VictorJuiz/thesis huggingface dataset:
Virus-Like Particles (VLPs) platform for the development of an effective melanoma vaccine

Melanoma is the least common type of skin-cancer but the deadliest one. Cancer immunotherapy is considered a powerful tool in cancer treatment. Nevertheless, therapeutic cancer vaccines have led so far to modest immune responses with little clinical impact. The first part of this work is focused on developing a personalized melanoma vaccine platform based on VLPs and copper-free click chemistry, enabling bedside production of personalized cancer vaccines. There is currently a debate in the field whether cancer-specific, non-mutated germ-line epitopes or mutated neo-epitopes are more powerful antigens for vaccination. To address this issue, we identified melanoma-specific germ-line T-cell epitopes by immunopeptidomic and neoantigens using exome sequencing. Different VLP-based vaccine cocktails were generated, and their immunogenecity was compared in melanoma murine models. We demonstrate that both neoantigens and germ-line epitopes can induce partial protection, but the best therapeutic effect is achieved when combining both. The second part of the thesis tested a new adjuvant microcrystalline tyrosine (MCT) in combination with VLP-based vaccine (CuMVTT). MCT, is an adjuvant that has been used in licensed allergen-immunotherapy products for decades. The adjuvant potential of MCT was also compared to Alum and B-type CpGs. MCT was similarly potent as CpGs and clearly superior to Alum when CD8+ T-cell responses and tumour protection were assessed. Combining a micron-sized adjuvant (MC) with nanoparticles (CuMVTT) appears a particularly attractive strategy as it optimally harnesses the drainage properties of the immune system. Thus, MCT may not only be used in marketed allergy products but may also be promising for induction of protective CTL response. Finally, we focused on delivering antigens and adjuvants in separate virus-like particles. This new technique would be beneficial when designing a personalized VLP-based vaccine as it would be handy to have a ready adjuvanted VLP which can be formulated with the patient’ vaccine at bed-side.

Advisor: Bachmann, M
The ethics of mourning in the narration of the self in the works of Marcel Proust and Andrei Tarkovsky

This thesis gives a new reading of the works of Marcel Proust and Andrei Tarkovsky. First, this intention originates in the apparent oversight in Proustian studies with regard to the ethical dimension of A la recherche du temps perdu: the narrator's relationship with the other is predominantly given a psychoanalytic interpretation. Second, the research is driven by the misrepresentation of Tarkovsky's philosophy that is reflected in the emphasis often placed on the religious aspect of his artistic output. Instead, my research explores the nature and importance of ethics in the works of Proust and Tarkovsky and, for that reason, looks at the themes of death in the Proustian novel and a number of Tarkovsky's films: the thesis posits that our awareness of mortality and meditations on death stem from our encounters with the death of the other and thus are essentially reflections on alterity that, in turn, impact our relationship with it. The study of the philosophical works of Jankélévitch, Levinas, Derrida and Deleuze is undertaken to elaborate these ideas and help understand the meaning behind the aesthetic choices of the artists. Finally, the research employs a phenomenological approach to exploring the works of Proust and Tarkovsky as it appears to fit best the format and objectives of the thesis. In addition to the novelty of attempting the concurrent research of the oeuvre of the artists who lived and created in different periods, cultures and genres, studying Proust and Tarkovsky together within the same theoretical framework and from the same thematic perspective enables us to compare the two artists in a way that exposes and corrects the present misconceptions and misrepresentations about their works and contributes to both Proustian and Tarkovskian scholarship.

Advisor: Howells, C
Moore, G
Healthcare use and costs in relation to body mass index in over one million middle-aged and older women in England

Rates of overweight and obesity worldwide have increased substantially in recent decades. In England, over 60% of adults are now overweight or obese. Because excess weight is associated with higher risks of chronic conditions, including type-2 diabetes, cardiovascular disease, osteoarthritis, and certain cancers, as well as with premature death, it constitutes a major health burden. It is also associated with higher total healthcare spending, but how the associations differ in different healthcare settings is not well understood.
I undertook a systematic literature review of studies that used individual participant data to estimate annual healthcare costs in relation to body mass index (BMI; in kg/m2). Compared to adults at healthy weight (i.e. BMI 18.5 to &LT;25 kg/m2), total annual healthcare costs were found to be 12% and 36% higher for overweight (BMI 25 to &LT;30 kg/m2) and obese (BMI >=20 kg/m2) adults, respectively. The associations were strongest for costs of medications (18% for overweight and 68% for obese adults), followed by inpatient care costs (12% and 34%), and ambulatory care costs (4% and 26%). Most of these studies used data from the United States, and were based on small-to-moderate numbers of participants, limiting their ability to reliably estimate healthcare costs in relation to grades of obesity or for different health conditions. There was no reliable evidence from individual participant data pertaining directly to the United Kingdom.
Using data on over one million middle-aged and older women in the prospective Million Women Study, linked to routine administrative data on deaths, inpatient and day-case admissions, and primary care services, I estimated annual rates and costs of hospital admissions, primary care consultations, prescription items issued, and monitoring and diagnostic tests in relation to body mass index. Every 2 kg/m2 higher BMI beyond 20 kg/m2 was associated with 7.4% higher annual hospital admission costs, 5.2% higher primary care consultation costs, and 9.9% higher prescription costs, but no clear association with test costs was identified. Projecting these results to the total population of women aged 55 to 79 years in England in 2013, 15% (£662 million) of hospital costs, 11% (£229 million) of primary care consultation costs, and 22% (£384 million) of prescription costs were attributable to overweight and obesity. Type-2 diabetes, and cardiovascular and musculoskeletal diseases were the major contributing conditions to the total excess weight attributable costs.
These findings will be useful to healthcare policy makers, commissioners, and providers in making investment and prioritisation decisions, and underline calls for greater investments in cost-effective interventions to reduce excess weight and prevent weight gain.

Advisor: Cairns, B
Mihaylova, B
Gray, A
Jebb, S
Imagined Poland. Representations of the nation state at the exhibitions of industry, craft and design, 1948–1974

This thesis examines the use of design in the construction of Poland’s national identity at the international exhibitions in the Cold War period. It is the first comprehensive study of Polish design discourse in any language that rests at the crossroads of design studies and cultural history. Based on original archival material, both written and visual, and oral interviews this thesis tracks the process of construction of Imagined Poland alongside the development of the design discipline during the three post-war decades. It charts the trajectory of these two narratives and examines their critical reception. In doing so this research casts new light on the relationship between design and political history in the Cold War Europe.
However, it is not a thesis about designed objects or spaces per se, but rather about their discursive qualities and the way that they were put in work to narrate the nation. Versatile and embedded in the cultural, economic and social contexts, design understand here in its broadest sense proved to be well suited to this role: it allowed political authorities, trade representatives and creative intelligentsia to address timely issues on their agendas. This thesis closely examines eight exhibitions organised in the Soviet Union, Italy, Belgium and Poland. The narratives of these events, as the thesis argues, reflected the state’s changing self-understanding towards international public opinion. It indicates that although Polish exhibitions were occasionally adjusted to the particular location, their themes were largely shaped in response to the political developments at home and in the Eastern Europe. By using exhibitions as a framework, this thesis offers a new perspective to study Polish international modernism and suggests a limited impact of ideology on the development of professional networks. Subsequently it provides a nuanced reading of Poland’s relationship with the Soviet Union, the Eastern Bloc and the rest of Europe beyond reductive paradigm of totalitarianism.

Keywords: cultural history
Cold War
exhibitions history
national identity
socialist modernity
Polish design
post-war modernity
Advisor: Betts, P
Investigating the toxicity and safety of radiotherapy for pancreatic cancer

The current level of understanding of the relationship of gastrointestinal toxicity with irradiation of the stomach, duodenum, and small bowel hampers the potential of radiotherapy to contribute effectively to achieving disease control for patients diagnosed with pancreatic cancer. The work in this thesis aimed to further this understanding through compilation and examination of existing informative data, and robust analysis of this relationship within a large cohort of patients treated with radiotherapy to the pancreas, and within a new clinical trial of stereotactic radiotherapy (SBRT).
A systematic literature review was undertaken and publications were identified that found dose-volume parameters for the stomach (V20Gy, V50Gy, D2cm3), duodenum (V25Gy-V55Gy) and small bowel (V40Gy, V50Gy, D2cm3) to be predictive of toxicity in pancreatic cancer. Parameters were fitted for the Lyman-Kutcher-Burman normal tissue complication probability model for the duodenum, using published cohort dose-volume histograms and the associated incidence of toxicity. Results were consistent with previous analyses, showing a dependence on exposure to high dose and small volume effect.
Published small bowel dose-volume histogram data was incorporated into meta-analysis and showed that, for rectal cancer, a significant volume effect exists for all clinically relevant doses (5 Gy to 50 Gy). This was not seen in data regarding irradiation for gynaecological cancer, where a volume effect was only observed at higher doses (40 Gy and over). This difference is thought to be primarily due to the concomitant chemotherapy used in the treatment of these malignancies.
Analysis of the toxicity outcomes for patients treated in the phase-II trials ARCII and SCALOP identified stomach dose-volume parameters predictive of acute gastrointestinal toxicity on multivariable analysis, alongside patient sex and the concomitant chemotherapy regimen utilised. Use of a statistical technique novel to radiotherapy dose-volume analysis was explored (canonical correlation) but was not shown to be superior to existing techniques.
Pre-trial radiotherapy quality assurance for the SPARC clinical trial of pre-operative SBRT was undertaken and found evidence of over-generous clinician contouring in definition of the primary tumour target volume. This was shown to have implications for modelled risk of treatment toxicity, however contouring improved with education and feedback from peers.
In conclusion, intensification of pancreatic cancer radiotherapy is likely to be safe and acceptable for patients, provided that dose to the neighbouring organs of the upper gastrointestinal tract is managed. This may be achieved through accurate target definition and optimisation of the treatment process with control of patient motion and image-guided intensity-modulated radiotherapy or SBRT. Concomitant chemotherapy is shown to be an important modifier of the radiotherapy dose-volume-toxicity relationship.

Keywords: Radiotherapy toxicity
Pancreas cancer
Radiotherapy
Advisor: Hawkins, M
Partridge, M
Aznar, M
Delving deep into fetal neurosonography: an image analysis approach

Ultrasound screening has been used for decades as the main modality to examine fetal brain development and to diagnose possible anomalies. However, basic clinical ultrasound examination of the fetal head is limited to axial planes of the brain and linear measurements which may have restrained its potential and efficacy. The recent introduction of three-dimensional (3D) ultrasound provides the opportunity to navigate to different anatomical planes and to evaluate structures in 3D within the developing brain. Regardless of acquisition methods, interpreting 2D/3D ultrasound fetal brain images require considerable skill and time.
In this thesis, a series of automatic image analysis algorithms are proposed that exploit the rich sonographic patterns captured by the scans and help to simplify clinical examination. The original contributions include:
1. An original skull detection method for 3D ultrasound images, which achieves mean accuracy of 2.2 ± 1.6 mm compared to the ground truth (GT). In addition, the algorithm is utilised for accurate automated measurement of essential biometry in standard examinations: biparietal diameter (mean accuracy: 2.1 ±1.4 mm) and head circumference (mean accuracy: 4.5 ± 3.7 mm).
2. A plane detection algorithm. It automatically extracts mid-sagittal plane that provides visualization of midline structures, which are crucial to assess central nervous system malformations. The automated planes are in accordance with manual ones (within 3.0±3.5°).
3. A general segmentation framework for delineating fetal brain structures in 2D images. The automatically generated predictions are found to be agreed with the manual delineations (mean dice-similarity coefficient: 0.79±0.07). As a by-product, the algorithm generated automated biometry. The results might be further utilized for morphological evaluation in future research.
4. An efficient localization model that is able to pinpoint the 3D locations of five key brain structures that are examined in a routine clinical examination. The predictions correlate with the ground truth: the average centre deviation is 1.8 ± 1.4 mm, and the size difference between them is 1.9 ± 1.5 mm. The application of this model may greatly reduce the time required for routine examination in clinical practice.
5. A 3D affine registration pipeline. Leveraging the power of convolutional neural networks, the model takes raw 3D brain images as input and geometrically transforms fetal brains into a unified coordinate system (proposed as a Fetal Brain Talairach system).
The integration of these algorithms into computer-assisted analysis tools may greatly reduce the time and effort to evaluate 3D fetal neurosonography for clinicians. Furthermore, they will assist understanding of fetal brain maturation by distilling 2D/3D information directly from the uterus.

Keywords: Machine learning
Image analysis
Ultrasound
Fetal brain
Advisor: Noble, J
A commentary on the ninth and tenth books of the Aithiopica of Heliodoros

This commentary attempts to combine the functions of a traditional textual and linguistic study with those of literary criticism. It deals with the many passages in the last two books of the Aithiopica where the text is in doubt or its meaning obscure, and discusses a variety of stylistic points, presenting parallels for many of Heliodoros' peculiar usages. It adduces comparative material to relate Heliodoros' geographical, anthropological and historical setting both to reality and to the beliefs and practices of the ancient world. It also offers the reader of Heliodoros a running commentary on larger issues of narrative technique, characterisation, structure and overall interpretation, shoving how Bks.9 & 10 form the climax of the novel; these elements together form a judgement on Heliodoros' stature as a writer and his success as a novelist.
The Introduction offers a connected treatment of four important themes: Section 1 discusses the dating of the Aithiopica and argues that it must have been written after Shapur's siege of Nisibis in AD 350, but that Heliodoros was not drawing on Julian's account of the siege; the possibility of a shared source is suggested; Section 2 discusses the religious background of the novel and rejects the religious interpretation, arguing that the many references to the supernatural do not shew a consistent view of divine intervention in human affairs and derive from a purely literary desire for unity and forward movement; Section 3 analyses Heliodoros' attempt to achieve realism and classifies the devices he uses; Section 4 discusses the author's prose style and isolates some characteristic features.

Keywords: Emesa
Heliodoros
Aithiopica
Advisor: Reeve, M
West, S
Aristotle on necessity, chance and explanation

Aristotle endorses a very striking doctrine connecting necessity with what seems to be a non-modal notion -- that of 'being or happening always'. He also forges a connection between the idea of 'happening by chance' and 'happening neither always nor for the most part'. These two connections form the subject of this essay. My guiding aim is to provide an account of what the 'always/necessary' doctrine involves and of why Aristotle might have held it. Reflection on the nature of the connection between 'by chance' and 'neither always nor for the most part' throws light on what Aristotle means by 'happening always', and, in consequence, on the nature of the link between 'always' and 'necessary'; it also suggests that the basis of this link is to be found in Aristotle's general conception of the natural world as the object of explanation and knowledge.
The primary texts upon which discussion of these connections must focus are De Caelo I. 12 and the analysis of chance in Physics II. 4—6. I discuss these two texts in turn, after a opening chapter which surveys the evidence for Aristotle's acceptance of the 'always/necessary‘ doctrine and considers the nature of the restrictions which he places on it. Chapter 2 comprises a translation of and commentary on Cael. I. 12, together with a translation and discussion of its companion chapter, I. 10. In Chapter 3, I examine the nature of Aristotle's argument in I. 12, and criticise various interpretations which see it as evidence that Aristotle's 'always/necessary' doctrine rests on a distinctive conception of possibility. The translation of and commentary on Phys. II. 4-6 (Chapter 4) are followed in Chapter 5 by a discussion of issues relating to the association of chance with 'neither always nor for the most part'. The final chapter returns to the question of the connection between 'always' and 'of necessity'.

Keywords: explanation
Physics
Aristotle
necessity
caelo
chance
Structural studies of human GABA-A receptors

Type-A γ-amino-butyric acid receptors (GABAARs) are pentameric ligand-gated ion channels (pLGICs), which mediate the majority of fast inhibitory neurotransmission in the animal central nervous system. Their dysfunction is related to numerous conditions including epilepsy, insomnia, anxiety, panic disorders, depression and schizophrenia. GABAARs are therefore major targets of clinically important drugs, including benzodiazepines and the intravenous general anaesthetics etomidate and propofol, as well as endogenous modulators, for example neurosteroids. Despite recent progress in structural biology of pLGICs, GABAAR structures remain notoriously elusive. Structural information available at the beginning of this project was limited to the benzamidine-bound homopentameric GABAAR-β3, in a desensitised conformation. A large number of fundamental questions, including the molecular architecture of physiological, heteromeric GABAARs, their signalling mechanisms, the binding and action modes of their numerous ligands, remained to be answered.
During this DPhil project, I employed structural biology techniques (X-ray crystallography and single particle cryo-electron microscopy) to further the molecular understanding of human GABAARs. I used subunit-specific llama nanobodies to aid crystallization of homomeric GABAA-β3 receptors, which led to a 3.16 Å structure in complex with the general anaesthetic etomidate. This structure elucidates the binding mode of the etomidate, the basis for its subunit selectivity and illustrates conformational changes it triggers. I then used cryo-electron microscopy to determine the first structure of a heteromeric GABAAR, the human α1b3g2, bound to an activating llama nanobody at a medium (5.2 Å) resolution. The numerous other insights obtained range from unambiguously establishing the subunit arrangement and stoichiometry, to proposing a mechanism for receptor assembly and discovering an unexpected role played by N-linked glycans in this process.
The work described here opens multiple avenues for future research. Immediate opportunities include high resolution structural characterization of heteromeric GABAARs, via cryo-electron microscopy, further development of nanobodies as novel, high affinity and subunit specific tools to modulate GABA-ergic signalling, and structural characterization of numerous small-molecule modulators, of clinical and physiological relevance, bound to human GABAARs.

Keywords: CNS
Inhibitory signalling
Protein production
Structural biology
Membrane proteins
Advisor: Aricescu, A
Bannerman, D