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Off-the-shelf dual CAR-iNKT cell immunotherapy eradicates medullary and leptomeningeal high-risk KMT2A-rearranged leukemia
Get PDFCurrent therapies, including autologous CAR-T immunotherapy, fail to cure half of infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2Ar-ALL), a disease characterized by frequent central nervous system involvement, poor treatment response, early relapse and lineage switching. More effective treatment strategies, including the availability of 'off-the-shelf' immunotherapies is particularly relevant in infants. PROM1/CD133 is a direct target of KMT2A-fusion oncoproteins and is expressed on leukemic cells. Allogeneic iNKT cells, 'innately' more powerful effectors than T cells can be deployed 'off-the-shelf' without risk of acute graft-versus-host disease. Here, we equip iNKT with CD19- and/or CD133-targeting CARs and investigate their anti-leukaemia activity against KMT2Ar-ALL in relevant in vitro and in vivo models. Compared to mono-specific counterparts and dual, bi-specific CAR-T, bi-specific CD19-CD133 CAR-iNKT have a more potent anti-leukemia activity, effectively targeting both CAR antigen-high and -low leukemia. Bi-specific CAR-iNKT eradicate medullary and, notably, leptomeningeal leukemia and induce sustained remissions without discernible hematologic toxicity. Mechanistically, the more potent anti-leukemia effect of CAR-iNKT over CAR-T cells is mediated by a pronounced CAR- and CAR antigen-dependent upregulation of the innate activating receptor NKG2D on CAR-iNKT and its engagement by its corresponding ligands on KMT2Ar-ALL cells. This ensures effective leukemia targeting even with downregulation of CD133 or CD19. Thus, by engaging with two different types of leukemia-associated antigens i.e., CAR antigens and NKG2D ligands, CAR-iNKT provide a powerful platform for the treatment of KMT2Ar-ALL. This approach can be readily adapted for other high-risk malignancies, including those with otherwise difficult to target leptomeningeal involvement
Y12C mutation disrupts IMPDH cytoophidia and alters cancer metabolism
Get PDFGuanosine triphosphate (GTP) is a building block for DNA and RNA, and plays a pivotal role in various cellular functions, serving as an energy source, enzyme cofactor and a key component of signal transduction. The activity of the rate‐limiting enzyme in de novo GTP synthesis, inosine monophosphate dehydrogenase (IMPDH), is regulated by nucleotide binding. Recent studies have illuminated that IMPDH octamers can assemble into linear polymers, adding another dimension to its enzymatic regulation. This polymerisation reduces IMPDH's sensitivity to the inhibitory effects of GTP binding, thereby augmenting its activity under conditions with elevated GTP levels. Within cells, IMPDH polymers may cluster to form the distinctive structure known as the cytoophidium, which is postulated to reflect the cellular demand for increased GTP concentrations. Nevertheless, the functional significance of IMPDH polymerisation in in vivo metabolic regulation remains unclear. In this study, we report the widespread presence of IMPDH cytoophidia in various human cancer tissues. Utilising the ABEmax base editor, we introduced a Y12C point mutation into IMPDH2 across multiple cancer cell lines. This mutation disrupts the polymerisation interface of IMPDH and prevents cytoophidium assembly. In some cancer xenografts, the absence of IMPDH polymers led to a downregulation of IMPDH, as well as the glycolytic and pentose phosphate pathways. Furthermore, mutant HeLa‐cell‐derived xenografts were notably smaller than their wild‐type counterparts. Our data suggest that IMPDH polymerisation and cytoophidium assembly could be instrumental in modulating metabolic homeostasis in certain cancers, offering insights into the clinical relevance of IMPDH cytoophidium
Unsettling subject English in the twenty‐first century
Get PDFThis paper uses examples from Australia and England to explore subject English with regard to the multiple metaphors inherent in the terms ‘settling’ and ‘unsettling’. In doing so we are concerned with imagining a future for a subject English curriculum which dislodges it from its imperial, colonial roots. In the first instance, we outline the existing approaches to unsettling English in England and Australia and the challenges and limitations of these approaches and strategies. We also discuss some of the structures and agents which are invested in maintaining the status quo: namely, curriculum and assessment; teacher practices and disciplinary norms; teacher knowledge and CPD; and student context and the purposes of English. We conclude with the implications for a systemic and multi‐layered approach to unsettling. We see this as an opening up of a comparative conversation about subject English across the Anglophone world, the different contexts of unsettling and what that subject might look like if it is to enact the justice imperatives of education in the twenty‐first century
Diaspora as partners: strengthening resilience of health systems and communities amidst aid volatility
Get PDFThe potential of virtual reality for enhancing the efficacy and acceptability of mindfulness training in non-clinical adults: a pilot randomised controlled trial
Get PDFMindfulness-based programmes (MBPs) have proven effective in enhancing mental health outcomes among non-clinical populations, yet they face significant attrition rates. The role of virtual reality (VR) in improving engagement and effectiveness within this context remains uncertain. To explore the potential acceptability and effectiveness of VR-based mindfulness interventions for mental health outcomes in non-clinical adults, we conducted a pilot randomised controlled trial (RCT) with pre-treatment and post-treatment measures, alongside pre-post VR session assessments. A total of 51 participants were randomly assigned to three groups: “MBP” alone (n = 15), “MBP + VR” (n = 20) and “Relaxation” therapy (n = 16), the latter serving as the control condition. We utilised the innovative technology of the MK360 immersive experiences system, offering auditory and visual stimuli that allowed participants to immerse themselves in a virtual world. “MBP + VR” demonstrated greater acceptability compared to “Relaxation” but equal acceptability to “MBP” alone. All study conditions showed significant reductions in psychological distress, the primary outcome. Notably, “MBP + VR” outperformed “Relaxation” in reducing psychological distress (p = .0.015), with large effects. Both MBP and MBP + VR showed superior results compared to the Relaxation group. MBP demonstrated greater improvements in depressive symptoms (DASS-21), positive affect (PANAS), the Observing facet of mindfulness (FFMQ), and several self-compassion measures (total SCS, Self-Kindness, lower Self-Judgment, and Mindfulness subscale). MBP + VR was superior in the total FFMQ score, the Observing facet, and the SCS Mindfulness subscale. Participants in the “MBP + VR” group experienced significant improvements in state mindfulness (across six short sessions in mindfulness-based VR environments) and emotional states (relaxation in all VR environments, reduced sadness in VR-environment 3, increased surprise in VR-environment 5, and decreased anxiety in VR-environment 6). They reported an intermediate sense of presence in each of the VR environments. Despite these promising results, further research in this area is warranted
Understanding bidirectional and transactional relations in parent and offspring mental health: using COVID-19 pandemic data to gain insights
No full textBackground: Bidirectional and transactional models propose that parents and children have the potential to influence each other’s mental health over time. While bidirectional associations have been widely studied, transactional processes involving parent internalising, offspring internalising, and offspring externalising symptoms remain underexplored. The COVID-19 pandemic was associated with marked changes in parent and offspring mental health, providing an enhanced opportunity to examine these dynamics across developmental stages and gender.Methods: We examined four waves of survey data from the UK-based longitudinal COVID19: Supporting Parents, Adolescents and Children during Epidemics (Co-SPACE) study collected between May 2020 and May 2021. Data from 2,349 parent-child dyads (4-16-yearold children) were analysed using multi-group (for age and gender) random intercept crosslagged panel modelling.Results: In the full sample, parent internalising symptoms significantly predicted increases in offspring internalising symptoms over time. Among primary school aged children (4–10 years), effects were parent-driven, with no evidence that changes in child symptoms predicted parent symptoms. In contrast, among secondary school aged children (11–16 years), we found bidirectional associations between parent internalising and offspring externalising symptoms, and some time-specific links with internalising symptoms. However, no sustained transactional loops (i.e., indirect effects forming a feedback cycle) were detected. Gender did not moderate any associations.Conclusions: These findings suggest that parent and offspring mental health symptoms may become more reciprocal as children grow older
Modelling three-phase mushy layers, with applications to air bubbles and oil droplets in sea ice
Get PDFA mushy layer is a reactive porous medium that forms during the partial solidification of a multicomponent liquid. Sea ice is a naturally occurring mushy layer that forms through the freezing of seawater in the polar oceans. This multiphase mixture of solid ice crystals, liquid brine, air bubbles, and other chemical species plays a critical role in Earth’s climate and ecosystems. Two-phase mushy layers, comprising a porous solid saturated with liquid, have been well studied; however, sea ice and other mushy layers in the natural environment often contain gaseous inclusions or other immiscible liquid phases, yielding a three-phase problem. This thesis formulates appropriate conservation equations for a three-phase mushy layer that accounts for the production, migration, and trapping of a third distinct phase in the pore space of sea ice. We use an idealised model of the pore geometry to derive a novel expression for the vertical flux of a buoyant third phase dispersed as bubbles/droplets in the liquid-filled pore space. The resulting model is applied to both air bubbles and oil droplets in sea ice. Two key dimensionless parameters arise: (1) the ratio of the bubble/droplet radius to the pore throat-radius and (2) the timescale of gas exsolution relative to the timescale of solidification in the mushy layer (in the case of a solid-liquid-gas system). We explore the three-phase mushy-layer model in a variety of settings. First, we examine the three-phase mushy layer found during the steady solidification of air-saturated saltwater in a Hele-Shaw cell. We show that neglecting the volume occupied by exsolved gas yields a reduced “tracer” model for the dissolved and free-phase gas that still describes the steady-state solution well. Then, we formulate a one-dimensional transient model for sea-ice evolution that includes parameterisations for brine convection, radiative transfer, and heat exchanges with the overlying atmosphere and snowpack, and with the underlying ocean. We validate this transient model against observations of first-year landfast sea ice at Barrow, Alaska. We use ice core measurements of bulk gas concentrations from Barrow to constrain the gas dynamics in our model and predict the seasonal evolution of the gas volume fraction and ice bulk density. This has implications for biogeochemical cycles in the Arctic and the estimation of ice thickness from remote sensing measurements. Finally, we investigate the impact of low levels of weathered oil droplets on landfast sea ice, and find that the increased absorption of solar radiation by these droplets can significantly enhance ice melt rates and delay the onset of the spring under-ice algal bloom compared with year-to-year variability. The results in this thesis have important implications for the future study of sea ice as a complex multiphase reactive material
Targeting Cardiac Metabolism in Heart Failure with PPARα Agonists: A Review of Preclinical and Clinical Evidence
Get PDFBackground and objective: Heart failure (HF) is associated with high morbidity, mortality, and healthcare costs. Its prevalence continues to rise, particularly in the context of ageing populations and increasing rates of metabolic comorbidities such as type 2 diabetes and obesity. We aimed to assess the therapeutic potential of repurposing PPARα agonists for the treatment of HF. Method: We conducted a comprehensive literature review to evaluate preclinical and clinical evidence investigating the potential of PPARα agonist drugs in reducing HF. We did not apply any restrictions on the study design. Results: The current body of evidence consists of preclinical mechanistic studies, emerging pharmacogenetic data, and post hoc analyses of large randomised clinical trials (RCTs) that included HF endpoints. No dedicated, HF-specific RCTs of PPARα agonists were identified. These studies support the hypothesis that PPARα agonists may link metabolic modulation with cardiac remodelling. Preclinical models demonstrate potential therapeutic benefits, such as enhanced myocardial energy metabolism and attenuation of fibrosis and inflammation, as well as context-dependent risks, including possible deleterious effects in advanced HF or off-target mechanisms. Prior failures of fibrates to improve cardiovascular outcomes in some trials and concerns in PPARα-deficient states underscore the complexity of metabolic therapies in HF. These findings support a more stratified, phenotype-driven approach to therapy. RCTs specifically designed to evaluate HF outcomes are essential to clarify whether PPARα agonists can complement established neurohormonal treatments, particularly in the context of the rising burden of HFpEF associated with obesity and type 2 diabetes. Conclusions: PPARα agonists represent a promising class within the emerging therapeutic framework of metabolic heart failure. They are inexpensive, generally well tolerated, and address several pathophysiological mechanisms of HF. Preliminary evidence suggests that fenofibrate may delay or prevent HF in high-risk diabetic populations. However, rigorous, dedicated trials are needed to establish their clinical utility
Dairy Consumption and Risk of Cardiovascular and Bone Health Outcomes in Adults: An Umbrella Review and Updated Meta-Analyses
Get PDFBackground/Objectives: The relationship between dairy consumption and cardiovascular or bone health outcomes remains controversial, with inconsistent findings across existing meta-analyses. In this study, we aimed to systematically evaluate and synthesize the evidence from published meta-analyses on dairy consumption and cardiovascular and bone health outcomes in adults, and to conduct updated meta-analyses incorporating recently published prospective cohort studies. Methods: We performed an umbrella review following PRISMA guidelines, searching published and grey literature up to April 2024. Meta-analyses evaluating dairy intake and its impact on cardiovascular and bone health outcomes were included. Updated meta-analyses were conducted for cardiovascular outcomes, while bone health outcomes were synthesized qualitatively. Methodological quality was assessed using the Joanna Briggs Institute checklist. Random-effects models were applied, and heterogeneity, small-study effects, excess significance, and prediction intervals were evaluated. Results: We included 33 meta-analyses (26 on cardiovascular, 7 on bone health outcomes). Updated meta-analyses showed that total dairy (RR: 0.96), milk (RR: 0.97), and yogurt (RR: 0.92) were significantly associated with reduced CVD risk. Total dairy and low-fat dairy were inversely linked to hypertension (RRs: 0.89, 0.87), and milk and low-fat dairy were associated with reduced stroke risk. Small-study effects were absent for most associations. Credibility was rated as “weak” for most associations, with total dairy and stroke, and total dairy and hypertension showing "suggestive" evidence. For bone health, dairy—especially milk—was linked to higher bone mineral density (BMD). Evidence on osteoporosis risk was mixed, and while total dairy and milk showed inconsistent associations with fractures, cheese and yogurt showed more consistent protective effects. Limited evidence suggested milk may reduce bone resorption markers. Conclusions: This review suggests that dairy consumption, particularly milk and yogurt, is modestly associated with reduced cardiovascular risk, while dairy intake appears to benefit BMD and fracture prevention. However, further research is needed to confirm these associations