tbuckley/cabot-search huggingface dataset:
HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis
Authors: Li Z Luo, Jung-Hyun Kim, Iliana Herrera, Shaoguang Wu, Xinqun Wu, Seong-Sik Park, Juyoung Cho, Leslie Cope, Lingling Xian, Bailey E West, Julian Calderon-Espinosa, Joseph Kim, Zanshé Thompson, Isha Maloo, Tatianna Larman, Karen L Reddy, Ying Feng, Eric R Fearon, Cynthia L Sears, Linda Resar
Journal: Journal of Clinical Investigation (2025)

Mutated tumor cells undergo changes in chromatin accessibility and gene expression, resulting in aberrant proliferation and differentiation, although how this occurs is unclear. HMGA1 chromatin regulators are abundant in stem cells and oncogenic in diverse tissues; however, their role in colon tumorigenesis is only beginning to emerge. Here, we uncover a previously unknown epigenetic program whereby HMGA1 amplifies Wnt signaling during colon tumorigenesis driven by inflammatory microbiota and/or Adenomatous polyposis coli (Apc) inactivation. Mechanistically, HMGA1 "opens" chromatin to upregulate the stem cell regulator, Ascl2, and downstream Wnt effectors, promoting stem and Paneth-like cell states while depleting differentiated enterocytes. Loss of just one Hmga1 allele within colon epithelium restrains tumorigenesis and Wnt signaling driven by mutant Apc and inflammatory microbiota. However, HMGA1 deficiency has minimal effects in colon epithelium under homeostatic conditions. In human colon cancer cells, HMGA1 directly induces ASCL2 by recruiting activating histone marks. Silencing HMGA1 disrupts oncogenic properties, whereas reexpression of ASCL2 partially rescues these phenotypes. Further, HMGA1 and ASCL2 are coexpressed and upregulated in human colorectal cancer. Together, our results establish HMGA1 as an epigenetic gatekeeper of Wnt signals and cell state under conditions of APC inactivation, illuminating HMGA1 as a potential therapeutic target in colon cancer.
Skin microbiome and dermatologic disorders
Authors: Tiffany C Scharschmidt, Julia A Segre
Journal: Journal of Clinical Investigation (2025)

Human skin acts as a physical barrier to prevent the entry of pathogenic microbes while simultaneously providing a home for commensal bacteria and fungi. Microbiome sequencing studies have demonstrated the unappreciated diversity and selectivity of these microbes. Functional studies have demonstrated the impact of specific strains to tune the immune system, sculpt the microbial community, provide colonization resistance, and promote epidermal barrier integrity. Recent studies have integrated the microbiome, immunity, and tissue integrity to understand their interplay in common disorders such as atopic dermatitis. In this Review, we explore microbiome shifts associated with cutaneous disorders with an eye toward how the microbiome can be mined to identify new therapeutic opportunities.
HMGA1 is a crucial mediator of colon tumorigenesis driven by the loss of APC
Authors: Yuxiang Wang, Mikayla Ybarra, Zhenghe Wang
Journal: Journal of Clinical Investigation (2025)

Colorectal cancer is the second leading cause of cancer death in the United States. The adenomatous polyposis coli (APC) pathway plays a critical role in colorectal tumorigenesis, but the mechanism is not fully understood. In this issue of the JCI, Luo and colleagues used genetically engineered mouse models to show that high mobility group A (HMGA1) is a critical mediator in the development of colon tumors driven by the loss of the Apc gene. HMGA1 activated the transcription of Achaete-Scute Family BHLH Transcription Factor 2 (ASCL2), which regulated intestinal stemness and promoted colon tumorigenesis.
Blood pressure regulation through circadian variation: PRDM16 as a target in vascular smooth muscle cells
Authors: M. Adriana Cuibus, Omar Abdel-Wahab
Journal: Journal of Clinical Investigation (2025)

The precise mechanisms of blood pressure (BP) regulation are not fully elucidated, and understanding BP regulation is crucial for managing hypertension and improving outcomes for cardiovascular disease. In this issue of the JCI, Wang et al. identified the transcription factor PR domain-containing protein 16 (PRDM16) as a regulator of both vascular smooth muscle cell contraction and the circadian response to BP control. PRDM16 directly transcriptionally controlled the expression of the adrenergic receptor α 1d and several clock genes crucial for BP circadian regulation. These findings identify a mechanism of how molecular pathways govern circadian BP variation, highlighting PRDM16 as a potential target for hypertension.
Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice
Authors: Wei Si, Xin Zhao, Ruitong Li, Yaopeng Li, Cui Ma, Xiaohan Zhao, Jason Bugno, Yuchang Qin, Junmin Zhang, Hongwei Liu, Liangliang Wang
Journal: Journal of Clinical Investigation (2025)

Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C+ monocytes. Mechanistically, LGG induced IL-10 production via the stimulator of IFN genes (STING)/TBK1/NF-κB (RELA) signaling pathway in intestinal Ly6C+ monocytes, enhancing their immune-suppressive function. Elevated IL-10 subsequently activated IL-10 signaling in Ly6C+ monocytes, resulting in an IL-10-based autocrine regulatory loop and inhibition of proinflammatory cytokine production. Furthermore, LGG shifted the gut microbial community and its metabolic functions, leading to intestinal immune responses against colitis. Fecal microbiota transplantation from LGG-colonized mice alleviated immune checkpoint blockade-associated colitis. Our findings highlight the importance of STING signaling in IL-10-dependent antiinflammatory immunity and establish an empirical basis for developing oral administration of live LGG as an efficient and safe therapeutic strategy against inflammatory colitis.
Correction: Prognostic impact of donor mitochondrial genomic variants in myelodysplastic neoplasms after stem-cell transplantation
Authors: Jing Dong, Shahram Arsang-Jang, Tao Zhang, Zhongyuan Chen, Yung-Tsi Bolon, Stephen Spellman, Raul Urrutia, Paul Auer, Wael Saber
Journal: Journal of Hematology & Oncology (2025)
CD25 downregulation by tumor exosomal microRNA‐15a promotes interleukin‐17‐producing γδ‐T‐cells‐mediated radioresistance in nasopharyngeal carcinoma
Authors: Xiwei Wang, Zheng Xiang, Yanmei Zhang, Chloe Ran Tu, Chunyu Huang, Yuet Chung, Wenyue Zhang, Manni Wang, Yinping Liu, Wenwei Tu
Journal: MedComm (2025)

Interleukin (IL)-17-producing γδ-T cells (γδT-17) are a major source of IL-17 within the tumor microenvironment and have been shown to influence tumor development and therapy outcomes in various cancers. However, the role and presence of γδT-17 cells in nasopharyngeal carcinoma (NPC) remain poorly understood. It is also unclear how these cells might affect radiotherapy, the primary treatment for NPC patients. In this study, we discovered that NPC tumor tissues were rich in γδT-17 cells. Exosomes released from NPC cells (NPC-Exos) could direct γδ-T cells to differentiate into γδT-17 cells. These NPC-Exos-induced γδT-17 cells were found to enhance radioresistance in NPC, both in vitro and in vivo. Blocking IL-17 secreted by NPC-Exos-induced γδT-17 cells restored NPC cell sensitivity to radiation and elevated radiation-induced cell death. Mechanistic studies revealed that NPC-Exos not only increased the release of IL-17-promoting cytokines IL-1β, IL-6, and IL-23 from dendritic cells, but also suppressed CD25/IL-2 signaling in γδ-T cells, facilitating γδT-17 differentiation. The suppression of CD25/IL-2 signaling was driven by microRNA-15a (miR-15a) carried by NPC exosomes. Furthermore, miR-15a inhibitors were able to prevent γδT-17 induction by NPC-Exos. Our findings reveal a novel immunoregulatory role of NPC-Exos and offer potential strategies to combat NPC radioresistance.
AhR Activation Transcriptionally Induces Anti-Microbial Peptide Alpha-Defensin 1 Leading to Reversal of Gut Microbiota Dysbiosis and Colitis
Authors: Manikandan Palrasu, Khadija Kakar, Amarnath Marudamuthu, Hamida Hamida, Shruthi Thada, Yin Zhong, Shanieka Staley, Philip Brandon Busbee, Jie Li, Monica Garcia-Buitrago, Mitzi Nagarkatti, Prakash Nagarkatti
Journal: Gut Microbes (2025)

Alpha-defensin 1 is a small antimicrobial peptide that acts as the first line of defense against pathogens. It is induced following microbial cues and inflammatory signals in neutrophils and Paneth cells in the small intestine, which suggests that it plays a role in microbial homeostasis in the gut. The gut microbial products also serve as ligands for the aryl hydrocarbon receptor (AhR), an environmental sensor. In the current study, we investigated if there is any crosstalk between AhR and alpha-defensin 1. Interestingly, we found a positive correlation between AhR and alpha-defensin 1 protein levels in ileal tissues from active Crohn's' (CD) patients and epithelial cells (IECs) from multiple models of murine colitis. In vitro downregulation of AhR led to inhibition of α-defensin 1, while activation of AhR induced α-defensin 1 in IECs. AhR directly targeted the dioxin response element 3 (DRE3) region on the α-defensin 1 promoter in IECs. AhR-mediated induction of α-defensin 1 in colitis mice reversed the gut microbial dysbiosis and alleviated colitis. Our data identify a novel signaling pathway in which AhR acts as a transcription factor for α-defensin 1, leading to regulation of homeostasis between gut microbiota, intestinal mucosa, and mucosal immunity.
AI prediction model for endovascular treatment of vertebrobasilar occlusion with atrial fibrillation
Authors: Zhi-Xin Huang, Andrea M Alexandre, Alessandro Pedicelli, Xuying He, Quanlong Hong, Yongkun Li, Ping Chen, Qiankun Cai, Aldobrando Broccolini, Luca Scarcia, Serena Abruzzese, Carlo Cirelli, Mauro Bergui, Andrea Romi, Erwah Kalsoum, Giulia Frauenfelder, Grzegorz Meder, Simona Scalise, Maria Porzia Ganimede, Luigi Bellini, Bruno Del Sette, Francesco Arba, Susanna Sammali, Andrea Salcuni, Sergio Lucio Vinci, Giacomo Cester, Luisa Roveri, Xianjun Huang, Wen Sun
Journal: npj Digital Medicine (2025)

Endovascular treatment (EVT) for vertebrobasilar artery occlusion (VBAO) with atrial fibrillation presents complex clinical challenges. This comprehensive multicenter study of 525 patients across 15 Chinese provinces investigated nuanced predictors beyond conventional metrics. While 45.1% achieved favorable outcomes at 90 days, our advanced machine learning approach unveiled subtle interaction effects among clinical variables not captured by traditional statistical methods. The predictive model distinguished high-risk subgroups by integrating multiple parameters, demonstrating superior prognostic precision compared to standard NIHSS-based assessments. Novel findings include nonlinear relationships between dyslipidemia, stroke severity, and functional recovery. The developed predictive algorithm (AUC 0.719 internally, 0.684 externally) offers a more sophisticated risk stratification tool, potentially guiding personalized treatment strategies in high-complexity VBAO patients with atrial fibrillation.
Measles-mumps-rubella vaccination at 6 months of age and the risk of atopic disease in the first year of life: Results from a Danish placebo-controlled randomised trial
Authors: Anne Cathrine Zimakoff, Andreas Jensen, Michelle Malon, Jesper Kiehn Sørensen, Dorthe Maria Vittrup, Signe Kjeldgaard Jensen, Emma Therese Bay, Jannet Svensson, Lone Graff Stensballe
Journal: Journal of Infection (2025)

In observational studies, childhood vaccinations have been associated with atopic diseases. However, results are conflicting and evidence from randomised trials is lacking. Atopic disease after interventional measles-mumps-rubella (MMR) vaccine was a pre-planned secondary outcome of the MMR trial, a randomised, double-blind, placebo-controlled trial in 6540 Danish infants in the high-income setting of Denmark. At two hospitals, infants 5-7 months of age were randomly assigned 1:1 to receive an intramuscular injection with M-M-R VaxPro or placebo (solvent only). Randomisation was stratified by site, sex, and prematurity (< 37 weeks of gestation). The infants were followed up in the Danish health registries to detect eczema, asthma-like disease, and allergic rhinoconjunctivitis, the composite outcome of the three diseases being the primary endpoint of the present study. The trial was registered in the EU Clinical Trials Registry (2016-001901-18) and ClinicalTrials.gov (NTC03780179). Between April 2019 and October 2021, 6540 infants were randomised (3266 MMR and 3274 placebo). There was no difference in the rate of atopic disease before 12 months of age between the MMR and placebo group (76 events MMR vs. 77 placebo), resulting in a hazard ratio of 0·98 (95% confidence interval 0·72 to 1·35). Secondary analyses with follow-up until 24 months of age yielded essentially identical results. Based on trial data in 6540 Danish infants randomised to MMR or placebo at 5-7 months, no association between MMR and atopic disease in early childhood was observed.
Retraction Notice to: ESCRT-mediated Uptake and Degradation of Brain-targeted α-synuclein Single Chain Antibody Attenuates Neuronal Degeneration In Vivo
Authors: Brian Spencer, Sharareh Emadi, Paula Desplats, Simona Eleuteri, Sarah Michael, Kori Kosberg, Jay Shen, Edward Rockenstein, Christina Patrick, Anthony Adame, Tania Gonzalez, Michael Sierks, Eliezer Masliah
Journal: Molecular Therapy (2025)
Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax
Authors: Caroline A. Coughlin, Dhanvantri Chahar, Marianna Lekakis, Abdessamad A. Youssfi, Lingxiao Li, Evan Roberts, Natalia Campos Gallego, Claude-Henry Volmar, Ola Landgren, Shaun Brothers, Anthony J. Griswold, Catalina Amador, Daniel Bilbao, Francesco Maura, Jonathan H. Schatz
Journal: Blood Cancer Journal (2025)
Evaluation and practical application of prompt-driven ChatGPTs for EMR generation
Authors: Hanlin Ding, Wenjie Xia, Yujia Zhou, Lei Wei, Yipeng Feng, Zi Wang, Xuming Song, Rutao Li, Qixing Mao, Bing Chen, Hui Wang, Xing Huang, Bin Zhu, Dongyu Jiang, Jingyu Sun, Gaochao Dong, Feng Jiang
Journal: npj Digital Medicine (2025)
Harmonizing flows: Leveraging normalizing flows for unsupervised and source-free MRI harmonization
Authors: Farzad Beizaee, Gregory A Lodygensky, Chris L Adamson, Deanne K Thompson, Jeanie L Y Cheong, Alicia J Spittle, Peter J Anderson, Christian Desrosiers, Jose Dolz
Journal: Medical Image Analysis (2025)

Lack of standardization and various intrinsic parameters for magnetic resonance (MR) image acquisition results in heterogeneous images across different sites and devices, which adversely affects the generalization of deep neural networks. To alleviate this issue, this work proposes a novel unsupervised harmonization framework that leverages normalizing flows to align MR images, thereby emulating the distribution of a source domain. The proposed strategy comprises three key steps. Initially, a normalizing flow network is trained to capture the distribution characteristics of the source domain. Then, we train a shallow harmonizer network to reconstruct images from the source domain via their augmented counterparts. Finally, during inference, the harmonizer network is updated to ensure that the output images conform to the learned source domain distribution, as modeled by the normalizing flow network. Our approach, which is unsupervised, source-free, and task-agnostic is assessed in the context of both adults and neonatal cross-domain brain MRI segmentation, as well as neonatal brain age estimation, demonstrating its generalizability across tasks and population demographics. The results underscore its superior performance compared to existing methodologies. The code is available at https://github.com/farzad-bz/Harmonizing-Flows.
Macrophage-targeting nano-formulated bicalutamide alleviates colitis by inducing MAP3K1-mediated degradation of NLRP3
Authors: Suqin Zhong, Suzhen Zhong, Yi Wu, Zhiyuan Liu, Yinyin Yang, Xinfeng Wang, Shanshan Li, Yu Wu, Xiaowan Huang, Yangyang Zhu, Zhengang Zhou, Youcui Xu, Longping Wen, Xueqing Yao
Journal: Journal of Controlled Release (2025)
Modulating the elasticity of milk exosome-based hybrid vesicles to optimize transepithelial transport and enhance oral peptide delivery
Authors: Peifu Xiao, Haoyang Yuan, Hongbing Liu, Chen Guo, Yupeng Feng, Wenpeng Zhao, Bohang Zhao, Tian Yin, Yu Zhang, Haibing He, Xing Tang, Jingxin Gou
Journal: Journal of Controlled Release (2025)
Potential of vB_Pa_ZCPS1 phage embedded in situ gelling formulations as an ocular delivery system to attenuate Pseudomonas aeruginosa keratitis in a rabbit model
Authors: Fatma Abdelrahman, Salsabil Makky, Hoda E Teba, Mona M Agwa, Marwa M Abd ElAziz, Ramy Awad, Yara Y Hassan, Abdallah S Abdelsattar, Ian F Connerton, Ayman El-Shibiny
Journal: Journal of Controlled Release (2025)
Combined loss of glyoxalase 1 and aldehyde dehydrogenase 3a1 amplifies dicarbonyl stress, impairs proteasome activity resulting in hyperglycemia and activated retinal angiogenesis
Authors: Shu Li, Hao Li, Katrin Bennewitz, Gernot Poschet, Michael Buettner, Ingrid Hausser, Julia Szendroedi, Peter Paul Nawroth, Jens Kroll
Journal: Metabolism (2025)
Self-assembling chemodrug fiber-hydrogel for transarterial chemoembolization and radiotherapy-enhanced antitumor immunity
Authors: Yisheng Peng, Hui Liu, Xiaoliu Liang, Lei Cao, Minglei Teng, Hu Chen, Zhenjie Li, Xuqi Peng, Jingsong Mao, Hongwei Cheng, Gang Liu
Journal: Journal of Controlled Release (2025)
Dynamic evolution of TCF3‐PBX1 leukemias at the single‐cell level under chemotherapy pressure
Authors: Mira Kusterer, Mari Lahnalampi, Minna Voutilainen, Alexandra Brand, Sandra Pennisi, Johana Norona, Gaia Gentile, Heike Herzog, Gabriele Greve, Michael Lübbert, Mikko Sipola, Emma Kaartinen, Roman Sankowski, Marco Prinz, Saskia Killmer, Marilyn S. Lago, Bertram Bengsch, Stepan R. Cysar, Konrad Aumann, Martin Werner, Justus Duyster, Olli Lohi, Merja Heinäniemi, Jesús Duque‐Afonso
Journal: HemaSphere (2025)

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. The translocation t(1;19), encoding the TCF3‐PBX1 fusion, is associated with intermediate risk and central nervous system (CNS) infiltration at relapse. Using our previously generated TCF3‐PBX1 conditional knock‐in mice, we established a model to study relapsed clones after in vivo chemotherapy treatment, CNS infiltration, and clonal dynamic evolution of phenotypic diversity at the single cell‐level using next‐generation sequencing technologies and mass cytometry. Mice transplanted with TCF3‐PBX1 + leukemia cells and treated with vehicle succumbed to disease, whereas 40% of treated mice with prednisolone or daunorubicin survived. Bulk and single‐cell RNA sequencing of FACS‐sorted GFP+ cells from TCF3‐PBX1 + leukemias arising after chemotherapy treatment revealed that apoptosis, interleukin‐, and TGFβ‐signaling pathways were regulated in CNS‐infiltrating leukemic cells. Across tissues, upregulation of the MYC signaling pathway was detected in persisting leukemic cells and its downregulation by BRD3/4 inhibition increased sensitivity to chemotherapy. In TCF3‐PBX1 + leukemia cells collected after chemotherapy treatment, mass cytometry identified increased phosphorylation of STAT3/5 upon preBCR stimulation, which was susceptible to inhibition by the proteasome inhibitor bortezomib. In summary, we developed a TCF3‐PBX1 + ALL mouse model and characterized relapsed disease after in vivo chemotherapy and cell phenotype dependence on microenvironment. Transcriptomics and phospho‐proteomics revealed distinct pathways that may underlie chemotherapy resistance and might be suitable for pharmacological interventions in human ALL.
Biofilm-associated proteins: from the gut biofilms to neurodegeneration
Authors: Jaione Valle
Journal: Gut Microbes (2025)

Human microbiota form a biofilm with substantial consequences for health and disease. Numerous studies have indicated that microbial communities produce functional amyloids as part of their biofilm extracellular scaffolds. The overlooked interplay between bacterial amyloids and the host may have detrimental consequences for the host, including neurodegeneration. This work gives an overview of the biofilm-associated amyloids expressed by the gut microbiota and their potential role in neurodegeneration. It discusses the biofilm-associated proteins (BAPs) of the gut microbiota, maps the amyloidogenic domains of these proteins, and analyzes the presence of bap genes within accessory genomes linked with transposable elements. Furthermore, the evidence supporting the existence of amyloids in the gut are presented. Finally, it explores the potential interactions between BAPs and α-synuclein, extending the literature on amyloid cross-kingdom interactions. Based on these findings, this study propose that BAP amyloids act as transmissible catalysts, facilitating the misfolding, accumulation, and spread of α-synuclein aggregates. This review contributes to the understanding of complex interactions among the microbiota, transmissible elements, and host, which is crucial for developing novel therapeutic approaches to combat microbiota-related diseases and improve overall health outcomes.
The early warning paradox
Authors: Hugh Logan Ellis, Edward Palmer, James T. Teo, Martin Whyte, Kenneth Rockwood, Zina Ibrahim
Journal: npj Digital Medicine (2025)

Machine learning models in healthcare aim to predict critical outcomes but often overlook existing Early Warning Systems' impact. Using data from King's College Hospital, we demonstrate how current evaluation methods can lead to paradoxical results. We discuss challenges in developing ML models from retrospective data and propose a novel approach focused on identifying when patients enter a 'risk state' through latent health representations, potentially transforming clinical decision-making.
Transcription of hepatitis B surface antigen shifts from cccDNA to integrated HBV DNA during treatment
Authors: Maraake Taddese, Tanner Grudda, Giulia Belluccini, Mark Anderson, Gavin Cloherty, Hyon S. Hwang, Monika Mani, Che-Min Lo, Naomi Esrig, Mark S. Sulkowski, Richard K. Sterling, Yang Zhang, Ruy M. Ribeiro, David L. Thomas, Chloe L. Thio, Ashwin Balagopal
Journal: Journal of Clinical Investigation (2025)

The cornerstone of functional cure for chronic hepatitis B (CHB) is hepatitis B surface antigen (HBsAg) loss from blood. HBsAg is encoded by covalently closed circular DNA (cccDNA) and HBV DNA integrated into the host genome (iDNA). Nucleos(t)ide analogues (NUCs), the mainstay of CHB treatment, rarely lead to HBsAg loss, which we hypothesized was due to continued iDNA transcription despite decreased cccDNA transcription. To test this, we applied a novel multiplex droplet digital PCR that identifies the dominant source of HBsAg mRNAs to 3436 single cells from paired liver biopsies from ten people with CHB and HIV receiving NUCs. With increased NUC duration, cells producing HBsAg mRNAs shifted from chiefly cccDNA to chiefly iDNA. This shift was due to both a reduction in the number of cccDNA-containing cells and diminished cccDNA-derived transcription per cell; furthermore, it correlated with reduced detection of proteins deriving from cccDNA but not iDNA. Despite this shift in the primary source of HBsAg, rare cells remained with detectable cccDNA-derived transcription, suggesting a source for maintaining the replication cycle. Functional cure must address both iDNA and residual cccDNA transcription. Further research is required to understand the significance of HBsAg when chiefly derived from iDNA.