Search results for: Maryam Mirzaie
4 Exploiting the Tumour Microenvironment in Order to Optimise Sonodynamic Therapy for Cancer
Authors: Maryam Mohammad Hadi, Heather Nesbitt, Hamzah Masood, Hashim Ahmed, Mark Emberton, John Callan, Alexander MacRobert, Anthony McHale, Nikolitsa Nomikou
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Sonodynamic therapy (SDT) utilises ultrasound in combination with sensitizers, such as porphyrins, for the production of cytotoxic reactive oxygen species (ROS) and the confined ablation of tumours. Ultrasound can be applied locally, and the acoustic waves, at frequencies between 0.5-2 MHz, are transmitted efficiently through tissue. SDT does not require highly toxic agents, and the cytotoxic effect only occurs upon ultrasound exposure at the site of the lesion. Therefore, this approach is not associated with adverse side effects. Further highlighting the benefits of SDT, no cancer cell population has shown resistance to therapy-triggered ROS production or their cytotoxic effects. This is particularly important, given the as yet unresolved issues of radiation and chemo-resistance, to the authors’ best knowledge. Another potential future benefit of this approach – considering its non-thermal mechanism of action – is its possible role as an adjuvant to immunotherapy. Substantial pre-clinical studies have demonstrated the efficacy and targeting capability of this therapeutic approach. However, SDT has yet to be fully characterised and appropriately exploited for the treatment of cancer. In this study, a formulation based on multistimulus-responsive sensitizer-containing nanoparticles that can accumulate in advanced prostate tumours and increase the therapeutic efficacy of SDT has been developed. The formulation is based on a polyglutamate-tyrosine (PGATyr) co-polymer carrying hematoporphyrin. The efficacy of SDT in this study was demonstrated using prostate cancer as the translational exemplar. The formulation was designed to respond to the microenvironment of advanced prostate tumours, such as the overexpression of the proteolytic enzymes, cathepsin-B and prostate-specific membrane antigen (PSMA), that can degrade the nanoparticles, reduce their size, improving both diffusions throughout the tumour mass and cellular uptake. The therapeutic modality was initially tested in vitro using LNCaP and PC3 cells as target cell lines. The SDT efficacy was also examined in vivo, using male SCID mice bearing LNCaP subcutaneous tumours. We have demonstrated that the PGATyr co-polymer is digested by cathepsin B and that digestion of the formulation by cathepsin-B, at tumour-mimicking conditions (acidic pH), leads to decreased nanoparticle size and subsequent increased cellular uptake. Sonodynamic treatment, at both normoxic and hypoxic conditions, demonstrated ultrasound-induced cytotoxic effects only for the nanoparticle-treated prostate cancer cells, while the toxicity of the formulation in the absence of ultrasound was minimal. Our in vivo studies in immunodeficient mice, using the hematoporphyrin-containing PGATyr nanoparticles for SDT, showed a 50% decrease in LNCaP tumour volumes within 24h, following IV administration of a single dose. No adverse effects were recorded, and body weight was stable. The results described in this study clearly demonstrate the promise of SDT to revolutionize cancer treatment. It emphasizes the potential of this therapeutic modality as a fist line treatment or in combination treatment for the elimination or downstaging of difficult to treat cancers, such as prostate, pancreatic, and advanced colorectal cancer.Keywords: sonodynamic therapy, nanoparticles, tumour ablation, ultrasound
Procedia PDF Downloads 1343 Autonomous Strategic Aircraft Deconfliction in a Multi-Vehicle Low Altitude Urban Environment
Authors: Loyd R. Hook, Maryam Moharek
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With the envisioned future growth of low altitude urban aircraft operations for airborne delivery service and advanced air mobility, strategies to coordinate and deconflict aircraft flight paths must be prioritized. Autonomous coordination and planning of flight trajectories is the preferred approach to the future vision in order to increase safety, density, and efficiency over manual methods employed today. Difficulties arise because any conflict resolution must be constrained by all other aircraft, all airspace restrictions, and all ground-based obstacles in the vicinity. These considerations make pair-wise tactical deconfliction difficult at best and unlikely to find a suitable solution for the entire system of vehicles. In addition, more traditional methods which rely on long time scales and large protected zones will artificially limit vehicle density and drastically decrease efficiency. Instead, strategic planning, which is able to respond to highly dynamic conditions and still account for high density operations, will be required to coordinate multiple vehicles in the highly constrained low altitude urban environment. This paper develops and evaluates such a planning algorithm which can be implemented autonomously across multiple aircraft and situations. Data from this evaluation provide promising results with simulations showing up to 10 aircraft deconflicted through a relatively narrow low-altitude urban canyon without any vehicle to vehicle or obstacle conflict. The algorithm achieves this level of coordination beginning with the assumption that each vehicle is controlled to follow an independently constructed flight path, which is itself free of obstacle conflict and restricted airspace. Then, by preferencing speed change deconfliction maneuvers constrained by the vehicles flight envelope, vehicles can remain as close to the original planned path and prevent cascading vehicle to vehicle conflicts. Performing the search for a set of commands which can simultaneously ensure separation for each pair-wise aircraft interaction and optimize the total velocities of all the aircraft is further complicated by the fact that each aircraft's flight plan could contain multiple segments. This means that relative velocities will change when any aircraft achieves a waypoint and changes course. Additionally, the timing of when that aircraft will achieve a waypoint (or, more directly, the order upon which all of the aircraft will achieve their respective waypoints) will change with the commanded speed. Put all together, the continuous relative velocity of each vehicle pair and the discretized change in relative velocity at waypoints resembles a hybrid reachability problem - a form of control reachability. This paper proposes two methods for finding solutions to these multi-body problems. First, an analytical formulation of the continuous problem is developed with an exhaustive search of the combined state space. However, because of computational complexity, this technique is only computable for pairwise interactions. For more complicated scenarios, including the proposed 10 vehicle example, a discretized search space is used, and a depth-first search with early stopping is employed to find the first solution that solves the constraints.Keywords: strategic planning, autonomous, aircraft, deconfliction
Procedia PDF Downloads 902 Comparison of Titanium and Aluminum Functions as Spoilers for Dose Uniformity Achievement in Abutting Oblique Electron Fields: A Monte Carlo Simulation Study
Authors: Faranak Felfeliyan, Parvaneh Shokrani, Maryam Atarod
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Introduction Using electron beam is widespread in radiotherapy. The main criteria in radiation therapy is to irradiate the tumor volume with maximum prescribed dose and minimum dose to vital organs around it. Using abutting fields is common in radiotherapy. The main problem in using abutting fields is dose inhomogeneity in the junction region. Electron beam divergence and lateral scattering may lead to hot and cold spots in the junction region. One solution for this problem is using of a spoiler to broaden the penumbra and uniform dose in the junction region. The goal of this research was to compare titanium and aluminum effects as a spoiler for dose uniformity achievement in the junction region of oblique electron fields with Monte Carlo simulation. Dose uniformity in the junction region depends on density, scattering power, thickness of the spoiler and the angle between two fields. Materials and Methods In this study, Monte Carlo model of Siemens Primus linear accelerator was simulated for a 5 MeV nominal energy electron beam using manufacture provided specifications. BEAMnrc and EGSnrc user code were used to simulate the treatment head in electron mode (simulation of beam model). The resulting phase space file was used as a source for dose calculations for 10×10 cm2 field size at SSD=100 cm in a 30×30×45 cm3 water phantom using DOSXYZnrc user code (dose calculations). An automatic MP3-M water phantom tank, MEPHYSTO mc2 software platform and a Semi-Flex Chamber-31010 with sensitive volume of 0.125 cm3 (PTW, Freiburg, Germany) were used for dose distribution measurements. Moreover, the electron field size was 10×10 cm2 and SSD=100 cm. Validation of developed beam model was done by comparing the measured and calculated depth and lateral dose distributions (verification of electron beam model). Simulation of spoilers (using SLAB component module) placed at the end of the electron applicator, was done using previously validated phase space file for a 5 MeV nominal energy and 10×10 cm2 field size (simulation of spoiler). An in-house routine was developed in order to calculate the combined isodose curves resulting from the two simulated abutting fields (calculation of dose distribution in abutting electron fields). Results Verification of the developed 5.9 MeV electron beam model was done by comparing the calculated and measured dose distributions. The maximum percentage difference between calculated and measured PDD was 1%, except for the build-up region in which the difference was 2%. The difference between calculated and measured profile was 2% at the edges of the field and less than 1% in other regions. The effect of PMMA, aluminum, titanium and chromium in dose uniformity achievement in abutting normal electron fields with equivalent thicknesses to 5mm PMMA was evaluated. Comparing R90 and uniformity index of different materials, aluminum was chosen as the optimum spoiler. Titanium has the maximum surface dose. Thus, aluminum and titanium had been chosen to use for dose uniformity achievement in oblique electron fields. Using the optimum beam spoiler, junction dose decreased from 160% to 110% for 15 degrees, from 180% to 120% for 30 degrees, from 160% to 120% for 45 degrees and from 180% to 100% for 60 degrees oblique abutting fields. Using Titanium spoiler, junction dose decreased from 160% to 120% for 15 degrees, 180% to 120% for 30 degrees, 160% to 120% for 45 degrees and 180% to 110% for 60 degrees. In addition, penumbra width for 15 degrees, without spoiler in the surface was 10 mm and was increased to 15.5 mm with titanium spoiler. For 30 degrees, from 9 mm to 15 mm, for 45 degrees from 4 mm to 6 mm and for 60 degrees, from 5 mm to 8 mm. Conclusion Using spoilers, penumbra width at the surface increased, size and depth of hot spots was decreased and dose homogeneity improved at the junction of abutting electron fields. Dose at the junction region of abutting oblique fields was improved significantly by using spoiler. Maximum dose at the junction region for 15⁰, 30⁰, 45⁰ and 60⁰ was decreased about 40%, 60%, 40% and 70% respectively for Titanium and about 50%, 60%, 40% and 80% for Aluminum. Considering significantly decrease in maximum dose using titanium spoiler, unfortunately, dose distribution in the junction region was not decreased less than 110%.Keywords: abutting fields, electron beam, radiation therapy, spoilers
Procedia PDF Downloads 1651 Geological, Geochronological, Geochemical, and Geophysical Characteristics of the Dalli Porphyry Cu-Au Deposit in Central Iran; Implications for Exploration
Authors: Hooshag Asadi Haroni, Maryam Veiskarami, Yongjun Lu
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The Dalli gold-rich porphyry deposit (17 Mt @ 0.5% Cu and 0.65 g/t Au) is located in the Urumieh-Dokhtar Magmatic Arc (UDMA), a small segment of the Tethyan metallogenic belt, hosting several porphyry Cu (Mo-Au) systems in Iran. This research characterizes the Dalli deposit to define exploration criteria in advanced exploration such as the drilling of possible blind porphyry centers. Geological map, trench/drill hole geochemical and ground magnetic data, and age dating and isotope trace element analyses, carried out at the John De Laeter Research Center of Curtin University, were used to characterize the Delli deposit. Mineralization at Dalli is hosted by NE-trending quartz-diorite porphyry stocks (~ 200m in diameter) intruded by a wall-rock andesite porphyry. Disseminated and stockwork Cu-Au mineralization is related to potassic alteration, comprising magnetite, late K-feldspar and biotite, and quartz-sericite-specularite overprint, surrounded by extensive barren argillic and propylitic alterations. In the peripheries of the porphyry centers, there are N-trending vuggy quartz veins, hosting epithermal Au-Ag-As-Sb mineralization. Geochemical analyses of drill core samples showed that the core of the porphyry stocks is low-grade, whereas the high-grade disseminated and stockwork mineralization (~ 1% Cu and ~ 1.2 g/t Au) occurred at the contact of the porphyry stocks and andesite porphyry. Geochemical studies of the drill hole and trench samples showed a strong correlation between Cu and Au and both show a second-order correlation with Fe and As. Magnetic survey revealed two significant magnetic anomalies, associated with intensive potassic alteration, in the reduced-to-the-pole magnetic map of the area. A relatively weaker magnetic anomaly, showing no surface porphyry expressions, is located on a lithocap, consisting of advanced argillic alteration, vuggy quartz veins, and surface expressions of epithermal geochemical signatures. The association of the lithocap and the weak magnetic anomaly could be indicative of a hidden mineralized porphyry center. Litho-geochemical analyses of the least altered Dalli intrusions and volcanic rocks indicated high Sr/Y (49-61) and Eu/Eu* (0.89-0.92), features typical of Cu porphyries. The U-Pb dating of zircons of the mineralized quartz diorite and andesite porphyry, carried out by laser ablation inductively coupled plasma mass spectrometry, yielded magmatic crystallization ages of 15.4-16.0 Ma (Middle Miocene). The zircon trace element concentrations of Dalli are characterized by high Eu/Eu* (0.3-0.8), (Ce/Nd)/Y (0.01-0.3), and 10000*(Eu/Eu*)/Y (2-15) ratios, similar to fertile porphyry suites such as the giant Sar-Cheshmeh and Qulong porphyry Cu deposits along the Tethyan belt. This suggests that the Middle Miocene Dalli intrusions are fertile and require extensive deep drillings to define their potential. Chondrite-normalized rare earth element (REE) patterns show no significant Eu anomalies, and are characterized by light-REE enrichments (La/Sm)n = 2.57–6.40). In normalized multi-element diagrams, analyzed rocks are characterized by enrichments in large ion lithophile elements (LILE) and depletions in high field strength elements (HFSE), and display typical features of subduction-related calc-alkaline magmas. The characteristics of the Dalli deposit provided several recognition criteria for detailed exploration of Cu-Au porphyry deposits and highlighted the importance of the UDMA as a potentially significant, economically important, but relatively underexplored porphyry province.Keywords: porphyry, gold, geochronology, magnetic, exploration
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