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EXCALIBER-RRMM: a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma
No full textMultiple myeloma (MM) is a plasma cell neoplasm that stems from the malignant transformation of clonal plasma cells. It is characterized by multiple periods of remission and relapse requiring multiple lines of therapy, with response to treatment and survival decreasing with each successive relapse. To achieve deep and durable responses in relapsed/refractory MM (RRMM), novel treatments are required. Iberdomide (IBER), an oral CELMoD™ agent, is associated with greater tumoricidal and immune-stimulatory effects than immunomodulatory drugs (IMiDs®). IBER has been shown to have synergy with dexamethasone (DEX) and daratumumab (DARA) in vitro. In a phase I/II trial, IBER in combination with DARA and DEX (IberDd) was well tolerated and demonstrated promising preliminary efficacy in patients with heavily pretreated RRMM, including patients refractory to IMiD agents, DARA, and proteasome inhibitors. EXCALIBER-RRMM is a unique confirmatory phase III trial that incorporates a 2-stage seamless design to firstly address dose optimization of IberDd, and secondly, to compare the efficacy and safety of the selected IberDd dose with DARA, bortezomib, and DEX in patients with early-line (1 or 2 prior lines of therapy) RRMM.Clinical trial registration: www.clinicaltrials.gov identifier is NCT04975997
Enhancement of Bread with Green Banana Flour: Impact on Polyphenol Content, Resistant Starch, Dietary fibre, Rheological Behaviour, and Physical Properties
No full text© 2025 Yasmeen Mohammad Y BASHMILBananas are among the most widely cultivated crops globally, with production exceeding 135 million tonnes annually. In Australia, bananas represent a major horticultural commodity; however, substantial quantities are discarded during postharvest handling, particularly at the green stage, due to deviations from the standardised physical appearance criteria set by the retail market. Green bananas are a rich source of resistant starch (RS), dietary fibre (DF), and phenolic compounds, including flavonoids and tannins, which exhibit potent antioxidant and prebiotic properties. These bioactive constituents make green banana flour (GBF) a promising functional ingredient for the food industry, particularly in bakery applications. This PhD research aimed to investigate the nutritional, physiological, and technological properties of Australian green banana cultivars and to evaluate the feasibility of incorporating GBF into bread formulations to enhance health benefits and promote sustainable food practices.
Six banana cultivars (Cavendish, Ladyfinger, Ducasse, Plantain, Red Dacca, and Monkey) were assessed at different ripening stages for their total phenolic (TPC), flavonoid (TFC), and tannin (TTC) contents, as well as antioxidant capacity. Advanced analytical techniques (LC-ESI-QTOF-MS/MS and HPLC-PDA) identified and quantified 24 phenolic compounds across the samples. Among studied cultivars, unripe Cavendish, Ladyfinger, and Ducasse exhibited high TPC (1.26, 1.91, and 2.60 mg GAE/g), TFC (0.02, 0.02, and 0.05 mg QE/g) and TTC (1.16, 1.64, and 3.68 mg CE/g), and strong antioxidant activity (106, 98, 107 mg AAE/g), respectively (p < 0.05). The flours of unripe Cavendish “Musa acuminata”, Ladyfinger “Musa paradisiaca L.”, and Ducasse “Musa balbisiana” cultivars were then evaluated for the bioaccessibility of RS, DF, and phenolic compounds using in vitro gastrointestinal (GI) digestion and colonic fermentation. Ladyfinger contained the highest RS (49 %) and Ducasse the greatest DF (38.7 %) (p < 0.05). Ladyfinger also showed the highest TPC (2.32 mg GAE/g), while Cavendish showed elevated TFC and TTC (0.06 mg QE/g and 3.2 mg CE/g, respectively) and exhibited pronounced antioxidant activity (DPPH, 0.89 mg TE/g). These effects were evident after both the intestinal phase and colonic fermentation at 12 and 24 h (p < 0.05), while substantial SCFA production, particularly acetate and butyrate, was observed during fermentation, indicating strong prebiotic potential. Furthermore, kaempferol in Cavendish remained relatively stable throughout the fermentation process, demonstrating the resilience of certain phenolics in the lower gut.
To assess functional applications, GBF was incorporated into white wheat bread at substitution levels of 5 %, 10 %, 15 %, 25 %, and 30 %. Dough rheology and bread quality were evaluated using MixoLab 2 and crumb structure analysis. 10 and 15 % GBF improved dough stability and resistance to overmixing in Ladyfinger (7.29 and 7.31 min), and increased starch gelatinization in Cavendish (1.77 and 1.84 Nm), as well as DF (7.1 and 9.1 %) and RS content (1.9 and 2.6 %) in Ladyfinger, compared with 3.8 % (DF) and 1.32% (RS) in control bread (p < 0.05), respectively. Interestingly, Cavendish and Ladyfinger flour provided superior outcomes compared to Ducasse. GBF-enriched breads were further assessed for polyphenol bioaccessibility and antioxidant activity after in vitro digestion. Phenolic bioaccessibility is critical, as only compounds released from the food matrix and absorbed can exert physiological benefits, including antioxidant and disease-preventive effects. Low bioaccessibility limits their availability for absorption and thereby diminishes the potential health impact of polyphenol-enriched foods. The 15 % Cavendish bread showed the highest TPC and TFC at 1.31 mg GAE/g and 0.05 mg QE/g, respectively, and antioxidant capacity (DPPH, 0.40 mg TE/g), while 15 % Ladyfinger bread exhibited the greatest TTC (17.4 mg CE/g) following stomach and intestinal phases (p < 0.05). Notably, SCFAs production remained high in Cavendish and Ducasse bread after fermentation, and phenolics from 10 % GBF bread retained significant bioaccessibility, which confirmed the health-promoting potential of these formulations. Although 15 % GBF inclusion yielded the highest polyphenol, RS, and DF contents and enhanced bioaccessibility and antioxidant activity compared with lower levels, bread quality parameters, particularly colour and texture, were negatively affected at this substitution. Therefore, 10 % inclusion emerged as the most suitable level, balancing enhanced nutritional value with desirable product quality.
Overall, this research demonstrates the viability of repurposing green bananas that is typically treated as waste, into functional nutritious bread products. By combining nutritional characterisation, in vitro digestion modelling, and technological assessment, the study offers a comprehensive foundation for the application of GBF in sustainable food systems. These results contribute to public health nutrition by supporting dietary diversification and gut health, while simultaneously addressing food waste reduction in the banana industry
Genome-wide gene expression profiles throughout human malaria parasite liver stage development in humanized mice
No full textGene expression of Plasmodium falciparum (Pf) liver-stage (LS) parasites has remained poorly characterized, although they are major vaccine and drug targets. Using a human liver-chimaeric mouse model and a fluorescent parasite line (PfNF54CSPGFP), we isolated PfLS and performed transcriptomics on key LS developmental phases. We linked clustered gene expression to ApiAP2, a major family of transcription factors that regulate the parasite life cycle. This provided insights into transcriptional regulation of LS infection and expression of essential LS metabolic and biosynthetic pathways. We observed expression of antigenically variant PfEMP1 proteins and the major Pf protein export machine PTEX and identified protein candidates that might be exported by LS parasites. Comparing Pf and P. vivax LS transcriptomes, we uncovered differences in their expression of sexual commitment factors. This data will aid LS research and vaccine and drug target identification for prevention of malaria infection
Learning from muscle to combat cancer
No full text© 2025 Alastair Albert Edward SaundersMany organs of the body are susceptible to both cancer growth, and to the establishment of metastatic tumours. Metastasis occurs through the spread of tumour cells through the bloodstream and lymphatics where they can traffic to all organs. Notably, these metastatic cells rarely colonise and grow within skeletal muscle. This observation is particularly striking given skeletal muscle comprises ~30-40% of body mass in adult humans. The reason for the failure of metastatic cell colonisation in skeletal muscle remains contentious in the literature.
Chapter 1 reviewed the biology of metastatic spread, and cancer cell colonisation. Metastasis is the leading cause of cancer related deaths; however, the mechanisms behind metastatic colonisation are not fully understood. The Transforming Growth Factor-beta (TGF-beta) signalling pathway, is a key regulator of metastatic cell dissemination. The role of this pathway in epithelial to mesenchymal transition (EMT) has been extensively characterised. However, the role of TGF-beta in colonisation and growth of disseminated tumour cells (DTC) is not as well established.
The review presented in Chapter 2 examined the current literature that investigates why striated muscle is resistant to both primary tumour initiation and metastatic tumour colonisation. There are multiple hypotheses presented in the literature that attempt to explain the failure of cancer cell metastasis to muscle. They include, 1) that blood flow restriction prevents metastatic outgrowth, 2) the contractile properties of muscle cause biomechanical destruction of cancer cells, 3) cancer cells fuse with muscle fibres, 4) muscle-secreted products deter cancer cell proliferation and 5) that disseminated tumour cells in muscle undergo high oxidative stress.
The data presented in Chapter 3 sought to investigate whether manipulation of the skeletal muscle microenvironment can induce metastasis in a tissue that is otherwise resistant to metastatic colonisation. The Transforming Growth Factor beta (TGF-beta) signalling network is a regulator of cancer metastasis, and of skeletal muscle homeostasis. We found that increasing expression of TGF-beta1 locally, with recombinant adeno-associated viral vectors (rAAV) in the muscle microenvironment, resulted in spontaneous metastases to muscle in the 4T1.2 tumour-bearing mouse model of metastatic breast cancer. This effect was not replicated with another TGF-beta ligand, Activin A, or with suppression of Bone Morphogenetic Proteins (BMP) with Noggin. The TGF-beta-induced muscle metastasis was associated with an increase in muscle-infiltrating immune cells. We repeated the experiment in Balb/c-nu/nu and NOD.SCID.gamma (NSG) mice and did not observe the same extent of muscle metastasis in these mice relative to wild type Balb/c mice, suggesting a role of the immune system in the TGF-beta-mediated phenotype. Furthermore, depletion of CD4+, but not CD8+ T cells with neutralising antibodies prevented muscle metastasis in the 4T1.2 tumour bearing model. The data show that TGF-beta can induce spontaneous metastasis in an otherwise hostile environment and support the hypothesis that TGF-beta may be an important mediator of cancer cell colonisation.
The aim of Chapter 4 was to translate the findings from Chapter 3 to organs that are traditionally vulnerable to metastasis, by testing the hypothesis that metastatic burden can be attenuated via antagonism of TGF-beta signalling, through measures intended to augment BMP signalling. BMP signalling has been well characterised as a suppressor of metastasis in triple negative breast cancer (TNBC). However, a barrier to the use of BMPs as a therapy is the relatively short half-life of recombinant BMPs. We therefore investigated whether an anti-viral drug, tilorone, which has been reported to increase expression of BMP ligands would be effective in a model of metastatic breast cancer. In 4T1.2 cells we observed no change in BMP ligand expression by qPCR. However, we also observed an increase in interferon (IFN)-responsive genes following tilorone administration. Tilorone reduced lung metastatic burden in mice-bearing 4T1.2 tumours, even when treatment commenced as late as tumour resection. In Balb/c mice lacking type I IFN receptors (IFNAR-/-) the survival improvements associated with tilorone treatment were negated, suggesting that tilorone exerts anti-metastatic effects through IFN receptors on host cells. IFN signalling has been shown to be necessary for a response to chemotherapy in some breast cancer patients. We found that tilorone improved survival in combination with doxorubicin in the 4T1.2 model. Consistently, this combination therapy resulted in an increased activation of lymphocytes in the primary tumour and pre-metastatic lungs. Although tilorone did not reduce metastasis through BMP signalling as initially hypothesised, the findings demonstrate the potential efficacy of tilorone in a model of TNBC.
The experiments presented in Chapter 5 trialled an alternative strategy to enhance BMP signalling in breast cancer. FKBP12 binds to the intracellular region of type I BMP receptors (BMPR), inhibiting intracellular BMP signalling. We tested the efficacy of FK506, an inhibitor of FKBP12, in multiple models of metastatic breast cancer. In NSG mice bearing MDA-MB-231-HM (231-HM) tumours of human origin, FK506 did not alter metastasis. However, we demonstrated that for FK506 to enhance BMP signalling in vitro, BMP ligands must be present. We trialled FK506 in mice receiving 231-HM cells with enforced BMP4 expression, and observed reduced metastasis in the lung, liver and spine. A limitation of this approach is that FK506 is an immunosuppressive drug. Therefore, we subsequently tested FKVP, an FK506 analogue, that does not induce immunosuppression. FKVP reduced metastases in spine and liver, but not in lung in Balb/c mice inoculated with 4T1.2 tumours. In combination with BMP4, FKVP reduced lung and liver metastatic burden. These data suggest that therapies that augment BMP signalling may be an effective strategy in metastatic TNBC, and that simultaneously increasing BMP ligand expression may enhance the efficacy of this strategy.
Another important consideration regarding the morbidity and mortality of people with metastatic breast cancer is the progressive loss of lean and fat mass, known as cancer-associated cachexia. Cancer-associated cachexia is a condition characterised by the debilitating loss of functional muscle and adipose tissue. The mechanisms of cancer cachexia in metastatic breast cancer have been understudied, in part due to a lack of reliable animal models of metastasis. The data presented in Chapter 6 characterised cachexia in mouse models of metastatic orthotopic breast cancer. We found that EMT6.5 tumour-bearing mice exhibited a significant loss of lean and fat mass, while 4T1.2 tumour-bearing mice displayed a milder cachexia phenotype. This loss of muscle mass was accompanied by hallmark signs of cachexia, including a reduction in surrogate markers of protein synthesis, increases in expression of E3-ubiquitin ligases and autophagy markers, a signature of immune cell infiltration, and perturbations in the architecture of the neuromuscular junction. These data support the clinical observations that patients with breast cancer can develop cachexia. These pre-clinical models could serve as useful tools to study the diversity of cachexia in cancer types where cachexia has been traditionally understudied. Chapter 7 considers the collected findings in terms of their significance in relation to the knowledge gaps in the field. Limitations and avenues for further study are also explored.
Overall, the findings presented in this dissertation highlight the importance of TGF-beta signalling in cancer cell metastasis. Of note, that TGF-beta1 can induce metastatic colonisation in muscle, a particularly hostile environment for cancer cells. Furthermore, the observations demonstrate the potential efficacy of small molecule approaches to promote BMP signalling in metastasis-prone organs, through removal of inhibition of BMPRs
Mon Laferte: Retro-Feminist Future Pop from Post-Dictatorship Chile
No full textBorn in 1983, at the tail end of Chile’s dictatorship (1973-1990), and becoming prominent as an artist in Chile in 2003 and later well-known across Latin America and worldwide, Mon Laferte’s career has been marked by its dynamic relationship with retro-futuristic aesthetics. Covering a range of genres, from futuristic Latin-Pop, the retro-Latin ballads of the 1960s, 1970s and 1980s, to Latin America’s folkloric traditions including Mexican regional music, bolero and even salsa, Laferte’s work combines the nostalgic sounds of the popular music of Latin America’s recent past with a set of intensely personal narratives. Utilizing Mark Fisher’s and Bifo Berardi’s theorizations of hauntology and lost futures, Simon Reynolds’ insights into the retro, and combining these with Ahmed’s insights on feminism, this article proposes that Mon Laferte’s work as a musician, lyricist, cover-artist, and producer of visual media, functions towards overcoming the dual traumas of Chile’s dictatorship and Latin America’s machismo, by producing an aesthetic territory that privileges feminine and traditionally feminized spaces, experiences, affects and discourses. In this way social traumas are enmeshed with personal ones, and a retro-futurist voice emerges, which side-steps masculine visions of the social and the political, proposing instead an introspective vision that is filtered through the feminine experience
Genome Sequencing in a Large Cohort of Patients with Developmental and Epileptic Encephalopathies of Unknown Aetiology.
No full text© 2025 Harshini Rachael ThiyagarajahDevelopmental and epileptic encephalopathies (DEEs) are a heterogeneous group of rare and devastating disorders that often manifest in infancy or childhood. Since the genetic diagnostic yield for this group is 50% on clinical testing, it is imperative to try and understand the aetiology for the remaining 50% of unsolved patients. Genome sequencing is now cost-effective and our knowledge of the non-coding genomic regions continues to expand. My study was designed to evaluate the effectiveness of genome sequencing in improving the genetic diagnostic yield of 234 patients with DEEs unsolved after prior testing.
I first interrogated variants in coding regions. I used a combination of interrogating the Genes4Epilepsy list of known epilepsy genes, previously reported pathogenic variants on ClinVar, and the latest machine learning approaches. Fifteen individuals were found to have pathogenic or likely pathogenic variants in coding regions. Thirteen were identified using the Genes4Epilepsy list, one was a recurrent variant on ClinVar, and one was found by machine learning. My results reinforce that coding variants are a significant contributor to developmental and epileptic encephalopathies of unknown aetiology. I have shown that interrogation of established genes is an important first-tier analysis, and that a combination of approaches can help reveal variants that may be missed on standard clinical genetic testing.
In the second round of analysis non-coding and structural variants were investigated in genome sequencing data to further increase diagnostic yield. These regions are not interrogated in standard clinical genetic testing. We analysed deep intronic regions for single nucleotide and structural variants in genome sequencing data from the remaining 219 individuals negative following coding variant analysis. Seven individuals were found to have pathogenic or likely pathogenic variants in non-coding regions. This included recurrent single nucleotide variants in RNU2-2 (n = 3), structural variants (n = 3) and a deep intronic variant that led to exon-skipping. These findings highlight the value of interrogating deep intronic regions to increase genetic diagnostic yield.
My thesis demonstrates the utility of using genome sequencing for genetic diagnosis of individuals with DEEs of unknown aetiology. This approach increased the genetic diagnostic yield by ~10%. The major outcomes are expansion of the phenotypic spectrum of known epilepsy genes and the detection of new variants and genetic mechanisms that is likely to lead to earlier genetic diagnosis, improved clinical management and new precision therapies
Intensified and Accelerated Rescue Infliximab Therapy for Acute Severe Ulcerative Colitis in Pregnancy: A Case Report
No full textAcute severe ulcerative colitis (ASUC) in pregnancy poses a clinical challenge with significant risk to both mother and fetus. Anti-TNF alpha therapy is known to be safe in pregnancy, however, data surrounding outcomes in ASUC is limited. In this report, we present the case of a pregnant patient of 10 weeks' gestation with ASUC successfully managed with intensified and accelerated infliximab therapy for a total dose of 35 mg/kg during a single admission. This case highlights the use of this therapeutic strategy, as a part of a multidisciplinary approach, to avoid the need for a high-risk colectomy
Victimization status among persons with disabilities and its predictors: Evidence from Bangladesh National Survey on Persons with Disabilities
No full textBackground Persons with disabilities often face various forms of victimization, yet there is limited research exploring this phenomenon in Bangladesh. This study aims to investigate the victimization status among persons with disabilities and identify its predictors. Methods Data of 4293 persons with disabilities analyzed in this study were extracted from the 2021 National Survey on Persons with Disabilities. Victimization status (yes, no) was considered as the outcome variables. Explanatory variables considered were factors at the individual, household, and community levels. A multilevel mixed-effect logistic regression model was used to explore the association of the outcome variable with explanatory variables by dividing the total sample into age groups of 0–17 years, 18–59 years, and ≥ 60 years. Results The study found that 44% of persons with disabilities in Bangladesh experienced victimization, primarily involving neighbours (90.64%), relatives (43.41%), friends (28.41%), and family members (27.07%). Among persons aged 0–17 years, increasing age was associated with a higher likelihood of being victimized, while residing in the wealthiest households or in certain divisions like Khulna and Rangpur was associated with lower likelihoods. Conversely, among respondents aged 18–59 and ≥ 60 years, increasing age was associated with a lower likelihood of being victimized. Unmarried respondents aged 18–59 years had an increased likelihood of victimization compared to married individuals. For persons with disabilities aged ≥ 60 years, a higher level of schooling was associated with a reduced likelihood of being victimized. We also found divisional differences in the likelihood of victimization, with respondents residing in Chattogram, Khulna, Mymensingh, Rangpur, and Sylhet reporting lower likelihoods compared to those residing in the Barishal division, among persons with disabilities aged 18–59 and ≥ 60 years. Conclusion This study’s findings underscore that around 4 in 10 persons with disabilities are being victimized. Tailored programs and awareness-building initiatives covering neighbours, relatives, friends, and family members of persons with disabilities are important to ensure dignified lives for this population
Residents’ values and experiences of public and private green space in a new greenfield housing estate
No full textPublic and private green spaces in new residential estates have a unique role in contributing to the establishment of new communities, yet the values that residents assign to these spaces are unexplored. In this study, we aimed to take a values-based approach to understanding residents’ experiences of public and private green spaces in a new greenfield residential estate in Victoria, Australia. We conducted semi-structured interviews with 16 residents living in the estate. Interview data were analysed thematically with a codebook, and three key dimensions of assigned values for urban green spaces were identified: psychological and experiential, natural and ecological, and social values. Social values of public green space were most important to interviewees, particularly in supporting a sense of community cohesion and identity in the new estate. Further, we found that residents value private and public green spaces for affording practices of care and stewardship, though opportunities for practicing care in public spaces were limited. The results demonstrate the importance of the nearby neighbourhood parks in the estate to which all residents have easy access, and the benefit of links between public and private outdoor spaces to reinforce a sense of belonging and connection. Community events and opportunities for stewardship in public green spaces, supported by developers, local councils and land managers, hold promise for building connections to community and place in the early years of new estate development
EFFECTIVENESS OF REHABILITATION INTERVENTIONS IN PATIENTS WITH COLORECTAL CANCER: AN OVERVIEW OF SYSTEMATIC REVIEWS
No full textOBJECTIVE: To evaluate existing evidence from published systematic reviews for the effectiveness and safety of rehabilitation interventions in adult patients with colorectal cancer. METHODS: A comprehensive literature search was conducted using medical/health science databases up to October 2024. Bibliographies of pertinent articles, journals, and grey literature were searched. Three reviewers independently selected potential reviews, assessed methodological quality, and graded the quality of evidence for outcomes using validated tools. RESULTS: Sixty systematic reviews (761 randomized controlled trials) evaluated 5 categories of rehabilitation interventions. Over half of the included reviews (n = 31) were of moderate-high quality. The findings suggest: moderate-quality evidence for exercise interventions for improving physical fitness and quality of life; high-quality evidence for nutritional interventions in reducing postoperative infections; high-quality evidence for multimodal prehabilitation for improved preoperative functional capacity; moderate-quality evidence for nutritional interventions for improving humoral immunity, reducing inflammation, and length of stay; moderate-quality evidence for acupuncture in improving gastrointestinal functional recovery; psychosocial interventions in improving short-term quality of life and mental health, and lifestyle interventions for improved quality of life. CONCLUSION: Rehabilitation interventions yielded positive effects across multiple outcomes. However, high-quality evidence is still needed to determine the most effective rehabilitation approaches for patients with colorectal cancer