variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy.

encodes a subunit shared by the BLOC-1 and BORC hetero-octameric complexes that regulate various endolysosomal processes. Here, we report the identification of seven distinct variants in in eleven individuals from seven independent families presenting with early psychomotor delay, hypotonia, spasticity, epileptic encephalopathy, optic atrophy, and leuko-axonopathy with hypomyelination. A subset of the affected individuals also have features of hypopigmentation and ocular albinism that are similar, although milder, than those of individuals with BLOC-1-related Hermansky-Pudlak syndrome.

From Gut to Lung: The Role of Bile Acids in Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD).

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a serious complication of rheumatoid arthritis (RA) that significantly increases both morbidity and mortality. Although advances have been made in elucidating the pathogenesis of RA-ILD, the specific roles of bile acids remain underexplored. Bile acids are known to modulate immune responses, potentially influencing the inflammatory processes central to RA-ILD; however, their exact mechanisms and therapeutic utility remain unclear.

Capillary constrictions prime cancer cell tumorigenicity through PIEZO1.

Metastasis is a hallmark of cancer and is responsible for the majority of cancer-related deaths. Evidence suggests that even a single cancer cell can spread and seed a secondary tumour. However, not all circulating tumour cells have this ability, which implies that dissemination and distal growth require adaptative mechanisms during circulation.

Development of a Digital Case-Based Knowledge Base to Support Rapid Learning in Precision Oncology.

Precision oncology hinges on the exchange of continuously evolving diagnostic and treatment knowledges, with individual patients providing valuable knowledge to supplement frequent scenarios where there are insufficient clinical trials evidence to inform care. We propose a novel architecture of a collaborative web-based community platform to support a learning health concept, organising physician-directed knowledge analysis to support rapid learning. This platform promotes knowledge sharing through systematic organisation and structuring of case studies.

Automating Precision Oncology Literature Curation: A Decision Tree Approach Using Large Language Models.

The curation of precision oncology knowledge bases requires intensive screening of scientific literature. Large Language Models (LLMs) offer potential to assist with knowledge extraction and curation through automated abstract screening, though their utility in this context remains unexplored. We developed a decision tree-based pipeline utilising LLMs to automate literature screening for precision oncology knowledge bases.

Prognostic and predictive value of baseline PSMA-PET total tumour volume and SUVmean in metastatic castration-resistant prostate cancer in ENZA-p (ANZUP1901): a substudy from a multicentre, open-label, randomised, phase 2 trial.

Background: Quantitative parameters derived from gallium-68 [Ga]Ga-prostate-specific membrane antigen (PSMA)-11 PET-CT (PSMA-PET-CT) such as whole-body standardised uptake value (SUV)mean and total tumour volume (PSMA-TTV) have shown prognostic value for response to lutetium-177 [Lu]Lu-PSMA-617 monotherapy in patients with prostate cancer. Adding [Lu]Lu-PSMA-617 to enzalutamide improved overall survival compared with enzalutamide in patients with metastatic castration-resistant prostate cancer in the ENZA-p trial. This prespecified substudy of ENZA-p evaluated baseline PSMA-PET quantitative parameters as predictive and prognostic biomarkers for enzalutamide plus [Lu]Lu-PSMA-617 and enzalutamide monotherapy.

PPARγ acetylation governs mammary adenocarcinoma tumor growth via acetylated residues that determine DNA sequence-specific binding.

Peroxisome proliferator-activated receptor γ (PPARγ), which is expressed in a variety of malignancies, governs biological functions through transcriptional programs. Defining the molecular mechanisms governing the selection of canonical versus non-canonical PPARγ binding sequences may provide the opportunity to design regulators with distinct functions and side effects. Acetylation at K268/293 in mouse Pparγ2 participates in the regulation of adipose tissue differentiation, and the conserved lysine residues (K154/155) in mouse Pparγ1 governs lipogenesis in breast cancer cells.

Inhibition of the Caveolin-1 pathway promotes apoptosis and overcomes pan-tyrosine kinase inhibitor resistance in hepatocellular carcinoma.

Resistance to multi-tyrosine kinase inhibitors (TKI) is a major clinical concern in advanced hepatocellular carcinoma (HCC). Herein, we aimed to uncover the mechanisms underlying pan-TKI resistance and to identify potential therapeutic targets. We used multiple TKI-resistant HCC cell lines to identify caveolin-1 (CAV1) as a key driver of therapeutic resistance.

Reaching new heights in neuroimmunology: a proposed model of care for the Murrumbidgee Local Health District.

Background: Access to specialised medical services in regional and remote areas of Australia faces significant challenges, resulting in delays in diagnosis and treatment, and ultimately poorer patient outcomes. This issue is prevalent across medical disciplines. This article focuses on neuroimmunology services in the Murrumbidgee Local Health District of regional New South Wales, and strategies to enhance comprehensive care for patients with these conditions.

IL-2 Complex Therapy Mitigates Humoral Rejection of Fully Mismatched Skin Allografts by Inhibiting IgG Alloantibody Formation.

Antibody-mediated rejection (ABMR) caused by donor-specific Abs (DSAs) is still the leading cause of late graft loss following clinical organ transplantation, and effective strategies to combat ABMR are still elusive. We previously showed that rIL-2 complexed with anti-IL-2 mAb clone JES6-1A12 (IL-2 cplx) leads to the selective expansion of regulatory T cells (Tregs) and the prolonged survival of MHC-mismatched skin allografts. Although the grafts were eventually rejected, mice failed to develop DSAs.

TiME for a change: The tumor microenvironment as the missing piece in cancer therapeutics.

Cancer treatments often fall short of durable cures, yet most therapeutic strategies neglect the tumor stroma. A concerted effort is needed to understand, model, target and reprogram the tumor 'soil', recognizing its profound influence on cancer from tumorigenesis to therapy resistance.

Identification of SEC16B as a novel regulator of glucose homeostasis.

Aims/hypothesis: Glucose homeostasis, essential for metabolic health, requires coordinated insulin and glucagon activity to maintain blood glucose balance. Dysregulation of glucose homeostasis causes hyperglycaemia and glucose intolerance, hallmark features of type 2 diabetes. While SEC16 homologue B (SEC16B), an endoplasmic reticulum export factor, has been linked to obesity, type 2 diabetes and lipid metabolism, its role in glucose regulation remains poorly defined.

Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features.

Objective: We aim to describe and characterize two unrelated Spanish families suffering from an autosomal dominant autophagic vacuolar myopathy caused by repeat expansions in PLIN4.

Methods: We evaluated the clinical phenotype and muscle imaging, and performed a genetic workup that included exome sequencing, muscle RNAseq, and long-read genome sequencing. Muscle pathology was assessed by means of histochemistry, electron microscopy, PLIN4, p62, LC3, and NBR1 immunofluorescence and/or western blotting.

Development of a Minimum Dataset for the Global Monitoring of the Safety and Efficacy of Growth Hormone Replacement in Adults With Growth Hormone Deficiency (AGHD).

Objective: To identify the minimum dataset (MDS) for the monitoring of safety and effectiveness of GH in adults with growth hormone deficiency (AGHD).

Design: Systematic review and expert consensus.

Methods: Outcomes for AGHD were identified through a systematic literature search in PubMed, Science Direct and Cochrane.

Readiness and leadership for the implementation of polygenic risk scores: Genetic healthcare providers' perspectives in the hereditary cancer context.

Genetic healthcare providers and organizations must be made ready for potential future clinical implementation of polygenic risk scores (PRS) for hereditary breast and ovarian (HBOC) cancer risk assessment. Understanding the multi-level factors that contribute to readiness for change will assist leaders with strategic planning and selection of facilitative implementation strategies, ultimately reducing resource wastage and increasing the likelihood of implementation success. Evidence is missing on the current state of readiness in the Australian cancer genomics sector.

Maximising adherent cell production via customisable and dissolvable bio-polymer microcarriers.

Large-scale cellular production systems offer a significant and diverse benefit impacting the therapeutic (stem cell and vaccine production) and cellular agriculture (lab-grown meat) sectors. Producing desired cells at mass can improve production yield whilst reducing the environmental and ethical burden associated with industrialised agriculture and production of therapeutic goods. Many existing large-scale cultivation strategies of adherent cells leverage the use of microcarriers (MCs) within bioreactors.

A dataset of estimated heterozygous individual and carrier couple frequencies for pan-ancestry carrier screening.

The data described in this publication supported the development and evaluation of pan-ancestry reproductive carrier screening panels for autosomal recessive (AR) and X-linked (XL) conditions. Raw data included combined sets of DNA variants in 1,350 AR/XL genes obtained from the ClinVar and gnomAD databases. The dataset enabled calculations of positive yield for individuals and couples across both ancestry-specific and pan-ancestry, optimised "Goldilocks"-ranked gene panels, addressing population-specific variations in the frequencies of heterozygous individuals and carrier couples.

Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat disorders.

Aggregation-prone polyglycine-containing proteins produced from expanded GGC repeats are implicated in an emerging family of neurodegenerative disorders. In this study, we showed that polyglycine itself forms aggregates that incorporate endogenous glycine-rich proteins, including FAM98B, a component of the transfer RNA (tRNA) ligase complex (tRNA-LC) that harbors the most glycine-rich sequence in the human proteome. Through this glycine-rich intrinsically disordered region (IDR), polyglycine sequesters and depletes the tRNA-LC, disrupting tRNA processing.

Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.

encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous missense variants that presented with developmental delay, intellectual disability, and movement disorders. Functional evaluation in revealed that all variants tested were damaging to gene function via a dominant negative genetic mechanism.

The Global Landscape of Genetic Variation in Parkinson's disease: Multi-Ancestry Insights into Established Disease Genes and their Translational Relevance.

Background: The genetic architecture of Parkinson's disease (PD) varies considerably across ancestries, yet most genetic studies have focused on individuals of European descent, limiting our insights into the genetic architecture of PD at a global scale.

Methods: We conducted a large-scale, multi-ancestry investigation of causal and risk variants in PD-related genes. Using genetic datasets from the Global Parkinson's Genetics Program, we analyzed sequencing and genotyping data from 69,881 individuals, including 41,139 affected and 28,742 unaffected, from eleven different ancestries, including ~30% of individuals from non-European ancestries.

CLDN18.2-targeting antibody-drug conjugate IBI343 in advanced gastric or gastroesophageal junction adenocarcinoma: a phase 1 trial.

Aberrant expression of claudin18.2 (CLDN18.2) has frequently been observed in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, making it a promising therapeutic target for this aggressive cancer.

Pathological IgE Production in Inborn Errors of Immunity and Beyond.

In this review, we examine different mechanisms for the generation of pathological IgE through the study of inborn errors of immunity (IEI). In particular, we focus on IEIs that are susceptible to atopic disease, such as severe eczema, eosinophilia, and/or food anaphylaxis; this group of approximately 50 genes has been coined primary atopic disorders (PADs). PADs link specific genes and pathways to atopic disease and the production of IgE and can provide insights into more common allergies experienced by the general population.

Scalable automated reanalysis of genomic data in research and clinical rare disease cohorts.

Reanalysis of genomic data in rare disease is highly effective in increasing diagnostic yields but remains limited by manual approaches. Automation and optimization for high specificity will be necessary to ensure scalability, adoption and sustainability of iterative reanalysis. We developed a publicly available automated tool, Talos, and validated its performance using data from 1,089 individuals with rare genetic disease.

Emerging Insights into Brown Adipose Tissue Crosstalk With Pancreatic β-Cells in Metabolic Regulation.

Brown adipose tissue (BAT), traditionally recognized for its role in thermogenesis, has emerged as an active endocrine organ that coordinates systemic energy expenditure with glucose homeostasis. This review explores the emerging concept of bidirectional crosstalk between BAT and pancreatic β-cells, focusing on potential mechanisms through which BAT may regulate insulin secretion and β-cell survival. In addition to its thermogenic function, BAT serves as a metabolic sink and secretes various hormones (batokines), metabolites, and exosomes that can influence β-cell function directly or indirectly.

Should Genetic Testing be Indicated and Implemented for Chronic Kidney Disease of Unknown Cause?

Advances in genetic testing have attributed many cases of clinically unexplained kidney disease (UKD) to monogenic disorders with such reclarified diagnoses optimizing and individualizing patient care. Patients affected by UKD despite reasonable nephrological workup can benefit from genetic testing because it can reveal etiology, end protracted diagnostic odysseys, inform prognosis, guide management, avoid unnecessary treatments, confer broader implications for family members including transplantation, enable genetic counseling, and guide reproductive care. Recent studies have found diagnostic yield of genetic testing in UKD is between 11% and 32%, even in those without family history of kidney disease, with variants most frequently identified in COL4A3-5.