tbuckley/cabot-search huggingface dataset:
Foxp3 confers long-term efficacy of chimeric antigen receptor-T cells via metabolic reprogramming
Authors: Congyi Niu, Huan Wei, Xuanxuan Pan, Yuedi Wang, Huan Song, Congwen Li, Jingbo Qie, Jiawen Qian, Shaocong Mo, Wanwei Zheng, Kameina Zhuma, Zixin Lv, Yiyuan Gao, Dan Zhang, Hui Yang, Ronghua Liu, Luman Wang, Wenwei Tu, Jie Liu, Yiwei Chu, Feifei Luo
Journal: Cell Metabolism (2025)

The tumor microenvironment, characterized by low oxygen tension and scarce nutrients, impairs chimeric antigen receptor (CAR)-T cell metabolism, leading to T cell exhaustion and dysfunction. Notably, Foxp3 confers a metabolic advantage to regulatory T cells under such restrictive conditions. Exploiting this property, we generated CAR-TFoxp3 cells by co-expressing Foxp3 with a third-generation CAR construct. The CAR-TFoxp3 cells exhibited distinct metabolic reprogramming, marked by downregulated aerobic glycolysis and oxidative phosphorylation coupled with upregulated lipid metabolism. This metabolic shift was driven by Foxp3's interaction with dynamin-related protein 1. Crucially, CAR-TFoxp3 cells did not acquire regulatory T cell immunosuppressive functions but instead demonstrated enhanced antitumor potency and reduced expression of exhaustion markers via Foxp3-mediated adaptation. The potent antitumor effect and absence of immunosuppression were confirmed in a humanized immune system mouse model. Our findings establish a metabolic reprogramming-based strategy to enhance CAR-T cell adaptability within the hostile tumor microenvironment while preserving therapeutic efficacy.
Fremanezumab for the Treatment of Patients With Migraine and Comorbid Major Depressive Disorder
Authors: Richard B. Lipton, Verena Ramirez Campos, Zipi Roth-Ben Arie, Maja Galic, Dimos Mitsikostas, Cristina Tassorelli, Lex Denysenko, Joshua M. Cohen
Journal: JAMA Neurology (2025)

Importance Migraine and major depressive disorder are frequently comorbid; however, evidence evaluating the efficacy of preventive migraine therapy in patients with both diseases is limited. Objective To evaluate the efficacy and safety of fremanezumab in adults with migraine and comorbid major depressive disorder. Design, Setting, and Participants The UNITE study was a double-blind, placebo-controlled, parallel-group, randomized clinical trial consisting of a 4-week screening period, 12-week double-blind period, and 12-week open-label extension (OLE), conducted between July 9, 2020, and August 31, 2022. The trial was conducted at 55 centers across 12 countries. Eligible patients were adults with episodic migraine (EM) or chronic migraine (CM), history of major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for 12 or more months before screening, and active symptoms of depression (9-item Patient Health Questionnaire score of 10 or more) at screening. Interventions Patients were randomized 1:1 to receive monthly fremanezumab (225 mg) or matched placebo. All patients in the OLE received quarterly fremanezumab (675 mg). Main Outcomes and Measures The primary end point was the mean change from baseline in monthly migraine days during the 12-week double-blind period. Results Of the 540 patients screened for the study, 353 patients (mean [SD] age, 42.9 [12.3] years; 310 female [88%]; EM, 48%; CM, 52%) were eligible and randomized to receive fremanezumab (n = 175) or placebo (n = 178). Mean (SE) change from baseline in monthly migraine days during the 12-week double-blind period was −5.1 (0.50; 95% CI, −6.09 to −4.13) for fremanezumab and −2.9 (0.49; 95% CI, −3.89 to −1.96) for placebo ( P &amp;amp;lt;.001). Mean (SE) change from baseline in the Hamilton Depression Rating Scale–17 Items score at week 8 was −6.0 (0.55; 95% CI, −7.10 to −4.95) for fremanezumab and −4.6 (0.54; 95% CI, −5.66 to −3.55) for placebo (least squares mean [SE] difference: −1.4 [0.61]; 95% CI, −2.61 to −0.22; P = .02). Adverse events were consistent with other fremanezumab trials. Results were maintained throughout the OLE. Conclusions and Relevance Treatment with fremanezumab compared with placebo resulted in significant reductions in monthly migraine days and depressive symptoms. No new safety concerns were observed. To the authors’ knowledge, this was the first placebo-controlled, randomized clinical trial, specifically designed to assess patients with migraine and comorbid depressive disorder, to demonstrate significant improvements in migraine and depressive symptoms with a single pharmacological intervention. Trial Registration ClinicalTrials.gov Identifier: NCT04041284
Effect of Empagliflozin on the Mechanisms Driving Erythropoiesis and Iron Mobilization in Patients With Heart Failure
Authors: João Pedro Ferreira, Stefan D Anker, Javed Butler, Gerasimos Filippatos, James L Januzzi, Elke Schueler, Marina Panova-Noeva, Kristiane Wetzel, Juergen Prochaska, Stuart J Pocock, Naveed Sattar, Mikhail Sumin, Faiez Zannad, Milton Packer
Journal: Journal of the American College of Cardiology (2025)
Ischemia on Dobutamine Stress Echocardiography Predicts Efficacy of PCI
Authors: Fiyyaz Ahmed-Jushuf, Michael J Foley, Christopher A Rajkumar, Shayna Chotai, Florentina A Simader, Danqi Wang, Krzysztof Macierzanka, Joban Sehmi, Gajen Kanaganayagam, Guy Lloyd, Niall Keenan, Nina Bual, John R Davies, Thomas R Keeble, Peter D O'Kane, Peter Haworth, Helen Routledge, Tushar Kotecha, Rupert Williams, Jehangir Din, Sukhjinder S Nijjer, Nick Curzen, Manas Sinha, Neil Ruparelia, Reto Gamma, James C Spratt, Graham D Cole, Frank E Harrell, James P Howard, Darrel P Francis, Matthew J Shun-Shin, Rasha K Al-Lamee
Journal: Journal of the American College of Cardiology (2025)
Defining enteric bacterial pathogenesis using organoids: <i>Citrobacter rodentium</i> uses EspC, an atypical mucinolytic protease, to penetrate mouse colonic mucus
Authors: Yan Chen, Ashley Gilliland, Qiaochu Liang, Xiao Han, Hyungjun Yang, Jocelyn Chan, Dominique Lévesque, Kyung-Mee Moon, Parandis Daneshgar, François-Michel Boisvert, Leonard Foster, Wesley F. Zandberg, Kirk Bergstrom, Hong B. Yu, Bruce A. Vallance
Journal: Gut Microbes (2025)

Enteric bacterial pathogens pose significant threats to human health; however, the mechanisms by which they infect the mammalian gut in the face of daunting host defenses remain to be fully defined. For the attaching and effacing (A/E) bacterial family member and murine pathogen Citrobacter rodentium, its virulence strategy appears to involve penetration of the colonic mucus barrier to reach the underlying epithelium. To better define these interactions, we grew colonoids under air-liquid interface (ALI) conditions, producing a thick mucus layer that mimicked in vivo mucus composition and glycosylation. C. rodentium's penetration of ALI-derived mucus was dramatically enhanced upon exposure to sialic acid, in concert with the secretion of two serine protease autotransporter of Enterobacteriaceae (SPATE) proteins, Pic and EspC. Despite Pic being a class II SPATE, and already recognized as a mucinase, it was EspC, a class I SPATE family member, that degraded ALI-derived mucus, despite class I SPATEs not previously shown to possess mucinase activity. Confirming this finding, E. coli DH5α carrying a plasmid that expresses C. rodentium-derived EspC was able to degrade the mucus. Moreover, recombinant EspC alone also displayed mucinolytic activity in a dose-dependent manner. Collectively, our results reveal the utility of ALI-derived mucus in modeling microbe-host interactions at the intestinal mucosal surface, as well as identify EspC as an atypical class I SPATE that shows significant mucinolytic activity toward ALI-derived mucus.
Safety and Lipid-Lowering Efficacy of Inclisiran Monotherapy in Patients without ASCVD: The VICTORION-Mono Randomized Clinical Trial
Authors: Pam R Taub, Alexis Gutierrez, Donavon Wewers, Elias Garcia Cantu, Hui Cao, Catrin Deck, Anastasia Lesogor, Denise Ott, Jorge Mena-Madrazo, Xiao Zang, R Scott Wright
Journal: Journal of the American College of Cardiology (2025)
Treatment of bullous pemphigoid with methotrexate is associated with a decreased mortality risk
Authors: Päivi Leisti, Anna Pankakoski, Laura Huilaja, Jari Jokelainen, Outi Varpuluoma, Jaana Panelius, Kaisa Tasanen
Journal: British Journal of Dermatology (2025)

Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease which typically affects elderly and causes an increased risk for death. This retrospective study of data from electronic health records of two Finnish university hospitals showed that treatment with metotrexate was associated with a significantly reduced mortality of BP patients compared to those treated with other drugs. In addition, we found that advanced age at diagnosis, concomitant type 2 diabetes, dementia, and mean value of circulating BP180 antibodies ≥60 U/ml were predictors for a poor outcome.
Janus kinase inhibitors enhance prostanoid biosynthesis in human whole blood in vitro: implications for cardiovascular side effects and prevention strategies
Authors: Sabreen Alabbasi, Stefania Tacconelli, Mirjam de Vries, Iva Gunnarsson, Vilija Oke, Marika Kvarnström, Alessandra De Michele, Patrizia Di Gregorio, Paola Patrignani, Helena Idborg, Per-Johan Jakobsson
Journal: Annals of the Rheumatic Diseases (2025)

Janus kinase inhibitors (JAKis) effectively treat chronic inflammatory diseases but are associated with cardiovascular side effects through unknown mechanisms. This study aimed to investigate the impact of JAKis on prothrombotic thromboxane (TX)A2 production in human whole blood (WB) as a possible mechanism. We evaluated the effects of 4 JAKis- tofacitinib, baricitinib, filgotinib, and upadacitinib (0.04-20.0 μM)-on TXB2 biosynthesis in clotting WB from healthy subjects, serving as a marker for platelet TXA2 generation. Additionally, we assessed the impact of these JAKis on TXB2 production in WB from healthy subjects, patients with systemic lupus erythematosus (SLE), and treatment-naïve patients with axial spondyloarthritis (axSpA) after 24-hour lipopolysaccharide (LPS) stimulation, as a marker of platelet and leukocyte prostanoid biosynthesis. All JAKis increased serum TXB2 production in clotting WB, although not in a concentration-dependent manner. In LPS-stimulated WB, tofacitinib (1 μM) significantly increased TXB2 production in healthy subjects (HSs) (42% ± 33%, n = 17), patients with SLE (57% ± 39%, n = 12), and patients with axSpA (31% ± 23%, n = 15). Baricitinib (1 μM) also increased TXB2 in HSs (30% ± 22%, n = 10). Upadacitinib showed a trend towards increased TXB2 (46% ± 40%, n = 7), while filgotinib did not (21% ± 19%, n = 7). Aspirin (100 μM) almost completely reduced serum TXB2 in the presence of all JAKis. The enhanced biosynthesis of TXA2 in platelets, with a minor contribution from leukocytes, may contribute to the increased cardiovascular risk associated with JAKis. Low-dose aspirin may offer a protective effect, warranting further investigations.
Bioglass‐Integrated Dynamic Hydrogels Improve Matrix‐Directed Repair of Cranial Defects through Cooperative Mechano‐Biochemical Regulation
Authors: Shuohan He, Huanhuan Zhao, Maohua Chen, Menghuan Li, Yi Wu, Hang Chen, Yan Zheng, Zhong Luo, Kaiyong Cai, Yan Hu
Journal: Advanced Healthcare Materials (2025)

Abstract Craniofacial injuries are common orthopedic traumas, but their effective restoration still remains a major challenge in the clinic, largely due to the lack of pro‐healing mesenchymal stem cells (MSCs) as well as intrinsically low osteogenic activities. Herein, a dynamic hydrogel system integrated with Aptamer 19S (Apt‐19S)‐loaded mesoporous bioglass nanoparticles (NBG@Apt‐19S) for craniofacial defect reconstruction is reported. The dynamic hydrogel is prepared with clinically tested biocompatible components including polyvinyl alcohol and oxidized sodium alginate (OSA). After implantation into the defect site, the integrated bioglass nanoparticles undergo gradual degradation to release Apt‐19S, which cooperates with the low stiffness of the hydrogel at the initial state to recruit MSCs to the scaffold‐bio interface. The concurrently released Ca 2+ ions would further coordinate with the carboxyl groups in OSA to drive gradual hydrogel stiffening, which can stimulate the vinculin‐talin mechanosensing pathway in recruited MSCs to activate the downstream YAP signaling, eventually promoting their osteogenic activities. The cooperative mechano‐biochemical pro‐osteogenesis activity of the dynamic hydrogel is validated both in vitro and rat models bearing critical‐size cranial defects, providing an approach for cranial defect reconstruction and healing in the clinic.
Paradoxical Activation of Entheseal Myeloid Cells by <scp>JAK1</scp> and <scp>TYK2</scp> Inhibitors via <scp>IL10</scp> Antagonism
Authors: Sami Giryes, Chi Wong, Charlie Bridgewood, Mark Harland, Ala Altaie, Nicole McDermott, Kerem Abacar, Abhay Rao, Almas Khan, Tristan McMillan, Peter Loughenbery, Robert Dunsmuir, Vishal Borse, Tom Macleod, Dennis McGonagle
Journal: Arthritis & Rheumatology (2025)

Background JAK inhibition (JAKi) is effective in seronegative spondyloarthropathy (SpA) spectrum disorders, but TYK2 inhibition failed in SpA spectrum ulcerative colitis, and tofacitinib showed minimal benefit in Crohn's Disease, which highlights the complex role for JAK‐STAT signaling in different inflammatory processes. In this study, we investigated whether JAKi might paradoxically activate entheseal innate immunity and aimed to identify the key regulatory cytokines involved in this process. Methods Spinal entheseal tissue was activated with TLR agonists, including TLR4 and IL‐1 family proteins and entheseal T cell were activated with anti‐CD3/anti‐CD28 plus IL‐23/IL‐1β. JAKi via upadacitinib (JAK1/JAK2), deucravacitinib (TYK2) and ritlecitinib (JAK3) inhibition was evaluated using multiplex cytokine assays, intracellular flow and bulk RNAseq and cytokine blocking or stimulation. Results Following IFNγ stimulation, JAK1 inhibition blocked STAT1 phosphorylation in entheseal cells and strongly blocked activated entheseal T cell TNFα, IL‐17A and IL‐17F production. The opposite effect was evident in entheseal myeloid cell with exaggerated TLR4 and other adjuvant‐mediated cytokine production including IL‐23 (~10‐fold increase; p &lt; 0.001) or TNFα (~10‐fold increase; p &lt; 0.0001). This myeloid effect was induced by upadacitinib and deucravacitinib, but not ritlecitinib, suggesting IL‐10R JAK1/TYK2 signaling. Bulk RNAseq showed multifaceted impact of JAKi on myeloid activation with strong M1 type monocyte polarisation under TLR4 stimulation and JAK1 inhibition confirmed by flow cytometry. Direct IL‐10 inhibition recapitulated inflammatory cytokine elevations and IL‐10R agonist largely, but not completely, rescued this phenotype. Conclusions These findings help explain the emergent efficacy of TYK2 blockade in SpA spectrum related arthritis that is not IL‐10 dependent but indicates why such strategies may not be a panacea for SpA spectrum disorder related intestinal inflammation. image
Engineering Assembloids to Mimic Graft‐Host Skeletal Muscle Interaction
Authors: Lucia Rossi, Beatrice Auletta, Luigi Sartore, Marco La Placa, Giada Cecconi, Pietro Chiolerio, Edoardo Maghin, Silvia Angiolillo, Eugenia Carraro, Onelia Gagliano, Cecilia Laterza, Nicola Elvassore, Martina Piccoli, Anna Urciuolo
Journal: Advanced Healthcare Materials (2025)

Abstract Skeletal muscle (SkM) tissue engineering aims to generate in vitro 3D products that can be implanted in patients to replace or repair damaged muscles. Having a humanized in vitro model able to mimic the interaction between the innervated recipient and the engineered SkMs at a functional level would greatly help in the evaluation of the graft potential. Here, a 3D in vitro model is developed that allows to investigation of the function, stability, and adaptability of the human neuromuscular (NM) system in response to an engineered SkM construct. To achieve this, decellularized SkMs (dSkM)‐based constructs are used as engineered SkM and human neuromuscular organoids (NMOs) as the recipient‐like NM system to create graft‐host SkM assembloids. We observed the migration of myogenic cells and invasion of neural axons from the NMO to the engineered SkM construct in the assembloids, with the generation of functional neuromuscular junctions (NMJs). Finally, assembloids are able to regenerate following acute damage, with SkM regeneration and functional recovery. Despite being limited by the absence of immunocompetent cells and vasculature, the data showed that the assembloid represents a useful tool to evaluate in vitro the response of the human innervated SkM to a potential tissue‐engineered SkM graft.
Dispersed Graphene Nanosheets Enhance Piezoelectricity of Poly (L‐lactic acid) Nanofibrous Scaffold to Promote Bone Defect Repair
Authors: Zhichao Feng, Shengming Zhang, Na Ren, Shuang Hu, Ailing Yin, Mengwei Dong, Li Chang, Aizhu Wang, Jingang Wang, Chunhui Sun, Shuping Wang, Chao Liu, Hong Liu
Journal: Advanced Healthcare Materials (2025)

Abstract The reconstruction of a localized electrical microenvironment at the defect site is considered an effective strategy to promote bone regeneration by mimicking the electrophysiological properties of natural bone tissue. Nano‐piezoelectric materials have attracted significant attention in recent years due to their ability to generate electrical fields under external stress. However, this process can sometimes lead to negative consequences, such as inflammation at the lesion site. Thus, it is of considerable interest to create an electric microenvironment through the deformation of piezoelectric and biodegradable nanomaterials during cellular movement. In this study, dispersed graphene (Gr) sheets are incorporated into poly (L‐lactic acid) (PLLA) to develop a piezoelectric nanofibrous scaffold via electrospinning. The results indicate that the nanofibrous scaffold exhibits excellent piezoelectric properties, with shear piezoelectricity directly correlating to the α‐phase content, which increases upon the addition of Gr. In vitro experiments show that PLLA/Gr scaffolds possess good cytocompatibility and promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In vivo, the PLLA/Gr nanofibrous scaffold demonstrates biocompatibility and effectively accelerates bone defect repair. This study highlights the potential of self‐powered, piezoelectric nanofibrous scaffolds as a promising therapeutic platform for the repair of complex bone defects.
Rational Design of Unsaturated, Thioether Ionizable Lipids for Enhanced In Vivo mRNA Delivery
Authors: Eleni Samaridou, Johanna Simon, Moritz Beck‐Broichsitter, Gary Davidson, Pavel A. Levkin
Journal: Advanced Healthcare Materials (2025)

Abstract Safe and functional delivery of delicate mRNA molecules to target tissues is a crucial step in the development of effective vaccines and therapeutic interventions. Lipid nanoparticles (LNP) are the most clinically advanced delivery vehicles for mRNA drugs and crucially rely on ionizable cationic lipids. However, the structure‐function relationships between ionizable lipids and efficient in‐vivo mRNA delivery remain poorly understood. Here, we focus on the rational design and sequential structural optimization of our ionizable lipids that performed well in vitro, but not in vivo. Through two distinct iterative optimization cycles—targeting the lipid tail and the headgroup—we studied how fusogenicity and pKa of ionizable lipids contribute to LNP delivery performance, in vivo. By engineering lipids with both unsaturated tails and more hydrophobic amino headgroups, we achieved both significant improvement of protein expression in vitro, reduced hemolysis risk, and more than 200‐fold improvement of in vivo mRNA delivery. When compared head‐to‐head to a market‐approved LNP benchmark, the newly developed ionizable lipids/LNP resulted in equally highly efficient in vivo mRNA delivery, with strong liver and spleen tropism upon intravenous injection, while matching the safety of the approved platform. Our findings are pivotal for the development of next‐generation mRNA‐LNP therapies and vaccines.
<scp>PIEZO1</scp> Activation‐Mediated Generation of Transgene‐Free Long‐Term Hematopoietic Stem Cells
Authors: Giorgia Scapin, Jennifer L. Cillis, Marie C. Goulard, Taylor C. Patch, Cintia E. Gomez Limia, Yichen Ding, Wenqiang Du, Priyanka R. Dharampuriya, Elliott J. Hagedorn, Heidi Anderson, Gabriel A. Musso, Caitlyn R. Curley, Emily M. Teets, Calum A. MacRae, Lalit Sehgal, Tzung K. Hsiai, Bradley W. Blaser, Dhvanit I. Shah
Journal: American Journal of Hematology (2025)

ABSTRACT The development of engraftable, long‐term reconstituting hematopoietic stem cells (LT‐HSC) from human pluripotent stem cells (hPSC) has been a long‐sought goal. Since HSCs are formed by a subset of endothelial cells in the ventral part of the dorsal aorta, we analyzed heartbeat‐mediated pulsatile displacement experienced by the walls of the dorsal aorta in zebrafish embryos. We found that pulsation‐mediated circumferential stretch was restricted to the ventral part of the dorsal aorta and activated Piezo1 to stimulate LT‐HSC formation. Stimulation of pulsation or Yoda1‐mediated Piezo1 activation promoted the formation of de novo LT‐HSCs from hemogenic endothelial cells derived from murine embryos or human pluripotent stem cells. These HSCs gave long‐term multilineage reconstitution of hematopoietic cells upon transplantation into immunocompromised mice. The formation of transgene‐free human LT‐HSCs that can engraft and reconstitute the hematopoietic system will facilitate the generation of off‐the‐shelf HSCs from hPSCs for use in cellular therapies.
Correction: Cytoplasmic DROSHA and non-canonical mechanisms of MiR-155 biogenesis in FLT3-ITD acute myeloid leukemia
Authors: Le Xuan Truong Nguyen, Bin Zhang, Dinh Hoa Hoang, Dandan Zhao, Huafeng Wang, Herman Wu, Yu-Lin Su, Haojie Dong, Sonia Rodriguez-Rodriguez, Brian Armstrong, Lucy Y Ghoda, Danilo Perrotti, Flavia Pichiorri, Jianjun Chen, Ling Li, Marcin Kortylewski, Russell C Rockne, Ya-Huei Kuo, Samer Khaled, Nadia Carlesso, Guido Marcucci
Journal: Leukemia (2025)
Renal tubular epithelial cells as an easily accessible biomarker for diagnosing AKI post cardiac surgery
Authors: Matthijs Oyaert, Joris Delanghe, Annelies Brouwers, Thierry Bové, Hannah Schaubroeck, Charlotte Delrue, Wim Vandenberghe, Marijn Speeckaert, Eric Hoste
Journal: Intensive Care Medicine (2025)