Australian Cancer Research Foundation

Niemann-Pick disease type C (NP-C) is the fifth most prevalent lysosomal disorder in Australia. Diagnostic delay is common, impacted by disease heterogeneity, limited awareness within clinical gateway services and exclusion from state-based newborn screening programmes. A formal diagnosis, once established, places a substantial burden on the whole family, the negative impact of which is far-reaching. A clear understanding of diagnostic pathways and management objectives in NP-C is critical for optimal care. To develop an Australian standard of care for individuals diagnosed with NP-C and their families, reflecting international best practice and tailored to the Australian healthcare system. The Australian NPC Disease Foundation Inc. convened a national, multidisciplinary collaboration including NP-C treating clinicians, allied health professionals and a community advisory group. Using an iterative consensus approach, published international guidance statements were reviewed, ratified, excluded or modified to align with the Australian context. Consensus outputs included a diagnostic algorithm, a multidisciplinary care framework and management-centred management statements. The collaborative process resulted in a unified Australian standard of care for NP-C. This framework incorporates the carer perspective, emphasises shared decision-making and situates NP-C within the broader context of 'childhood dementias.' Consensus statements provide practical, evidence-aligned guidance on early recognition, diagnostic referral pathways and multidisciplinary management throughout disease progression. This initiative represents the first Australia-specific standard of care for NP-C. It is hoped that adoption of the framework will lead to improved experiences for Australians living with NP-C and their carers as they navigate the healthcare setting.

The three-dimensional (3D) organization of the human genome plays a critical role in regulating gene expression and is frequently disrupted in cancer. However, how key factors like Heterochromatin Protein 1 alpha (HP1α) and Transforming Growth Factor beta (TGFβ) remodel this architecture to drive tumorigenesis remains poorly understood. We investigated the effects of HP1α knockdown and TGFβ treatment on higher-order chromatin structure and gene expression in human mammary epithelial cells. Our findings reveal that HP1α depletion and TGFβ stimulation exert distinct and opposing effects on genome compartmentalization and sub compartmentalization. HP1α knockdown drives a genome-wide shift of chromatin from transcriptionally inactive B compartments to active A compartments. This is accompanied by a stepwise redistribution of A subcompartments toward the most transcriptionally active state (A3), and the upregulation of oncogenic genes involved in EMT and proliferation. In contrast, TGFβ treatment promotes chromatin compaction, increases the proportion of B compartments, and drives a stepwise reduction in active A subcompartments. Our results highlight the differential roles of HP1α and TGFβ in shaping the 3D genome and underscore how precise, stepwise architectural changes contribute to malignant transformation. This study provides critical insight into how chromatin architecture acts as a regulatory layer in breast cancer development.

Cytokines signal by bringing receptor subunits together, but the role of receptor geometry in shaping signaling remains unclear because natural ligands enforce fixed assemblies. Here, we present a de novo protein design platform that rigidly scaffolds receptor-binding domains into defined spatial arrangements. Applying this across IL-7, type I and III interferons, IL-10, gp130, β common, and synthetic receptor pairs, we show that by varying geometry, we can bias pSTAT pathway usage and tune functional outcomes. Geometric control allowed us to decouple pSTAT1 from pSTAT5 in IL-7, separate antigen presentation (MHC-I) from checkpoint induction (PD-L1) in type I interferons, and suppress pro-inflammatory IFNγ secretion while retaining anti-inflammatory activity in IL-10. We further created minimal IL-6 and IL-3 agonists and strengthened synthetic receptor pairings inaccessible with present cytokines. These results establish receptor geometry as a central determinant of cytokine activity and provide a platform for programmable immune modulation.

Fluorescence recovery after photobleaching (FRAP) has remained a powerful tool to probe intracellular dynamics. FRAP relies on two aspects: (1) localized excitation resulting in photobleaching, and (2) fluorescence recovery of the bleached volume which provides insight into kinetics. Existing FRAP systems are limited by a trade-off between time and spatial multiplexing due to galvanometric scanning methods, precluding the study of multiple independent positions simultaneously as well as advanced widefield imaging modes. Hence, they may not capture the dynamic and non-isotropic environments in biological studies. In this paper, we utilize phase profiles corresponding to an array of Fresnel lenses and diffractive masks to switch between simultaneous FRAP of independent spatial positions whilst maintaining epifluorescence, highly inclined laminated optical sheet (HILO), and total internal reflection fluorescence (TIRF) microscopy modalities. Our approach bridges high contrast fluorescence imaging (HILO and TIRF) and a multi-position FRAP technique using a single spatial light modulator. As such, this technique enables high contrast bleaching and screening across volumes, which we envision will be of value to areas such as single particle tracking and single molecule imaging where dynamic photobleaching is necessary to measure fast events across the field of view in a single versatile instrument.

Abstract Despite advances in therapy, specific subtypes Acute Myeloid Leukaemia (AML) remains largely incurable. The first-in-class RNA Polymerase I (Pol I) inhibitor, CX-5461, has demonstrated promising activity in both haematological malignancies and solid tumours by selectively inhibiting ribosome biogenesis to induce nucleolar stress, a critical vulnerability in rapidly proliferating cancer cells. CX-5461 has undergone clinical trials for the treatment of both solid and haematological malignancies, and 2nd generation Pol I inhibitor PMR-116 has also entered clinical trials, underscoring the translational potential of drugs that target RNA Polymerase I. To enhance the therapeutic efficacy of Pol I inhibition and prevent the emergence of resistance, we conducted a cell line-based unbiased screen of FDA-approved drugs to identify compounds that might synergise with CX-5461. This screen revealed that the pan-CDK inhibitors Dinaciclib and Flavopiridol enhance nucleolar stress pathway (NSP) activation and are strong candidates for combinatorial therapy with CX-5461. Further analysis showed that the combination of CX-5461 and Dinaciclib acts synergistically across a genetically diverse panel of human AML cell lines. This synergy is dependent on an intact NSP, with both agents independently stabilising p53, but with distinct phenotypic outcomes: Dinaciclib induces rapid apoptosis, whereas CX-5461 primarily enforces cell cycle arrest. This functional complementarity results in efficient tumour cell clearance and likely accounts for the delayed onset of therapy resistance. Importantly, combination treatment with CX-5461 and Dinaciclib significantly improved survival in murine models of AML and reduced colony formation in primary human AML samples. Together these findings provide preclinical evidence for a novel combination treatment strategy that leverages nucleolar stress and cell cycle control to enhance treatment outcomes in AML, paving the way for clinical translation of Pol I-CDK co-targeting therapies.

Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an "all or none" phenomenon. Subtle alterations of the cytokine:receptor complex can result in differential or selective signaling and underpin a variety of diseases including chronic inflammatory conditions and cancers. Structural biology techniques, such as X-ray crystallography and cryo-electron microscopy alongside cell biology studies, are providing detailed insights into cytokine receptor signaling. Recently, we found that the IL-3 receptor ternary complex forms higher-order assemblies, like those found earlier for the GM-CSF receptor, and demonstrated that functionally distinct biological signals arise from different IL-3 receptor oligomeric assemblies. As we enhance our understanding of the structural nuances of cytokine-receptor interactions, we foresee a new era of theranostics whereby structurally guided mechanism-based manipulation of cytokine signaling through rational/targeted protein engineering will harness the full potential of cytokine biology for precision medicine.

Platelet adhesion and activation is fundamental to the formation of a hemostatic response to limit loss of blood and instigate wound repair to seal a site of vascular injury. The process of platelet aggregate formation is supported by the coagulation system driving injury-proximal formation of thrombin, which converts fibrinogen to insoluble fibrin. This highly coordinated series of molecular and membranous events must be routinely achieved in flowing blood, at vascular fluid shear rates that place significant strain on molecular and cellular interactions. Platelets have long been recognized to be able to slow down and adhere to sites of vascular injury and then activate and recruit more platelets that forge and strengthen adhesive ties with the vascular wall under these conditions. It has been a major challenge for the Platelet Research Community to construct experimental conditions that allow precise definition of the molecular steps occurring under flow. This brief review will discuss work to date from our group, as well as others that has furthered our understanding of platelet function in flowing blood.