J Transl Med [JOURNAL]
Sun
200 papers
AI in esophageal cancer: advances, barriers to clinical translation, and perspectives for digital health.
Yang Y, Jia X, Wang X … +5 more , Cao P, Zhu J, Wang C, Yang Z, Wen Q
J Transl Med · 2026 Jun · PMID 42243967 · Full text
BACKGROUND: Esophageal cancer (EC) remains one of the leading causes of cancer-related mortality worldwide. Accurate staging, treatment planning, and prognostic assessment are essential for improving clinical management...
BACKGROUND: Esophageal cancer (EC) remains one of the leading causes of cancer-related mortality worldwide. Accurate staging, treatment planning, and prognostic assessment are essential for improving clinical management and patient outcomes. In recent years, artificial intelligence (AI) approaches integrating clinicopathological, imaging, and genomic data have shown considerable potential in these areas. MAIN BODY: Over the past two years, research in this field has advanced rapidly, supported by the growing availability of large datasets and increasing adoption of multicenter external validation. Recent studies suggest that AI can improve real-time diagnosis and enhance the prediction of treatment response in patients with EC. CONCLUSIONS: This review summarizes recent advances in AI applications for esophageal cancer, discusses current challenges, and highlights future directions for research and clinical implementation.
MOTS-c: How a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases.
Amado CA, Agüero J, García-Unzueta M … +3 more , Berja A, Lavín BA, Martín-Audera P
J Transl Med · 2026 Jun · PMID 42243958 · Full text
BACKGROUND: MOTS-c is a mitochondrial-derived microprotein (mitokine) encoded within the 12 S rRNA gene that exerts intracrine, paracrine, and endocrine effects across multiple tissues. Although initially described as a...
BACKGROUND: MOTS-c is a mitochondrial-derived microprotein (mitokine) encoded within the 12 S rRNA gene that exerts intracrine, paracrine, and endocrine effects across multiple tissues. Although initially described as a regulator of metabolic homeostasis, growing evidence indicates that MOTS-c also modulates oxidative and toxic stress, inflammation, autophagy, cell death (apoptosis, ferroptosis, pyroptosis, among others), mitochondrial dysfunction, and immune responses-key mechanisms involved in acute and chronic respiratory diseases. MAIN BODY: Available experimental and clinical studies suggest that circulating MOTS-c levels are reduced in different forms of acute respiratory distress, while exogenous administration attenuates lung injury in preclinical models. Remote ischemic preconditioning appears to exert part of its protective effects through MOTS-c release. In contrast, chronic respiratory diseases such as chronic obstructive pulmonary disease, obstructive sleep apnea, and asthma are characterized by decreased MOTS-c concentrations, reflecting severe mitochondrial dysfunction and reduced cytoprotective capacity. Preliminary observations suggest increased MOTS-c levels in lung cancer, potentially related to NRF2-mediated antioxidant responses, although these findings require further validation. CONCLUSIONS: Current evidence positions MOTS-c as a promising biomarker and potential therapeutic candidate in respiratory medicine. Well-designed translational and multicenter clinical studies are needed to determine whether modulation or supplementation of MOTS-c can influence disease progression and clinical outcomes in inflammatory lung diseases.
Personalized therapeutic platform: organoid models for hepatic malignancies.
Zhou Z, Ma T, Tang N … +8 more , Zheng H, Wang L, Liu S, Lu X, Liu B, Zhu X, Qi L, Shen J
J Transl Med · 2026 Jun · PMID 42243923 · Full text
BACKGROUND: Patient responses to therapeutic agents in hepatic malignancies are highly variable, yet the field lacks robust in vitro models for predicting individual drug responsiveness. Patient-derived organoids (PDOs)...
BACKGROUND: Patient responses to therapeutic agents in hepatic malignancies are highly variable, yet the field lacks robust in vitro models for predicting individual drug responsiveness. Patient-derived organoids (PDOs) that faithfully recapitulate the biological characteristics of parental tumors offer a promising platform for personalized drug testing. METHODS: We established PDOs from fresh tumor tissues of 29 patients with hepatic malignancies, achieving a success rate of 79.31% (23/29). Histological staining confirmed high morphological and phenotypic consistency between PDOs and original tumor tissues. Drug sensitivity testing was performed using a panel of standard-of-care therapeutics, and model stability was assessed through serial passaging and cryopreservation. Clinical correlation was evaluated by comparing PDO-predicted sensitivity with observed treatment responses in 16 patients followed prospectively. RESULTS: The established PDOs maintained structural and functional fidelity to parental tumors and demonstrated reproducible drug sensitivity profiles across serial passaging and cryopreservation. In a prospective clinical validation, patients whose treatment matched PDO-predicted sensitive agents showed significantly improved objective response rate (ORR: 36.36%, 95% CI: 10.93-69.21) and disease control rate (DCR: 90.91%, 95% CI: 58.72-99.77), compared to those receiving PDO-predicted resistant therapies (ORR: 0%, DCR: 20%). CONCLUSION: This study establishes a robust and clinically validated PDO platform for hepatic malignancies that accurately predicts patient-specific drug responses. The model demonstrates high reproducibility and stability, supporting its utility for guiding personalized therapy selection and improving outcomes in patients with liver cancer.
Unraveling the regulatory role of intercellular communication in intestinal immune cells mediated by H₂ in sepsis recovery through single-cell RNA sequencing.
Luo Y, Zhao Y, Liu J … +13 more , Liu B, Zhang Z, Jiang Y, Zhang Y, Wang XT, Li S, Zhao N, Li X, Xiong D, Zhao X, Wang S, Zhang W, Lang B
J Transl Med · 2026 Jun · PMID 42237393 · Full text
BACKGROUND: Sepsis is a life-threatening condition with dysregulated immune responses, where the intestinal immune system plays a pivotal role. While hydrogen gas (H₂) has shown therapeutic potential, its precise impact...
BACKGROUND: Sepsis is a life-threatening condition with dysregulated immune responses, where the intestinal immune system plays a pivotal role. While hydrogen gas (H₂) has shown therapeutic potential, its precise impact on intestinal immune cell communication remains elusive. METHODS: We employed a murine model of sepsis induced by cecal ligation and puncture (CLP). Mice were divided into control, sepsis, and H₂-treated sepsis groups. A comprehensive approach combining single-cell RNA sequencing (scRNA-seq) of intestinal tissues with histological, biochemical, and functional analyses was used to dissect the immune landscape and H₂'s effects. RESULTS: H₂ treatment significantly ameliorated intestinal injury, reduced epithelial barrier leakage (evidenced by decreased serum DAO and FITC-dextran), and suppressed systemic inflammation. scRNA-seq revealed that H₂ restored sepsis-induced perturbations in both B and T cell subsets. It normalized the aberrant expansion of non-functional B cells and rectified T cell differentiation trajectories, promoting a functional balance. Mechanistically, H₂ modulated key genes (e.g., Stat3, Ccl5, Foxo1) and critical pathways including oxidative phosphorylation, B cell receptor signaling, and Foxo signaling. Furthermore, cell-cell communication analysis demonstrated that H₂ robustly enhanced the weakened interactions between T cells, B cells, and epithelial cells, particularly via the CCL signaling network. CONCLUSION: Our study elucidates that H₂ therapy alleviates sepsis by systemically reprogramming the intestinal immune micro environment at the single-cell level. This is achieved by normalizing immune cell subsets, rewiring intercellular communication, and ultimately rebalancing the inflammatory response, positioning H₂ as a promising immunomodulatory agent for sepsis.
Multi-omics biomarkers in endometrial receptivity: from mechanisms to clinical translation.
Chen X, Feng P, Zhang J … +6 more , Wu J, Xie Z, Huang J, Yang X, He F, Chen R
J Transl Med · 2026 Jun · PMID 42237386 · Full text
BACKGROUND: Endometrial receptivity (ER) serves as a critical determinant for successful embryo implantation, yet its molecular complexity and limited clinical assessment methods pose significant challenges. Despite adva...
BACKGROUND: Endometrial receptivity (ER) serves as a critical determinant for successful embryo implantation, yet its molecular complexity and limited clinical assessment methods pose significant challenges. Despite advancements in assisted reproductive technology (ART), recurrent implantation failure (RIF) linked to ER abnormalities persists, creating a need for precise, non-invasive diagnostics. MAIN BODY: This review outlines ER research, from the biology of the window of implantation (WOI) to the roles of immune components and the microbiome in shaping the receptive microenvironment. Multi-omics integration reveals regulatory networks across transcriptomic, epigenomic, proteomic, and metabolomic levels, with uterine fluid biomarkers emerging as promising non-invasive candidates. The analysis further covers how chronic endometritis (CE), adenomyosis, and polycystic ovary syndrome (PCOS) impair ER: through mechanisms including inflammatory imbalance, microbial dysbiosis, abnormal extracellular matrix remodeling, and hormonal dysregulation. Commercial ER tests face limitations, including insufficient evidence and inconsistent results, which undermine their clinical reliability. CONCLUSIONS: A significant translational gap remains between biomarker discovery and clinical application. Current challenges involve technical standardization and data integration, and poor model generalizability. Future progress requires combining multi-omics with artificial intelligence (AI) to establish standardized clinical pathways, advancing ER assessment into precision medicine, and improving global infertility management.
Proteomics in bone malignancies: from bulk profiling to single-cell and ultra-low-input technologies.
Chen J, Luo J, Ni N … +9 more , Zhang J, Jiang L, Wu H, Wen S, Hu N, Li J, Deng G, Song S, Shi X
J Transl Med · 2026 Jun · PMID 42237373 · Full text
BACKGROUND: Bone malignancies, particularly high-grade primary bone sarcomas, remain clinically challenging due to early dissemination, marked heterogeneity, and limited progress in systemic therapies for metastatic or r...
BACKGROUND: Bone malignancies, particularly high-grade primary bone sarcomas, remain clinically challenging due to early dissemination, marked heterogeneity, and limited progress in systemic therapies for metastatic or relapsed disease. While genomics and transcriptomics have clarified structural complexity and transcriptional programs, they provide only an indirect view of the functional machinery that ultimately drives invasion, immune escape, and therapy resistance. Proteomics and phosphoproteomics offer a complementary and often non-redundant layer by reporting protein abundance, pathway activity states, and actionable targets at the execution level. However, the strength of proteomics evidence is currently uneven across bone malignancy entities, with osteosarcoma providing the most mature cohort-scale multi-omics context, while emerging cohort-scale proteomics is increasingly available for selected entities such as Ewing sarcoma. MAIN BODY: In this Review, we synthesize recent advances in mass spectrometry-based proteomics for bone malignancies, using osteosarcoma as the primary exemplar where cohort-scale proteomics / phosphoproteomics-integrated studies are most mature, while selectively incorporating evidence from other bone tumors and skeletal metastasis contexts. To address evidence heterogeneity explicitly, we highlight where conclusions are supported by cohort-scale tumor proteomics/proteogenomics versus where evidence remains exploratory, model-driven, or cross-entity extrapolations). We summarize key results from bulk tissue proteomics, circulating proteomics, extracellular vesicle (EV) and secretome profiling, and highlight how these data have revealed recurrent biological axes including extracellular matrix remodeling and cell-matrix signaling, metabolic rewiring and stress-response programs, and immune/stromal contexture. We further discuss how multi-omics integration refines molecular subtyping, links bulk signatures to functional dependencies, and supports biomarker prioritization with translational intent (e.g., secretome-informed circulating candidates). We additionally provide a practical comparison of proteomics workflows (label-free DDA/DIA, isobaric labeling, phosphoproteomics, top-down, and low-input/single-cell methods) and summarize key barriers to clinical implementation (pre-analytics, standardization, QC governance, and assay/regulatory considerations). CONCLUSIONS: Finally, we outline emerging single-cell and ultra-low-input proteomics technologies and propose a staged roadmap for their implementation in bone tumor research, emphasizing feasibility atlases, integrated multi-omics cohorts, and translation into targeted assays and clinically deployable risk models. Collectively, available evidence suggests that proteomics may become an increasingly important pillar for precision medicine in bone malignancies by bridging molecular alterations to actionable functional states and cellular mechanisms. Real-world translation will require fit-for-purpose study designs, harmonized SOPs and multicenter benchmarking, and disciplined down-selection of discovery signatures into validated targeted assays that demonstrably add value beyond existing clinical predictors.
Integrated isothermal shift assay and multi-omics identify melittin as a novel EGFR-targeting peptide to suppress NSCLC.
Zhong C, Gong J, Wei L … +4 more , Xie RF, Shi P, Yao H, Huang J
J Transl Med · 2026 Jun · PMID 42237319 · Full text
BACKGROUND: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, highlighting the urgent need for novel therapeutic agents. Melittin (MEL), a bioactive peptide, exhibits potent antitumo...
BACKGROUND: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, highlighting the urgent need for novel therapeutic agents. Melittin (MEL), a bioactive peptide, exhibits potent antitumor activity; however, its clinical translation is limited by an incomplete understanding of its molecular mechanism. Furthermore, the development of peptide-based therapeutics is often constrained by the lack of systematic approaches to identify their specific cellular targets. METHODS: To address these challenges, we established a multi-dimensional framework integrating biophysical validation with omics analysis. We evaluated the specific anti-NSCLC efficacy of MEL in vitro and in a PC9 xenograft mouse model. The direct molecular target of MEL was deconvoluted using a combination of isothermal shift assay (iTSA), cellular thermal shift assay (CETSA), and bio-layer interferometry (BLI), supported by AlphaFold3-based structural modeling. Mechanistic insights were obtained through quantitative proteomic and phosphoproteomic profiling of tumor tissues, followed by validation using shRNA-mediated gene knockdown. RESULTS: MEL demonstrated selective cytotoxicity against NSCLC cells and suppressed tumor growth in vivo, with minimal toxicity toward normal human bronchial epithelial cells. Isothermal shift assay and CETSA revealed that MEL treatment significantly enhanced the thermal stability of epidermal growth factor receptor (EGFR), indicating direct target engagement. This interaction was further confirmed by BLI, which showed high binding affinity (KD = 18.6 nM), and structural modeling predicted a specific interaction interface. Proteomic and phosphoproteomic analyses indicated that MEL binding inhibited EGFR phosphorylation, thereby attenuating the downstream ERK and STAT3 signaling cascades and inducing autophagy-dependent apoptosis. Importantly, the antitumor effects of MEL were significantly attenuated in EGFR-knockdown cells, confirming its dependency on this target. CONCLUSIONS: This study identifies EGFR as a direct molecular target of MEL in NSCLC, supporting the potential of MEL as a novel peptide-based EGFR inhibitor. Furthermore, our integrated biophysical and omics strategy provides a valuable methodological reference for systematic peptide target identification, thereby facilitating clinical translation.
Biomimetic nanoplatform M-MPDA@CeO2 coated with macrophage membrane in acute lung injury: characterization and function evaluation.
Luo Y, Wei Y, Wei F … +7 more , Guo L, Xie G, Zhuoyi L, Tang X, Chen H, Zhang J, Li Z
J Transl Med · 2026 Jun · PMID 42237311 · Full text
The pathogenesis of acute lung injury (ALI) is characterized by a dysregulated hyperinflammatory cascade initiated by activated pulmonary macrophages. Conventional nanoparticles exhibit limited therapeutic efficacy in AL...
The pathogenesis of acute lung injury (ALI) is characterized by a dysregulated hyperinflammatory cascade initiated by activated pulmonary macrophages. Conventional nanoparticles exhibit limited therapeutic efficacy in ALI due to their insufficient penetration across the pulmonary mucus barrier and inability to inhibit the exacerbated inflammatory cascade within the pathogenic microenvironment. To address these limitations, this study developed a novel macrophage membrane-biomimetic nano-delivery system designed to enhance biocompatibility, achieve targeted delivery to inflammatory sites, and exert synergistic antioxidant effects. The nanocomposite was constructed by loading cerium dioxide (CeO) nanoparticles onto mesoporous polydopamine (MPDA) and further functionalizing the surface with macrophage membranes through engineering strategies, yielding the M-MPDA@CeO formulation. The physicochemical properties of M-MPDA@CeO was systematically characterized, and its function in reactive oxygen species (ROS) scavenging, antioxidation, macrophage polarization was evaluated in vitro. Using an LPS-induced ALI mouse model, the therapeutic potential of M-MPDA@CeO was assessed in terms of anti-inflammatory and oxidative activities. Results demonstrated that the MPDA@CeO nanocomposite effectively scavenges ROS, alleviates LPS-induced oxidative damage, promotes M2 macrophage polarization, and selectively accumulates at inflammatory sites in ALI. This biomimetic nanoparticle drug delivery system offers a promising strategy for improving ALI treatment, with potential implications for both preclinical research and clinical translation.
Breaking the immune barrier: construction of cartilaginous organoids using alpha-1,3-galactosyltransferase-deficient pig cartilage-derived particles.
Jiang H, Wang S, Zhou Z … +15 more , Chen J, Huang C, Liu W, Jia Z, Wu J, Ye J, Xiong Y, Qian T, Wu Y, Guan Y, Huang W, He R, Ma C, Peng J, Wang A
J Transl Med · 2026 Jun · PMID 42237310 · Full text
BACKGROUND: Articular cartilage injuries exhibit limited self-repair capacity due to avascularity and other intrinsic properties, leading to high disability rates and posing clinical challenges. In recent years, cartilag...
BACKGROUND: Articular cartilage injuries exhibit limited self-repair capacity due to avascularity and other intrinsic properties, leading to high disability rates and posing clinical challenges. In recent years, cartilaginous organoids (CORGs) have emerged as a promising tissue engineering strategy, offering new hope for cartilage regeneration and repair. However, biomaterials used in constructing CORGs still face challenges such as immunogenicity and biocompatibility during clinical translation. In particular, xenogeneic biomaterials, which contain natural antigens like the α-1,3-galactose (α-Gal) epitope, are prone to trigger severe host immune rejection. Gene editing technology, especially knocking out the gene encoding α-1,3-galactosyltransferase (GGTA1), holds promise for producing low-immunogenicity donor animals, such as α-Gal knockout pigs (α-Gal KO pigs). MAIN BODY: In this study, through in vitro and in vivo experiments, a humanized mouse subcutaneous implantation model was established to verify the low immunogenicity of cartilage tissues from α-Gal KO pigs. Subsequently, cartilage-derived particles (CDPs) were prepared from α-Gal KO pig cartilage and further used to construct CORGs. Finally, the ability of these CORGs to form new cartilaginous tissue ectopically was validated in a nude mouse subcutaneous model. CONCLUSIONS: This study explores the low immunogenicity of gene-edited porcine cartilage tissue and constructs a novel xenogeneic dECM-based cartilage organoid with ectopic chondrogenic capability. This approach is expected to overcome immune rejection barriers and pave a novel strategic avenue for the clinical translation of cartilage organoids.
Decomposing the genetic risk of autism spectrum disorder into discrete molecular subtypes underlie clinical heterogeneity based on transcriptome profile.
Luo L, Gao X, Pang T … +5 more , Pang K, Wang T, Guo H, Yang L, Chang S
J Transl Med · 2026 Jun · PMID 42237307 · Full text
BACKGROUND: Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental condition with a complex genetic architecture. While over a thousand risk genes have been cataloged, a fundamental challenge remains...
BACKGROUND: Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental condition with a complex genetic architecture. While over a thousand risk genes have been cataloged, a fundamental challenge remains how this vast genetic landscape translates into diverse clinical manifestations. To address this, we propose a "many-to-few" framework, shifting from traditional "many-to-one" convergence model toward an intrinsic organizational architecture where disparate ASD risk genes funnel into discrete molecular dimensions. METHODS: By leveraging similarity network fusion (SNF) to integrate bulk and single-nucleus RNA sequencing data, we decomposed the 311 ASD reliable risk genes into three stable, spatiotemporally distinct molecular subtypes. These subtypes represent coordinated expression programs that integrate functionally diverse genes, such as those involved in synaptic signaling, mRNA stabilization, and histone modification. Mapping de novo variants from the SPARK cohort onto these subtypes enabled stratification of probands into three genetically defined subgroups (S1-S3) with divergent clinical profiles. RESULTS: Transcriptomic decomposition partitioned the 311 reliable risk genes into three stable molecular subtypes, Synaptic Signaling (C1), mRNA Stabilization (C2), and Histone Modification (C3), exhibiting divergent spatiotemporal trajectories and cell-type-specific enrichment. Patient subgroups stratified based on these molecular subtypes displayed significant differences in adaptive functioning, core symptoms, and psychiatric comorbidities, while a reference group (S4) lacking de novo variants of these highly reliable ASD risk genes exhibited the most preserved functions. Furthermore, diverging rare and common genetic liability profiles across subgroups, particularly between S1 and S3, provide empirical support for a molecular subtype-based liability threshold model. CONCLUSIONS: Our study establishes a biologically informed framework that links intrinsic molecular subtypes to multidimensional phenotypic constellation, advancing mechanistic insight and offering translational potential for precision stratification and intervention.
Inverse relationship between neoantigen clonality and T-cell activity reveals distinct immune phenotypes in HNSCC.
Saravi B, Singh DD, Schorn L … +12 more , Lommen J, Schrader F, Wilkat M, Vollmer A, Vollmer M, Hartmann S, Hörner M, Adhikari K, Roider E, Wollborn J, Kübler N, Sproll C
J Transl Med · 2026 Jun · PMID 42237160 · Full text
BACKGROUND: Neoantigens derived from tumour-specific mutations are critical targets for T-cell recognition, yet the relationship between neoantigen clonality and immune response in head and neck squamous cell carcinoma (...
BACKGROUND: Neoantigens derived from tumour-specific mutations are critical targets for T-cell recognition, yet the relationship between neoantigen clonality and immune response in head and neck squamous cell carcinoma (HNSCC) remains poorly understood. We hypothesised that clonal neoantigens, being present in all tumour cells, would drive T-cell exhaustion through persistent antigen exposure. METHODS: We analysed 527 HNSCC tumours from The Cancer Genome Atlas. Neoantigens were predicted using pVACseq with MHCflurry binding prediction for patient-specific HLA class I alleles. We computed a Clonality Score (binder-weighted variant allele frequency normalised by neoantigen count) to quantify clonal origin independent of total burden. T-cell exhaustion was assessed using a 17-gene expression signature, alongside TIDE dysfunction scores and the Pan-Immune Score. Cox proportional hazards models with interaction terms tested whether prognostic effects of clonality depended on immune context. RESULTS: Contrary to our hypothesis, neoantigen clonality showed strong inverse correlations with T-cell infiltration-associated signatures, including a 17-gene exhaustion/activation panel (ρ = -0.41, P = 9.8 × 10⁻²²), TIDE dysfunction (ρ = -0.53, P = 6.7 × 10⁻³⁸), and Pan-Immune Score (ρ = -0.50, P = 8.5 × 10⁻³³). Tumours stratified into four phenotypes: Hot/Low Clonality (33%) exhibited high immune infiltration and cytolytic activity; Cold/High Clonality (33%) showed minimal immune engagement despite abundant clonal neoantigens. High clonality also associated with reduced antigen presentation machinery expression (ρ = -0.31, P = 1.0 × 10⁻¹²), suggesting impaired antigen visibility as a potential upstream mechanism. Survival analysis revealed a significant clonality × immune status interaction (P = 0.034). In 'hot' tumours, high clonality predicted improved survival (HR = 0.72, P = 0.043), whereas clonality had no prognostic effect in 'cold' tumours (HR = 1.00, P = 0.98). CONCLUSIONS: Neoantigen clonality inversely predicts T-cell activity in HNSCC, identifying high-clonality tumours as immunologically 'cold' despite abundant tumour-specific antigens. Crucially, the prognostic benefit of clonality is realised only when T-cell effectors are present, reconciling our findings with the paradigm that clonal neoantigens represent optimal immunological targets. This context-dependent relationship generates the hypothesis that neoantigen clonality, when interpreted alongside immune context, may help identify patients who could benefit from immune-priming strategies prior to checkpoint inhibitor therapy, pending validation in immunotherapy-treated cohorts.
Immunological differences in atopic dermatitis across age groups: insights from single-cell multi-omics.
Baldonado GCL, Kumar S, Jin J … +7 more , Fang X, Ildardashty A, Braun M, Neuhaus IM, Mathes E, Bhutani T, Liao W
J Transl Med · 2026 Jun · PMID 42231444 · Full text
BACKGROUND: Atopic dermatitis (AD) occurs across all ages but presents distinct clinical and immunologic features between children, adults, and older adults. The molecular programs underlying these age-specific immune di...
BACKGROUND: Atopic dermatitis (AD) occurs across all ages but presents distinct clinical and immunologic features between children, adults, and older adults. The molecular programs underlying these age-specific immune differences remain poorly understood. METHODS: We performed single-cell multi-omics profiling of peripheral blood mononuclear cells (PBMCs) from 29 AD patients and 29 matched healthy controls (HC), spanning pediatric (0-17 years), adult (18-59 years), and geriatric (≥60 years) groups. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we simultaneously quantified transcriptomic (RNA) and surface proteomic (ADT) profiles across ~280,000 immune cells. Integrated analyses identified 30 immune subsets for cell-type proportion and differential expression analyses. Machine-learning classifiers were trained on significant gene and protein features to distinguish AD subgroups by age. RESULTS: Compared with HC, AD blood showed enrichment of CD14+ monocytes, plasmacytoid dendritic cells, and CD4+ proliferating T cells, and differential gene expression analysis of AD vs HC revealed downstream Th2-associated signatures shared across all age groups. Within AD, pediatric patients had increased γδ T cells, naïve CD4+, and naïve CD8+ T cells, while geriatric patients exhibited more CD4+ cytotoxic and CD8+ central memory T cells, indicating a shift from naive to effector predominance with aging. Transcriptomic and proteomic analyses revealed distinct programs: pediatric AD was enriched for IL-10 and cytokine-cytokine receptor signaling; adult AD demonstrated activation of metabolic and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/Th1/Th17 pathways; and geriatric AD exhibited reduced adaptive immune activity but increased innate signaling. Machine-learning models based on differentially expressed genes and proteins accurately classified AD age groups (transcript-based F1 = 0.70, AUC = 0.79), identifying stable markers such as IRF2, PDK4, ZFP90, CD21, CD94, and CD122. CONCLUSIONS: Single-cell multi-omics profiling revealed age-specific transcriptional and immunological programs overlaid on a shared Th2-driven inflammatory foundation in AD. Rather than discrete disease states, pediatric, adult, and geriatric AD each exhibited distinct molecular signatures: developmental and cytoskeletal in children, stress-response and chronic inflammatory in adults, and innate and metabolic in geriatric individuals. These findings support age-group molecular subtyping and age-tailored therapeutic strategies across the AD lifespan.
Near infrared photo-bacterialflora modulation technology realized controlling periodontitis: modulation of disease-associated dysbiosis in oral microbiota using near infrared photo-antibacterial targeting therapy (NIR-PAT).
Maruyama H, Sato K, Sakai K … +7 more , Yasui H, Okada R, Xinheng L, Umeda K, Rahman S, Nguyen VS, Hibi H
J Transl Med · 2026 Jun · PMID 42231422 · Full text
BACKGROUND: Periodontitis is a complex polymicrobial disease driven by synergistic interactions within a dysbiotic oral community. Within this network, Porphyromonas gingivalis acts as a keystone pathogen that orchestrat...
BACKGROUND: Periodontitis is a complex polymicrobial disease driven by synergistic interactions within a dysbiotic oral community. Within this network, Porphyromonas gingivalis acts as a keystone pathogen that orchestrates the pathogenic transformation of the microbiota. Current broad-spectrum antimicrobials often disrupt the entire microbial ecosystem and release immunogenic lipopolysaccharides (LPS). We aimed to develop a targeted approach, Near-Infrared Photo-Antibacterial Targeting Therapy (NIR-PAT), using an antibody-photosensitizer conjugate (IgY-IR700) to reduce P. gingivalis load within this polymicrobial complex and modulate the community profile. METHODS: We evaluated the binding and bactericidal mechanism of NIR-PAT in vitro compared to antimicrobial photodynamic therapy (aPDT), using scanning electron microscopy (SEM) and endotoxin assays. In vivo, a ligature-induced periodontitis mouse model was used to assess therapeutic effects on alveolar bone resorption and microbiome community structure (16 S rRNA sequencing). RESULTS: In vitro, NIR-PAT eliminated P. gingivalis without affecting human cells. SEM analysis revealed a distinct mechanism: unlike aPDT, which caused bacterial disintegration, NIR-PAT induced lethal transmembrane perforations while maintaining structural integrity. In parallel, endotoxin assays demonstrated that NIR-PAT treatment significantly suppressed LPS release compared to aPDT. In vivo, NIR-PAT treatment significantly inhibited alveolar bone resorption. Crucially, microbiome analysis demonstrated that NIR-PAT did not merely eliminate the environment but induced a compositional shift toward a health-associated profile. By suppressing Porphyromonas, the treatment facilitated the partial restoration of commensal genera such as Streptococcus, disrupting the dysbiotic network. CONCLUSIONS: This study suggests that NIR-PAT functions as a "Near-Infrared Photo-Bacterialflora Modulation (NIR-PBAM)" technology. By targeting a keystone pathogen within the polymicrobial community, NIR-PBAM offers a strategy to partially restore microbial balance while presenting a potential advantage in limiting LPS release, thus overcoming the ecological disruption caused by conventional broad-spectrum antimicrobials.
Chronic liver diseases aggravate radiation-induced intestinal injury through taurocholic acid dysregulation.
Wang B, Wang Q, Dong Y … +7 more , Li Y, Liu J, Xiao Y, Qiu J, Dong J, Xiao H, Cui M
J Transl Med · 2026 Jun · PMID 42231401 · Full text
BACKGROUND: Chronic liver diseases (CLDs) are pervasive health issue worldwide, whereas radiation-induced intestinal injury is a frequent and consequential complication of abdominopelvic radiotherapy. Although these two...
BACKGROUND: Chronic liver diseases (CLDs) are pervasive health issue worldwide, whereas radiation-induced intestinal injury is a frequent and consequential complication of abdominopelvic radiotherapy. Although these two pathological states often coexist clinically, the effects of CLDs on the development and severity of enteric radiation damage remain poorly understood. Therefore, the aim of this study was to investigate the effects of CLDs on radiation-induced intestinal injury and to elucidate the underlying mechanisms involved. METHODS: Mouse models of CCl-induced liver injury or alcoholic fatty liver disease were established. Single-cell RNA sequencing was conducted to understand the repertoire of small intestinal crypts. The gut microbiota was assessed using 16 S rRNA gene sequencing. Untargeted metabolomics, along with experiments using cell lines, intestinal organoids and mouse models, was utilized to identify key effector molecules and explore their mechanism of action. RESULTS: CLDs reshaped the intestinal cellular landscape and exacerbated radiation-induced intestinal syndrome through bile acid-mediated hepatoenteric signalling. Liver injury shifted the gut microbiota, enriching Lachnospiraceae and other taxa, which led to abnormal elevation of taurocholic acid (TCA) in serum. Under radiation exposure, TCA overload disrupted intestinal homeostasis through three synergistic mechanisms. First, TCA compromised intestinal stem cell vitality, lowering the self-renewal and regenerative properties of the irradiated small intestine. Second, TCA activated Notch signalling in stem cells, impeding the differentiation of irradiated intestinal progenitors towards the secretory lineage to disrupt the differentiation trajectory. Third, TCA accumulated in irradiated absorptive enterocytes, destroying mitochondrial membrane integrity and hastening intrinsic apoptosis, contributing to radiation-induced cell death. Potential therapeutic strategies, including liver-protective agents, microbiota-targeted interventions, and mitochondrial protective compounds, have been proposed to mitigate the worsening intestinal toxicity associated with CLDs comorbidity during radiotherapy. CONCLUSIONS: This study offers a detailed mechanistic understanding of how dysregulation of hepato-enteric crosstalk negatively affects the sensitivity of the intestines to ionizing radiation and proposes potential therapeutic approaches to reduce intestinal complications in patients with concurrent chronic liver diseases who are undergoing irradiation.
GZMBCD4CD8 T cells in rheumatoid arthritis: a potential therapeutic target for IL-27 intervention.
Xue J, Jiang S, Jia H … +9 more , Wang W, Li W, Wang Y, Zhuang J, Wei X, Li H, Chu M, Zhang L, Zhang J
J Transl Med · 2026 Jun · PMID 42231345 · Full text
OBJECTIVE: Peripheral CD4CD8 double-positive (DP) T cells have been implicated in the pathogenesis of autoimmune diseases; however, the precise pathogenic mechanisms of circulating DP T cells remain unclear. This study a...
OBJECTIVE: Peripheral CD4CD8 double-positive (DP) T cells have been implicated in the pathogenesis of autoimmune diseases; however, the precise pathogenic mechanisms of circulating DP T cells remain unclear. This study aims to identify the key pathogenic DP T cell subset and develop corresponding targeted therapeutic strategies for autoimmune diseases, including rheumatoid arthritis (RA). METHODS: We utilized single-cell RNA sequencing (scRNA-seq) to profile DP T cells from peripheral blood of RA patients and healthy controls (HC), with variations in key subset frequencies validated by flow cytometry. Integrated analysis of differentially expressed genes, pseudotime trajectory, and cell-cell communication identified the IL-27/ANXA1 signaling axis. For in vitro validation, DP T cells from RA patients were treated with recombinant IL-27 (rIL-27) or anti-IL-27 neutralizing antibody (anti-IL-27), and the frequency of ANXA1GZMB cells was assessed by flow cytometry. In a collagen-induced arthritis (CIA) mouse model, systemic administration of rIL-27 or anti-IL-27 was performed; splenic DP T cells and the GZMB subset were analyzed by flow cytometry, ANXA1 expression in sorted GZMB DP T cells was quantified by RT-qPCR, and joint inflammation was evaluated clinically and histopathologically. RESULTS: scRNA-seq revealed a distinct GZMB DP T cell subset in RA patients, characterized by significant downregulation of IL27RA and ANXA1-mediated aberrant communication with monocytes. Flow cytometry confirmed the expansion of GZMB DP T cells in peripheral blood of RA patients compared with HC. In vitro, IL-27 suppressed the proportion of ANXA1 cells among DP T cells, whereas IL-27 blockade reversed this effect. In CIA mice, IL-27 treatment reduced the splenic GZMB DP T frequency and alleviated joint swelling, while IL-27 inhibition exacerbated arthritis. Mechanistically, IL-27 constrains DP T cell-mediated pathogenic responses via an ANXA1-dependent pathway. CONCLUSION: GZMBCD4CD8 T cells represent a potential pathogenic subset within DP T cells that actively contributes to RA progression. Importantly, IL-27 appears to exert therapeutic effects by modulating DP T cell differentiation-particularly the GZMB DP T cell subset-and suppressing ANXA1-mediated intercellular communication between GZMBCD4CD8 T cells and monocytes, thereby offering a potential treatment strategy for RA.
Body-weight-specific and shared metabolomic responses to acute sleep loss in young adults.
Good L, Brandão LEM, van Egmond LT … +7 more , Khoonsari PE, Erngren I, Carlsson H, Fredriksson R, Kultima K, Benedict C, Cedernaes J
J Transl Med · 2026 Jun · PMID 42231340 · Full text
INTRODUCTION: Insufficient sleep increases the risk of weight gain and metabolic dysfunction, while obesity is linked to disrupted sleep and metabolic impairment. Although both conditions are tightly interconnected, it r...
INTRODUCTION: Insufficient sleep increases the risk of weight gain and metabolic dysfunction, while obesity is linked to disrupted sleep and metabolic impairment. Although both conditions are tightly interconnected, it remains unclear whether body weight status determines how acute sleep loss alters metabolite levels. We aimed to assess whether acute sleep loss elicits different metabolic responses in individuals with and without obesity, and whether these responses are modified by sex. METHODS: In a within-subject, randomized crossover study, 42 adults (mean age 24.9 years; 18 women, 24 men; 18 with obesity; 24 with normal weight) completed one night of total sleep deprivation (TSD) and one night of normal sleep (NS; 8 h). Morning fasted blood samples were analyzed using targeted metabolomics. Mixed-effects models were used to assess within-individual changes from NS to TSD, and to determine the magnitude and direction of these changes within each body weight group and sex. RESULTS: In response to TSD compared with NS, tryptophan levels increased (+12%, FDR < 0.05) only in participants with obesity, while histidine, L-kynurenine, and creatinine levels decreased (4-21%, FDR < 0.05) only in normal-weight individuals. Notably, the kynurenine-to-tryptophan ratio decreased after TSD in both groups, and levels of circulating medium-chain acylcarnitines (+26-39%) increased within both weight groups - together indicating shared metabolic responses to acute sleep deprivation. Exploratory sensitivity analyses indicated that several of these responses were sex-specific. Polysomnography-based sleep architecture during NS, available in a subset of 36 participants, was largely comparable between body weight groups, suggesting that observed metabolic differences were not attributable to baseline differences in sleep structure. CONCLUSIONS: Acute sleep loss elicits both shared and body-weight-specific changes in circulating metabolites in young adults. These findings indicate that body-weight status shapes which metabolic pathways respond to a single night of sleep loss, and in what direction, but larger studies are required to confirm the body weight- and sex-specific findings. Given that acute sleep loss is a common metabolic stressor that increases cardiometabolic risk, these differences may contribute to mechanistic hypotheses about the heightened vulnerability to metabolic dysregulation in individuals with obesity who are frequently exposed to sleep loss.
CircRNA profiles of extracellular vesicle-enriched fractions from ART suppressed pregnant women living with HIV identifies interactome networks key to inflammation and viral latency.
Brena D, Schuch V, Huang MB … +11 more , Sheth A, Tisdale T, Mehta C, Badell ML, Floyd R, Dawning A, Bashi A, Chan A, Chakraborty R, Bond V, Johnson EL
J Transl Med · 2026 Jun · PMID 42231329 · Full text
BACKGROUND: Despite virologic suppression with ART, pregnant people living with HIV (PLWH) experience a disparate risk of chronic non-AIDS-related morbidities (NAMs) during pregnancy compared to people without HIV infect...
BACKGROUND: Despite virologic suppression with ART, pregnant people living with HIV (PLWH) experience a disparate risk of chronic non-AIDS-related morbidities (NAMs) during pregnancy compared to people without HIV infection including preterm labor and small for gestational age. Many studies postulate that NAMs reflect immunological dysfunction from underlying continuous inflammation. Extracellular vesicles (EV) are fundamental to both HIV immune pathogenesis and maternal-placental-fetal systemic intercellular networking. Circular RNAs (CircRNA) are enriched within EVs and are readily transmissible with disease-specific functional outcomes in recipient cell populations. However, there is limited research addressing the intersection of EV circRNA and HIV during pregnancy. METHODS: Small RNA (smRNA) cargo of EV-enriched fractions derived from the plasma of pregnant PLWH (n = 8) was compared to that of pregnant people living without HIV (PLWoH, n = 10) using low-input RNA sequencing (Illumina PE150). Differential circRNA profiles were used to construct circRNA-miRNA-gene regulatory maps and circRNA-protein interactions (circInteractome and miRTarbase). Gene set enrichment analysis (GSEA) using Reactome on the predicted genes from the interactome networks, provided insights into the regulatory roles of the differentially expressed circRNAs of EV-enriched fractions. RESULTS: Differential expression analysis identified 27 significantly upregulated circRNAs of EV-enriched fractions for pregnant PLWH as compared to pregnant PLWoH. GSEA revealed physiological pathways influential to HIV reservoir establishment, latency, replication, immune activation, immunosenescence, as well as maternal-placental-fetal immune cross talk. FUS, AGO2, and EIF4A3 were the top circRNA binding proteins and are involved in scaffolding for circRNA biogenesis, EV sorting, and miRNA sponging. High-density miRNA-binding circRNAs of EV-enriched fractions highlighted circRNA-mediated suppression of HIV inhibitory mechanisms including extensive binding of hsa-miR-326 and hsa-miR-548c-3p. CONCLUSIONS: While many studies have compared plasma RNA profiles for PLWH compared to PLWoH, few have conducted this analysis for EVs, and we were unable to find a study specific to the unique combination of exploring RNA cargo of EV-enriched fractions in PLWH during pregnancy. This study aims to address the knowledge gap for NAMs in pregnancy by investigating EV-based intercellular communication. The results imply that novel EV circRNA-mediated regulatory mechanisms may contribute to HIV persistence, inflammation, and immune modulation in pregnancy.
Prospective germline exome and machine learning-based risk score identify predictive and prognostic biomarkers of immunotherapy outcomes in advanced non-small cell lung cancer.
González-Hernández A, Ríos A, Onieva JL … +12 more , Cantero A, Rivero-Aguilar M, Paz-López G, Rueda-Domínguez A, Garrido-Barros M, Martínez-Gálvez B, Zafra J, Figueroa-Ortiz LC, Pérez-Ruiz E, Benítez JC, Barragán I, Oliver J
J Transl Med · 2026 Jun · PMID 42231301 · Full text
BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). However, a substantial proportion of patients do not experience durable clinical be...
BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). However, a substantial proportion of patients do not experience durable clinical benefits, and established tumour biomarkers, such as PD-L1 expression and tumour mutational burden, often show limited predictive value. The potential of inherited germline variants to predict immunotherapy outcomes in NSCLC remains a critical and underexplored area. METHODS: We prospectively enrolled 117 patients with advanced NSCLC treated with ICI-based regimens at two centres in Spain. Germline whole-exome sequencing (WES) was performed on pretreatment blood samples. Exonic and intronic variants were annotated and integrated with comprehensive clinical data. We applied XGBoost and LASSO machine learning models to identify predictive germline variants and clinical features, and subsequently trained them to predict treatment response and progression-free survival (PFS). This approach produced a novel clinical-germline risk score, generating both a global model and a specific model for the lung adenocarcinoma (LUAD) histological subtype. RESULTS: XGBoost significantly outperformed penalised regression (LASSO), achieving a robust cross-validated area under the curve (AUC) of 0.845 for predicting treatment response in the validation cohort. Our models identified several novel germline loci that were significantly associated with immunotherapy outcomes. Variants in SLC6A16, SIGLEC11, PDE4E, and OR10H5 were associated with reduced PFS, whereas variants in CCZ1B and PHLDB1 were associated with extended PFS. Lymph node metastasis was confirmed as the sole independent clinical predictor of poor response (OR 2.07, P = 0.008). A predictive algorithm that included these individual variables generated a clinical-germline risk score that successfully stratified patients into high- and low-risk groups with markedly different median PFS (low-risk: 18 months vs. high-risk: 7 months, log-rank P < 0.001), retaining discriminatory power across histological subgroups. CONCLUSIONS: The integration of specific germline variants as the output of advanced machine learning analysis of the exome with key clinical features provides accurate and novel predictive information for immunotherapy in NSCLC. This approach not only uncovers new genetic biomarkers but also supports the clinical adoption of composite risk scores for personalised precision immunotherapy, paving the way for improved patient selection and stratification.
A multicenter, prospective sibling oocyte study revealed that HyperSperm improves the number and quality of embryos in patients undergoing in vitro fertilization.
Oscoz-Susino N, Gómez-Elías MD, Bisioli C … +13 more , Horton M, Papayannis M, Martino E, Kopcow L, Attie M, Lavolpe M, Carizza C, Luque GM, Graf CB, Monserrat VT, Navall E, Buffone MG, Krapf D
J Transl Med · 2026 Jun · PMID 42231286 · Full text
BACKGROUND: Assisted reproductive technologies (ART), including in vitro fertilization (IVF), have transformed the treatment of infertility; however, success rates remain suboptimal. HyperSperm is a novel capacitation te...
BACKGROUND: Assisted reproductive technologies (ART), including in vitro fertilization (IVF), have transformed the treatment of infertility; however, success rates remain suboptimal. HyperSperm is a novel capacitation technology designed to enhance sperm function by promoting hyperactivation without compromising acrosomal integrity or sperm viability. Previous studies have shown that HyperSperm improves human sperm motility parameters and increases embryo development in mice and humans, as well as implantation rates in mice. The present study aimed to evaluate the clinical utility of HyperSperm in IVF. METHODS: A prospective sibling oocyte study was conducted in 41 IVF patients (ClinicalTrials.gov identifier: NCT05680363). Semen samples from each patient were divided and processed using either standard preparation protocols or the HyperSperm protocol. Fertilization outcomes, embryo development, blastocyst formation, embryo quality, and euploidy rates assessed by preimplantation genetic testing for aneuploidy (PGT-A) were compared between conditions. RESULTS: HyperSperm treatment was associated with significantly higher blastocyst development rates compared with standard preparation (55.6% vs. 47.9%, p = 0.0038), resulting in a greater number of blastocysts per cycle. Moreover, embryos generated following HyperSperm treatment exhibited improved morphological quality and a higher euploidy rate as determined by PGT-A. CONCLUSIONS: HyperSperm improves key developmental outcomes in IVF, increasing blastocyst yield, embryo quality, and chromosomal normality. These findings support the translational potential of HyperSperm as a clinically relevant strategy to enhance early embryo competence and improve IVF efficiency.
FTO-modulated mA demethylation and upregulation of KIF11 mRNA promotes retinal microvascular dysfunction in diabetic retinopathy.
Lin C, Cao C, Cui S … +3 more , Guo J, Xin Y, Shao J
J Transl Med · 2026 May · PMID 42226292 · Full text
BACKGROUND: The N6-methyladenosine (mA) demethylation of mRNAs is critical for the progression of diabetic retinopathy (DR). Fat mass and obesity-associated protein (FTO) has been reported to be overexpressed in DR and i...
BACKGROUND: The N6-methyladenosine (mA) demethylation of mRNAs is critical for the progression of diabetic retinopathy (DR). Fat mass and obesity-associated protein (FTO) has been reported to be overexpressed in DR and is considered to be an important epitranscriptomic regulator (mA eraser) in retinal angiogenesis. The principle of Kinesin family member 11 (KIF11) gene in DR is unclear. METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) was used to screen abnormal mA modification in vitreous body samples of proliferative DR (PDR) patients. CCK-8 and EdU assays were employed to detect the proliferation and DNA synthesis in human retinal microvascular endothelial cells (hRECs), while Transwell, wound healing, and tube formation assays were used to evaluate migration and angiogenesis. In addition, the levels of RNA and mA modified mRNA were tested using quantitative RT-PCR (qRT-PCR) and methylated RNA immunoprecipitation-qRT-PCR (MeRIP-qRT-PCR); the protein levels were tested via western blot. RNA binding protein immunoprecipitation-qRT-PCR (RIP-qRT-PCR) was used to test the interaction between FTO and mA modified mRNA. A 16-week diabetic retinopathy (DR) rat model was induced by streptozotocin (STZ), and 5 µL of AAV9 virus (1 × 10 vg/mL) was intravitreally injected every 8 weeks. The retinas were extracted and subjected to Evans blue leakage and retinal trypsin digestion assays, while the retinal paraffin sections were subjected to hematoxylin and eosin (H&E) staining, immunohistochemical or immunofluorescence assays. RESULTS: MeRIP-Seq and RIP-RT-qPCR indicated that KIF11 should be a downstream target of FTO. Regarding qRT-PCR and MeRIP-qRT-PCR, in vitreous body samples from patients with PDR and hRECs under hyperglycemic conditions, expressed enhanced levels of FTO and KIF11, whereas the mA methylation of KIF11 was decreased. The overexpression of KIF11 enhanced the proliferation, DNA synthesis, migration, wound healing and tube formation of hRECs by affecting the downstream PI3K/AKT/mTOR and β-catenin/c-myc pathways, while the knockdown of KIF11 had the opposite effects. In STZ-induced DR rats, overexpression of FTO and KIF11 significantly promoted retinal leakage, acellular capillary formation, pericyte loss, fibrosis, and gliosis in DR progression, whereas the knockdown of FTO and KIF11 mitigated these phenomena. CONCLUSION: Our findings demonstrated that the mA demethylation of KIF11 mRNA, as modulated by FTO, provides a potential target for the clinical therapy of DR retinal microvascular dysfunction.
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