tbuckley/cabot-search huggingface dataset:
Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration
Authors: Rocio Vicario, Stamatina Fragkogianni, Maria Pokrovskii, Carina Meyer, Estibaliz Lopez-Rodrigo, Yang Hu, Masato Ogishi, Araitz Alberdi, Ann Baako, Oyku Ay, Isabelle Plu, Véronique Sazdovitch, Sebastien Heritier, Fleur Cohen-Aubart, Natalia Shor, Makoto Miyara, Florence Nguyen-Khac, Agnes Viale, Ahmed Idbaih, Zahir Amoura, Marc K Rosenblum, Haochen Zhang, Elias-Ramzey Karnoub, Palash Sashittal, Akhil Jakatdar, Christine A Iacobuzio-Donahue, Omar Abdel-Wahab, Viviane Tabar, Nicholas D Socci, Olivier Elemento, Eli L Diamond, Bertrand Boisson, Jean-Laurent Casanova, Danielle Seilhean, Julien Haroche, Jean Donadieu, Frederic Geissmann
Journal: Neuron (2025)

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders associated with mitogen-activated protein (MAP)-kinase-activating mutations and an increased risk of neurodegeneration. We found microglial mutant clones in LCH and ECD patients, whether or not they presented with clinical symptoms of neurodegeneration, associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the rhombencephalon gray nuclei. Neurological symptoms were associated with PU.1+ clone size (p = 0.0003) in patients with the longest evolution of the disease, indicating a phase of subclinical incipient neurodegeneration. Genetic barcoding analysis suggests that clones may originate from definitive or yolk sac hematopoiesis, depending on the patients. In a mouse model, disease topography was attributable to a local clonal proliferative advantage, and microglia depletion by a CSF1R-inhibitor limited neuronal loss and improved survival. These studies characterize a neurodegenerative disease associated with clonal proliferation of inflammatory microglia. The long preclinical stage represents a therapeutic window before irreversible neuronal depletion.
UCNPs@PVP‐Hemin‐GOx@CaCO<sub>3</sub> Nanoplatform for Ferroptosis Self‐Amplification Combined with Calcium Overload
Authors: Yuping Xu, Mingming Ren, Runzhi Deng, Jiajia Meng, Lingxia Xu, Wenbo Zhao, Yanhong Ni, Chun Mao, Shirong Zhang
Journal: Advanced Healthcare Materials (2025)

Abstract Due to the complexity of the tumor microenvironment (TME), current tumor treatments cannot achieve satisfactory results. A nanocomposite material, UCNPs@PVP‐Hemin‐GOx@CaCO 3 (UPHGC NPs) is developed that responds to the TME and controls release to achieve multimodal synergistic therapy in tumor tissues. UPHGC NPs mediate photodynamic therapy (PDT), chemodynamic therapy (CDT), and starvation therapy (ST) synergistically, ultimately inducing self‐amplification of ferroptosis. The Hemin loaded in UPHGC NPs exhibits peroxidase (POD) activity, which can react with H 2 O 2 to produce ·OH (CDT) and generate the maximum amount of ·O 2 − (PDT) under UV excitation from upconversion materials. Hemin can also consume glutathione (GSH), downregulate glutathione peroxidase 4 (GPX4), and combine with PDT/CDT to induce lipid peroxidation (LPO), leading to ferroptosis. In addition, Glucose oxidase (GOx) provides sufficient H 2 O 2 for the ·OH production, amplifying ROS generation to further enhance ferroptosis. The gluconic acid produced by GOx during the ST process synergizes with the TME's acidic conditions to promote Ca 2+ release, induce intracellular calcium overload, enhance oxidative stress, lead to mitochondrial dysfunction, and ultimately kill tumor cells through mitochondrial damage. Furthermore, the externally mineralized calcium carbonate can prevent premature drug release in normal tissues.
A Neuroimmune‐Oncology Microphysiological Analysis Platform (NEO‐MAP) for Evaluating Astrocytic Scar Formation and Microgliosis in Glioblastoma Microenvironment
Authors: Yen N. Diep, Hee Jung Park, Xiaohui Zhu, Jin Ho Nam, Jin‐Kyoung Shim, Jong Hee Chang, Dang Du Nguyen, Inki Kim, Dong‐Gyu Jo, Luke P. Lee, Mijin Yun, Hansang Cho
Journal: Advanced Healthcare Materials (2025)

Abstract Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor, characterized by its heterogeneity in cellular components, including reactive astrocytes and microglia. Since neuroimmune responses like astrogliosis and microgliosis gain recognition as vital factors in brain tumor progression, there is a growing need for clinically relevant models that assess the interactions between astrocytes, microglia, and GBM. Here, a NEuroimmune‐Oncology Microphysiological Analysis Platform (NEO‐MAP) is presented as a “new map” to observe astrocytic scar formation and microgliosis in response to GBM. NEO‐MAP based on pathophysiological principles is designed to replicate the GBM‐glia interactions, multi‐phenotypic microglia activities, scar‐forming astrocytes with chondroitin sulfate proteoglycans (CSPGs) in the extracellular matrix, and the biophysical characteristics of the astrocytic scar barrier. The NEO‐MAP reveals that inhibiting mTORC2 in GBM promotes the proinflammatory transformation of astrocytes and enhanced astrocytic scar formation. Astrocytes that form scars prompted microglia to change from the M2 to M1 phenotype, enhancing chemotherapy sensitivity. Tissues from GBM patients show a significant correlation between reduced mTORC2 activity and increased astrogliosis, alongside a decrease in M2‐polarized microgliosis, aligning with the NEO‐MAP findings. Overall, the NEO‐MAP is foreseen as a clinically significant tool for exploring tumor‐glia interactions, opening avenues for drug development aimed at the tumor microenvironment.
Validation of Diagnostic Utility of Washout CYFRA 21-1 in Lymph Node Metastasis of Thyroid Cancer
Authors: Jeongmin Lee, Yuri Shin, Jeongun Kwak, Hye Lim Park, Sohee Lee, Mee Kyung Kim, Ja Seong Bae, Chan Kwon Jung, So Lyung Jung, Jung-Min Lee, Sang-Ah Chang, Dong-Jun Lim
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Traditional methods, fine-needle aspiration cytology (FNAC) and washout thyroglobulin (Tg), do not always provide sufficient accuracy for diagnosing lymph node (LN) metastasis in thyroid cancer. This study aimed to validate the diagnostic performance of washout cytokeratin fragment 21-1 (CYFRA 21-1) as a complementary biomarker for diagnosing metastatic LNs in thyroid cancer and to explore its relationship with molecular analysis and distant metastasis. Patients and Methods: In this retrospective cohort study involving 230 LNs in 224 patients with PTC, FNAC, washout Tg, and CYFRA 21-1 levels were measured in suspicious LNs. The final LN outcomes were confirmed by surgical histology. Results: Among the 230 LNs, 145 (63.0%) were benign and 85 (37.0%) were metastatic. The optimal cut-off value for washout CYFRA 21-1 was established at 1.12 ng/mL (Area under curve AUC, 0.959; 95% confidence interval CI, 0.936-0.982) with sensitivity of 93.4% and specificity of 97.8%. The cut-off value for washout Tg was 12.61 ng/mL (AUC 0.832, 95% CI, 0.772-0.892). The diagnostic performance of CYFRA 21-1 remained consistent across the preoperative (1.14 ng/mL) and postoperative assessment (1.10 ng/mL). The combination of FNAC and washout CYFRA 21-1 showed high sensitivity (93.1%), specificity (95.6%), negative predictive value (95.3%), and diagnostic accuracy (94.6%) than FNAC with washout Tg. Washout CYFRA 21-1 level was associated with TERT mutations (odds ratio, OR 3.35, P&amp;lt;0.001), LN metastasis (OR 5.43, P=0.019), and distant metastasis (OR 4.27, P =0.019). Conclusions: Incorporating washout CYFRA 21-1 into the diagnostic process improves the accuracy of metastatic LN detection in thyroid cancer.
The breaking point where repeat expansion triggers neuronal collapse in Huntington’s disease
Authors: Michael D. Flower, Sarah J. Tabrizi
Journal: Cell Genomics (2025)

Somatic CAG expansion drives neuronal loss in Huntington's disease (HD), but how expansion results in pathogenesis has remained unclear. Handsaker et al.1 use single-cell RNA and repeat length sequencing to reveal a phased model of expansion and toxicity, highlighting a critical tipping point beyond 150 CAG repeats where neuronal identity collapses and cells die.
Distance matters: How protein regulators facilitate enhancer-promoter interactions and transcription
Authors: Masahiro Nagano, Anders S. Hansen
Journal: Cell Genomics (2025)

Cohesin, transcription factors (TFs), and mediator complex components regulate gene expression partly by regulating enhancer-promoter (E-P) communication. A new study combined E-P distance-controlled reporter screens with the inhibition or degradation of regulatory proteins and uncovered a distance-dependent effect across cohesin, TFs, and mediator complex components.
Update on Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome
Authors: Maria Isabel Achatz, Anita Villani, Alison A. Bertuch, Gaëlle Bougeard, Vivian Y. Chang, Andrea S. Doria, Bailey Gallinger, Lucy A. Godley, Mary-Louise C. Greer, Junne Kamihara, Payal P. Khincha, Wendy K. Kohlmann, Christian P. Kratz, Suzanne P. MacFarland, Luke D. Maese, Kara N. Maxwell, Sarah G. Mitchell, Yoshiko Nakano, Stefan M. Pfister, Jonathan D. Wasserman, Emma R. Woodward, Judy E. Garber, David Malkin
Journal: Clinical Cancer Research (2025)

Abstract Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition condition characterized by a high lifetime risk for a wide spectrum of malignancies associated with germline pathogenic/likely pathogenic (P/LP) variants in the TP53 tumor suppressor gene. Secondary malignant neoplasms are particularly common. Early cancer detection through surveillance enables early intervention and leads to improved clinical outcomes with reduced tumor-related mortality and treatment-related morbidity. Since the 2017 publication of LFS tumor surveillance guidelines from the inaugural AACR Childhood Cancer Predisposition Workshop, understanding the genotype:phenotype relationships in LFS have evolved, and adaptations of the guidelines have been implemented in institutions worldwide. The “Toronto Protocol” remains the current standard for life-long surveillance; however, as outlined in this Perspective, modifications should be considered as to the use of certain modalities to target organs in an age-dependent manner. The Working Group’s recommendations have also been extended to include a more detailed outline for surveillance in the adult TP53 P/LP variant carrier population based on the recognition that early education of both practitioners and patients on what to expect after the transition from childhood/adolescence to young adulthood is important in preparing them for changes in surveillance strategies. In this perspective, we provide an up-to-date clinical overview of LFS, and present our updated consensus tumor surveillance recommendations from the 2023 AACR Childhood Cancer Predisposition Workshop.
A Self‐Priming Pyroptosis‐Inducing Agent for Activating Anticancer Immunity
Authors: Yanjie Li, Hanxin Feng, Huang Yang, Yi Wang, Yuan Ding, Zhengwei Mao, Yang Du, Weilin Wang
Journal: Advanced Healthcare Materials (2025)

Abstract Pyroptosis, a form of programmed cell death mediated by the gasdermin family, has emerged as a promising strategy for inducing anti‐tumor immunity. However, efficiently inducing pyroptosis in tumor cells remains a significant challenge due to the limited activation of key mediators like caspases in tumor tissues. Herein, a self‐priming pyroptosis‐inducing agent (MnNZ@OMV) is developed by integrating outer membrane vesicles (OMVs) with manganese dioxide nanozymes (MnNZ) to trigger pyroptosis in tumor cells. OMVs, derived from Escherichia coli , are coated onto spiny MnNZ to prepare MnNZ@OMV. Once internalized by tumor cells, MnNZ@OMV responds to elevated intracellular glutathione (GSH) levels, releasing Mn 2 ⁺ and OMV components. This leads to GSH depletion and Mn 2 ⁺‐catalyzed reactive oxygen species generation, which triggers NF‐κB translocation and prime caspase‐11 expression. Subsequently, lipopolysaccharides from OMVs activate caspase‐11, resulting in GSDMD cleavage and pyroptosis induction. MnNZ@OMV significantly induces tumor pyroptosis in vivo, promoting dendritic cell maturation and CD8⁺ T cell activation, leading to robust anti‐tumor effects. Collectively, this study presents a novel self‐priming approach for inducing tumor cell pyroptosis through the noncanonical caspase‐11/GSDMD pathway, offering a promising avenue for future cancer immunotherapy.
Spatial transcriptomics identifies novel Pseudomonas aeruginosa virulence factors
Authors: Hao Zhou, Oscar Negrón, Serena Abbondante, Michaela Marshall, Brandon Jones, Edison Ong, Nicole Chumbler, Christopher Tunkey, Groves Dixon, Haining Lin, Obadiah Plante, Eric Pearlman, Mihaela Gadjeva
Journal: Cell Genomics (2025)

Highlights•Spatial transcriptome analysis captures host and pathogen signatures•Integrating spatial data allows the prediction of bacterial burden at infected sites•Transcript enrichment analysis highlights virulence mechanismsSummaryTo examine host-pathogen interactions, we leveraged a dual spatial transcriptomics approach that simultaneously captures the expression of Pseudomonas aeruginosa genes alongside the entire host transcriptome using a murine model of ocular infection. This method revealed differential pathogen- and host-specific gene expression patterns in infected corneas, which generated a unified transcriptional map of infection. By integrating these data, we developed a predictive ridge regression model trained on images from infected tissues. The model achieved an R2 score of 0.923 in predicting bacterial burden distributions and identifying novel biomarkers associated with disease severity. Among iron acquisition pathogen-specific gene transcripts that showed significant enrichment at the host-pathogen interface, we discovered the novel virulence mediator PA2590, which was required for bacterial virulence. This study therefore highlights the power of combining bacterial and host spatial transcriptomics to uncover complex host-pathogen interactions and identify potentially druggable targets.Graphical abstract
Missing regulatory effects on complex traits: Contribution of distal variants
Authors: Sool Lee, Hakhamanesh Mostafavi
Journal: Cell Genomics (2025)

Most genetic effects on complex traits lie in non-coding regions, yet many show no regulatory activity in standard gene expression assays. In this issue of Cell Genomics, Arthur et al.1 add early development-like cell types and chromatin assays, showing that distal variants missed in expression assays partly explain this discrepancy.
Infection by Clonally Related <i>Mycobacterium abscessus</i> Isolates: The Role of Drinking Water
Authors: Rachel M. Thomson, Nicole Wheeler, Rebecca E. Stockwell, Josephine Bryant, Steven L Taylor, Lex E. X. Leong, Trieu Le, Geraint B Rogers, Robyn Carter, Laura J Sherrard, Harry Powell, Graham Simpson, Kirby Patterson-Fahy, Claire E. Wainwright, R. Andres Floto, Julian Parkhill, Scott C. Bell
Journal: American Journal of Respiratory and Critical Care Medicine (2025)

Mycobacterium abscessus group bacteria (MABS) cause lethal infections in people with chronic lung diseases. Transmission mechanisms remain poorly understood; the detection of dominant circulating clones (DCCs) has suggested potential for person-to-person transmission. This study aimed to determine the role of drinking water in the transmission of MABS. A total of 289 isolates were cultured from respiratory samples (231) and drinking water sources (58) across Queensland, Australia. Whole genome sequences were analysed to identify DCCs and determine relatedness. Half of the isolates (144, 49·8%) clustered with previously described DCCs, of which 30 formed a clade within DCC5. Pangenomic analysis of the water-associated DCC5 clade revealed an enrichment of genes associated with copper resistance. Four instances of plausible epidemiological links were identified between genomically-related clinical and water isolates. We provide evidence that drinking water is a reservoir for MABS and may be a vector in the chain of MABS infection.
Deep Learning Estimation of Small Airways Disease from Inspiratory Chest CT: Clinical Validation, Repeatability, and Associations with Adverse Clinical Outcomes in COPD
Authors: Muhammad F. A. Chaudhary, Hira A. Awan, Sarah E Gerard, Sandeep Bodduluri, Alejandro P. Comellas, Igor Barjaktarevic, R. Graham Barr, Christopher B. Cooper, Craig J Galban, MeiLan Han, Jeffrey L Curtis, Nadia N Hansel, Jerry A Krishnan, Martha G. Menchaca, Fernando J. Martinez, Jill Ohar, Luis G. Vargas Buonfiglio, Robert Paine, Surya P Bhatt, Eric A. Hoffman, Joseph M Reinhardt
Journal: American Journal of Respiratory and Critical Care Medicine (2025)

Quantifying functional small airways disease (fSAD) requires additional expiratory computed tomography (CT) scan, limiting clinical applicability. Artificial intelligence (AI) could enable fSAD quantification from chest CT scan at total lung capacity (TLC) alone (fSADTLC). To evaluate an AI model for estimating fSADTLC, compare it with dual-volume parametric response mapping fSAD (fSADPRM), and assess its clinical associations and repeatability in chronic obstructive pulmonary disease (COPD). We analyzed 2513 participants from the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS). Using a randomly sampled subset (n = 1055), we developed a generative model to produce virtual expiratory CTs for estimating fSADTLC in the remaining 1458 SPIROMICS participants. We compared fSADTLC with dual volume, parametric response mapping fSADPRM. We investigated univariate and multivariable associations of fSADTLC with FEV1, FEV1/FVC, six-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), and FEV1 decline. The results were validated in a subset (n = 458) from COPDGene study. Multivariable models were adjusted for age, race, sex, BMI, baseline FEV1, smoking pack years, smoking status, and percent emphysema. Inspiratory fSADTLC showed a strong correlation with fSADPRM in both SPIROMICS (Pearson's R = 0.895) and COPDGene (R = 0.897) cohorts. Higher fSADTLC levels were significantly associated with lower lung function, including lower postbronchodilator FEV1 (L) and FEV1/FVC ratio, and poorer quality of life reflected by higher total SGRQ scores, independent of percent CT emphysema. In SPIROMICS, individuals with higher fSADTLC experienced an annual decline in FEV1 of 1.156 mL (relative decrease; 95% CI: 0.613, 1.699; P < 0.001) per year for every 1% increase in fSADTLC. The rate of decline in COPDGene was slightly lower at 0.866 mL / year (relative decrease; 95% CI: 0.345, 1.386; P < 0.001) for percent increase in fSADTLC. Inspiratory fSADTLC demonstrated greater consistency between repeated measurements with a higher intraclass correlation coefficient (ICC) of 0.99 (95% CI: 0.98, 0.99) compared to fSADPRM [ICC: 0.83 (95% CI: 0.76, 0.88)]. Small airways disease can be reliably assessed from a single inspiratory CT scan using generative AI, eliminating the need for an additional expiratory CT scan. fSAD estimation from inspiratory CT correlates strongly with fSADPRM, demonstrates a significant association with FEV1 decline, and offers greater repeatability.
Climate Change &amp; COPD: A GOLD Science Committee Review
Authors: David M.G. Halpin, John Balmes, MeiLan K. Han, Alberto Papi, Fernando J. Martinez, Maria Montes de Oca, Obianuju B Ozoh, Sundeep Salvi, Don D. Sin, Jinping Zheng, Alvar Agusti, Claus Vogelmeier
Journal: American Journal of Respiratory and Critical Care Medicine (2025)
Exacerbating the Problem: COPD and Atrial Fibrillation
Authors: Sam Bartlett-Pestell, Tom Wong, Jadwiga A. Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2025)

"Exacerbating the Problem: COPD and Atrial Fibrillation." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
KLF family members control expression of genes required for tissue macrophage identities
Authors: Kathleen Pestal, Leianna C. Slayden, Gregory M. Barton
Journal: The Journal of Experimental Medicine (2025)

Tissue-resident macrophages adopt distinct gene expression profiles and exhibit functional specialization based on their tissue of residence. Recent studies have begun to define the signals and transcription factors that induce these identities. Here we describe an unexpected and specific role for the broadly expressed transcription factor Krüppel-like factor 2 (KLF2) in the development of embryonically derived large cavity macrophages (LCMs) in the serous cavities. KLF2 not only directly regulates the transcription of genes previously shown to specify LCM identity, such as retinoic acid receptors and GATA6, but also is required for induction of many other transcripts that define the identity of these cells. Our results suggest that KLF4 may similarly regulate the identity of alveolar macrophages in the lung. These data demonstrate that broadly expressed transcription factors, such as group 2 KLFs, can play important roles in the specification of distinct identities of tissue-resident macrophages.
Rurality Status and Cardiovascular Events/Survival in Older Men With Prostate Cancer
Authors: Stephanie Jiang, Vraj Patel, Nickolas Stabellini, Biplab Datta, Priyanshu Nain, Lakshya Seth, Harikrishnan H. Kunhiraman, Darryl Nettles, Sarah Malik, Sagar A. Patel, Manali Rupji, Kevin Ward, Jeffrey M. Switchenko, Justin X. Moore, Neal L. Weintraub, Avirup Guha
Journal: Journal of the National Comprehensive Cancer Network (2025)

Background: Rural areas have higher cardiovascular disease (CVD) incidence and age-adjusted mortality rates in the general population. However, the impact of rurality on CVD development and outcomes in patients with prostate cancer (PC) remains unclear. Patients and Methods: This retrospective cohort study used the SEER-Medicare database to analyze males aged ≥65 years diagnosed with PC between 2009 and 2017. The primary exposures were patient rurality status (metropolitan, urban, or rural) and patient–provider rurality, which combined the provider’s status (metropolitan vs nonmetropolitan) with the patient’s rurality. The primary outcomes included post-PC CVD (comprising heart failure, atrial fibrillation, acute myocardial infarction, peripheral artery disease, and ischemic stroke), cardiovascular mortality (CVDm), prostate cancer–specific mortality (PCSm), and all-cause mortality. Multivariable Fine-Gray and extended Cox models were used to assess the impact of rurality impact on these outcomes. Results: A total of 103,327 older men were included in the study, of whom 3,631 were from rural areas and 1,857 were rural patients with nonmetropolitan providers. Compared with metropolitan patients, those from rural areas had a 28% higher risk of PCSm (subdistribution hazard ratio [SHR], 1.28; 95% CI, 1.14–1.44) and a 15% higher risk of all-cause mortality (adjusted hazard ratio [aHR], 1.15; 95% CI, 1.07–1.23). Compared with urban patients, rural patients had a 7% higher risk of CVD (SHR, 1.07; 95% CI, 1.01–1.13). No significant differences were observed in CVDm. Among patients receiving androgen deprivation therapy (n=16,811), rurality was associated with a 27% higher risk of PCSm (SHR, 1.27; 95% CI, 1.07–1.51) and a 29% higher risk of all-cause mortality (aHR, 1.29; 95% CI, 1.12–1.49). Rural patients who received care from nonmetropolitan providers had higher risks of PCSm and all-cause mortality compared with those treated by metropolitan providers. Conclusions: Rurality is associated with higher risks of CVD, PCSm, and all-cause mortality compared with metropolitan and urban patients. Provider rurality further increases these risks, underscoring the critical role of health care access and quality in rural health disparities.