The Role of ATPase Inhibitor Protein, IF1 in the Regulation of Both Mitochondrial Funcion and Ca2+ Homeostasis in Tumor Cells

Tumor cells exhibit metabolic differences with respect to non-transformed cells. An important feature of cancer cells is the switch towards glycolysis to compensate the increased energy demand. Many biochemical mechanisms contribute to enhancing the glycolysis rate, one of which is the inhibition of the mitochondrial F1FO-ATPase by its endogenous inhibitor, IF1. When the electron transport is impaired, the mitochondrial electrochemical gradient collapses leading to the activation of ATP synthase hydrolytic activity in order to restore the proton gradient essential for cell function. Under these circumstances, the acidification of the mitochondrial matrix induces IF1 to inhibit the ATP synthase blocking the reversal of the enzyme and saving ATP. Furthermore, a putative binding site for calmodulin in IF1 sequence has been uncovered, suggesting that IF1 may contribute to the regulation of Ca2+ levels. Therefore, the intracellular Ca2+ handling was analysed in scrambled and IF1-silenced HeLa cells: the data obtained showed that mitochondrial Ca2+ uptake was higher in IF1 KD cells with respect to controls upon stimulation with Thapsigargin. This result was related with both the higher membrane potential and MCU expression found in IF1 KD cells, suggesting a role of IF1 in Ca2+ signalling regulation. In the light of the above, tumor cells bioenergetics were addressed in the presence or the absence of IF1 in order to shed light on its role in cancer cells bioenergetics. For this purpose, the inner membrane potential was investigated in IF1 silenced 143B cells under normoxic (21% O2) and hypoxic (0.5% O2) conditions, and related to ATP content, respiration rate, OXPHOS enzymes levels: our results showed that in normoxia IF1 may actively contribute to enhancing OXPHOS efficiency, whereas in hypoxia, a selective advantage concerning cell growth and proliferation was detected in IF1 expressing cells, suggesting that IF1 plays important role(s) in cells exposed to hypoxia/anoxia

Life gain in Italian smokers who quit

This study aims to estimate the number of life years gained with quitting smoking in Italian smokers of both sexes, by number of cigarettes smoked per day (cig/day) and age at cessation. All-cause mortality tables by age, sex and smoking status were computed, based on Italian smoking data, and the survival curves of former and current smokers were compared. The more cig/day a man/woman smokes, and the younger his/her age of quitting smoking, the more years of life he/she gains with cessation. In fact, cessation at age 30, 40, 50, or 60 years gained, respectively, about 7, 7, 6, or 5, and 5, 5, 4, or 3 years of life, respectively, for men and women that smoked 10-19 cig/day. The gain in life years was higher for heavy smokers (9 years for >20 cig/day) and lower for light smokers (4 years for 1-9 cig/day). Consistently with prospective studies conducted worldwide, quitting smoking increases life expectancy regardless of age, gender and number of cig/day. The estimates of the number of years of life that could be gained by quitting smoking, when computed specifically for a single smoker, could be used by physicians and health professionals to promote a quit attempt. © 2014 by the authors; licensee MDPI, Basel, Switzerland

Au2phen and Auoxo6, Two Dinuclear Oxo-Bridged Gold({III}) Compounds, Induce Apoptotic Signaling in Human Ovarian A2780 Cancer Cells

Au(2)phen ((2,9-dimethyl-1,10-phenanthroline)(2)Au(2)(µ-O)(2))(PF(6))(2) and Auoxo6 ((6,6′-dimethyl-2,2′-bipyridine)(2)Au(2)(µ-O)(2))(PF(6))(2) are two structurally related gold(III) complexes that were previously reported to display relevant and promising anticancer properties in vitro toward a large number of human cancer cell lines. To expand the knowledge on the molecular mechanisms through which these gold(III) complexes trigger apoptosis in cancer cells, further studies have been performed using A2780 ovarian cancer cells as reference models. For comparative purposes, parallel studies were carried out on the gold(III) complex AuL12 (dibromo(ethylsarcosinedithiocarbamate)gold(III)), whose proapoptotic profile had been earlier characterized in several cancer cell lines. Our results pointed out that all these gold(III) compounds manifest a significant degree of similarity in their cellular and proapoptotic effects; the main observed perturbations consist of potent thioredoxin reductase inhibition, disruption of the cell redox balance, impairment of the mitochondrial membrane potential, and induction of associated metabolic changes. In addition, evidence was gained of the remarkable contribution of ASK1 (apoptosis-signal-regulating kinase-1) and AKT pathways to gold(III)-induced apoptotic signaling. Overall, the observed effects may be traced back to gold(III) reduction and subsequent formation and release of gold(I) species that are able to bind and inhibit several enzymes responsible for the intracellular redox homeostasis, in particular the selenoenzyme thioredoxin reductase

Invariant NKT cells contribute to chronic lymphocytic leukemia surveillance and prognosis

Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant CD5(+) B lymphocytes in blood, bone marrow and lymphoid organs. CD1d-restricted invariant Natural Killer T (iNKT) cells are innate-like T lymphocytes strongly implicated in tumor surveillance. We investigated the impact of iNKT cells in the natural history of the disease both in Eμ;-Tcl1 (Tcl1) CLL mouse model and 68 CLL patients. We found that Tcl1-CLL cells express CD1d and iNKT cells critically delay the disease onset, but become functionally impaired upon disease progression. In patients, disease progression correlates also with high CD1d expression on CLL cells and impaired iNKT cells. Conversely, disease stability correlates with negative/low CD1d expression on CLL cells and normal iNKT cells, suggesting an indirect leukemia control. iNKT cells indeed hinder CLL survival in vitro by restraining CD1d-expressing Nurse Like Cells, a relevant pro-leukemia macrophage population. Finally, multivariate analysis identifies iNKT cell frequency as independent predictor of disease progression. Together, these results support iNKT cell contribution to CLL immune-surveillance and highlight iNKT cell frequency as prognostic marker for disease progression

Effects of a prevention program on multiple health-compromising behaviours in adolescence: A cluster randomized controlled trial.

We aimed to assess the effectiveness of 'Paesaggi di Prevenzione', a school-based prevention program delivered by trained teachers and designed to tackle smoking, alcohol misuse, dietary risks, and physical inactivity in adolescence. We evaluated the program between 2010 and 2013 with a two-arm, parallel-group, multicentre cluster randomized controlled trial in which schools were the units of randomization. We collected data on health-compromising behaviours using self-reported measurements of behaviour frequency administered before and after program implementation. We used multivariable mixed-effects logistic regression models to estimate program effects on health-compromising behaviours. The analysis sample included 3410 middle school students and 1651 high school students. Among middle school students, mean age at baseline was 12 years (standard deviation [SD] 0.5 years), 51% were boys, and 41% had high socioeconomic status [SES] (defined as having at least one parent/guardian with university level education). In high school students, mean age at baseline was 14 years (SD 0.7 years), 56% were boys, and 31% had high SES. The program did not have effects on smoking, alcohol misuse, and physical activity. The program had iatrogenic effects in regard to some eating behaviours, resulting in (i) lower odds of fruit consumption among middle-school students (odds ratio [OR] 0.82; 95% confidence interval [CI] 0.68-0.99) and (ii) lower odds of having breakfast every day in high-school students at the post-intervention measurement (OR 0.76; 95%CI 0.58-0.99) but not at one-year follow-up (OR 0.94; 95%CI 0.69-1.28). Due to the possibility of unintended effects, we advise against disseminating 'Paesaggi di Prevenzione' in its present form. TRIAL REGISTRATION: ISRCTN00953701

Effect of Functional Fitness on Plasma Oxidation Level in Elders: Reduction of the Plasma Oxidants and Improvement of the Antioxidant Barrier

Aging is characterized by a progressive decline in the physiological function due to the gradual alteration of molecules, cells and tissues. Reactive oxygen species (ROS) are the by-product of aerobic metabolism, and their increase is physiologically counteracted by the activation of the antioxidant machinery. A typical hallmark of aging is the imbalance of such equilibrium, due to either an increase of the amount of radicals or a failure of the antioxidant system. Literature reports that physical exercise is able to restore and maintain the homeostasis of oxidants and antioxidants during aging. Recently, growing interest has been turned to functional fitness, a special physical activity aimed to enhance the ability to perform everyday tasks, such as dressing, climbing stairs and preparing meals. The aim of this work was to assess whether a 24 weeksfunctional fitness program carried out on 28 elderly participants (57-86 years old) could be able to improve their oxidative status. For this purpose, dROMs (diacron Reactive Oxygen Metabolites) and BAP (Biological Antioxidant Potential) were analysed at the beginning and at the end of the study. Furthermore, both plasma and saliva protein carbonylation levels were explored through proteomics analysi

Emerging Role of MicroRNAs in the Therapeutic Response in Cervical Cancer: A Systematic Review

Cervical cancer is a common female cancer, with nearly 600,000 cases and more than 300,000 deaths worldwide every year. From a clinical point of view, surgery plays a key role in early cancer management, whereas advanced stages are treated with chemotherapy and/or radiation as adjuvant therapies. Nevertheless, predicting the degree of cancer response to chemotherapy or radiation therapy at diagnosis in order to personalize the clinical approach represents the biggest challenge in locally advanced cancers. The feasibility of such predictive models has been repeatedly assessed using histopathological factors, imaging and nuclear methods, tissue and fluid scans, however with poor results. In this context, the identification of novel potential biomarkers remains an unmet clinical need, and microRNAs (miRNAs) represent an interesting opportunity. With this in mind, the aim of this systematic review was to map the current literature on tumor and circulating miRNAs identified as significantly associated with the therapeutic response in cervical cancer; finally, a perspective point of view sheds light on the challenges ahead in this tumor

Burden of respiratory disease attributable to secondhand smoke exposure at home in children in Spain (2015)

This study aimed to estimate the number of incident cases and hospital admissions attributable to secondhand smoke (SHS) exposure at home for asthma, otitis media (OM), and lower respiratory infections (LRI) in children in Spain. The burden of respiratory disease caused by SHS exposure was estimated in terms of incident cases and hospitalized cases for asthma, OM, and LRI. Estimates were calculated using the population attributable fraction. The age-specific (0-1 year, 0-4 years, 5-11 years, and 0-11 years) prevalence of SHS exposure in children was estimated through a telephone survey performed in a representative sample of Spanish households with children in 2016. The risk estimates for all diseases were selected from international meta-analyses. The number of hospitalized cases was obtained for each disease from the Hospital Minimum Data Set provided by the Ministry of Health of Spain. Incident cases were obtained from the Global Health Data Exchange. In 2015, SHS exposure caused an estimated total of 136,403 incident cases of the following respiratory diseases: 9058 (8.5%) cases of asthma, 120,248 (8.5%) of OM, and 7097 (13.5%) of LRI in children aged 0-14 years old in Spain. Likewise, SHS exposure caused a total of 3028 hospitalized cases, with 379 (8.5%) for asthma and 167 (8.5%) for OM in children 0-11 years old, and 2482 (11.6%) for LRI in children <2 years old. The high burden of respiratory disease attributed to SHS exposure supports the need to improve protection of children against SHS exposure by extending smoke-free regulations to homes and cars