tbuckley/cabot-search huggingface dataset:
Targeting PGE2 mediated senescent neuron improves tumour therapy
Authors: Jianyi Zhao, Linshi Wu, Gang Cai, Dan Ou, Keman Liao, Jian Yang, Li Zhou, Renhua Huang, Shukai Lin, Xi Huang, Qi Lv, Juxiang Chen, Lu Cao, Jiayi Chen, Yingying Lin
Journal: Neuro-Oncology (2025)

Abstract Background Recent studies have highlighted bidirectional signalling between tumours and neurons; however, the interactions between tumours and neurons in response to radio-/chemotherapy remain obscure, which hampers the tumour treatment. Methods Glioblastoma organoids (GBOs) and primary neuron coculture, targeted metabonomics, RNA pulldown, mass spectrum, co-immunoprecipitation, RNA-sequencing, transcript/protein validations and multi-electrode arrays were performed to analyse neuron-tumour interaction in response to therapy. In vivo validations were conducted in orthotopic mouse models. Diagnostic and prognostic values were evaluated in serum, tissue-microarray as well as TCGA. Results GBOs recruited and induced pro-tumour-survival senescent neurons upon radiation/chemotherapeutic treatment. Targeted metabonomics revealed that significantly increased tumour-derived prostaglandin E2 (PGE2) induced neuronal senescence phenotype. Screening of enzymes involved in PGE2 synthesis identified prostaglandin E synthase 3 (PTGES3) as the key enzyme responsible for PGE2 upregulation. Biochemical studies revealed that irradiation or chemotherapeutic drug-triggered asparagine endopeptidase (AEP) specifically cleaved eIF4A1 to produce teIF4A1-C, which dissociated from DDX6 and recruited eIF4A3 and PABPN1 to promote the mRNA stability of PTGES3. Elevated PGE2 reciprocally enhanced AEP expression. Inhibiting PGE2 or AEP reduced neuronal senescence and delayed tumour progression. Strikingly, single-cell analysis further showed that expressions of AEP/PTGES3/EIF4A1 in tumour cells were consistent with senescent neuronal CDKN1A in high-neuronal-connectivity glioblastoma. The serum PGE2 concentration was elevated after radiation and higher in resistant glioblastoma patients. High expression of PTGES3 was associated with a poor prognosis. Conclusions Our study revealed that the AEP/PGE2 feedback loop modulates tumour-induced neuronal senescence upon radio-/chemotherapy and highlight the therapeutic value to improve tumour therapy.
Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy
Authors: Rafik Tadros, Sean L Zheng, Christopher Grace, Paloma Jordà, Catherine Francis, Dominique M West, Sean J Jurgens, Kate L Thomson, Andrew R Harper, Elizabeth Ormondroyd, Xiao Xu, Pantazis I Theotokis, Rachel J Buchan, Kathryn A McGurk, Francesco Mazzarotto, Beatrice Boschi, Elisabetta Pelo, Michael Lee, Michela Noseda, Amanda Varnava, Alexa M C Vermeer, Roddy Walsh, Ahmad S Amin, Marjon A van Slegtenhorst, Nicole M Roslin, Lisa J Strug, Erika Salvi, Chiara Lanzani, Antonio de Marvao, Jason D Roberts, Maxime Tremblay-Gravel, Genevieve Giraldeau, Julia Cadrin-Tourigny, Philippe L L'Allier, Patrick Garceau, Mario Talajic, Sarah A Gagliano Taliun, Yigal M Pinto, Harry Rakowski, Antonis Pantazis, Wenjia Bai, John Baksi, Brian P Halliday, Sanjay K Prasad, Paul J R Barton, Declan P O'Regan, Stuart A Cook, Rudolf A de Boer, Imke Christiaans, Michelle Michels, Christopher M Kramer, Carolyn Y Ho, Stefan Neubauer, Paul M Matthews, Arthur A M Wilde, Jean-Claude Tardif, Iacopo Olivotto, Arnon Adler, Anuj Goel, James S Ware, Connie R Bezzina, Hugh Watkins
Journal: Nature Genetics (2025)
Microbiome dysbiosis, neutrophil recruitment and mesenchymal transition of mesothelial cells promotes peritoneal metastasis of colorectal cancer
Authors: Qingguo Li, Yiwei Xiao, Lingyu Han, Wenqin Luo, Weixing Dai, Hongsheng Fang, Renjie Wang, Ye Xu, Sanjun Cai, Ajay Goel, Fan Bai, Guoxiang Cai
Journal: Nature Cancer (2025)
Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings
Authors: Sean L. Zheng, Sean J. Jurgens, Kathryn A. McGurk, Xiao Xu, Chris Grace, Pantazis I. Theotokis, Rachel J. Buchan, Catherine Francis, Antonio de Marvao, Lara Curran, Wenjia Bai, Chee Jian Pua, Hak Chiaw Tang, Paloma Jorda, Marjon A. van Slegtenhorst, Judith M. A. Verhagen, Andrew R. Harper, Elizabeth Ormondroyd, Calvin W. L. Chin, Antonio de Marvao, Marjon A. van Slegtenhorst, James S. Ware, Antonis Pantazis, John Baksi, Brian P. Halliday, Paul Matthews, Yigal M. Pinto, Roddy Walsh, Ahmad S. Amin, Arthur A. M. Wilde, Stuart A. Cook, Sanjay K. Prasad, Paul J. R. Barton, Declan P. O’Regan, R. T. Lumbers, Anuj Goel, Rafik Tadros, Michelle Michels, Hugh Watkins, Connie R. Bezzina, James S. Ware
Journal: Nature Genetics (2025)

Abstract Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.
Hippocampus shapes entorhinal cortical output through a direct feedback circuit
Authors: Tanvi Butola, Melissa Hernández-Frausto, Stefan Blankvoort, Marcus Sandbukt Flatset, Lulu Peng, Ariel Hairston, Cara Deanne Johnson, Margot Elmaleh, Amanda Amilcar, Fabliha Hussain, Claudia Clopath, Clifford Kentros, Jayeeta Basu
Journal: Nature Neuroscience (2025)
<i>TAX1BP3</i> Causes TRPV4-Mediated Autosomal Recessive Arrhythmogenic Cardiomyopathy
Authors: Robin M. Perelli, Enya R. Dewars, Heidi Cope, Alexander S. Behura, Anna Q. Ponek, Angelina M. Sala, Zhushan Zhang, Padmapriya Muralidharan, Mary E. Moya-Mendez, Amy Berkman, Gabrielle G. Monaco, Molly C. Sullivan, Jordan E. Ezekian, Qixin Yang, Bo Sun, Leonie M. Kurzlechner, Tulsi Asokan, Andrew M. Breglio, M. Jay Campbell, Zebulon Z. Spector, Catherine W. Rehder, Paul C. Tang, Cynthia A. James, Hugh Calkins, Vandana Shashi, Andrew P. Landstrom
Journal: Circulation Research (2025)

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is one of the leading causes of sudden cardiac death in children, young adults, and athletes and is characterized by the fibro-fatty replacement of the myocardium, predominantly of the right ventricle. Sixty percent of patients with ACM have a known genetic cause, but for the remainder, the etiology is unknown. This lack of mechanistic understanding has also slowed the development of disease-modifying therapies, and children with ACM have a high degree of morbidity and mortality. METHODS: Induced pluripotent stem cells (iPSCs) from 3 family members were differentiated into cardiac myocytes (CMs). Calcium imaging was conducted by labeling calcium with CAL-520 and confocal imaging to capture calcium sparks after iPSC-CMs were electrically paced. A cardiac-specific, inducible knockout mouse (Tax1bp3 −/− ) was made and intracardiac electrophysiology studies conducted to observe arrhythmia inducibility following pacing. RESULTS: We identified a kindred with multiple members affected by ACM cosegregating with biallelic variants in the gene TAX1BP3 , which encodes the protein TAX1BP3 (Tax1-binding protein 3). iPSC-CMs derived from this kindred demonstrated increased intracellular lipid droplets, induction of TRPV4 (transient receptor potential vanilloid type 4) expression, and inducible TRPV4 current. This was associated with depletion of the intracellular sarcoplasmic reticulum Ca 2+ store and increased RyR2 (ryanodine receptor 2)-mediated store Ca 2+ leak and delayed afterdepolarizations, a known mechanism of Ca 2+ -mediated arrhythmogenesis. Similarly, Tax1bp3 cardiac-specific knockout mice had increased Ca 2+ leak and were predisposed to ventricular arrhythmias compared with wild-type mice. Ca 2+ leak in both the iPSC-CMs and mouse ventricular myocytes was rescued by small molecule TRPV4 inhibition. This strategy also effectively reduced Ca 2+ leak in a PKP2 (plakophilin 2) p.His773AlafsX8 iPSC-CM model of ACM. CONCLUSIONS: We conclude that TAX1BP3 is associated with rare autosomal recessive ACM through TRPV4-mediated Ca 2+ leak from RyR2. Further, TRPV4 current inhibition has the potential to be a new therapeutic target for ACM.
Multiomic Analysis of Calf Muscle in Peripheral Artery Disease and Chronic Kidney Disease
Authors: Kyoungrae Kim, Trace Thome, Caroline Pass, Lauren Stone, Nicholas Vugman, Victoria Palzkill, Qingping Yang, Kerri A. O’Malley, Erik M. Anderson, Brian Fazzone, Feng Yue, Scott A. Berceli, Salvatore T. Scali, Terence E. Ryan
Journal: Circulation Research (2025)

BACKGROUND: Chronic kidney disease (CKD) has emerged as a significant risk factor that accelerates atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the modulators underlying this exacerbated pathobiology are ill-defined. Recent work has demonstrated that uremic toxins are associated with limb amputation in PAD and have pathological effects in both the limb muscle and vasculature. Herein, we use multiomics to identify novel modulators of disease pathobiology in patients with PAD and CKD. METHODS: A cross-sectional study enrolled 4 groups of participants: controls without PAD or CKD (n=28), patients with PAD only (n=46), patients with CKD only (n=31), and patients with both PAD and CKD (n=18). Both targeted (uremic toxins) and nontargeted metabolomics in plasma were performed using mass spectrometry. Calf muscle biopsies were used to measure histopathology, perform bulk and single-nucleus RNA sequencing, and assess mitochondrial function. Differential gene and metabolite analyses, as well as pathway and gene set enrichment analyses, were performed. RESULTS: Patients with both PAD and CKD exhibited significantly lower calf muscle strength and smaller muscle fiber areas compared with controls and those with only PAD. Compared with controls, mitochondrial function was impaired in patients with CKD, with or without PAD, but not in PAD patients without CKD. Plasma metabolomics revealed substantial alterations in the metabolome of patients with CKD, with significant correlations observed between uremic toxins (eg, kynurenine and indoxyl sulfate) and both muscle strength and mitochondrial function. RNA sequencing analyses identified downregulation of mitochondrial genes and pathways associated with protein translation in patients with both PAD and CKD. Single-nucleus RNA sequencing further highlighted a mitochondrial deficiency in muscle fibers along with unique remodeling of fibro-adipogenic progenitor cells in patients with both PAD and CKD, with an increase in adipogenic cell populations. CONCLUSIONS: CKD significantly exacerbates ischemic muscle pathology in PAD, as evidenced by diminished muscle strength, reduced mitochondrial function, and altered transcriptome profiles. The correlation between uremic toxins and muscle dysfunction suggests that targeting these metabolites may offer therapeutic potential for improving muscle health in PAD patients with CKD.
Association Between Prevalence of Anemia and Asthma Severity
Authors: Mi‐So Kim, Hye‐Won Lee, Min Sik Choi, Hyun Seung Lee, Heung‐Woo Park, Kiyon Rhew
Journal: Allergy (2025)

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
The Direct and Indirect Role of IgE on Airway Epithelium in Asthma
Authors: Christian Domingo, William W. Busse, Nicola A. Hanania, Muyesser Ertugrul, Lauren A. Millette, Tina Maio‐Twofoot, Xavier Jaumont, Oscar Palomares
Journal: Allergy (2025)

ABSTRACT Asthma is a chronic airway inflammatory disorder, affecting over 350 million people worldwide, with allergic asthma being the most common form of the disease. Allergic asthma is characterized by a type 2 (T2) inflammatory response triggered by numerous allergens beginning in the airway epithelium, which acts as a physical barrier to allergens as well as other external irritants including infectious agents, and atmospheric pollutants. T2 inflammation is propagated by several key cell types including T helper 2 (Th2) cells, eosinophils, mast cells, and B cells. Immunoglobulin E (IgE), produced by B cells, is a key molecule in allergic airway disease and plays an important role in T2 inflammation, as well as being central to remodeling processes within the airway epithelium. Blocking IgE with omalizumab has been shown to be efficacious in treating allergic asthma however, the role of IgE on airway epithelial cells is less communicated. Developing a deeper explanation of the complex network of interactions between IgE and the airway epithelium will facilitate an improved understanding of asthma pathophysiology. This review discusses the indirect and direct roles of IgE on airway epithelial cells, with a focus on allergic asthma disease.
Multidrug micelles and sonopermeation for chemotherapy co-delivery to brain tumors
Authors: Anshuman Dasgupta, Jan-Niklas May, Geir Klinkenberg, Helena C Besse, Eva Miriam Buhl, Diana Moeckel, Rahaf Mihyar, Quim Peña, Armin Azadkhah Shalmani, Christopher Hark, Anne Rix, Susanne Koletnik, Josbert Metselaar, Yang Shi, Wim E Hennink, Gert Storm, Dannis van Vuurden, Chrit Moonen, Mario Ries, Ruth Schmid, Fabian Kiessling, Twan Lammers
Journal: Journal of Controlled Release (2025)
Unveiling spatial heterogeneity in medulloblastoma: a multi-omics analysis of cellular state and geographical organization
Authors: Jiankang Li, Hailong Liu, Ziwei Wang, Jiao Zhang, Xuan Chen, Craig Daniels, Xiaochong Wu, Olivier Saulnier, Hiromichi Suzuki, Pasqualino De Antonellis, Alexandra Rasnitsyn, Winnie Ong, Evan Y Wang, Liam D Hendrikse, Yu Su, Yu Tian, Dongming Han, Ruohan Wang, Jialin Mo, Fei Liu, Kaiwen Deng, Dongyang Wang, Zhaoyang Feng, Yifei Jiang, Yanong Li, Yuting Ma, Zijia Liu, Meiyu Li, Peiyi Tian, Yanfeng Shi, Yong Jiang, Tao Yang, Shouwei Li, Jianfeng Liang, Jingchuan Wu, Ying Wang, Wanjing Zou, Yina Jiang, Lusheng Wang, Fang Chen, Xin Jin, Shuaicheng Li, Xiaoguang Qiu, Chunde Li, Ya Gao, Yujie Tang, Michael D Taylor, Tao Jiang
Journal: Neuro-Oncology (2025)

Despite numerous studies on medulloblastoma (MB) cell heterogeneity, the spatial characteristics of cellular states remain unclear. We analyze single-nucleus and spatial transcriptomes and chromatin accessibility from human MB spanning four subgroups, to identify malignant cell populations and describe the spatial evolutionary trajectories. The spatial CNVs patterns and niches were analyzed to investigate the cellular interactions. Three main malignant cell populations were identified, including progenitor-like, cycling and differentiated populations. Gene signatures of cell populations strongly correlate to clinical outcomes. These tumor cell populations are geographically organized as stem-like and mature regions, highlighting their spatially heterogeneous nature. Progenitor-like and cycling cells are mainly concentrated in stem-like regions, whereas various differentiated populations are primarily distributed in mature regions. By analyzing chromosomal alterations, we find that stem-like region typically harbors a single pattern of CNVs, reflecting high originality and uniformity, which is in stark contrast to mature region exhibiting multiple patterns with a broader range of biological functions. Projecting cellular state program onto spatial sections fully illustrates the evolution from stem-like region to various functional zones in mature region, which is correlated to microenvironmental components along the paths to maintain stemness or promote differentiation. Conclusions. This multi-omics database comprehensively facilitates the understanding of MB spatial evolutionary organization.
How can the gut microbiome be targeted to fight multidrug-resistant organisms?
Authors: Benjamin Davido, Blair Merrick, Ed Kuijper, Nicolas Benech, Lena M Biehl, Silvia Corcione
Journal: The Lancet Microbe (2025)

The rise of antimicrobial resistance presents a challenge to public health, undermines the efficacy of antibiotics, and compromises the management of infectious diseases. Gut colonisation by multidrug-resistant organisms, such as multidrug-resistant Enterobacterales and vancomycin-resistant enterococci, is associated with increased morbidity and mortality rates, as well as health-care costs. Of late, the role of the gut microbiome in combating colonisation by multidrug-resistant organisms, which could precede invasive infection, has garnered interest. Innovative interventions, including faecal microbiota transplantation, probiotics, phage therapy, and bacterial consortia, represent potential preventive or therapeutic options to counteract colonisation by multidrug-resistant organisms. In this Personal View, we have synthesised the current findings on these interventions and elucidated their potential as solutions to the crisis of antimicrobial resistance.
Phage-inspired targeting of antibiotic-loaded polymeric micelles for enhanced therapeutic efficacy against monomicrobial sepsis
Authors: Tulin Ozbek, Hatice Demir, Senanur Dokuz, Semra Tasdurmazli, Utku Ozbey, Mehmet Ozbil, Murat Topuzogullari, Irfan Cinar, Murat Karamese, Selina Aksak Karamese, Serap Acar, Omer Faruk Bayrak, Elif Cadirci
Journal: Journal of Controlled Release (2025)
Evaluating the survival benefits of adjuvant immunotherapy in muscle-invasive urothelial carcinoma: A real-world experience.
Authors: Mazyar Zahir, Chirag Doshi, Domenique Escobar, Leilei Xia, Gus Miranda, Jie Cai, Anne K. Schuckman, Hooman Djaladat, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2025)

750 Background: Despite current guidelines recommendations to administer adjuvant nivolumab following radical cystectomy (RC) in patients with adverse pathologies, regardless of prior neoadjuvant chemotherapy (NAC), evidence on the long-term efficacy of ICIs remains sparse. This study aims to evaluate the potential survival benefits of the two most common ICIs, Nivolumab and Pembrolizumab, in patients with muscle-invasive bladder cancer (MIBC) at a single institution. Methods: We queried our IRB-approved, prospectively maintained institutional RC database for all patients who underwent RC from January 2017 (following FDA approval for ICIs in MIBC) to July 2022. Patients with pT3-4a and/or N+ after RC, or ypT2-4a and/or N+ after NAC + RC, were included and categorized into two groups: those who received adjuvant ICI (ICI+) and those who did not (ICI-). Demographic, clinical, and survival data were retrieved from our database. Multivariable Cox regressions were performed to adjust for potential confounding variables. Results: A total of 191 patients were included, with 38 (19.9%) receiving adjuvant ICI (30 Nivolumab and 8 Pembrolizumab). The table outlines the patient characteristics, stratified by adjuvant ICI treatment. With a median follow up of 17.9 months, overall survival (OS) was 97.4% in the ICI+ group and 66.0% in the ICI- group (p = .003). Recurrence-free survival (RFS) was 84.2% and 67.9% in the ICI+ and ICI- groups, respectively (p=.206). in the ICI- group, 10 out of 49 (20.4%) recurrences were local or regional (i.e. urethral or ureteral), while all recurrences (N=6) in the ICI+ group were distant. Multivariable Cox regressions demonstrated that, after adjusting for age and pathological stage, adjuvant ICI was associated with significantly improved OS (HR = 0.08 [95%CI: 0.01, 0.59], p = .013), but not RFS (HR = 0.43 [95%CI: 0.18, 1.04], p = .062). Conclusions: Our results corroborated the beneficial effect of ICIs on OS. Although the improvement in RFS did not reach statistical significance, ICIs showed a trend toward positive clinical impact. A notable finding was the potential for ICIs to alter the recurrence pattern in MIBC. Although limited by a small sample size, this study represents one of the first real-world evaluations of adjuvant ICI efficacy in a single-institution cohort. Demographics and baseline clinical characteristics. ICI+ (N=38) ICI- (N=153) p Age (years) 68.7 ± 8.6 71.6 ± 10.4 .060 Sex (Male) 27 (71.1%) 118 (77.1%) .433 Charleson Comorbidity Index 0 9 (23.7%) 31 (20.3%) .886 1 6 (15.8%) 27 (17.6%) ≥ 2 23 (60.5%) 95 (62.1%) Pathological staging OC (&lt; (y)pT2; pN0) 3 (7.9%) 29 (19.0%) .013 EV (&gt; (y)pT2; pN0) 11 (28.9%) 67 (43.8%) LN+ (pN+) 24 (63.2%) 57 (37.2%) Neoadjuvant Chemotherapy (yes) 30 (79.0%) 85 (55.6%) .008
Phase 3 OMAHA-004 study of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA.
Authors: Christian Gratzke, Donald Charles Vile, Zheng Hong Chen, Chris Garratt, Christian Heinrich Poehlein, Jelena Todoric, Karim Fizazi
Journal: Journal of Clinical Oncology (2025)

TPS301 Background: Androgen receptor (AR) somatic mutation activation is a resistance mechanism to AR-directed therapies (ADT) in mCRPC. Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR-directed therapies in patients with mCRPC. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. By blocking the first step of the enzymatic pathway, opevesostat has the potential to inhibit all steroid hormones involved in AR signaling activation. In the phase 1/2 CYPIDES study, opevesostat had antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations (1). The randomized, open-label, phase 3 OMAHA-004 trial (NCT06136650) will evaluate the efficacy and safety of opevesostat versus abiraterone or enzalutamide in patients with molecularly unselected mCRPC previously treated with 1 prior NHA. Methods: Eligible patients have mCRPC that progressed during ADT ≤6 months before screening and during/after 1 NHA for hormone-sensitive prostate cancer or non-mCRPC. Approximately 1500 patients (375 with, 1125 without AR-LBD mutations) will be randomly assigned 1:1 to receive opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone). Primary endpoints are radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR) and overall survival in AR-LBD mutation–positive and –negative disease, separately. Secondary endpoints include time to initiation of first subsequent anticancer therapy or death; objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR; and safety. Recruitment is ongoing. 1. Fizazi et al. NEJM Evid. 2024. Clinical trial information: NCT06136650 .