107 research outputs found
Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models
No full textImmune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells. However, a substantial number of patients treated with ICB develop relapse or do not respond, which has been partly attributed to the immune-suppressive effect of tumour hypoxia. We have previously demonstrated that the mitochondrial complex III inhibitor atovaquone alleviates tumour hypoxia both in human xenografts and in cancer patients by decreasing oxygen consumption and consequently increasing oxygen availability in the tumour. Here, we show that atovaquone alleviates hypoxia and synergises with the ICB antibody anti-PD-L1, significantly improving the rates of tumour eradication in the syngeneic CT26 model of colorectal cancer. The synergistic effect between atovaquone and anti-PD-L1 relied on CD8+ T cells, resulted in the establishment of a tumour-specific memory immune response, and was not associated with any toxicity. We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention
Introduction to the National Cancer Imaging Translational Accelerator (NCITA): a UK-wide infrastructure for multicentre clinical translation of cancer imaging biomarkers
No full textThe National Cancer Imaging Translational Accelerator (NCITA) is creating a UK national coordinated infrastructure for accelerated translation of imaging biomarkers for clinical use. Through the development of standardised protocols, data integration tools and ongoing training programmes, NCITA provides a unique scalable infrastructure for imaging biomarker qualification using multicentre clinical studies
Sociality and the rate of molecular evolution
No full textCopyright © The Author 2005. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved.The molecular clock does not tick at a uniform rate in all taxa but may be influenced by species characteristics. Eusocial species (those with reproductive division of labor) have been predicted to have faster rates of molecular evolution than their nonsocial relatives because of greatly reduced effective population size; if most individuals in a population are nonreproductive and only one or few queens produce all the offspring, then eusocial animals could have much lower effective population sizes than their solitary relatives, which should increase the rate of substitution of "nearly neutral" mutations. An earlier study reported faster rates in eusocial honeybees and vespid wasps but failed to correct for phylogenetic nonindependence or to distinguish between potential causes of rate variation. Because sociality has evolved independently in many different lineages, it is possible to conduct a more wide-ranging study to test the generality of the relationship. We have conducted a comparative analysis of 25 phylogenetically independent pairs of social lineages and their nonsocial relatives, including bees, wasps, ants, termites, shrimps, and mole rats, using a range of available DNA sequences (mitochondrial and nuclear DNA coding for proteins and RNAs, and nontranslated sequences). By including a wide range of social taxa, we were able to test whether there is a general influence of sociality on rates of molecular evolution and to test specific predictions of the hypothesis: (1) that social species have faster rates because they have reduced effective population sizes; (2) that mitochondrial genes would show a greater effect of sociality than nuclear genes; and (3) that rates of molecular evolution should be correlated with the degree of sociality. We find no consistent pattern in rates of molecular evolution between social and nonsocial lineages and no evidence that mitochondrial genes show faster rates in social taxa. However, we show that the most highly eusocial Hymenoptera do have faster rates than their nonsocial relatives. We also find that social parasites (that utilize the workers from related species to produce their own offspring) have faster rates than their social relatives, which is consistent with an effect of lower effective population size on rate of molecular evolution. Our results illustrate the importance of allowing for phylogenetic nonindependence when conducting investigations of determinants of variation in rate of molecular evolution.Lindell Bromham and Remko Ley
Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen
No full textColony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization
Comparison of the Buckling Performance of Grid Stiffened and Sandwich Structures designed for Wind Turbine Blade Trailing Panels
No full textFuture wind turbines require larger rotor blade radius, leading to an increase of rotor swept area. The larger rotor swept area results in more energy production of the wind turbine. Further increase is however limited as a result of the structural weight, which induces a large bending moment and could result in buckling of the rotor blade. An innovative design solution resulting in a lower weight blade design could be acquired by introducing a grid stiffened structure as a substitution of the conventional sandwich structure. Design and analysis showed an increase in specific stiffness of the grid stiffened structure for higher loading conditions. In an attempt to validate the obtained results, one sandwich and one orthogrid panel has been manufactured and tested.Aerospace Engineerin
Liquid crystalline polymers in crosslinked systems and coatings
No full textThis essay contains a literature research about liquid cristalline polymers in crosslinked systems and coatings. An attempt has been made to give an overall picture of the development of the investigations into liquid crystalline elastomers and the use of liquid crystalline polymers in coatings. Syntheses and characterizations of liquid crystalline (lc) elastomers based on side chain polysiloxanes and side chain, main chain and combined chain poly(meth)acrylates are described. Then the viscoelastic behaviour and orientations of these lc elastomers are discussed. Further the application of lc polymers in coatings are discussed. The lc elastomers combine rubber properties properties, which combination results in technological and scientifical interest.Applied SciencesChemical Technology and Materials ScienceTechnologie van Macromoleculaire Stoffe
(Opto)mechanical design of the Single Laser Adaptive Optics system for ELT/METIS
No full textThe Mid-infrared ELT Imager and Spectrograph (METIS), which will be one of the first-light instruments on the Extremely Large Telescope (ELT), will be equipped with an Adaptive Optics (AO) system that will use a natural guide star as reference for the correction of the wavefront errors, introduced by the atmospheric turbulence. Even though this system will suffice for the achievement of the instrument’s primary science goals, it will not allow for observations of additional objects of interest, due to the limited sky coverage it offers. In order to increase the sky coverage of the instrument, a supplementary AO system, which will use a single laser guide star as reference, is planned to be added at a later stage. In the present thesis, a possible solution for the (opto)mechanical design of this laser-assisted AO system is provided, which ensures compliance with the predetermined mass, volume and budget limits.Aerospace Engineerin
Two-way Augmented Reality Co-location Under Telemedicine Context
No full textThe medical care responsibilities are often on the shoulders of nonprofessionals such as captains who are equipped with forty hours of designated training every five years. However, this training is neither enough for the captains to handle medical incidents nor releases their stress during the treatment. Currently, captains have very limited support from a medical expert, only via phone call or email from the Radio Medical Services. Thus, the authors explored that how the two-way augmented reality (AR) can support the collaboration between captains and doctors for a better quality of care. A Human-Centred Design approach is applied in this study, including field study and user testing. The lean user experience method was applied with fast prototyping-testing loops. The main findings are AR played an essential role to boost confidence on the captain's side, and the real value of AR is in supporting medical skills like suturing and abdominal searching. This study serves as a pilot research, thus it was limited by small sample size and qualitative method. Improving the communication between the captains and doctors is key for future studies.Accepted Author ManuscriptApplied Ergonomics and Desig
An exploratory research into the design of a medical product-service setup with 2-way augmented reality for the maritime sector
No full textCaptains are responsible for the medical care of their crewmembers. To do this, they receive one week of training every five years during which they study the knowledge and practice the skills and processes to handle medical incidents on board. The week of training is not enough for the captains to handle medical incidents confidently and they are in need of support.Currently, the support for captains is limited to phone calls and email with a doctor from the Radio Medical Services. MedAssist.online invented 2-way-AR technology, a unique method of merging two realities into one using tablets and a green screen. The merging of two realities creates the possibility to give instructions to the captain using hands as an overlay on the video. The 2-way-AR video function is put at the centre of a service which is designed to match the treatment journey and increase the number of interactions between a doctor and captain. A service which uses live video with the addition of 2-way-AR technology has the potential to become the telemedicine solution that boosts the confidence of the captains and their treatment performance. Boosting confidence is essential to help the captain be decisive in his actions. However, the real value of 2-way-AR is in supporting the captain perform medical skills like stitching and abdominal searches. This thesis researched the tablet positions and camera positions on both sides of the communication. For the doctor set-ups for different tablet positions were designed and tested to give him optimal control over his hands to give instructions. On the captain side, the camera position and tablet position were explored, built and tested. The set-up is evaluated on the understanding of the doctor of the captain's situation, his ability to interpret and implement the instructions and the flexibility of the set-up for multiple medical scenarios. From testing various set-ups, it was concluded that an additional camera on the captain side improves the ease of understanding for the doctor and his ability to give instructions. At the same time, the captain can put the tablet in a position where he can easily switch between the patient and tablet to implement the instructions, without the tablet obstructing his work area. This thesis has focussed on the physical set-ups of the tablet, camera and green screen on the captain and doctor side. The final test showed improvements in the new set-up design over the old, but there is an opportunity to improve the communication between the doctor and captain.Integrated Product Design | Medisig
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