tbuckley/cabot-search huggingface dataset:
A parallel tonotopically arranged thalamocortical circuit for sound processing
Authors: Zhikai Zhao, Xiaojing Tang, Yiheng Chen, Jie Tao, Mahiber Polat, Zhiqi Yang, Linhan Yang, Meng Wang, Shanshan Liang, Kuan Zhang, Yun Zhang, Chunqing Zhang, Lina Wang, Yanjiang Wang, Arthur Konnerth, Hongbo Jia, Wei Xiong, Xiang Liao, Sunny C Li, Xiaowei Chen
Journal: Neuron (2025)
Dynamics of Mutant Hematopoietic Progenitor Cells Are Not Associated with Clinical Outcomes in Multiple Myeloma
Authors: Camila Guerrero, Maria-Jose Larrayoz, Irache Erdozain, Noemi Puig, Maria-Teresa Cedena, Catarina Maia, Amagoia Mañu, Natalia Gordillo, Oihane Churruca, Diego Alignani, Sarai Sarvide, Iria Vazquez, Cristina Perez, Albert Oriol, Laura Rosinol, Rafael Ríos-Tamayo, Marta-Sonia Gonzalez-Perez, Ana-Pilar Gonzalez-Rodriguez, Felipe de Arriba, Jose M. Moraleda, Jesus Martin, Luis Palomera, Valentin Cabañas, Maria-Jose Calasanz, Joaquin Martinez-Lopez, Maria-Victoria Mateos, Joan Bladé, Juan-Jose Lahuerta, Jesus F. San-Miguel, Bruno Paiva
Journal: Blood Cancer Discovery (2025)

Abstract Mutant hematopoietic progenitor cells (HPC) may expand under high-dose melphalan- and lenalidomide-based regimens and give rise to hematologic second primary malignancies (SPM) in multiple myeloma. To determine whether genetic screening of mutant HPCs may facilitate individualized treatment to minimize the risk of SPMs, we sequenced a myeloid gene panel in 555 longitudinal CD34+ samples from 348 patients with multiple myeloma treated with lenalidomide-containing regimens and found that 23% carried mutant HPCs at diagnosis, which was associated with higher tumor burden and altered myelo-erythropoiesis, although not with inferior survival nor the development of SPMs. There was considerable fluctuation of mutant HPCs, particularly during maintenance, including the frequency of TP53 mutations increasing from 1% at diagnosis to 7% after treatment. Whereas these findings could speculate on the interest of monitoring mutant HPCs during maintenance for the potential identification of patients at greater risk of developing SPMs, overall, our study does not support the genetic screening for clonal hematopoiesis (CH) in multiple myeloma. Significance: SPMs that develop in patients with multiple myeloma have a deleterious impact on survival. Patients with CH may be at risk of developing SPMs, which could potentially be avoided through individualized treatment. However, our results suggest that screening for CH at diagnosis has limited utility.
Genome-wide nucleosome footprints of plasma cfDNA predict preterm birth: A case-control study
Authors: Zhiwei Guo, Ke Wang, Xiang Huang, Kun Li, Guojun Ouyang, Xu Yang, Jiayu Tan, Haihong Shi, Liangping Luo, Min Zhang, Bowei Han, Xiangming Zhai, Jinhai Deng, Richard Beatson, Yingsong Wu, Fang Yang, Xuexi Yang, Jia Tang
Journal: PLoS Medicine (2025)

Background Preterm birth (PTB) occurs in approximately 11% of all births worldwide, resulting in significant morbidity and mortality for both mothers and their offspring. Identifying pregnancies at risk of preterm birth during early pregnancy may help improve interventions and reduce its incidence. Plasma cell-free DNA (cfDNA), derived from placenta and other maternal tissues, serves as a dynamic indicator of biological processes and pathological changes in pregnancy. These properties establish cfDNA as a valuable biomarker for investigating pregnancy complications, including PTB. Methods and findings To date, there are few methods available for PTB prediction that have been developed with large sample sizes, high-throughput screening, and validated in independent cohorts. To address this gap, we established a large-scale, multi-center case-control study involving 2,590 pregnancies (2,072 full-term and 518 preterm) from three independent hospitals to develop a spontaneous preterm birth classifier. We performed whole-genome sequencing on cfDNA, focusing on promoter profiling (read depth of promoter regions spanning from −1 to +1 kb around transcriptional start sites). Using four machine learning models and two feature selection algorithms, we developed classifiers for predicting preterm birth. Among these, the classifier based on the support vector machine model, named PTerm ( P romoter profiling classifier for pre term prediction), exhibited the highest area under the curve (AUC) value of 0.878 (0.852–0.904) following leave-one-out cross-validation. Additionally, PTerm exhibited strong performance in three independent validation cohorts, achieving an overall AUC of 0.849 (0.831–0.866). Conclusions In summary, PTerm demonstrated high accuracy in predicting preterm birth. Additionally, it can be utilized with current non-invasive prenatal test data without changing its procedures or increasing detection cost, making it easily adaptable for preclinical tests.
Quaking–cZFP609 Axis Remedies Aberrant Plasticity of Vascular Smooth Muscle Cells via Mediating Platelet‐Derived Growth Factor Receptor β Degradation
Authors: Yong‐Qing Dou, Xiao‐Yun Zhang, Rui‐Juan Guo, Xiao‐Fu Huang, Yu Song, Xin‐Long Liu, Jie Shi, Fan‐Qin Li, Dan‐Dan Zhang, Peng Kong, Lei Nie, Han Li, Fan Zhang, Mei Han
Journal: MedComm (2025)

ABSTRACT Vascular smooth muscle cell (VSMC) plasticity is crucial for the repair after vascular injury. However, the high plasticity of VSMCs may make them transform into pathogenic phenotypes. Here, we show that VSMCs overexpressing Sirtuin 1 (SIRT1) exhibit a reduced phenotypic plasticity in the context of platelet‐derived growth factor (PDGF)‐BB treatment. SIRT1 activated Quaking (QKI)–cZFP609 axis is involved in the plasticity regulation in the VSMCs. Mechanically, SIRT1 deacetylates K133 and K134 of QKI and mediates its activation. Activated QKI binds the QKI response elements located in the upstream and downstream of the cZFP609‐forming exons in ZFP609 pre‐mRNA to mediate cZFP609 production. Furthermore, the acetylation of QKI is increased by inhibiting SIRT1 with the selective and potent inhibitor EX527 or deletion of SIRT1, accompanied with parallel decrease in cZFP609 formation. Final, we identify that cZFP609 directs PDGF receptor (PDGFR)β sorting into endosomal/lysosomal pathway and degradation by bridging PDGFRβ and Rab7, resulted in attenuating Raf–MEK–ERK cascade activation downstream of PDGFRβ signaling. Overexpression of cZFP609 remedies aberrant plasticity and overproliferation of VSMCs, and ameliorates neointimal formation. Together, these results highlight that modulating the QKI–cZFP609 axis may help propel repair without stenosis as a therapeutic strategy in vascular injury.
Cost‐Effectiveness of Ferritin Screening Thresholds for Iron Deficiency in Reproductive‐Age Women
Authors: Daniel Wang, Manraj Sra, Samira Glaeser‐Khan, Daniel Y. Wang, Ranya Moshashaian‐Asl, Satoko Ito, Adam Cuker, George Goshua
Journal: American Journal of Hematology (2025)

ABSTRACT Iron deficiency (ID) is a top five leading cause of disability‐adjusted life‐years in women of reproductive age around the world. Despite its enormous health burden, no screening guidelines exist for the detection and treatment of ID in women of reproductive age. We sought to determine the cost‐effectiveness of screening versus no screening for ID in women of reproductive age in the United States. A lifetime simulation of women of reproductive age was conducted using a Markov cohort model under three strategies: (1) no screening, (2) screening at a ferritin threshold of 15 μg/L, and (3) screening at a ferritin threshold of 25 μg/L, from the US health system perspective, and at a willingness‐to‐pay threshold of $100 000/quality‐adjusted life year (QALY). Epidemiologically informed ID prevalence estimates sourced from the National Health and Nutrition Examination Survey were employed for model parameterization. The primary outcome was the incremental cost‐effectiveness ratio (ICER, in $/QALY). Base‐case results for the three strategies accrued $209 700, $210 200, and $210 200 discounted lifetime costs and 23.6, 24.0, and 24.4 discounted lifetime QALYs, respectively. Screening at a ferritin threshold of 25 μg/L was the cost‐effective intervention with an ICER of $680/QALY (95% credible interval $350–$750/QALY). In dual base‐case analyses examining intravenous rather than oral iron repletion for treatment, screening at a ferritin threshold of 25 μg/L remained the cost‐effective intervention with an ICER of $2300/QALY (95% CI $1800–$3800/QALY). In probabilistic sensitivity analyses, screening at a ferritin threshold of 25 μg/L was the cost‐effective intervention in 100% of 10 000 s order Monte Carlo iterations.
Advancements in Diagnostics and Therapeutics for Cancer of Unknown Primary in the Era of Precision Medicine
Authors: Ting Zhao, Xiaowei Zhang, Xin Liu, Qifeng Wang, Xichun Hu, Zhiguo Luo
Journal: MedComm (2025)

ABSTRACT Cancer of unknown primary (CUP), a set of histologically confirmed metastases that cannot be identified or traced back to its primary despite comprehensive investigations, accounts for 2–5% of all malignancies. CUP is the fourth leading cause of cancer‐related deaths worldwide, with a median overall survival (OS) of 3–16 months. CUP has long been challenging to diagnose principally due to the occult properties of primary site. In the current era of molecular diagnostics, advancements in methodologies based on cytology, histology, gene expression profiling (GEP), and genomic and epigenomic analysis have greatly improved the diagnostic accuracy of CUP, surpassing 90%. Our center conducted the world's first phase III trial and demonstrated improved progression‐free survival and favorable OS by GEP‐guided site‐specific treatment of CUP, setting the foundation of site‐specific treatment in first‐line management for CUP. In this review, we detailed the epidemiology, etiology, pathogenesis, as well as the histologic, genetic, and clinical characteristics of CUP. We also provided an overview of the advancements in the diagnostics and therapeutics of CUP over the past 50 years. Moving forward, we propose optimizing diagnostic modalities and exploring further‐line treatment regimens as two focus areas for future studies on CUP.
Patient-reported outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia patients treated with ponatinib or imatinib: results from the PhALLCON trial
Authors: Ajibade Ashaye, Ling Shi, Ibrahim Aldoss, Pau Montesinos, Pankit Vachhani, Vanderson Rocha, Cristina Papayannidis, Jessica T Leonard, Maria R Baer, Jose-Maria Ribera, James McCloskey, Jianxiang Wang, Sujun Gao, Deepali Rane, Shien Guo
Journal: Leukemia (2025)

Abstract In the Phase 3 PhALLCON trial (NCT03589326), ponatinib demonstrated superior efficacy and comparable safety profile versus imatinib in adults with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Here we report patient-reported outcomes (PRO) from PhALLCON assessed as exploratory endpoints using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EQ-5D-5L. Primary PRO domains included FACT-G physical well-being, FACT-Leu subscale (FACT-LeuS), Trial Outcome Index (TOI), FACT-Leu total score, FACT-G total score, and EQ-5D visual analogue scale. Differences in least-squares mean score changes from baseline to the end of induction (EOI)/consolidation (EOC) and time to confirmed improvement/deterioration were analyzed. Overall treatment tolerability was assessed using the FACT-GP5. Analyses included 238 patients (ponatinib 159, imatinib 79) with ≥1 PRO assessment. Least-squares mean changes from baseline favored ponatinib, with significant and meaningful differences in FACT-LeuS, TOI, and FACT-Leu total score at EOI and across the primary domains except for FACT-LeuS at EOC. Median time to confirmed improvement was shorter with ponatinib versus imatinib for key measures. Ponatinib-treated patients tended to report being less bothered by treatment side effects as assessed by FACT-GP5. These findings highlight ponatinib’s potentially favorable impact on health-related quality of life, supporting its use as frontline treatment for Ph+ ALL.
Risk-Based Primary Prevention of Heart Failure: A Scientific Statement From the American Heart Association
Authors: Sadiya S. Khan, Khadijah Breathett, Lynne T. Braun, Sheryl L. Chow, Deepak K. Gupta, Carolyn Lekavich, Donald M. Lloyd-Jones, Chiadi E. Ndumele, Carlos J. Rodriguez, Larry A. Allen
Journal: Circulation (2025)

The growing morbidity, mortality, and health care costs related to heart failure (HF) underscore the urgent need to prioritize its primary prevention. Whereas a risk-based approach for HF prevention remains in its infancy, several key opportunities exist to actualize this paradigm in clinical practice. First, the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America HF guidelines provided recommendations, for the first time, on the clinical utility of multivariable risk equations to estimate risk of incident HF. Second, the American Heart Association recently developed the PREVENT (Predicting Risk of Cardiovascular Disease Events) equations, which not only enable prediction of incident HF separately, but also include HF in the prediction of total cardiovascular disease. Third, the predominant phenotype of HF risk has emerged as the cardiovascular-kidney-metabolic syndrome. Fourth, the emergence of novel therapies that prevent incident HF (eg, sodium-glucose cotransporter-2 inhibitors) and target multiple cardiovascular-kidney-metabolic axes demonstrate growing potential for risk-based interventions. Whereas the concept of risk-based prevention has been established for decades, it has only been operationalized for atherosclerotic cardiovascular disease prevention to date. Translating these opportunities into a conceptual framework of risk-based primary prevention of HF requires implementation of PREVENT-HF (Predicting Risk of Cardiovascular Disease Events–Heart Failure) equations, targeted use of cardiac biomarkers (eg, natriuretic peptides) and echocardiography for risk reclassification and earlier detection of pre-HF, and definition of therapy-specific risk thresholds that incorporate net benefit and cost-effectiveness. This scientific statement reviews the current evidence for accurate risk prediction, defines strategies for equitable prevention, and proposes potential strategies for the successful implementation of risk-based primary prevention of HF.
T <sub>reg</sub> Cells Attenuate Pulmonary Venous Remodeling in PH-LHD via NLRC3 Signaling
Authors: Gulinigeer Zhakeer, Yanxi Zeng, Guangxi E., Nuerbiyemu Maimaitiaili, Peinan Ju, Hongyun Yao, Yefei Shi, Ming Zhai, Ke Li, Jianhui Zhuang, Yunshan Cao, Qing Yu, Wenhui Peng
Journal: Circulation Research (2025)

BACKGROUND: Pulmonary venous remodeling is a key pathological feature of pulmonary hypertension associated with left heart disease (PH-LHD). This study aims to investigate the role of regulatory T (T reg ) cells in this process. METHODS: We used mouse models with transverse aortic constriction and cell depletion of Foxp3-DTR/tdTomato mice to examine T reg cells’ function around pulmonary veins in PH-LHD in vivo. To confirm the effect of Nlrc3 −/− T reg cells on PH-LHD, we utilized 3 mouse models: Nlrc3 knockout mice, athymic mice, and endothelial cell lineage tracing Cdh5CreERT2 +/ − -mT/mG +/ − mice. The interaction proteins and signaling pathways of T reg cells during endothelial-to-mesenchymal transition were elucidated by protein docking prediction, coimmunoprecipitation and cocultivation of T reg cells with venous endothelial cells. RESULTS: T reg cells were abundant around pulmonary veins of transverse aortic constriction–induced PH-LHD and were essential for promoting inflammation resolution and inhibiting pulmonary venous remodeling. Nlrc3 expression was reduced in mice and patients with PH-LHD. NLRC3 (nucleotide-oligomerization domain-like receptor family CARD domain containing 3) deficiency inhibited T reg cell proliferation and impaired their immunosuppressive and endothelial-to-mesenchymal transition–protective effects. Mechanistically, NLRC3 interacted with TRAM (TRIF-related adaptor molecule) and regulated IRF3/NF-κB (nuclear factor-κB) p65 signaling in CD4 + T cells. NLRC3-deficient T reg cells promoted IL (interleukin)-18 expression through IRF3/NF-κB p65 signaling, and thus IL-18 secretion activated endothelial RTK (receptor tyrosine kinase) signaling, favoring endothelial-to-mesenchymal transition progression in pulmonary veins and PH-LHD progress. This process was reversible with IL-18 binding protein in vivo. CONCLUSIONS: NLRC3 is crucial for T reg cells to prevent pulmonary venous remodeling in PH-LHD, primarily by modulating IL-18 secretion, which inhibits endothelial-to-mesenchymal transition and thereby improves disease progression and prognosis.
Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice
Authors: Ying Liu, Ezequiel Dantas, Miriam Ferrer, Ting Miao, Mujeeb Qadiri, Yifang Liu, Aram Comjean, Emma E Davidson, Tiffany Perrier, Tanvir Ahmed, Yanhui Hu, Marcus D Goncalves, Tobias Janowitz, Norbert Perrimon
Journal: Nature Metabolism (2025)

Abstract Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk , key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6–JAK–STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.
Orally Administered Zn<sub>x</sub>Ce<sub>y</sub>O<sub>2</sub>/Se Hydrogel with Effective Antioxidant Activity for Treating Inflammatory Bowel Disease by Inhibiting Ferroptosis
Authors: Lingling Kan, Tongsheng Li, Weinan Zhang, Ziwen Zheng, Guoqiang Zhang, Yu Jin, Wanni Wang, Haisheng Qian, Lingling Xu
Journal: Advanced Healthcare Materials (2025)

Abstract Oxidative stress leads to intestinal barrier damage, which induces immune responses to occur and further promotes oxidative stress exacerbating inflammatory bowel disease (IBD). In this work, the multifunctional Zn x Ce y O 2 /Se (ZCSO) nanozyme wrapped with acid‐resistant calcium alginate hydrogel designed for oral administration is prepared. The ZCSO nanozyme can promote the activation of the Nrf2 oxidative stress pathway, then significantly improve the efficiency of scavenging reactive oxygen species (ROS) and up‐regulate the protein expression of glutathione peroxidase 4 (GPx4), which is closely related to the inhibition of ferroptosis. In addition, the ZCSO nanozyme inhibiting the growth of some pathogenic bacteria proliferating due to oxidative stress shows a positive regulation of the intestinal flora and reduces the secretion of pro‐inflammatory factors and the levels of inflammatory macrophages, achieving the significant preventive and delayed therapeutic effect of colitis mice. Consequently, the distinctive properties of ZCSO nanozyme render it a promising candidate for the treatment of IBD by effectively scavenging ROS, thereby interrupting the detrimental cycle between oxidative stress and immune response, ultimately promoting the proliferation of epithelial cells to reestablish the integrity of the intestinal mucosal barrier.
pH and Glucose Dual‐Responsive Hydrogels Promoted Diabetic Wound Healing by Remodeling the Wound Microenvironment
Authors: Yifan Zhou, Fanjia Dai, Sifang Zhao, Zelong Li, Hongze Liang, Xiao Wang, Lingling Zhao, Hui Tan
Journal: Advanced Healthcare Materials (2025)

Abstract The microenvironment of diabetic wounds is complicated and characterized by hyperglycemia, hyperinflammation, persistent infection, hypoxia, and ischemia, making wound restoration and healing extremely challenging. Therefore, functional hydrogel dressings with the ability to regulate the microenvironment of diabetic wounds are a promising strategy for the treatment of diabetic wounds. In this study, a pH/glucose dual‐responsive hydrogel based on phenylboric acid‐modified carboxymethyl chitosan (CMCSPBA), aldehyde‐terminated polyethylene glycol (PEGCHO), and polyvinyl alcohol (PVA) has been developed for diabetic wound treatment via Schiff base and phenylboric ester interactions. Glucose oxidase (GOX), catalase (CAT), and deferoxamine mesylate (DFO) are incorporated into the hydrogel to endow it with multi‐functionality. In the hyperglycemic environment of diabetic wounds, a benign feedback loop is formed through the synergistic action of each component of the hydrogel, which enables the reshaping of the microenvironment of diabetic wounds by adjusting the pH and glucose, alleviating oxidative stress and hypoxia, regulating the inflammatory response, inhibiting bacterial infection, and promoting angiogenesis, thus accelerating diabetic wound healing in streptozotocin (STZ)‐induced diabetic mice.
Programmed death-ligand 1 regulates ameloblastoma growth and recurrence
Authors: Linzhou Zhang, Hao Lin, Jiajie Liang, Xuanhao Liu, Chenxi Zhang, Qiwen Man, Ruifang Li, Yi Zhao, Bing Liu
Journal: International Journal of Oral Science (2025)

Abstract Tumor cell-intrinsic programmed death-ligand 1 (PD-L1) signals mediate tumor initiation, progression and metastasis, but their effects in ameloblastoma (AM) have not been reported. In this comprehensive study, we observed marked upregulation of PD-L1 in AM tissues and revealed the robust correlation between elevated PD-L1 expression and increased tumor growth and recurrence rates. Notably, we found that PD-L1 overexpression markedly increased self-renewal capacity and promoted tumorigenic processes and invasion in hTERT + -AM cells, whereas genetic ablation of PD-L1 exerted opposing inhibitory effects. By performing high-resolution single-cell profiling and thorough immunohistochemical analyses in AM patients, we delineated the intricate cellular landscape and elucidated the mechanisms underlying the aggressive phenotype and unfavorable prognosis of these tumors. Our findings revealed that hTERT + -AM cells with upregulated PD-L1 expression exhibit increased proliferative potential and stem-like attributes and undergo partial epithelial‒mesenchymal transition. This phenotypic shift is induced by the activation of the PI3K-AKT-mTOR signaling axis; thus, this study revealed a crucial regulatory mechanism that fuels tumor growth and recurrence. Importantly, targeted inhibition of the PD-L1-PI3K-AKT-mTOR signaling axis significantly suppressed the growth of AM patient-derived tumor organoids, highlighting the potential of PD-L1 blockade as a promising therapeutic approach for AM.