Use of VEGFR-2 targeted microbubbles (BR55, Bracco imaging) for the early ultrasound evaluation of response to antiangiogenic treatment in a xenograft model of hepatocarcinoma

Aim: To evaluate the early response to treatment to an antiangiogenetic drug (sorafenib) in a heterotopic murine model of hepatocellular carcinoma (HCC) using ultrasonographic molecular imaging. Material and Methods: the xenographt model was established injecting a suspension of HuH7 cells subcutaneously in 19 nude mice. When tumors reached a mean diameter of 5-10 mm, they were divided in two groups (treatment and vehicle). The treatment group received sorafenib (62 mg/kg) by daily oral gavage for 14 days. Molecular imaging was performed using contrast enhanced ultrasound (CEUS), by injecting into the mouse venous circulation a suspension of VEGFR-2 targeted microbubbles (BR55, kind gift of Bracco Swiss, Geneve, Switzerland). Video clips were acquired for 6 minutes, then microbubbles (MBs) were destroyed by a high mechanical index (MI) impulse, and another minute was recorded to evaluate residual circulating MBs. The US protocol was repeated at day 0,+2,+4,+7, and +14 from the beginning of treatment administration. Video clips were analyzed using a dedicated software (Sonotumor, Bracco Swiss) to quantify the signal of the contrast agent. Time/intensity curves were obtained and the difference of the mean MBs signal before and after high MI impulse (Differential Targeted Enhancement-dTE) was calculated. dTE represents a numeric value in arbitrary units proportional to the amount of bound MBs. At day +14 mice were euthanized and the tumors analyzed for VEGFR-2, pERK, and CD31 tissue levels using western blot analysis. Results: dTE values decreased from day 0 to day +14 both in treatment and vehicle groups, and they were statistically higher in vehicle group than in treatment group at day +2, at day +7, and at day +14. With respect to the degree of tumor volume increase, measured as growth percentage delta (GPD), treatment group was divided in two sub-groups, non-responders (GPD>350%), and responders (GPD<200%). In the same way vehicle group was divided in slow growth group (GPD<400%), and fast growth group (GPD>900%). dTE values at day 0 (immediately before treatment start) were higher in non-responders than in responders group, with statistical difference at day 2. While dTE values were higher in the fast growth group than in the slow growth group only at day 0. A significant positive correlation was found between VEGFR-2 tissue levels and dTE values, confirming that level of BR55 tissue enhancement reflects the amount of tissue VEGF receptor. Conclusions: the present findings show that, at least in murine experimental models, CEUS with BR55 is feasable and appears to be a useful tool in the prediction of tumor growth and response to sorafenib treatment in xenograft HCC.

Simulazione dinamica di un veicolo dotato di powertrain ibrido endotermico-elettrico

Nel panorama motoristico ed automobilistico moderno lo sviluppo di motori a combustione interna e veicoli è fortemente influenzato da diverse esigenze che spesso sono in contrasto le une con le altre. Infatti gli obiettivi di economicità e riduzione dei costi riguardanti la produzione e la commercializzazione dei prodotti sono in contrasto con gli sforzi che devono essere operati dalle case produttrici per soddisfare le sempre più stringenti normative riguardanti le emissioni inquinanti ed i consumi di carburante dei veicoli. Fra le numerose soluzioni presenti i veicoli ibridi rappresentano una alternativa che allo stato attuale è già presente sul mercato in varie forme, a seconda della tipologie di energie accoppiate. In letteratura è possibile trovare numerosi studi che trattano l’ottimizzazione dei componenti o delle strategie di controllo di queste tipologie di veicoli: in moltissimi casi l’obiettivo è quello di minimizzare consumi ed emissioni inquinanti. Normalmente non viene posta particolare attenzione agli effetti che l’aggiunta delle macchine elettriche e dei componenti necessari per il funzionamento delle stesse hanno sulla dinamica del veicolo. Il presente lavoro di tesi è incentrato su questi aspetti: si è considerata la tipologia di veicoli ibridi termici-elettrici di tipo parallelo andando ad analizzare come cambiasse il comportamento dinamico del veicolo in funzione del tipo di installazione considerato per la parte elettrica del powertrain. In primo luogo è stato quindi necessario costruire ed implementare un modello dinamico di veicolo che permettesse di applicare coppie alle quattro ruote in maniera indipendente per considerare diverse tipologie di powertrain. In seguito si sono analizzate le differenze di comportamento dinamico fra il veicolo considerato e l’equivalente versione ibrida e i possibili utilizzi delle macchine elettriche per correggere eventuali deterioramenti o cambiamenti indesiderati nelle prestazioni del veicolo.

Improvement of The Driver Simulator Control and Comparison Between Driver-Road-Vehicle Interaction in Real and Simulated Environment

The present doctoral thesis discusses the ways to improve the performance of driving simulator, provide objective measures for the road safety evaluation methodology based on driver’s behavior and response and investigates the drivers' adaptation to the driving assistant systems. The activities are divided into two macro areas; the driving simulation studies and on-road experiments. During the driving simulation experimentation, the classical motion cueing algorithm with logarithmic scale was implemented in the 2DOF motion cueing simulator and the motion cues were found desirable by the participants. In addition, it found out that motion stimuli could change the behaviour of the drivers in terms of depth/distance perception. During the on-road experimentations, The driver gaze behaviour was investigated to find the objective measures on the visibility of the road signs and reaction time of the drivers. The sensor infusion and the vehicle monitoring instruments were found useful for an objective assessment of the pavement condition and the drivers’ performance. In the last chapter of the thesis, the safety assessment during the use of level 1 automated driving “ACC” is discussed with the simulator and on-road experiment. The drivers’ visual behaviour was investigated in both studies with innovative classification method to find the epochs of the distraction of the drivers. The behavioural adaptation to ACC showed that drivers may divert their attention away from the driving task to engage in secondary, non-driving-related tasks.

Active Control of the Acoustic Field in a Vehicle Cabin

In this thesis, a thorough investigation on acoustic noise control systems for realistic automotive scenarios is presented. The thesis is organized in two parts dealing with the main topics treated: Active Noise Control (ANC) systems and Virtual Microphone Technique (VMT), respectively. The technology of ANC allows to increase the driver's/passenger's comfort and safety exploiting the principle of mitigating the disturbing acoustic noise by the superposition of a secondary sound wave of equal amplitude but opposite phase. Performance analyses of both FeedForwrd (FF) and FeedBack (FB) ANC systems, in experimental scenarios, are presented. Since, environmental vibration noises within a car cabin are time-varying, most of the ANC solutions are adaptive. However, in this work, an effective fixed FB ANC system is proposed. Various ANC schemes are considered and compared with each other. In order to find the best possible ANC configuration which optimizes the performance in terms of disturbing noise attenuation, a thorough research of \gls{KPI}, system parameters and experimental setups design, is carried out. In the second part of this thesis, VMT, based on the estimation of specific acoustic channels, is investigated with the aim of generating a quiet acoustic zone around a confined area, e.g., the driver's ears. Performance analysis and comparison of various estimation approaches is presented. Several measurement campaigns were performed in order to acquire a sufficient duration and number of microphone signals in a significant variety of driving scenarios and employed cars. To do this, different experimental setups were designed and their performance compared. Design guidelines are given to obtain good trade-off between accuracy performance and equipment costs. Finally, a preliminary analysis with an innovative approach based on Neural Networks (NNs) to improve the current state of the art in microphone virtualization is proposed.

First steps in underwater photogrammetry with the support of an unmanned underwater vehicle

The evolution of modern and increasingly sensitive image sensors, the increasingly compact design of the cameras, and the recent emergence of low-cost cameras allowed the Underwater Photogrammetry to become an infallible and irreplaceable technique used to estimate the structure of the seabed with high accuracy. Within this context, the main topic of this work is the Underwater Photogrammetry from a geomatic point of view and all the issues associated with its implementation, in particular with the support of Unmanned Underwater Vehicles. Questions such as: how does the technique work, what is needed to deal with a proper survey, what tools are available to apply this technique, and how to resolve uncertainties in measurement will be the subject of this thesis. The study conducted can be divided into two major parts: one devoted to several ad-hoc surveys and tests, thus a practical part, another supported by the bibliographical research. However the main contributions are related to the experimental section, in which two practical case studies are carried out in order to improve the quality of the underwater survey of some calibration platforms. The results obtained from these two experiments showed that, the refractive effects due to water and underwater housing can be compensated by the distortion coefficients in the camera model, but if the aim is to achieve high accuracy then a model that takes into account the configuration of the underwater housing, based on ray tracing, must also be coupled. The major contributions that this work brought are: an overview of the practical issues when performing surveys exploiting an UUV prototype, a method to reach a reliable accuracy in the 3D reconstructions without the use of an underwater local geodetic network, a guide for who addresses underwater photogrammetry topics for the first time, and the use of open-source environments.