Activity and mechanisms of action of novel organosulfur derivatives of the HDAC inhibitor Valproic Acid in human experimental models of non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) represents the leading cause of cancer death worldwide, and 5-year survival is about 16% for patients diagnosed with advanced lung cancer and about 70-90% when the disease is diagnosed and treated at earlier stages. Treatment of NSCLC is changed in the last years with the introduction of targeted agents, such as gefitinib and erlotinib, that have dramatically changed the natural history of NSCLC patients carrying specific mutations in the EGFR gene, or crizotinib, for patients with the EML4-ALK translocation. However, such patients represent only about 15-20% of all NSCLC patients, and for the remaining individuals conventional chemotherapy represents the standard choice yet, but response rate to thise type of treatment is only about 20%. Development of new drugs and new therapeutic approaches are so needed to improve patients outcome. In this project we aimed to analyse the antitumoral activity of two compounds with the ability to inhibit histone deacethylases (ACS 2 and ACS 33), derived from Valproic Acid and conjugated with H2S, in human cancer cell lines derived from NSCLC tissues. We showed that ACS 2 represents the more promising agent. It showed strong antitumoral and pro-apoptotic activities, by inducing membrane depolarization, cytocrome-c release and caspase 3 and 9 activation. It was able to reduce the invasive capacity of cells, through inhibition of metalloproteinases expression, and to induce a reduced chromatin condensation. This last characteristic is probably responsible for the observed high synergistic activity in combination with cisplatin. In conclusion our results highlight the potential role of the ACS 2 compound as new therapeutic option for NSCLC patients, especially in combination with cisplatin. If validated in in vivo models, this compound should be worthy for phase I clinical trials.

String inflationary models with non-monotonic slow-roll and detectable tensor modes

The first chapter of this work has the aim to provide a brief overview of the history of our Universe, in the context of string theory and considering inflation as its possible application to cosmological problems. We then discuss type IIB string compactifications, introducing the study of the inflaton, a scalar field candidated to describe the inflation theory. The Large Volume Scenario (LVS) is studied in the second chapter paying particular attention to the stabilisation of the Kähler moduli which are four-dimensional gravitationally coupled scalar fields which parameterise the size of the extra dimensions. Moduli stabilisation is the process through which these particles acquire a mass and can become promising inflaton candidates. The third chapter is devoted to the study of Fibre Inflation which is an interesting inflationary model derived within the context of LVS compactifications. The fourth chapter tries to extend the zone of slow-roll of the scalar potential by taking larger values of the field φ. Everything is done with the purpose of studying in detail deviations of the cosmological observables, which can better reproduce current experimental data. Finally, we present a slight modification of Fibre Inflation based on a different compactification manifold. This new model produces larger tensor modes with a spectral index in good agreement with the date released in February 2015 by the Planck satellite.

Experimentation with different thermodynamic cycles used for pKa calculations on carboxylic acids using Complete Basis Set and Gaussian-n Models combined with CPCM Continuum Solvation Methods

Complete basis set and Gaussian-n methods were combined with Barone and Cossi's implementation of the polarizable conductor model (CPCM) continuum solvation methods to calculate pKa values for six carboxylic acids. Four different thermodynamic cycles were considered in this work. An experimental value of −264.61 kcal/mol for the free energy of solvation of H+, ΔGs(H+), was combined with a value for Ggas(H+) of −6.28 kcal/mol, to calculate pKa values with cycle 1. The complete basis set gas-phase methods used to calculate gas-phase free energies are very accurate, with mean unsigned errors of 0.3 kcal/mol and standard deviations of 0.4 kcal/mol. The CPCM solvation calculations used to calculate condensed-phase free energies are slightly less accurate than the gas-phase models, and the best method has a mean unsigned error and standard deviation of 0.4 and 0.5 kcal/mol, respectively. Thermodynamic cycles that include an explicit water in the cycle are not accurate when the free energy of solvation of a water molecule is used, but appear to become accurate when the experimental free energy of vaporization of water is used. This apparent improvement is an artifact of the standard state used in the calculation. Geometry relaxation in solution does not improve the results when using these later cycles. The use of cycle 1 and the complete basis set models combined with the CPCM solvation methods yielded pKa values accurate to less than half a pKa unit. © 2001 John Wiley & Sons, Inc. Int J Quantum Chem, 2001

Non-water-suppressed proton MR spectroscopy improves spectral quality in the human spinal cord

Magnetic resonance spectroscopy enables insight into the chemical composition of spinal cord tissue. However, spinal cord magnetic resonance spectroscopy has rarely been applied in clinical work due to technical challenges, including strong susceptibility changes in the region and the small cord diameter, which distort the lineshape and limit the attainable signal to noise ratio. Hence, extensive signal averaging is required, which increases the likelihood of static magnetic field changes caused by subject motion (respiration, swallowing), cord motion, and scanner-induced frequency drift. To avoid incoherent signal averaging, it would be ideal to perform frequency alignment of individual free induction decays before averaging. Unfortunately, this is not possible due to the low signal to noise ratio of the metabolite peaks. In this article, frequency alignment of individual free induction decays is demonstrated to improve spectral quality by using the high signal to noise ratio water peak from non-water-suppressed proton magnetic resonance spectroscopy via the metabolite cycling technique. Electrocardiography (ECG)-triggered point resolved spectroscopy (PRESS) localization was used for data acquisition with metabolite cycling or water suppression for comparison. A significant improvement in the signal to noise ratio and decrease of the Cramér Rao lower bounds of all metabolites is attained by using metabolite cycling together with frequency alignment, as compared to water-suppressed spectra, in 13 healthy volunteers.

Magnetization exchange observed in human skeletal muscle by non-water-suppressed proton magnetic resonance spectroscopy

Many metabolites in the proton magnetic resonance spectrum undergo magnetization exchange with water, such as those in the downfield region (6.0-8.5 ppm) and the upfield peaks of creatine, which can be measured to reveal additional information about the molecular environment. In addition, these resonances are attenuated by conventional water suppression techniques complicating detection and quantification. To characterize these metabolites in human skeletal muscle in vivo at 3 T, metabolite cycled non-water-suppressed spectroscopy was used to conduct a water inversion transfer experiment in both the soleus and tibialis anterior muscles. Resulting median exchange-independent T(1) times for the creatine methylene resonances were 1.26 and 1.15 s, and for the methyl resonances were 1.57 and 1.74 s, for soleus and tibialis anterior muscles, respectively. Magnetization transfer rates from water to the creatine methylene resonances were 0.56 and 0.28 s(-1) , and for the methyl resonances were 0.39 and 0.30 s(-1) , with the soleus exhibiting faster transfer rates for both resonances, allowing speculation about possible influences of either muscle fibre orientation or muscle composition on the magnetization transfer process. These water magnetization transfer rates observed without water suppression are in good agreement with earlier reports that used either postexcitation water suppression in rats, or short CHESS sequences in human brain and skeletal muscle.

Non-photorealistic rendering of virtual implant models for computer-assisted fluoroscopy-based surgical procedures

Surgical navigation systems visualize the positions and orientations of surgical instruments and implants as graphical overlays onto a medical image of the operated anatomy on a computer monitor. The orthopaedic surgical navigation systems could be categorized according to the image modalities that are used for the visualization of surgical action. In the so-called CT-based systems or 'surgeon-defined anatomy' based systems, where a 3D volume or surface representation of the operated anatomy could be constructed from the preoperatively acquired tomographic data or through intraoperatively digitized anatomy landmarks, a photorealistic rendering of the surgical action has been identified to greatly improve usability of these navigation systems. However, this may not hold true when the virtual representation of surgical instruments and implants is superimposed onto 2D projection images in a fluoroscopy-based navigation system due to the so-called image occlusion problem. Image occlusion occurs when the field of view of the fluoroscopic image is occupied by the virtual representation of surgical implants or instruments. In these situations, the surgeon may miss part of the image details, even if transparency and/or wire-frame rendering is used. In this paper, we propose to use non-photorealistic rendering to overcome this difficulty. Laboratory testing results on foamed plastic bones during various computer-assisted fluoroscopybased surgical procedures including total hip arthroplasty and long bone fracture reduction and osteosynthesis are shown.

Implementation of a phenomenological evaporation model into a porous network simulation for water management in low temperature fuel cells

A phenomenological transition film evaporation model was introduced to a pore network model with the consideration of pore radius, contact angle, non-isothermal interface temperature, microscale fluid flows and heat and mass transfers. This was achieved by modeling the transition film region of the menisci in each pore throughout the porous transport layer of a half-cell polymer electrolyte membrane (PEM) fuel cell. The model presented in this research is compared with the standard diffusive fuel cell modeling approach to evaporation and shown to surpass the conventional modeling approach in terms of predicting the evaporation rates in porous media. The current diffusive evaporation models used in many fuel cell transport models assumes a constant evaporation rate across the entire liquid-air interface. The transition film model was implemented into the pore network model to address this issue and create a pore size dependency on the evaporation rates. This is accomplished by evaluating the transition film evaporation rates determined by the kinetic model for every pore containing liquid water in the porous transport layer (PTL). The comparison of a transition film and diffusive evaporation model shows an increase in predicted evaporation rates for smaller pore sizes with the transition film model. This is an important parameter when considering the micro-scaled pore sizes seen in the PTL and becomes even more substantial when considering transport in fuel cells containing an MPL, or a large variance in pore size. Experimentation was performed to validate the transition film model by monitoring evaporation rates from a non-zero contact angle water droplet on a heated substrate. The substrate was a glass plate with a hydrophobic coating to reduce wettability. The tests were performed at a constant substrate temperature and relative humidity. The transition film model was able to accurately predict the drop volume as time elapsed. By implementing the transition film model to a pore network model the evaporation rates present in the PTL can be more accurately modeled. This improves the ability of a pore network model to predict the distribution of liquid water and ultimately the level of flooding exhibited in a PTL for various operating conditions.

Using water balance models to approximate the effects of climate change on spring catchment discharge : Mt. Hanang, Tanzania

This project addresses the potential impacts of changing climate on dry-season water storage and discharge from a small, mountain catchment in Tanzania. Villagers and water managers around the catchment have experienced worsening water scarcity and attribute it to increasing population and demand, but very little has been done to understand the physical characteristics and hydrological behavior of the spring catchment. The physical nature of the aquifer was characterized and water balance models were calibrated to discharge observations so as to be able to explore relative changes in aquifer storage resulting from climate changes. To characterize the shallow aquifer supplying water to the Jandu spring, water quality and geochemistry data were analyzed, discharge recession analysis was performed, and two water balance models were developed and tested. Jandu geochemistry suggests a shallow, meteorically-recharged aquifer system with short circulation times. Baseflow recession analysis showed that the catchment behavior could be represented by a linear storage model with an average recession constant of 0.151/month from 2004-2010. Two modified Thornthwaite-Mather Water Balance (TMWB) models were calibrated using historic rainfall and discharge data and shown to reproduce dry-season flows with Nash-Sutcliffe efficiencies between 0.86 and 0.91. The modified TMWB models were then used to examine the impacts of nineteen, perturbed climate scenarios to test the potential impacts of regional climate change on catchment storage during the dry season. Forcing the models with realistic scenarios for average monthly temperature, annual precipitation, and seasonal rainfall distribution demonstrated that even small climate changes might adversely impact aquifer storage conditions at the onset of the dry season. The scale of the change was dependent on the direction (increasing vs. decreasing) and magnitude of climate change (temperature and precipitation). This study demonstrates that small, mountain aquifer characterization is possible using simple water quality parameters, recession analysis can be integrated into modeling aquifer storage parameters, and water balance models can accurately reproduce dry-season discharges and might be useful tools to assess climate change impacts. However, uncertainty in current climate projections and lack of data for testing the predictive capabilities of the model beyond the present data set, make the forecasts of changes in discharge also uncertain. The hydrologic tools used herein offer promise for future research in understanding small, shallow, mountainous aquifers and could potentially be developed and used by water resource professionals to assess climatic influences on local hydrologic systems.

Non-invasive measurement of steroids in fish-holding water: important considerations when applying the procedure to behaviour studies

Fish behaviourists are increasingly turning to non-invasive measurement of steroid hormones in holding water, as opposed to blood plasma. When some of us met at a workshop in Faro, Portugal, in September, 2007, we realised that there were still many issues concerning the application of this procedure that needed resolution, including: Why do we measure release rates rather than just concentrations of steroids in the water? How does one interpret steroid release rates when dealing with fish of different sizes? What are the merits of measuring conjugated as well as free steroids in water? In the ‘static’ sampling procedure, where fish are placed in a separate container for a short period of time, does this affect steroid release—and, if so, how can it be minimised? After exposing a fish to a behavioural stimulus, when is the optimal time to sample? What is the minimum amount of validation when applying the procedure to a new species? The purpose of this review is to attempt to answer these questions and, in doing so, to emphasize that application of the non-invasive procedure requires more planning and validation than conventional plasma sampling. However, we consider that the rewards justify the extra effort.

Water transport in complex, non-wetting porous layers with applications to water management in low temperature fuel cells

An experimental setup was designed to visualize water percolation inside the porous transport layer, PTL, of proton exchange membrane, PEM, fuel cells and identify the relevant characterization parameters. In parallel with the observation of the water movement, the injection pressure (pressure required to transport water through the PTL) was measured. A new scaling for the drainage in porous media has been proposed based on the ratio between the input and the dissipated energies during percolation. A proportional dependency was obtained between the energy ratio and a non-dimensional time and this relationship is not dependent on the flow regime; stable displacement or capillary fingering. Experimental results show that for different PTL samples (from different manufacturers) the proportionality is different. The identification of this proportionality allows a unique characterization of PTLs with respect to water transport. This scaling has relevance in porous media flows ranging far beyond fuel cells. In parallel with the experimental analysis, a two-dimensional numerical model was developed in order to simulate the phenomena observed in the experiments. The stochastic nature of the pore size distribution, the role of the PTL wettability and morphology properties on the water transport were analyzed. The effect of a second porous layer placed between the porous transport layer and the catalyst layer called microporous layer, MPL, was also studied. It was found that the presence of the MPL significantly reduced the water content on the PTL by enhancing fingering formation. Moreover, the presence of small defects (cracks) within the MPL was shown to enhance water management. Finally, a corroboration of the numerical simulation was carried out. A threedimensional version of the network model was developed mimicking the experimental conditions. The morphology and wettability of the PTL are tuned to the experiment data by using the new energy scaling of drainage in porous media. Once the fit between numerical and experimental data is obtained, the computational PTL structure can be used in different types of simulations where the conditions are representative of the fuel cell operating conditions.

Landscapes of Education and the New Role of Social Work International Models of How to Combine Formal, Non-formal and Informal Education

Landscapes of education are a new topic within the debate about adequate and just education and human development for everybody. In particular, children and youths from social classes affected by poverty, a lack of prospects or minimal schooling are a focal group that should be offered new approaches and opportunities of cognitive and social development by way of these landscapes of education. It has become apparent that the traditional school alone does not suffice to meet this need. There is no doubt that competency-based orientation and employability are core areas with the help of which the generation now growing up will manage the start of its professional career. In addition and by no means less important, the development involves individual, social, cultural and societal perspectives that can be combined under the term of human development. In this context, the Capability Approach elaborated by Amartya Sen and Martha Nussbaum has developed a more extensive concept of human development and related it to empirical instruments. Using the analytic concept of individual capabilities and societal opportunities they shaped a socio-political formula that should be adapted in particular to modern social work. Moreover, the Capability Approach offers a critical foil with regard to further development and revision of institutionalised approaches in education and human development.