VictorJuiz/thesis huggingface dataset:
Investigating multi-modal therapy with radiotherapy, vascular-targeted photodynamic therapy and immunotherapy in pre-clinical models of prostate cancer

Radiotherapy enhances innate and adaptive anti-tumour immunity. It is unclear whether this effect may be harnessed by combining immunotherapy or vascular-targeted photodynamic therapy with radiotherapy fractions used to treat prostate cancer. Firstly, the aim of this study was to investigate the tumour immune microenvironment and tumour vascular responses of pre-clinical prostate cancer models to radiotherapy. Having defined this landscape, the effects of combining fractionated radiotherapy with anti-PD-L1 immune checkpoint blockade or vascular-targeted photodynamic therapy on tumour growth delay was investigated. 3 x 5 Gy caused tumour growth delay in TRAMP-C1 and MyC-CaP. Tumour immune microenvironment changes in TRAMP-C1 at 7 days post-radiotherapy included increased tumour-associated macrophages and dendritic cells and upregulation of PD-1/PD-L1, CD8+ T-cell, dendritic cell, and regulatory T-cell genes. At tumour regrowth post 3 x 5Gy the tumour immune microenvironment flow-cytometry was similar to control tumours, however CD8+, natural killer and dendritic cell gene transcripts were reduced. PD-L1 inhibition plus 3 x 5 Gy in TRAMP-C1 did not enhance tumour growth delay versus monotherapy. Fractionated radiotherapy induced 'vascular normalisation' changes in prostate cancer flank tumour allografts, improving vascular function as demonstrated using dynamic contrast-enhanced magnetic resonance imaging. Fractionated radiotherapy followed by vascular-targeted photodynamic therapy significantly delayed tumour growth in flank prostate cancer allograft pre-clinical models, compared with monotherapy with fractionated radiotherapy or vascular-targeted photodynamic therapy, and improved overall survival. This research suggests that multi-modal therapies for prostate cancer beyond immunotherapy may be necessary to achieve radiotherapy-induced anti-tumour responses. Combining fractionated radiotherapy with vascular-targeted photodynamic therapy may be a promising multimodal approach in prostate cancer therapy. This research provides proof-of-concept for this multimodality treatment to inform early phase clinical trials.

Keywords: vascular-targeted photodynamic therapy
animal models
tumour immune microenvironment
prostate cancer
ionising radiation
Advisor: Bryant, R
Mills, I
Muschel, R
Using aerosol Bacille Calmette-Guérin in non-human primates to model the immune response to Mycobacterium Tuberculosis: a translational bridge between preclinical models and clinical trials

Tuberculosis (TB) is a major cause of death worldwide. We have a limited understanding of how the human immune system responds to Mycobacterium tuberculosis (M.tb), the main infectious agent that causes TB. In this project, non-human primates (NHPs) were exposed by aerosol to 1x107 colony forming units (CFU) of Bacille Calmette-Guérin (aeBCG). BCG is a live attenuated strain of Mycobacterium bovis, which can be used as a model of M.tb infection, and was safe to deliver to NHPs in a controlled manner.
The immune response to aeBCG was characterised across different tissue compartments: blood, broncho-alveolar lavage (BAL), lymph nodes (LNs) and lung. There was little overall change in the immune parameters measured in either rhesus or cynomolgus macaques (RM or CM) at Day 2 (D2), D7 or D14 after aeBCG. Expression of cluster of differentiation-161 (CD161) on lymphocyte subsets was an early marker of this response at Week 2 (Wk2).
Purified Protein Derivative (PPD)-specific interferon-gamma (IFNg)-producing spot forming unit (SFU) frequency increased from Wk4 to Wk16 after aeBCG. The peak immune response, measured by flow cytometry was at Wk12. PPD-specific immunoglobulin-G (IgG) titre increased at Wk9 in serum. The kinetic of the immune response to aeBCG measured was similar, but delayed, compared to the previously published immune response to intradermal (ID) BCG6, 8. The aeBCG delivery method (mask or mouthpiece) had no effect on the observed changes in immune parameters. Data from animals in both delivery groups were combined (n=16).
A parallel experimental clinical medicine study showed the peak immune response to 1x107 CFU aeBCG in humans was at D7 (McShane group, Oxford – ClinicalTrials.gov ID: NCT03912207). The differences in immune response kinetic detected between NHPs and humans shown in this project have not been previously described and merit further study.

Keywords: TB
macaque
NHP
aerosol
human
Mycobacterium
model
Tuberculosis
non human primate
BCG
Advisor: McShane, H
Sharpe, S
White, A
Satti, I
Development of new multicomponent reactions for 1,3,4-oxadiazole synthesis

Chapter 1 introduces the chemistry of 1,3,4-oxadiazoles with a specific focus on currently available strategies, and methodologies for their synthesis. Five distinct synthetic approaches – 1) dehydration of 1,2-diacylhydrazines; 2) oxidative cyclizations of N-acyl hydrazones; 3) C-H functionalization of 2-substituted 1,3,4-oxadiazoles; 4) rearrangements of N-H tetrazoles; 5) reactions using (N-isocyanoimino)triphenylphosphorane (NIITP) as a three atom CNN source – are discussed in detail and their limitations evaluated.

Chapter 2 focuses on a novel three-component reaction for the reductive synthesis of α-amino 1,3,4-oxadiazoles (or heterodiazoles), from tertiary amides and lactams, feedstock carboxylic acids (or appropriate C-, S-, N-Brønsted acids), and NIITP. Taking advantage of the mild and chemoselective reductive activation of tertiary amides provided by the combination of Vaska’s complex and 1,1,3,3-tetramethyldisiloxane (TMDS) the reaction was applied to the late-stage functionalization of ten drug-like amides and carboxylic acids and culminated in the synthesis of three heterodiazole-fused drug-drug conjugates.

Chapter 3 demonstrates that N-carbamoyl imines, with carboxylic acid (or N-acyl sulfonamide) coupling partners and NIITP, can efficiently generate N-carbamoyl α-amino 1,3,4-oxadiazole (or 1,2,4-triazole) structures in a three-component reaction – expanding the existing scope of C=N electrophiles used with NIITP. A successful scale-up of this methodology allowed the gram-scale synthesis of a primary α-amino 1,3,4-oxadiazole, and a subsequent investigation into its derivatization.

Chapter 4 presents the merger of two modern approaches for 1,3,4-oxadiazole synthesis – 2-substituted 1,3,4-oxadiazole construction using NIITP and the C-H functionalization of 2-substituted 1,3,4-oxadiazoles – into a one-pot and multicomponent protocol for synthesis of 2,5-disubstituted, or 2-amino-5-substituted, 1,3,4-oxadiazoles. A preliminary investigation into the use of nucleophilic secondary amine coupling partners for synthesis of 2-amino-5-substituted 1,3,4-oxadiazoles is additionally discussed.

Keywords: 3
organic chemistry
4-oxadiazole
1
multicomponent reactions
Advisor: Dixon, D
Venerating saints and constructing cults in an age of reform: male and female monastic communities and their saints in late tenth- and early eleventh-century England

Why was there a proliferation of saint-making in late tenth- and early eleventh-century England? New saints, ancient saints, universal saints, and obscure saints were venerated with striking vigour. Litanies, calendars, prayerbooks, and Latin and vernacular hagiographical collections attest to a remarkable and devoted interest in the saints of Christian history in this period. The answer to this striking development lies with those responsible for the care of the saints: monasteries and nunneries. While not the unique owners of saints’ relics, both male and female monastic congregations nonetheless presented themselves as uniquely qualified custodians. They achieved this representation by capitalising on an ideology of reform monasticism which began to develop in the second half of the tenth century. Traditionally labelled the ‘Benedictine Reform,’ this period in English history has been studied primarily from the perspective of three episcopal leaders who promoted the reform of monastic life. This thesis foregrounds congregations, rather than the bishops, and reveals that ‘reform’ operated dynamically and outside the control of these reformers. The ideology crafted by the reformers elevated monastic men and women to an exceptional status. Sensitive to the potential of this ideology, new male and female congregations integrated the rhetoric of reform into their cults. They created new cults and revived ancient ones with the rhetoric of reform and monastic exceptionalism. Over the course of the late tenth and early eleventh century, monastic virtue and the language of sanctity became blended as male and female congregations embedded themselves in a scheme of Christian history and an increasingly diverse religious landscape.

Keywords: sanctity
nunneries
monasticism
cults
monasteries
Anglo-Saxon England
Benedictine reform
10th century
reform
saints
monastic reform
liturgy
Advisor: Foot, S
From local to global: biodiversity estimation and implications

Biodiversity describes the variety of life from genes to species and ecosystems, providing essential ecosystem services for humans. However, global biodiversity is in peril due to unsustainable human appropriation of ecosystem products and ecosystem transformations to other utilisations. Meanwhile, due to complex spatial patterns and highly dynamic changes, data describing and explaining biodiversity are also heterogeneous. Studies that used longitudinal and cross-sectional data to investigate global diversity change sometimes draw divergent inferences. This suggests an urgent need for helpful diversity estimation to account for the complex interactions amongst species, humans, and natural and built environments. In this thesis, I focus on spatial sample coverage, scale, structure and human-nature interaction that may influence diversity estimation. I also demonstrate that proper diversity estimates are essential for evidence-based conservation by testing whether conservation translocation (i.e., rewilding) can fill native functional gaps effectively.

First (Chapter 2), based on neutral community models, I demonstrate that spatial sampling coverage and scales can reconcile divergent inferences on global diversity trends. I show that estimated diversity trends in a landscape with declined diversity can be both increased and decreased in the case where spatial sampling coverage is small, and the local survey scale is imprecise. Next (Chapter 3), I analyse the spatial distribution of diversity time-series recognised as having similar behaviours in temporal variation. I find that spatial diversity patterns can be independent of geographic structure if incorporating information of continued diversity change in the past. Expanding to a perspective of longitudinal analyses (Chapter 4), I illustrate that survey behaviours may respond differently to habitat change during long-term biological survey programmes. I find a significant proportion of survey cessations were associated with habitat change. As habitat change often causes diversity loss, this implies a failure in recording decreased diversity in studies estimating temporal diversity trends. Finally (Chapter 5), I shift to a conservation context and contrast rewilding with three other processes that influence native diversity. I show that effects of different processes vary much in infilling or expanding native functional space and functional diversity change caused by rewilding species are idiosyncratic.

Overall, this thesis contributes to elucidating the relationship between actual and estimated nature across scales, notably in diversity estimates. It also demonstrates how spatial structure, scale, and community history may influence estimated diversity patterns and the direct causal implications for shaping conservation strategies. Together, these findings form a foundation for expanding our understanding of the ecological implications of diversity estimation and the mechanisms underpinning this (Chapter 6).

Advisor: Sheldon, B
Grenyer, R
Gaston, K
Mechanistic studies of DNA repair and genome instability

The accurate repair of DNA damage is essential for protecting cells from undergoing cell death or accumulating mutations. The multi-topical work presented within this thesis focuses on the mechanistic study of DNA repair and sources of genome instability.
Interstrand crosslinks (ICLs) are toxic DNA lesions that block the essential cellular processes of transcription and replication. The mechanisms of ICL repair pathways in non-dividing cells are poorly characterized. This study aims to determine the mechanisms for a transcription- associated ICL repair pathway. After developing an in vitro biochemical system to study ICL repair, it is demonstrated that the CSB transcription-coupled repair factor can directly stimulate the SNM1A exonuclease in the unhooking of ICLs. A novel functional stimulatory interaction between the XPF-ERCC1 endonuclease and the SNM1A exonuclease is also identified. The experiments described here suggest that transcription-associated repair of ICLs may result in formation of toxic DSBs that are repaired by non-homologous end joining.
It was recently identified that cancer cells with microsatellite instability (MSI) undergo cell death after genetic knockdown of the Werner helicase (WRN), though the mechanism for this is unknown. We provide evidence that depletion of WRN in MSI cells generates DNA double- strand breaks (DSBs) at (TA)n microsatellite repeats. In MSI cancer cells, (TA)n microsatellite repeats undergo expansion and form stable non-B DNA cruciform structures. If these structures are not unwound by the WRN helicase, they are cleaved by the MUS81-EME1 nuclease, resulting in DSB formation across the genome. This study identifies expanded (TA)n repeats as a biomarker for MSI cells’ synthetic lethal dependence on WRN and supports the concept of developing WRN inhibitors for the treatment of MSI cancers.
Neurons are long-lived, post-mitotic cells that are believed to face high rates of endogenous DNA damage. Surprisingly little is known about the causes of endogenous DNA damage in neurons and where in the genome the damage occurs. We demonstrate that DNA single- strand breaks (SSBs) occur at neuronal enhancers. These SSBs are largely repaired through PARP1, XRCC1, and Pol β-dependent mechanisms. The sites of these breaks overlap with sites of TET-mediated oxidation of 5-methylcytosine, suggesting that demethylation of DNA could be the source of endogenous SSB formation at neuronal enhancers. This work highlights a novel research technique called S1-END-seq for the genomic mapping of DNA SSBs.

Keywords: microsatellite instability
cockayne syndrome
non-dividing cell
SNM1A
neurodegeneration
single strand break
XPF
DNA repair
neurons
MUS81-EME1
transcription
genome instability
demethylation
cruciform
WRN
cancer
interstrand crosslink
Advisor: McHugh, P
Wilson, D
Nussenzweig, A
Geometric insights from supergravity in the AdS/CFT correspondence

The aim of this thesis is to explore new constructions in supergravity to gain insights into the AdS4
/CFT3
and AdS5
/CFT4
correspondences.
We start by deriving a simple formula for the action of any supersymmetric solution to minimal gauged supergravity in the AdS4
/CFT3
correspondence. We find that the holographically renormalized action localizes to the fixed points of a supersymmetric Killing vector and may then be expressed entirely in terms of topological data. In this sense, the gravitational partition function localizes in the bulk. Our general formula reproduces all known examples in the literature and makes predictions for new solutions, assuming they exist.
Also in D=4
, N=2
minimal gauged supergravity, we sudy a class of accelerating, rotating and dyonic black holes in AdS4
. %When the acceleration is non-vanishing, These D=4
black hole metrics have conical singularities but we find a new way to desingularize them by uplifting to solutions of D=11
supergravity using a regular Sasaki-Einstein SE7
manifold. These D=11
solutions are associated to M2-branes wrapped around a two-dimensional weighted projective space, WCP
1
[n−,n+]
, also known as a spindle, and we find that supersymmetry is not preserved through a usual topological twist. We also discuss the supersymmetric and extremal limits of these solutions and compute the entropy of these black holes, arguing that it should be possible to derive it from certain N=2
, d=3
quiver gauge theories compactified on a spinning spindle with magnetic flux.
In the AdS5
/CFT4
correspondence we continue exploring these ideas by constructing AdS3×WCP
1
[n−,n+]
solutions of different D=5
supergravity theories. Again we find that these solutions can be uplifted to find smooth solutions in D=10/11
and that supersymmetry is preserved in a different way than through the topological twist. Our construction suggests a path to the dual d=2
, N=(0,2)
SCFTs in the IR, associated to D3 or M5 branes wrapped on a spindle. We make a precision test of this conjecture by computing the central charge and R-symmetry of the field theories and find agreement with the gravity computations in all cases.

Keywords: AdS/CFT correspondence
string theory
supergravity
Advisor: Sparks, J
Zintl ions as molecular analogues of liquid alloys for C–H activation

This thesis describes the reactivity of the tris-hypersilyl substituted nonagermanide Zintl cluster [KGe9(Hyp)3] (Hyp = Si(SiMe3)3) towards group 9 and 10 transition metal organometallic complexes. The resulting Zintl clusters were then modified and tested in catalysis as molecular models for transition metal–main group element alloys (TMMGAs).
Firstly, nickel germanide clusters were synthesised, which were formed by vertex addition or substitution chemistry and further studied using cyclic voltammetry.
Next, the rhodium germanide cluster [Rh(COD){Ge9(Hyp)3}] (COD = 1,5-cyclooctadiene) was targeted in order to prepare a reactive metal alkene complex on the [Ge9(Hyp)3] support. This was then used as the first Zintl cluster based homogeneous catalyst in catalytic alkene hydrogenation.
This cluster was then modified by ligand substitution at the rhodium centre to produce highly fluctional clusters with the general formula [Rh(L){Ge9(Hyp)3}] (L = C2Me2, DPPE, PMe3, PPh3, IMe4, (Cp)2WH2). These were studied in catalytic processes which involve H–H and C–H bond activation.
Finally, [Rh(COD){Ge9(Hyp)3}] was modified by the addition of group 9 and 10 metal alkene fragments to the germanium support, showing that the cluster can be controllably expanded towards homo- and hetero-multimetallic clusters.

Keywords: rhodium
catalysis
organometallics
nickel
inorganic
xluster
Zintl
Advisor: Goicoechea, J
Weller, A
Robust localization in urban and natural environments

This thesis proposes methods for global localization in urban and natural environments. The proposed approaches focus on segment-based localization systems for loop closures in the context of SLAM, alleviating the need for explicit fine-tuning or parameter fitting.
Initial analysis of current state-of-the-art systems are conducted and their performance in urban and natural environments is evaluated. We propose a hybrid feature descriptor method that does not rely only on the geometry of objects, but also considers the distribution of points within those objects. The segmentation differences encountered in natural environments are addressed by a novel key pose extraction technique.
Inspired by the ability of deep networks to generalize to multiple terrains, we propose a novel deep architecture capable of generalizing between natural and urban scenes. We design a state-of-the-art point cloud based network with efficiency in mind that is also deployable on computationally constrained platforms, such as drones, legged robots, or UGVs. The proposed objective function recognizes similar objects without any semantic information. We also extract a matchability score between segments that we use in a probabilistic geometric verification stage for coarse registration.
The analysis of the point-based architectures led to exploration of the bot- tlenecks in the computational complexity of these models. We propose a sub- sampling method allowing us to shrink an existing network architecture with- out sacrifice in performance. In addition, substantial analysis are presented on different training and test data variation for all the localization methods. The evaluation was performed on data from over 300 km of driving, that we manually pre-processed and made available to the community.
The final contribution is a method for learning keypoint regions that can be applied to any differentiable descriptor. The proposed framework is a substitute for the first step in segment-based localization systems.
This thesis also presents two applications of the above contributions. First, motivated by the expressive power of the geometric features, we propose a verification system that seeks to predict when localization failures occur in the environment. Specifically, we leverage some of the geometric features from our localization system to propose a classifier that predicts alignment risk based on overlap and degenerate geometric constraints. Second, we en- capsulate the proposed loop closure method into a full SLAM system which is also deployed on the ANYmal quadrupedal robot. The proposed deep learned loop closure method shows improved scalability when compared to geometric-based loop closure systems.

Keywords: localization
keypoint detection
point cloud
mapping
LIDAR
SLAM
Advisor: Fallon, M
A lipid-based parallel processor for chemical signals

A key goal of drug delivery and bottom-up synthetic biology is to construct structures that interact with their environment. Biological cells and tissues can process several external chemical signals, often in parallel, without cross-talk. However, so far, cell- and tissue-like structures with only one signalling pathway have been generated. Here, using lipid-bounded aqueous compartments, we build a three-compartment processor with an architecture analogous to that of dual-core central processing units. Each compartment is optimised for a distinct task such as signal transmission, sensing, and enzymatic processing. Recombinantly generated pore-forming membrane protein alpha-hemolysin in the signal transmission compartment enables fast exchange of chemicals between the processing compartments and the external environment. The processor can receive two chemical signals from the environment, process them orthogonally, and produce an output for each signal. The output can be fluorescence or the production and release of a molecule into the external environment. We build the processor from the bottom up, in a modular fashion. In two compartment processors containing a signal transmission compartment and another compartment of varying contents, we demonstrate signal release, signal intake, enzymatic DNA cleavage and enzymatic hydrolysis. We then combine various compartments to build three-compartment processors able to process chemical signals in parallel.

Advisor: Bayley, H
Booth, M