Dynamic generation of test cases with metaheuristics

The resolution of optimization problems is of great interest nowadays and has encouraged the development of various information technology methods to attempt solving them. There are several problems related to Software Engineering that can be solved by using this approach. In this paper, a new alternative based on the combination of population metaheuristics with a Tabu List to solve the problem of test cases generation when testing software is presented. This problem is of great importance for the development of software with a high computational cost and which is generally hard to solve. The performance of the solution proposed has been tested on a set of varying complexity programs. The results obtained show that the method proposed allows obtaining a reduced test data set in a suitable timeframe and with a greater coverage than conventional methods such as Random Method or Tabu Search.I Workshop Innovación en Sistemas de Software (WISS)Red de Universidades con Carreras en Informática (RedUNCI

Dosimetry studies for radiation therapy with photons and radiobiology using low-energy protons.

Tesis llevada a cabo para conseguir el grado de Doctor por la Universidad de Sevilla--2017-09-15This thesis work is based on the knowledge about the interaction of radiation with matter to develop new methods with the aim of applying them to the radiation therapy and radiobiology, specifically to dose measurements in radiation therapy, dose measurements with low energy proton beams and DNA damages caused by these protons on cancer cells. Thus, it presents two main parts: one regarding the presentation of a novel prototype based on silicon detector technology for treatment verification in radiotherapy, and the other, the instrumentation and the methodology for low energy proton beam characterization, dosimetry, with a special focus on the response of radiochromic films to protons, and finally the application on biological samples to study the DNA damage produced by protons. The first part of this work presents a novel system with improved performances with respect to a previous system which was filed for a patent in September 13th 2011 at the OEMP - “Oficina Espa˜nola de Patentes y Marcas”- Ministry of Industry, Tourism and Commerce, under reference number P201101009. This work was also published in specialized reviews and thesis works. The characterization of the response in terms of absorbed dose of this novel detector was presented Here, this study was repeated because of some modifications introduced in the electronics and in one of the detector’s cables, which was modified due to a breakdown. The application of this system for complex treatment verification providing a 2D dose map reconstruction in the axial plane is presented for the first time in this thesis work. The second part of the work presents the installation of instrumentation for dosimetry and radiobiology studies using proton beams produced by the 3 MV Tandem accelerator at Centro Nacional de Acceleradores, Sevilla. The original work within this part can be divided into three main points: i) the elaboration of a protocol which allows to obtain a beam profile with low current and an homogeneous profile over the whole sample surface; ii) dosimetry with low energy protons using ionization chambers and radiochromic films; iii) study of the dosimetry at the Bragg peak. Last, the application of these studies to the irradiation of cell cultures is presented and preliminary results of the DNA damage produced by protons are shown.Peer reviewe

Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain

Background: L-acetylcarnitine, a drug marketed for the treatment of chronic pain, causes analgesia by epigenetically up-regulating type-2 metabotropic glutamate (mGlu2) receptors in the spinal cord. Because the epigenetic mechanisms are typically long-lasting, we hypothesized that analgesia could outlast the duration of L-acetylcarnitine treatment in models of inflammatory and neuropathic pain. Results: A seven-day treatment with L-acetylcarnitine ( 100 mg/kg, once a day, i.p.) produced an antiallodynic effect in the complete Freund adjuvant mouse model of chronic inflammatory pain. L-Acetylcarnitine-induced analgesia persisted for at least 14 days after drug withdrawal. In contrast, the analgesic effect of pregabalin, amitryptiline, ceftriaxone, and N-acetylcysteine disappeared seven days after drug withdrawal. L-acetylcarnitine treatment enhanced mGlu2/3 receptor protein levels in the dorsal region of the spinal cord. This effect also persisted for two weeks after drug withdrawal and was associated with increased levels of acetylated histone H3 bound to the Grm2 gene promoter in the dorsal root ganglia. A long-lasting analgesic effect of L-acetylcarnitine was also observed in mice subjected to chronic constriction injury of the sciatic nerve. In these animals, a 14-day treatment with pregabalin, amitryptiline, tramadol, or L-acetylcarnitine produced a significant antiallodynic effect, with pregabalin displaying the greatest efficacy. In mice treated with pregabalin, tramadol or L-acetylcarnitine the analgesic effect was still visible 15 days after the end of drug treatment. However, only in mice treated with L-acetylcarnitine analgesia persisted 37 days after drug withdrawal. This effect was associated with an increase in mGlu2/3 receptor protein levels in the dorsal horns of the spinal cord. Conclusions: Our findings suggest that L-acetylcarnitine has the unique property to cause a long-lasting analgesic effect that might reduce relapses in patients suffering from chronic pain

Oxidative Stress as a predictor of cardiovascular events in coronari artery disease patients

Abstract Background: Enhanced oxidative stress has been associated with atherosclerosis and coronary artery disease (CAD). However, the predictive value of circulating oxidative stress biomarkers for cardiovascular events (CE) in patients with CAD has remained poorly understood. Aim: To assess the prognostic significance of reactive oxygen metabolites, estimated as index of oxidative stress in serum samples by means of a commercial kit (ROMs, Diacron, Italy) on the rate of mortality and major adverse CE (MACE) in CAD. Methods: A study of 93 consecutive patients with angiographically documented CAD (75 males, age: 68?10 years, mean?SD) was made during a mean follow-up of 66 months until the occurrence of one of the following CE: cardiac and all cause death, non-fatal myocardial infarction and coronary revascularization [percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG)]. Patient data were retrospectively collected from the Institute\u27s electronic databank that saves demographic, clinical, instrumental and follow-up data of all patients admitted to our department. Results: The Kaplan-Meier survival estimates showed a significantly worst outcome in patients presenting elevated ROM level (>75th percentile, corresponding to 481 AU) (log rank=11, 7.5, 5.1; p<0.001, p<0.01, p<0.05 for cardiac and all cause death and MACEs, respectively). In a multivariate Cox regression model, elevated oxidative stress remained a significant predictor of cardiac and all cause death [hazard ratio (HR) 3.9, 95% confidence interval, 95% (CI) 1.4-11.1, p=0.01; HR=2.6, 95% CI 1.1-6.2, p=0.02) and MACE (HR=1.8, 95% CI 1.1-3.1, p=0.03)]. Conclusions: The estimation of ROMs may represent an additional prognostic tool in the assessment of CE in CAD patients

Feasibility Study of a Proton Irradiation Facility for Radiobiological Measurements at an 18 MeV Cyclotron

A feasibility study of an experimental setup for the irradiation of biological samples at the cyclotron facility installed at the National Centre of Accelerators (Seville, Spain) is presented. This cyclotron, which counts on an external beam line for interdisciplinary research purposes, produces an 18 MeV proton beam, which is suitable for the irradiation of mono-layer cultures for the measurement of proton cell damages and Relative Biological Effectiveness (RBE) at energies below the beam nominal value. Measurements of this kind are of interest for proton therapy, since the variation of proton RBE at the distal edge of the Bragg curve may have implications in clinical proton therapy treatments. In the following, the characteristics of the beam line and the solutions implemented for the irradiation of biological samples are described. When dealing with the irradiation of cell cultures, low beam intensities and broad homogeneous irradiation fields are required, in order to assure that all the cells receive the same dose with a suitable dose rate. At the cyclotron, these constraints have been achieved by completely defocusing the beam, intercepting the beam path with tungsten scattering foils and varying the exit-window-to-sample distance. The properties of the proton beam thus obtained have been analysed and compared with Monte Carlo simulations. The results of this comparison, as well as the experimental measurement of the lateral dose profiles expected at the position of samples are presented. Meaningful dose rates of about 2–3 Gy/min have been obtained. Homogeneous lateral dose profiles, with maximum deviations of 5%, have been measured at a distance of approximately 50 cm in air from the exit window, placing a tungsten scattering foil of 200 μm in the beam path

Molecular Portrait of Clear Cell Renal Cell Carcinoma: An Integrative Analysis of Gene Expression and Genomic Copy Number Profiling

Renal cell carcinoma (RCC) incidence accounts for about 3 to 10 cases per 100,000 individuals with a predilection for adult males over 60 year old (1.6:1 male/female ratio) (Chow, 2010; Nese, 2009). In Europe, about 60,000 individuals are affected by RCC every year, with a mortality rate of about 18,000 subjects and an incidence rate for all stages steadily rising over the last three decades. Although inherited forms occur in a number of familial cancer syndromes, as the well-known von Hippel-Lindau (VHL) syndrome, RCC is commonly sporadic (Cohen & McGovern, 2005; Kaelin, 2007) and, as recently highlighted by the National Cancer Institute (NCI), influenced by the interplay between exposure to environmental risk factors and genetic susceptibility of exposed individuals (Chow et al., 2010). Being poorly symptomatic in early phases, many cases become clinically detectable only when already advanced and, as such, therapy-resistant (Motzer, 2011). Based on histology, RCC can be classified into several subtypes, i.e., clear cell (80% of cases), papillary (10%), chromophobe (5%) and oncocytoma (5%), each one characterized by specific histo- pathological features, malignant potential and clinical outcome (Cohen & McGovern, 2005). Patient stratification is normally achieved using prognostic algorithms and nomograms based on multiple clinico-pathological factors such as TNM stage, Fuhrman nuclear grade, tumor size, performance status, necrosis and other hematological indices (Flanigan et al., 2011), although the most efficient predictors of survival and recurrence are based on nuclear grade alone (Nese et al., 2009). As recently reviewed by Brannon et al. (Brannon & Rathmell, 2010), a finer RCC subtype classification could be obtained exploiting the vast amount of genomic and transcriptional data that have been presented in numerous studies. For instance, several authors proposed a molecular classification of RCC based on differential gene expression profiles, with any subtype characterized by the activation of distinct gene sets (Brannon, 2010; Furge, 2004; Skubitz, 2006; Su\u308ltmann, 2005; Zhang, 2008), while others identified RCC-specific biomarkers (e.g. CA9, ki67, VEGF proteins, phosphorylated AKT, PTEN, HIF-1). Lately, it has been reported that microRNAs, a small class of non coding RNA molecules, could contribute to RCC development at different levels and may represent a new group of potential tumor biomarkers (Redova et al., 2011). Despite the numerous efforts in dissecting the molecular features of RCC through functional genomics, not a single transcriptional signature or biomarker has gained approval for clinical application yet (Arsanious, 2009; Eichelberg, 2009; Lam, 2007; Yin-Goen, 2006), so that the identification of novel molecular markers to improve early diagnosis and prognostic prediction and of candidate targets to develop new therapeutic approaches remains of primary importance for this pathology

Pelagic cephalopods of the central Mediterranean Sea determined by the analysis of the stomach content of large fish predators

The pelagic cephalopod fauna of the central Mediterranean Sea was investigated through stomach content analyses of large fish predators. A total of 124 Xiphias gladius, 22 Thunnus thynnus, 100 Thunnus alalunga, and 25 Tetrapturus belone were analyzed. Overall, 3,096 cephalopods belonging to 23 species and 16 families were identified. The cephalopod fauna in the study area is dominated by Sepiolidae, Ommastrephidae, and Onychoteuthidae. The sepiolid Heteroteuthis dispar was the most abundant species (n = 1,402) while the ommastrephid Todarodes sagittatus showed the highest biomass. They can be considered key-species in the pelagic food web of the study area. The neutrally buoyant Histioteuthis bonnellii, H. reversa, and Chiroteuthis veranyi seem to characterize the deeper water layers. Given the difficulty in sampling pelagic cephalopods, the presence of cephalopod beaks in the stomach of predators represents a fundamental tool to assess the biodiversity and the ecological importance of these taxa in the marine ecosystem

Efficacy of an enterovaccine in recurrent episodes of diarrhea in the dog – a pilot study

Recurrent episodes of self-limiting diarrhea in the dog, due to sudden dietary changes and to stressful or exciting situations, are conditions sometimes difficult to treat. Colifagina®, a commercially available bacterial enterovaccine, showed, in previous studies performed on experimentally induced colitis in mice, to be able to improve both disease activity index and histological appearance, increase colonic secretion of IgA, and reduce inflammatory chemokine secretion. In the present study Colifagina® was administered to five dogs presenting recurrent episodes of self-limiting diarrhea and to one dog presenting chronic diarrhea. During the follow-up period, almost all patients decreased the number of episodes of abnormal defecation and the fecal score of such episodes improved in five out of six dogs. Even if further studies are needed to understand the exact potential of the compound, in dogs presenting recurrent episodes of self-limiting diarrhea due to sudden dietary changes and/or stressing or exciting situations, Colifagina® seems to be helpful in managing most of these patients

Efficacy of an enterovaccine in recurrent episodes of diarrhea in the dog: a pilot study

Recurrent episodes of self-limiting diarrhea in the dog, due to sudden dietary changes and to stressful or exciting situations, are conditions sometimes difficult to treat. Colifagina ® , a commercially available bacterial enterovaccine, showed, in previous studies performed on experimentally induced colitis in mice, to be able to improve both disease activity index and histological appearance, increase colonic secretion of IgA, and reduce inflammatory chemokine secretion. In the present study Colifagina ® was administered to five dogs presenting recurrent episodes of self-limiting diarrhea and to one dog presenting chronic diarrhea. During the follow-up period, almost all patients decreased the number of episodes of abnormal defecation and the fecal score of such episodes improved in five out of six dogs. Even if further studies are needed to understand the exact potential of the compound, in dogs presenting recurrent episodes of self-limiting diarrhea due to sudden dietary changes and/or stressing or exciting situations, Colifagina ® seems to be helpful in managing most of these patients