,000), Italy. It included 85 out-patients (mean age of 67.8 ± 8.6 years) followed by Clinic of Respiratory Diseases of the University Federico II. Every patient underwent spirometry demonstrating airflow obstruction not fully reversible according to ERS/ATS criteria for COPD diagnosis (Tiffenau index less than 70% after administration of salbutamol, a beta2 agonist drug). Patients enrolled had diagnosed COPD since 2 years and suffered at least one exacerbation in the previous year. None of the patients had been treated with carbocisteine or other mucolytic agent for a longer period of time than 7 days and no more than 4 times in the previous year to the enrollment. All of them assumed daily 2.7 g of carbocisteine lysine salt for a year in addition to their basic therapy. RESULTS: The comparison of exacerbation frequency between the previous year (T0) and the end of study treatment (T12), documents a statistically significant reduction of exacerbations(number of exacerbations at T0: 2 [1,3] vs number of exacerbations at T12: 1 [1,2]; p < 0.001).Quality of life was also reported and showed a statistically significant improvement at the end of the study (p < 0.001).We did not find correlation between reducing exacerbation frequency and exposure to cigarette smoking, passive smoking exposure in childhood, the use of inhaled steroids, the level of education of our patients and the GOLD stadium. INTERPRETATION: Daily administration of a mucolytic drug such as carbocisteine for prolonged periods in addition to the bronchodilator therapy can be considered a good strategy for reducing exacerbation frequency in COPD.

Targeting protein kinase A in cancer therapy: an update.

Protein Kinase A (PKA) is a well known member of the serine-threonin protein kinase superfamily. PKA, also known as cAMP-dependent protein kinase, is a multi-unit protein kinase that mediates signal transduction of G-protein coupled receptors through its activation upon cAMP binding. The widespread expression of PKA subunit genes, and the myriad of mechanisms by which cAMP is regulated within a cell suggest that PKA signaling is one of extreme importance to cellular function. It is involved in the control of a wide variety of cellular processes from metabolism to ion channel activation, cell growth and differentiation, gene expression and apoptosis. Importantly, since it has been implicated in the initiation and progression of many tumors, PKA has been proposed as a novel biomarker for cancer detection, and as a potential molecular target for cancer therapy. Here, we highlight some features of cAMP/PKA signaling that are relevant to cancer biology and present an update on targeting PKA in cancer therapy.

Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease.

The importance of genetics and epigenetic changes in the pathogenesis of non alcoholic fatty liver disease (NAFLD) has been increasingly recognized. Adiponectin has a central role in regulating glucose and lipid metabolism and controlling inflammation in insulin-sensitive tissues and low adiponectin levels have been linked to NAFLD. APPL1 and APPL2 are adaptor proteins that interact with the intracellular region of adiponectin receptors and mediate adiponectin signaling and its effects on metabolism. The aim of our study was the evaluation of a potential association between variants at APPL1 and APPL2 loci and NAFLD occurrence. The impact on liver damage and hepatic steatosis severity has been also evaluated. To this aim allele frequency and genotype distribution of APPL1- rs3806622 and -rs4640525 and APPL2-rs 11112412 variants were evaluated in 223 subjects with clinical diagnosis of NAFLD and compared with 231 healthy subjects. The impact of APPL1 and APPL2 SNPs on liver damage and hepatic steatosis severity has been also evaluated. The minor-allele combination APPL1-C/APPL2-A was associated with an increased risk of NAFLD (OR = 2.50 95% CI 1.45-4.32; p<0.001) even after adjustment for age, sex, body mass index, insulin resistance (HOMA-IR), triglycerides and adiponectin levels. This allele combination carrier had higher plasma alanine aminotransferase levels (Diff = 15.08 [7.60-22.57] p = 0.001) and an increased frequency of severe steatosis compared to the reference allele combination (OR = 3.88; 95% CI 1.582-9.531; p<0.001). In conclusion, C-APPL1/A-APPL2 allele combination is associated with NAFLD occurrence, with a more severe hepatic steatosis grade and with a reduced adiponectin cytoprotective effect on liver.

A new pleiotropic effect of statins in elderly: modulation of telomerase activity.

Recent evidence suggests a link between statins and telomere biology. Whether statin treatment may modulate telomerase activity and affect telomere erosion rate is unknown. We aimed at investigating the potential impact of statin therapy on peripheral blood mononuclear cells telomerase activity, its implication on LTL variability, and its association with telomere shortening rates along with aging. The cross-sectional study was conducted in 230 subjects (age range: 30-86 y) stratified according to statins treatment. LTL was measured by quantitative polymerase chain reaction and telomerase activity by a PCR-ELISA protocol. Subjects on statin treatment showed higher telomerase activity (P<0.0001) and longer LTL (P=0.028) levels compared to the nonstatin group. Statin therapy was associated with higher telomerase activity independently of multiple covariates, including age, gender, smoking habits, lipid, systemic inflammation, glucose, and blood pressure levels (P=0.019). Indeed, subjects on statin treatment showed significant lower telomere erosion along with aging. Every 1 y increment in age, LTL decreases by 0.058 Kb in no statin and 0.033 Kb in statin groups, respectively, as well as the major difference in telomere attrition between groups was found after the age of 65 yr (P<0.0001). In summary, statins, modulating telomerase activity, affect telomere erosion along with aging.

Mediterranean diet, telomere maintenance and health status among elderly.

Leukocyte telomere length (LTL) and rate of telomere shortening are known biomarkers of aging while, numerous studies showed that Mediterranean diet (MD) may boost longevity. We studied association between telomere length, telomerase activity and different adherence to MD and its effects on healthy status. The study was conducted in 217 elderly subjects stratified according Mediterranean diet score (MDS) in low adherence (MDS≤3), medium adherence (MDS 4-5) and high adherence (MDS≥6) groups. LTL was measured by quantitative polymerase chain reaction and telomerase activity by a PCR-ELISA protocol. High adherence group showed longer LTL (p = 0.003) and higher telomerase activity (p = 0.013) compared to others. Linear regression analysis including age, gender, smoking habit and MDS showed that MDS was independently associated with LTL (p = 0.024) and telomerase activity levels (p = 0.006). Telomerase activity was independently associated with LTL (p = 0.007) and negatively modulated by inflammation and oxidative stress. Indeed, telomerase levels were associated with healthy status independently of multiple covariates (p = 0.048). These results support a novel role of MD in promoting health-span suggesting that telomere maintenance, rather than LTL variability is the major determinant of healthy status among elderly.

Inorganic Phosphate as a Novel Signaling Molecule with Antiproliferative Action in MDA-MB-231 Breast Cancer Cells.

Inorganic phosphate (Pi) is an essential nutrient for living organisms. It plays a key role in diverse physiological functions, including osteoblast differentiation and skeletal mineralization. Relevantly, Pi is emerging as an important signaling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression, and protein abundance in many cell types. To our knowledge, the consequences of elevated Pi on behavior of breast cancer cells have been poorly addressed. In this study we investigate the effects of Pi on proliferation of MDA-MB-231 breast cancer cells. We report that Pi inhibits proliferation of MDA-MB-231 cells by slowing cell cycle progression, without apoptosis occurrence. We found that Pi causes cells to accumulate in G1 phase in a time-dependent manner. Accordingly, G1 accumulation was associated with a decrease of cyclin A and cyclin E and an increase of cell cycle inhibitors p21 and p27 protein levels, respectively. Moreover, the Pi-induced antiproliferative effect was dynamically accompanied by profound changes in ERK1/2 and STAT3 protein and phosphorylation levels in response to Pi. Altogether, our data represent the first evidence of Pi acting as a novel signaling molecule in MDA-MB-231 breast cancer cells, capable of eliciting a strong antiproliferative action and suggest that targeting Pi levels at local sites might represent the rationale for developing novel strategies for therapeutic intervention in triple-negative breast cancer.

Synergistic cytotoxic effects of inorganic phosphate and chemotherapeutic drugs on human osteosarcoma cells.

Novel therapeutic approaches are required for the treatment of osteosarcoma. Combination chemotherapy is receiving increased attention in order to identify compounds that may increase the therapeutic index of clinical anticancer drugs. In this regard, naturally occurring molecules with antitumor activity and with limited toxicity to normal tissues have been suggested as possible candidates for investigation of their synergistic efficacy in combination with antineoplastic drugs. Inorganic phosphate (Pi) is an essential nutrient for living organisms. Relevantly, Pi has emerged as an important signaling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression and protein abundance in many cell types. Previously, we showed that Pi inhibits proliferation and aggressiveness of U2OS human osteosarcoma cells and that Pi is capable of inducing sensitization of osteosarcoma cells to doxorubicin in a p53-dependent manner. In this study, we extended the role of Pi in the chemosensitivity of osteosarcoma cells to other anticancer drugs. Specifically, we report and compare the antiproliferative effects of a combination between Pi and doxorubicin, Taxol and 5-fluorouracil (5-FU) treatments. We found that Pi increases the antiproliferative response to both Taxol and doxorubicin to a similar extent. On the other hand, Pi did not potentiate the anticancer effects induced by 5-FU. These effects were paralleled by apoptosis induction and were cell cycle-dependent. The clinical significance of our data and their potential therapeutic applications for improving osteosarcoma treatment are discussed.

Inorganic phosphate as a signaling molecule: a potential strategy in osteosarcoma treatment.

Inorganic phosphate (Pi) is an essential nutrient to living organisms. It plays a key role in diverse biological processes, including osteoblast differentiation and skeletal mineralization. Maintenance of proper Pi homeostasis is a critical event, as any deviation from that state can lead to several acute and chronic disease states and influence the ageing process and lifespan. Serum Pi level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, renal tubular reabsorption and depends mainly on the activity of Na/Pi cotransporters. Pi is abundant in the diet and intestinal absorption of Pi is efficient and minimally regulated. The kidney is a major regulator of Pi homeostasis and can increase or decrease its Pi reabsorptive capacity to accommodate Pi need. Relevantly, Pi is emerging as an important signalling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression and protein abundance in many cell types. However, little is known about the initial events involving the detection of changes in serum or local Pi concentrations and the subsequent downstream regulation cascade. Previously, we provided evidence that Pi inhibits proliferation and aggressiveness of human osteosarcoma U2OS cells identifying adenylate cyclase, beta3 integrin, Rap1, ERK1/2 as proteins whose expression and function are relevantly affected in response to Pi. More recently, we demonstrated that Pi is capable also of inducing sensitization of osteosarcoma cells to doxorubicin in a p53-dependent manner and through a mechanism involving ERK1/2 down-regulation. This review summarizes the current knowledge regarding inorganic phosphate as a novel specific signaling molecule in bone and other cell types in mammals and discuss how targeting Pi levels at local sites might represent a potential strategy for improving osteosarcoma therapy.

Integrating leptin and cAMP signalling pathways in triple-negative breast cancer cells.

Breast cancer is a major cause of cancer death in women in the world. Triple-negative breast cancers, which accounts for 10-20% of all mammary tumours, are characterised by an aggressive phenotype, are often found in younger women and have been associated with poor prognosis. Obesity increases the risk for triple-negative breast cancer occurrence. Because triple-negative breast cancer patients are unresponsive to current targeted therapies and other treatment options are only partially effective, new pharmacological approaches are warranted. The obesity-linked adipokine, leptin, is a well known mitogen/survival factor in breast cancer cells and several studies have addressed the role of leptin in breast cancer pathogenesis and progression. Surprisingly, recent in vitro studies have shown that leptin enhances the anti-proliferative effects of cAMP elevation in triple-negative breast cancer cells by apoptosis induction. In the current review, we discuss on the role of cAMP as a growth suppressor and of leptin as a growth promoting factor in breast cancer cells and we will focus on the molecular pathways involved in the antiproliferative interaction between leptin and cAMP elevation. The rationale for the possible development of a simple, cheap and innovative approach for therapeutic intervention in triple-negative breast cancer, based on the use of cAMP elevating drugs at lower and tolerable doses, will be also discussed.

Inorganic phosphate enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin via a p53-dependent pathway.

Osteosarcoma is the most common malignant primary bone tumor in children and adolescents. The clinical outcome for osteosarcoma remains discouraging despite aggressive surgery and intensive radiotherapy and chemotherapy regimens. Thus, novel therapeutic approaches are needed. Previously, we have shown that inorganic phosphate (Pi) inhibits proliferation and aggressiveness of human osteosarcoma U2OS cells identifying adenylate cyclase, beta3 integrin, Rap1, ERK1/2 as proteins whose expression and function are relevantly affected in response to Pi. In this study, we investigated whether Pi could affect chemosensitivity of osteosarcoma cells and the underlying molecular mechanisms. Here, we report that Pi inhibits proliferation of p53-wild type U2OS cells (and not of p53-null Saos and p53-mutant MG63 cells) by slowing-down cell cycle progression, without apoptosis occurrence. Interestingly, we found that Pi strongly enhances doxorubicin-induced cytotoxicity in U2OS, and not in Saos and MG63 cells, by apoptosis induction, as revealed by a marked increase of sub-G1 population, Bcl-2 downregulation, caspase-3 activation, and PARP cleavage. Remarkably, Pi/doxorubicin combination-induced cytotoxicity was accompanied by an increase of p53 protein levels and of p53 target genes mdm2, p21 and Bax, and was significantly reduced by the p53 inhibitor pifithrine-alpha. Moreover, the doxorubicin-induced cytotoxicity was associated with ERK1/2 pathway inhibition in response to Pi. Altogether, our data enforce the evidence of Pi as a novel signaling molecule capable of inhibiting ERK pathway and inducing sensitization to doxorubicin of osteosarcoma cells by p53-dependent apoptosis, implying that targeting Pi levels might represent a rational strategy for improving osteosarcoma therapy.

On the recognition of emotional vocal expressions: motivations for a holistic approach.

Human beings seem to be able to recognize emotions from speech very well and information communication technology aims to implement machines and agents that can do the same. However, to be able to automatically recognize affective states from speech signals, it is necessary to solve two main technological problems. The former concerns the identification of effective and efficient processing algorithms capable of capturing emotional acoustic features from speech sentences. The latter focuses on finding computational models able to classify, with an approximation as good as human listeners, a given set of emotional states. This paper will survey these topics and provide some insights for a holistic approach to the automatic analysis, recognition and synthesis of affective states.

Effects of PPARs agonists on cardiac metabolism in littermate and cardiomyocyte-specific PPAR-γ-knockout (CM-PGKO) mice.

Understanding the molecular regulatory mechanisms controlling for myocardial lipid metabolism is of critical importance for the development of new therapeutic strategies for heart diseases. The role of PPARγ and thiazolidinediones in regulation of myocardial lipid metabolism is controversial. The aim of our study was to assess the role of PPARγ on myocardial lipid metabolism and function and differentiate local/from systemic actions of PPARs agonists using cardiomyocyte-specific PPARγ -knockout (CM-PGKO) mice. To this aim, the effect of PPARγ, PPARγ/PPARα and PPARα agonists on cardiac function, intra-myocyte lipid accumulation and myocardial expression profile of genes and proteins, affecting lipid oxidation, uptake, synthesis, and storage (CD36, CPT1MIIA, AOX, FAS, SREBP1-c and ADPR) was evaluated in cardiomyocyte-specific PPARγ-knockout (CM-PGKO) and littermate control mice undergoing standard and high fat diet (HFD). At baseline, protein levels and mRNA expression of genes involved in lipid uptake, oxidation, synthesis, and accumulation of CM-PGKO mice were not significantly different from those of their littermate controls. At baseline, no difference in myocardial lipid content was found between CM-PGKO and littermate controls. In standard condition, pioglitazone and rosiglitazone do not affect myocardial metabolism while, fenofibrate treatment significantly increased CD36 and CPT1MIIA gene expression. In both CM-PGKO and control mice submitted to HFD, six weeks of treatment with rosiglitazone, fenofibrate and pioglitazone lowered myocardial lipid accumulation shifting myocardial substrate utilization towards greater contribution of glucose. In conclusion, at baseline, PPARγ does not play a crucial role in regulating cardiac metabolism in mice, probably due to its low myocardial expression. PPARs agonists, indirectly protect myocardium from lipotoxic damage likely reducing fatty acids delivery to the heart through the actions on adipose tissue. Nevertheless a direct non-PPARγ mediated mechanism of PPARγ agonist could not be ruled out.

Magnetic resonance imaging is an accurate and reliable method to evaluate non-cystic fibrosis paediatric lung disease.

BACKGROUND AND OBJECTIVE: Chest MRI is increasingly used to assess pulmonary diseases, but its utility compared with high-resolution computed tomography (HRCT) has never been evaluated in children using specific performance outcomes. The aim of this study was to assess the accuracy and reliability of MRI compared with HRCT in children with non-cystic fibrosis (CF) chronic lung disease. METHODS: Fifty subjects aged 5.9-20 years, with primary ciliary dyskinesia (n = 17), primary immunodeficiency (n = 17) or recurrent pneumonia (n = 16), underwent chest HRCT and MRI. The prevalence of lung abnormalities on HRCT was evaluated, and sensitivity, specificity, accuracy and positive and negative likelihood ratios for MRI versus HRCT were calculated. MRI and HRCT scans were also assessed using a modified Helbich score. RESULTS: Bronchiectasis, mucous plugging, peribronchial wall thickening, consolidation, bullae, abscesses and emphysema were detected by HRCT in 72, 68, 66, 60, 10, 8 and 8% of subjects, respectively. Sensitivity, specificity, accuracy and positive and negative likelihood ratios for MRI were good or excellent for most of the changes that were assessed. Median total Helbich scores for HRCT and MRI were 10 (range 0-20) and 10 (range 0-18), respectively. There was good-to-excellent agreement between the two techniques for all scores (r ≥ 0.8). A Bland-Altman plot confirmed this agreement between total scores (bias value: 0.2 ± 1.18; 95% limits of agreement of mean difference: -2.12-2.52). CONCLUSIONS: Chest MRI was equivalent to HRCT to determine the extent of lung disease in children with non-CF lung disease. The findings support the use of chest MRI as an alternative to HRCT in diagnostic pathways for paediatric chronic lung disorders.

Progression of lung disease in primary ciliary dyskinesia: is spirometry less accurate than CT?

Despite its extensive use, there is no evidence that spirometry is useful in the assessment of progression of lung disease in primary ciliary dyskinesia (PCD). We hypothesize that high-resolution computed tomography (HRCT) is a better indicator of PCD lung disease progression than spirometry. We retrospectively evaluated two paired spirometry and HRCT examinations from 20 PCD patients (age, 11.6 years; range, 6.5-27.5 years). The evaluations were performed in stable state and during unstable lung disease. HRCT scans were scored blind by two raters. Compared to the first assessment, at the second evaluation spirometry did not change while HRCT scores significantly worsened (P < 0.01). Age was significantly related to HRCT total (r = 0.5; P = 0.02) and bronchiectasis scores (r = 0.5; P = 0.02). At both evaluations, HRCT total score correlated with FEV(1) (r = -0.5, P = 0.01; r = -0.7, P = 0.001, respectively) and FVC Z scores (r = -0.6, P = 0.006; r = -0.7, P = 0.001, respectively), and bronchiectasis score was related to FEV(1) (r = -0.5, P = 0.03; r = -0.6; P = 0.002, respectively) and FVC Z scores (r = -0.6, P = 0.008; r = -0.7, P = 0.001, respectively). No relationship was found between the change in HRCT scores and the change in spirometry. In PCD, structural lung disease may worsen despite spirometry being stable.

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity.

A large array of gene involved in human longevity seems to be in relationship with insulin/IGF1 pathway. However, if such genes interact each other, or with other genes, to reduce the age-related metabolic derangement and determine the long-lived phenotype has been poorly investigated. Thus, we tested the role of interchromosomal interactions among IGF1R, IRS2, and UCP2 genes on the probability to reach extreme old age in 722 unrelated Italian subjects (401 women and 321 men; mean age, 62.83 ± 25.30 years) enrolled between 1998 and 1999. In particular, the G/A-IGF1R, Gly/Asp-IRS2, and Ala/Val-UCP2 allele combination was tested for association with longevity, metabolic profile and energy expenditure parameters. The effect on all-cause and cause-specific mortality rate was also assessed after a mean follow-up of 6 years. The analysis revealed that AAV allele combination is associated with a decreased all-cause mortality risk (HR, 0.72; 95% CI, 0.63-0.91; p = 0.03) and with a higher probability to reach the extreme of old age (OR, 3.185; 95% CI, 1.63-6.19; p = 0.0006). The analysis also revealed lower HOMA-IR (Diff, -0.532, 95% CI, 0.886-0.17; p = 0.003), higher respiratory quotient (Diff, 0.0363, 95% CI, 0.014-0.05; p = 0.001), and resting metabolic rate (Diff, 101.80693, 95% CI, -5.26-204.278; p = 0.038) for AAV allele combination. In conclusion, A-IGF1R/Asp-IRS2/Val-UCP2 allele combination is associated with a decreased all-cause mortality risk and with an increased chance of longevity. Such an effect is probably due to the combined effect of IGF1R, IRS2, and UCP2 genes on energy metabolism and on the age-related metabolic remodeling capacity.

cAMP Elevation Down-Regulates ß3 Integrin and Focal Adhesion Kinase and Inhibits Leptin-Induced Migration of MDA-MB-231 Breast Cancer Cells.

Breast cancer is one of the most common malignancies and a major cause of cancer death among women worldwide. The high mortality rate associated with breast cancer is mainly due to a propensity of the tumor to metastasize, even if small or undetectable. Given the relevant role of leptin in breast cancer growth and metastasis, novel strategies to counteract biological effects of this obesity-linked cytokine are warranted. Recently, we demonstrated that in MDA-MB-231 breast cancer cells, intracellular cAMP elevation completely abrogates both ERK1/2 and STAT3 phosphorylation in response to leptin. Very surprisingly, this provided evidence that when cAMP levels are increased, leptin drives cells towards apoptosis associated with a marked decrease of Bcl2 protein levels and accompanied by down-regulation of protein kinase A (PKA). The aim of the current study was to investigate the role of cAMP in leptin-associated motility of breast cancer cells. Here we show that cAMP elevation completely prevents leptin-induced migration of MDA-MB-231 breast cancer cells. Interestingly, the inhibition by cAMP-elevating agents of leptin-mediated cell migration is accompanied by a strong decrease of ß3 integrin subunit and focal adhesion kinase (FAK) protein levels. Analysis of the underlying cAMP-dependent molecular mechanisms revealed that PKA blockers partly counteract the inhibition of leptin-induced migration and completely prevent the antiproliferative action by cAMP elevation. Moreover, a cAMP analogue that specifically activates Epac and not PKA has an inhibitory effect on leptin-induced cell migration as well. The present study confirms initial evidence for the efficacy of cAMP elevation against oncogenic effects of leptin, identifies ß3 integrin subunit and FAK as proteins strongly down-regulated by cAMP elevation, and suggests that both cAMP/PKA- and cAMP/Epac-dependent pathways are involved in inhibition of leptin-induced migration of MDA-MB-231 breast cancer cells. The potential clinical significance and therapeutic applications of our data are discussed.

The IRS2 Gly1057Asp variant is associated with human longevity.

BACKGROUND: Reduced insulin and insulin-like growth factor-1 (IGF-1) signaling extends the life span of invertebrate and mammals. Recently, reduced insulin receptor substrate-2 (IRS2) signaling was found associated with increased longevity in mice. The aim of our study was to evaluate whether a common polymorphism (Gly1057Asp) in human IRS2 gene is associated with human longevity. METHODS: Six hundred seventy-seven participants (289 males and 388 females) between 16 and 104 years of age, categorized as long lived (LL; >85 years old) or controls (C; <85 years old), were genotyped for Gly1057Asp-IRS2 locus variability (rs1805097). All participants, contacted at home or in their institution or selected from Italian geriatric and internal medicine or geriatric rehabilitation structures, underwent to a clinical, biochemical, and functional characterization, with particular attention to the insulin and IGF-1 signaling. Insulin resistance (Homeostasis Model Assessment [HOMA]-IR), insulin sensitivity (HOMA IS), and ss-cell function (HOMA-B cell) were calculated by the HOMA2 calculator v2.2 (www.dtu.ox.ac.uk/homa). RESULTS: In the whole population, homozygous IRS2(Asp/Asp) participants were more represented among LL versus C participants (16.7% vs 12.0%; p = .04). The association between IRS2 gene polymorphism with longevity (being LL) was independent of anthropometric and metabolic covariates (odds ratio: 2.07, 95% confidence interval [CI] = 1.38-3.12; p = .001). Categorizing participants into percentiles by age, IRS2(Asp/Asp) participants were more likely to reach extreme old age (>or=90 percentile, 96-104 years; odds ratio: 2.03, 95% CI = 1.39-2.99; p = .0003). CONCLUSIONS: These results support the hypothesis that the IRS2 branch of the insulin and IGF signaling is associated with human longevity. Further studies will be necessary for replicating our finding in an independent larger population group with sufficient power before the association between IRS2 gene polymorphism and longevity can be regarded as proven. Furthermore, studies of genetic and/or environmental background interactions may be useful after basic replication is complete.