Tumor acidosis in malignant progression and therapy

Cancer still represents one of the leading causes of death despite the advances achieved during the past years. Improving the outcome of cancer patients requires the identification of more affective therapeutic strategies and a better understanding of the molecular mechanisms involved in the progression of the disease. Recently, the tumor metabolic reprogramming has been included in the hallmarks of cancer and one features associated with tumor metabolism is acidosis, which represents an environmental pressure contributing to the selection of malignant cells. For its contribution to tumor progression and therapy-resistance, the acidic tumor environment is being investigated as a target for cancer therapy. In this study, we have characterized the catabolic autophagic process as a fundamental survival mechanism acting in cancer cells exposed to acidic conditions in order to adapt to the harsh environment. This finding, coupled to the role of autophagy in drug-resistance, suggests the use of autophagy inhibitors in cancer treatment as a strategy to better target malignant cells localized in a metabolically stressed environment and considered responsible for tumor progression, invasion, chemoresistance and disease relapse. We have observed that the autophagy inhibitor Chloroquine used in clinical studies is not the optimal drug for this purpose since it fails to inhibit the autophagic process and to induce toxicity on cancer cells in acidic conditions. Therefore, we aimed at identifying more effective compounds also active in conditions of acidosis. Salinomycin, also known to specifically kill cancer stem cells showed a preferential cytotoxic activity in cells under acidosis, a phenomenon associated with its ability to inhibit autophagy also at low pH. Finally, we developed a model of drug screening performed on cancer cells chronically adapted to pH 6.8 in order to identify compounds targeting cells in metabolic stress conditions. We identified Verteporfin as a promising new anticancer drug able to target colon carcinoma cells adapted to low pH better than cells in physiological conditions through a mechanism that still need to be further investigated. We can conclude that a better understanding of the cellular mechanisms involved in the cell adaptation to tumor acidosis is important for the identification of new therapeutic targets and selective anticancer drugs overcoming acidosis-mediated drug-resistance

Airport slot allocation in Europe: economic efficiency and fairness

We propose a mechanism for solving the airport slot allocation problem in Europe. We consider the interdependence of the slots at different airports, and we maximize the efficiency of the system. Through an experimental analysis we quantitatively assess the cost imposed by grandfather rights, which constitute one of the main principles of the current slot allocation mechanism. Moreover, we introduce the possibility to fairly redistribute costs among airlines through monetary compensations. Our results suggest that it is possible to remove grandfather rights without significantly penalizing airlines.Air Traffic Management; Airport slot allocation; Compensation mechanism; SESAR.

Metaheuristic algorithms for the simultaneous slot allocation problem

In this paper, we formalize the simultaneous slot allocation problem. It is an extension of the problem currently tackled for allocating airport slots: it deals with all airports simultaneously and it enforces the respect of airspace sector capacities. By solving this novel problem, the system may overcome some major inefficiencies that characterize the current slot allocation process. We tackle the simultaneous slot allocation problem with two algorithms based on metaheuristics, namely Iterated Local Search and Variable Neighborhood Search, and with an integer linear programming model: for each of these three algorithms, we allow a fixed computation time, and we take the best solution found during that time as the final solution. We compare these algorithms on randomly generated instances, and we show that, when small instances are to be tackled, metaheuristics are competitive with the exact model. When medium or large instances are to be tackled, the exact model suffers some major issues in terms of memory and computation time requirements. Metaheuristics, instead, can deal with very large instances, achieving very high quality results.Air Traffic Management; Airport slot allocation; Metaheuristics; Integer linear programming

Exploration in stochastic algorithms: An application on MAX-MIN Ant System

In this paper a definition of the exploration performed by stochastic algorithms is proposed. It is based on the observation through cluster analysis of the solutions generated during a run. The probabilities associated by an algorithm to solution components are considered. Moreover, a consequent method for quantifying the exploration is provided. Such a measurement is applied to MAX-MIN Ant System. The results of the experimental analysis allow to observe the impact of the parameters of the algorithm on the exploration.exploration, cluster analysis, MAX-MIN Ant System

Real Time Railway Traffic Management Modeling Track-Circuits

The real time railway traffic management seeks for the train routing and scheduling that minimize delays after an unexpected event perturbs the operations. In this paper, we propose a mixed-integer linear programming formulation for tackling this problem, modeling the infrastructure in terms of track-circuits, which are the basic components for train detection. This formulation considers all possible alternatives for train rerouting in the infrastructure and all rescheduling alternatives for trains along these routes. To the best of our knowledge, we present the first formulation that solves this problem to optimality. We tested the proposed formulation on real perturbation instances representing traffic in a control area including the Lille Flandres station (France), achieving very good performance in terms of computation time

Solving the real-time Railway Traffic Management Problem with Benders decomposition

In railway, when a disruption occurs, the traffic may be perturbed, as a result, conflicts and delays may emerge. Modifying trains route and schedule to limit delay propagation in the network is the focus of the real-time Railway Traffic Management Problem (rtRTMP). In this work, we addressed the solution of the rtRTMP using a Benders decomposition approach. The decomposition algorithm is applyed to the mixed integer linear programming formulation of the problem. We test the algorithm to instances representing traffic in the junction of Gonesse, in France. The results are promising

An integer programming formulation to allocate series of slots on an airport network

Several authors have introduced mathematical formulations for the airport slot allocation process, and the initial allocation in particular. They mostly replicate the current IATA process, performed on an airport-by- airport basis. However, airports are part of a network. The initial slot allocation should therefore be performed simultaneously at all airports, accounting for flight times to link departures and arrivals. [1] proposes an integer programming formulation to allocate a set of single-day slots on a network of airports. Extending that formulation, this paper additionally models the IATA rule stating that series rather than individual slots are to be allocated. A series of slots includes at least 5 slots at the same time and day-of-the-week, distributed regularly in a season. The objective of the allocation is to minimise airline costs due to the non-allocation of series of slots, their temporal displacement, and the deviation from the requested block or turnaround time for slots of coupled series. Preliminary experiments are based on a network of 152 European airports and consider about 300000 slot requests for seven Fridays of the 2017 summer season. Results quantify the increase of airline costs as a function of congestion. [1] Pellegrini P, Bolic T, Castelli L, Pesenti R, 2017. SOSTA: An effective model for the simultaneous optimisation of airport slot allocation. Transportation Research Part E: Logistics and Transportation Review 99:34-53

Arquitectura vernácula e identidad cultural en asentamientos rurales en declive

La despoblació i l'abandó de les zones rurals és un fenomen que es repeteix a escala global i de manera transversal a la majoria dels territoris i cultures. Aquest procés de declivi afecta especialment a l'arquitectura vernacla, per la seva modesta materialitat i per tant els valors culturals que en ella resideixen, tant de caràcter material com immaterial. Aquest treball analitza la situació de l'arquitectura vernacla rural en zones en declivi en tres regions d'escala i plantejament cultural tan diferents com les àrees meridionals de la Xina, el Marroc i Espanya, prenent com a referència elements tipològics propis de cada regió. Aprofundeix en experiències en les quals el patrimoni cultural en perill es transforma en força dinamitzadora del territori sobre el qual s'assenta i obre la porta a solucions tant de conservació i valorització dels seus propis elements com de resolució dels problemes socioculturals de fons. La recerca identifica aspectes genèrics i universals del procés de retracció, així com condicions específiques de cadascun dels diversos territoris d'estudi. El treball va trobar com els casos presos en consideració comparteixen algunes condicions en l'enfrontament de les conseqüències de la contracció, com ara dificultats d'adaptació, distància administrativa, fragilitat patrimonial.The depopulation and abandonment of rural areas is a phenomenon that is repeated on a global scale and is transversal to most territories and cultures. This shrinking process particularly affects vernacular architecture, due to its modest materiality and therefore the cultural values that reside in it, both of a material and immaterial nature. This work analyses the situation of rural vernacular architecture in shrinking areas in three regions of different scales and cultural approaches as the southern areas of China, Morocco and Spain, taking as reference typological elements specific to each region. The research delves into experiences in which the endangered cultural heritage is transformed into a dynamizing force for the territory on which it is based and opens the door to different solutions both for the conservation and valorisation of its own elements and for the resolution of the underlying socio-cultural problems. The research identifies generic and universal aspects of the shrinking process, as well as specific conditions of each of the various study territories. The work found how the cases taken into consideration share some conditions in dealing with the consequences of the shrinkage, such as adaptation difficulties, administrative distance, heritage fragility.La despoblación y el abandono de las zonas rurales es un fenómeno que se repite a escala global y de forma transversal a la mayoría de los territorios y culturas. Este proceso de declive afecta especialmente a la arquitectura vernácula, por su modesta materialidad y por tanto los valores culturales que en ella residen, tanto de carácter material como inmaterial. Este trabajo analiza la situación de la arquitectura vernácula rural en zonas en declive en tres regiones de escala y planteamiento cultural tan distintos como las áreas meridionales de China, Marruecos y España, tomando como referencia elementos tipológicos propios de cada región. Profundiza en experiencias en las que el patrimonio cultural en peligro se transforma en fuerza dinamizadora del territorio sobre el que se asienta y abre la puerta a soluciones tanto de conservación y valorización de sus propios elementos como de resolución de los problemas socioculturales de fondo. La investigación identifica aspectos genéricos y universales del proceso de retracción, así como condiciones específicas de cada uno de los diversos territorios de estudio. El trabajo encontró cómo los casos tomados en consideración comparten algunas condiciones en el enfrentamiento de las consecuencias de la contracción, tales como dificultades de adaptación, distancia administrativa, fragilidad patrimonial.Peer Reviewe

Effects of Loud Noise Exposure on DNA Integrity in Rat Adrenal Gland

Loud noise is generally considered an environmental stressor causing negative effects on acoustic, cardiovascular, nervous, and endocrine systems. In this study, we investigated the effects of noise exposure on DNA integrity in rat adrenal gland evaluated by the comet assay. The exposure to loud noise (100 dBA) for 12 hr caused a significant increase of DNA damage in the adrenal gland. Genetic alterations did not decrease 24 hr after the cessation of the stimulus. We hypothesize that an imbalance of redox cell status is responsible for the induction and persistence of noise-induced cellular damage