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Transduction Efficiency in Clinical CAR T-Cell Products: A Retrospective Study at a Single Center

Transduction efficiency is a critical determinant of CAR T-cell manufacturing quality. Analysis of 204 clinical CAR T-cell products revealed that transduction efficiency is shaped primarily by manufacturing workflows and protocol-dependent starting material composition. Higher transduction efficiency was associated with early memory-like cellular states, providing insights into optimizing CAR T-cell.

Advanced iPSC-based modelling of LMNA-related congenital muscular dystrophy enables development of genetic therapies for muscle laminopathies

LMNA-related congenital muscular dystrophy (L-CMD) is a devastating early-onset muscle disease caused by dysfunctional nuclear lamina. Current models fail to capture the complexity of human muscle pathology, limiting translational progress. This study overcomes this limitation by establishing a robust, human iPSC-based platform for modelling L-CMD and testing gene editing strategies.

Leveraging host-cell modulators of adeno-associated vector transduction to tailor viral biodistribution

AAV gene therapies are powerful but often limited by inefficient or unwanted tissue delivery. This study maps host genes that help or hinder AAV transduction, revealing that transiently tuning these factors can reshape vector biodistribution, offering a new strategy to improve gene therapy precision.

In vivo engineering of T cells with a synthetic cytokine receptor enables selective enrichment and expansion of anti-CD22 CAR T cells

In preclinical studies, UB-VV400, an off-the-shelf, investigational lentiviral drug product, generates fully human anti-CD22 CAR T cells in vivo without the need for lymphodepletion. Activation of the synthetic rapamycin-activated cytokine receptor drives selective CAR T cell expansion and enrichment, resulting in complete tumor clearance and B cell depletion.

A combinatorial EV-miRNA signature mediates the anti-tumoral activity of NFAT3-regulated extracellular vesicles in aggressive cancers

NFAT3-regulated extracellular vesicles deliver a combinatorial miRNA signature that suppresses proliferation and invasion in aggressive breast and pancreatic cancer models. This study identifies the underlying molecular programs targeted by the miRNA combination and supports extracellular vesicles as a promising platform for multi-target RNA-based cancer therapy.

Tissue-specific silencing of synthetic mRNAs by de-targeting elements maps vaccination-competent tissues and allows Cas9 de-immunization

Sasso and colleagues leveraged organ-specific miRNAs by engineering synthetic mRNA vaccines containing miR target sites to generate a functional map of immunologically competent organs. This work lays the foundation for novel vaccines designed to target the most immunologically proficient organs. They subsequently applied this approach to de-immunize Cas9, rendering it immunologically masked.

Triple-AAV intein-mediated gene therapy ameliorates dystrophic phenotype in MDC1A mice

To overcome the strict packaging limits of AAV vectors, this study utilizes a triple-AAV system paired with orthogonal split inteins to reconstitute the exceptionally large LAMA2 protein. This scarless, multi-vector approach successfully rescues the dystrophic phenotype in vivo, offering a scalable platform for large-gene therapies.

Repurposing base editors for targeted knockin and simultaneous multiplex knockouts to generate allo-CAR T cells with minimal translocations

Wagner and colleagues develop BEKI (Base Editor-mediated Knock-In), a non-viral platform that combines targeted transgene insertion with simultaneous gene knockouts in a single step. BEKI-engineered CAR T cells show markedly reduced chromosomal rearrangements compared with conventional nuclease-based approaches, advancing safer manufacturing of multiplex-edited cell therapies for cancer and autoimmune diseases.

Repurposing triamterene as chloride intracellular channel 1 inhibitor via ligand-based approach for glioblastoma

Currently no effective therapies are available for glioblastoma. Florio and colleagues identified, via computational screening, triamterene as a CLIC1 blocker that suppresses human glioblastoma stem cell proliferation, invasiveness, and tumor growth. Triamterene also enhances temozolomide and radio-chemotherapy efficacy, making it a repurposed therapeutic candidate for glioblastoma treatment in future clinical applications.

Teacher Geometry Shapes Learnability in Teacher-Student Networks

arXiv:2609.09595v1 Announce Type: cross Abstract: Teacher-student systems, in which a teacher neural network generates training labels so that a student neural network can learn to implement the same function, are widely used as an abstract setting to study learning. However, the structure of the teachers is often overlooked by assuming randomly-generated, normally-distributed parameters. This hides substantial variation in how learnable different teachers are. We formalize learnability as the success rate of converging to the global minimum, as a function of overparameterization, learning algorithm, student initialization distribution, and teacher geometry. We both identify an easy distribution that maximizes node dissimilarity and a hard distribution that minimizes it, and show that these two distributions induce markedly different success rates across a large range of settings and for different activation functions. To explain the gap, we study the loss landscape of small neural networks that contain two distinct kinds of suboptimal local minima, out-of-bounds (OOB) minima at the edge of the data distribution and interior minima within. Assuming infinite data and a fast readout layer, we analytically reduce the loss landscape of small networks to two dimensions, showing that the region of attraction of interior minima changes as a function of teacher structure. In larger networks, maximally dissimilar teachers induce more interior minima, while minimally dissimilar teachers induce more OOB minima. Motivated by these analyses, we show that differentially increasing the learning rate of the readout layer and decreasing the learning rate of the inner biases increases success rates. These findings provide an important step in narrowing the gap between the study of teacher-student networks and more structured functions that arise in practice.

HiRAD: A Flexible Large-Scale AGV Routing System

arXiv:2609.09752v1 Announce Type: cross Abstract: Automatic Guided Vehicles (AGVs) substantially boost warehouse throughput, but routing large-scale AGV fleets remains challenging. Classical Multi-Agent Pathfinding solvers suffer from exploding combinatorial complexity and super-quadratic runtime, while relying on idealized grid or piecewise-linear motion models that mismatch real-world kinematics. Recent Reinforcement Learning (RL) solutions improve flexibility via decentralized agent policies but depend on discretized spatiotemporal representations, require millions of episodes to converge, and incur full-map observation at every step, which leads to large models, slow convergence, and high inference latency that violates real-time industrial control constraints. To address these bottlenecks, we propose HiRAD, a hierarchical RL framework for continuous-space AGV routing with real-time guarantees: (1) a step-level spatiotemporal representation that translates continuous motion into a differentiable RL problem, (2) a hierarchical strategy that splits heading choice from velocity control to reduce the action space, and (3) an asynchronous event-driven decision pipeline that lowers inference complexity from O(n^2) to O(n) and cuts per-step latency by as much as 71 percent. Across random graphs and two warehouse maps, HiRAD reduces makespan by 45 percent to 63 percent and shortens end-to-end runtime.

Zero-shot World Models Are Developmentally Efficient Learners

arXiv:2604.10333v2 Announce Type: replace Abstract: Young children demonstrate early abilities to understand their physical world, estimating depth, motion, object coherence, interactions, and many other aspects of physical scene understanding. Children are both data-efficient and flexible cognitive systems, creating competence despite extremely limited training data, while generalizing to myriad untrained tasks -- a major challenge even for today's best AI systems. Here we introduce a novel computational hypothesis for these abilities, the Zero-shot World Model (ZWM). ZWM is based on three principles: a sparse temporally-factored predictor that decouples appearance from dynamics; zero-shot estimation through approximate causal inference; and composition of inferences to build more complex abilities. We show that ZWM can be learned from the first-person experience of a single child, rapidly generating competence across multiple physical understanding benchmarks. It also shows progressive, staged emergence of capacities during learning and builds brain-like internal representations. Our work presents a blueprint for efficient and flexible learning from human-scale data, advancing both a computational account of children's early physical understanding and a path toward data-efficient AI systems.

PRIME-SVR: Physics-infoRmed Implicit Multi-Echo Slice-to-Volume Reconstruction for Fetal T2 mapping

arXiv:2607.20136v2 Announce Type: replace-cross Abstract: Slice-to-volume reconstruction (SVR) is the standard method for obtaining high-resolution (HR) 3D fetal brain volumes from motion-corrupted 2D MRI slice stacks acquired in multiple orientations. Existing SVR methods are optimized and validated only for clinical-range echo times (TEs), limiting their use at non-clinical TEs and making them incompatible with quantitative T2 mapping, a protocol- and center-independent biomarker of fetal brain maturation requiring HR reconstructions across multiple TEs. We present PRIME-SVR, the first implicit neural representation (INR) framework for joint HR reconstruction from multi-echo MRI. A single fully connected network models a continuous function from spatial coordinates to signal intensities across TEs, while a second network estimates slice-specific acquisition degradations. Cross-TE coherence is enforced via a Bloch equation-derived regularization penalizing deviations from expected T2 decay, with adaptive weighting that strengthens coupling for degraded stacks. The method is fully self-supervised. We validate PRIME-SVR on 39 in vivo fetal acquisitions (13 subjects x 3 TEs) from two centers, two vendors, and two field strengths (1.5 T and 0.55 T). Compared to state-of-the-art SVR, PRIME-SVR improves reconstruction sharpness by 47%, anatomical accuracy by 30%, and cross-TE structural consistency by 14%. It enables reconstruction at late TEs previously inaccessible to SVR, yielding the first 0.8 mm isotropic T2 maps at 0.55 T and the first T2 maps derived from INR-based SVR. PRIME-SVR also accelerates quantitative imaging by reducing the data needed for multi-TE reconstruction, cutting acquisition from 15 to 10 minutes while keeping T2 accuracy within 1.7% in white and deep gray matter, or to 5 minutes with a mean T2 error of 2.3% for high-quality acquisitions.

Investigating Hyperparameter Optimization and Transferability for ES-HyperNEAT: A TPE Approach

arXiv:2609.00449v2 Announce Type: replace-cross Abstract: Neuroevolution of Augmenting Topologies (NEAT) and its advanced version, Evolvable-Substrate HyperNEAT (ES-HyperNEAT), have shown great potential in developing neural networks. However, their effectiveness heavily depends on the selection of hyperparameters. This study investigates the optimization of ES-HyperNEAT hyperparameters using the Tree-structured Parzen Estimator (TPE) on the MNIST classification task, exploring a search space of over 3 billion potential combinations. TPE effectively navigates this vast space, significantly outperforming random search in terms of mean, median, and best accuracy. During the validation process, the best hyperparameter configuration found by TPE achieves an accuracy of 29.00% on MNIST, surpassing previous studies while using a smaller population size and fewer generations. The transferability of the optimized hyperparameters is explored in logic operations and Fashion-MNIST tasks, revealing successful transfer to the more complex Fashion-MNIST problem but limited to simpler logic operations. This study emphasizes a method to unlock the full potential of neuroevolutionary algorithms and provides insights into the hyperparameters' transferability across tasks of varying complexity.

When Does a Laugh Begin? Structured Annotator Disagreement in Temporal Laughter Localization

arXiv:2609.06646v2 Announce Type: replace-cross Abstract: Annotators routinely disagree on laughter boundaries and subtle chuckles, yet temporal laughter localization typically evaluates against a single reference annotation. We show that this disagreement is structured rather than random noise. Re-annotating the SMILE-Temporal benchmark (672 videos, 1,683 events) with 3-5 annotators per video (alpha = 0.757), we find systematic patterns: disagreement is 1.73 times larger at offsets than onsets, far more common for chuckles than full laughs (77% vs. 20%), and predictable from event attributes (AUC = 0.831). Evaluating against a single annotator breaks down under this structure: system scores shift by 0.246 F1 depending on the chosen ground truth, correctly ranking systems only 69.7% of the time (vs. 80% against all annotators). We propose a disagreement-calibrated evaluation that scores predictions against the full annotator distribution using conformally calibrated tolerance bands (wider at offsets, 0.727s, than onsets, 0.5s). The per-annotator annotations and analysis code are available at https://github.com/WSCSports/MTLLFM-temporal-laughter-localization.

Omni Interaction Agent Technical Report

arXiv:2609.08977v2 Announce Type: replace-cross Abstract: In this work, we present Gander, an end-to-end model that unifies omni perception, realtime interaction, and agentic capabilities within a single framework. In contrast to turn-based conventional paradigms, Gander continuously receives streaming inputs across multiple modalities, including video, speech, and text, enabling natural full-duplex interaction in both everyday conversations and complex workflow-oriented agent scenarios. Users can interrupt the model at any time, while the model can also proactively provide intermediate feedback or ask follow up questions. To natively support these capabilities, Gander adopts two key architectural designs: 1) It employs a Cerebellum-Brain collaborative framework, in which the Cerebellum is responsible for realtime interaction and omni conversational capabilities, while the Brain handles complex reasoning and higher-level agentic tasks. The two components interact continuously through tool calling and the agent orchestration runtime. 2) The Cerebellum is built upon a streaming Thinker-Talker architecture, user inputs and model outputs are further flattened into an ordered token stream at the chunk level, providing a unified representation for low latency, continuous interaction. We conduct comprehensive evaluations of Gander across four dimensions: conversational ability, omni understanding, interactive capability, and agentic intelligence. Internal human evaluations demonstrate that Gander maintains the natural and expressive spoken dialogue capabilities of SOTA open source models while achieving competitive performance in omni interaction. Gander also demonstrates robustness in challenging real-world scenarios, including background noise interference, multi-party interactions, and backchannel communication. We release Gander together with its models, code, and data to facilitate further research and development in the community.

“Small” Large Language Models in the Hospital: Evaluation Study on Real-World Data in a Resource-Constrained Setting

Background: Large language models (LLMs) are increasingly being deployed in health care, but their use and deployment in many real-world hospital environments pose significant challenges and concerns. In particular, state-of-the-art commercial models store or process data externally, which is often in conflict with ensuring patient data protection. At the same time, using LLMs locally is limited by the lack of available computing infrastructure. Small open-source LLMs that do not require substantial computing resources could offer a practical way to resolve these tensions, but their medical utility in real-world local contexts, especially in non-English languages, has not been sufficiently evaluated. Objective: This study aimed to evaluate the feasibility of small, locally deployable open-source LLMs for clinically relevant tasks in a resource-constrained hospital setting and to propose a reproducible framework for institution-specific evaluation before deployment. Methods: We evaluated 6 open-source LLMs ranging from 8B to 24B parameters (from the Mistral, Phi4, Falcon3, Llama3.1, and Meditron3 families) in a zero-shot setting across 7 tasks covering 4 clinical use cases: information extraction, medical text translation, text generation, and clinical decision support. We used deidentified French clinical data from a Swiss tertiary hospital, including discharge letters, clinical notes, and structured electronic health records. Performance was assessed using task-specific metrics, such as precision, recall, F1-score, embedding-based semantic similarity, recall-oriented understudy for gisting evaluation (ROUGE) score, readability indices, and human review by clinicians. Results: Model performance varied substantially between tasks. In the simplest retrieval task (needle-in-the-haystack), several models performed strongly, with Llama3.1 achieving an F1-score of 99.81% and Mistral-small achieving 99.71%. In contrast, performance was poor in more complex tasks. For detecting protected health information, the best-performing LLMs achieved only modest overall macro–F1-scores (0.33-0.34), substantially below a fine-tuned Robustly Optimized BERT Pretraining Approach (RoBERTa) baseline (0.94). In the task of extracting immune-related adverse events from discharge notes, the highest overall macro–F1-score was 0.35 with Phi4. For medical text translation, Phi4 ranked highest in embedding-based evaluation, whereas Meditron3-Phi4 performed the worst, with clinician reviews identifying hallucinations in 55% of its outputs. In the task of summarizing discharge letters, quality was low across all models, with the best penalized ROUGE score reaching only 0.169 with Llama3.1. In the tasks of generating patient-friendly discharge note summaries and clinical decision support, clinician ratings generally ranged from dissatisfied to neutral, and no model achieved consistently satisfactory performance. Conclusions: Small open-source LLMs appear feasible for simple retrieval-oriented tasks in local hospital deployments but are currently inadequate for more complex applications, such as clinical decision support, deidentification, extraction of adverse events, and medical summarization. These findings highlight the importance of locally grounded evaluation tailored to specific use cases and the need for robust institutional evaluation frameworks to ensure safe and reliable deployment. Trial Registration:

Innovative pathological and therapeutic approaches for poorly cohesive gastric cancer

Front Oncol. 2026 Aug 25;16:1842715. doi: 10.3389/fonc.2026.1842715. eCollection 2026.

ABSTRACT

Poorly cohesive gastric cancer (PCGC) represents a biologically distinct subtype of gastric cancer, characterized by diffuse growth, marked intratumoral heterogeneity, and a consistently worse prognosis compared with other histological subtypes. Despite advances in pathological classification and molecular profiling, treatment strategies remain largely independent of histological subtype, and no specific therapeutic approaches have been established for PCGC. In this review, we summarize current evidence on the biological features, diagnostic challenges, and emerging therapeutic strategies, with a focus on novel targeted agents and innovative treatment platforms. Recent years have witnessed the development of therapies directed against specific molecular targets, including HER2, PD-L1, CLDN18.2, FGFR2b, and TROP2, as well as the introduction of antibody-drug conjugates and bispecific antibodies, progressively expanding the therapeutic landscape of gastric cancer. However, their clinical impact in poorly cohesive tumors remains to be fully defined. In parallel, advances in digital pathology, artificial intelligence, and multi-omics approaches are providing new opportunities to improve diagnostic reproducibility, refine prognostic stratification, and support personalized treatment strategies by integrating histomorphological and molecular tumor features. Overall, the convergence of novel therapeutic strategies and advanced diagnostic technologies may pave the way toward a more precise and biologically informed management of PCGC, although further validation and integration into clinical practice are required.

PMID:42713041 | PMC:PMC13550965 | DOI:10.3389/fonc.2026.1842715

Innovative pathological and therapeutic approaches for poorly cohesive gastric cancer

Front Oncol. 2026 Aug 25;16:1842715. doi: 10.3389/fonc.2026.1842715. eCollection 2026.

ABSTRACT

Poorly cohesive gastric cancer (PCGC) represents a biologically distinct subtype of gastric cancer, characterized by diffuse growth, marked intratumoral heterogeneity, and a consistently worse prognosis compared with other histological subtypes. Despite advances in pathological classification and molecular profiling, treatment strategies remain largely independent of histological subtype, and no specific therapeutic approaches have been established for PCGC. In this review, we summarize current evidence on the biological features, diagnostic challenges, and emerging therapeutic strategies, with a focus on novel targeted agents and innovative treatment platforms. Recent years have witnessed the development of therapies directed against specific molecular targets, including HER2, PD-L1, CLDN18.2, FGFR2b, and TROP2, as well as the introduction of antibody-drug conjugates and bispecific antibodies, progressively expanding the therapeutic landscape of gastric cancer. However, their clinical impact in poorly cohesive tumors remains to be fully defined. In parallel, advances in digital pathology, artificial intelligence, and multi-omics approaches are providing new opportunities to improve diagnostic reproducibility, refine prognostic stratification, and support personalized treatment strategies by integrating histomorphological and molecular tumor features. Overall, the convergence of novel therapeutic strategies and advanced diagnostic technologies may pave the way toward a more precise and biologically informed management of PCGC, although further validation and integration into clinical practice are required.

PMID:42713041 | PMC:PMC13550965 | DOI:10.3389/fonc.2026.1842715

Breaking timescales with generative sampling of conformational transitions

Nature, Published online: 09 September 2026; doi:10.1038/s41586-026-11025-1

A generative committor-guided path-sampling framework reconstructs rare biomolecular transition pathways and reveals the underlying thermodynamics and kinetics without using predefined collective variables or brute-force sampling, at an acceptable computational cost.
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