VictorJuiz/thesis huggingface dataset:
The role of HER4 in relation to trastuzumab resistance and prognosis in HER2 positive breast cancer
Keywords: nuclear HER4
HER2 positive
trastuzumab resistance
breast cancer

Background
Trastuzumab resistance imposes a major limitation to the successful treatment of HER2 positive breast cancer. The expression of HER4 and its prognostic value is controversial in breast cancer. Furthermore, its role in trastuzumab treatment and resistance in HER2 positive breast cancer has not been reported.
Methods
The effects of trastuzumab on HER4 cleavage and its localisation were studied in both parental and trastuzumab-resistant SKBR3 and BT474 cells using western blot, RT-PCR, nuclear fractionation and confocal microscopy. Tissue microarrays consisting of a cohort of HER2 positive breast cancer patients were stained for HER4 by immunohistochemistry and the results were correlated with patients’ outcome. This study also assessed HER4 expression in the tumor samples from a window study of trastuzumab alone or in combination with neoadjuvant chemotherapy in HER2 positive breast cancer patients.
Results
Trastuzumab treatment upregulated HER4 mRNA, and increased expression of both 80 and 180 kDa HER4 protein isoforms, and induced nuclear translocation of 80kDa HER4 protein isoforms, which the results similar to heregulin stimulation. This was also seen in trastuzumab resistant cells although HER480kDa and nuclear HER4 decreased upon overnight withdrawal of trastuzumab in resistant cell lines. In addition, knockdown of HER4 protein expression by specific siRNAs increased trastuzumab sensitivity and reversed trastuzumab resistance in SKBR3 and BT474 cells, confirming the importance of HER4 in trastuzumab response. This study also showed that trastuzumab-induced HER4 nuclear translocation is due to HER4 activation and cleavage since γ-secretase inhibitor (GSi) and neratinib prevented the process when combined with trastuzumab treatment, correlating with an increased apoptosis and decreased cell viability. There was also increased nuclear HER4 expression in tumors from both BT474 xenografts and from patients with breast cancer treated with trastuzumab monotherapy. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was a poor prognostic factor in HER2 positive breast cancer.
Conclusions
This study suggests HER4 activation, cleavage and nuclear translocation play a key role in trastuzumab resistance in HER2 positive breast cancer. Nuclear HER4 could be a novel predictive and prognostic biomarker in HER2 positive breast cancer patients.
A study of B→DK and D0 production using D0→K+pi-pi+pi- decays at LHCb
Keywords: flavor physics
RICH
flavour physics
charm production
LHCb

A study of B(→)DK and D0 production using D0(→)K+pi-pi+pi- decays at LHCb
A precision measurement of the CKM angle γ from tree-level processes is one of the principal goals of the LHCb experiment. Two important channels for the extraction of γ are B±→D0K± and B±→D̅ 0K±; a first study of these modes is presented using an integrated luminosity of Lint=35.6 ± 3.6pb−1 at a pp centre-of-mass collision energy of √—s=7TeV. A measurement is made of the ratio of branching fractions BDK/BDπ= Γ(B±→DK±)/Γ(B±→Dπ±)= 0.057 ± 0.007 ± 0.004 using B±→(K±π∓π±π∓)DK± and B±→(K±π∓π±π∓)Dπ± four-body D decay modes. This has an uncertainty competitive with the previous world average of (7.6 ± 0.6)%. A measurement is also made of the rate asymmetry between B−→(K−π+π−π+)DK− and B+→(K+π−π+π−)DK+ decays,
Ac K3π
fav
=    Γ(B−→(K−π+π−π+)DK−)−Γ(B+→(K+π−π+π−)DK+)
Γ(B−→(K−π+π−π+)DK−)+Γ(B+→(K+π−π+π−)DK+)   = 0.01 ± 0.11 ± 0.06.
As expected, this result is consistent with zero within statistical and systematic uncertainties.
The D0/D̅ 0 production cross-section in bins oftransverse momentum and rapidity from prompt D0→K−π+π−π+ decays (and its charge conjugate) is presented, usingLint= 14.96 ± 0.52nb-1 of √—s=7TeV LHCb pp collision data. This measurement is important for testing predictions of QCD theoretical models, and determining LHCb's sensitivity to measurements of CPviolation, mixing measurements and rare decays of charmed hadrons. The results are compared to predictions from two different theoretical models and from the default LHCb tuning of the PYTHIA Monte Carlo event generator, and the results shown to be in good agreement. The cross-section results are also compared to an independent LHCb measurement in the D0→K−π+ decay channel.
LHCb analyses rely on the ability to identify kaons and pions with a high efficiency and low mis-identification rate, achieved by two Ring Imaging Cherenkov (RICH) detectors. To ensure optimal performanceof the RICH detectors, the time alignment of the Level-0 (L0) front-end electronics modules has been optimised using a combination of a pulsed laser system installed in the LHCb cavern and pp collision data. After the time-alignment procedure, the L0 modules have been time-aligned to within approximately ±1ns across both detectors.
‘Better active today than radioactive tomorrow!’ : transnational opposition to nuclear energy in France and West Germany, 1968-1981
Keywords: transnational
1968
1970s
nuclear power
social movements
Europe
West Germany
nuclear energy
protest
France

This thesis examines the opposition to civil nuclear energy in France and West Germany during the 1970s, arguing that small-scale interactions among its diverse participants led to broad changes in their personal lives and political environments. Drawing extensively on oral history interviews with former activists as well as police reports, media coverage and protest ephemera, this thesis shows how individuals at the grassroots built up a movement that transcended national (and social) borders.
They were able to do so in part because nuclear power was such a multivalent symbol at the time. Residents of towns near planned power stations felt that nuclear technology represented an intervention in their community by state and industry, a potential threat to their health, wealth and way of life. In the decade after 1968, concerns like these coalesced with criticisms of capitalism, the state, militarism and consumer society that were being made by a more politicised constituency. This made the anti-nuclear movement both broad-based and highly fragmented. Activist networks linked people across existing national, political and social boundaries, but the social world of activism was subject to its own divisions (such as between locals and outsiders or between militant and non-violent activists).
By analysing both the transnational dimensions and internal divisions of the anti-nuclear movement, this thesis revises the homogenising concepts of social movements that are prevalent in much of the existing sociological and political science literature. At the same time, it situates the anti-nuclear movement historically within the decade of upheaval that was the 1970s, while moving individual activists from the margins to the centre of protest history.
The evolutionary economic geography of climate change
Keywords: Economic Geography
Adaptation
Mitigation
Climate Change

The evolutionary economic geography of climate change is concerned with the processes by which the landscapes of greenhouse gas emissions and vulnerability to climate change are transformed from within over time. Unlike neoclassical economics, evolutionary economic geography is interested in how economic change is driven by innovation and shaped by structural, historical, and contextual factors at different scales. This thesis articulates an evolutionary economic geography perspective on three debates: (1) What factors influence human systems’ capacity to adapt to climate change, and how can these factors be assessed? (2) What forces drive and inhibit economic change towards low-carbon economies, and how should governments induce and manage such shifts? (3) What role should climate finance play in promoting developing countries’ shifts to low-emitting and climate-resilient economies, and how should it be managed? The thesis includes five academic papers. The first reviews the literature on vulnerability and adaptation. It argues that the adaptive capacity of human systems is constrained by structural and historical factors, and that the rich data necessary to identify these factors can only be obtained through qualitative research methods. The next two papers offer case studies from the Global Islands’ Vulnerability Research Adaptation and Policy Development project, which assess the adaptive capacity of Soufriere, Saint Lucia and Whitehouse, Jamaica, respectively. The fourth paper examines the mechanics of three low-carbon shifts in Brazil: the diffusion of no-till agriculture, the decrease in the deforestation rate in the Amazon, and the growth of the ethanol biofuel industry. It found that the driving forces behind each of the shifts were far more varied and complex than the price-based market dynamics analysed in neoclassical economics. The final paper argues that climate finance will need to perform a variety of functions beyond attracting low-carbon private investment. It concludes that the institutional architecture governing climate finance should enable direct access to national governments to incentivise them to implement sustainable innovation policy regimes.
Remorse and retribution: justifying mitigation at sentencing
Keywords: mitigation
remorse
punishment
sentencing
retribution

Remorse can be a powerful source of mitigation at sentencing. However, there is a lack of formal justification for this practice and a paucity of theoretical literature engaging with this issue. Addressing this gap, this thesis offers a comprehensive justification for why an offender’s remorse should mitigate the punishment he receives. It begins by discussing the emotion of remorse – its nature and value. With reference to broadly-retributive theories of punishment, it then considers various arguments that could be offered to justify the mitigating effect of remorse on the offender’s sentence. It rejects two arguments: either remorse constitutes some of the offender’s deserved punishment or remorse reduces the seriousness of the offence. Instead, it develops a justification inspired by philosophical work distinguishing blameworthiness and blaming. The thesis argues that, in the context of sentencing, a broadly-conceived dialogical model of censure is the most legitimate. Remorse, as the offender’s ideal input into the dialogue about the offence, modifies the subsequent censure required. If censure seeks a response, and this response is already forthcoming, to nonetheless continue to seek this response as if it were absent devalues the censure. Von Hirsch and Ashworth’s assertions that censure appeals to the offender as a rational moral agent, and their adherence to certain quasiretributive values, are shown to provide further support for these arguments. If the deserved censure is mitigated, then so is the corresponding punishment communicating this censure. The thesis next explores how this justification for mitigation compares with ‘mercy’ justifications, arguing that the justification offered in this thesis operates more internally to deserved censure, and is more principled, so is preferable on these grounds. In conclusion, the thesis considers the implications of its arguments for sentencing practice and whether it is a concern that they are valid only within ‘censure’ theories of punishment.
Toward an ecology of addiction: overeaters anonymous and weight watchers in a culture of consumption
Keywords: twelve-step programmes
dieting
compulsive eating
obesity
addiction
weight loss
stigma
nutrition
commercial weight-loss programmes

There is increasing evidence that aspects of human eating may be 'addictive'. Much of the existing literature examining this focuses on specific foods or individual pathologies of 'addiction'. Qualitative research methods, in particular content analysis, offers a rich opportunity to better understand 'addictive' aspects of human eating through the stories shared by those who have experienced compulsive eating. This research examines two different organizations that use storytelling as a tool for changing eating behaviours. Overeaters Anonymous (OA) and Weight Watchers (WW) began in the United States in the early 1960s as mutual support groups designed to help members with problems of compulsive overeating. This research examines: 1) the ways that OA and WW addressed 'addictions' with food when they were first formed; 2) how each organization has changed over time; and 3) the ways that identities are constructed through the telling of stories within each programme. For this thesis, I used historical analysis, in-person and online participant observation, and content analysis as research methods. I found that while OA and WW once similarly addressed 'addictions' with food, this is no longer the case. WW no longer understands their members as fundamentally different from others in the ways that they eat, and OA now welcomes members with a variety of different compulsive eating behaviours. However, similar themes regarding identity emerged from the OA and WW stories used in this research. OA and WW members describe that they acquire different belief systems regarding health and how to eat in each programme. In comparing these two organizations, how each has changed over time and the shifts in identity described by OA and WW members, this research identifies aspects of everyday living that members of both groups similarly highlight as important factors influencing compulsive eating. Based on these findings, I then assess to what extent a new framework for understanding 'addiction' may be needed, and conclude by suggesting further areas of research that would be suitable for constructing this.
A study of central exclusive production at LHCb
Keywords: particle detectors
Particle physics
Large Hadron Collider
Central Exclusive Production

This thesis presents an analysis of the central exclusive production (CEP) of χc mesons in proton-proton collisions at a centre-of-mass energy of 8 TeV, using data collected with the LHCb detector corresponding to an effective integrated luminosity of 126.3 ± 4.3 pb⁻¹. Candidate χc decays are reconstructed in the K+K- and π+π- final states, where the final state particles have pseudorapidities between 2.5 and 4.5. The products of the cross sections and branching fractions are measured as
σ × 𝓑(χc0 → K+K-) = 28.0 ± 2.8 ± 13.9 pb,
σ × 𝓑(χc0 → π+π-) = 20.3 ± 2.4 ± 8.1 pb,
σ × 𝓑(χc2 → K+K-) &LT; 12.1 pb,
σ × 𝓑(χc2 → π+π-) &LT; 10.5 pb,
where the first uncertainties are statistical and the second systematic, and limits are set at the 95% confidence level. A major source of systematic uncertainty is the determination of the fraction of the selected data which is CEP rather than inelastic backgrounds.
Also described is HERSCHEL, a new subdetector installed at LHCb during the first long shutdown of the LHC. This is a system of forward shower counters which will provide CEP analyses with event-by-event rejection of inelastic backgrounds. The pseudorapidity coverage and detection efficiency of HERSCHEL are determined using Monte Carlo simulations. The pseudorapidity coverage extends to |η| ≥ 10 due to the showering of collision products at the aperture limit. With a photoelectron threshold yield of 0.2 times the yield in the mean minimum bias event, the detection efficiency for single diffractive events is predicted to be 89% in the forward direction and 91% in the backward direction.
‘Communicative sentencing: exploring the perceptions of young offenders in the community’
Keywords: Youth Justice
Offender's Perceptions
Criminology
Youth Justice System
Law
Communicative theories of punishment
Young Offenders

The purpose of this thesis is to investigate young offenders’ first-hand views of community punishment within the context of the extant literature on communicative theories of sentencing. Fuelled by the traditional marginalisation of young offenders’ views of penal interventions, and drawing upon the qualitative information yielded by fifty semi-structured interviews with 16-18 year old offenders, the study purports to enhance our understanding of the penal messages that punishment communicates to those who experience it. This research initiative is premised on the belief that an empirically-driven research project of this nature can contribute to an improved understanding of the relationship between the youth justice system’s preventive and rehabilitative aims and how offenders themselves perceive the communicative dimensions traditionally attributed to punishment. The Introduction contains the genesis of this investigation and establishes the parameters of the inquiry. Chapter Two analyses the available literature on offenders’ views and argues the case for further research. The third chapter examines the literature on communicative sentencing and anchors the project firmly within the relevant academic debate against which the study’s findings are analysed. Chapter Four contains a detailed account of the methodology employed and prefaces the analysis of findings. While Chapters Five and Six examine the penal messages offenders perceive during sentencing, Chapter Seven explores conceptual issues relating to the communicative functions interviewees ascribed to hard treatment and censure. The next chapter takes cognisance of how offenders conceptualise the penal messages that are transmitted to them during the administration of their sentences. The Conclusion examines the implications of the study’s findings for theory and policy, and proposes a cultural shift from an overly sceptical perspective which does not always afford much value to offenders’ viewpoints, to the creation of a new framework which will allow for greater offender participation.
Unnatural amino acids as metal-mediated probes of biological function
Keywords: chemical biology
unnatural amino acids
protein chemistry
proteomics

Conjugation reactions on proteins have been used to access various post-translational modifications, for targeted delivery of drugs, for microscopy, and in studying receptor-ligand interactions. However, the ability to modify native proteins is constrained by the reactive functionalities of naturally occurring amino acids. This has driven research into the incorporation of unnatural amino acids (UAAs) into proteins. Research in this area has been motivated both by the possibility of increasing the breadth of chemical techniques for protein modification by introducing novel 'bio-orthogonal' reactive groups via UAA incorporation, as well as generating well-defined conjugates by the site-selective incorporation of these UAAs into proteins. The objective of this thesis is to both expand the diversity of UAAs for access to new metal-mediated reactions on proteins, as well as to utilise these reactions to reveal functional information about a range of biological systems. A brief introduction into current protein conjugation and UAA incorporation methods will be made in Chapter 1.
In Chapter 2, the genetic incorporation of alkene-bearing UAAs into recombinant proteins expressed in both bacterial and mammalian systems is discussed. This technique is demonstrated to enable Ru-catalysed olefin cross-metathesis (CM) reactions on the resultant proteins. This work builds upon previously established methods to chemically incorporate CM handles onto proteins. The rational design of UAAs, as well as assays and modelling studies to screen them for recognition by the cellular incorporation machinery are discussed in detail. The expression of a range of alkene-tagged recombinant proteins, their complete characterisation, as well as the development of a more general protocol for on-protein CM is elucidated.
In Chapter 3, the utility of UAA incorporation to probe mammalian cell translation systems is examined. Incorporation of an azide-bearing UAA, in addition to heavy stable-isotope labelled amino acids is used to uncover a previously unreported system of protein synthesis in mammalian cell nuclei, along with rapid metabolic degradation of the synthesised peptides. Various orthogonal methods for the detection of this system as well as possible reasons for its conservation are discussed.
In Chapter 4, UAA incorporation and metal-mediated bioconjugation reactions are utilised in the development of a novel and generally applicable proteomics technique. This technique is used to determine quantitative changes in cell proteomes in response to external stimuli, and may be applied to systems to which traditional proteomics techniques cannot, such as ex vivo primary cells.
Finally, in Chapter 5, further applications of UAA incorporation are discussed. Preliminary results are reported in efforts to use UAAs in the vibrational Raman microscopic imaging of biological systems, in generating HIV vaccines, and inducing T-cell stimulation.
Ethical issues in research ethics governance and their application to the Malaysian context
Keywords: research ethics

Evidence available shows that the ethics review process in Malaysia suffers from a range of problems (Kaur, 2011). These problems may be the result of a lack of training given for REC members and relatedly, it may stem from a lack of understanding of the role of RECs. Since Malaysia is striving to promote the country as a research hub for international collaboration, it is important that the ethics review system that is in place is well set up to ensure only ethical research are being approved. The aim of this thesis is to develop three important key elements of a framework that can be used to provide practical guidance for RECs and their governance in Malaysia. These three important elements of the ethics review process are: - the role of RECs, the criteria of REC membership and the acceptability of variation in decisions made between different RECs. These analysis is then applied to the Malaysian context. My initial recommendation is for RECs to adopt the Daniels and Sabin (1997) accountability for reasonableness model to assist with the decision-making process. The adoption of the model helps to clarify the role of RECs and can be used as a basis to develop the criteria for REC membership as well as to provide a better understanding of the acceptability of variation in decisions between different RECs.