Publications by Year: 2026

Cancer evolution is a complex and dynamic process, yet most treatment strategies remain static. Infrequent tumor sampling has limited our ability to counteract the transient adaptive states that precede resistance. To address this gap, ARPA-H launched the ADAPT program, an initiative aimed at transforming cancer care by aligning therapies with real-time tumor evolution. Within this framework, the ASCEND-CRC trial aims to uncover early adaptive mechanisms and identify biomarkers to guide therapeutic decision-making in metastatic colorectal cancer (CRC). The study moves beyond single pre-treatment biomarkers by integrating multimodal profiling to longitudinally track tumor evolution and define an actionable set of dynamic biomarkers that inform treatment decisions. Together with other ADAPT initiatives, ASCEND-CRC represents a paradigm shift in precision oncology, establishing a scalable platform to intercept resistance.

ADAPT is a nationwide initiative to transform cancer care by detecting and responding to tumor evolution in real time. Integrating multimodal data, interpretable AI, and an evolutionary clinical trial platform, ADAPT predicts emerging resistance traits and guides treatment adjustments as tumors change. A unified national infrastructure enables continuous learning across patients, linking discovery directly to care. By making therapy responsive to tumor changes, ADAPT delivers a scalable model designed to improve outcomes in precision oncology.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert cardiometabolic benefits beyond weight loss, yet their systemic proteomic mechanisms remain incompletely defined. We profiled short-term liraglutide-induced protein changes and compared them with published semaglutide signatures.

METHODS: In a randomized, double-blind, placebo-controlled, crossover trial (NCT02944500), 20 adults with obesity received liraglutide 3 mg daily or placebo for 5 weeks, separated by a 3-week washout. Plasma and serum samples underwent SomaScan v4.1 profiling of 6249 proteins. Mixed-effects models tested Time×Treatment interactions with and without weight adjustment. Results were benchmarked against the 30-protein semaglutide STEP 1/2 signature.

RESULTS: Liraglutide significantly modulated 124 proteins (57 FDR < 0.05); 85 % of effects persisted after weight adjustment, indicating largely weight-independent actions. Upregulated proteins included pancreatic enzymes (PNLIP, CTRB1/2, PRSS2), while endothelial and fibrotic markers (ACE, NOS3, FAP) were downregulated. Myostatin (MSTN) was strongly suppressed (log₂ fold change -0.41; p = 1.7 × 10-6), with concurrent rises in its inhibitors WFIKKN2 and BMPR1A. Liraglutide shared 70-75 % directional overlap with semaglutide, with 25-30 % unique effects enriched in vascular, neurodevelopmental, and musculoskeletal pathways. A semaglutide-based classifier distinguished liraglutide from placebo (AUC = 0.82; sensitivity 0.89; specificity 0.60). Downregulated proteins were genetically linked to coronary artery disease and type 2 diabetes (FDR < 0.05).

CONCLUSIONS/INTERPRETATION: Short-term liraglutide reproduces the core GLP-1RA proteomic fingerprint while uniquely suppressing myostatin and vascular remodeling pathways. These rapid, largely weight-independent molecular responses indicate early cardioprotective and myostatin-inhibitor signaling changes that could be relevant for future muscle-preserving strategies, supporting individualized GLP-1RA use beyond weight loss alone.

PURPOSE: This study examined the relationship between executive functioning (EF) and core features associated with autism in children aged 2 and 4 years. EF encompasses a set of goal-directed skills that enable organized thoughts and behavior which develop rapidly during the preschool period. To examine concurrent associations between EF and early autism expression, we analyzed whether EF performance relates to observed social communication and repetitive behaviors during parent-child interactions.

METHODS: Participants included 110 autistic children aged 24 to 60 months diagnosed with autism. Developmental and cognitive abilities were assessed using the Mullen Scales of Early Learning. Social communication and repetitive behaviors associated with autism were coded from 10-minute free play parent-child videos using the Brief Observation of Social Communication Change (BOSCC), yielding total social communication, restricted/repetitive behaviors scores, and overall total scores. An EF score was derived from a test battery that included measurements of set-shifting, working memory, inhibition, and delay. Regression analyses were conducted to assess EF's contribution to autism expression, controlling for cognitive ability.

RESULTS: For 2-year-olds, EF was not related to observed autism behaviors after controlling for cognition. Conversely, for 4-year-olds, EF related to overall behaviors associated with autism observed during parent-child interactions.

CONCLUSION: Findings of an association between EF and autism-related behaviors observed in parent-child interactions by preschool at age 4 but not in toddlerhood at age 2 highlight potential developmental differences in the relation between EF and autism-related behaviors. Longitudinal and experimental research is needed to establish directionality and malleability of EF and autism-related behaviors.

Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to  1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.

PURPOSE: To map advanced and metastatic cancer survivorship research in Australia and characterize studies according to the priority research themes outlined by the US National Cancer Institute (NCI).

METHODS: Systematic scoping review. MEDLINE, PsycINFO, Embase and CINAHL were searched from inception to December 2024 for cancer survivorship studies conducted in Australia, with studies reporting data for people with advanced or metastatic cancer classified using NCI's priority research themes.

RESULTS: We identified 483 studies, of which 72 (14.9%) recruited and reported data for participants with advanced or metastatic cancer, focusing on: psychosocial research (51.4%); healthcare delivery (16.7%); health behaviors (12.5%); symptom management (11.1%); and epidemiology and surveillance (8.3%). Most were conducted within individual Australian states (72.2%) and involved multiple cancer types (41.7%). Study designs included qualitative (44.4%), cross-sectional (34.7%), cohort (16.7%), case-control (1.4%), case report (1.4%) and mixed methods (1.4%). Forty-two tumor-specific studies were identified including breast (33.3%), hematological (21.4%); prostate (11.9%); bowel/colorectal (11.9%), gynecological (9.5%), melanoma (7.1%), head and neck (2.4%), and lung (2.4%) cancers. Nearly a quarter of studies recruited participants via cancer registries (22.2%).

CONCLUSIONS: Few cancer survivorship studies included people with advanced or metastatic cancer in Australia. We offer six recommendations to support funders, clinicians, policymakers, and researchers to improve representation of advanced or metastatic cancer survivors in survivorship research programs. Similar efforts in other countries are needed.

IMPLICATIONS FOR CANCER SURVIVORS: Increasing numbers of people are living long-term with advanced or metastatic cancer. The purposeful inclusion of these people in cancer survivorship research and care programs will improve health outcomes.

BACKGROUND: We know relatively little about how mental health varies across countries around the world or among demographic groups in diverse nations and cultures.

METHODS: The current study addresses these issues by analyzing symptoms of depression and anxiety using data from the Global Flourishing Study (GFS), an international, nationally-representative survey of 202,898 individuals from 22 geographically, economically, and culturally diverse countries collected in 2022-2023.

RESULTS: Here we show that proportions of individuals with substantial symptoms of depression range from 0.14 in Poland to 0.50 in the Philippines. These two countries report the lowest and highest substantial symptoms of anxiety as well (0.13 and 0.48, respectively). Lower-income, non-Western countries tend to have higher proportions of both outcomes compared with higher-income, predominantly Western nations. Symptoms of depression and anxiety also vary across age, gender, marital status, education, employment status, religious service attendance, and immigration status in one or more countries. The results of random effects meta-analyses show that several demographic factors are significant predictors of both outcome variables when the results for all 22 countries are pooled.

CONCLUSIONS: While being mindful of varying cultural contexts and possible translation and interpretive issues with the survey questions, the results suggest substantial variations in symptoms of both depression and anxiety across nations and key demographic groups. This work lays the foundation for future longitudinal GFS studies of mental health from a cross-national and global perspective.

Dominant negative pathogenic variants in KIF1A result in an allelically heterogeneous neurodegenerative condition that manifests as a variable clinical phenotype including seizures, cognitive deficits, optic nerve atrophy, spasticity, and peripheral neuropathy. One potential therapeutic strategy is allele-specific knockdown of pathogenic transcripts. However, targeting the over 100 known unique pathogenic variants is challenging. Alternatively, different pathogenic KIF1A variants in multiple patients can be knocked down by targeting shared common polymorphisms with antisense oligonucleotides, provided that the pathogenic variants are in cis with the targeted polymorphisms. Here, we use long-read sequencing data from fifty-six individuals to phase for polymorphisms. We identify four common polymorphisms that, if targetable, would make it possible for 54 of these individuals to receive antisense oligonucleotide therapy. Using patient-derived glutamatergic neurons, we characterize and quantify a cell-autonomous phenotype, dendrite neurite outgrowth length. In vitro we further demonstrate that antisense oligonucleotide-mediated knockdown of the pathogenic transcript rescues the dendrite neurite outgrowth phenotype in neurons from a patient with the P305L variant.

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke, with a 5-year mortality of up to 70 %. Disease-modifying treatments to improve neurological outcomes in ICH survivors represent a critical unmet need. Neuroinflammation contributes significantly to ongoing secondary brain injury and long-term morbidity in ICH. We and others have shown that B cells are potent modulators of the inflammatory response, capable of acquiring a regulatory phenotype within injured microenvironments. Here, we investigated the effects of a single intraparenchymal application of mature naïve splenic B lymphocytes in a murine model of collagenase-induced ICH. In vivo tracking of luciferase-expressing B cells showed that the exogenous cells remained localized at the delivery site for up to 2 weeks. Delayed intraparenchymal B cell application at 24 h post-ICH was associated with acute neuroprotection of motor function in wire grip and rotarod assays and significant cognitive neuroprotection at 30 days post-injury in a Y maze paradigm. B cell administration was associated with reduced inflammasome activation at the injury site, diminished infiltration of CD8+ cytotoxic T cells in the injured hemisphere, and a regulatory shift in cytokine production in infiltrating monocytes/macrophages and natural killer cells. Systemically, modest increases in inflammatory cytokines and in regulatory markers were observed in myeloid cells in the spleen of animals treated with B cells intraparenchymally. These findings support intraparenchymal delivery of naïve B lymphocytes as a promising cell-based therapy for ICH, capable of facilitating functional neuroprotection via dynamic immunomodulation of adjacent immune populations.

Costimulatory blockade has emerged as a promising alternative to conventional immunosuppression with the potential to reduce chronic allograft injury and minimize drug-related toxicities, including nephrotoxicity, cardiometabolic complications, and malignancies. Belatacept, the most extensively studied agent, has been associated with improved allograft function and reduced donor-specific antibody formation, although it is also associated with increased risk of acute, early graft rejection and increased risk for infections due to cytomegalovirus, Epstein-Barr virus, and Pneumocystis jirovecii. These effects may reflect the impact of costimulatory blockade on naïve T cell activation, although relatively sparing memory responses. Susceptibility to infections is, therefore, influenced by prior infectious exposures and the maintenance of immune memory in the face of diverse adjunctive immunosuppressive programs. Next-generation approaches, including Fc-silent anti-CD154 antibodies and CD28-directed therapies, are in early clinical trials with infectious complications incompletely defined. Recently, immunosuppression for clinical xenotransplantation has included costimulatory blockade as a component of generally complex immunosuppressive regimens; intensive microbiological surveillance will provide insights into any associated xenozoonotic infections. Successful integration of costimulatory blockade in allotransplantation and clinical xenotransplantation requires further prospective trials coupled with robust microbiological surveillance.