Synthesis, radiolabeling and preclinical evaluation of gold-nanomaterial based boron carriers as drug delivery systems: Potential application to boron neutron capture therapy

121 p.En la presente tesis se describe la preparación y caracterización de nanopartículas de oro de diversos tamaños y formas geométricas (nanoesferas y nanorods), funcionalizadas simultáneamente con polietilenglicol y moléculas ricas en boro, como potenciales herramientas terapéuticas en el contexto de la terapia por captura de neutrones (BNCT). Las nanopartículas preparadas se han caracterizado utilizando una batería de técnicas, incluyendo microscopía electrónica de transmisión, dispersión dinámica de luz, espectrofotometría UV-Vis, espectroscopía Raman y espectroscopía fotoelectrónica de rayos X. Posteriormente, los nanosistemas se han marcado con isótopos emisores de positrones para evaluar su biodistribución y su capacidad de acumularse en el tumor, utilizando para ello dos modelos animales de cáncer, generados mediante inoculación sub-cutánea de células tumorales de origen humano en ratones inmunodeprimidos. Dos de los nanosistemas ensayados han mostrado buena capacidad de acumulación en los tumores, con concentraciones alcanzadas alrededor del 5% de la dosis administrada por gramo de tejido, mostrado su potencial como herramientas terapéuticas. Además, los nanorods podrían utilizarse en abordajes duales, combinando BNCT con terapia fototérmica

Synthesis, radiolabeling and preclinical evaluation of gold-nanomaterial based boron carriers as drug delivery systems: Potential application to boron neutron capture therapy

121 p.En la presente tesis se describe la preparación y caracterización de nanopartículas de oro de diversos tamaños y formas geométricas (nanoesferas y nanorods), funcionalizadas simultáneamente con polietilenglicol y moléculas ricas en boro, como potenciales herramientas terapéuticas en el contexto de la terapia por captura de neutrones (BNCT). Las nanopartículas preparadas se han caracterizado utilizando una batería de técnicas, incluyendo microscopía electrónica de transmisión, dispersión dinámica de luz, espectrofotometría UV-Vis, espectroscopía Raman y espectroscopía fotoelectrónica de rayos X. Posteriormente, los nanosistemas se han marcado con isótopos emisores de positrones para evaluar su biodistribución y su capacidad de acumularse en el tumor, utilizando para ello dos modelos animales de cáncer, generados mediante inoculación sub-cutánea de células tumorales de origen humano en ratones inmunodeprimidos. Dos de los nanosistemas ensayados han mostrado buena capacidad de acumulación en los tumores, con concentraciones alcanzadas alrededor del 5% de la dosis administrada por gramo de tejido, mostrado su potencial como herramientas terapéuticas. Además, los nanorods podrían utilizarse en abordajes duales, combinando BNCT con terapia fototérmica

UHPLC in the Analysis of Drug Components

The main objective of this article is to highlight the new trends that have emerged in the enhancement of the HPLC which have given rise to the use of UHPLC. This innovative tool is much more reliable and effective as compared to HPLC, in the investigation of many chemical compounds. In this article, special insight is given on the changes that have been made with regards to both instruments. In this article focus is also placed on the implementation of UPLC in various fields of interest, in order to enhance the processes for which it is utilized. The pros and cons of the utilization of this method are also addressed in this article, along with other relevant characteristics of the same

Optimization of solid oxide fuel cell interconnect design

Performance of solid oxide fuel cells (SOFC) is dependent of a set of complex physical and chemical processes occurring simultaneously. Interconnect for SOFC is important as it provides electrical connection between anode of one individual cell to the cathode of neighboring one. It also acts as a physical barrier to protect the air electrode material from the reducing environment of the fuel on the fuel electrode side, and it equally prevents the fuel electrode material from contacting with oxidizing atmosphere of the oxidant electrode side. A three-dimensional numerical model has been developed to evaluate the SOFC including the current collector, rectangular duct gas flow channels, gas diffusion electrodes and electrolyte layer. This model takes into account the hydrodynamic multi-component fluid flow and heat transfer analysis. Numerical results from the developed model using finite element method (COMSOL®) show that the predicted polarization curve is in very good agreement with the published data. Simulations were also performed for different interconnect design cases obtained by varying electrode/interconnect contact area using finite volume method (Fluent®) to investigate the thermal and hydrodynamic behavior and finite element method (COMSOL®) to investigate the electrical performance. The optimization is carried out by considering 25% interconnect contact area as the design criteria for maximum temperature gradient limitation. The best interconnect design with 60% interconnect contact area has been chosen which shows good thermal behavior with considerable power output among the different design cases. Simulations show a decreasing power density and reduction of temperature gradient for an increasing contact area. Parametric studies of the fuel cell for different mass flows, hydraulic diameters and interconnect material properties for optimized design have also been performed. Results reveal that the flow rate will have minor impact on the electrical performance compared to the effect of material properties. Strontium doped LaCrO 3 has shown better performance than calcium or magnesium doped LaCrO 3 . Decreasing the hydraulic diameter improves the mass transport situation along the length of the flow channel

Developing a Computer Vision-Based Decision Support System for Intersection Safety Monitoring and Assessment of Vulnerable Road Users

Vision-based trajectory analysis of road users enables identification of near-crash situations and proactive safety monitoring. The two most widely used sur-rogate safety measures (SSMs), time-to-collision (TTC) and post-encroachment time (PET)—and a recent variant form of TTC, relative time-to-collision (RTTC)—were investigated using real-world video data collected at ten signalized intersections in the city of San Diego, California. The performance of these SSMs was compared for the purpose of evaluating pedestrian and bicyclist safety. Prediction of potential trajectory intersection points was performed to calculate TTC for every interacting object, and the average of TTC for every two objects in critical situations was calculated. PET values were estimated by observing potential intersection points, and frequencies of events were estimated in three critical levels. Although RTTC provided useful information regarding the relative distance between objects in time, it was found that in certain conditions where objects are far from each other, the interaction between the objects was incorrectly flagged as critical based on a small RTTC. Comparison of PET, TTC, and RTTC for different critical classes also showed that several interactions were identified as critical using one SSM but not critical using a different SSM. These findings suggest that safety evaluations should not solely rely on a single SSM, and instead a combination of different SSMs should be considered to ensure the reliability of evaluations. Video data analysis was conducted to develop object detection and tracking models for automatic identification of vehicles, bicycles, and pedestrians. Outcomes of machine vision models were employed along with SSMs to build a decision support system for safety assessment of vulnerable road users at signalized intersections. Promising results from the decision support system showed that automated safety evaluations can be performed to proactively identify critical events. It also showed challenges as well as future directions to enhance the performance of the system

Gold Nanoparticles as Boron Carriers for Boron Neutron Capture Therapy: Synthesis, Radiolabelling and In Vivo Evaluation

Background: Boron Neutron Capture Therapy (BNCT) is a binary approach to cancer therapy that requires accumulation of boron atoms preferentially in tumour cells. This can be achieved by using nanoparticles as boron carriers and taking advantage of the enhanced permeability and retention (EPR) effect. Here, we present the preparation and characterization of size and shape-tuned gold NPs (AuNPs) stabilised with polyethylene glycol (PEG) and functionalized with the boron-rich anion cobalt bis(dicarbollide), commonly known as COSAN. The resulting NPs were radiolabelled with 124I both at the core and the shell, and were evaluated in vivo in a mouse model of human fibrosarcoma (HT1080 cells) using positron emission tomography (PET). Methods: The thiolated COSAN derivatives for subsequent attachment to the gold surface were synthesized by reaction of COSAN with tetrahydropyran (THP) followed by ring opening using potassium thioacetate (KSAc). Iodination on one of the boron atoms of the cluster was also carried out to enable subsequent radiolabelling of the boron cage. AuNPs grafted with mPEG-SH (5 Kda) and thiolated COSAN were prepared by ligand displacement. Radiolabelling was carried out both at the shell (isotopic exchange) and at the core (anionic absorption) of the NPs using 124I to enable PET imaging. Results: Stable gold nanoparticles simultaneously functionalised with PEG and COSAN (PEG-AuNPs@[4]) with hydrodynamic diameter of 37.8 0.5 nm, core diameter of 19.2 1.4 nm and -potential of 18.0 0.7 mV were obtained. The presence of the COSAN on the surface of the NPs was confirmed by Raman Spectroscopy and UV-Vis spectrophotometry. PEG-AuNPs@[4] could be efficiently labelled with 124I both at the core and the shell. Biodistribution studies in a xenograft mouse model of human fibrosarcoma showed major accumulation in liver, lungs and spleen, and poor accumulation in the tumour. The dual labelling approach confirmed the in vivo stability of the PEG-AuNPs@[4]. Conclusions: PEG stabilized, COSAN-functionalised AuNPs could be synthesized, radiolabelled and evaluated in vivo using PET. The low tumour accumulation in the animal model assayed points to the need of tuning the size and geometry of the gold core for future studies

Auto Segmentation of Lung in Non-small Cell Lung Cancer Using Deep Convolution Neural Network

Segmentation of Lung is the vital first step in radiologic diagnosis of lung cancer. In this work, we present a deep learning based automated technique that overcomes various shortcomings of traditional lung segmentation and explores the role of adding “explainability” to deep learning models so that the trust can be built on these models. Our approach shows better generalization across different scanner settings, vendors and the slice thickness. In addition, there is no initialization of the seed point making it complete automated without manual intervention. The dice score of 0.98 is achieved for lung segmentation on an independent data set of non-small cell lung cancer

In vivo multimodal imaging of adenosine A1 receptors in neuroinflammation after experimental stroke

Adenosine A(l) receptors (A(l)ARs) are promising imaging biomarkers and targets for the treatment of stroke. Nevertheless, the role of A(l)ARs on ischemic damage and its subsequent neuroinflammatory response has been scarcely explored so far. Methods: In this study, the expression of A(1)ARs after transient middle cerebral artery occlusion (MCAO) was evaluated by positron emission tomography (PET) with [F-18]CPFPX and immunohistochemistry (IHC). In addition, the role of AIARs on stroke inflammation using pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [F-18]DPA-714 (TSPO) and [F-18]FLT (cellular proliferation), as well as IHC and neurofunctional studies. Results: In the ischemic territory, [F-18]CPFPX signal and IHC showed the overexpression of A(l)ARs in microglia and infiltrated leukocytes after cerebral ischemia. Ischemic rats treated with the AAR agonist ENBA showed a significant decrease in both [F-18]DPA-714 and [F-18]FLT signal intensities at day 7 after cerebral ischemia, a feature that was confirmed by IHC results. Besides, the activation of A(l)AR promoted the reduction of the brain lesion, as measured with T2W-MRI, and the improvement of neurological outcome including motor, sensory and reflex responses. These results show for the first time the in vivo PET imaging of A(l)AR expression after cerebral ischemia in rats and the application of [F-18]FLT to evaluate glial proliferation in response to treatment. Conclusion: Notably, these data provide evidence for A(l)AR playing a key role in the control of both the activation of resident glia and the de novo proliferation of microglia and macrophages after experimental stroke in rats.The authors would like to thank A. Leukona and V. Salinas for technical support in the radiosynthesis. This study was funded by grants from the Spanish Ministry of Education and Science/FEDER RYC-201722412, SAF2016-75292-R, SAF2017-87670-R and PID2019-107989RB-I00, the Basque Government (IT1203/19, BIO18/IC/006) and CIBERNED. Maria Ardaya holds a fellowship from the University of Pais Vasco. Ana Joya acknowledges funding from Fundacio La Marato de TV3 (17/C/2017). Juan Jose Gutierrez acknowledges funding from Euskampus Fundazioa. Jordi Llop also acknowledges The Spanish Ministry of Economy and Competitiveness (Grant CTQ2017-87637-R). Part of the work has been performed under the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (Grant No. MDM-2017-0720)

International expert panel consensus on fat grafting of the breast

Background: Autologous fat grafting has broad applications in reconstructive and aesthetic breast surgery as a natural filler and for its regenerative purposes. Despite the widespread use of fat grafting, there remains no shared consensus on what constitutes the optimal fat grafting technique and its oncological safety. For this reason, the authors of this study have organized a Survey and an International Consensus Conference that was held at the Aesthetic Breast Meeting in Milan (December 15, 2018). Methods: All studies on fat grafting, both for breast aesthetic and reconstructive purposes, were electronically screened. The literature review led to 17 "key questions" that were used for the Survey. The authors prepared a set of 10 "key statements" that have been discussed in a dedicated face-to-face session during the meeting. Results: The 10 key statements addressed all the most debated topics on fat grafting of the breast. Levels of evidence for the key statements ranged from III to IV with 2 statements (20%) supported by a level of evidence III and 6 statements (60%) by level of evidence IV. Overall consensus was reached for 2 statements (20%) with >75% agreement reached for 7 statements. Conclusions: The survey demonstrated a diversity of opinion and attitude among the panelists with regard to technique. Clear recommendations for evidence-based clinical practice for fat grafting use both in aesthetic and reconstructive breast surgery could not be defined due to the scarcity of level 1 or 2 studies