Valutazione precoce della risposta a Sorafenib nel Carcinoma Epatocellulare mediante quantificazione dell'Ecografia con contrasto con software Sonotumor

Scopo dello studio: Stabilire se cambiamenti della perfusione di una lesione target di epatocarcinoma (HCC), valutati quantitativamente mediante ecografia con contrasto (CE-US) alla settimana 2 e 4 di terapia con sorafenib, possono predire la progressione di malattia alla settimana 8, valutata con la tomografia computerizzata o la risonanza magnetica con mezzo di contrasto (TC-RM) usando i criteri RECIST/RECIST modificati (response evaluation criteria in solid tumors). Pazienti e metodi: Il comitato etico ha approvato lo studio ed i pazienti hanno fornito un consenso informato scritto prima dell’arruolamento. Lo studio è stato effettuato su un campione di soggetti con epatocarcinoma avanzato o non suscettibile di trattamento curativo, in monoterapia con sorafenib. La valutazione della risposta tumorale è stata effettuata con TC o RM a 2 mesi usando i criteri RECIST/RECIST modificati. La CE-US è stata effettuata entro 1 settimana prima dell’inizio del trattamento con sorafenib e durante la terapia alla settimana 2, 4, 8, 16 e 32. I parametri quantitativi funzionali sono stati ottenuti impiegando un software dedicato. I cambiamenti dei valori dei parametri suddetti tra il tempo zero ed i punti temporali successivi sono stati confrontati con la risposta tumorale basata sui criteri RECIST/RECIST modificati. Risultati: La riduzione dei valori dei parametri relativi alla perfusione tumorale, in particolare di WiAUC e PE (parametri correlati con il volume ematico), al T2/T4 (settimana 2, 4), predice la risposta tumorale a 2 mesi, valutata secondo i criteri RECIST e RECIST modificati, risultata indicativa di malattia stabile (responders). Conclusione: L’ecografia con contrasto può essere impiegata per quantificare i cambiamenti della vascolarizzazione tumorale già alla settimana 2, 4 dopo la somministrazione di sorafenib nei pazienti con HCC. Questi precoci cambiamenti della perfusione tumorale possono essere predittivi della risposta tumorale a 2 mesi e possono avere un potenziale nella valutazione precoce dell'efficacia della terapia antiangiogenica nell’epatocarcinoma.

CT perfusion image processing: analysis of liver tumors

Perfusion CT imaging of the liver has potential to improve evaluation of tumour angiogenesis. Quantitative parameters can be obtained applying mathematical models to Time Attenuation Curve (TAC). However, there are still some difficulties for an accurate quantification of perfusion parameters due, for example, to algorithms employed, to mathematical model, to patient’s weight and cardiac output and to the acquisition system. In this thesis, new parameters and alternative methodologies about liver perfusion CT are presented in order to investigate the cause of variability of this technique. Firstly analysis were made to assess the variability related to the mathematical model used to compute arterial Blood Flow (BFa) values. Results were obtained implementing algorithms based on “ maximum slope method” and “Dual input one compartment model” . Statistical analysis on simulated data demonstrated that the two methods are not interchangeable. Anyway slope method is always applicable in clinical context. Then variability related to TAC processing in the application of slope method is analyzed. Results compared with manual selection allow to identify the best automatic algorithm to compute BFa. The consistency of a Standardized Perfusion Index (SPV) was evaluated and a simplified calibration procedure was proposed. At the end the quantitative value of perfusion map was analyzed. ROI approach and map approach provide related values of BFa and this means that pixel by pixel algorithm give reliable quantitative results. Also in pixel by pixel approach slope method give better results. In conclusion the development of new automatic algorithms for a consistent computation of BFa and the analysis and definition of simplified technique to compute SPV parameter, represent an improvement in the field of liver perfusion CT analysis.

Valorization of pomaces from the mechanical extraction of virgin olive oils in dairy animal feeding

This research work is aimed at the valorization of two types of pomace deriving from the extra virgin olive oil mechanical extraction process, such as olive pomace and a new by-product named “paté”, in the livestock sector as important sources of antioxidants and unsaturated fatty acids. In the first research the suitability of dried stoned olive pomace as a dietary supplement for dairy buffaloes was evaluated. The effectiveness of this utilization in modifying fatty acid composition and improving the oxidative stability of buffalo milk and mozzarella cheese have been proven by means of the analysis of qualitative and quantitative parameters. In the second research the use of paté as a new by-product in dietary feed supplementation for dairy ewes, already fed with a source of unsaturated fatty acids such as extruded linseed, was studied in order to assess the effect of this combination on the dairy products obtained. The characterization of paté as a new by-product was also carried out, studying the optimal conditions of its stabilization and preservation at the same time. The main results, common to both researches, have been the detection and the characterization of hydrophilic phenols in the milk. The analytical detection of hydroxytyrosol and tyrosol in the ewes’ milk fed with the paté and hydroxytyrosol in buffalo fed with pomace showed for the first time the presence in the milk of hydroxytyrosol, which is one of the most important bioactive compounds of the oil industry products; the transfer of these antioxidants and the proven improvement of the quality of milk fat could positively interact in the prevention of some human cardiovascular diseases and some tumours, increasing in this manner the quality of dairy products, also improving their shelf-life. These results also provide important information on the bioavailability of these phenolic compounds.

Sperm analysis of patients after successful treatment of childhood acute lymphoblastic leukemia with chemotherapy

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with radiotherapy are at risk for impaired fertility. Whether chemotherapy alone is also long-term gonadotoxic is unclear. We assessed gonadal function in 11 male ALL-survivors treated with the same chemotherapy regimen and compared sperm analysis to healthy men. While sex hormone levels were normal in all subjects, 5/11 survivors showed pathological sperm concentration and 4/11 a decreased total sperm count compared to WHO criteria. Compared to healthy controls, all quantitative parameters in semen analysis of survivors were decreased. This suggests that treatment with chemotherapeutic agents alone, even in moderate doses, might have a gonadotoxic effect.

Impact of a 4th generation iterative reconstruction technique on image quality in low-dose computed tomography of the chest in immunocompromised patients

PURPOSE To determine the image quality of an iterative reconstruction (IR) technique in low-dose MDCT (LDCT) of the chest of immunocompromised patients in an intraindividual comparison to filtered back projection (FBP) and to evaluate the dose reduction capability. MATERIALS AND METHODS 30 chest LDCT scans were performed in immunocompromised patients (Brilliance iCT; 20-40 mAs; mean CTDIvol: 1.7 mGy). The raw data were reconstructed using FBP and the IR technique (iDose4™, Philips, Best, The Netherlands) set to seven iteration levels. 30 routine-dose MDCT (RDCT) reconstructed with FBP served as controls (mean exposure: 116 mAs; mean CDTIvol: 7.6 mGy). Three blinded radiologists scored subjective image quality and lesion conspicuity. Quantitative parameters including CT attenuation and objective image noise (OIN) were determined. RESULTS In LDCT high iDose4™ levels lead to a significant decrease in OIN (FBP vs. iDose7: subscapular muscle 139.4 vs. 40.6 HU). The high iDose4™ levels provided significant improvements in image quality and artifact and noise reduction compared to LDCT FBP images. The conspicuity of subtle lesions was limited in LDCT FBP images. It significantly improved with high iDose4™ levels (> iDose4). LDCT with iDose4™ level 6 was determined to be of equivalent image quality as RDCT with FBP. CONCLUSION iDose4™ substantially improves image quality and lesion conspicuity and reduces noise in low-dose chest CT. Compared to RDCT, high iDose4™ levels provide equivalent image quality in LDCT, hence suggesting a potential dose reduction of almost 80%.

Phytoplankton in the surface desalted lens of the Kara Sea

Phytoplankton of a surface strongly desalinated water lens was investigated on the basis of materials collected during Cruise 57 of R/V Akademik Mstislav Keldysh in September 2007. The lens with salinity <18 psu had area of ca. 19000 sq. km and was located in the northwestern part of the Kara Sea near the eastern coast of Novaya Zemlya. It was a specific biotope that had been isolated from surrounding waters for more than three months. In the investigated area 66 algae species were identified. The maximal species diversity was found in the upper layers of the desalinated lens, where species number was 1.5 to 3 times higher than in other parts of the water column. Phytoplankton abundance in the upper layers of the lens was 1.5 to 4.5 times higher than in its lower part and generally higher than below the picnocline. Diatoms were the most abundant group in the upper layers of the lens, while flagellates dominated in the subpicnocline part of the water column. Maximal values of phytoplankton biomass were observed everywhere in the upper layers of the lens, where they were 1.2 to 3.7 times higher than in the lower part of the lens and 1.3 to 7.2 times higher than in the layer below the picnocline. Dinoflagellates generally gave the most contribution to total phytoplankton biomass. Phytoplankton of the desalinated surface lens in the northwestern part of the Kara Sea by its composition and quantitative parameters had the nearest resemblance to a phytocenosis that we observed two weeks later at a shallow desalinated shelf closely adjacent to the Ob estuary.

Modelización del cálculo de Indicadores Ambientales, a partir de sensores ópticos de alta resolución temporal a bordo de satélite

La presente tesis doctoral tiene por objeto el estudio y análisis de técnicas y modelos de obtención de parámetros biofísicos e indicadores ambientales, de manera automatizada a partir de imágenes procedentes de satélite de alta resolución temporal. En primer lugar se revisan los diferentes programas espaciales de observación del territorio, con especial atención a los que proporcionan dicha resolución. También se han revisado las metodologías y procesos que permiten la obtención de diferentes parámetros cuantitativos y documentos cualitativos, relacionados con diversos aspectos de las cubiertas terrestres, atendiendo a su adaptabilidad a las particularidades de los datos. En segundo lugar se propone un modelo de obtención de parámetros ambientales, que integra información proveniente de sensores espaciales y de otras fuentes auxiliares utilizando, en cierta medida, las metodologías presentadas en apartados anteriores y optimizando algunas de las referidas o proponiendo otras nuevas, de manera que se permita dicha obtención de manera eficiente, a partir de los datos disponibles y de forma sistemática. Tras esta revisión de metodologías y propuesta del modelo, se ha procedido a la realización de experimentos, con la finalidad de comprobar su comportamiento en diferentes casos prácticos, depurar los flujos de datos y procesos, así como establecer las situaciones que pueden afectar a los resultados. De todo ello se deducirá la evaluación del referido modelo. Los sensores considerados en este trabajo han sido MODIS, de alta resolución temporal y Thematic Mapper (TM), de media resolución espacial, por tratarse de instrumentos de referencia en la realización de estudios ambientales. También por la duración de sus correspondientes misiones de registro de datos, lo que permite realizar estudios de evolución temporal de ciertos parámetros biofísicos, durante amplios periodos de tiempo. Así mismo. es de destacar que la continuidad de los correspondientes programas parece estar asegurada. Entre los experimentos realizados, se ha ensayado una metodología para la integración de datos procedentes de ambos sensores. También se ha analizado un método de interpolación temporal que permite obtener imágenes sintéticas con la resolución espacial de TM (30 m) y la temporal de MODIS (1 día), ampliando el rango de aplicación de este último sensor. Asimismo, se han analizado algunos de los factores que afectan a los datos registrados, tal como la geometría de la toma de los mismos y los episodios de precipitación, los cuales alteran los resultados obtenidos. Por otro lado, se ha comprobado la validez del modelo propuesto en el estudio de fenómenos ambientales dinámicos, en concreto la contaminación orgánica de aguas embalsadas. Finalmente, se ha demostrado un buen comportamiento del modelo en todos los casos ensayados, así como su flexibilidad, lo que le permite adaptarse a nuevos orígenes de datos, o nuevas metodologías de cálculo. Abstract This thesis aims to the study and analysis of techniques and models, in order to obtain biophysical parameters and environmental indicators in an automated way, using high temporal resolution satellite data. Firstly we have reviewed the main Earth Observation Programs, paying attention to those that provide high temporal resolution. Also have reviewed the methodologies and process flow diagrams in order to obtain quantitative parameters and qualitative documents, relating to various aspects of land cover, according to their adaptability to the peculiarities of the data. In the next stage, a model which allows obtaining environmental parameters, has been proposed. This structure integrates information from space sensors and ancillary data sources, using the methodologies presented in previous sections that permits the parameters calculation in an efficient and automated way. After this review of methodologies and the proposal of the model, we proceeded to carry out experiments, in order to check the behavior of the structure in real situations. From this, we derive the accuracy of the model. The sensors used in this work have been MODIS, which is a high temporal resolution sensor, and Thematic Mapper (TM), which is a medium spatial resolution instrument. This choice was motivated because they are reference sensors in environmental studies, as well as for the duration of their corresponding missions of data logging, and whose continuity seems assured. Among the experiments, we tested a methodology that allows the integration of data from cited sensors, we discussed a proposal for a temporal interpolation method for obtaining synthetic images with spatial resolution of TM (30 m) and temporal of MODIS (1 day), extending the application range of this one. Furthermore, we have analyzed some of the factors that affect the recorded data, such as the relative position of the satellite with the ground point, and the rainfall events, which alter the obtained results. On the other hand, we have proven the validity of the proposed model in the study of the organic contamination in inland water bodies. Finally, we have demonstrated a good performance of the proposed model in all cases tested, as well as its flexibility and adaptability.

DCE@urLAB: a dynamic contrast-enhanced MRI pharmacokinetic analysis tool for preclinical data

Background DCE@urLAB is a software application for analysis of dynamic contrast-enhanced magnetic resonance imaging data (DCE-MRI). The tool incorporates a friendly graphical user interface (GUI) to interactively select and analyze a region of interest (ROI) within the image set, taking into account the tissue concentration of the contrast agent (CA) and its effect on pixel intensity. Results Pixel-wise model-based quantitative parameters are estimated by fitting DCE-MRI data to several pharmacokinetic models using the Levenberg-Marquardt algorithm (LMA). DCE@urLAB also includes the semi-quantitative parametric and heuristic analysis approaches commonly used in practice. This software application has been programmed in the Interactive Data Language (IDL) and tested both with publicly available simulated data and preclinical studies from tumor-bearing mouse brains. Conclusions A user-friendly solution for applying pharmacokinetic and non-quantitative analysis DCE-MRI in preclinical studies has been implemented and tested. The proposed tool has been specially designed for easy selection of multi-pixel ROIs. A public release of DCE@urLAB, together with the open source code and sample datasets, is available at http://www.die.upm.es/im/archives/DCEurLAB/ webcite.

Laser machining steel for moulds: a case study

Laser beam machining is a non-traditional subtractive manufacturing process, a form of machining, in which a laser is directed towards the work piece for machining. This process uses thermal energy to remove material from metallic or non-metallic surfaces. The laser is focused onto the surface to be worked and the thermal energy of the laser is transferred to the surface, heating and melting or vaporizing the material. Laser beam machining is best suited for brittle materials with low conductivity, but can be used on most materials. The role of the technical equipment in laser milling is to perform a controllable action of the laser radiation on the material to be treated. The laser is the main unit of the equipment and it is characteristics determine to great extent the qualitative and quantitative parameters of the technological treatments. In this work, I had to study the laser milling process parameter selection for process planning operations from start to finish. It was important to have an understanding about laser milling and laser processing parameters for different materials. As a result from the laser milling, the surface finish will have different surface properties such as, surface hardness, surface roughness, friction and tribology etc.. During the process, I gained knowledge about the historical and conceptual framework of laser milling, the different parameters of a laser milling and how the laser milling parameters influence the surface properties of the machined parts.

Estandarización del método para alcoholemias por cromatografía de gases

La ingesta de etanol se ha relacionado a consecuencias lamentables a nivel social, familiar y jurídico; siendo importante el desarrollo de métodos de detección de etanol en sangre, prueba más confiable a nivel cuantitativo. En el presente trabajo se realizó la primera fase de la optimización de un método para el análisis de alcoholemia por cromatografía de gases con inyección directa y detección de ionización de llama (GC-FID). Se realizó la optimización de algunos parámetros cualitativos y cuantitativos, incluyendo tiempos de retención estables, selectividad del método demostrado por la ausencia de sustancias interferentes en el análisis; linealidad a bajos niveles con un coeficiente de determinación de R2 = 0.996. La aplicabilidad del método en un pool de 33 muestras con distintas concentraciones de etanol tomadas cómo puntos de referencia de baja, media y alta concentración. La cuantificación se realizó por estandarización interna mediante el uso de un estándar interno (n-butanol) y la estandarización externa mediante la curva de calibración a 4 niveles.

Whole-cell-analysis of live cardiomyocytes using wide-field interferometric phase microscopy.

We apply wide-field interferometric microscopy techniques to acquire quantitative phase profiles of ventricular cardiomyocytes in vitro during their rapid contraction with high temporal and spatial resolution. The whole-cell phase profiles are analyzed to yield valuable quantitative parameters characterizing the cell dynamics, without the need to decouple thickness from refractive index differences. Our experimental results verify that these new parameters can be used with wide field interferometric microscopy to discriminate the modulation of cardiomyocyte contraction dynamics due to temperature variation. To demonstrate the necessity of the proposed numerical analysis for cardiomyocytes, we present confocal dual-fluorescence-channel microscopy results which show that the rapid motion of the cell organelles during contraction preclude assuming a homogenous refractive index over the entire cell contents, or using multiple-exposure or scanning microscopy.

A single-sided NMR approach to study structural differences of bovine articular tissue

This thesis work has been developed in collaboration between the Department of Physics and Astronomy of the University of Bologna and the IRCCS Rizzoli Orthopedic Institute during an internship period. The study aims to investigate the sensitivity of single-sided NMR in detecting structural differences of the articular cartilage tissue and their correlation with mechanical behavior. Suitable cartilage indicators for osteoarthritis (OA) severity (e.g., water and proteoglycans content, collagen structure) were explored through four NMR parameters: T2, T1, D, and Slp. Structural variations of the cartilage among its three layers (i.e., superficial, middle, and deep) were investigated performing several NMR pulses sequences on bovine knee joint samples using the NMR-MOUSE device. Previously, cartilage degradation studies were carried out, performing tests in three different experimental setups. The monitoring of the parameters and the best experimental setup were determined. An NMR automatized procedure based on the acquisition of these quantitative parameters was implemented, tested, and used for the investigation of the layers of twenty bovine cartilage samples. Statistical and pattern recognition analyses on these parameters have been performed. The results obtained from the analyses are very promising: the discrimination of the three cartilage layers shows very good results in terms of significance, paving the way for extensive use of NMR single-sided devices for biomedical applications. These results will be also integrated with analyses of tissue mechanical properties for a complete evaluation of cartilage changes throughout OA disease. The use of low-priced and mobile devices towards clinical applications could concern the screening of diseases related to cartilage tissue. This could have a positive impact both economically (including for underdeveloped countries) and socially, providing screening possibilities to a large part of the population.

Genetic parameters and mapping quantitative trait loci associated with tibia traits in broilers.

Abstract: Selection among broilers for performance traits is resulting in locomotion problems and bone disorders, once skeletal structure is not strong enough to support body weight in broilers with high growth rates. In this study, genetic parameters were estimated for body weight at 42 days of age (BW42), and tibia traits (length, width, and weight) in a population of broiler chickens. Quantitative trait loci (QTL) were identified for tibia traits to expand our knowledge of the genetic architecture of the broiler population. Genetic correlations ranged from 0.56 +/- 0.18 (between tibia length and BW42) to 0.89 +/- 0.06 (between tibia width and weight), suggesting that these traits are either controlled by pleiotropic genes or by genes that are in linkage disequilibrium. For QTL mapping, the genome was scanned with 127 microsatellites, representing a coverage of 2630 cM. Eight QTL were mapped on Gallus gallus chromosomes (GGA): GGA1, GGA4, GGA6, GGA13, and GGA24. The QTL regions for tibia length and weight were mapped on GGA1, between LEI0079 and MCW145 markers. The gene DACH1 is located in this region; this gene acts to form the apical ectodermal ridge, responsible for limb development. Body weight at 42 days of age was included in the model as a covariate for selection effect of bone traits. Two QTL were found for tibia weight on GGA2 and GGA4, and one for tibia width on GGA3. Information originating from these QTL will assist in the search for candidate genes for these bone traits in future studies.

Femoroacetabular impingement: normal values of the quantitative morphometric parameters in asymptomatic hips.

OBJECTIVE: To determine the means and the reference intervals of the quantitative morphometric parameters of femoroacetabular impingement (FAI) in normal hips with high-resolution computed tomography (CT). METHODS: We prospectively included 94 adult individuals who underwent CT for thoracic, abdominal or urologic pathologies. Patients with a clinical history of hip pathology and/or with osteoarthritis on CT were excluded. We calculated means and 95 % reference intervals for imaging signs of cam-type (alpha angle at 90° and 45° and femoral head-neck offset) and pincer-type impingement (acetabular version angle, lateral centre-edge angle and acetabular index). RESULTS: The 95 % reference interval limits were all far beyond the abnormal thresholds found in the literature for cam-type and to a lesser extent for pincer-type FAI. The upper limits of the reference intervals for the alpha angles (at 90°/45°) were 68°/83° (men) and 69°/84° (women), compared to thresholds from the literature (50°, 55° or 60°). Reference intervals were similar between genders for cam-type parameters, and slightly differed for pincer-type. CONCLUSION: The 95 % reference intervals of morphometric measurements of FAI in asymptomatic hips were beyond the abnormal thresholds, which was especially true for cam-type FAI. Our results suggest the need for redefining the current morphometric parameters used in the diagnosis of FAI. KEY POINTS: ? 95 % reference intervals limits of FAI morphotype were beyond currently defined thresholds. ? Reference intervals of pincer-type morphotype measurements were close to current definitions. ? Reference intervals of cam-type morphotype measurements were far beyond the current definitions. ? Current morphometric definitions of cam-type morphotype should be used with care.

Extracting quantitative structural parameters for disordered polymers from neutron scattering data

The organization of non-crystalline polymeric materials at a local level, namely on a spatial scale between a few and 100 a, is still unclear in many respects. The determination of the local structure in terms of the configuration and conformation of the polymer chain and of the packing characteristics of the chain in the bulk material represents a challenging problem. Data from wide-angle diffraction experiments are very difficult to interpret due to the very large amount of information that they carry, that is the large number of correlations present in the diffraction patterns.We describe new approaches that permit a detailed analysis of the complex neutron diffraction patterns characterizing polymer melts and glasses. The coupling of different computer modelling strategies with neutron scattering data over a wide Q range allows the extraction of detailed quantitative information on the structural arrangements of the materials of interest. Proceeding from modelling routes as diverse as force field calculations, single-chain modelling and reverse Monte Carlo, we show the successes and pitfalls of each approach in describing model systems, which illustrate the need to attack the data analysis problem simultaneously from several fronts.