tbuckley/cabot-search huggingface dataset:
Acetylsalicylic acid aggravates anaphylaxis in a PGE2-dependent manner
Authors: Philipp Globig, Payam Morakabati, Veronika Höfer, Diana M Willmes, Magda Babina, Margitta Worm
Journal: Journal of Clinical Investigation (2025)

Acetylsalicylic acid (ASA) can exert proanaphylactic effects, but the extent of this phenomenon and its underlying mechanisms are undefined. Yet, low homeostatic prostaglandin E2 (PGE2) levels have been associated with anaphylaxis. In this study, we investigated whether the proanaphylactic effect of ASA is PGE2 dependent. We assessed the effect of ASA in experimental anaphylaxis models, analyzed a large dataset of patients with anaphylaxis, and performed titrated allergen challenges in ASA-treated allergic individuals. Registry data indicated an increased risk for severe anaphylaxis in patients with ASA comedication. ASA pretreatment aggravated allergen-dependent anaphylaxis in mice, whereas histamine-induced anaphylaxis remained unaffected. Exacerbation was due to reduced PGE2, as its stabilization or the use of prostanoid E receptor (EP) agonists reversed the proanaphylactic effects of ASA. EP2-, EP3-, and EP4 receptor-deficient mice revealed that each receptor individually contributed to ASA susceptibility. In patients with allergy, prior ASA intake increased skin responsiveness to allergen but not to histamine. Conversely, the responses of basophils to ex vivo FcεRI aggregation remained unaltered, indicating that ASA operated by enhancing the stimulability of mast cells in a PGE2-dependent manner. Collectively, our data reveal a central role of the PGE2 network in ASA-aggravated anaphylaxis. EP receptors could be potential targets to prevent or alter the outcome of anaphylaxis.
Endothelial OX40 activation facilitates tumor cell escape from T cell surveillance through S1P/YAP-mediated angiogenesis
Authors: Baoyu He, Rou Zhao, Baogui Zhang, Hongli Pan, Jilan Liu, Lunhua Huang, Yingying Wei, Dong Yang, Jing Liang, Mingyi Wang, Mingsheng Zhao, Sen Wang, Fengyun Dong, Junfeng Zhang, Yanhua Zhang, Xu Zhang, Xiao Zhang, Guanjun Dong, Huabao Xiong, Qingli Bie, Bin Zhang
Journal: Journal of Clinical Investigation (2025)

Understanding the complexity of the tumor microenvironment is vital for improving immunotherapy outcomes. Here, we report that the T cell costimulatory molecule OX40 was highly expressed in tumor endothelial cells (ECs) and was negatively associated with the prognosis of patients, which is irrelevant to T cell activation. Analysis of conditional OX40 loss- and gain-of-function transgenic mice showed that OX40 signal in ECs counteracted the antitumor effects produced in T cells by promoting angiogenesis. Mechanistically, leucine-rich repeat-containing GPCR5 (Lgr5+ ) cancer stem cells induced OX40 expression in tumor ECs via EGF/STAT3 signaling. Activated OX40 interacted with Spns lysolipid transporter 2 (Spns2), obstructing the export of sphingosine 1-phosphate (S1P) and resulting in S1P intracellular accumulation. Increased S1P directly bound to Yes 1-associated protein (YAP), disrupting its interaction with large tumor suppressor kinase 1 (LATS1) and promoting YAP nuclear translocation. Finally, the YAP inhibitor verteporfin enhanced the antitumor effects of the OX40 agonist. Together, these findings reveal an unexpected protumor role of OX40 in ECs, highlighting the effect of nonimmune cell compartments on immunotherapy.
Imatinib on target in stroke recovery
Authors: Hae Ryong Kwon, Lorin E. Olson
Journal: Journal of Clinical Investigation (2025)

Ischemic stroke causes scars in the CNS that impede functional recovery, and there is a need for therapeutics to improve recovery after the acute phase. Scar-resident myofibroblasts and the PDGF pathway have been implicated in stroke pathology. In this issue of the JCI, Protzmann et al. report that inhibition of PDGF-CC or its receptor, PDGFRα, reduces the myofibroblast population and improves functional recovery after ischemic stroke in mice. Importantly, PDGFRα inhibition was effective in improving functional recovery even when initiated 24 hours after stroke, which suggests opportunities for later treatment by targeting the PDGF pathway. This study demonstrates the therapeutic potential of enhancing stroke recovery even after acute damage and blood-brain barrier dysfunction has already occurred.
Patterns of autoantibody expression in multiple sclerosis identified through development of an autoantigen discovery technology
Authors: Europe B DiCillo, Evgueni Kountikov, Minghua Zhu, Stefan Lanker, Danielle E Harlow, Elizabeth R Piette, Weiguo Zhang, Brooke Hayward, Joshua Heuler, Julie Korich, Jeffrey L Bennett, David Pisetsky, Thomas Tedder
Journal: Journal of Clinical Investigation (2025)

Multiple sclerosis (MS) is a debilitating autoimmune disease of the CNS, which is characterized by demyelination and axonal injury and frequently preceded by a demyelinating event called clinically isolated syndrome (CIS). Despite the importance of B cells and autoantibodies in MS pathology, their target specificities remain largely unknown. For an agnostic and comprehensive evaluation of autoantibodies in MS, we developed and employed what we believe to be a novel autoantigen discovery technology, the Antigenome Platform. This Platform is a high-throughput assay comprising large-fragment (approximately 100 amino acids) cDNA libraries, phage display, serum antibody screening technology, and robust bioinformatics analysis pipelines. For autoantibody discovery, we assayed serum samples from CIS patients who received either placebo or treatment who were enrolled in the REFLEX clinical trial, which assessed the effects of IFN-β-1a (Rebif) clinical and MRI activity in patients with CIS. Serum autoantibodies from patients with CIS were significantly and reproducibly enriched for known and previously unreported protein targets; 166 targets were selected by over 10% of patients' sera. Further, 10 autoantibody biomarkers associated with disease activity and 17 associated with patient response to IFN-β-1a therapy. These findings indicate widespread autoantibody production in MS and provide biomarkers for continued study and prediction of disease progression.
Bacteriophage therapy for multidrug-resistant infections: current technologies and therapeutic approaches
Authors: Minyoung Kevin Kim, Gina A Suh, Grace D Cullen, Saumel Perez Rodriguez, Tejas Dharmaraj, Tony Hong Wei Chang, Zhiwei Li, Qingquan Chen, Sabrina I Green, Rob Lavigne, Jean-Paul Pirnay, Paul L Bollyky, Jessica C Sacher
Journal: Journal of Clinical Investigation (2025)

Bacteriophage (phage) therapy has emerged as a promising solution to combat the growing crisis of multidrug-resistant (MDR) infections. There are several international centers actively engaged in implementation of phage therapy, and recent case series have reported encouraging success rates in patients receiving personalized, compassionate phage therapy for difficult-to-treat infections. Nonetheless, substantial hurdles remain in the way of more widespread adoption and more consistent success. This Review offers a comprehensive overview of current phage therapy technologies and therapeutic approaches. We first delineate the common steps in phage therapy development, from phage bank establishment to clinical administration, and examine the spectrum of therapeutic approaches, from personalized to fixed phage cocktails. Using the framework of a conventional drug development pipeline, we then identify critical knowledge gaps in areas such as cocktail design, formulation, pharmacology, and clinical trial design. We conclude that, while phage therapy holds promise, a structured drug development pipeline and sustained government support are crucial for widespread adoption of phage therapy for MDR infections.
Strategies for promoting neurovascularization in bone regeneration
Authors: Xin-Ling Li, Yu-Qing Zhao, Li Miao, Yan-Xin An, Fan Wu, Jin-Yu Han, Jing-Yuan Han, Franklin R. Tay, Zhao Mu, Yang Jiao, Jing Wang
Journal: Military Medical Research (2025)

Abstract Bone tissue relies on the intricate interplay between blood vessels and nerve fibers, both are essential for many physiological and pathological processes of the skeletal system. Blood vessels provide the necessary oxygen and nutrients to nerve and bone tissues, and remove metabolic waste. Concomitantly, nerve fibers precede blood vessels during growth, promote vascularization, and influence bone cells by secreting neurotransmitters to stimulate osteogenesis. Despite the critical roles of both components, current biomaterials generally focus on enhancing intraosseous blood vessel repair, while often neglecting the contribution of nerves. Understanding the distribution and main functions of blood vessels and nerve fibers in bone is crucial for developing effective biomaterials for bone tissue engineering. This review first explores the anatomy of intraosseous blood vessels and nerve fibers, highlighting their vital roles in bone embryonic development, metabolism, and repair. It covers innovative bone regeneration strategies directed at accelerating the intrabony neurovascular system over the past 10 years. The issues covered included material properties (stiffness, surface topography, pore structures, conductivity, and piezoelectricity) and acellular biological factors [neurotrophins, peptides, ribonucleic acids (RNAs), inorganic ions, and exosomes]. Major challenges encountered by neurovascularized materials during their clinical translation have also been highlighted. Furthermore, the review discusses future research directions and potential developments aimed at producing bone repair materials that more accurately mimic the natural healing processes of bone tissue. This review will serve as a valuable reference for researchers and clinicians in developing novel neurovascularized biomaterials and accelerating their translation into clinical practice. By bridging the gap between experimental research and practical application, these advancements have the potential to transform the treatment of bone defects and significantly improve the quality of life for patients with bone-related conditions.
Lipid metabolic reprograming: the unsung hero in breast cancer progression and tumor microenvironment
Authors: Mengting Wan, Shuaikang Pan, Benjie Shan, Haizhou Diao, Hongwei Jin, Ziqi Wang, Wei Wang, Shuya Han, Wan Liu, Jiaying He, Zihan Zheng, Yueyin Pan, Xinghua Han, Jinguo Zhang
Journal: Molecular Cancer (2025)

Aberrant lipid metabolism is a well-recognized hallmark of cancer. Notably, breast cancer (BC) arises from a lipid-rich microenvironment and depends significantly on lipid metabolic reprogramming to fulfill its developmental requirements. In this review, we revisit the pivotal role of lipid metabolism in BC, underscoring its impact on the progression and tumor microenvironment. Firstly, we delineate the overall landscape of lipid metabolism in BC, highlighting its roles in tumor progression and patient prognosis. Given that lipids can also act as signaling molecules, we next describe the lipid signaling exchanges between BC cells and other cellular components in the tumor microenvironment. Additionally, we summarize the therapeutic potential of targeting lipid metabolism from the aspects of lipid metabolism processes, lipid-related transcription factors and immunotherapy in BC. Finally, we discuss the possibilities and problems associated with clinical applications of lipid‑targeted therapy in BC, and propose new research directions with advances in spatiotemporal multi-omics.
Zombie neurons in epilepsy: a burgeoning role for senescence in drug-resistant epilepsy
Authors: Gemma L Carvill
Journal: Journal of Clinical Investigation (2025)

Cellular senescence is a cell state induced by irreparable cellular damage. The hallmark of senescence is cell cycle exit, yet neurons, which are postmitotic from birth, have also been found to undergo senescence. Neuronal senescence is prevalent in aging as well as in neurodegenerative disease. However, a role for senescence in epilepsy is virtually unexplored. In this issue of the JCI, Ge and authors used resected brain tissue from individuals with drug-resistant epilepsy, a genetic knockout mouse model, and a chemoconvulsant mouse model, to demonstrate a subset of cortical pyramidal senescent neurons that likely contribute to the pathophysiology of epilepsy. These findings highlight senescence as a possible target in precision-therapy approaches for epilepsy and warrant further investigation.
Bridging the gap: insights into sensorimotor deficits in NMDA receptor antibody encephalitis
Authors: Puneet Opal, Geoffrey T Swanson
Journal: Journal of Clinical Investigation (2025)

N-methyl-d-aspartate (NMDA) receptor-mediated autoimmune encephalitis (NMDAR-AE) is the most common cause of autoimmune encephalitis, especially in children and young adults. The disorder is caused by antibodies directed against the GluN1 protein, an obligatory constituent of NMDA receptors, which are key signaling molecules in brain development, learning and memory, and executive function. The manuscript by Zhou et al. offers key insights into aberrant development of cortical pathways that may underly persistent sensorimotor deficits associated with this encephalitis in a newly generated mouse model. This study convincingly links transient exposure to a patient-derived anti-GluN1 mAb during a critical developmental period to lasting disruptions in interhemispheric connectivity through callosal projections. These findings provide insight into the impact of a prevalent autoimmune disorder on fundamental aspects of brain development and establish a model system that could be further employed to probe other aspects of NMDAR-AE pathogenesis.
Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy
Authors: Qianqian Ge, Jiachao Yang, Fei Huang, Xinyue Dai, Chao Chen, Jingxin Guo, Mi Wang, Mengyue Zhu, Yijie Shao, Yuxian Xia, Yu Zhou, Jieqiao Peng, Suixin Deng, Jiachen Shi, Yiqi Hu, Huiying Zhang, Yi Wang, Xiaoqun Wang, Xiao-Ming Li, Zhong Chen, Yousheng Shu, Jun-Ming Zhu, Jianmin Zhang, Ying Shen, Shumin Duan, Shengjin Xu, Li Shen, Jiadong Chen
Journal: Journal of Clinical Investigation (2025)

The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult to determine the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA-seq approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2, and NFKBIA, which associate with mTOR pathway, inflammatory response, and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, γ-H2AX, and β-Gal, and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of patients with drug-resistant epilepsy with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent marker expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and what we believe to be new insights into the pathophysiological mechanisms of drug-resistant epilepsy.
Basic science and translational implications of current knowledge on neuroendocrine tumors
Authors: Lynnette Fernandez-Cuesta, Nicolas Alcala, Emilie Mathian, Jules Derks, Chrissie Thirlwell, Talya Dayton, Ilaria Marinoni, Aurel Perren, Thomas Walter, Matthieu Foll
Journal: Journal of Clinical Investigation (2025)

Neuroendocrine tumors (NETs) are a diverse group of malignancies that can occur in various organs, with a notable prevalence in the lungs and gastrointestinal tract, which are the focus of this Review. Although NETs are rare in individual organs, their incidence has increased over recent decades, highlighting the urgent need for current classification systems to evolve by incorporating recent advances in the understanding of NET biology. Several omics studies have revealed molecular subtypes, which, when integrated into existing classification frameworks, may provide more clinically relevant insights for patients with NETs. This Review examines recent progress in elucidating the biology of NETs, with a particular emphasis on the tumor microenvironment and cells of origin. The existence of different cells of origin, which may contribute to distinct molecular groups, along with profiles of immune infiltration - despite being generally low - could explain the emergence of more aggressive cases and the potential for metastatic progression. Given the molecular heterogeneity of NETs and the diversity of their microenvironments and different cells of origin, there is an urgent need to develop morphomolecular classification systems. Such systems would make it possible to better characterize tumor progression, identify new therapeutic targets, and, ultimately, guide the development of personalized therapies.
2’-FL and cross-feeding bifidobacteria reshaped the gut microbiota of infants with atopic dermatitis ex vivo and prevented dermatitis in mice post-microbiota transplantation through retinol metabolism activation
Authors: Ce Qi, Zhongxia Li, Huayu Tu, Fang Sun, Wenbo Guo, Can Di, Ruikun He, Xiaolei Ze, Lintao Zhang, Ruijuan Gao, Pengyue Hu, Wenjing Yang, Kexin Li, Jiayi Liu, Xiaonan Pan, Zilu Jin, Jin Sun
Journal: Gut Microbes (2025)

2'-Fucosyllactose (2'-FL), a predominant human milk oligosaccharide, plays a crucial role in the development of the infant gut microbiota and immune system. However, the microbiota of infants with atopic dermatitis (AD) often has difficulty utilizing 2'-FL. Here, we found that strains from human milk, Bifidobacterium bifidum FN120 and Bifidobacterium longum subsp. longum FN103, utilized 2'-FL for growth by cross-feeding. Through an ex vivo continuous fermentation system, we found that 2'-FL and cross-feeding bifidobacteria synergistically enhanced the production of short-chain fatty acids (SCFAs), particularly acetate and propionate, while reshaping the gut microbiota in infants with AD. The reshaped microbiota was then transplanted into oxazolone-induced mice. We observed that AD symptoms in mice were effectively prevented, with significant changes in the ileum microbiota and increased intestinal SCFA levels. RNA sequencing analysis of Peyer's patches in the small intestine revealed activation of the retinol metabolic pathway. Nontargeted metabolomics analysis revealed a significant increase in plasma retinoate levels, which correlated markedly with AD-related markers. Collectively, our study demonstrated that supplementation with cross-feeding bifidobacteria and 2'-FL reshaped the gut microbiota, activated retinol metabolic pathways, promoted immune tolerance, and thereby prevented AD. Our findings provide novel insights into the therapeutic potential of combining prebiotics and probiotics to modulate the gut - skin axis and support immune tolerance in early life, offering a promising strategy for infantile AD management and prevention.
The spread of CTX-M-Type extended-spectrum beta-lactamases in China: epidemiology and evolutionary analyses
Authors: Keyi Yu, Zhenzhou Huang, Xiao Liu, He Gao, Xuemei Bai, Zhiwen Sun, Duochun Wang
Journal: Journal of Infection (2025)

CTX-M-type extended-spectrum beta-lactamases (ESBLs) have shown a high level of global transmission, with limited systematic understanding of their epidemic patterns in China. A comprehensive analysis covering 1974-2023 identified 133 (3.2%) blaCTX-Ms-producing strains among 4146 strains from 25 Chinese cities across 82 genera were performed. Integrating with public database strains (n=431), the study comprised 564 blaCTX-Ms-positive isolates sourced from 19 provinces (1986-2022) including 300 (53.2%) clinical and 228 (40.4%) environmental blaCTX-Ms. The most frequent sources of infection were diarrhea (44%), upper respiratory tract infection (22.2%) and urinary tract infection (14%). Phylogenetic studies indicated CTX-M-1 and CTX-M-9 emerged as the predominant subgroups. Lineages exhibited diverse mutation sites without being restricted by geographical conditions. Ka/Ks ratio distribution varied significantly among lineages (P<0.05). Lineages 1 (L1) and L2 were characterized by neutral or purifying selection, whereas L3 was mainly under purifying selection. Adaptive evolution was noted at different loci within each lineage. The influence of geographic distance on phylogeny varied distinctly across different lineages. Notably, for Lineage L3, there was a remarkably strong correlation observed, which implies that human activities exerted a more substantial influence on genetic distances compared to geography. This research provides valuable insights into the epidemiology, genotypic diversity, and evolutionary traits of blaCTX-Ms in China, supporting health risk assessment for early warning systems.
Magnetic Resonance Cholangiopancreatography with Construction of Three-dimensional Models in Children with Cystic Bile Ducts Dilatations
Authors: N. A. Sholohov, O. V. Lukovkina
Journal: Radiology - Practice (2025)

Objective . Evaluation of the possibility of magnetic resonance cholangiopancreatography with the construction of three-dimensional models in children with cystic dilation of the bile ducts. Materials and methods . 73 children with cystic dilation of the bile ducts were examined: 47 girls (64 %) and 26 boys (36 %). The age of the patients ranged from 5 days of life to 17 years 7 months. All children were examined by ultrasound and MRCP with the construction of 3D-models. Results . During the MRCP study, 43 children (58.9 %) were found to have fusiform cystic bile ducts and 30 children (41.1 %) had spherical cystic bile ducts. The variability of intrahepatic ducts in children with cystic bile ducts was assessed. It was found that in children with choledochal cyst and the presence of APBS, the risk of developing pancreatitis is 5.13 times higher than in children with normal duct fusion, the results are statistically significant (p &lt; 0.05). It was shown that computer 3D processing improves the efficiency of the method in diagnosing cystic dilation of the bile ducts in children, allowing to overcome the limitations in the form of projection superposition of anatomical structures. Thus, statistically significant differences were obtained in the construction of 3D models compared to the analysis of only MRCP images in relation to the assessment of the variability of the fusion of intrahepatic ducts (χ² = 34, p &lt; 0.001), variants of the cystic duct return (χ² = 46, p &lt; 0.001), when analyzing the type of abnormal pancreatobiliary anastomosis (χ² = 46, p &lt; 0.001). Conclusion . MRCP allows non-invasively, without radiation exposure and intravenous contrast, to obtain a complete picture of the topography of the extrahepatic bile and pancreatic ducts, which allows planning the course of surgical intervention and avoiding damage to important anatomical structures. Supplementing the standard MRCP study with the construction of 3D models improves the effectiveness of the method in diagnosing cystic dilation of the bile ducts in children, allowing to overcome limitations in the form of projection layering of anatomical structures, which allows to reduce or completely eliminate intraoperative studies.