ARB: Phase II window of opportunity study of short-term preoperative treatment with enzalutamide in ER-positive and triple-negative breast cancer

The androgen receptor (AR) is expressed in 60-80% of breast cancers (BC) across all molecular phenotypes, with a higher incidence in oestrogen receptor positive (ER+) BC compared to ER negative tumours. In ER+ disease, AR-expression has been linked to endocrine resistance which might be reversed with combined treatment targeting ER and AR. In triple negative BCs (TNBC), preclinical and clinical investigations have described a subset of patients that express the AR and are sensitive to androgen blockade, providing a novel therapeutic target. Enzalutamide, a potent 2nd generation anti-androgen, has demonstrated substantial preclinical and clinical anti-tumour activity in AR+ breast cancer. Short-term preoperative window of opportunity studies are a validated strategy for novel treatments to provide proof-of-concept and define the most appropriate patient population by directly assessing treatment effects in tumour tissue before and after treatment. The ARB study aims to assess the anti-tumour effects of enzalutamide in early ER+ breast cancer and TNBC, to identify the optimal target population for further studies and to directly explore the biologic effects of enzalutamide on BC and stromal cells. Methods: ARB is an international, investigator sponsored WOO phase II study in women with newly diagnosed primary ER+ BC or AR+ TNBC of ≥ 1cm. The study has two cohorts. In the ER+ cohort, postmenopausal patients will be randomised 2:1 to receive either enzalutamide (160mg OD) plus exemestane (50mg OD) or exemestane (25mg OD). In the TNBC cohort, AR+ will receive single agent treatment with enzalutamide (160mg OD). Study treatment is planned for 15–29 days, followed by surgery or neo-adjuvant therapy. Tissue and blood samples are collected before treatment and on the last day of study treatment. The primary endpoint is inhibition of tumour-cell proliferation, as measured by change in Ki67 expression, determined centrally by 2 investigators. Secondary endpoints include induction of apoptosis (Caspase3), circulating hormone levels and safety. ARB aims to recruit ≈235 patients from ≈40 sites in the UK, Germany, Spain and USA. The study is open to recruitment.

The proof of Kontsevich's periodicity conjecture on noncommutative birational transformations

For an arbitrary associative unital ring RR, let J1J1 and J2J2 be the following noncommutative, birational, partly defined involutions on the set M3(R)M3(R) of 3×33×3 matrices over RR: J1(M)=M−1J1(M)=M−1 (the usual matrix inverse) and J2(M)jk=(Mkj)−1J2(M)jk=(Mkj)−1 (the transpose of the Hadamard inverse).

We prove the surprising conjecture by Kontsevich that (J2∘J1)3(J2∘J1)3 is the identity map modulo the DiagL×DiagRDiagL×DiagR action (D1,D2)(M)=D−11MD2(D1,D2)(M)=D1−1MD2 of pairs of invertible diagonal matrices. That is, we show that, for each MM in the domain where (J2∘J1)3(J2∘J1)3 is defined, there are invertible diagonal 3×33×3 matrices D1=D1(M)D1=D1(M) and D2=D2(M)D2=D2(M) such that (J2∘J1)3(M)=D−11MD2(J2∘J1)3(M)=D1−1MD2.

Restoring function after neuromuscular trauma: novel paradigms for enhancing volitional control of neural activity in untethered environments and vHAB, a gamified therapy platform

Thesis (Ph.D.)--University of Washington, 2016-08

Development and application of sensitive genome-wide platforms to study the genetic and epigenetic (DNA methylation) makeup of gametes and early bovine embryos

Pour ce projet, nous avons développé une plateforme pour l’analyse pangénomique de la méthylation de l’ADN chez le bovin qui est compatible avec des échantillons de petites tailles. Cet outil est utilisé pour étudier les caractéristiques génétiques et épigénétiques (méthylation de l’ADN) des gamètes soumis aux procédures de procréation médicalement assisitée et des embryons précoces. Dans un premier temps, une plateforme d’analyse de biopuces spécifiques pour l’étude de la méthylation de l’ADN chez l’espèce bovine a été développée. Cette plateforme a ensuite été optimisée pour produire des analyses pangénomiques de méthylation de l’ADN fiables et reproductibles à partir d’échantillons de très petites tailles telle que les embryons précoces (≥ 10 ng d’ADN a été utilisé, ce qui correspond à 10 blastocystes en expansion). En outre, cet outil a permis d’évaluer de façon simultanée la méthylation de l’ADN et le transcriptome dans le même échantillon, fournissant ainsi une image complète des profils génétiques et épigénétiques (méthylation de l’ADN). Comme preuve de concept, les profils comparatifs de méthylation de l’ADN spermatique et de blastocystes bovins ont été analysés au niveau de l’ensemble du génome. Dans un deuxième temps, grâce à cette plateforme, les profils globaux de méthylation de l’ADN de taureaux jumeaux monozygotes (MZ) ont été analysés. Malgré qu’ils sont génétiquement identiques, les taureaux jumeaux MZ ont des descendants avec des performances différentes. Par conséquent, l’hypothèse que le profil de méthylation de l’ADN spermatique de taureaux jumeaux MZ est différent a été émise. Dans notre étude, des différences significatives entre les jumeaux MZ au niveau des caractéristiques de la semence ainsi que de la méthylation de l’ADN ont été trouvées, chacune pouvant contribuer à l’obtention de performances divergentes incongrues des filles engendrées par ces jumeaux MZ. Dans la troisième partie de ce projet, la même plateforme a été utilisée pour découvrir les impacts d’une supplémentation à forte concentration en donneur de méthyle universel sur les embryons précoces bovins. La supplémentation avec de grandes quantités d’acide folique (AF) a été largement utilisée et recommandée chez les femmes enceintes pour sa capacité bien établie à prévenir les malformations du tube neural chez les enfants. Cependant, plus récemment, plusieurs études ont rapporté des effets indésirables de l’AF utilisé à des concentrations élevées, non seulement sur le développement de l’embryon, mais aussi chez les adultes. Au niveau cellulaire, l’AF entre dans le métabolisme monocarboné, la seule voie de production de S-adénosyl méthionine (SAM), un donneur universel de groupements méthyles pour une grande variété de biomolécules, y compris l’ADN. Par conséquent, pour résoudre cette controverse, une forte dose de SAM a été utilisée pour traiter des embryons produits in vitro chez le bovin. Ceci a non seulement permis d’influencer le phénotype des embryons précoces, mais aussi d’avoir un impact sur le transcriptome et le méthylome de l’ADN. En somme, le projet en cours a permis le développement d’une plateforme d’analyse de la méthylation de l’ADN à l’échelle du génome entier chez le bovin à coût raisonnable et facile à utiliser qui est compatible avec les embryons précoces. De plus, puisque c’est l’une des premières études de ce genre en biologie de la reproduction bovine, ce projet avait trois objectifs qui a donné plusieurs nouveaux résultats, incluant les profils comparatifs de méthylation de l’ADN au niveau : i) blastocystes versus spermatozoïdes ; ii) semence de taureaux jumeaux MZ et iii) embryons précoces traités à de fortes doses de SAM versus des embryons précoces non traités.

An iterative analytical design framework for the optimal designing of an off-grid renewable energy based hybrid smart micro-grid

Creative ways of utilising renewable energy sources in electricity generation especially in remote areas and particularly in countries depending on imported energy, while increasing energy security and reducing cost of such isolated off-grid systems, is becoming an urgently needed necessity for the effective strategic planning of Energy Systems. The aim of this research project was to design and implement a new decision support framework for the optimal design of hybrid micro grids considering different types of different technologies, where the design objective is to minimize the total cost of the hybrid micro grid while at the same time satisfying the required electric demand. Results of a comprehensive literature review, of existing analytical, decision support tools and literature on HPS, has identified the gaps and the necessary conceptual parts of an analytical decision support framework. As a result this research proposes and reports an Iterative Analytical Design Framework (IADF) and its implementation for the optimal design of an Off-grid renewable energy based hybrid smart micro-grid (OGREH-SμG) with intra and inter-grid (μG2μG & μG2G) synchronization capabilities and a novel storage technique. The modelling design and simulations were based on simulations conducted using HOMER Energy and MatLab/SIMULINK, Energy Planning and Design software platforms. The design, experimental proof of concept, verification and simulation of a new storage concept incorporating Hydrogen Peroxide (H2O2) fuel cell is also reported. The implementation of the smart components consisting Raspberry Pi that is devised and programmed for the semi-smart energy management framework (a novel control strategy, including synchronization capabilities) of the OGREH-SμG are also detailed and reported. The hybrid μG was designed and implemented as a case study for the Bayir/Jordan area. This research has provided an alternative decision support tool to solve Renewable Energy Integration for the optimal number, type and size of components to configure the hybrid μG. In addition this research has formulated and reported a linear cost function to mathematically verify computer based simulations and fine tune the solutions in the iterative framework and concluded that such solutions converge to a correct optimal approximation when considering the properties of the problem. As a result of this investigation it has been demonstrated that, the implemented and reported OGREH-SμG design incorporates wind and sun powered generation complemented with batteries, two fuel cell units and a diesel generator is a unique approach to Utilizing indigenous renewable energy with a capability of being able to synchronize with other μ-grids is the most effective and optimal way of electrifying developing countries with fewer resources in a sustainable way, with minimum impact on the environment while also achieving reductions in GHG. The dissertation concludes with suggested extensions to this work in the future.

Security through Obscurity: Layout Obfuscation of Digital Integrated Circuits using Don't Care Conditions

Contemporary integrated circuits are designed and manufactured in a globalized environment leading to concerns of piracy, overproduction and counterfeiting. One class of techniques to combat these threats is circuit obfuscation which seeks to modify the gate-level (or structural) description of a circuit without affecting its functionality in order to increase the complexity and cost of reverse engineering. Most of the existing circuit obfuscation methods are based on the insertion of additional logic (called “key gates”) or camouflaging existing gates in order to make it difficult for a malicious user to get the complete layout information without extensive computations to determine key-gate values. However, when the netlist or the circuit layout, although camouflaged, is available to the attacker, he/she can use advanced logic analysis and circuit simulation tools and Boolean SAT solvers to reveal the unknown gate-level information without exhaustively trying all the input vectors, thus bringing down the complexity of reverse engineering. To counter this problem, some ‘provably secure’ logic encryption algorithms that emphasize methodical selection of camouflaged gates have been proposed previously in literature [1,2,3]. The contribution of this paper is the creation and simulation of a new layout obfuscation method that uses don't care conditions. We also present proof-of-concept of a new functional or logic obfuscation technique that not only conceals, but modifies the circuit functionality in addition to the gate-level description, and can be implemented automatically during the design process. Our layout obfuscation technique utilizes don’t care conditions (namely, Observability and Satisfiability Don’t Cares) inherent in the circuit to camouflage selected gates and modify sub-circuit functionality while meeting the overall circuit specification. Here, camouflaging or obfuscating a gate means replacing the candidate gate by a 4X1 Multiplexer which can be configured to perform all possible 2-input/ 1-output functions as proposed by Bao et al. [4]. It is important to emphasize that our approach not only obfuscates but alters sub-circuit level functionality in an attempt to make IP piracy difficult. The choice of gates to obfuscate determines the effort required to reverse engineer or brute force the design. As such, we propose a method of camouflaged gate selection based on the intersection of output logic cones. By choosing these candidate gates methodically, the complexity of reverse engineering can be made exponential, thus making it computationally very expensive to determine the true circuit functionality. We propose several heuristic algorithms to maximize the RE complexity based on don’t care based obfuscation and methodical gate selection. Thus, the goal of protecting the design IP from malicious end-users is achieved. It also makes it significantly harder for rogue elements in the supply chain to use, copy or replicate the same design with a different logic. We analyze the reverse engineering complexity by applying our obfuscation algorithm on ISCAS-85 benchmarks. Our experimental results indicate that significant reverse engineering complexity can be achieved at minimal design overhead (average area overhead for the proposed layout obfuscation methods is 5.51% and average delay overhead is about 7.732%). We discuss the strengths and limitations of our approach and suggest directions that may lead to improved logic encryption algorithms in the future. References: [1] R. Chakraborty and S. Bhunia, “HARPOON: An Obfuscation-Based SoC Design Methodology for Hardware Protection,” IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems, vol. 28, no. 10, pp. 1493–1502, 2009. [2] J. A. Roy, F. Koushanfar, and I. L. Markov, “EPIC: Ending Piracy of Integrated Circuits,” in 2008 Design, Automation and Test in Europe, 2008, pp. 1069–1074. [3] J. Rajendran, M. Sam, O. Sinanoglu, and R. Karri, “Security Analysis of Integrated Circuit Camouflaging,” ACM Conference on Computer Communications and Security, 2013. [4] Bao Liu, Wang, B., "Embedded reconfigurable logic for ASIC design obfuscation against supply chain attacks,"Design, Automation and Test in Europe Conference and Exhibition (DATE), 2014 , vol., no., pp.1,6, 24-28 March 2014.

Repellent effects of Melaleuca alternifolia (tea tree) oil against cattle tick larvae (Rhipicephalus australis) when formulated as emulsions and in β-cyclodextrin inclusion complexes

Rhipicephalus australis (formerly Boophilus microplus) is a one host tick responsible for major economic loss in tropical and subtropical cattle production enterprises. Control is largely dependent on the application of acaricides but resistance has developed to most currently registered chemical groups. Repellent compounds that prevent initial attachment of tick larvae offer a potential alternative to control with chemical toxicants. The repellent effects of Melaleuca alternifolia oil (TTO) emulsions and two β-cyclodextrin complex formulations, a slow release form (SR) and a modified faster release form (FR), were examined in a series of laboratory studies. Emulsions containing 4% and 5% TTO applied to cattle hair in laboratory studies completely repelled ascending tick larvae for 24 h whereas 2% and 3% formulations provided 80% protection. At 48 h, 5% TTO provided 78% repellency but lower concentrations repelled less than 60% of larvae. In a study conducted over 15 days, 3% TTO emulsion applied to cattle hair provided close to 100% repellency for 2 days, but then protection fell to 23% by day 15. The FR formulation gave significantly greater repellency than the emulsion and the SR formulation from day 3 until the end of the study (P < 0.05), providing almost complete repellency at day 3 (99.5%), then decreasing over the period of the study to 49% repellency at day 15. Proof of concept is established for the use of appropriately designed controlled-release formulations to extend the period of repellency provided by TTO against R. australis larvae.

Design of a speed meter interferometer proof-of-principle experiment

The second generation of large scale interferometric gravitational wave (GW) detectors will be limited by quantum noise over a wide frequency range in their detection band. Further sensitivity improvements for future upgrades or new detectors beyond the second generation motivate the development of measurement schemes to mitigate the impact of quantum noise in these instruments. Two strands of development are being pursued to reach this goal, focusing both on modifications of the well-established Michelson detector configuration and development of different detector topologies. In this paper, we present the design of the world's first Sagnac speed meter (SSM) interferometer, which is currently being constructed at the University of Glasgow. With this proof-of-principle experiment we aim to demonstrate the theoretically predicted lower quantum noise in a Sagnac interferometer compared to an equivalent Michelson interferometer, to qualify SSM for further research towards an implementation in a future generation large scale GW detector, such as the planned Einstein telescope observatory.

On the application of contextual IoT service discovery in Information Centric Networks

The continuous flow of technological developments in communications and electronic industries has led to the growing expansion of the Internet of Things (IoT). By leveraging the capabilities of smart networked devices and integrating them into existing industrial, leisure and communication applications, the IoT is expected to positively impact both economy and society, reducing the gap between the physical and digital worlds. Therefore, several efforts have been dedicated to the development of networking solutions addressing the diversity of challenges associated with such a vision. In this context, the integration of Information Centric Networking (ICN) concepts into the core of IoT is a research area gaining momentum and involving both research and industry actors. The massive amount of heterogeneous devices, as well as the data they produce, is a significant challenge for a wide-scale adoption of the IoT. In this paper we propose a service discovery mechanism, based on Named Data Networking (NDN), that leverages the use of a semantic matching mechanism for achieving a flexible discovery process. The development of appropriate service discovery mechanisms enriched with semantic capabilities for understanding and processing context information is a key feature for turning raw data into useful knowledge and ensuring the interoperability among different devices and applications. We assessed the performance of our solution through the implementation and deployment of a proof-of-concept prototype. Obtained results illustrate the potential of integrating semantic and ICN mechanisms to enable a flexible service discovery in IoT scenarios.

Development of paper-based color test-strip for drug detection in aquatic environment: Application to oxytetracycline

The wide use of antibiotics in aquaculture has led to the emergence of resistant microbial species. It should be avoided/minimized by controlling the amount of drug employed in fish farming. For this purpose, the present work proposes test-strip papers aiming at the detection/semi-quantitative determination of organic drugs by visual comparison of color changes, in a similar analytical procedure to that of pH monitoring by universal pH paper. This is done by establishing suitable chemical changes upon cellulose, attributing the paper the ability to react with the organic drug and to produce a color change. Quantitative data is also enabled by taking a picture and applying a suitable mathematical treatment to the color coordinates given by the HSL system used by windows. As proof of concept, this approach was applied to oxytetracycline (OXY), one of the antibiotics frequently used in aquaculture. A bottom-up modification of paper was established, starting by the reaction of the glucose moieties on the paper with 3-triethoxysilylpropylamine (APTES). The so-formed amine layer allowed binding to a metal ion by coordination chemistry, while the metal ion reacted after with the drug to produce a colored compound. The most suitable metals to carry out such modification were selected by bulk studies, and the several stages of the paper modification were optimized to produce an intense color change against the concentration of the drug. The paper strips were applied to the analysis of spiked environmental water, allowing a quantitative determination for OXY concentrations as low as 30 ng/mL. In general, this work provided a simple, method to screen and discriminate tetracycline drugs, in aquaculture, being a promising tool for local, quick and cheap monitoring of drugs.

Low‑cost origami fabrication of 3D self‑aligned hybrid microfluidic structures

[EN] 3D microfluidic device fabrication methods are normally quite expensive and tedious. In this paper, we present an easy and cheap alternative wherein thin cyclic olefin polymer (COP) sheets and pressure sensitive adhesive(PSA) were used to fabricate hybrid 3D microfluidic structures, by the Origami technique, which enables the fabrication of microfluidic devices without the need of any alignment tool. The COP and PSA layers were both cut simultaneously using a portable, low-cost plotter allowing for rapid prototyping of a large variety of designs in a single production step. The devices were then manually assembled using the Origami technique by simply combining COP and PSA layers and mild pressure. This fast fabrication method was applied, as proof of concept, to the generation of a micromixer with a 3D-stepped serpentine design made of ten layers in less than 8 min. Moreover, the micromixer was characterized as a function of its pressure failure, achieving pressures of up to 1000 mbar. This fabrication method is readily accessible across a large range of potential end users, such as educational agencies (schools,universities), low-income/developing world research and industry or any laboratory without access to clean room facilities, enabling the fabrication of robust, reproducible microfluidic devices.

Surface acoustic wave streaming in a PDMS microfluidic system: effect of frequency and fluid geometry & A remote ultrasonic glucose sensor

This thesis describes two separate projects. The first is a theoretical and experimental investigation of surface acoustic wave streaming in microfluidics. The second is the development of a novel acoustic glucose sensor. A separate abstract is given for each here. Optimization of acoustic streaming in microfluidic channels by SAWs Surface Acoustic Waves, (SAWs) actuated on flat piezoelectric substrates constitute a convenient and versatile tool for microfluidic manipulation due to the easy and versatile interfacing with microfluidic droplets and channels. The acoustic streaming effect can be exploited to drive fast streaming and pumping of fluids in microchannels and droplets (Shilton et al. 2014; Schmid et al. 2011), as well as size dependant sorting of particles in centrifugal flows and vortices (Franke et al. 2009; Rogers et al. 2010). Although the theory describing acoustic streaming by SAWs is well understood, very little attention has been paid to the optimisation of SAW streaming by the correct selection of frequency. In this thesis a finite element simulation of the fluid streaming in a microfluidic chamber due to a SAW beam was constructed and verified against micro-PIV measurements of the fluid flow in a fabricated device. It was found that there is an optimum frequency that generates the fastest streaming dependent on the height and width of the chamber. It is hoped this will serve as a design tool for those who want to optimally match SAW frequency with a particular microfluidic design. An acoustic glucose sensor Diabetes mellitus is a disease characterised by an inability to properly regulate blood glucose levels. In order to keep glucose levels under control some diabetics require regular injections of insulin. Continuous monitoring of glucose has been demonstrated to improve the management of diabetes (Zick et al. 2007; Heinemann & DeVries 2014), however there is a low patient uptake of continuous glucose monitoring systems due to the invasive nature of the current technology (Ramchandani et al. 2011). In this thesis a novel way of monitoring glucose levels is proposed which would use ultrasonic waves to ‘read’ a subcutaneous glucose sensitive-implant, which is only minimally invasive. The implant is an acoustic analogy of a Bragg stack with a ‘defect’ layer that acts as the sensing layer. A numerical study was performed on how the physical changes in the sensing layer can be deduced by monitoring the reflection amplitude spectrum of ultrasonic waves reflected from the implant. Coupled modes between the skin and the sensing layer were found to be a potential source of error and drift in the measurement. It was found that by increasing the number of layers in the stack that this could be minimized. A laboratory proof of concept system was developed using a glucose sensitive hydrogel as the sensing layer. It was possible to monitor the changing thickness and speed of sound of the hydrogel due to physiological relevant changes in glucose concentration.

Specification of a smart meter/actuator description mechanism & development of a mobile application

Home Automation holds the potential of realizing cost savings for end users while reducing the carbon footprint of domestic energy consumption. Yet, adoption is still very low. High cost of vendor-supplied home automation systems is a major prohibiting factor. Open source systems such as FHEM, Domoticz, OpenHAB etc. are a cheaper alternative and can drive the adoption of home automation. Moreover, they have the advantage of not being limited to a single vendor or communication technology which gives end users flexibility in the choice of devices to include in their installation. However, interaction with devices having diverse communication technologies can be inconvenient for users thus limiting the utility they derive from it. For application developers, creating applications which interact with the several technologies in the home automation systems is not a consistent process. Hence, there is the need for a common description mechanism that makes interaction smooth for end users and which enables application developers to make home automation applications in a consistent and uniform way. This thesis proposes such a description mechanism within the context of an open source home automation system – FHEM, together with a system concept for its application. A mobile application was developed as a proof of concept of the proposed description mechanism and the results of the implementation are reflected upon.

RCOS: Real time context sharing across a fleet of smart mobile devices

Today, biodiversity is endangered by the currently applied intensive farming methods imposed on food producers by intermediate actors (e.g.: retailers). The lack of a direct communication technology between the food producer and the consumer creates dependency on the intermediate actors for both producers and the consumers. A tool allowing producers to directly and efficiently market produce that meets customer demands could greatly reduce the dependency enforced by intermediate actors. To this end, in this thesis, we propose, develop, implement and validate a Real Time Context Sharing (RCOS) system. RCOS takes advantage of the widely used publish/subscribe paradigm to exchange messages between producers and consumers, directly, according to their interest and context. Current systems follow a topic-based model or a content-based model. With RCOS, we propose a context-awareness approach into the matching process of publish/subscribe paradigm. Finally, as a proof of concept, we extend the Apache ActiveMQ Artemis software and create a client prototype. We evaluate our proof of concept for larger scale deployment.