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Development of fragment-bearing cyclic peptides as first-in-class therapeutics against ALT-positive osteosarcomas
No full textOsteosarcoma is the most common type of primary bone malignancy that arises during the
adolescent growth spurt and disproportionately affects young people. With no targeted therapy
available, patients diagnosed with osteosarcoma are predominantly treated with high-dose
chemotherapy combined with disabling amputation or limb salvage surgery, leaving significant
burden on survivors. A novel strategy for treating osteosarcoma is to target a DNA repair mechanism
known as Alternative Lengthening of Telomeres (ALT), which is required by over 60% of
osteosarcomas for continued growth. Since there is no evidence of ALT activation in healthy somatic
cells, inhibition of ALT offers a significant window for therapeutic intervention against osteosarcoma.
ALT activity can be targeted by disrupting two well-defined protein-protein interactions (PPIs),
FANCM-BTR and TRF2. Both PPIs exhibit well-defined binding interfaces, each providing a suitable
site for competitive targeting that is structurally defined and ready for novel inhibitor discovery. The
FANCM-BTR target is mediated by hydrophobic interactions between a 12-mer peptide from the
FANCMMM2 domain and the RMI1/2 heterodimer, while TRF2 recruits other telomeric protein
components via its TRFH domain that prefers a conserved binding motif.
This thesis reports first-in-class de novo cyclic peptide inhibitors against FANCM-BTR and
TRF2TRFH by implementation of fragment-based drug discovery and mRNA display. These cyclic
peptides serve as novel chemical tools for further investigation on the biochemical mechanism of
FANCM-RMI1/2 and TRF2TRFH in regulating ALT activity and potential targeted therapy for ALTpositive
osteosarcomas. The proof-of-concept fragment-incorporated RaPID screen also provides a
novel platform for hit-to-lead generation and structure-activity relationship studies of de novo cyclic
peptides containing fragment-bearing amino acids as intracellular PPI inhibitors with high affinity and
target specificity
Neuromorphic Imaging Cytometry
No full textImaging flow cytometry is an indispensable cell-analytic tool that provides multi-parametric measurements with high-dimensional feedback derived from single-cell images. It enables profound insights into cell signalling, co-localisation, cell-to-cell interaction and deoxyribonucleic acid studies. However, the traditional frame-based sensor adopted in imaging flow cytometry can inhibit its performance, bound by the triangle of imaging constraints: speed, resolution and sensitivity; increasing one parameter can lead to degradation in others. This trade-off correlation has fundamentally hindered the development and generalisation of imaging flow cytometry. In addition, the rich spatial information acquired through imaging flow cytometry has exceptional uses with machine learning models to automate cell analysis, gating and revealing rare cell events.
Herein, we introduced a neuromorphic imaging cytometry approach to characterise cells with superior temporal resolution, data efficiency and fluorescence sensitivity. Taking advantage of data sparsity in neuromorphic vision, the proposed platform and curated dataset were combined with hybrid spiking neural network models to perform cell classification and enable in-depth analysis. To the best of our knowledge, our research enabled the first novelty of neuromorphic-enabled cytometry applications.
This dissertation encompassed the entire research milestones including the initial conceptualisation of neuromorphic imaging cytometry with artificial particles; implementation of fundamental cytometric functions; object detection with biological cells; advanced machine learning cell analysis by a lightweight model on convoluted cell classes and morphologies. Combining the data sparsity in neuromorphic imaging with a lightweight hybrid spiking neural network model and operation platform, this paradigm can become a fundamental backbone for next-generation, machine learning-driven cytometry
Addressing Challenges in Estimating Treatment Effects in Oncology Clinical Trials
No full textAccurate estimation of treatment effects in randomised controlled trials (RCTs) is crucial for guiding clinical care, informing regulatory decisions, and optimising healthcare resource allocation. In oncology RCTs, where benefits are often modest but meaningful, small estimation errors can substantially impact clinical and policy decisions. This thesis examines four scenarios that challenge accurate treatment effect estimation: (1) non-randomised comparisons of concomitant therapies, (2) treatment switching after disease progression, (3) pooling of phase 2 and 3 data, and (4) early declaration of superiority at interim analysis.
Chapter 3 used target trial emulation to assess non-randomised comparisons in metastatic prostate cancer trials, finding no clear survival benefit from adding chemotherapy to enzalutamide. It provides a framework for such analyses but cautions against overreliance without randomised confirmation.
Chapter 4 examined treatment switching in two Lu-177 PSMA trials. Advanced statistical adjustments showed switching had minimal impact on effect estimates; survival differences arose from comparator choices. Careful comparator selection and statistical adjustments are crucial when switching occurs.
Chapter 5 investigated pooling phase 2/3 data in INTEGRATE trials. Adjusting for treatment switching and winner’s curse preserved consistency between phases. Prospective pooling under closed testing is feasible if misalignment risks are evaluated.
Chapter 6 analyzed interim superiority declarations in 71 RCTs, finding overestimation bias, especially early. Penalised methods mitigated bias. Case studies (ENZAMET, KEYNOTE-426) highlighted how trial dynamics affect interpretation. Interim timing and estimator choice are critical for robust decisions.
This thesis integrates advanced statistics into trial design and analysis, thereby improving the estimation of treatment effects for more reliable clinical and policy decisions
Sexual and Reproductive Health of Rohingya Refugees In Bangladesh: A Systematic Review
No full textIntroduction: The Rohingya refugees in Bangladesh, a severely persecuted ethnic minority of Myanmar, face numerous challenges related to their sexual and reproductive health (SRH), including access to appropriate services. This systematic review examines the SRH status of Rohingya refugee women in Bangladesh, focusing on barriers to accessing SRH services and interventions to address their specific SRH needs.
Methods: Following PRISMA guidelines, a systematic search was conducted across databases, including PubMed, CINAHL, Embase, Web of Science, and Scopus, as well as gray literature, from August 2017 to July 2023. Both quantitative and qualitative studies were included, with data extraction and analysis performed independently by two authors using a narrative synthesis approach.
Results: Out of 394 citations, ten studies met the criteria. The findings revealed that 48.9% of Rohingya women were unaware of SRH service access, only 11% received frequent (once fortnightly) visits by family planning personnel, 70% lacked knowledge about HIV/STIs, and over two-thirds believed that family planning required husband approval. The prevalence of contraceptive use was 50.9%, with cultural and religious beliefs and gender dynamics significantly influencing family size decisions.
Discussion: Cultural preferences impacted family size decisions, and limited awareness of permanent birth control widened the SRH education gap. The review emphasizes the need for comprehensive, community-based interventions, including door-to-door visits, culturally tailored outreach programs, and SRH education within refugee camps. To address the SRH needs of Rohingya women, adopting a multifaceted approach that promotes SRH education, improves service accessibility, and empowers women to make informed reproductive choices is essential
Balinese Social Entrepreneurs and the Pursuit of Harmony
No full textUsing four Balinese case studies in the crafts, arts, disability, and hospitality sectors, this thesis examines the question of why Balinese engage in social entrepreneurial activities and what makes Balinese social entrepreneurs distinctive. In Bali and across the world, social entrepreneurs represent a set of social actors positioned uniquely to provide new solutions to social issues. As this thesis shows, there are ancestral values that may (not) fit with imposed Western values behind social entrepreneurship. Thus, my original contribution to knowledge is the analysis of Balinese actors within a dynamic interplay of ancestral and Western values. This approach is informed by the idea that Balinese social actions are characterised by heterogeneous elements that coalesce to create unique and dynamic social entrepreneurial networks leading to collective agency. The Balinese environment is articulated in terms of the tri hita karana philosophy — a three-fold pathway to perceived harmony between people, gods, and nature that underpins actions and profoundly influences policymaking. Thus, Balinese act in environments encompassing interdependent objects that accumulate discourse and hold agency through events — visible and invisible — that they encounter. The entanglements with ideologies, events, and objects cannot be separated from personal values. Such values are permeated through networks, which have the capacity to inform practitioners, scholars, and policymakers in ethical decision-making. One’s values are critical guiding principles within one’s belief system about how one ought to behave. Yet, Balinese values are not necessarily a mirror of tri hita karana, and as the case studies suggest, the relationships between ancestral and Western values are complex. The case studies lead to a typology of Balinese value dimensions (spiritual, social, material and political) of overlapping and downscaled themes that emerged through the four unique social entrepreneurial networks: Tinta, Buaya, Cahaya, and Rasa. Importantly, I argue that values are time-bound and fluid, and they undergo reinterpretation over time, through actions and their connection to historical events. Accordingly, this thesis conceptualises Balinese social entrepreneurs as ancestral value-laden actors whose personal values shape moral actions and relationships
Chiroptical Switching in Molecular and Extended Framework Systems
No full textChiroptical switches are stimuli-responsive materials whose properties can be reversibly altered by external stimuli. Chiroptical switches are of great interest for applications in optical displays, optoelectronics, and chiral sensing. This thesis explores the design, synthesis, and characterisation of novel chiroptical switches in both molecular and framework systems. Chapter 3 presents the synthesis of enantiomers (S/R)-1,1′-binaphthalene-2,2′-bis(1,8-naphthalimide), combining an axially chiral binaphthalene scaffold with redox-active 1,8-naphthalimide groups. Their chiroptical and electronic behaviours were investigated via UV-vis, CD, and EPR spectroelectrochemistry, revealing reversible redox-modulated chiroptical switching with excellent sensitivity and stability.
Chapter 4 reports the chiral ferrocene amino acid bioconjugates, L/D-Fc(MeLeu)2. Chirality arises from intramolecular hydrogen bonding that induces an axially chiral conformation. Their chiroptical response was found to be solvent dependent, with more intense signals in nonpolar solvents. Temperature-modulated chiroptical switching was also demonstrated, with CD intensity increasing upon cooling. Redox-modulated switching via reversible oxidation of the ferrocene core was also performed, successfully achieving dual-responsive chiroptical switching. Concentration effects on switching reversibility and stability are discussed.
Chapter 5 details the synthesis of lanthanide-based MOFs, [Ln2(CBA)2(H2O)4]·4H2O (Ln = La, Ce, Pr, Nd), using chiral ligand (4-carboxybenzoyl)-L-aspartic acid (H3CBA). These MOFs were found to be achiral due to ligand racemisation during synthesis. Strategies to prevent this and the underlying causes are examined. A second chiral ligand, N-(4-carboxyphenyl)-L-alanine (H2CPA), successfully yielded a chiral MOF with Cd(NO3)2·4H2O.
This work advances the understanding of stimuli-responsive chiroptical materials and offers key insights into promising areas of future exploration
An exploration of ‘Alcohol and Other Drugs and Mental Health’ counselling with migrant Iranian men in Australia
No full textThis study explores the relationship between forced migration, mental health, and alcohol and other drug (AOD) use among Iranian migrant men in Australia, focusing on their help-seeking behaviours and the effectiveness of available mental health and addiction services. It also provides guidance for bilingual counsellors, particularly female practitioners, supporting this population.
The research used a two-phase qualitative design, grounded in social constructionist and feminist frameworks. Phase One involved 30 in-depth focus group interviews with Iranian migrant men who experienced AOD use and mental health issues, conducted at the Drug and Alcohol Multicultural Education Centre (DAMEC). Phase Two employed autoethnography, where the researcher—a bilingual Iranian migrant and female counsellor—reflected on her experiences in providing services, complemented by additional focus group data.
Key findings revealed how pre-migration trauma, detention, cultural dislocation, and post-migration challenges like racism and housing instability affect mental health and AOD use. Language barriers, stigma, and a lack of culturally competent services were significant obstacles to seeking help. The study also highlighted challenges faced by female counsellors in providing care to male clients. Participants expressed increased trust in female counsellors who could speak their language and address their broader needs, including housing and legal support. Group counselling, initially met with resistance, was found to be beneficial.
The findings fill a critical gap in understanding the experiences of Iranian migrant men with AOD and mental health issues, offering recommendations for policy and service improvements. It emphasizes the need for bilingual, culturally competent counsellors, particularly women, in Australia’s mental health and addiction services to foster engagement, reduce stigma, and improve care
Examining Approaches to the Kindergarten Literacy Block
No full textDesigning and executing inclusive literacy practice that is grounded in both the principles of inclusion and the evidence-base related to the teaching of literacy is a fundamental but challenging endeavour for teachers. Discourse regarding literacy practice in the political and research domains, in Australia and internationally, has commonly emphasised school- and system-wide issues that are far removed from classroom teachers’ control. These issues include: problems of resourcing; administrative concerns; amendments to initial teacher education; changes at a government level; and isolated research debates concerning the merits of specific pedagogical components and approaches. Such discourse represents a distraction from the construction of inclusive, integrated classroom literacy practice that is effective for all students as teachers’ primary concern. Given recent changes to syllabus requirements which are state-specific, and the significance of the first year of formal schooling, kindergarten classrooms in New South Wales (NSW) represent an important context in which to examine inclusive literacy practice. Accordingly, this thesis explores the conceptualisation, examination and interpretation of a framework for inclusive literacy education which uses the Inclusive Pedagogical Approach (Florian & Spratt, 2013) as a lens through which to consider classroom literacy practice. This exploration moves beyond the theoretical and methodological constraints of previous studies in both fields. The study employs mixed methods and uses both qualitative and quantitative data gathered from a survey of 266 kindergarten teachers in Sydney, NSW, alongside three case study observations and interviews with teachers from the survey sample. The triangulation of the data allows for a detailed exploration of classroom practice and the professional judgements that underpin inclusive literacy education. The framework for inclusive literacy education has broad implications for: addressing the need for improvements in student literacy achievement (United Nations, 2015); enabling the pursuit of improvements in classroom teachers’ practice; and illuminating potential areas of focus for professional learning within education sectors and initial teacher education. It also lays the foundation for further exploratory research in this domain (Swedberg, 2020)
Genital Psoriasis: Clinical Features, Management, and Impact on Quality of Life
No full textGenital psoriasis is a chronic inflammatory skin condition that has been reported in up to 63% of patients with psoriasis on other parts of their skin. It has a profound impact on quality of life and sexual function which is overlooked by current severity scores. Despite its prevalence and disease burden, genital psoriasis remains largely under-reported and under-treated. Historically, this has been due to the impracticality and limited efficacy data of standard psoriasis treatments when applied to genital skin. However, there have been recent advancements with several new agents currently being developed and evaluated for genital psoriasis. This thesis aims to provide an overview of the current evidence regarding the clinical features of genital psoriasis, available management options and tools for assessing patients’ quality of life. This thesis also investigates the patterns of care of vulval psoriasis in paediatric and adult population in Australia through a retrospective chart review of a single dermatology referral centre. Lastly, this thesis also examines the quality-of-life impact of adult vulval psoriasis to highlight areas of focus and improvement for clinicians.
Chapter one of this thesis highlights this often-neglected genital involvement of psoriasis and its quality-of-life impact. Additionally, it discusses the current management options for genital psoriasis in adults available in Australia. Chapter two investigates the presentation of vulval psoriasis in adults, looking at their clinical features, topicals and systemic treatments, commenting on the current landscape of Pharmaceutical Benefits Schedule. Chapter three explores the presentation of paediatric vulval psoriasis, exploring its clinical features and management strategies used in Australia. Finally, Chapter 4 presents a summary of the thesis findings, commenting on directions for future research
Research Paper for Legal Aid NSW: Increasing Supports for Vulnerable People Leaving Custody Who Are at Risk of Reoffending
No full textThis report, prepared for Legal Aid NSW, examines strategies to support vulnerable people leaving custody who are at risk of reoffending. It analyses throughcare programs across Australia and internationally, including in New Zealand, the United Kingdom, and Norway, to identify best practices for reducing recidivism. The research highlights barriers to reintegration such as housing insecurity, unemployment, and inadequate post-release support, and emphasises the effectiveness of holistic, individualised throughcare models. Recommendations include improved coordination of support services, better program evaluation, and increased access to stable housing and community-based rehabilitation to break cycles of disadvantage and reduce repeat offending in NSW