Anzac Research Institute

Abstract Charcot-Marie-Tooth (CMT) neuropathy is a clinically and genetically heterogeneous group of diseases characterised by the length dependent axonal degeneration of peripheral nerves. We previously mapped a rare form of X-linked CMT, CMTX3, to a 5.7-Mb interval on chromosome Xq26.3-q27.1 and excluded the coding region of all known genes in the linkage interval for mutations. Whole genome sequencing subsequently identified a 78-kb region of chromosome 8q24.3, that had been duplicated and inserted into the CMTX3 locus between the genes HAPSTR2 and SOX3 . The 78-kb insertion, which contains a partial transcript of ARHGAP39 , fully segregated in families with CMTX3 and was absent in neurologically normal controls. To retain the CMTX3 insertion and investigate its consequences in appropriate neuronal tissue, we generated induced pluripotent stem cells (iPSC) from CMTX3 fibroblasts. Using bulk RNA sequencing of patient-derived spinal motor neurons, ARHGAP39 was deemed non-pathogenic by excluding both the formation of novel fusion transcripts and dosage effects from the partial duplication. Subsequent NanoString expression analyses of candidate genes within the CMTX3 locus, across different stages of neuronal differentiation, identified spatiotemporal dysregulation of SOX3. NanoString showed reduced SOX3 expression in patient iPSC. RNA sequencing detected SOX3 downregulation in CMTX3 neuroepithelial progenitor cells, which was further confirmed by quantitative proteomics. Given the early onset and relatively rapid progression of CMTX3, these data prioritise SOX3 as a leading candidate gene, consistent with its role as one of the earliest transcription factors expressed in the developing nervous system and a key regulator of neuronal fate.

Not available.

Abstract Disclosure: R.J. Marriott: None. K. Murray: None. L. Antonio: None. S. Bhasin: None. A.S. Dobs: None. L. Flicker: None. D.J. Handelsman: None. G.J. Hankey: None. R. Wilkening: None. A.M. Matsumoto: None. C. Ohlsson: None. E.S. Orwoll: None. D.M. Vanderschueren: None. H.W. Vesper: None. G.A. Wittert: None. F.C. Wu: None. B.B. Yeap: None. Aims: Whether differences in sex hormones relate to cancer, particularly prostate cancer, risk in men remains uncertain. We sought to clarify associations of testosterone, dihydrotestosterone and sex hormone-binding globulin (SHBG) with cancer risk via individual participant data (IPD) meta-analyses of major prospective cohort studies of community-dwelling men with testosterone measured using mass spectrometry. Methods: Eligible studies were identified via systematic literature review to July 2019, with bridge searches to March 2024. Ten studies provided IPD (24,510 men; 276,931 participant-years; 2847 cancer deaths), one provided aggregate data (1535 men; 184 cancer deaths). Five studies provided IPD for incident prostate cancer (12,280 men; 151,373 participant-years; 918 events). Two-stage random effects meta-analyses controlled for age, prior cancer, BMI, marital status, alcohol, smoking, physical activity, hypertension and diabetes. Results: Men with baseline testosterone at or below the lowest quintile median (Q1; 8.2 nmol/L), had higher risk of cancer death relative to Q5 (Q1:Q5 hazard ratio [HR]=1.15, 95% confidence interval [CI]=1.01-1.31). Baseline testosterone was not associated with risk of incident non-fatal and fatal cancer, nor incident prostate cancer. Men with lower baseline dihydrotestosterone had a higher risk of cancer death (Q1:Q5 HR=1.21, 95%CI=1.04-1.41), but not incident fatal and non-fatal cancer. SHBG was non-linearly associated with risk of cancer death (Q3:Q5 HR=0.79, 95%CI=0.66-0.95; Q4:Q5 HR=0.85, 95%CI=0.76-0.96). SHBG was not associated with incident non-fatal and fatal cancer. Men with lower baseline SHBG had higher risk of incident prostate cancer (Q1:Q5, HR=1.31, 95%CI=1.08-1.60; Q2:Q5 HR=1.26, 95%CI=1.04-1.52). Relative heterogeneity was negligible to moderate (estimates of I2 had 95%CI from 0.0-65.4%). Summary estimates from IPD were robust to the inclusion of aggregate data. Conclusions: Men with lower testosterone or dihydrotestosterone concentrations had higher risk, and men with mid-range SHBG lower risk, of cancer death. Testosterone was not associated with prostate cancer risk, while men with lower SHBG had a higher risk of incident prostate cancer. Testosterone, dihydrotestosterone and SHBG are biomarkers for cancer risk. The association between SHBG and prostate cancer risk merits further evaluation. Presentation: Saturday, July 12, 2025

As the global population ages, research on the biology of ageing and its role in chronic disease is expanding, alongside a growing clinical focus on the unique needs of older adults. In the past, the liver was not thought to undergo substantial age-related changes, nor was there thought to be any liver disease characteristic of older adults. Current studies challenge this perspective, revealing that ageing substantially influences liver pathophysiology at the organ level and within each of the liver cell types. These observations have implications for understanding the pathogenesis of liver diseases common in older adults, including hepatocellular carcinoma, hypoxic hepatitis and metabolic dysfunction-associated steatotic liver disease. Previously, managing older patients with liver disease mostly addressed age-related changes in drug metabolism and liver function tests. However, current clinical practice increasingly emphasizes age-specific issues such as frailty, sarcopenia, multimorbidity and polypharmacy. Given the liver's pivotal role in systemic metabolism, immunity and detoxification, ageing of the liver can contribute to systemic diseases. In the future, interventions that target ageing biology might offer new treatment options for liver diseases. Here, we review those age-related changes in the liver that have substantial biological and clinical consequences for older adults.

At an elite international level, professional sports have a well-established fairness-based binary sex classification which is challenged by male-bodied athletes with female gender identity, notably male-to-female transgender and XY Disorders of Sex Development (DSD) individuals seeking to compete in female events. For sports where success depends on power and/or endurance, physical advantages stemming from male puberty, which produces men's circulating testosterone concentrations 20-30 times those of children or women at any age, leading to larger and stronger muscles, bones, cardiorespiratory functions and blood hemoglobin. Yet complete suppression of endogenous testosterone after male puberty leaves a legacy of reduced but not eliminated physical advantages. Hence a protected female category in power sports is essential to allow women a fair and safe chance at the fame and fortune derived from success. For community, recreational and youth sports, or those without male physical advantages invoking safety or fairness issues, inclusivity may prevail.

To describe how crowdsourcing contests soliciting art, letters, stories, and poetry were focused on promoting well-being and health information dissemination from the public to the public. LIGHT (Leaders Igniting Generational Healing and Transformation) launched three online crowdsourcing open calls that were designed using the World Health Organization Tropical Diseases Research (WHO/TDR) practical guide on crowdsourcing in health and health research, which includes the following steps: convening a steering committee, promoting the open call, receiving and judging entries, recognizing finalists, and sharing solutions. The crowdsourcing open calls were held online via the Submittable platform. A total of 508 submissions by the public were evaluated with the majority of authors and artists identified as female (25.4%) followed by male (15.4%) and ages ranging from 11 to 82years old. This study utilized crowdsourcing open call contests to engage the public in generating art, letters, stories, and poetry as strategies to effectively promote well-being and disseminate health information to the public. Effectiveness and creativity of the crowdsourced submissions in proposing new strategies for promoting well-being and disseminating health information through art, letters, stories, and poetry. The three crowdsourcing open calls received 508 eligible entries (Open call 1=155; Open call 2=191; Open call 3=162). Informed by the combined and modified design justice principles creativity, connections, and community, six unique dissemination strategies emerged for dissemination: (a) positive intersectionality, (b) destigmatization, (c) strength-based, (d) collective approach, (e) cultural identity, and (f) unity in healing. Collectively, there was consensus to innovate dissemination strategies to enhance the appeal of research findings and health communication. Rebuilding and building public-driven dissemination strategies will involve reimagining and innovating current dissemination approaches. LIGHT shows the feasibility of engaging a diverse broad audience to generate ideas and perspectives on promoting health information dissemination to the public.

Wound healing is a central physiological process that restores the barrier properties of the skin after injury, comprising close coordination between several cell types (including fibroblasts and macrophages) in the wound bed. The complex mechanisms involved are executed and regulated by an equally complex, reciprocal signalling network involving numerous signalling molecules such as catabolic and anabolic inflammatory mediators (e.g., cytokines, chemokines). In chronic wound environments, the balance in the molecular signatures of inflammatory mediators is usually impaired. Thus, we compared the ability of a collagen-based wound matrix against a synthetic wound matrix to attract fibroblasts and macrophages that deliver these signalling molecules. In particular, the balance between pro- and anti- inflammatory cytokine secretion was assessed. We found that the natural collagen-based matrix was the most efficient adhesive substrate to recruit and activate fibroblasts and macrophages on its surface. These cells secreted a variety of cytokines, and the natural biomaterial exhibited a more balanced secretion of pro- and anti-inflammatory mediators than the synthetic comparator. Thus, our study highlights the ability of native collagen matrices to modulate inflammatory mediator signatures in the wound bed, indicating that such devices may be beneficial for wound healing in the clinical setting.