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INTRODUCTIONPolygenic risk score (PRS) identifies individuals at high genetic risk for Alzheimer's disease (AD),but its utility in predicting cognitive trajectories and AD pathologies remains unclear. We optimized PRS (optPRS) for AD,investigated its association with cognitive trajectories and AD phenotypes of cerebral organoids.METHODSUsing genome‐wide association study (GWAS) summary statistics from a European population,we developed optPRS to predict AD in Korean individuals (n = 1634). We analyzed the association between optPRS and cognitive trajectories (n = 771). We generated induced pluripotent stem cell–derived cerebral organoids from patients with high (n = 3) and low (n = 4) optPRS to evaluate amyloid beta (Aβ) and phosphorylated tau (p‐tau) levels.RESULTSOptPRS predicted AD dementia and Aβ positivity,independent of apolipoprotein E (APOE). Higher optPRSs correlated with rapid cognitive decline. Cerebral organoids from the high optPRS group exhibited increased Aβ insolubility and p‐tau levels.CONCLUSIONOptPRS predicted cognitive decline and AD phenotypes of cerebral organoids,supporting its use in risk assessments and drug‐screening platform. View Publication

MYCN amplification without concurrent RB1 mutations characterizes a rare yet highly aggressive subtype of retinoblastoma; however,its precise developmental origins and therapeutic vulnerabilities remain incompletely understood. Here,we modeled this subtype by lentiviral-mediated MYCN overexpression in human pluripotent stem cell-derived retinal organoids,revealing a discrete developmental window (days 70–120) during which retinal progenitors showed heightened susceptibility to transformation. Tumors arising in this period exhibited robust proliferation,expressed SOX2,and lacked CRX,consistent with origin from primitive retinal progenitors. MYCN-overexpressing organoids generated stable cell lines that reproducibly gave rise to MYCN-driven tumors when xenografted into immunodeficient mice. Transcriptomic profiling demonstrated that MYCN-overexpressing organoids closely recapitulated molecular features of patient-derived MYCN-amplified retinoblastomas,particularly through activation of MYC/E2F and mTORC1 signaling pathways. Pharmacological screening further identified distinct therapeutic vulnerabilities,demonstrating distinct subtype-specific sensitivity of MYCN-driven cells to transcriptional inhibitors (THZ1,Flavopiridol) and the cell-cycle inhibitor Volasertib,indicative of a unique oncogene-addicted state compared to RB1-deficient retinoblastoma cells. Collectively,our study elucidates the developmental and molecular mechanisms underpinning MYCN-driven retinoblastoma,establishes a robust and clinically relevant human retinal organoid platform,and highlights targeted transcriptional inhibition as a promising therapeutic approach for this aggressive pediatric cancer subtype. View Publication

Embryonic stem cells (ESC) are pluripotent,with the potential to differentiate into multiple cell types,making them a valuable tool for regenerative medicine and disease therapy. However,common culture methods face challenges,including strict operating procedures and high costs. Currently,Leukemia inhibitory factor (LIF),an indispensable bioactive protein for ESC culture,is typically applied to maintain self-renewal and pluripotency,but its instability and high cost limit its effectiveness in stable culture conditions. Hence,we have developed an innovative strategy using a soluble nanomaterial,metal-organic polyhedra (MOPs),to effectively maintain the self-renewal and pluripotency of ESC. The selected amino-modified vanadium-based MOP not only exhibits excellent biocompatibility and high stability but also possesses similar or even superior biological functions compared to commercial LIF. Due to the precise structure of MOPs,the active site responsible for maintaining ESC pluripotency has been identified and regulated at the molecular level. The new ESC culture method significantly reduces costs,simplifies preparation,and enhances the practicality of biopharmaceutical preparation and storage. This represents the first case of using MOPs to maintain self-renewal of ECS,opening an avenue for introducing advanced materials into the development of innovative ESC culture methods. Subject terms: Biomaterials - cells,Chemical biology View Publication