Westmead Institute for Medical Research

BK polyomavirus (BKPyV) is a common opportunistic infection in kidney transplant recipients, typically reactivating in the context of immunosuppression. Although asymptomatic in immunocompetent individuals, reactivation in transplant recipients can cause BKPyV-associated nephropathy (BKPyVAN), a leading cause of graft dysfunction and loss. BKPyV viremia affects approximately 10%-15% of transplant recipients, and once BKPyVAN is established, the risk of graft failure can exceed 50%. The current standard of care involves immunosuppression reduction to restore virus-specific immunity, but this approach increases the risk of acute and chronic rejection. Intravenous immunoglobulin (IVIg), which contains antiviral and immunomodulatory antibodies, has been proposed as an adjunctive therapy, although evidence supporting its efficacy remains limited to small observational studies. The BEAT-BK trial is a multicenter, adaptive, randomized controlled trial comparing standard immunosuppression reduction with or without IVIg in kidney and simultaneous pancreas-kidney transplant recipients with BKPyV viremia or biopsy-confirmed BKPyVAN. The trial will enroll participants aged 2 y and older, randomizing them 1:1 to receive standard care alone or in combination with a total IVIg dose of 2 g/kg for 8 wk. An adaptive Bayesian design will permit interim analyses with the potential for early trial success or futility. The primary endpoint is a composite ordinal outcome at 12 wk, incorporating death, graft loss, estimated glomerular filtration rate decline, acute rejection, viral load, and degree of immunosuppression reduction. Secondary outcomes include viral clearance, development of BKPyVAN and donor-specific antibodies, infections, malignancy, quality of life, and cost-effectiveness. This trial will provide the first high-quality evidence on the role of IVIg in BKPyV management and inform clinical decision-making in posttransplant care.

Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to treatment, with mortality rates largely unchanged despite advances in cancer therapies. For ∼80% of borderline, non-resectable, or metastatic cases, chemotherapy is predominantly palliative, underscoring the need for improved drug delivery approaches. This study presents the development, characterization and in vivo evaluation of a novel polymeric implant loaded with 5-fluorouracil, irinotecan, and oxaliplatin (FIRINOX). Scanning electron microscopy of FIRINOX implants showed internal microstructure was preserved upon drug loading, while micro-CT and X-ray imaging revealed valuable insights into the morphology and degradation of implants retrieved from in vivo experiments. In murine PDAC models, dose-escalation identified 4 × FIRINOX implants as the maximum tolerated dose, while 2 × implants achieved significant therapeutic efficacy at lower doses than IV administration, without compromising animal safety. In healthy pigs, 20 × FIRINOX implants were well-tolerated, as confirmed by histopathology and blood analysis. Finally, laser ablation-inductively coupled plasma-mass spectrometry imaging and microbiome analysis confirmed localized drug perfusion within tissues, and minimal off-target effects, including preservation of gut microbiota diversity. These findings support the potential of this implantable platform to improve outcomes in borderline or non-resectable PDAC and enhance tolerability of cytotoxic chemotherapy through localized, controlled delivery, addressing a key gap where current treatment options are limited.

Pan-arterial diseases, including atherosclerosis (AS), aortic aneurysm and dissection (AAD), and peripheral arterial disease (PAD), impose a substantial global health burden. Although ambient temperature has been implicated in individual arterial conditions, its association with mortality across the pan-arterial spectrum remains incompletely understood. To evaluate the association between ambient temperature and mortality from pan-arterial diseases across the United States. We analysed mortality data for adults aged ≥25 years with AS, AAD, or PAD in the United States CDC WONDER database from 1999 to 2023. Age-adjusted mortality rates (AAMR) and average annual percent change (AAPC) were estimated. Monthly air-temperature metrics (1999-2023) were linked at the United States Census region level. Seasonal variation was assessed using analysis of variance. Associations between temperature and mortality were examined using Spearman correlation, Poisson regression with lag structures, and distributed lag non-linear models (DLNM), with results expressed as relative risks (RR) per 10°F increase in temperature. Between 1999 and 2023, AAMRs declined for AS, AAD, and PAD, yet mortality burden remained substantial. Mortality from all three conditions was consistently higher in winter than in summer across Census regions. Monthly mean temperature was inversely correlated with crude mortality for pan-arterial diseases (P < 0.05). In the Northeast, cumulative RR per +10°F across lags 0-3 months was 0.919 for AS, 0.945 for AAD, and 0.953 for PAD, with similar patterns observed in other regions. DLNM analyses demonstrated a predominantly cold-related excess risk, with acute effects and regional heterogeneity at higher temperatures. Lower ambient temperatures are associated with increased mortality from pan-arterial diseases in the United States. These findings highlight shared vulnerability to cold exposure across arterial diseases and support winter-focused preventive and healthcare preparedness strategies.

BackgroundTo combat hepatocellular carcinoma (HCC) disease heterogeneity and growing mortality, there is an urgent need for targeted and personalized therapeutics. While syngeneic mouse models are commonly used for preclinical validation of these therapeutics, the lack of genetically characterized murine cell lines adds uncertainty to the study of drug‐gene interactions in these models. We previously generated a novel murine cell line, A52, from a diethylnitrosamine (DEN)‐induced adiponectin‐knockout mouse model. Here, we present a comprehensive genomic and transcriptomic characterization of the A52 cell line.MethodsA52 cells were grown in various culture medium compositions to investigate robustness to simple media. Whole‐genome sequencing (WGS) and RNAseq were performed on A52 cells from both cell culture and syngeneic tumor tissue, as well as a reference cell line representing non‐tumor cells, AML‐12.ResultsA52 was found to show robust growth in all medium compositions. Substantial chromosomal instability was observed in A52, including trisomy 15 and notable amplifications of oncogenic loci such as Myc and Cd274 (PDL‐1), alongside frequent small variants and structural rearrangements. Notably, the cell line harbors the common HCC driver Braf V584E mutation, and a novel Plk1 p.R364W variant predicted as a driver mutation. Transcriptomic profiling defined a distinct “A52 gene signature” enriched in EGFR‐ERBB signaling and cell migration pathways. Integrative analyses demonstrated that the A52 gene signature aligns closely with a subset of human HCC lacking CTNNB1 mutations.ConclusionThis study provides a critical genetic resource, facilitating more precise preclinical modeling and therapeutic validation in HCC.

We read with great interest the paper published in the journal by Ghani et al., which demonstrated that lean individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) face a dramatically higher risk of all-cause mortality compared to their non-lean counterparts [1]. This important revelation challenges long-held beliefs and necessitates a re-evaluation of risk stratification in MASLD that extends beyond body mass index (BMI). Steatotic liver disease (SLD), particularly MASLD, exhibits a substantial heterogeneity, as exemplified among non-obese subjects [2], which represents a considerable proportion of the MASLD population, though it is still largely unexplored. Notably, MASLD is a multisystemic disease that increases the risk of cardiovascular disease, chronic kidney disease, diabetes, and various extrahepatic cancers, with metabolic dysfunction representing the core pathogenesis basis linking these conditions [2]. Acknowledging the interconnected link between metabolic disorders and aiming to promote a holistic management approach for them, the American Heart Association (AHA) introduced the Cardiovascular-Kidney-Metabolic (CKM) syndrome term in 2023, as a progressive risk continuum, starting with Stage 0, where individuals have no risk factors, up to Stage 4 which encompasses overt clinical cardiovascular manifestations, including heart failure, coronary artery disease, stroke, or atrial fibrillation, along with metabolic and renal dysfunction [3]. Thus, building on the work of Ghani et al. [1], we sought to investigate the CKM risk among lean MASLD (L-MAFLD) patients for determining the risk of systemic metabolic dysfunction in this population. To this end, we utilized the NHANES database (2017–2020), comparing CKM risk among 111 individuals with L-MASLD and 1206 lean controls without MASLD aged 20–79, with available relevant variables for this analysis. Results revealed a markedly elevated risk of ASCVD among L-MASLD individuals compared to their lean counterparts (38.8% vs. 20.6%, p < 0.001). Additionally, the prevalence of coronary heart disease (11.7% vs. 3.1%, p < 0.001) and recent heart attacks (9.9% vs. 2.6%, p < 0.001) was significantly higher among L-MASLD individuals. Moreover, stratification by CKM stage highlights a stepwise increase in CKM prevalence among L-MASLD patients relative to lean controls, with risk markedly rising in Stage 3 (31.5% vs. 17.4%) and Stage 4 (16.2% vs. 8.2%), p < 0.001, for both comparisons (Table 1). In conclusion, we demonstrated that L-MASLD subjects have an elevated cardiometabolic risk compared to their lean counterparts without MASLD, further emphasizing the importance of consideration of metabolic dysfunction in the pathogenesis of the disease [4, 5]. This evidence insists on the urgent need for increased awareness of lean MASLD in clinical practice and research initiatives. The data that support the findings of this study are available in NHANES at https://www.cdc.gov/nchs/nhanes. These data were derived from the following resources available in the public domain: NHANES 2017–2020, https://www.cdc.gov/nchs/nhanes.