Enhancing the effect of Tumour necrosis factor - Related Apoptosis Inducing Ligand (TRAIL) in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a cancer which originates from the pleura, a layer lining the lungs. The prognosis is bleak as patients who receive standard of care chemotherapy have a median overall survival of approximately 12 months. Tumour necrosis factor - Related Apoptosis Inducing Ligand (TRAIL) is a protein involved in activating the extrinsic apoptosis pathway via engagement with death receptors located on the surface of cells. Following activation of this intracellular cascade, cells undergo apoptosis. We have previously shown that when MPM cells have loss of function mutations in BRCA-1 associated protein 1 (BAP1) they sensitise to TRAIL. BAP1 is involved in several other key cellular functions such as DNA damage response, cell cycle regulation, cell growth and differentiation. Moreover, TRAIL selectively seeks out transformed cells and activates apoptosis making this a therapy of great interest. Methods of utilising TRAIL include recombinant TRAIL (rTRAIL) or through lentiviral transduction of mesenchymal stromal cells expressing TRAIL on their surface (MSCTRAIL). The work I present in this thesis attempts to amplify the effect of TRAIL exploiting key areas that govern its function. I show in vitro that BAP1 plays a non-critical role in homologous recombination and by attempting to exploit this through synthetic lethality using PARP inhibition, a marginal differential response is seen between mutant and wild type cell lines. In addition, I explore the relationship between TRAIL and the immune system. I go on to show that a strong anti-tumour synergistic relationship exists between host immune cells and TRAIL, validated through the development of a syngeneic platform using pleural effusion derived cell lines and matched immune cells from the same patient. Finally, I present work evaluating the role of heat shock protein 90 (HSP90) inhibition and TRAIL confirming a synergistic relationship between the two

Resolution of airway remodelling in a mouse model of chronic allergic asthma

Asthma is associated with chronic airway inflammation and progressive airway remodelling. However, the dynamics of the development of these features and their spontaneous and pharmacological reversibility are still poorly understood. We have therefore investigated the dynamics of airway remodelling and repair in an experimental asthma model and studied how pharmacological intervention affects these processes. Using BALB/c mice, the kinetics of chronic asthma progression and resolution were characterised in absence and presence of inhaled corticosteroid (ICS) treatment. Airway inflammation and remodelling was assessed by the analysis of bronchoalveolar and peribronichal inflammatory cell infiltrate, Goblet cell hyperplasia, collagen deposition and smooth muscle thickening. Chronic allergen exposure resulted in early (goblet cell hyperplasia) and late remodelling (collagen deposition and smooth muscle thickening). After four weeks of allergen cessation eosinophilic inflammation, goblet cell hyperplasia and collagen deposition were resolved, full resolution of lymphocyte inflammation and smooth muscle thickening was only observed after eight weeks. ICS therapy when started before the full establishment of chronic asthma reduced the development of lung Inflammation, decreased goblet cell hyperplasia and collagen deposition, but did not affect smooth muscle thickening. These effects of ICS on airway remodelling were maintained for a further four weeks even when therapy was discontinued. Utilising a model of experimental chronic asthma we have shown that repeated allergen exposure induces reversible airway remodelling and inflammation in mice. Therapeutic intervention with ICS was partially effective in inhibiting the transition from acute to chronic asthma by reducing airway inflammation and remodelling but was ineffective in preventing smooth muscle hypertrophy

Arabic tweeps dialect prediction based on machine learning approach

In this paper, we present our approach for profiling Arabic authors on twitter, based on their tweets. We consider here the dialect of an Arabic author as an important trait to be predicted. For this purpose, many indicators, feature vectors and machine learning-based classifiers were implemented. The results of these classifiers were compared to find out the best dialect prediction model. The best dialect prediction model was obtained using random forest classifier with full forms and their stems as feature vector

Desenvolupament d’un sistema de monitoratge de la qualitat de l’aire en el transport públic

Amb la crisi sanitària que està vivint el món a causa del coronavirus, moltes són les preocupacions i pors dels ciutadans. Les activitats es limiten i s'evita al màxim les aglomeracions de persones per evitar els contagis. Encara així hi ha serveis essencials que per la seva naturalesa sempre concentraran a un gran nombre de persones, es tracta del transport públic. Buscant resoldre les preocupacions dels ciutadans i sob retot donar eines i informació de forma pública per a la conscienciació de la societat, aquest treball busca el desenvolupament d'un sistema capaç de monitorar la qualitat de l'aire al transport públic de la ciutat, inicialment a la ciutat de Barcelona. El desenvolupament del treball engloba un estudi de salut per a definir els components que mesura el sistema i un estudi basat en una recerca acadèmica sobre la influència del coronavirus a l'aire, resultant amb l'exclusió d'aquest del sistema a causa de la dificultat i incertesa de la seva mesura a l'aire. Es desenvolupa un prototip per a la validació del sistema, buscant la seva escalabilitat, la seva adaptació al transport públic i la validació de la tecnologia que sustenta el projecte, la creació d'una xa rxa basada en el IoT (Internet of Things) que sigui capaç de reportar la informació de forma dinàmica en temps real perquè sigui visualitzada pels usuaris del servei a través d'una aplicació mòbil. En aquest document també s'ha inclòs les següents fases pe r a la implementació del projecte en un marc real, així com línies futures per a la millora d'aques

Control of a brushless permanent magnet machine using an integrated torque sensor in place of a rotor position sensor

The work presented in this thesis proposes the use of measured torque feedback from an integrated, low cost surface acoustic wave (SAW) torque transducer in place of a position sensor to control brushless permanent magnet (BLPM) machines. The BLPM machine closed loop control requires knowledge of the rotor position to control stator current and maximum torque per ampere. The electrical position feedback to control the phase current requires a position sensor or position sensorless technique. Position sensors such as absolute encoder or resolver are needed for position information, in the absolute encoder, an accurately patterned disk rotates between a light source and a detector giving a unique digital output signal for every shaft position. However, each bit in the digital world represents an independent track on the encoder disk, resulting in a complex and costly sensors. Brushless resolvers operation is based on inductive coupling between stator and rotor winding. The resolver with its resolver to digital converter also gives precise absolute position information, but again the cost is often prohibitive. So the disadvantages of the position sensors are the added cost and size to the machine. The position sensorless techniques for the BLPM machine are based on obtaining position from the terminal voltages and currents based on estimating the back electro-magnetic force (EMF), flux-linkage or inductance which from position can be estimated. The disadvantages of the back-EMF and flux-linkage techniques are (1) that they behave poorly at zero and low speed (2) behave poorly for load disturbances since load torque is estimated from machine parameters which can change. The inductance techniques work at zero and low speed, however the disadvantages are (1) in a surface mounted machine there is no saliency so any variation of winding inductances with rotor position arises from magnetic saturation; (2) the back-EMF dominates the rate-of-change in the current; (3) the variation of incremental inductances with rotor position undergoes two cycles per single electrical cycle of the brushless pm machine causing an ambiguity in sensed position; (4) the distortion due to the nonlinearities in the inverter; (5) the load offsets and the noise caused by signal injection. This thesis develops a start-up routine and operation algorithms that enhance the performance of position sensorless control of brushless permanent magnet machines at all speeds, including zero speed, and loads by using a machine integrated, low-cost, SAW torque transducer in place of the rotor position sensor.EThOS - Electronic Theses Online ServicePublic Authority of Applied Education in KuwaitGBUnited Kingdo