tbuckley/cabot-search huggingface dataset:
Ultrasound-activated erythrocyte membrane-camouflaged Pt (II) layered double hydroxide enhances PD-1 inhibitor efficacy in triple-negative breast cancer through cGAS-STING pathway-mediated immunogenic cell death
Authors: Yanjie Wu, Zhiyu Zhao, Mengli Ma, Weijin Zhang, Wei Liu, Xiaochen Liang, Ting Zhao, Yi Luo, Yunjie Wang, Mengqi Li, Tingting Li, Cong Liu, Xian Luo, Shengyu Wang, Wanyun Li, Wei Zeng, Hong Wang, Wengang Li, Ting Wu, Zhihai Ke, Fanghong Luo
Journal: Theranostics (2024)

Rationale: Immunogenic cell death (ICD) offers a promising avenue for the treatment of triple-negative breast cancer (TNBC). However, optimizing immune responses remains a formidable challenge. This study presents the design of RBCm@Pt-CoNi layered double hydroxide (RmPLH), an innovative sonosensitizer for sonodynamic therapy (SDT), aimed at enhancing the efficacy of programmed cell death protein 1 (PD-1) inhibitors by inducing robust ICD responses. Methods: Pt-CoNi layered double hydroxide (LDH) nanocages were synthesized using a two-step method, followed by functionalization with red blood cell membranes to prepare RmPLH. The in vitro assessments included evaluations of cell toxicity, cellular uptake, and sonodynamic effects of RmPLH. Key mechanisms-such as oxidative stress, DNA damage, pyroptosis, cGAS/STING pathway activation, and inhibition of cellular migration and invasion-were explored under varying treatment conditions in 4T1 cells. Tumor-bearing mice were employed to evaluate tumor-targeting capabilities and the synergistic tumor-suppressive effects of RmPLH combined with PD-1 inhibitors. Comprehensive safety evaluations, including blood tests, biochemical analyses, and histopathological examinations, were also conducted. Results: The synthesized Pt-CoNi LDH exhibited a uniform rhombic dodecahedral nanocage morphology with an average particle size of approximately 231 nm. Encapsulation with red blood cell membranes conferred prolonged systemic circulation, enhanced tumor targeting, and reduced immune clearance for RmPLH. Upon ultrasound (US) stimulation, the LDH released substantial levels of reactive oxygen species (ROS) and platinum ions. The ROS effectively induced endoplasmic reticulum stress and ferroptosis, while platinum ions facilitated DNA crosslinking, triggering significant DNA damage. ROS-induced pyroptosis released inflammatory mediators and damage-associated molecular patterns (DAMPs), which activated the cGAS/STING pathway and reinforced ICD. Combining RmPLH with PD-1 inhibitors significantly enhanced therapeutic efficacy against TNBC. Furthermore, safety assessments confirmed the excellent biocompatibility and biosafety of RmPLH. Conclusion: The integration of RmPLH with PD-1 inhibitors substantially amplifies ICD, fostering robust antigen-specific T cell immunity and offering a promising therapeutic strategy for TNBC. This study represents a pioneering application of Pt (II)-based LDH nanocages in oncology, laying a foundation for future innovations in tumor immunotherapy.
Light-eye-body axis: exploring the network from retinal illumination to systemic regulation
Authors: Yi Zeng, Rong Rong, Mengling You, Peng Zhu, Jinglin Zhang, Xiaobo Xia
Journal: Theranostics (2024)

The human body is an intricate system, where diverse and complex signaling among different organs sustains physiological activities. The eye, as a primary organ for information acquisition, not only plays a crucial role in visual perception but also, as increasing evidence suggests, exerts a broad influence on the entire body through complex circuits upon receiving light signals which is called non-image-forming vision. However, the extent and mechanisms of light's impact on the body through the eyes remain insufficiently explored. There is also a dearth of comprehensive reviews elucidating the intricate interplay between light, the eye, and the systemic connections to the entire body. Herein, we propose the concept of the light-eye-body axis to systematically encapsulate the extensive non-image-forming effects of light signals received by the retina on the entire body. We reviewed the visual-neural structure basis of the light-eye-body axis, summarized the mechanism by which the eyes regulate the whole body and the current research status and challenges within the physiological and pathological processes involved in the light-eye-body axis. Future research should aim to expand the influence of the light-eye-body axis and explore its deeper mechanisms. Understanding and investigating the light-eye-body axis will contribute to improving lighting conditions to optimize health and guide the establishment of phototherapy standards in clinical practice.
A metagenome-wide study of the gut virome in chronic kidney disease
Authors: Pan Zhang, Ruochun Guo, Shiyang Ma, Hongli Jiang, Qiulong Yan, Shenghui Li, Kairuo Wang, Jiang Deng, Yanli Zhang, Yue Zhang, Guangyang Wang, Lei Chen, Lu Li, Xiaoyan Guo, Gang Zhao, Longbao Yang, Yan Wang, Jian Kang, Shanshan Sha, Shao Fan, Lin Cheng, Jinxin Meng, Hailong Yu, Fenrong Chen, Danni He, Jinhai Wang, Shuxin Liu, Haitao Shi
Journal: Theranostics (2024)

Rationale: Chronic kidney disease (CKD) is a progressively debilitating condition leading to kidney dysfunction and severe complications. While dysbiosis of the gut bacteriome has been linked to CKD, the alteration in the gut viral community and its role in CKD remain poorly understood. Methods: Here, we characterize the gut virome in CKD using metagenome-wide analyses of faecal samples from 425 patients and 290 healthy individuals. Results: CKD is associated with a remarkable shift in the gut viral profile that occurs regardless of host properties, disease stage, and underlying diseases. We identify 4,649 differentially abundant viral operational taxonomic units (vOTUs) and reveal that some CKD-enriched viruses are closely related to gut bacterial taxa such as Bacteroides, [Ruminococcus], Erysipelatoclostridium, and Enterocloster spp. In contrast, CKD-depleted viruses include more crAss-like viruses and often target Faecalibacterium, Ruminococcus, and Prevotella species. Functional annotation of the vOTUs reveals numerous viral functional signatures associated with CKD, notably a marked reduction in nicotinamide adenine dinucleotide (NAD+) synthesis capacity within the CKD-associated virome. Furthermore, most CKD viral signatures are reproducible in the gut viromes of diabetic kidney disease and several other common diseases, highlighting the considerable universality of disease-associated viromes. Conclusions: This research provides comprehensive resources and novel insights into the CKD-associated gut virome, offering valuable guidance for future mechanistic and therapeutic investigations.
Optimized circular RNA vaccines for superior cancer immunotherapy
Authors: Hongwu Yu, Yifan Wen, Wenqian Yu, Liang Lu, Yu Yang, Chengye Liu, Zhixiang Hu, Zhuting Fang, Shenglin Huang
Journal: Theranostics (2024)

Rationale: Circular RNA (circRNA) has gained attention as a promising platform for mRNA vaccines due to its stability, sustained protein expression, and intrinsic immunostimulatory properties. This study aimed to design and optimize a circRNA cancer vaccine platform by screening for efficient internal ribosome entry sites (IRES) and enhancing circRNA translation efficiency for improved cancer immunotherapy. Methods: We screened 29 IRES elements to identify the most efficient one for immune cell translation, ultimately discovering the Enterovirus A (EV-A) IRES. Using SHAPE-MaP technology, we analyzed the secondary structure of circRNA and introduced targeted mutations and deletions to optimize translation efficiency. Additionally, we investigated the regulatory roles of spacer sequences and microRNA recognition sites in circRNA design and examined the mechanisms behind IRES-mediated translation initiation. Results: The EV-A IRES was identified as the most efficient for immune cell translation. Structural modifications and optimization of spacer sequences enhanced the translation efficiency of circRNA. Comparative studies demonstrated that circRNA vaccines induced stronger T cell immune responses and exhibited superior tumor prevention and therapeutic efficacy compared to traditional linear mRNA vaccines. Conclusion: The optimized tumor antigen circRNA vaccine platform offers a stable, efficient alternative to conventional mRNA vaccines for cancer immunotherapy, with enhanced immune responses and improved therapeutic outcomes. This work lays the foundation for developing circRNA-based vaccines as a novel strategy for cancer treatment.
Cardiomyocyte S1PR1 promotes cardiac regeneration via AKT/mTORC1 signaling pathway
Authors: Xiuxiang Liu, Jinnan Yue, Caixia Zhou, Yunhao Duan, Xiaoli Chen, Jie Liu, Shougang Zhuang, Yu Luo, Jinjin Wu, Yuzhen Zhang, Lin Zhang
Journal: Theranostics (2024)

Aims: Lower vertebrates and some neonatal mammals are known to possess the ability to regenerate cardiomyocyte and fully recover after heart injuries within a limited period. Understanding the molecular mechanisms of heart regeneration and exploring new ways to enhance cardiac regeneration hold significant promise for therapeutic intervention of heart failure. Sphingosine 1-phospahte receptor 1 (S1PR1) is highly expressed in cardiomyocytes and plays a crucial role in heart development and pathological cardiac remodeling. However, the effect of cardiomyocyte-expressing S1PR1 on heart regeneration has not yet been elucidated. This study aims to investigate the role of cardiomyocyte S1PR1 in cardiac regeneration following heart injuries. Methods and Results: We generated cardiomyocyte (CM)-specific S1pr1 knock-out mice and demonstrated that CM-specific S1pr1 loss-of-function severely reduced cardiomyocyte proliferation and inhibited heart regeneration following apex resection in neonatal mice. Conversely, AAV9-mediated CM-specific S1pr1 gain-of-function significantly enhanced cardiac regeneration. We identified that S1PR1 activated the AKT/mTORC1/CYCLIN D1 and BCL2 signaling pathways to promote cardiomyocyte proliferation and inhibit apoptosis. Moreover, CM-targeted gene delivery system via AAV9 to overexpress S1PR1 significantly increased cardiomyocyte proliferation and improved cardiac functions following myocardial infarction in adult mice, suggesting a potential method to enhance cardiac regeneration and improve cardiac function in the injured heart. Conclusions: This study demonstrates that CM-S1PR1 plays an essential role in cardiomyocyte proliferation and heart regeneration. This research provides a potential strategy by CM-targeted S1PR1 overexpression as a new therapeutic intervention for heart failure.
Shear stress unveils patient-specific transcriptional signatures in PAH: Towards personalized molecular diagnostics
Authors: Corey Wittig, Jakob M König, Xiaoke Pan, Jurjan Aman, Harm-Jan Bogaard, Paul B Yu, Wolfgang M Kuebler, Katharina Baum, Robert Szulcek
Journal: Theranostics (2024)

Rationale: Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by increased pulmonary blood pressures and regional inhomogeneities in flows, with diagnostic and treatment challenges arising from diverse underlying pathogenic mechanisms. Conventional in vitro models often obscure the mechanistic nuances of PAH by failing to replicate the dynamic mechanical environment of the diseased lung, limiting the identification of specific molecular patterns. To address this, we employed an in vitro shear stress model simulating physiological or pathological conditions to explore the transcriptional heterogeneity of human pulmonary microvascular endothelial cells (hPMECs) from PAH patients and healthy controls within their respective biomechanical context. Methods & Results: hPMECs from PAH patients and controls were exposed to static, low shear stress (LSS), and high shear stress (HSS) conditions, followed by bulk RNA-sequencing. While increasing shear stress resulted in a greater number of differentially expressed genes, traditional grouped analysis showed minimal overall transcriptional differences. Further, pathway enrichment analysis indicated common shear-induced responses in both groups, suggesting that standard analysis methods may mask meaningful disease-specific changes. Crucially, detailed dimensionality reduction analyses revealed pronounced inter-patient variability among PAH donors in response to increasing shear stress, facilitating the identification of 398 genes driving this transcriptional heterogeneity. Unsupervised clustering of these high-variability genes enabled the sub-classification of patients based on their unique transcriptomic profiles, each linked to specific combinations of PAH associated pathogenic pathways such as mesenchymal transition, inflammation, metabolism, extracellular matrix remodeling, and cell cycle/DNA damage signaling. Importantly, re-analysis of published peripheral blood mononuclear cell (PBMC) omics data from PAH patients confirmed the clinical feasibility to utilize these high-variability genes as a non-invasive, accessible approach for molecular patient stratification. Conclusion: Our study uncovers patient-specific transcriptomic patterns in PAH, providing a novel molecular sub-classification strategy. These findings represent a significant step toward personalized molecular diagnostics in PAH and eventual therapeutic interventions for clinically well-defined PAH patients, with potential applications in clinically accessible cell populations such as PBMCs.
Macrophage-based pathogenesis and theranostics of vulnerable plaques
Authors: Fei Fang, Erxiang Wang, Mengjia Fang, Hongyan Yue, Hanqiao Yang, Xiaoheng Liu
Journal: Theranostics (2024)

Vulnerable plaques, which are high-risk features of atherosclerosis, constitute critical elements in the disease's progression due to their formation and rupture. Macrophages and macrophage-derived foam cells are pivotal in inducing vulnerability within atherosclerotic plaques. Thus, understanding macrophage contributions to vulnerable plaques is essential for advancing the comprehension of atherosclerosis and devising novel therapeutic and diagnostic strategies. This review provides an overview of the pathological characteristics of vulnerable plaques, emphasizes macrophages' critical role, and discusses advanced strategies for their diagnosis and treatment. It aims to present a comprehensive macrophage-centered perspective for addressing vulnerable plaques in atherosclerosis.
KCNN4 as a Genomic Determinant of Cytosolic Delivery by the Attenuated Cationic Lytic Peptide L17E
Authors: Masashi Kuriyama, Hisaaki Hirose, Yoshimasa Kawaguchi, Junya Michibata, Masashi Maekawa, Shiroh Futaki
Journal: Molecular Therapy (2025)
Hyperactive delta isoform of PI3Kinase enables long distance regeneration of adult rat corticospinal tract
Authors: Karova Kristyna, Polcanova Zuzana, Knight Lydia, Suchankova Stepanka, Nieuwenhuis Bart, Holota Radovan, Herynek Vit, Machova Urdzikova Lucia, Turecek Rostislav, Kwok C Jessica, Joelle van den Herik, Verhaagen Joost, Eva Richard, Fawcett W James, Jendelova Pavla
Journal: Molecular Therapy (2025)

Neurons in the central nervous system (CNS) lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonises PI3K signalling by hydrolysing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3. This study explores if increased PIP3 generation can promote long-distance regeneration in adults. We used a hyperactive PI3K, PI3Kδ (PIK3CD), to boost PIP3 levels in mature cortical neurons and assessed CST regeneration after SCI. Adult rats received AAV1-PIK3CD and AAV1-eGFP, or AAV1-eGFP alone, in the sensorimotor cortex concurrent with a C4 dorsal SCI. Transduced neurons showed increased pS6 levels, indicating elevated PI3K/Akt/mTOR signalling. CST regeneration, confirmed with retrograde tracing, was evaluated up to 16 weeks post-injury. At 12 weeks, ∼100 axons were present at lesion sites, doubling to 200 by 16 weeks, with regeneration indices of 0.1 and 0.2, respectively. Behavioural tests showed significant improvements in paw reaching, grip strength, and ladder rung walking in PIK3CD-treated rats, corroborated by electrophysiological recordings of cord dorsum potentials and distal flexor muscles EMG. Thus, PI3Kδ upregulation in adult cortical neurons enhances axonal regeneration and functional recovery post-SCI.
Abstract 9149: Mechanism of Thyroid-Hormone-Deficiency-Caused Cardiac Injury in a Rat Model: Effects of Left Ventricle and Myocyte Functional Performance, [Ca2+]i Transient Response and Beta-Adrenergic Modulation
Authors: Qun Shao, Heng-Jie Cheng, Michael F Callahan, Steven H Wong, Deborah J Wesley, Wei-Min Li, Che Ping Cheng
Journal: Circulation (2011)

Background. Thyroid hormone deficiency is associated in some patients with the development of congestive cardiomyopathy. However, the mechanism is unclear. Although hemodynamic abnormalities have b...
Glutamic-pyruvic transaminase 1 deficiency–mediated metabolic reprogramming facilitates colorectal adenoma-carcinoma progression
Authors: Li Xiong, Xin Yang, Huashan Liu, Xianrui Wu, Tanxing Cai, Ming Yuan, Liang Huang, Chi Zhou, Xiaobin Zheng, Wenxin Li, Ziwei Zeng, Shujuan Li, Ping Lan, Liang Kang, Zhenxing Liang
Journal: Science Translational Medicine (2025)

The tumorigenesis of colorectal cancer (CRC) often follows the normal-adenoma-carcinoma (N-A-C) sequence. However, the molecular mechanisms underlying colorectal adenoma carcinogenesis remain largely unknown. Here, we analyzed transcriptomic profile changes in normal, advanced adenoma, and carcinoma tissues from patients with CRC, revealing that glutamic-pyruvic transaminase 1 ( GPT1 ) in colorectal tissues was down-regulated during the N-A-C process and correlated with poor CRC prognosis. Mechanistically, GPT1 was transcriptionally activated by Krüppel-like factor 4 (KLF4). GPT1 reprogrammed metabolism and suppressed CRC tumorigenesis in cells and mouse models not only through enzyme-dependent α-ketoglutarate (α-KG) production and WNT signaling inhibition but also through enzyme-independent disruption of the folate cycle through binding with methylenetetrahydrofolate dehydrogenase 1–like (MTHFD1L). Furthermore, we identified poliumoside as a GPT1 activator that restrained CRC progression in cells, patient-derived CRC organoids, and patient-derived xenograft (PDX) models of CRC. Our study uncovers a role for GPT1 in CRC tumorigenesis and shows that poliumoside is a potential drug for the prevention and treatment of CRC.
G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic α cells
Authors: Varun Bahl, Reut Rifkind, Eric Waite, Zenab Hamdan, Catherine Lee May, Elisabetta Manduchi, Benjamin F. Voight, Michelle Y. Y. Lee, Mark Tigue, Nicholas Manuto, Benjamin Glaser, Dana Avrahami, Klaus H. Kaestner
Journal: Science Translational Medicine (2025)

Elevated glucagon concentrations have been reported in patients with type 2 diabetes (T2D). A critical role for α cell–intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the glucose-6-phosphatase catalytic subunit 2 ( G6PC2 ) locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c. Here, we found that trait-associated variants in the G6PC2 promoter are located in open chromatin not just in β but also in α cells and documented allele-specific G6PC2 expression of linked variants in human α cells. Using α cell–specific gene ablation of G6pc2 in mice, we showed that this gene plays a critical role in controlling glucose suppression of amino acid–stimulated glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology, findings that we confirmed in primary human α cells. Collectively, our data demonstrate that G6PC2 affects glycemic control via its action in α cells and possibly suggest that G6PC2 inhibitors might help control blood glucose through a bihormonal mechanism.
An inflammatory state defines a high-risk T-lineage acute lymphoblastic leukemia subgroup
Authors: Mark Gower, Ximing Li, Alicia G. Aguilar-Navarro, Brian Lin, Minerva Fernandez, Gibran Edun, Mursal Nader, Vincent Rondeau, Andrea Arruda, Anne Tierens, Anna Eames Seffernick, Petri Pölönen, Juliette Durocher, Elvin Wagenblast, Lin Yang, Ho Seok Lee, Charles G. Mullighan, David Teachey, Marissa Rashkovan, Cedric S. Tremblay, Daniel Herranz, Tomer Itkin, Sanam Loghavi, John E. Dick, Gregory Schwartz, Maria Agustina Perusini, Hassan Sibai, Johann Hitzler, Tanja A. Gruber, Mark Minden, Courtney L. Jones, Igor Dolgalev, Soheil Jahangiri, Anastasia N. Tikhonova
Journal: Science Translational Medicine (2025)

T-lineage acute lymphoblastic leukemia (ALL) is an aggressive cancer comprising diverse subtypes that are challenging to stratify using conventional immunophenotyping. To gain insights into subset-specific therapeutic vulnerabilities, we performed an integrative multiomics analysis of bone marrow samples from newly diagnosed T cell ALL, early T cell precursor ALL, and T/myeloid mixed phenotype acute leukemia. Leveraging cellular indexing of transcriptomes and epitopes in conjunction with T cell receptor sequencing, we identified a subset of patient samples characterized by activation of inflammatory and stem gene programs. These inflammatory T-lineage samples exhibited distinct biological features compared with other T-lineage ALL samples, including the production of proinflammatory cytokines, prevalence of mutations affecting cytokine signaling and chromatin remodeling, an altered immune microenvironment, and poor treatment responses. Moreover, we found that, although inflammatory T-lineage ALL samples were less sensitive to dexamethasone, they exhibited unique sensitivity to a BCL-2 inhibitor, venetoclax. To facilitate classification of patients with T-lineage ALL, we developed a computational inflammatory gene signature scoring system, which stratified patients and was associated with disease prognosis in three additional patient cohorts. By identifying a high-risk T-lineage ALL subtype on the basis of an inflammatory score, our study provides a framework for targeted therapeutic approaches for these challenging-to-treat cancers.