Citations

AbstractBackgroundOvarian juvenile granulosa cell tumors (juvGCT) are rare sex cord‐stromal tumors that occur primarily in children and adolescents. This study summarizes the clinical presentation and outcomes of patients with juvGCT.MethodsPatients were enrolled in the International Ovarian and Testicular Stromal Tumor and/or International Pleuropulmonary Blastoma/DICER1 Registries. Available medical records were abstracted, and pathology was centrally reviewed. Surgical staging was classified using the 2014 International Federation of Gynecology and Obstetrics (FIGO) criteria.ResultsIn total, 70 patients with juvGCT enrolled and were diagnosed between 2001 and 2024; most patients (81%, 57 of 70) presented with FIGO stage I disease. Adjuvant chemotherapy was given in 30% (21 of 70); all regimens were platinum‐based. Three‐year event‐free survival among patients with stage IA tumors was 80.2% (95% confidence interval [CI], 62.4%–100.0%), IC1 was 87.4 (95% CI, 72.4%–100.0%), IC2‐IC3 was 63.6% (95% CI, 40.7%–99.5%), and II‐IV was 48% (95% CI, 24.6%–93.8%). Of the patients with recurrent juvGCT with known mitotic index (MI), all had MI greater than 19 mitoses per 10 high power fields (HPF) at diagnosis.ConclusionOutcomes were worse for patients with FIGO stage ≥IC2 disease and for tumors with >19 mitoses per 10 HPF. Given the prognostic significance of MI, the authors strongly recommend the assessment of MI for all juvGCTs. More information about tumor biology is critical to identify which patients may benefit from adjuvant chemotherapy and to facilitate the development of novel therapies.

Abstract Cancer can recur when a subset of tumor cells, denoted here as persister cells, are able to survive therapy and re-enter the cell cycle. The precise mechanisms that confer the persister state and whether it is characteristic of a subgroup of cells or arises from multiple cellular lineages remain poorly understood. We hypothesize that an epigenetic signature underlies the drug-tolerant persister state, characterized by transcriptional and chromatin accessibility changes that promote survival of residual cancer following chemotherapy. To identify clinically relevant features of persister cells in untreated tumors and residual disease, we performed single-cell multiomic profiling (snRNA+snATAC) on a cohort of non-malignant fallopian tube, treatment-naïve, and neoadjuvant chemotherapy (NACT)-treated high-grade serous ovarian cancer (HGSOC) samples. We identified differences in gene expression and open chromatin between naïve and residual patient tumors following chemotherapy. Although only a small proportion of the differentially expressed genes enriched in residual HGSOC overlapped with established gene sets for chemo-response and patient prognosis, the epigenomic analysis revealed activity of several DNA-binding factors that are both enriched upon chemotherapy and also high in resistant tumors prior to treatment. From this analysis, we identified an epigenetic signature that precedes expression and defines the persister state. This epigenetic signature also correlated with chemotherapy sensitivity and resistance using patient-derived xenograft models of HGSOC. Gene regulatory networks driven by the persister signature are involved in the activation of oncogenic pathways, including changes to the cell cycle promoting quiescence and stress response. Further study of the persister cells identified by this epigenetic signature may increase understanding of the mechanisms underlying persister cell survival and reveal new vulnerabilities that could be exploited to delay or prevent cancer recurrence.

Mitochondria show context-specific heterogeneity in their morphometry. Previously, we reported that acute TNFα exposure increased O 2 consumption rate (OCR) and mitochondrial volume density, but decreased OCR per mitochondrion. TNFα also altered mitochondrial distribution and motility. To assess TNFα-mediated subcellular mitochondrial structural and functional heterogeneity, we used a confocal-based quantitative histochemical technique to determine the maximum velocity of succinate dehydrogenase reaction. Our findings highlight that mitochondria within cells exhibit functional heterogeneity, which is disrupted during inflammation.

Abstract Age-related cognitive decline results from complex interactions between neuroendocrine and neurometabolic processes that undergo lifelong degredation, yet the mechanisms underlying these interactions remain poorly understood. This study examined the effects of diabetes and sex on functional brain networks across aging through analysis of two large cohorts (N=1,621 total) using both 3T and 7T functional MRI, complemented by spatial transcriptomic data from over 14,000 genes from six post-mortem brains. Four networks— cingulo-opercular, default mode, salience, and lateral somatomotor—exhibited significant functional decline in both individuals with diabetes and independently in males. Gene expression analysis of vulnerable networks revealed significant overexpression of insulin-dependent glucose transporters, dopaminergic and GABAergic synaptic genes, and VEGFA-VEGFR2 pathway components. These findings suggest functionally-specific circuit vulnerability to metabolic and hormonal dysregulation, potentially offering targets for early intervention before irreversible neurodegeneration occurs.

Abstract Different large language models (LLMs) have the potential to complement one another. We introduce an iterative multi-LLM consensus framework for annotating single-cell RNA sequencing data. This framework outperforms the best state-of-the-art method by nearly 15% in mean accuracy (77.3% vs 61.3%) across 50 diverse datasets from 26 tissues, encompassing over 8 million cells. By leveraging cross-model deliberation, our framework quantifies uncertainty, identifies ambiguous clusters for expert review, provides transparent reasoning chains, and minimizes the effort and expertise needed for cell type annotation in large-scale studies. Additionally, our framework enables users to seamlessly integrate new LLMs.

Abstract Objectives There is limited knowledge on how providers and patients in the emergency department (ED) use electronic health records (EHRs) to facilitate the diagnostic process. While EHRs can support diagnostic decision-making, EHR features that are not user-centered may increase the likelihood of diagnostic error. We aimed to identify how EHRs facilitate or impede the diagnostic process in the ED and to identify opportunities to reduce diagnostic errors and improve care quality. Materials and Methods We conducted semistructured interviews with 10 physicians, 15 nurses, and 8 patients across 4 EDs. Data were analyzed using a hybrid thematic analysis approach, which blends deductive (ie, using multiple conceptual frameworks) and inductive coding strategies. A team of 4 coders performed coding. Results We identified 4 themes, 3 at the care team level and 1 at the patient level. At the care team level, the benefits of the EHR in the diagnostic process included (1) customizing features to facilitate diagnostic workup and (2) aiding in communication. However, (3) EHR-driven protocols were found to potentially burden the care process and reliance on asynchronous communication could impede team dynamics. At the patient-level, we found that (4) patient portals facilitated meaningful patient engagement through timely delivery of results. Discussion While EHRs can improve the diagnostic process, they can also impair communication and increase workload. Electronic health record design should leverage provider-created tools to improve usability and enhance diagnostic safety. Conclusions Our findings have important implications for health information technology design and policy. Further work should assess optimal ways to release patient results via the EHR portal.

Background/Objectives: Precision medicine is not just hype. Instead, it represents a high bar for developing more effective, safer, and better-tolerated therapies in medicine, without exception in psychiatry, including bipolar disorder (BD). A burgeoning body of narrative reviews and perspective papers has already appraised the boundaries of precision medicine in BD. Methods: This brief perspective follows a narrative, critical approach focusing explicitly on the antipsychotic management of BD using precision approaches. Results: While most controversies align with those previously appraised in BD’s overall precision medicine approach, specific insights are provided herein. Conclusions: Beyond other implications and the strengthened call for valid diagnostic coding systems, the implementation of shared decision-making tools and pharmacogenomics studies focusing on persons with BD are particularly warranted.