Generation and characterization of mouse models of Small cell lung cancer and Basal cell carcinoma for the preclinical evaluation of new therapies

Background. Human small cell lung cancer (SCLC) accounting for approximately 15-20% of all lung cancers, is an aggressive tumor with high propensity for early regional and distant metastases. Although the initial tumor rate response to chemotherapy is very high, SCLC relapses after approximately 4 months in ED and 12 months in LD. Basal cell carcinoma (BCC) is the most prevalent cancer in the western world, and its incidence is increasing worldwide. This type of cancer rarely metastasizes and the death rate is extraordinary low. Surgery is curative for most of the patients, but for those that develop locally advanced or metastatic BCC there is currently no effective treatment. Both types of cancer have been deeply investigated and genetic alterations, MYCN amplification (MA) among the most interesting, have been found. These could become targets of new pharmacological therapies. Procedures. We created and characterized novel BLI xenograft orthotopic mouse models of SCLC to evaluate the tumor onset and progression and the efficacy of new pharmacological strategies. We compared an in vitro model with a transgenic mouse model of BCC, to investigate and delineate the canonical HH signalling pathway and its connections with other molecular pathways. Results and conclusions. The orthotopic models showed latency and progression patterns similar to human disease. Chemotherapy treatments improved survival rates and validated the in vivo model. The presence of MA and overexpression were confirmed in each model and we tested the efficacy of a new MYCN inhibitor in vitro. Preliminar data of BCC models highlighted Hedgehog pathway role and underlined the importance of both in vitro and in vivo strategies to achieve a better understanding of the pathology and to evaluate the applicability of new therapeutic compounds

Geotechnical characterization of mixed sandy and silty soils using piezocone tests: Analysis of partial drainage phenomena and rate effects on the experimental soil response

The cone penetration test (CPT), together with its recent variation (CPTU), has become the most widely used in-situ testing technique for soil profiling and geotechnical characterization. The knowledge gained over the last decades on the interpretation procedures in sands and clays is certainly wide, whilst very few contributions can be found as regards the analysis of CPT(u) data in intermediate soils. Indeed, it is widely accepted that at the standard rate of penetration (v = 20 mm/s), drained penetration occurs in sands while undrained penetration occurs in clays. However, a problem arise when the available interpretation approaches are applied to cone measurements in silts, sandy silts, silty or clayey sands, since such intermediate geomaterials are often characterized by permeability values within the range in which partial drainage is very likely to occur. Hence, the application of the available and well-established interpretation procedures, developed for ‘standard’ clays and sands, may result in invalid estimates of soil parameters. This study aims at providing a better understanding on the interpretation of CPTU data in natural sand and silt mixtures, by taking into account two main aspects, as specified below: 1)Investigating the effect of penetration rate on piezocone measurements, with the aim of identifying drainage conditions when cone penetration is performed at a standard rate. This part of the thesis has been carried out with reference to a specific CPTU database recently collected in a liquefaction-prone area (Emilia-Romagna Region, Italy). 2)Providing a better insight into the interpretation of piezocone tests in the widely studied silty sediments of the Venetian lagoon (Italy). Research has focused on the calibration and verification of some site-specific correlations, with special reference to the estimate of compressibility parameters for the assessment of long-term settlements of the Venetian coastal defences.

The Influence of Baseline Metabolic Rate and Exercise Training on Cardio-Respiratory Dynamics

Speeding the VO2 kinetics results in a reduction of the O2 deficit. Two factors might determine VO2 kinetics: oxygen delivery to muscle (Tschakovsky and Hughson 1999) and a muscle 'metabolic inertia' (Grassi et al. 1996). Therefore, in study 1 we investigated VO2 kinetics and cardiovascular system adaptations during step exercise transitions in different regions of the moderate domain. In study 2 we investigated muscle oxygenation and cardio-pulmonary adaptations during step exercise tests before, after and over a period of training. Study 1 methods: Seven subjects (26 ± 8 yr; 176 ± 5 cm; 69 ± 6 kg) performed 4 types of step transition from rest (0-50W; 0-100W) or elevate baseline (25-75W; 25-125W). GET and VO2max were assessed before testing. O2 uptake and were measured during testing. Study 2 methods: 10 subjects (25 ± 4 yr; 175 ± 9 cm; 71 ± 12 kg) performed a step transition test (0 to 100 W) before, after and during 4 weeks of endurance training (ET). VO2max and GET were assessed before and after of ET (40 minutes, 3 times a week, 60% O2max). VO2 uptake, Q and deoxyheamoglobin were measured during testing. Study 1 results: VO2 τ and the functional gain were slower in the upper regions of the moderate domain. Q increased more abruptly during rest to work condition. Q τ was faster than VO2 τ for each exercise step. Study 2 results: VO2 τ became faster after ET (25%) and particularly after 1 training session (4%). Q kinetics changed after 4 training sessions nevertheless it was always faster than VO2 τ. An attenuation in ∆[HHb] /∆VO2 was detectible. Conclusion: these investigations suggest that muscle fibres recruitment exerts a influence on the VO2 response within the moderate domain either during different forms of step transition or following ET.

Salinity Effect on Horticultural Crops: Morphological, Physiological, and Biomolecular Elements of Salinity Stress Response

Among abiotic stresses, high salinity stress is the most severe environmental stress. High salinity exerts its negative impact mainly by disrupting the ionic and osmotic equilibrium of the cell. In saline soils, high levels of sodium ions lead to plant growth inhibition and even death. Salt tolerance in plants is a multifarious phenomenon involving a variety of changes at molecular, organelle, cellular, tissue as well as whole plant level. In addition, salt tolerant plants show a range of adaptations not only in morphological or structural features but also in metabolic and physiological processes that enable them to survive under extreme saline environments. The main objectives of my dissertation were understanding the main physiological and biomolecular features of plant responses to salinity in different genotypes of horticultural crops that are belonging to different families Solanaceae (tomato) and Cucurbitaceae (melon) and Brassicaceae (cabbage and radish). Several aspects of crop responses to salinity have been addressed with the final aim of combining elements of functional stress response in plants by using several ways for the assessment of plant stress perception that ranging from destructive measurements (eg. leaf area, relative growth rate, leaf area index, and total plant fresh and dry weight), to physiological determinations (eg. stomatal conductance, leaf gas exchanges, water use efficiency, and leaf water relation), to the determination of metabolite accumulation in plant tissue (eg. Proline and protein) as well as evaluation the role of enzymatic antioxidant capacity assay in scavenging reactive oxygen species that have been generated under salinized condition, and finally assessing the gene induction and up-down regulation upon salinization (eg. SOS pathway).