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Strategies to enhance CAR T cell function in solid tumours utilising coding and non-coding genes
Get PDFCancer immunotherapy has emerged as an effective treatment to provide benefits to cancer patients. One of the main treatment modalities of cancer immunotherapy is the adoptive transfer of T cells with genetically engineered receptors known as chimeric antigen receptor (CAR), which has recently emerged as a promising approach for haematological cancers. Although some success has been achieved in treating leukaemia, treatment of solid tumours by this approach is limited mainly due to poor infiltration of cancer targeting lymphocytes and their inhibition by immunosuppressive tumour microenvironment (TME) created by hypoxia, low pH, and immunosuppressive metabolites within solid tumours.
In this thesis, we attempted to exploit immunosuppressive metabolites (e.g. adenosine and low pH) in solid TME to reduce their suppressive effect on T cells by designing chimeric receptors with CXCR3 signalling domain fused to the extracellular metabolite sensing receptor. Functionality of these chimeric receptors were assessed using calcium flux assay, ERK phosphorylation assay and migration assays. While the assays were effective at assessing signal transduction via non-modified CXCR3 in response to the cognate ligand, CXCL11, signalling via chimeric receptors was not detected in the presence of respective stimuli.
Immunosuppressive molecules in TME also activate protein kinase A (PKA) in T cells which results in the localization of the PKA regulatory subunit 1A (PRKAR1A) to the immune synapse inhibiting several central proteins involved in the T-cell signalling cascade and leading to T cell inactivation. While research have targeted PRKAR1A using peptides to supress its activity, we used a different approach by overexpressing microRNAs (miRNAs) to downregulate PRKAR1A expression. Overexpression of either miR96/183 or miR155 significantly downregulated PRKAR1A expression in HEK293 cells at both mRNA and protein level. We further validated PRKAR1A 3' UTR as a direct target of both miRNAs using luciferase assay. Additionally, miR96/183 and miR155 were found to target other inhibitory proteins of TCR signalling such as TET2, FOXO3 and PTPN2 which might have additional advantage to enhance T cell activation. Consistently, overexpression of miRNA96/183 enhanced IL-2 production while overexpression of miR155 enhanced both IL-2 production and CD69 expression on Jurkat T cells following anti-CD3/CD28 stimulation compared to controls with normal expression of respective microRNAs.
We revisited the tetracycline-inducible sleeping beauty system to expand miRNA overexpression approach in CAR T cell therapy and generated a vector to induce miRNA/coding gene overexpression in the presence of tetracycline while constitutively expressing second generation HER2 CAR. To study the effect of miRNA overexpression in HER2 CAR in primary human T cells, a third-generation lentiviral system was also optimised by exploring both single and dual promoter systems to co-express non-coding (miRNA) and coding genes (HER2-CAR and GFP) from the same vector. Although cytokine production (IL-2 and IFN-γ) and CD69 expression were similar between HER2 CAR±miRNA transduced T cells when co-cultured with HER2 positive MCF-7 cells, the profile of phenotypic marker expression was different.
Overall, this thesis demonstrates that the miRNA overexpression in T cells could be a useful approach to combat intrinsic inhibitory molecules. The modified sleeping beauty vector and the lentiviral vectors developed in this study can be utilized to combine CAR T cell therapy with other approaches to enhance the efficacy of the treatment in cancer immunotherapy. Therefore, this thesis provides useful resource for the development of various strategies in future to enhance the efficacy of anti-cancer T cells or CAR T cells in solid tumour
New Zealand interest and participation in the Labour traffic prior to Bishop Patteson's death, 21 September 1871
No full textAs interest in the virgin Pacific Islands grew in the 1860s, it was inevitable that those New Zealanders closely involved in the peculiar difficulties of cotton plantations should see the recruitment of labour with the cold eye of necessity. Their narrow-minded countrymen loved to be shocked by the moving reports of Melanesian missionaries regarding traffic in human souls. Theses said, “We know of causes, induced… enticed… secured… seized…detained…” (Report of the Melanesian Mission, 1870, pp.3&4); and New Zealand men and vessels did not escape the well-founded condemnation. On an official level, the Britain of the South did not recognize such practices and endeavoured to impress its integrity upon the Colonial Office. It is within the scope of this essay to examine the nature, extent and purpose of any New Zealand participation, and where possible to assess the immediate and potential importance of that participation. [Extract from Introduction
ECG Classification with Patient-Dependent Normalization and Multi-step Classifier.
No full textElectrocardiogram (ECG) is an important tool for monitoring abnormal heartbeats. Machine learning has been used to facilitate the process of identifying the beats from the ECG data. In this research, we undertook the challenging tasks of building an ECG heartbeat classifier under the inter-patient paradigm. Based on finding significant differences of feature importance in the intra- and inter-patient scenarios, a customised framework design is proposed. The customised framework design includes two novels contributions. These are the patient-dependent normalization to deal with the disparity within the ECG records and the cascading ensemble classifier framework to further increase classification accuracy. MIT-BIH dataset was used as a benchmark for a fair comparison with other algorithms. We followed the Association for the Advancement of Medical Instrumentation (AAMI) for handling and experimenting with the ECG data. Results from our system were comparable to those of similar systems with jk index of 0.728, normal beat’s F1 score of 95.80%, SVEB beat’s F1 score of 58.48%, and VEB beat’s F1 score of 87.57%. Feature analysis for different beat types showed that R-peak’s attributes largely helped with the distinction of these beat types. In the future, it may be wise to experiment with other datasets to demonstrate the generalizability of our system
The Tartan Front: Daily life in Scotland during the Second World War
No full textThis thesis examines society and culture in Scotland during the Second World War, exploring the evidence for a uniquely Scottish experience of war. The cultural narrative of the British home front during the Second World War has long centered on the notion of a People’s War: a civilian front line of high morale, confidence in ultimate victory, and united within a ‘national’ community. Historical research has, largely, concentrated on London, neglecting the home front experiences of those within other nations in Britain. This thesis addresses this shortcoming by investigating life on the Scottish home front. It explores Scottish responses to wartime disruptions, and examines the motivations, cultural trends, and internal fissures that influenced behaviour during the Second World War. Moreover, it reflects upon the underlying tension between conformity and resistance to both State and war.
Through a series of thematic chapters, this document details everyday life and work in Scotland between 1939 and 1945. It focuses on the evacuation scheme, the moral crisis, industrial discontent and anti-war activity, morale, holidays, everyday life and leisure, and the rural sector. It draws upon a diverse range of intelligence reports, official documents, newspaper and magazine articles, diaries, and questionnaire responses to shed light on Scottish home front life. The findings illuminate everyday life in Scotland during a time of war, but also add to a scant historiographical body of work on ‘ordinary life’ in Scotland. In addition, this study challenges the popular cultural narrative of the British home front as a united national community during the Second World War. Ultimately, this thesis concludes that the Scottish response to war was shaped by history, national identity, cultural legacy, and internal division
E Tū Kahikatea: An Evaluation of the Tū Kahika Foundation Year Scholarship at the University of Otago
Get PDFThe purpose of this thesis is to evaluate the Tū Kahika Foundation Year Scholarship at the University of Otago. The Tū Kahika Foundation Year Scholarship is a recruitment intervention that assists Māori secondary school leavers who may be socio-economically and, or educationally disadvantaged to enter into and through the Foundation Year Health Sciences course at the University of Otago Language Centre and Foundation Year. Tū Kahika aims to increase academic preparedness of Māori secondary school leavers for future tertiary health sciences study and a career in Māori health. Tū Kahika has reached its 10 year anniversary and it is timely to undertake a detailed evaluation that will investigate the effectiveness of Tū Kahika in relation to academic pathways, and its impact on recipients.
This thesis has four main research questions:
(1) What is the socio-demographic and education profile of the recipients of the Tū Kahika Foundation Year Scholarship?
(2) What is the impact of Tū Kahika on the recipients of the Tū Kahika Foundation Year Scholarship?
(3) What are the recommendations for quality-improvement of the Tū Kahika Foundation Year Scholarship?
(4) To what extent is the Tū Kahika Foundation Year Scholarship transferrable to other educational settings?
This evaluation used a two-phase, mixed-methods quantitative and qualitative design steeped in Kaupapa Māori Evaluation methodology. An online survey to all Tū Kahika Foundation Year Scholarship recipients (2010-2019), followed by ten kanohi-ki-te-kanohi (face to face) semi-structured qualitative interviews were used.
Findings suggest that the socio-demographic and education profile of recipients of the Tū Kahika Foundation Year Scholarship is diverse and positively contributing towards increasing the Māori student population at the University of Otago. Results suggest that the Tū Kahika Foundation Year Scholarship is positively impacting recipients academically, financially and through increasing sense of belonging at university.
This research identified four critical success factors of Tū Kahika including whakawhanaungatanga (fostering a sense of family and community amongst Māori students working together to achieve goals and having a wide peer support network), mana motuhake (empowering students to have a positive university experience), manaakitanga (providing holistic, wrap-around support) and tino rangatiratanga (prioritising Māori student success at university). This research also identified resource-dependent and non-resource dependent suggestions for improvement. Resource-dependent suggestions include more financial, academic, pastoral and hauora hinengaro (mental health) support, as well as more opportunities for whakawhanaungatanga (process of establishing relationships, relating well to others), tuākana-tēina (older sibling – younger sibling relationship) engagement, Kaupapa Māori and te reo Māori. Non-resource dependent suggestions include encouragement to keep extra-curricular activities, part-time jobs etc. and encouragement to expand social circles beyond fellow Tū Kahika scholarship recipients.
In conclusion, this research highlights that the Tū Kahika Foundation Year Scholarship is impacting recipients positively through the identified critical success factors. These critical success factors are transferable to other educational settings delivering foundation-level learning for Māori secondary school leavers
Effects of bathymetry, wave environment and sea level on rip current dynamics in a wave-resolving model
No full textRip currents and nearshore circulation are important as they influence sediment transport and have the potential to be hazardous to beach users. Obtaining field observations of the flow characteristics is expensive thus the need for cheaper options to gain understanding into how they work. Nearshore wave models can be used to provide insight on rip development despite being unsuitable for providing exact forecasts of beach response. This study aimed to simulate rip current formation under varying bathymetric and wave conditions.
A nearshore Boussinesq wave model (FUNWAVE) was used to simulate wave-driven currents in two bathymetric conditions: one domain based on bathymetric data collected from Ocean Beach, Dunedin, New Zealand, and the other using the same bathymetric data averaged to create an alongshore uniform domain with a single rip channel. Simulations were run that tested the effects of incrementally increasing the complexity of the wave field on both bathymetries. Variables included in the wave field were frequency distribution, directional spread and mean incidence. One set of wave conditions was also selected for use in simulations that represented high and low tide conditions at Ocean Beach.
Simulations with large significant wave heights (1.5 m) were less likely to retain material in the surf zone with ~10-15% fewer tracers retained compared to simulations with 0.5 m waves. Simulations of the alongshore averaged bathymetry all formed rip currents near the channel while more complex wave conditions generated eddies and multiple exit pathways from the surf zone. Complex conditions in both the bathymetry and wave field lead to the formation of multiple exit pathways from the surf zone. With increasingly “real-life” conditions, rip current dynamics became less tied to bathymetric variability.
Larger significant wave height was the most significant contributor to wave orbital velocity increase. Simulations with a large significant wave height featured a higher proportion of the domain exceeding the erosive threshold for wave orbital velocity.
Rip currents at Ocean Beach vary depending on the wave conditions with significant wave height and directional spread being particularly important. In addition, the amount of sediment exiting the surf zone is controlled by different processes that depend on wave conditions. For less energetic conditions the number of exit pathways will be important, in more energetic conditions sediment will likely leave the surf zone regardless of the directional spread or mean incidence of the wave field
NZDep2018 analysis of census 2018 variables - TA03: Kaipara District
No full textFor further information about data sources, interpretation of the graphs, and cautions, please see the separate Introduction Chapter
All data relating to the 2018 census is provided by Stats NZ, https://www.stats.govt.nz/
NZDep2018 analysis of census 2018 variables - TA29: Wairoa District
No full textFor further information about data sources, interpretation of the graphs, and cautions, please see the separate Introduction Chapter
All data relating to the 2018 census is provided by Stats NZ, https://www.stats.govt.nz/
Executive function and the pragmatics of language in children with varying levels of inattention, hyperactivity, and impulsivity
Get PDFADHD is a common disorder that develops in childhood. Beyond the diagnostic criteria, ADHD can lead to deficits in several functional domains, including executive functioning and pragmatic language ability. There has been little research into how executive functioning and pragmatic language ability are related and how that relationship is affected in an ADHD population. Past literature has drawn connections between these aspects individually but not extensively in a single model. There is debate about which executive functions play the most prominent role in one’s pragmatic language ability; higher-order or lower-order. The current study aimed to investigate whether executive functioning deficits explained the deficits in pragmatic language ability commonly seen in children with ADHD. Participants were 106 children aged between 7 and 12 years old. Executive functioning and ADHD symptom severity scores were obtained using standardised measures, and pragmatic language ability was assessed by applying a specifically tailored scoring protocol to 15-minute conversations between the child and a caregiver. Initial results revealed some inconsistencies with past literature with ADHD symptom severity showing no association with pragmatic language ability. However, there was a mediation effect of working memory on the relationship between ADHD symptom severity and pragmatic language ability, partially supporting the initial hypothesis. The findings are discussed regarding their implications in a clinical setting, and future research possibilities are suggested
Demographic and reproductive variability within and among subpopulations of temperate reef fishes
Get PDFTraditionally, fisheries management has assumed that all fish within a marine population contribute the same per unit biomass to population growth. However, it has become evident that older, larger individuals may contribute more to the reproductive output and success. Relatively small subpopulations may sustain a large population network, by contributing a reproductive surplus to the larval pool. For the sustainable management of marine fish populations, it is crucial to understand the reproductive contribution of populations and individual fish within populations, how populations are structured and connected, and how populations interact with the environment.
The present work aimed to elucidate how spatial differences in habitat quality affect marine fish populations, with particular focus on spatial variations in population demographics and reproductive output among subpopulations distributed across seascapes. Firstly, I compared demographic parameters, such as the length-frequency distributions, sex ratios, length-at-sex-change, and potential fecundity among five subpopulations of blue cod (Parapercis colias) in the Marlborough Sounds and Tasman Bay (Chapter 2). Secondly, I used stable isotopic values and stomach contents of blue cod subpopulations to investigate the effect of long-term trawling and dredging in Tasman Bay on the trophic niche of blue cod compared to subpopulations inhabiting biogenic reefs in the Marlborough Sounds (Chapter 3). Thirdly, I inferred population structure and movement from multivariate trace element signatures of otoliths from blue cod subpopulations within and among the Marlborough Sounds and Tasman Bay (Chapter 4). To investigate the contribution to the reproductive output and success of individuals within a population, I used proxies for larval fitness and viability to compare cohorts of larvae produced by different aged and sized female sea perch (Helicolenus percoides) (Chapter 5). Lastly, I explored the effect of maternal nutrition, inferred by fatty acid biomarkers, on larval traits on the day of parturition and larval viability and cohorts of larvae produced by female sea perch sampled from two distinct subpopulations from the Otago shelf and Fiordland (Chapter 6).
Three out of the five sampled subpopulations of blue cod from the Marlborough Sounds and Tasman Bay were severely truncated towards a larger proportion of smaller individuals. Sex change, from female to male, occurred at extremely small lengths, resulting in a sex ratio skewed towards a large proportion of small males among four out of five subpopulations. Consequentially, the estimated population batch fecundity was low among these male-dominated subpopulations. Isotopic niches and niche breadths of blue cod subpopulations from the Tasman Bay regions were smaller than those of subpopulations from the Marlborough Sounds. Movement, as inferred by multivariate otolith trace elemental signatures, was low between subpopulations from the Marlborough Sounds and Tasman Bay. However, subpopulations within the Marlborough Sounds likely displayed a source-sink dynamic, where the outer Sounds subpopulation supported the inner Sounds subpopulation with adults. The two subpopulations likely shared a larval source pool.
Older, larger females of sea perch were proportionally more fecund than younger, smaller females. These older, larger females also produced cohorts of larvae with larger oil globules than did younger, smaller females. Cohorts of larvae, with larger oil globules on the day of parturition, had faster growth rates and survived longer in fed treatments, than cohorts of larvae with smaller oil globules. When larval cohorts were compared between subpopulations from the Otago shelf and the inner Fiordland, cohorts produced by females from the Otago shelf had smaller oil globules on the day of parturition than cohorts of larvae produced by females from Fiordland. Among cohorts of larvae produced by females from Fiordland, the concentrations of the essential fatty acids docosahexaenoic acid (DHA) and arachidonic acid (ARA) were higher, and the eicosapentaenoic acid (EPA)/ARA ratio was lower than in cohorts of larvae produced by females from the Otago shelf.
The results of my research indicated that long-term overexploitation in the Marlborough Sounds and Tasman Bay has likely caused sex-change to occur at smaller sizes, resulting in the higher abundance of smaller males, which resulted in lower population fecundity. Smaller trophic niches of blue cod subpopulations from Tasman Bay compared to those of blue cod from the Marlborough Sounds were coincidental with differences in habitat degradation as a result of intensified bottom trawling and dredging within Tasman Bay. Blue cod populations within the Marlborough Sounds showed complex source-sink population structures and likely shared larval source pools, highlighting the importance of considering population structure when designing and implementing management strategies. Older, larger maternal sea perch produced cohorts of larvae that were more viable than those produced by younger, smaller females, emphasising that an old-growth age structure within populations may ensure larval survival and, ultimately, recruitment. Larval viability was not only affected by maternal age and size, but also by maternal nutrition, which resulted in unique visual and osmoregulatory larval adaptations to the low-light, low-productivity environment of the inner Fiordland. Fisheries management should aim to protect population structure, trophic interactions, and critical habitat simultaneously to sustain marine populations effectively