J Transl Med [JOURNAL]
Sun
200 papers
Baseline retinal nerve fiber layer thickness as a predictive biomarker for endoscopic optic canal decompression in NAION: towards a precision medicine approach.
Yao Z, Chen Z, Yu B … +6 more , Wu N, Hu R, Peng H, Zhu M, Wu W, Yan W
J Transl Med · 2026 Jun · PMID 42260536 · Full text
BACKGROUND: Nonarteritic anterior ischemic optic neuropathy (NAION) remains a major cause of blindness with no consensus on treatment. The heterogeneity of patient outcomes suggests that a "one-size-fits-all" approach is...
BACKGROUND: Nonarteritic anterior ischemic optic neuropathy (NAION) remains a major cause of blindness with no consensus on treatment. The heterogeneity of patient outcomes suggests that a "one-size-fits-all" approach is ineffective. This study aimed to identify structural biomarkers to define the therapeutic window for endoscopic transnasal optic canal decompression (ETOCD) and explore its mechanism via vascular reperfusion imaging. METHODS: Seventy-one patients diagnosed with NAION were included and categorized into two groups: an ETOCD group (n = 30) and a medical management group (n = 41). Best-corrected visual acuity (BCVA), visual field index (VFI), mean deviation (MD), pattern standard deviation (PSD), and retinal nerve fiber layer (RNFL) thickness were assessed at baseline and 3 months after treatment. Optical coherence tomography angiography (OCTA) was utilized to evaluate microvascular recovery. Multivariable regression and interaction analyses were performed to investigate RNFL as a predictive biomarker. RESULTS: While ETOCD showed superior overall efficacy (Adjusted β = -0.41, P < 0.001), a critical treatment-by-biomarker interaction was identified (P for interaction = 0.014). Patients with moderate edema (RNFL < 150 μm) exhibited a profound therapeutic response (OR 7.88, 95% CI: 2.07-29.94, P = 0.002), whereas those with massive edema derived minimal benefit. OCTA analysis in responders revealed significant radial peripapillary capillary reperfusion, providing mechanistic support of the "osseous compartment syndrome" hypothesis. CONCLUSION: We identified baseline RNFL thickness (< 150 μm) as a potential predictive biomarker for surgical success in NAION. These findings support an alternative therapeutic strategy from empiric treatment to biomarker-guided precision decompression, bridging the gap between anatomical pathology and surgical intervention. TRIAL REGISTRATION: Retrospectively registered.
Synergistic senolytic-regenerative therapy significantly extends healthspan and lifespan.
Ichim TE, Markov N, Lopes G … +17 more , Pascual KA, Evans A, Reznik R, Bykoriz V, Fortunati CA, Minev B, Ramos RA, Bajnath A, Lin E, Hu J, Marincola FM, Rath A, Barrett B, Jurow A, Sankhala KK, Furman D, Reznik BN
J Transl Med · 2026 Jun · PMID 42260530 · Full text
BACKGROUND: Current barriers to achieving radical life extension include the inability to use syngeneic, youthful mesenchymal stem cells (MSCs) and the anti-regenerative effects of senescence-associated secretory phenoty...
BACKGROUND: Current barriers to achieving radical life extension include the inability to use syngeneic, youthful mesenchymal stem cells (MSCs) and the anti-regenerative effects of senescence-associated secretory phenotype (SASP) factors. We aim to overcome this by a combination approach in which senescent cell burden is reduced utilizing SenoVax™ a dendritic cell based senolytic immunotherapy combined with syngeneic pluripotent stem cell derived MSC. METHODS: We induced hepatic injury and accelerated aging using two established murine models: carbon tetrachloride (CCl₄) mediated liver injury and doxorubicin induced systemic senescence. Animals were treated with control, SenoVax, pMSCs or the combination. Outcomes included biochemical and histologic indices of liver injury, circulating and tissue biomarkers of senescence (IL-11, YKL-40, IL-6, IL-23 R) and regeneration (Klotho, FGF-2, neo-VEGF, GDF-11), RESULTS: Both CCl₄ and doxorubicin induced a robust senescent phenotype characterized by increased pro-inflammatory and pro-fibrotic mediators and downregulation of regenerative biomarkers. Combined senolytic and pMSC therapy outperformed mono therapies and produced clear synergistic benefits, including significant biochemical improvement of liver failure parameters, reversal of accelerated aging features, and restoration of regenerative signaling pathways. Senolytic monotherapy yielded partial improvements, while pMSCs alone showed limited activity in the presence of a high senescent-cell burden. CONCLUSIONS: These findings support a mechanistic model in which senescent cells and SASP factors directly suppress MSC-mediated tissue repair. Targeted senolytic immunotherapy enhances the efficacy of regenerative interventions and represents a promising combinatorial strategy for chronic disease management and potentially for modifying biological aging itself. CLINICAL TRIAL NUMBER: Not applicable.
Heat shock protein-mediated remodeling of the bone immune microenvironment: mechanisms and precision therapeutic strategies for osteoporosis.
An J, Bai J, Li L … +3 more , Li X, Zhang Y, Lv H
J Transl Med · 2026 Jun · PMID 42260517 · Full text
BACKGROUND: Osteoporosis is a systemic bone disorder marked by reduced bone mass and deteriorating bone microstructure, commonly associated with inflammation, oxidative stress, and imbalances in immune homeostasis. Among...
BACKGROUND: Osteoporosis is a systemic bone disorder marked by reduced bone mass and deteriorating bone microstructure, commonly associated with inflammation, oxidative stress, and imbalances in immune homeostasis. Among the key mechanisms underlying Osteoporosis progression, disruption of the bone immune microenvironment has emerged as a critical scientific issue. Heat shock proteins (HSPs), as highly conserved molecular chaperones and stress-responsive proteins, not only prevent protein misfolding and aggregation under stress conditions to maintain protein homeostasis, but also participate in immune signaling and adaptive stress responses, thereby playing important roles in preserving bone metabolic homeostasis. This review aims to systematically examine the roles of HSP families-HSPB, HSP40, HSP70, HSP90, and HSP110-in bone remodeling, the balance between osteogenesis and osteoclastogenesis, and the interaction between endoplasmic reticulum stress and mitochondrial energy metabolism. The review also highlights the dual roles of HSPs in regulating bone immune homeostasis. HSPs participate at the cellular level in regulating osteoblast, osteoclast, and bone marrow mesenchymal stem cell function. Current evidence suggests that HSPs act as both molecular chaperones and stress-responsive immune modulators, regulating the balance between bone formation and bone resorption and remodeling the bone immune microenvironment. This review also summarizes HSP-targeted therapeutic strategies, including small molecules, natural products, neutralizing antibodies, physical stimulation, and gene- and cell-based therapies. CONCLUSION: Research on HSPs is shifting from molecular mechanisms toward precision intervention. Future studies should integrate the "bone-muscle-immune axis" with artificial intelligence and multi-omics technologies to construct a "heat shock response-bone immune" network, identify novel therapeutic targets, and promote personalized prevention and treatment of osteoporosis.
Spatiotemporal heterogeneity of neutrophil extracellular traps in hepatocellular carcinoma microenvironment and targeted therapy progress.
Zheng Y, Jia G, Li B … +3 more , Li C, Zhang J, Yu X
J Transl Med · 2026 Jun · PMID 42260515 · Full text
BACKGROUND: Neutrophil extracellular traps (NETs) form a spatiotemporally heterogeneous defensive architecture within the tumor microenvironment (TME), representing a newly identified multi-dimensional biological barrier...
BACKGROUND: Neutrophil extracellular traps (NETs) form a spatiotemporally heterogeneous defensive architecture within the tumor microenvironment (TME), representing a newly identified multi-dimensional biological barrier system. Particularly in hepatocellular carcinoma (HCC), this system drives the heterogeneous evolution of the TME through the integration of mechanical stress transduction (YAP/TAZ activation) and protease-mediated signaling network remodeling (reconfiguration of intercellular signaling via proteolytic enzymes like MMP9, e.g. the MMP9/TGF-β axis). MAIN BODY: The NET-driven heterogeneous evolution of the HCC TME is characterized by region-specific epithelial-mesenchymal transition (EMT) progression, metabolic reprogramming of tumor cells, and the formation of immunosuppressive niches within the TME. These changes collectively reshape the TME's biological properties, alter the energy landscape of tumor cells (a framework describing dynamic metabolic/functional states of tumor cells shaped by microenvironmental cues), and maintain their stem cell properties, ultimately contributing to therapeutic heterogeneity and cross-regional drug resistance. Existing targeted therapeutic strategies against NETs in HCC and their clinical translational potential are analyzed herein. CONCLUSIONS: This review systematically synthesizes the spatiotemporal heterogeneity of NETs in the HCC microenvironment and their functional roles, providing new insights into HCC treatment.
C3 cancer-associated fibroblast-derived GAS6 promotes cervical cancer metastasis via activation of AXL signaling pathway in a syngeneic orthotopic mouse model.
Zhan J, Liu D, Ye J … +7 more , Peng X, Liu X, Lu W, Li M, Li T, Zhong L, Zhang C
J Transl Med · 2026 Jun · PMID 42260511 · Full text
BACKGROUND: Metastatic cervical cancer remains a leading cause of cancer-related death in women, although several mouse models of metastatic cervical cancer exist, many fail to preserve an immunocompetent primary tumor m...
BACKGROUND: Metastatic cervical cancer remains a leading cause of cancer-related death in women, although several mouse models of metastatic cervical cancer exist, many fail to preserve an immunocompetent primary tumor microenvironment, limiting their ability to adequately model metastatic progression. This study aimed to establish a syngeneic orthotopic cervical cancer model that faithfully reproduces the metastatic cascade and defines cellular interactions associated with metastasis in tumor microenvironment. METHODS: U14 cells derived from mouse cervical cancer were engineered to stably express luciferase (U14-Luc) for the detection of micrometastases via bioluminescence imaging. The syngeneic orthotopic mouse model was established by intra-cervically injecting U14-Luc into immunocompetent C57BL/6 mice under direct visualization. Primary and metastatic tumor burden were detected by in vivo or ex vivo organ bioluminescence imaging. Histological analysis of tumor tissues was performed using Hematoxylin-Eosin staining. Single-cell RNA sequencing was used to identify cellular interactions and molecular pathways in primary tumors (PTs) and paired lymph node metastasis tumors (LNMTs). RESULTS: In this mouse model, primary tumors consistently developed near the external cervical os and vaginal fornix. By day 14 post-injection, cancer cells had invaded into the pelvic viscera, particularly the rectum, and disseminated to regional lymph nodes. By day 28, distant metastases, predominantly in the lungs, were observed. Single-cell analysis revealed that crosstalk between cancer cells and T cells in LNMT promoted immune escape via the SPP1 pathway. Additionally, a C3 fibroblast subtype enriched in the PTs was correlated with unfavorable prognosis in cervical cancer patients. These C3 fibroblasts enhanced tumor invasiveness through activation of the GAS6/AXL pathway. CONCLUSIONS: This syngeneic orthotopic mouse model effectively replicates the metastatic cascade of cervical cancer. Its ability to closely mimic the tumor microenvironment makes this model a valuable immunocompetent orthotopic platform for investigating the metastatic mechanism and evaluating novel therapeutic strategies for cervical cancer.
FAM135B suppresses glioblastoma angiogenesis via stabilizing the IKK complex and inactivating the NF-κB/IL-6 signaling pathway.
Wang C, Zhang F, Hao L … +11 more , Zhang Y, Feng C, Weng N, Hu P, Lin W, Chen T, Wang T, Zhang Y, Ke Y, Zhao L, Chen Z
J Transl Med · 2026 Jun · PMID 42260484 · Full text
BACKGROUND: Glioblastoma multiforme (GBM), the most aggressive primary central nervous system malignancy in adults, is hallmarked by robust angiogenesis and pronounced heterogeneity, with the mesenchymal subtype linked t...
BACKGROUND: Glioblastoma multiforme (GBM), the most aggressive primary central nervous system malignancy in adults, is hallmarked by robust angiogenesis and pronounced heterogeneity, with the mesenchymal subtype linked to the poorest prognosis. The median survival of GBM patients is merely ~ 14 months, and approved anti-angiogenic agents like bevacizumab only yield short-term benefits without improving overall survival, highlighting the urgent need for novel anti-angiogenic targets. FAM135B, a brain-enriched protein-coding gene, is implicated in tumorigenesis and chemoresistance in other cancers, but its role and underlying mechanism in GBM angiogenesis remain unelucidated. METHODS: Bioinformatic analysis: Gene Set Variation Analysis (GSVA), single-cell and spatial transcriptomic analyses were performed on GBM datasets from TCGA, CGGA and other databases to screen angiogenesis-related genes and explore the correlation between FAM135B expression and clinical prognosis. In vitro experiments: FAM135B-overexpressing/knockdown GBM cell models were constructed. Tube formation, Transwell migration and colony formation assays were used to detect the angiogenic potential of human umbilical vein endothelial cells (HUVECs) treated with GBM cell-conditioned medium. Co-immunoprecipitation, mass spectrometry, Western blot, RT-qPCR and ELISA were applied to verify protein-protein interactions and detect the expression of cytokines and signaling pathway molecules. Dual-luciferase reporter assays confirmed the transcriptional regulation of FAM135B. In vivo experiments: Nude mouse orthotopic and subcutaneous GBM xenograft models were established to assess the effect of FAM135B on tumor growth, angiogenesis and mouse survival. Rescue experiments with NF-κB inhibitor PDTC and recombinant IL-6 were conducted to validate the key role of the NF-κB/IL-6 axis. Clinical sample validation: Immunohistochemistry and magnetic resonance imaging were used to analyze the correlation between FAM135B expression, microvessel density and prognosis in 72 GBM clinical samples. STATISTICAL ANALYSIS: SPSS 19.0 was used for data analysis with Kaplan-Meier, t-tests and Log-rank tests; the significance level was set at P < 0.05. RESULTS: FAM135B is a novel key regulator of GBM angiogenesis, with significantly downregulated expression in GBM tissues (especially the mesenchymal subtype). Low FAM135B expression correlates with enhanced endothelial cell communication, high angiogenic potential and poor progression-free/overall survival in GBM patients. FAM135B inhibits GBM angiogenesis in vitro and in vivo: its overexpression suppresses HUVEC tube formation, migration and colony formation, while knockdown exerts the opposite effect. In orthotopic xenografts, FAM135B overexpression slows tumor growth, prolongs mouse survival, and reduces intratumoral microvessel formation and M2 macrophage infiltration. FAM135B downregulates IL-6 expression to inhibit the JAK/STAT signaling pathway: its expression is negatively correlated with pro-angiogenic cytokines (notably IL-6) in GBM. FAM135B overexpression reduces IL-6 transcription and secretion in GBM cells, thereby inhibiting JAK/STAT phosphorylation in HUVECs; high FAM135B expression in GBM tissues is associated with low IL-6 and CD31 levels. FAM135B binds to the IKK complex (IKKα/IKKβ) to stabilize it, inhibit IKKβ activation and P65 phosphorylation, and block the canonical NF-κB signaling pathway, which is the upstream mechanism of IL-6 downregulation. Co-overexpression of IKBKB partially reverses the anti-angiogenic effect of FAM135B, and PDTC rescues NF-κB activation induced by FAM135B knockdown. HNF4A is the upstream positive transcription factor of FAM135B: it directly binds to two key sites in the FAM135B promoter to promote its transcription and protein expression. HNF4A expression is positively correlated with FAM135B and favorable GBM prognosis; its overexpression inhibits GBM angiogenesis, and this effect is abrogated by FAM135B knockdown. CONCLUSION: FAM135B acts as a critical negative regulator of GBM angiogenesis, whose low expression contributes to high tumor angiogenic potential and poor patient prognosis. Mechanistically, HNF4A transcriptionally upregulates FAM135B, which then binds to and stabilizes the IKK complex, inactivating the NF-κB signaling pathway and downregulating IL-6 expression, ultimately inhibiting the JAK/STAT-mediated angiogenic process. FAM135B also remodels the GBM tumor microenvironment by reducing M2 macrophage infiltration. Targeting the HNF4A/FAM135B/NF-κB/IL-6 signaling axis provides a novel and promising therapeutic strategy for GBM anti-angiogenic therapy.
Bacteroides-derived endocannabinoid-like commendamide attenuates skeletal muscle ferroptosis in vitro: implications for Duchenne muscular dystrophy.
Di Muraglia N, De Vito M, Panza E … +10 more , Pagano E, Vitale RM, Piscitelli F, Villano R, Capasso R, Pota V, Pace C, Dongiovanni S, Di Marzo V, Iannotti FA
J Transl Med · 2026 Jun · PMID 42251435 · Full text
OBJECTIVE: The gut microbiota regulates skeletal muscle physiology, with an increasingly recognised role in Duchenne muscular dystrophy (DMD), the most severe X-linked myopathy. Unlike previous studies, we focussed on th...
OBJECTIVE: The gut microbiota regulates skeletal muscle physiology, with an increasingly recognised role in Duchenne muscular dystrophy (DMD), the most severe X-linked myopathy. Unlike previous studies, we focussed on the genus Bacteroides and its metabolites, assessing their abundance in DMD mice and patients to clarify their potential contribution to the disease. METHODS: The relative abundance of Bacteroides species was analysed in fecal samples from dystrophic mdx mice and DMD patients, compared with age-matched healthy controls, using PCR-based tecniques. Synthetic and analitical chemistry approaches followed by cell-based assays, in silico and bioinformatic analyses, were employed to identify an unknown mechanism of action of the Bacteroides-derived metabolites. RESULTS: DMD patients and mdx mice exhibited a significant reduction in commensal Bacteroides species, including Bacteroides vulgatus, known producers of SCFAs and commendamide, an endocannabinoid-like molecule with largely uncharacterized biological functions. In skeletal muscles of mdx mice, we observed biochemical features consistent with increased susceptibility to ferroptosis. In murine C2C12 cells and primary human myotubes exposed to the ferroptosis inducer erastin, commendamide conferred significant protective effects, which were further enhanced in the presence of SCFAs. Additionally, we discovered that commendamide acts as an endogenous activator of PPARα and PPARγ, with PPARα preferentially promoting the transcription of the antioxidant genes Gpx4 and Nrf2. CONCLUSION: These findings provide new insights into the gut-muscle axis in DMD, suggesting that the depletion of Bacteroides vulgatus and its metabolites may contribute to skeletal muscle degeneration. In vitro evidence demonstrates that commendamide, through PPARα signaling; and SCFAs, enhances antioxidant mechanisms. Overall, these results support further investigation of microbiota-derived metabolites as postbiotic candidates for DMD therapy.
N-Methyl-D-aspartate receptors: structure, signaling and roles in atherosclerosis.
Cai J, Luo ZQ, Zhang M … +3 more , Zhao ZW, Ren L, Cheng HP
J Transl Med · 2026 Jun · PMID 42251425 · Full text
Atherosclerosis, a chronic inflammatory disease of the arterial wall, is a leading cause of cardiovascular diseases worldwide. The complex pathogenesis of atherosclerosis involves genetic predisposition, environmental fa...
Atherosclerosis, a chronic inflammatory disease of the arterial wall, is a leading cause of cardiovascular diseases worldwide. The complex pathogenesis of atherosclerosis involves genetic predisposition, environmental factors, and immune responses. N-Methyl-d-aspartate receptors (NMDARs), a subclass of glutamate receptors, are critical for synaptic plasticity, learning, and memory in the central nervous system (CNS). Non-neuronal NMDARs are poorly understood compared to neuronal receptors, but there is a developing consensus that they have distinct structural and functional properties when activated by glutamate and NMDARs co-agonists. Emerging evidence indicates that non-neuronal NMDARs may participate in an array of physiological and pathophysiological processes, including but not limited to driving macrophage polarization, lipid dysregulation in macrophages, inflammation response, vascular smooth muscle cells phenotype switching and endothelial dysfunction, thereby fueling atherogenesis. This review discusses the association between NMDARs genes and atherosclerosis risk, molecular mechanisms underlying NMDARs-mediated regulation of atherosclerosis-related cells, and potential therapeutic implications. Besides, we introduce some pharmacological tools that can be used for studying NMDARs outside the CNS, which reflect modern subunit-selective agents to provide more precise insight into NMDARs mediate the various effects. Overall, the study of NMDARs may provide insights into the pathogenesis of atherosclerosis and lead to the development of more effective therapeutic strategies.
RAD21 regulation of the enhancer-promoter chromatin loop of RAD51 promotes PARPi resistance in ovarian cancer.
Gou R, Chang X, Cheng H … +5 more , Ye X, Liu O, Hu Y, Lin B, Li X
J Transl Med · 2026 Jun · PMID 42251422 · Full text
BACKGROUND: Although poly (ADP-ribose) polymerase inhibitors (PARPi) have been established to enhance ovarian cancer outcomes, the emergence of drug resistance poses considerable clinical challenges. METHODS: In this stu...
BACKGROUND: Although poly (ADP-ribose) polymerase inhibitors (PARPi) have been established to enhance ovarian cancer outcomes, the emergence of drug resistance poses considerable clinical challenges. METHODS: In this study, we constructed a Hi-C atlas to systematically characterize the effect of olaparib on chromatin organization at multiple hierarchical scales, namely, chromosomes, A/B compartments, topologically associating domains, and chromatin loops. To investigate the effects of PARPi on expression of the cohesion subunit RAD21, we established olaparib-resistant ovarian cancer cell line. Furthermore, we examined the effects of RAD21 on the functions of ovarian cancer cells and spheroids based on cell proliferation, apoptosis, and comet assays. In addition, by performing integrated analyses using ChIP-seq datasets, ChIP-qPCR, and chromosome conformation capture assays, we assessed the influence of RAD21 on the enhancer-promoter interactions of a homologous recombination repair gene. Moreover, on the basis of our findings in previous studies using clinical samples, we further evaluated the clinical value of RAD21 in multiple databases. RESULTS: Genome-wide Hi-C heatmap analysis revealed that olaparib led to a reduction in the genome-wide contact frequency for long distance interactions, altered the degree of chromatin compartmentalization, and promoted compartment switching in ovarian cancer. Differences between the olaparib-treated and control cells with respect to topologically associating domain boundaries and chromatin loops were found to be associated with key cellular functions, such as DNA repair and transcriptional mis-regulation in cancer. Furthermore, PARPi treatment was observed to induce the expression of RAD21, whereas an upregulation of RAD21 promoted proliferation and inhibited apoptosis in ovarian cancer spheroids. Mechanistically, we obtained evidence to indicate that by maintaining enhancer-promoter interactions within chromatin conformation, RAD21 regulates the transcription of RAD51, thereby mediating olaparib resistance in ovarian cancer. The high expression of RAD21 was found to show a significant association with poor overall and progression-free survival in patients with ovarian cancer. CONCLUSIONS: Our findings in this study indicate that RAD21 could serve as a potential therapeutic target for overcoming olaparib resistance in ovarian cancer, and provide new insights into the mechanisms underlying the resistance to PARPi from the perspective of chromatin organization.
Long-read sequencing technologies and bioinformatics: a new perspective for decoding DNA methylation modifications.
Hou H, Zhang Y, Ma Y … +3 more , Han Y, Li J, Zhang R
J Transl Med · 2026 Jun · PMID 42251418 · Full text
BACKGROUND: DNA methylation is a crucial epigenetic regulatory mechanism in eukaryotes, and its dysregulation is closely associated with numerous diseases. Recent advances in long-read sequencing (LRS) have transformed t...
BACKGROUND: DNA methylation is a crucial epigenetic regulatory mechanism in eukaryotes, and its dysregulation is closely associated with numerous diseases. Recent advances in long-read sequencing (LRS) have transformed the ability to comprehensively characterize the methylation modifications in DNA, including the technically difficult genomic regions. However, the translation of this technological potential into reliable biological insights relies heavily on accurate computational analysis of raw signal data. Currently, a growing number of bioinformatic tools have emerged, demonstrating superior performance in LRS-based methylation detection. MAIN BODY: Our review first briefly describes the detection principles and technological improvement of LRS, and then provides a comprehensive overview of the existing LRS-based methylation detection tools and related benchmarking studies. We further explore the applications in biomedical research, the current challenges, and the future perspective of LRS-based methylation detection. CONCLUSIONS: By highlighting the research progress and key issues in the field, this review aims to provide researchers with an essential framework to advance the further development and application of LRS-based methylation detection.
G.AI: an AI-driven platform for phenotype standardization, variant interpretation and structured clinical reporting in rare disease genomic diagnosis.
Wang Z, Chen X, Tang L … +3 more , Wu X, Huang A, Zhang H
J Transl Med · 2026 Jun · PMID 42251412 · Full text
BACKGROUND: The diagnosis of rare diseases increasingly relies on the interpretation of high-throughput next-generation sequencing (NGS) data. As sequencing volume expands, the analytical burden grows substantially, and...
BACKGROUND: The diagnosis of rare diseases increasingly relies on the interpretation of high-throughput next-generation sequencing (NGS) data. As sequencing volume expands, the analytical burden grows substantially, and manual workflows become increasingly difficult to scale and prone to inconsistency. To address these challenges, we developed G.AI, an interpretable and traceable artificial intelligence (AI)-assisted genomic analysis platform that integrates automated phenotype standardization, variant pathogenicity ranking, and structured clinical reporting. METHODS: The platform uses a modular architecture comprising data parsing, AI-driven inference, and structured report generation. Performance was assessed using 39,156 multicenter whole-exome sequencing (WES)/ parent-child trio sequencing (WES Trio) cases from China, including 7,097 confirmed pathogenic/likely pathogenic (P/LP) single-nucleotide variants (SNVs) positive cases. Key evaluation metrics included phenotype-model concordance, Top-1, Top-3 and Top-20 variant pathogenicity ranking accuracy and workflow efficiency. RESULTS: The AI-Human Phenotype Ontology (HPO) phenotype standardization model achieved 94% concordance with manual review. The pathogenicity-ranking model reached Top-1 95%, Top-3 98%, and Top-20 99.6% accuracy among positive cases, with metabolic disorders achieving 100% Top-3 accuracy. Additional analysis on non-diagnostic cases demonstrated low false prioritization rates and good model specificity. Total analysis time decreased from 4 to 6 h to 48 ± 12 min, demonstrating a significant improvement in efficiency. CONCLUSION: By integrating automated phenotype processing, variant annotation, and AI-driven pathogenicity evaluation, G.AI substantially enhances the accuracy, consistency, and scalability of rare disease variant interpretation. Its transparent and traceable workflow provides a robust foundation for large-scale clinical genomic applications.
Research on GM1 bound bMSCs loaded with SF hydrogel for spinal cord injury repair.
Yu Q, Zhang HY, Song Y … +4 more , Wang L, Zhang XY, Xu YJ, Chen C
J Transl Med · 2026 Jun · PMID 42251374 · Full text
BACKGROUND: Monosialotetrahexosylganglioside (GM1), a major ganglioside component, is expressed in the spinal cords of mammals. Gangliosides have been shown to play important roles in various physiological processes, inc...
BACKGROUND: Monosialotetrahexosylganglioside (GM1), a major ganglioside component, is expressed in the spinal cords of mammals. Gangliosides have been shown to play important roles in various physiological processes, including neuronal protection, neurorepair, and stem cell differentiation. Bone marrow-derived mesenchymal stem cells (bMSCs) were expected to be a good source of cells for clinical transplantation and repair due to their abundance, easy accessibility and lack of ethical restrictions. They can also be induced to differentiate into neurons. However, there is still no ideal delivery material or method that allows the sustained and controlled release of GM1 and bMSCs for clinical use in spinal cord injury (SCI). Silk fibroin (SF)-based hydrogels have emerged as a promising strategy for local, controlled, and sustained drug release in the treatment of various diseases. METHODS: In this study, we developed a SF-based hydrogel for the sustained delivery of GM1 and bMSCs (GM1 + bMSCs@SF hydrogel) and evaluated its therapeutic effect in a rat model of SCI. RESULTS: The GM1 + bMSCs@SF hydrogel showed sustained GM1 release in vitro. Treatment with the GM1 + bMSCs@SF hydrogel increased cell cycle exit and neuronal differentiation 1 (Cend1) expression, reduced neuronal pyroptosis and apoptosis, and promoted the differentiation of bMSCs into neurons. Double immunofluorescence staining confirmed a decrease in cell pyroptosis. Moreover, rats treated with the GM1 + bMSCs@SF hydrogel showed significant improvement in motor function recovery, with the Basso, Beattie and Bresnahan (BBB) score at 8 weeks reaching about 71.4% of the normal level, compared with about 30% in the SCI group. CONCLUSIONS: This study will minimize neuronal damage by innovatively using SF hydrogel loaded with GM1 and bMSCs for spinal cord injury repair. It will also explore the molecular mechanisms underlying post-traumatic spinal cord injury repair, opening new therapeutic avenues for spinal cord injury treatment.
Association of baseline immune cell composition with CAR-T cell expansion and survival in Relapsed/Refractory large B-Cell lymphoma.
Liu XD, Wang HN, Zeng LJ … +5 more , Liang YZ, Li FL, Zhu JY, Cong J, Wang L
J Transl Med · 2026 Jun · PMID 42251370 · Full text
BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy in relapsed/refractory large B-cell lymphoma (R/R LBCL), yet nearly 40-60% of patients fail to achieve durable responses....
BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy in relapsed/refractory large B-cell lymphoma (R/R LBCL), yet nearly 40-60% of patients fail to achieve durable responses. The mechanisms underlying interpatient variability in CAR-T expansion and persistence remain incompletely understood. In this exploratory study, we preliminarily investigated the associations between baseline peripheral blood immune subsets, CAR-T expansion kinetics, and clinical outcomes. METHODS: We retrospectively analyzed 33 patients with R/R LBCL who received CD19/CD22 bispecific chimeric antigen receptor T-cell therapy (CAR2219) at our center. Peripheral blood samples were analyzed by flow cytometry. CAR-T cell expansion was monitored longitudinally, and group-based trajectory modeling (GBTM) classified patients into expansion patterns. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analysis and Cox regression. Twenty-two patients received tislelizumab (a PD-1 inhibitor) as maintenance therapy (200 mg intravenously every 3 weeks) starting on day 28 after CAR-T infusion. This regimen was not used as prior therapy, bridging therapy, or co-infusion, rather, it was designed to potentially enhance CAR-T persistence after the initial expansion phase. Given the small sample size (n = 33) and the exploratory nature of the analyses, all findings are hypothesis-generating only and require validation in large prospective cohorts. RESULTS: Two distinct CAR-T expansion trajectories were identified: a low-expansion group (Group 1, n = 18) and a high-expansion group (Group 2, n = 15). Compared to Group 1, Group 2 exhibited higher peak expansion (Cmax, p < 0.001), greater total exposure (area under the curve (AUC), p < 0.001), and delayed time to peak (Tmax, 14 days vs. 10 days). Group 2 had higher baseline naive T cells (FDR-adjusted p = 0.024), helper T cells (FDR-adjusted p = 0.006), and CD4/CD8 ratio (FDR-adjusted p = 0.049), and fewer activated regulatory T cells (Tregs) (FDR-adjusted p = 0.018). Higher CD4/CD8 ratio associated with longer PFS (HR 0.41, 95% CI 0.17-0.73, p = 0.047). In exploratory subgroup analyses, a directional trend toward longer PFS was noted among patients with high baseline PD-1 expression who received PD-1 inhibitor maintenance therapy, whereas no such trend was observed in those without maintenance. These hypothesis-generating observations require validation in larger prospective cohorts. CONCLUSION: Baseline immune cell composition may associate with CAR-T expansion and outcomes in R/R LBCL. Exploratory subgroup analyses suggested that the direction of association between baseline PD-1 expression and PFS may differ according to receipt of PD-1 inhibitor maintenance therapy (initiated on day 28 post-infusion), though no statistical significance was reached in either subgroup. Current evidence does not support the clinical use of baseline PD-1 expression as a predictive biomarker, and further validation in prospective studies is warranted.
NSUN2/m5C/TPI1 axis promotes glycolysis and immune evasion in breast cancer.
Song X, Li Q, Xiao Z … +2 more , Luo H, Li X
J Transl Med · 2026 Jun · PMID 42251361 · Full text
BACKGROUND: Aerobic glycolysis and immune evasion drive tumor development. 5-methylcytosine (m5C) methyltransferase NSUN2 acts as an oncogene in breast cancer (BC), but the molecular mechanisms remain incompletely elucid...
BACKGROUND: Aerobic glycolysis and immune evasion drive tumor development. 5-methylcytosine (m5C) methyltransferase NSUN2 acts as an oncogene in breast cancer (BC), but the molecular mechanisms remain incompletely elucidated. This study aimed to investigate the role of NSUN2 in BC and the underlying mechanisms. METHODS: In vitro experiments were conducted to determine cell proliferation, glycolysis, and immune evasion. Tumor growth was evaluated using a tumor-bearing mouse model. The interplay among NSUN2, YBX1, and TPI1 was evaluated by RNA immunoprecipitation, methylated RNA immunoprecipitation, and dual-luciferase reporter assay. RESULTS: The results showed that NSUN2 and TPI1 were highly expressed in BC cells. NSUN2 knockdown inhibited BC cell proliferation, glycolysis, and immune evasion, which was reversed by TPI1 overexpression. NSUN2 enhanced TPI1 stability by facilitating the m5C modification, which was recognized by YBX1. Moreover, overexpression of TPI1 reversed the inhibition of tumor growth, glycolysis, and immune cell infiltration induced by NSUN2 silencing in vivo. CONCLUSIONS: In conclusion, NSUN2 accelerates the progression of BC by promoting glycolysis and immune evasion. Mechanistically, NSUN2 promotes m5C methylation of TPI1 in a YBX1-dependent manner, which is associated with increased PD-L1 expression and immune-evasive phenotypes. These findings suggest that NSUN2 may be an effective therapeutic target for BC.
Exercise reveals precocious-subclinical cardiovascular and muscular dysfunction in transfusion dependent beta-thalassemia (TDT) patients without cardiac iron overload.
Braggio M, Ceolan J, Minoia A … +7 more , Villaboni S, Mazzi F, Federti E, Valenti MT, Franceschi L, Carbonare LD, Cominacini M
J Transl Med · 2026 Jun · PMID 42251345 · Full text
BACKGROUND: Transfusion-dependent β-thalassemia (TDT) is characterized by reduced exercise capacity due to chronic hemolytic anemia, iron overload cardiomyopathy, and potential skeletal muscle alterations. Early cardiova...
BACKGROUND: Transfusion-dependent β-thalassemia (TDT) is characterized by reduced exercise capacity due to chronic hemolytic anemia, iron overload cardiomyopathy, and potential skeletal muscle alterations. Early cardiovascular and muscular dysfunction in the absence of cardiac iron overload remains poorly characterized. METHODS: In this exploratory study, 9 TDT patients without cardiac iron overload and with normal body mass index (BMI) were matched with 9 healthy controls. Cardiopulmonary exercise testing combined with lung ultrasound (LUS-CPET) was used to assess exercise-induced lung congestion and diastolic dysfunction. Serum biomarkers of endothelial activation (ICAM-1) and muscle-metabolic function (FGF21, miR-577) were evaluated. Resting echocardiography, handgrip strength, and body composition by bioelectrical impedance analysis (BIA) were also assessed. RESULTS: At rest, cardiac output and diastolic function were comparable between groups. However, during LUS-CPET, TDT patients exhibited significantly lower VO₂max, O₂ pulse, and chronotropic index, along with increased B-lines, consistent with exercise-induced diastolic dysfunction. TDT patients also showed reduced lean body mass and handgrip strength. FGF21 levels were elevated at rest and post-exercise, whereas miR-577 levels were reduced. Post-exercise ICAM-1 levels were significantly higher in TDT patients compared to controls. CONCLUSIONS: LUS-CPET may represent a useful non-invasive approach to identify early exercise-induced diastolic dysfunction in TDT patients without cardiac iron overload. Altered FGF21 and miR-577 profiles suggest the presence of metabolic dysregulation associated with early skeletal muscle deconditioning.
Immunological consequences of senescence in physiology and pathology.
Zubova A, Pietrocola F, Morsli S
J Transl Med · 2026 Jun · PMID 42249480 · Full text
BACKGROUND: Cellular senescence is a sublethal stress response characterized by a durable cell-cycle arrest and the acquisition of a complex secretory program known as the senescence-associated secretory phenotype (SASP)...
BACKGROUND: Cellular senescence is a sublethal stress response characterized by a durable cell-cycle arrest and the acquisition of a complex secretory program known as the senescence-associated secretory phenotype (SASP), which can profoundly influence local and systemic immunity. In physiological contexts-including embryonic development, tissue repair, and acute tumour suppression-senescent cells coordinate the recruitment and activation of immune cells, enabling their timely immune-mediated clearance and facilitating tissue remodelling and restoration of homeostasis. However, during aging and chronic disease, immune surveillance mechanisms frequently become compromised, allowing senescent cells to accumulate and persist within tissues. MAIN BODY: The persistence of senescent cells results in sustained SASP signalling that promotes chronic inflammation, immune dysfunction, and tissue remodelling processes linked to fibrosis, metabolic impairment, tumour progression, and defective tissue repair. In parallel, increasing evidence indicates that immune cells themselves can acquire senescent or senescence-like states, thereby weakening immunosurveillance and generating self-reinforcing feedback loops that further amplify senescent cell accumulation and tissue dysfunction. In this review, we synthesize recent advances in understanding the bidirectional interactions between senescent cells and the immune system across physiological and pathological contexts, with particular emphasis on the mechanisms that govern immune recognition, clearance, and immune evasion. CONCLUSIONS: A deeper understanding of the reciprocal interplay between senescent cells and the immune system provides an important conceptual framework for the development of new therapeutic strategies. Interventions aimed at modulating senescence-immune crosstalk - including immune-mediated senolytic approaches, checkpoint modulation, and immune rejuvenation - may offer promising opportunities to restore immune surveillance, limit the detrimental consequences of persistent senescence, and ultimately improve outcomes in age-related diseases.
Astrocyte-specific NRCAM deficiency promotes GABAergic synapse pruning to drive central sensitization in bone cancer pain.
Zhang Z, Hou Y, Mao Y … +11 more , Jiang L, Lu C, Yu J, Huang Y, Xu R, Huang S, Zhang X, Zhu H, Zhang W, Sun Y, Ma Z
J Transl Med · 2026 Jun · PMID 42249478 · Full text
BACKGROUND: Astrocytic activation is critically involved in the development and maintenance of bone cancer pain (BCP). Recent studies have shown that astrocytes participate in synaptic remodeling through synaptic phagocy...
BACKGROUND: Astrocytic activation is critically involved in the development and maintenance of bone cancer pain (BCP). Recent studies have shown that astrocytes participate in synaptic remodeling through synaptic phagocytosis, whereas neuronal cell adhesion molecule (NRCAM) restricts the extension of perisynaptic astrocytic processes and exerts an anti-phagocytic effect. However, whether astrocyte-mediated synaptic phagocytosis contributes to BCP remains to be explored. Hence, this study investigated the role of astrocytic NRCAM deficiency in synaptic remodeling and central sensitization in BCP. METHODS: A mouse model of BCP was established by intrafemoral inoculation of fibrosarcoma cells. Pain-related behaviors were evaluated by spontaneous pain assessment and mechanical withdrawal threshold testing. Bone destruction and tumor infiltration were examined by hematoxylin and eosin staining. Synaptic alterations and astrocytic activation were assessed by western blotting and immunofluorescence. Astrocyte-mediated synaptic engulfment was analyzed using immunofluorescence, three-dimensional reconstruction, magnetic-activated cell sorting, and Golgi-Cox staining. Moreover, fluorocitrate was used to inhibit the astrocytic activation. Astrocytic NRCAM was overexpressed via adeno-associated virus (AAV)-mediated gene delivery. RESULTS: Fibrosarcoma cell inoculation induced persistent spontaneous pain and mechanical hyperalgesia in C3H/HeN mice, accompanied by trabecular bone destruction and tumor infiltration. In the spinal cord, expression of the excitatory synaptic markers VGLUT1 and PSD95 was increased, whereas expression of the inhibitory synaptic markers VGAT and Gephyrin was decreased, together with marked astrocytic activation. Multiple complementary assays consistently showed that astrocytes engulfed both excitatory and inhibitory synapses, with a clear preference for GABAergic synapses. Pharmacological inhibition of astrocytic activation with fluorocitrate alleviated pain behaviors and improved synaptic remodeling. NRCAM expression was significantly downregulated in tumor-bearing mice. Restoration of astrocytic NRCAM expression by AAV markedly reduced astrocyte-mediated engulfment towards GABAergic synapses, had minimal effect on excitatory synapses, and significantly attenuated BCP. CONCLUSIONS: Reactive astrocytes preferentially phagocytose GABAergic synapses in BCP, thereby contributing to synaptic imbalance and central sensitization. This process is associated with downregulation of astrocytic NRCAM. Restoring astrocytic NRCAM alleviates BCP by suppressing excessive astrocyte-mediated phagocytosis of GABAergic synapses. These findings identify astrocytic NRCAM-dependent synaptic phagocytosis as an unrecognized mechanism underlying BCP and as a potential therapeutic target.
Hyperbaric oxygen therapy improves clinical symptoms and functional capacity and modulates thalamic connectivity in ME/CFS: a prospective cohort study.
Kim L, Cammà G, Peters CK … +13 more , Mantwill M, Müller O, Leprêtre N, Heindrich C, Rust R, Krill M, Hartung TJ, Reeß LG, Krohn S, Heymann CV, Wittke K, Finke C, Scheibenbogen C
J Transl Med · 2026 Jun · PMID 42249466 · Full text
BACKGROUND: Hyperbaric oxygen therapy (HBOT) has been proposed as a treatment for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but evidence remains limited. This study evaluated its clinical effectiveness...
BACKGROUND: Hyperbaric oxygen therapy (HBOT) has been proposed as a treatment for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but evidence remains limited. This study evaluated its clinical effectiveness and feasibility, as well as associated functional brain changes. METHODS: Thirty patients with ME/CFS (mean age 42.3 ± 11.7 years; 7 males, 23 females) received 40 HBOT sessions. Clinical outcomes were assessed at baseline, during treatment, and four weeks post-treatment. The primary outcome was change in the physical functioning subscale of the Short Form-36 Health Survey (SF-36 PF). Secondary outcomes included severity of core symptoms assessed via questionnaires, exercise capacity, handgrip strength, cognitive performance, orthostatic intolerance, and brain magnetic resonance imaging (MRI; volumetry and functional connectivity [FC]). Thirty age- and sex-matched healthy controls (mean age 42.3 ± 11.3 years; 7 males, 23 females) were included for MRI comparison. RESULTS: SF-36 PF significantly improved during HBOT compared with baseline (g = 0.71, p = 0.006). SF-36 pain (p = 0.002, g = 0.79) and Chalder Fatigue Scale also showed clinically meaningful reductions (p < 0.001, g = -0.87). Exercise capacity (g = 0.66), muscle strength (g = 0.40), and information processing speed (g = 0.52) improved significantly after treatment (all p < 0.05). Treatment adherence was high and tolerability was favorable, with no major adverse events reported. Functional MRI analyses revealed increased thalamic FC in ME/CFS patients compared to healthy controls in bilateral sensorimotor (p < 0.001, t = 5.65, FDR-corrected) and visuo-occipital regions (p < 0.001, t = 5.40, FDR-corrected) at baseline. Following HBOT, thalamic hyperconnectivity shifted toward patterns observed in healthy controls. Responders, defined as a ≥ 10 points increase in SF-36 PF, showed greater reductions in thalamic hyperconnectivity than non-responders (p < 0.001, t = -4.34 to -5.18, FDR-corrected). CONCLUSIONS: HBOT was well tolerated and associated with significant improvements in physical functioning, fatigue, pain, and cognitive performance in ME/CFS. The post-treatment shift in thalamocortical connectivity toward healthy control patterns and its association with clinical response support the hypothesis that functional thalamic dysregulation contributes to ME/CFS pathophysiology and may be modulated by HBOT. This provides a network-level rationale for controlled trials to confirm therapeutic efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT06118138. Registered 01 November 2023 - Retrospectively registered, https://clinicaltrials.gov/study/NCT06118138?cond=ME%2FCFSamp;term=HBOTamp;rank=1 .
Gut microbiota in PCOS: key microbial changes, potential mechanisms and clinical applications.
Shi S, Ma J, Jing X … +2 more , Wang J, Sun X
J Transl Med · 2026 Jun · PMID 42249447 · Full text
BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a complex endocrine-metabolic disorder manifesting with reproductive and metabolic dysfunction. Its pathogenesis remains incompletely understood, prompting investigation be...
BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a complex endocrine-metabolic disorder manifesting with reproductive and metabolic dysfunction. Its pathogenesis remains incompletely understood, prompting investigation beyond traditional frameworks. The gut microbiota, a key regulator of host metabolism and immunity, has emerged as a significant factor in PCOS development. MAIN BODY: Patients with PCOS exhibit gut microbial dysbiosis, characterized by altered diversity, specific taxonomic shifts (e.g., reduced Lachnospira), and functional impairments including decreased short-chain fatty acid production. This ecological imbalance affects the pathology of PCOS through the "metabolism-immune-endocrine" network, exacerbating insulin resistance, chronic inflammation, and hormonal imbalances like hyperandrogenism, which in turn further disrupts microbial homeostasis. Targeting the microbiota through dietary strategies (e.g., Mediterranean, ketogenic diets), probiotics, prebiotics, and synbiotics shows therapeutic promise in ameliorating PCOS features. CONCLUSIONS: The gut microbiota plays a pivotal role in PCOS pathophysiology and represents a novel therapeutic target. Current limitations include study heterogeneity and unresolved mechanistic details. Future research should focus on large-scale longitudinal studies and developing precise microbiota-based interventions to advance personalized management and improve outcomes in PCOS.
Varenicline-mediated cholinergic activation through α4β2 nAChR inhibits microglial neuroinflammation and alleviates neuropathic pain and depression following spinal cord injury.
Cheng L, Lai S, Wang Y … +8 more , Zhu X, Song S, Lu DZ, Yang Y, Xu LL, Cai B, Wang J, Zeng H
J Transl Med · 2026 Jun · PMID 42243976 · Full text
BACKGROUND: Spinal cord injury (SCI) often leads to neuropathic pain. Chronic pain is frequently comorbid with depression and is often refractory, becoming a focal point in clinical and basic research. Neuroprotective pa...
BACKGROUND: Spinal cord injury (SCI) often leads to neuropathic pain. Chronic pain is frequently comorbid with depression and is often refractory, becoming a focal point in clinical and basic research. Neuroprotective pathways activated by nicotinic acetylcholine receptors (nAChRs) are attractive therapeutic targets for neurodegenerative diseases. The α4β2 nAChR agonist varenicline has been shown to alleviate pain, reduce functional disability, and improve cognitive aspects; however, understanding of its effects and mechanisms on neuropathic pain following SCI remains limited. PURPOSE: We hypothesize that varenicline regulates cholinergic activity in microglia by activating α4β2 nAChRs, thereby inhibiting neuroinflammation. We aimed to elucidate this mechanism to provide new therapeutic strategies for alleviating comorbid neuropathic pain and depression following SCI. METHODS: We used a rat T3 spinal cord compression injury model. Behavioural assessments, immunofluorescence, and transcriptomics were employed to investigate the effects of varenicline on mechanical and cold hypersensitivity as well as changes in negative mood in T3-SCI model rats. We analysed the expression of sensory afferent neurons and cholinergic neurons in the dorsal horn of the spinal cord among the different treatment groups. Additionally, we assessed the impact of varenicline on neuroinflammation and nAChRs following SCI. RESULTS: Following T3-SCI, the expression of nAChRs, including acetylcholine (ACh) neurotransmitter vesicles, ACh transporters, ACh metabolism enzymes, α4β2 nAChRs, and α7 nAChRs, and cholinergic activity were significantly suppressed, accompanied by an increase in microglia-dominated neuroinflammation. Varenicline pretreatment significantly enhanced impaired cholinergic neurotransmission and α4β2 nAChR expression following SCI; furthermore, it simultaneously inhibited the widespread activation and proliferation of microglia/macrophage-mediated neuroinflammation. Varenicline suppressed the sprouting of calcitonin gene-related peptide afferent fibres in the dorsal horn of the spinal cord after SCI. Additionally, varenicline reduced pain hypersensitivity and negative emotional aspects of depression following SCI. Varenicline also improved the Th1/Th2 immune balance after SCI. CONCLUSION: Varenicline can activate α4β2 nAChRs on neurons and enhance cholinergic activity after SCI. It is also associated with a significant suppression of widespread microglia-mediated neuroinflammation and the promotion of immune balance between Th1 and Th2 cells following injury. Moreover, varenicline appears to alleviate neuropathic pain and the negative emotional components of depression after SCI.
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